ERBB2 inhibitors

Abstract

A compound having the structure of formula (I): JPEG2026514055000465.jpg84165 or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof (wherein E, L, R 3a , R 3b , R 3c , R 3d , R 5b , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , X 1 , X 2 , Z 1 , and Z 2 are as defined herein). A pharmaceutical composition comprising the compound and its use in a method of treating a disease are also described. Briefly, the present disclosure provides compounds (e.g., their stereoisomers, tautomers, or pharmaceutically acceptable salts) that can be used alone or in combination with other therapeutic agents.

Description

[Technical Field]

[0001] This disclosure relates to substituted pyrimidopyrimidine compounds that act as human epidermal growth factor receptor 2 (ErbB2) inhibitors. This disclosure also provides compounds of formula (I) and pharmaceutically acceptable salts thereof, as well as the use of the compounds for the treatment of abnormal cell growth (e.g., cancer) in subjects. [Background technology]

[0002] Human epidermal growth factor receptor 2 (ErbB2) is a member of the epidermal growth factor receptor family that possesses tyrosine kinase activity. ErbB2 plays a crucial role in signaling cascades in biochemical pathways involved in cell growth and differentiation. Amplification and mutations of ErbB2 are known to lead to uncontrolled cell proliferation in cancers (e.g., breast cancer, bladder cancer, colorectal cancer, and lung cancer). Existing therapies (including, but not limited to, monoclonal antibodies, bispecific antibodies, and kinase inhibitors) still present problems of high relapse rates and acquired resistance.

[0003] Current kinase inhibitors may be effective treatments for cancer, but their use may be limited due to insufficient selectivity for ErbB2 compared to EGFR. EGFR-related toxicities (e.g., gastrointestinal effects and rash) may necessitate regimen modifications (e.g., discontinuation or dose reduction), leading to suboptimal target coverage and reduced efficacy.

[0004] Furthermore, ErbB2 exon 20 YVMA insertion is associated with a higher incidence of brain metastases in NSCL cancer patients with ErbB2 mutations. Brain-penetrating ErbB2 inhibitors effective against ErbB2 mutations (e.g., YVMA) may be useful in treating patients with brain metastases.

[0005] There remains a need to identify potent, brain-penetrant, mutant-active ErbB2 inhibitors that spare EGFR for the treatment of patients having cancer or other proliferative diseases or conditions caused by alterations in ErbB2. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0006] Briefly, the present disclosure provides compounds (e.g., their stereoisomers, tautomers, or pharmaceutically acceptable salts) that can be used alone or in combination with other therapeutic agents.

[0007] In one embodiment, a compound having the structure of formula (I):

Chemical formula

[0008] , R 3b , R 3c , R 3d , R 5b , R 8 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , X 1 , X 2 , Z 1 , and Z 2 are as defined herein.

[0008] Also provided are pharmaceutical compositions comprising one or more of the compounds of formula (I) above and an additional therapeutic agent.

[0009] In other embodiments, provided are methods of treatment by administering to a subject in need thereof a compound of formula (I) above or a pharmaceutical composition comprising a compound of formula (I) for treating a disease.

[0010] Various aspects and embodiments will be described in more detail below. Such aspects and embodiments may take many different forms, and the exemplary ones disclosed herein should not be construed as limiting; rather, these embodiments are provided so that the disclosure is complete and comprehensive and its scope is fully conveyed to those skilled in the art. [Modes for carrying out the invention]

[0011] I. Definition For convenience, specific terms used in this specification, examples, and claims are set forth herein. Unless otherwise noted, all technical and scientific terms used in this disclosure have the same meaning as those commonly understood by those skilled in the art to which this disclosure pertains.

[0012] Where a range of values ​​is provided, each intermediate value between the upper and lower limits of that range, and any other specified or intermediate values ​​within that specified range, are intended to be included within the scope of this disclosure. For example, if the range is 1mM to 8mM, then 2mM, 3mM, 4mM, 5mM, 6mM, and 7mM are also intended to be expressly disclosed, as well as the range of non-integer values ​​greater than or equal to 1mM and the range of non-integer values ​​less than or equal to 8mM.

[0013] The singular forms "a," "an," and "the" include multiple referents unless otherwise explicitly stated in the context. Therefore, for example, a reference to "polymer" includes a single polymer as well as two or more of the same or different polymers, and a reference to "excipient" includes a single excipient as well as two or more of the same or different excipients, and so on.

[0014] The term "approximately" shall, in particular, include a deviation of plus or minus 5 percent with respect to a given quantity.

[0015] The compositions of this disclosure include, are essentially composed of, or may consist of the disclosed components.

[0016] All percentages, parts, and ratios are based on the total weight of the composition, and all measurements are taken at approximately 25 degrees Celsius unless otherwise specified.

[0017] As used herein and in the appended claims, unless otherwise stated, the following meanings apply: "Amino" refers to the -NH2, -NHR, or -NR2 radical. "Cyano" refers to the -CN radical. "Hydroxyl" refers to the -OH radical. "Imino" refers to an =NH or =NR substituent. "Nitro" refers to the -NO2 radical. "Oxo" refers to an =O substituent. "Thioz" refers to the =S substituent. "Trifluoromethyl" refers to the -CF3 radical, Hydrazide or hydrazino refers to an NN substituent. Each R in "amino" or "imino" is a suitable substituent as described herein, and the R group is chiral, isomers are intended and included herein.

[0018] "Alkyl" refers to a linear saturated acyclic monovalent hydrocarbon radical or a branched saturated acyclic monovalent hydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8 or 1 to 6 carbon atoms, which are bonded to the remainder of the molecule by single bonds. These include, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Optionally substituted alkyl radicals, as far as their valence allows, are independently halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, -OR ’ -OC(O)-R ’ , -N(R ’ )2, -C(O)R'', -C(O)OR ’ ,-C(O)N(R ’ )2, -N(R’ )C(O)OR''', -N(R ’ )C(O)R''', -N(R ’ )S(O) t R'''(t is 1 or 2), -S(O) t OR'''(t is either 1 or 2), -S(O) p R'''(where p is 0, 1, or 2), and -S(O) t N(R ’ An alkyl radical optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of )2 (where t is 1 or 2), and each R ’ R'' is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl; each R'' is independently hydrogen, cycloalkyl, aryl, heterocyclyl, or heteroaryl; and each R''' is independently alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0019] "alkoxy" is the formula -OR a It refers to the radical of R a This is an alkyl radical containing 1 to 12 carbon atoms as defined above. The alkyl portion of an arbitrarily substituted alkoxy radical is arbitrarily substituted as defined above for alkyl radicals.

[0020] "Alkoxyalkyl" is defined by formula -R a -OR b It refers to the radical of R a However, it is alkylene, R b However, it is an alkyl as defined above. The alkyl and alkylene portions of the arbitrarily substituted alkoxyalkyl radical are arbitrarily substituted as defined above for the alkyl radical and alkylene chain, respectively.

[0021] "Aralkill" is formula -R a -R b It refers to the radical of R aHowever, it is alkylene, R b However, these are aryl compounds as described herein. The optionally substituted alkylene and aryl portions of the aralkyl compounds are optionally substituted as described herein for alkylene and aryl compounds, respectively.

[0022] "Aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring radical containing 6 to 18 carbon atoms, where polycyclic aryl rings are bicyclic, tricyclic, or tetracyclic. Aryl radicals include, but are not limited to, groups such as fluorenyl, phenyl, and naphthyl. Optionally substituted aryls are independently alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, heteroaryl, heteroarylalkyl, and -R''-OR ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ ,-R''-C(O)N(R ’ )2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R'''(t is 1 or 2), -R''-S(O) t OR'''(t is either 1 or 2), -R''-S(O) p R'''(where p is 0, 1, or 2), and -R''-S(O) t N(R ’ An aryl radical which is optionally substituted with one, two, three, four, or five substituents selected from the group consisting of )2 (where t is 1 or 2), and each R ’R'' is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R'' is independently directly bonded or linear or branched alkylene or alkenylene chain; and each R''' is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, or heteroaryl.

[0023] "Arylalkoxy" refers to a group of the formula -OR (where R is aralkyl). Optionally substituted arylalkoxy is an arylalkoxy that is optionally substituted as described herein for aralkyl. In some embodiments, the arylalkoxy is benzyloxy.

[0024] "Cycloalkyl" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon radical having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, and being saturated or unsaturated, with the remainder of the molecule bonded by single bonds. Polycyclic hydrocarbon radicals are bicyclic, tricyclic, or tetracyclic systems. Unsaturated cycloalkyls contain 1, 2, or 3 carbon-carbon double bonds and / or 1 carbon-carbon triple bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, dekalinyl, etc. Optionally substituted cycloalkyls are independently alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R''-OR ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ ,-R''-C(O)N(R ’ )2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’)C(O)R''', -R''-N(R ’ )S(O) t R'''(t is 1 or 2), -R''-S(O) t OR'''(t is either 1 or 2), -R''-S(O) p R'''(where p is 0, 1, or 2), and -R''-S(O) t N(R ’ )2 (where t is 1 or 2) optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group, and each R is a cycloalkyl radical, ’ R'' is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R'' is independently directly bonded or a linear or branched alkylene or alkenylene chain; and each R''' is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl.

[0025] A "deuterated compound" is a compound in which one or more hydrogen atoms are substituted with deuterium atoms. Deuterated drugs may be derivatives of active compounds. Deuterated drugs may be prodrugs. Deuteration can alter the physical properties, metabolic properties, activity, or safety of a drug.

[0026] A "derivative" is a related chemical species that can be derived from a similar compound through a chemical reaction. These may include minor chemical modifications, atomic substitution with deuterated atoms, atomic substitution with stable or radioactive isotopes, or other modifications that confer desired properties to the compound.

[0027] "Condensation" refers to any ring system described herein that is condensed to an existing ring structure in the compound of the present invention. If the condensed ring system is a heterocyclyl or heteroaryl, any carbon atom on the existing ring structure that becomes part of the condensed ring system may be replaced by a nitrogen atom.

[0028] "Halo" refers to halogen substituents (bromo, chloro, fluoro, and iodine).

[0029] A "haloalkyl" refers to an alkyl radical defined as being further substituted with one or more halogen substituents. The number of halo substituents in a haloalkyl ranges from 1 to the total number of hydrogen atoms that can be substituted with halo substituents (e.g., perfluoroalkyls). Non-limiting examples of haloalkyls include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, and 1-bromomethyl-2-bromoethyl. In the case of an arbitrarily substituted haloalkyl, the hydrogen atoms bonded to the carbon atoms of the alkyl portion of the haloalkyl radical may be arbitrarily substituted with substituents defined above for the arbitrarily substituted alkyl.

[0030] A "haloalkenyl" refers to an alkenyl radical as defined above, which is further substituted with one or more halo substituents. The number of halo substituents in a haloalkenyl ranges from one to the total number of hydrogen atoms that can be substituted with halo substituents (e.g., perfluoroalkenyls). Non-limiting examples of haloalkenyls include 2,2-difluoroethenyl and 3-chloropropa-1-enyl. In the case of an arbitrarily substituted haloalkenyl, the hydrogen atoms bonded to the carbon atom of the alkenyl portion of the haloalkenyl radical may be arbitrarily substituted with substituents defined above for the arbitrarily substituted alkenyl group.

[0031] A "haloalkynyl" refers to an alkynyl radical as defined above, which is further substituted with one or more halo substituents. The number of halo substituents in a haloalkynyl ranges from one to the total number of hydrogen atoms that can be substituted with halo substituents (e.g., perfluoroalkynyls). Non-limiting examples of haloalkynyls include 3-chloropropa-1-inyl. The alkynyl portion of a haloalkynyl radical may be further optionally substituted, as defined above for the alkynyl group.

[0032] "Heteroarylalkyl" is a compound of the formula -R a -R b It refers to the radical of R a However, it is alkylene, R b However, these are heteroaryls as described herein. The alkylene and heteroaryl portions of the optionally substituted heteroarylalkyls are optionally substituted as described herein for alkylene and heteroaryls, respectively.

[0033] A "heterocyclyl" refers to a stable 3-18 member non-aromatic cyclic radical having 2-12 carbon atoms and containing a total of 1-6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. Heterocyclyl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic cyclic systems. Bicyclic, tricyclic, or tetracyclic heterocyclyls are fused rings, spirocyclic rings, and / or bridging ring systems. Heterocyclyl radicals may be saturated or unsaturated. Unsaturated heterocyclyls contain 1, 2, or 3 carbon-carbon double bonds and / or 1 carbon-carbon triple bond. Optionally substituted heterocyclyls are independently alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R''-OR ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ ,-R''-C(O)N(R ’ )2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R'''(t is 1 or 2), -R''-S(O) t OR'''(t is either 1 or 2), -R''-S(O) p R'''(where p is 0, 1, or 2), and -R''-S(O) t N(R’ ) 2 (where t is 1 or 2) and is a heterocyclyl radical optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of; each R ’ is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R''' is independently a direct bond or a straight or branched alkylene or alkenylene chain; each R''' is independently alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. A nitrogen, carbon, or sulfur atom within the heterocyclyl radical may be optionally oxidized (when the substituent is oxo and present on the heteroatom); a nitrogen atom is (when the substituent is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R''-OR ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ , -R''-C(O)N(R ’ )2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R''' (where t is 1 or 2), -R''-S(O) t OR''' (where t is 1 or 2), -R''-S(O) p R''' (where p is 0, 1, or 2), and -R''-S(O) t N(R ’ )2 (where t is 1 or 2), and R'' is a straight or branched alkylene or alkenylene chain, R ’And R''' may optionally be quaternized (as defined above). Examples of optionally substituted heterocyclyl radicals include, but are not limited to, azetidinyl, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0034] "Heterocyclylene" refers to a heterocyclyl in which one hydrogen atom is replaced by a bond valency. Optionally substituted heterocyclylenes are substituted as described herein for heterocyclyls.

[0035] A "heteroaryl" refers to a 5-18 membered ring radical containing at least one aromatic ring, having 1-17 carbon atoms, and containing a total of 1-10 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heteroaryl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems. Bicyclic, tricyclic, or tetracyclic heteroaryl radicals are fused rings and / or bridging ring systems. Optionally substituted heteroaryls are independently alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, oxo, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, -R''-OR ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ ,-R''-C(O)N(R ’)2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R'''(t is 1 or 2), -R''-S(O) t OR'''(t is either 1 or 2), -R''-S(O) t R'''(where p is 0, 1, or 2), and -R''-S(O) t N(R ’ A heteroaryl molecule that is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of )2 (where t is 1 or 2), and each R ’ However, each R''' is independently a hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl radical; each R''' is independently a directly bonded, linear, or branched alkylene or alkenylene chain; and each R''' is alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. The nitrogen, carbon, or sulfur atom in the heterocyclyl radical may optionally be oxidized (if the substituent is oxo and present on the heteroatom) such that at least one ring in the heteroaryl remains aromatic, and the nitrogen atom may be (if the substituent is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R''-OR ’ , -R''-OC(O)-R ’ , -R''-N(R ’ )2, -R''-C(O)R ’ , -R''-C(O)OR ’ ,-R''-C(O)N(R ’ )2, -R''-N(R ’ )C(O)OR''', -R''-N(R ’ )C(O)R''', -R''-N(R ’ )S(O) t R'''(t is 1 or 2), -R''-S(O) t OR'''(t is either 1 or 2), -R''-S(O) pR'''(where p is 0, 1, or 2), and -R''-S(O) t N(R ’ )2 (where t is 1 or 2), and R'' is a linear or branched alkylene or alkenylene chain, R ’ (and if R''' is as defined above) the heteroaryl may be optionally quaternized, provided that at least one ring in the heteroaryl remains aromatic. Examples of optionally substituted heteroaryl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxynyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, f Lanonyl, isothiazolyl, imidazolyl, indazolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthyl, naphthylidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxylanyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridadinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).

[0036] The term "pharmaceutically acceptable" is used herein to mean a compound, salt, composition, dosage form, etc., that is suitable for use in contact with human and / or other mammalian tissues without excessive toxicity, irritation, allergic response, or other problems or complications, within the bounds of sound medical judgment, and that has a reasonable benefit / risk ratio. In some aspects, "pharmaceutically acceptable" means that it is approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally accepted pharmacopoeia for use in animals (e.g., mammals), more specifically, in humans.

[0037] A "prodrug" is a compound that, after administration, is metabolized or otherwise chemically converted to its active site. A prodrug may be a derivative of an active compound. A prodrug may be active or inactive before being converted to its active form in vivo.

[0038] The term “treatment” is used herein for example in relation to methods of treating inflammatory or gastrointestinal diseases and generally includes the administration of a compound or composition that reduces the frequency of symptoms of a medical condition (e.g., autoimmune disease, inflammatory disease, gastrointestinal disease) or delays its onset in a subject compared to a subject that has not been administered the compound or composition. This may include regressing, reducing, or preventing symptoms, clinical signs, and the underlying pathology of a condition in a manner that improves or stabilizes the condition of the subject (e.g., regression of symptoms of autoimmune or inflammatory diseases, e.g., improvement of the MAYO score in the treatment of ulcerative colitis).

[0039] The embodiments disclosed herein encompass all pharmaceutically acceptable compounds of the (I)-(IL) compounds that are isotope-labeled by substituting one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine (for example, respectively, 2 H, 3 H, 11 C,13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I) is one example. These radiolabeled compounds may be useful in determining or measuring the efficacy of a compound by characterizing, for example, the site and mode of action, or the binding affinity to pharmacologically important sites of action. Certain isotope-labeled (I)-(IL) compounds (e.g., those incorporating radioisotopes) are useful in studying the tissue distribution of drugs and / or substrates. Tritium, a radioisotope (i.e., 3 H) and carbon-14 (that is, 14 C) is particularly useful for this purpose, given its ease of implementation and the simplicity of its detection means.

[0040] Heavy isotopes (for example, deuterium, i.e., 2 Substitution with H) may offer certain therapeutic benefits resulting from greater metabolic stability (e.g., extended in vivo half-life or reduced required dosage), and is therefore preferable in certain circumstances.

[0041] Substitution with positron-emitting isotopes such as 11C, 18F, 15O, and 13N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotope-labeled compounds (I) to (IL) can generally be prepared by conventional methods known to those skilled in the art, or by using appropriate isotope-labeling reagents instead of previously used unlabeled reagents, in a manner similar to the preparations and examples described below.

[0042] Embodiments disclosed herein encompass in vivo metabolites of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Accordingly, this disclosure includes compounds produced by processes comprising administering the disclosed compounds to mammals for a period of time sufficient to produce their metabolites. Such products are typically identified by administering a detectable amount of the radiolabeled compound of this disclosure to an animal (e.g., a rat, mouse, guinea pig, monkey) or a human, allowing sufficient time for metabolism to occur, and separating the conversion products from urine, blood, or other biological samples.

[0043] "Pharmacologically acceptable salts" include both acid addition salts and base addition salts.

[0044] "Pharmacologically acceptable acid addition salts" are those that retain the biological effects and properties of the free base and are undesirable from a biological or other standpoint, and include inorganic acids (e.g., but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g., but not limited to acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonate, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid) This refers to salts formed with gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid (TFA), undecylenic acid, etc.

[0045] "Pharmacologically acceptable base addition salts" refer to salts that retain the biological efficacy and properties of a free acid and are undesirable from a biological or other standpoint. These salts are prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Preferred inorganic salts are salts of ammonium, sodium, potassium, calcium, and magnesium. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines (e.g., naturally occurring substituted amines), cyclic amines, and salts of basic ion exchange resins (e.g., ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamine, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc.). Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0046] "Pharmaceutical composition" means a combination of the compounds of this disclosure with a medium commonly accepted in the art for the delivery of biologically active compounds to mammals (e.g., humans). Such mediums include all pharmaceutically acceptable carriers, diluents, and excipients.

[0047] "Effective dose" or "therapeutic dose" refers to the amount of the compound disclosed that, when administered to a mammal (preferably a human), is sufficient to perform a treatment in the mammal (preferably a human). The amount of compound constituting a "therapeutic dose" will vary depending on the compound, the symptoms and their severity, the method of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art with knowledge and consideration of the disclosure.

[0048] A “stereoisomer” refers to a compound that is composed of the same atoms bonded together by the same bonds but has different, incompatible three-dimensional structures. This disclosure considers various stereoisomers and mixtures thereof and includes “enantiomers,” which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed. This disclosure also considers “diastereomers,” which refer to non-mirror images of non-identical stereoisomers. Diastereomers arise when two or more stereoisomers of a compound have different configurations at one or more equivalent stereocenters and are not mirror images of each other.

[0049] "Tautomerism" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomers of any such compound.

[0050] As used herein, “abnormal cell growth” means cell growth that does not depend on normal regulatory mechanisms (e.g., loss of contact inhibition), unless otherwise specified. Abnormal cell growth may be benign (not cancerous) or malignant (cancerous).

[0051] By reserving the right to exclude or dismiss any individual member of any such group (e.g., a sub-range or combination of sub-ranges within the group) that can be claimed according to the scope or in any similar manner, no claim may be made for any reason less than the maximum extent of this disclosure. Furthermore, by reserving the right to exclude or dismiss any individual substituent, analog, compound, ligand, structure or any group thereof, or any member of the claimed group, no claim may be made for any reason less than the maximum extent of this disclosure.

[0052] Throughout this disclosure, various patents, patent applications, and publications are referenced. The full disclosures of these patents, patent applications, and publications are incorporated by reference to more completely describe the most advanced technology known to those skilled in the art as of the date of this disclosure. In the event of any conflict between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0053] II. Compounds The compounds described herein are ErbB2 inhibitors. In one embodiment, a compound having the structure of formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof of the same compound are provided: [ka] (In the formula, X 1 CR 1 or N; X 2 CR 2 or N; Y 1 CR 4 or N; Y 2 CR 5a or N; Y 3 is C or N; Y 4 CR 6 or NR 6 Y 5 CR 7 , O, or NR 7 Y 6 is C or N; R1 , R 2 , R 3a , R 3b , R 3c , R 3d , R 4 , R 5a , R 5b , and R 7 Each of these is independently H, halo, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 heteroalkyl; R 6 R is H, C1-C3 alkyl, C1-C3 deuterated alkyl, or C1-C3 haloalkyl; 8 and R 9 Each is independently H or C1-C3 alkyl; Z 1 -NR 9 -, -O-, -S-, or direct bond; Z 2 -NR 9 - or a direct bond; L is a C1-C4 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, condensed heterodicyclic, bridged heterodicyclic, heterospirocyclic, or a direct bond; E is an α,β-unsaturated carbonyl or a C2-C4 alkyne conjugated carbonyl; [ka] Each of these atoms is independently a single or double bond, as long as its valence allows.

[0054] In one embodiment, Y 2 CR 5a Or N. In some embodiments, Y 2 CR 5a In some embodiments, Y 2 It is N.

[0055] In one embodiment, Y 4 CR 6 or NR 6 In some embodiments, Y 4 CR 6 In some embodiments, Y 4 , NR 6 That is the case.

[0056] In one embodiment, Y 6 is C or N. In some embodiments, Y 6 C is C. In some embodiments, Y 6 It is N.

[0057] In one embodiment, Y 2 CR 5a Y 4 , NR 6 Y 6 C is C. In one embodiment, Y 2 N is Y 4 is NR 6 Y 6 C is C. In one embodiment, Y 2 CR 5a Y 4 CR 6 Y 6 C is C. In one embodiment, Y 2 N is Y 4 CR 6 Y 6 It is C.

[0058] In one embodiment, the compound has one of the following structures: (IA) to (ID): [ka] [ka] The compound may also have stereoisomers, tautomers, or pharmaceutically acceptable salts thereof. In some embodiments, the compound has the structure of formula (IA): [ka]

[0059] In some embodiments, the compound has the structure of formula (IB): [ka]

[0060] In some embodiments, the compound has the structure of formula (IC): [ka]

[0061] In some embodiments, the compound has the structure of formula (ID): [ka] In one embodiment, Y 5 CR 7 , O, or NR 7 In some embodiments, Y 5 CR 7 In some embodiments, Y 5 It is O. 5 , NR 7 That is the case.

[0062] In one embodiment, Y 3 is C or N. In some embodiments, Y 3 C is C. In some embodiments, Y 3 It is N.

[0063] In one embodiment, Y 5 N is Y 3 It is C.

[0064] In one embodiment, the compound has one of the following structures: (IA-1) to (IB-1): [ka] The compound may also have stereoisomers, tautomers, or pharmaceutically acceptable salts thereof. In some embodiments, the compound has the structure (IA-1): [ka]

[0065] In some embodiments, the compound has the structure (IB-1): [ka]

[0066] In one embodiment, Y 5 CR 7 Y 3 C is R 7 H is H.

[0067] In one embodiment, the compound has one of the following structures: (IA-2) to (IB-2): [ka] The compound may also have stereoisomers, tautomers, or pharmaceutically acceptable salts thereof. In some embodiments, the compound has the structure (IA-2): [ka]

[0068] In some embodiments, the compound has the structure (IB-2): [ka]

[0069] In one embodiment, R 6 is H, C1-C3 alkyl, C1-C3 deuterated alkyl, or C1-C3 haloalkyl. In some embodiments, R 6 H is H. In some embodiments, R 6 is a C1-C3 alkyl group. In some embodiments, R 6 is a C1-C3 deuterated alkyl. In some embodiments, R 6 is a C1-C3 haloalkyl. In certain embodiments, R 6is a C1 haloalkyl. In a particular embodiment, R 6 is CHF2 or CF3. In some embodiments, R 6 is CHF2. In some embodiments, R 6 This is CF3.

[0070] In one embodiment, the structure R is (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2). 6 R is a C1-C3 haloalkyl. In some embodiments, the structure R is (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2). 6 R is a C1 haloalkyl. In certain embodiments, R is of the structure (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2). 6 This is CHF2 or CF3. In certain embodiments, the structure R of (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2) is used. 6 This is CHF2. In certain embodiments, the structure R of (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2) is used. 6 This is CF3.

[0071] In one embodiment, the structure of (IA-1), (IA-2), or (IB-2) is R 6 It is a C1-C3 haloalkyl. In some embodiments, the structure of (IA-1), (IA-2), or (IB-2) is R 6 is a C1 haloalkyl. In certain embodiments, R of the structure (IA-1), (IA-2), or (IB-2) is used. 6 This is CHF2 or CF3. In certain embodiments, the R of the structure of (IA-1), (IA-2), or (IB-2) 6 This is CHF2. In certain embodiments, the structure of (IA-1), (IA-2), or (IB-2) is R 6 This is CF3.

[0072] In one embodiment, Z1 -NR 9 -, -O-, -S-, or direct bond. In some embodiments, Z 1 -NR 9 -. In some embodiments, Z 1 is -O-. In some embodiments, Z 1 is -S-. In some embodiments, Z 1 This is a direct bond.

[0073] In one embodiment, Z 2 -NR 9 -or direct coupling. In some embodiments, Z 2 -NR 9 -. In some embodiments, Z 2 This is a direct bond.

[0074] In one embodiment, Z 1 and Z 2 These are direct bonds. In this regard, the compound has the following structure: [ka] (In the formula, [ka] (This represents a connection to the remainder of the structure of (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2).

[0075] In one embodiment, Z 1 -NR 9 -, -O-, or -S-, Z 2 This is a direct bond. In this regard, the compound has the following structure: [ka] (In the formula, [ka] (This represents a connection to the remainder of the structure of (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2).

[0076] In one embodiment, Z 1 This is a direct bond, Z 2 -NR 9 -In this regard, the compound has the following structure: [ka] (In the formula, [ka] (This represents a connection to the remainder of the structure of (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2).

[0077] In one embodiment, Z 1 and Z 2 These are, respectively, -NR 9 -In this regard, the compound has the following structure: [ka] (In the formula, [ka] (This represents a connection to the remainder of the structure of (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2).

[0078] In one embodiment, R 8 and R 9 Each is independently H or C1-C3 alkyl. In one embodiment, R 8 is H or C1-C3 alkyl. In some embodiments, R 8 H is H. In some embodiments, R 8 is a C1-C3 alkyl group. In one embodiment, R 9 is H or C1-C3 alkyl. In some embodiments, R9 H is H. In some embodiments, R 9 is a C1-C3 alkyl group. In some embodiments, R 9 is H or C1 alkyl. In certain embodiments, R 9 is H or CH3. In some embodiments, R 9 H is H. In some embodiments, R 9 This is CH3.

[0079] In one embodiment, R 1 , R 2 , R 3a , R 3b , R 3c , R 3d , R 4 , R 5a , R 5b , and R 7 Each of these is independently H, halo, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 heteroalkyl. In some embodiments, R 1 , R 2 , R 3a , R 3b , R 3c , R 3d , R 4 , R 5a , R 5b , and R 7 Each of these is independently H, halo, C1 alkyl, C1-C2 haloalkyl, or C1-C3 heteroalkyl. In some embodiments, R 1 , R 2 , R 3a , R 3b , R 3c , R 3d , R 4 , R 5a , R 5b , and R 7 These are, independently, H, F, Cl, CH3, CH2CF3, CF3, CHF2, CH2OCH3, CD3, OCHF2, OCF3, or OCH3.

[0080] In one embodiment, R 1 and R 2These are, independently, H, F, CH3, or OCH3. In some embodiments, R 1 is H, F, CH3, or OCH3. In some embodiments, R 1 H is H. In some embodiments, R 1 F is F. In some embodiments, R 1 is CH3. In some embodiments, R 1 In some embodiments, R 2 is H, F, CH3, or OCH3. In some embodiments, R 2 H is H. In some embodiments, R 2 F is F. In some embodiments, R 2 is CH3. In some embodiments, R 2 This is OCH3.

[0081] In one embodiment, R 3a , R 3b , R 3c , and R 3d These are, independently, H, CH3, OCH3, CH2OCH3, OCHF2, OCF3, F, or Cl. In some embodiments, R 3a is H, CH3, OCH3, CH2OCH3, OCHF2, OCF3, F, or Cl. In some embodiments, R 3a H is H. In some embodiments, R 3a is CH3. In some embodiments, R 3a In some embodiments, R 3a is CH2OCH3. In some embodiments, R 3a is OCHF2. In some embodiments, R 3a This is OCF3. In some embodiments, R 3a F is F. In some embodiments, R 3a is Cl. In some embodiments, R 3b H is H. In some embodiments, R 3b is CH3. In some embodiments, R3b In some embodiments, R 3b is CH2OCH3. In some embodiments, R 3b is OCHF2. In some embodiments, R 3b This is OCF3. In some embodiments, R 3b F is F. In some embodiments, R 3b is Cl. In some embodiments, R 3c H is H. In some embodiments, R 3c is CH3. In some embodiments, R 3c In some embodiments, R 3c is CH2OCH3. In some embodiments, R 3c is OCHF2. In some embodiments, R 3c This is OCF3. In some embodiments, R 3c F is F. In some embodiments, R 3c is Cl. In some embodiments, R 3d H is H. In some embodiments, R 3d is CH3. In some embodiments, R 3d In some embodiments, R 3d is CH2OCH3. In some embodiments, R 3d is OCHF2. In some embodiments, R 3d This is OCF3. In some embodiments, R 3d F is F. In some embodiments, R 3d It is Cl.

[0082] In one embodiment, R 4 is H, F, CH3, CH2OCH3, or CH2CF3. In some embodiments, R 4 H is H. In some embodiments, R 4 F is F. In some embodiments, R 4 is CH3. In some embodiments, R 4is CH2OCH3. In some embodiments, R 4 It is CH2CF3.

[0083] In one embodiment, R 5a and R 5b These are, independently, H, CH3, F, or OCH3. In some embodiments, R 5a is H, CH3, F, or OCH3. In some embodiments, R 5a H is H. In some embodiments, R 5a is CH3. In some embodiments, R 5a F is F. In some embodiments, R 5a In some embodiments, R 5b is H, CH3, F, or OCH3. In some embodiments, R 5b H is H. In some embodiments, R 5b is CH3. In some embodiments, R 5b F is F. In some embodiments, R 5b This is OCH3.

[0084] In one embodiment, R 7 is H or C1 alkyl. In some embodiments, R 7 H is H. In some embodiments, R 7 is a C1 alkyl group. In some embodiments, R 7 is H or CH3. In some embodiments, R 7 This is CH3.

[0085] In one embodiment, R 8 is H or C1 alkyl. In some embodiments, R 8 H is H. In some embodiments, R 8 is a C1 alkyl group. In some embodiments, R 8 is H or CH3. In some embodiments, R 8 This is CH3.

[0086] In one embodiment, this compound [ka] It has one of the following structures: [ka] (In the formula, [ka] (represents a connection to the remainder of the structure of (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2)). In some embodiments, the compound is [ka] It has, [ka] This represents a connection to the remainder of the structure of (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2). In some embodiments, the compound is [ka] It has, [ka] This represents a connection to the remainder of the structure of (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2). In some embodiments, the compound is [ka] It has, [ka] This represents a connection to the remainder of the structure of (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2). In some embodiments, the compound is [Chemical formula] has, [Chemical formula] represents a connection to the remainder of the structure of (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2). In some embodiments, the compound [Chemical formula] has, [Chemical formula] represents a connection to the remainder of the structure of (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2). In some embodiments, the compound [Chemical formula] has, [Chemical formula] represents a connection to the remainder of the structure of (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2). In some embodiments, the compound [Chemical formula] has, [Chemical formula] represents a connection to the remainder of the structure of (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2). In some embodiments, the compound [Chemical formula] has, [Chemical formula] represents a connection to the remainder of the structure of (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2). In some embodiments, the compound

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0087] In one embodiment, L is a C1-C4 alkyl, a C3-C8 cycloalkyl, a C3-C8 heterocycloalkyl, a condensed heterobicycle, a bridged heterobicycle, a heterospirocycle, or a direct bond. In some embodiments, L is a C1-C4 alkyl. In some embodiments, L is a C3-C8 cycloalkyl. In some embodiments, L is a C3-C8 heterocycloalkyl. In some embodiments, L is a condensed heterobicycle. In some embodiments, L is a bridged heterobicycle. In some embodiments, L is a heterospirocycle. In some embodiments, L is a direct bond.

[0088] In one embodiment, the C3-C8 heterocycloalkyl, condensed heterodicycle, bridging heterodicycle, and heterospiro ring of L have 1 to 3 nitrogen atoms. In some embodiments, the C3-C8 heterocycloalkyl of L has 1 to 3 nitrogen atoms. In some embodiments, the condensed heterodicycle of L has 1 to 3 nitrogen atoms. In some embodiments, the bridging heterodicycle of L has 1 to 3 nitrogen atoms. In some embodiments, the heterospiro ring of L has 1 to 3 nitrogen atoms.

[0089] In one embodiment, the C3-C8 heterocycloalkyl, condensed heterobicycle, bridging heterobicycle, and heterospirocycle of L have 1 to 2 nitrogen atoms. In some embodiments, the C3-C8 heterocycloalkyl of L has 1 to 2 nitrogen atoms. In some embodiments, the condensed heterobicycle of L has 1 to 2 nitrogen atoms. In some embodiments, the bridging heterobicycle of L has 1 to 2 nitrogen atoms. In some embodiments, the heterospirocycle of L has 1 to 2 nitrogen atoms.

[0090] In one embodiment, the C3-C8 heterocycloalkyl, condensed heterodicycle, bridging heterodicycle, and heterospiro ring of L are unsaturated heterocycles. In some embodiments, the C3-C8 heterocycloalkyl of L is an unsaturated heterocycle. In some embodiments, the condensed heterodicycle of L is an unsaturated heterocycle. In some embodiments, the bridging heterodicycle of L is an unsaturated heterocycle. In some embodiments, the heterospiro ring of L is an unsaturated heterocycle.

[0091] In one embodiment, L's C3-C8 heterocycloalkyl is azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1,2-diadinane, 1,3-diadinane, 1,4-diadinane, azapan, diazepan, or azocan. In some embodiments, L's C3-C8 heterocycloalkyl is azetidine. In some embodiments, L's C3-C8 heterocycloalkyl is pyrrolidine. In some embodiments, L's C3-C8 heterocycloalkyl is imidazolidine. In some embodiments, L's C3-C8 heterocycloalkyl is pyrazolidine. In some embodiments, L's C3-C8 heterocycloalkyl is piperidine. In some embodiments, L's C3-C8 heterocycloalkyl is 1,2-diadinane. In some embodiments, L's C3-C8 heterocycloalkyl is 1,3-diadinane. In some embodiments, the C3-C8 heterocycloalkyl of L is 1,4-diadinane. In some embodiments, the C3-C8 heterocycloalkyl of L is azapane. In some embodiments, the C3-C8 heterocycloalkyl of L is diazepane. In some embodiments, the C3-C8 heterocycloalkyl of L is azocane.

[0092] In one embodiment, the condensed heterobicycle of L is 3-azabicyclo[3.1.0]heptane, 2,5-diazabicyclo[4.2.0]octane, octahydropyrrolo[3.4.c]pyrrole, octahydropyrrolo[3.4.b]pyrrole, octahydro-1H-pyrrolo[3.4.c]pyridine, decahydro-2,6-naphthyridine, 2,5-diazabicyclo[4.1.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, or 3,6-diazabicyclo[3.1.0]hexane. In some embodiments, the condensed heterobicycle of L is 3-azabicyclo[3.1.0]heptane. In some embodiments, the condensed heterobicycle of L is 2,5-diazabicyclo[4.2.0]octane. In some embodiments, the condensed heterobicycle of L is octahydropyrrolo[3.4.c]pyrrole. In some embodiments, the condensed heterobicycle of L is octahydro-1H-pyrrolo[3.4.c]pyridine. In some embodiments, the condensed heterobicycle of L is decahydro-2,6-naphthyridine. In some embodiments, the condensed heterobicycle of L is 2,5-diazabicyclo[4.1.0]heptane. In some embodiments, the condensed heterobicycle of L is 3,6-diazabicyclo[3.2.0]heptane. In some embodiments, the condensed heterobicycle of L is 3,6-diazabicyclo[3.1.0]hexane. In some embodiments, the condensed heterobicycle of L is octahydropyrrolo[3.4.b]pyrrole.

[0093] In one embodiment, the cross-linked heterobiring of L is 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, 3-oxa-9-azabicyclo[3.3.1]nonane, 3-oxa-9-azabicyclo[3.3.1]nona-6-ene, 9-azabicyclo[3.3.1]nona-2-ene, 8-azabicyclo[3.2.1]octa-2-ene, or 3,6-diazabicyclo[3.1.1]heptane. In some embodiments, the cross-linked heterobicycle of L is 3,8-diazabicyclo[3.2.1]octane. In some embodiments, the cross-linked heterobicycle of L is 2,5-diazabicyclo[2.2.2]octane. In some embodiments, the cross-linked heterobicycle of L is 8-azabicyclo[3.2.1]octane. In some embodiments, the cross-linked heterobicycle of L is 3-azabicyclo[3.2.1]octane. In some embodiments, the cross-linked heterobicycle of L is 3,6-diazabicyclo[3.2.1]octane. In some embodiments, the cross-linked heterobicycle of L is 9-azabicyclo[3.3.1]nonane. In some embodiments, the cross-linked heterobicycle of L is 3-oxa-9-azabicyclo[3.3.1]nonane. In some embodiments, the bridging heterobicycle of L is 3-oxa-9-azabicyclo[3.3.1]nona-6-ene. In some embodiments, the bridging heterobicycle of L is 9-azabicyclo[3.3.1]nona-2-ene. In some embodiments, the bridging heterobicycle of L is 8-azabicyclo[3.2.1]octa-2-ene. In some embodiments, the bridging heterobicycle of L is 3,6-diazabicyclo[3.1.1]heptane.

[0094] In one embodiment, the heterospiro ring of L is 2,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5]nonane, 2,8-diazaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 4,8-diazaspiro[2.5]octane, 5,9-diazaspiro[3.5]nonane, 6,10-diazaspiro[4.5]decane, or 1,5-diazaspiro[5.5]undecane. In some embodiments, the heterospiro ring of L is 2,6-diazaspiro[3.3]heptane. In some embodiments, the heterospiro ring of L is 1,6-diazaspiro[3.3]heptane. In some embodiments, the heterospiro ring of L is 2-azaspiro[3.3]heptane. In some embodiments, the heterospiro ring of L is 1,6-diazaspiro[3.4]octane. In some embodiments, the heterospiro ring of L is 2,6-diazaspiro[3.4]octane. In some embodiments, the heterospiro ring of L is 2,7-diazaspiro[3.5]nonane. In some embodiments, the heterospiro ring of L is 2,8-diazaspiro[4.5]decane. In some embodiments, the heterospiro ring of L is 3,9-diazaspiro[5.5]undecane. In some embodiments, the heterospiro ring of L is 4,8-diazaspiro[2.5]octane. In some embodiments, the heterospiro ring of L is 5,9-diazaspiro[3.5]nonane. In some embodiments, the heterospiro ring of L is 6,10-diazaspiro[4.5]decane. In some embodiments, the heterospiro ring of L is 1,5-diazaspiro[5.5]undecane.

[0095] In one embodiment, the C3-C8 heterocycloalkyl, condensed heterodicyclic, cross-linked heterodicyclic, and heterospiro rings of L are further substituted with deuterium, halo, C1-C6 alkyl, or C1-C6 heteroalkyl. In some embodiments, the C3-C8 heterocycloalkyl, condensed heterodicyclic, cross-linked heterodicyclic, and heterospiro rings of L are further substituted with deuterium, halo, C1-C3 alkyl, or C1-C3 heteroalkyl. In some embodiments, the C3-C8 heterocycloalkyl, condensed heterodicyclic, cross-linked heterodicyclic, and heterospiro rings of L are -D, -F, -CH3, -CF3, -CHF2, -CH2F, -CH2CHF2, -CH2CH3, -CH(CH3)2, -CH2OH, -CH2OCH3, [ka] Alternatively, it is replaced with -CH2CCN.

[0096] In one embodiment, the C3-C8 heterocycloalkyl group is further -D, -F, -CH3, -CF3, -CHF2, -CH2F, -CH2CHF2, -CH2CH3, -CH(CH3)2, -CH2OH, -CH2OCH3, [ka] Or it is substituted with -CH2CCN. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -D. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -F. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -CH3. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -CF3. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -CHF2. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -CH2F. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -CH2CHF2. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -CH2CH3. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -CH(CH3)2. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -CH2OH. In some embodiments, the C3-C8 heterocycloalkyl group is further substituted with -CH2OCH3. In some embodiments, the C3-C8 heterocycloalkyl group is further substituted with [ka] It is substituted with. In some embodiments, the C3-C8 heterocycloalkyl is further substituted with -CH2CCN.

[0097] In one embodiment, the condensed heterobiring is further -D, -F, -CH3, -CF3, -CHF2, -CH2F, -CH2CHF2, -CH2CH3, -CH(CH3)2, -CH2OH, -CH2OCH3, [ka] Or it is substituted with -CH2CCN. In some embodiments, the condensed heterodicycle is further substituted with -D. In some embodiments, the condensed heterodicycle is further substituted with -F. In some embodiments, the condensed heterodicycle is further substituted with -CH3. In some embodiments, the condensed heterodicycle is further substituted with -CF3. In some embodiments, the condensed heterodicycle is further substituted with -CHF2. In some embodiments, the condensed heterodicycle is further substituted with -CH2F. In some embodiments, the condensed heterodicycle is further substituted with -CH2CHF2. In some embodiments, the condensed heterodicycle is further substituted with -CH2CH3. In some embodiments, the condensed heterodicycle is further substituted with -CH(CH3)2. In some embodiments, the condensed heterodicycle is further substituted with -CH2OH. In some embodiments, the condensed heterodicycle is further substituted with -CH2OCH3. In some embodiments, the condensed heterodicycle is further, [ka] It is substituted with. In some embodiments, the condensed heterobicycle is further substituted with -CH2CCN.

[0098] In one embodiment, the crosslinked heterobiring is further -D, -F, -CH3, -CF3, -CHF2, -CH2F, -CH2CHF2, -CH2CH3, -CH(CH3)2, -CH2OH, -CH2OCH3, [ka] Or it is substituted with -CH2CCN. In some embodiments, the bridging heterodicyclic is further substituted with -D. In some embodiments, the bridging heterodicyclic is further substituted with -F. In some embodiments, the bridging heterodicyclic is further substituted with -CH3. In some embodiments, the bridging heterodicyclic is further substituted with -CF3. In some embodiments, the bridging heterodicyclic is further substituted with -CHF2. In some embodiments, the bridging heterodicyclic is further substituted with -CH2F. In some embodiments, the bridging heterodicyclic is further substituted with -CH2CHF2. In some embodiments, the bridging heterodicyclic is further substituted with -CH2CH3. In some embodiments, the bridging heterodicyclic is further substituted with -CH(CH3)2. In some embodiments, the bridging heterodicyclic is further substituted with -CH2OH. In some embodiments, the bridging heterodicyclic is further substituted with -CH2OCH3. In some embodiments, the bridging heterodicyclic is further, [ka] It is substituted with. In some embodiments, the crosslinked heterobicycle is further substituted with -CH2CCN.

[0099] In one embodiment, the heterospiro ring is further -D, -F, -CH3, -CF3, -CHF2, -CH2F, -CH2CHF2, -CH2CH3, -CH(CH3)2, -CH2OH, -CH2OCH3, [ka] Or it is substituted with -CH2CCN. In some embodiments, the heterospiro ring is further substituted with -D. In some embodiments, the heterospiro ring is further substituted with -F. In some embodiments, the heterospiro ring is further substituted with -CH3. In some embodiments, the heterospiro ring is further substituted with -CF3. In some embodiments, the heterospiro ring is further substituted with -CHF2. In some embodiments, the heterospiro ring is further substituted with -CH2F. In some embodiments, the heterospiro ring is further substituted with -CH2CHF2. In some embodiments, the heterospiro ring is further substituted with -CH2CH3. In some embodiments, the heterospiro ring is further substituted with -CH(CH3)2. In some embodiments, the heterospiro ring is further substituted with -CH2OH. In some embodiments, the heterospiro ring is further substituted with -CH2OCH3. In some embodiments, the heterospiro ring is further, [ka] It is substituted with. In some embodiments, the heterospiro ring is further substituted with -CH2CCN.

[0100] In one embodiment, the C3-C8 heterocycloalkyl, condensed heterodicycle, bridged heterodicycle, and heterospiro ring of L are monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or octasubstituted. In some embodiments, the C3-C8 heterocycloalkyl of L is monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or octasubstituted. In some embodiments, the condensed heterodicycle of L is monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or octasubstituted. In some embodiments, the bridged heterodicycle of L is monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or octasubstituted. In some embodiments, the heterospiro ring of L is monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or octasubstituted.

[0101] In one embodiment, L is a C2-C4 alkyl or a C4-C5 cycloalkyl. In some embodiments, L is a C2-C4 alkyl. In some embodiments, L is a C4-C5 cycloalkyl. In some embodiments, the C1-C4 alkyl of L is -(CH2)2- or -CH2C(CH3)2. In some embodiments, the C1-C4 alkyl of L is -(CH2)2-. In some embodiments, the C1-C4 alkyl of L is -CH2C(CH3)2.

[0102] In one embodiment, L is a C3-C8 cycloalkyl group. [ka] And * is Z 2 This indicates the location of the connection to [the target].

[0103] In one embodiment, L has one of the following structures: [ka] [ka]

[0104] (In the formula, * represents Z 2 (Indicates the position of connection with). In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] That is the case.

[0105] In one embodiment, E is an α,β-unsaturated carbonyl or a C2-C4 alkyne conjugated carbonyl. In some embodiments, E is an α,β-unsaturated carbonyl. In some embodiments, E is a C2-C4 alkyne conjugated carbonyl. In some embodiments, the α,β-unsaturated carbonyl or C2-C4 alkyne conjugated carbonyl of E may further be a halo, C1-C3 alkyl, C1-C3 alkylhalo, C1-C6 heteroalkyl, -(CH2) n It is substituted with C3-C7 heterocycloalkyl groups or combinations thereof, where n is an integer between 1 and 3.

[0106] In one embodiment, the α,β-unsaturated carbonyl of E has one of the following structures: [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] In some embodiments, the α,β-unsaturated carbonyl of E is [ka] That is the case.

[0107] In one embodiment, the C2-C4 alkyne conjugated carbonyl is either a C2 alkyne conjugated carbonyl or a C3 alkyne conjugated carbonyl. In some embodiments, the C2-C4 alkyne conjugated carbonyl is a C2 alkyne conjugated carbonyl. In some embodiments, the C2-C4 alkyne conjugated carbonyl is a C3 alkyne conjugated carbonyl. In a particular embodiment, the C2-C4 alkyne conjugated carbonyl has the following structure: [ka] In some embodiments, the C2-C4 alkyne conjugated carbonyl is [ka] That is the case.

[0108] In one embodiment, E has one of the following structures: [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] In some embodiments, E is [ka] That is the case.

[0109] In one embodiment, the compounds of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2) have one of the following structures shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21]

[0110] As can be understood, the compounds described herein enable the development of new therapies for diseases without requiring novel chemicals, special reagents, or manufacturing methods.

[0111] Mai. Pharmaceutical composition Other embodiments relate to pharmaceutical compositions. In one embodiment, the pharmaceutical composition comprises one (or more) of the compounds described above and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In yet another embodiment, the pharmaceutical composition comprises the compounds disclosed herein and additional therapeutic agents (e.g., anticancer agents). Non-limiting examples of such additional therapeutic agents are described below herein.

[0112] Preferred routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, intraocular, transpulmonary, transmucosal, transdermal, vaginal, ocular, transnasal, and topical administration. In addition, parenteral delivery, as just one example, includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0113] In certain embodiments, the compounds described herein are administered topically rather than systemically, often as depot preparations or sustained-release formulations, for example, by direct injection of the compound into an organ. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the compounds are delivered by a targeted drug delivery system, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target an organ and are selectively taken up by the organ. In yet another embodiment, the compounds described herein are provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In yet another embodiment, the compounds described herein are administered topically.

[0114] In the treatment methods according to embodiments of the present disclosure, an effective amount of at least one of the compounds of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2) is administered to a subject who is suffering from or has been diagnosed with such disease, disorder, or condition. The effective amount or dose may be determined by a method, e.g., modeling, dose escalation studies, or clinical trials (e.g., mode or route of administration, drug delivery, pharmacokinetics of the drug, severity and course of the disease, disorder, or condition, previous or ongoing treatment of the subject, the subject's health status and response to the drug, and the judgment of the treating physician).

[0115] The compounds disclosed herein are effective over a wide range of dosages. For example, in adult treatment, dosages of approximately 0.001–0.1 mg, 0.01–0.1 mg, 0.5–5 mg, 0.5–10 mg, 0.01–10 mg, 0.1–10 mg, 10–5000 mg, 100–5000 mg, 1000–4000 mg, or 1000–3000 mg per day are examples of dosages used in some embodiments. The exact dosage will depend on the route of administration, the form in which the compound is administered, the recipient, the recipient's body weight, and the preferences and experience of the attending physician.

[0116] In some embodiments, the compounds of the Disclosure are administered as a single dose. In one embodiment, the single dose is administered orally. In another embodiment, the single dose is administered by injection. However, other routes may be used as needed. In some embodiments, the compounds of the Disclosure are administered multiple times. In some embodiments, the doses are approximately once, twice, three, four, five, six times, or more than six times per day. In other embodiments, the doses are approximately once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compounds of the Disclosure and another agent (e.g., an additional anticancer agent) are administered together approximately once to six times per day. In another embodiment, the administration of the compounds and agents of the Disclosure continues for less than approximately seven days. In yet another embodiment, the administration continues for approximately six days, ten days, fourteen days, twenty-eight days, two months, six months, or more than one year. In some cases, continuous administration is achieved and maintained for as long as necessary.

[0117] Administration of the compounds of the Disclosure may be continued for as long as necessary. In some embodiments, the compounds of the Disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the Disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the Disclosure are administered continuously and chronically, for example, to treat chronic effects.

[0118] In some embodiments, the compounds of this disclosure are administered in individual dosage forms. It is known in the art that individualization of the drug regimen is necessary for optimal therapy due to inter-subject variability in the pharmacokinetics of the compounds.

[0119] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the disclosed compounds into preparations that can be used as pharmaceuticals. The appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable method, carrier, and excipient may be used to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0120] This specification provides pharmaceutical compositions comprising one or more compounds of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2) and a pharmaceutically acceptable carrier. Pharmaceutical compositions comprising one or more compounds selected from the compounds of formula (I)-(IL) and a pharmaceutically acceptable diluent(s), excipient(s), and carrier(s) are also provided herein. In certain embodiments, the compounds described are administered as a pharmaceutical composition in which one or more compounds selected from the compounds of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2) are mixed with other active ingredients, such as in combination therapy. All combinations of active substances described in the following combination therapy section and throughout this disclosure are incorporated herein. In certain embodiments, the pharmaceutical composition comprises one or more compounds of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2).

[0121] As used herein, pharmaceutical compositions refer to mixtures of one or more compounds selected from the compounds of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2), and other chemical components (e.g., carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients). In certain embodiments, the pharmaceutical composition facilitates the administration of the compound to an organism. In some embodiments, a therapeutically effective amount of one or more compounds selected from the compounds of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2) provided herein is administered as a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount varies depending on the severity of the disease, the age and relative health status of the subject, the efficacy of the compound used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0122] In one embodiment, one or more compounds selected from the compounds of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2) are formulated as an aqueous solution. In certain embodiments, the aqueous solution is selected from, as just one example, a physiologically suitable buffer (e.g., Hanks' solution, Ringer's solution, or physiological saline buffer). In other embodiments, one or more compounds selected from the compounds of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2) are formulated for transmucosal administration. In certain embodiments, the transmucosal formulation includes a penetrating agent suitable for the barrier to be penetrated. In yet another embodiment in which the compounds described herein are formulated for other parenteral injections, the suitable formulation includes an aqueous or non-aqueous solution. In specific embodiments, such a solution includes a physiologically suitable buffer and / or excipients.

[0123] In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated in oral dosage forms, including, but not limited to, tablets, powders, pills, sugar-coated tablets, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0124] In certain embodiments, oral pharmaceutical preparations are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, adding suitable adjuvants as needed, and then processing the granular mixture to obtain tablets or sugar-coated tablet cores. Suitable excipients include, in particular, fillers, e.g., sugars (e.g., lactose, sucrose, mannitol, sorbitol); cellulose preparations (e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose); or others (e.g., polyvinylpyrrolidone (PVP or povidone) or calcium phosphate). In certain embodiments, disintegrants are optionally added. Disintegrants include, but are not limited to, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or pharmaceutically acceptable salts thereof (e.g., sodium alginate).

[0125] In one embodiment, the oral dosage form (e.g., pills, capsules, or tablets) comprises one or more suitable layers or coatings. In certain embodiments, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains additional components (e.g., just as an example, gum arabic, talc, polyvinylpyrrolidone, carbopole gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures). Dyes and / or pigments are also optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments are optionally used to characterize different combinations of doses of the active compound.

[0126] In certain embodiments, at least one therapeutically effective amount of the compounds described herein is formulated into other oral dosage forms. These oral dosage forms include push-in capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers (e.g., glycerol and sorbitol). In certain embodiments, the push-in capsules contain the active ingredient mixed with one or more fillers. The fillers include, in just a few examples, lactose, binders (e.g., starch) and / or lubricants (e.g., talc and magnesium stearate), and optionally, stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, in just a few examples, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0127] In further embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In certain embodiments, the injectable formulation is presented in a single dosage form (e.g., an ampoule) or a multi-dose container. Preservatives are optionally added to the injectable formulation. In yet another embodiment, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. The parenteral injection formulation optionally contains a formulation agent (e.g., a suspending agent, a stabilizer, and / or a dispersant). In a specific embodiment, the pharmaceutical formulation for parenteral administration comprises an aqueous solution of the active compound in a water-soluble form. In additional embodiments, a suspension of one or more compounds selected from the compounds of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2) is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, but are not limited to, fatty oils (e.g., sesame oil), synthetic fatty acid esters (e.g., ethyl oleate or triglycerides), or liposomes. In certain embodiments, the aqueous injection suspension contains a substance that increases the viscosity of the suspension (e.g., sodium carboxymethylcellulose, sorbitol, or dextran). Optionally, the suspension contains a suitable stabilizer or agent to increase the solubility of the compound, enabling the preparation of high-concentration solutions. Alternatively, in other embodiments, the active ingredient is in powder form for preparation with a suitable vehicle (e.g., a sterile, pyrogenic, water-free substance) before use.

[0128] A pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent, or excipient and one or more compounds selected from the compounds of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2) as an active ingredient. The active ingredient is in the form of a free acid or free base or a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also called polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included in the range of compounds described herein. Furthermore, the compounds described herein include non-solvated and solvated forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). The solvated forms of the compounds presented herein are also considered to be disclosed herein. Furthermore, the pharmaceutical composition may optionally include other drugs or pharmaceuticals, carriers, adjuvants (e.g., preservatives, stabilizers, humectants, or emulsifiers), dissolution accelerators, pharmaceutically acceptable salts for adjusting osmotic pressure, buffers, and / or other substances of therapeutic value.

[0129] Methods for preparing compositions comprising the compounds described herein include formulating the compound(s) with one or more inert, pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid compositions. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions for dissolving the compound, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, ointments, suspensions, and creams. The forms of pharmaceutical compositions described herein include solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid before use, or emulsions. These compositions also optionally contain small amounts of non-toxic auxiliary substances (e.g., wetting agents, emulsifiers, and pH buffers).

[0130] In some embodiments, a pharmaceutical composition comprising one or more compounds selected from the compounds of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2) may take the form of a liquid, for example (the drug may exist as a solution, a suspension, or both). Typically, when the composition is administered as a suspension, a first portion of the drug is present in the solution, and a second portion of the drug is present in the form of particles in the suspension within a liquid matrix. In some embodiments, the liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0131] In certain embodiments, the aqueous suspension contains one or more polymers as a suspending agent. The polymers include water-insoluble polymers (e.g., cellulose polymers, e.g., hydroxypropyl methylcellulose) and water-soluble polymers (e.g., crosslinked carboxyl-containing polymers). Specific pharmaceutical compositions described herein include, for example, mucosal adhesive polymers selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0132] The pharmaceutical composition may optionally also include a solubilizer that assists the solubility of one or more compounds selected from the compounds of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2). The term “solubilizer” generally includes agents that result in the formation of micelle solutions or true solutions of the drug. Certain acceptable nonionic surfactants (e.g., polysorbate 80) are useful as solubilizers, as are ophthalmologically acceptable glycols, polyglycols (e.g., polyethylene glycol 400), and glycol ethers.

[0133] Furthermore, the pharmaceutical composition may optionally contain one or more pH adjusters or buffers (e.g., acids (e.g., acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid); bases (e.g., sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane); and buffers (e.g., citrate / dextrose, sodium bicarbonate, and ammonium chloride)). Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0134] The composition may optionally also include one or more pharmaceutically acceptable salts in amounts necessary to bring the osmotic pressure concentration of the composition within an acceptable range. Such pharmaceutically acceptable salts include those having a sodium, potassium, or ammonium cation and an anion of chloride, citric acid, ascorbic acid, boric acid, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite; preferred pharmaceutically acceptable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0135] Other pharmaceutical compositions may optionally include one or more preservatives for inhibiting microbial activity. Suitable preservatives include mercury-containing substances (e.g., merfen and thiomersal); stabilized chlorine dioxide; and quaternary ammonium compounds (e.g., benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride).

[0136] The composition may contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil); and polyoxyethylene alkyl ethers and alkylphenyl ethers (e.g., octoxynol 10, octoxynol 40).

[0137] The composition may contain one or more antioxidants to enhance chemical stability as needed. Suitable antioxidants include, but are not limited to, ascorbic acid and sodium metabisulfite.

[0138] In certain embodiments, the aqueous suspension composition is packaged in a single-dose container that cannot be resealed. Alternatively, a resealable container for multiple doses is used, in which case the composition typically contains a preservative.

[0139] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery media or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In additional embodiments, the compounds described herein are delivered using a sustained-release system (e.g., a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent). A variety of sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compound over a period of several weeks to up to 100 days or more. Depending on the chemical properties and biological stability of the therapeutic agent, additional measures for protein stabilization are used.

[0140] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelating agents, thiol-containing compounds, and / or other common stabilizers. Examples of such stabilizers include, but are not limited to, (a) glycerol in approximately 0.5% to 2% w / v, (b) methionine in approximately 0.1% to 1% w / v, (c) monothioglycerol in approximately 0.1% to 2% w / v, (d) EDTA in approximately 1 mM to 10 mM, (e) ascorbic acid in approximately 0.01% to 2% w / v, (f) polysorbate 80 in approximately 0.003% to 0.02% w / v, (g) polysorbate 20 in approximately 0.001% to 0.05% w / v, (h) arginine, (i) heparin, (j) dextransulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations (e.g., magnesium and zinc); or (n) combinations thereof.

[0141] In some embodiments, the concentrations of one or more compounds selected from the compounds of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2) provided in the pharmaceutical composition are 90%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, and 17. 0.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9 %, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0. 0.8%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or greater than 0.0001%w / w, %w / v, or %v / v. In another embodiment, the amount of a compound selected from the compounds of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2) in the pharmaceutical composition is an amount between any two of the values ​​listed in the above statement (e.g., about 2-70 w / w%, 3.5-80 w / w%, 1-30 w / w%, etc.).

[0142] In some embodiments, the concentration of one or more compounds selected from the compounds of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2) provided in the pharmaceutical compositions of the present disclosure is approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to The percentages are approximately 26%, 0.06% to 25%, 0.07% to 24%, 0.08% to 23%, 0.09% to 22%, 0.1% to 21%, 0.2% to 20%, 0.3% to 19%, 0.4% to 18%, 0.5% to 17%, 0.6% to 16%, 0.7% to 15%, 0.8% to 14%, 0.9% to 12%, and 1% to 10% in the range of w / w, w / v, or v / v.

[0143] In some embodiments, the amounts of one or more compounds selected from the compounds of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2) provided in the pharmaceutical composition of the present disclosure are 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g. g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g or less.

[0144] In some embodiments, the amount of one or more compounds selected from the compounds of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2) provided in the pharmaceutical composition of the present disclosure is in the range of 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0145] Packaging materials used for packaging the pharmaceutical compositions described herein include, for example, those found in U.S. Patents No. 5,323,907, No. 5,052,558, and No. 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging materials suitable for the selected formulation and mode of administration and treatment. For example, a container(s) may optionally contain one or more compounds described herein, either in the composition or in combination with another agent disclosed herein. A container(s) may optionally have a sterile access port (for example, a container may be an intravenous solution bag or vial with a stopper puncturable with a subcutaneous needle). Such a kit may optionally contain a compound with an identification description or label or instructions for use relating to its use in the methods described herein.

[0146] For example, a kit typically includes one or more additional containers, each containing one or more different materials (e.g., optionally, concentrated forms of reagents, and / or devices) that are commercially and user-desirable in relation to the use of the compounds described herein. Non-limiting examples of such materials include buffers, diluents, filters, needles, syringes; labels for carriers, packaging, containers, vials, and / or tubes that describe the contents and / or instructions for use; and accompanying documentation, including instructions for use. Typically, a set of instructions for use is also included. Labels are optionally on or attached to the container. For example, a label is on the container if the letters, numbers, or other symbols forming it are affixed, molded, or etched onto the container itself; and a label is associated with the container if it is present, for example, as accompanying documentation, inside the container or within a carrier that also holds the container. Furthermore, labels are used to indicate that the contents are intended for a specific therapeutic use. Additionally, labels may indicate instructions for use of the contents, for example, in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device containing one or more unit dosage forms comprising the compounds provided herein. For example, the pack contains metal foil or plastic foil (e.g., a blister pack). Alternatively, the pack or dispenser device may be accompanied by instructions for administration, or the pack or dispenser may be accompanied by a notice affixed to the container in the format prescribed by the government agency regulating the manufacture, use, or sale of the pharmaceutical, the notice reflecting that the form of the drug for human or veterinary administration has been approved by the government agency. Such instructions for use may be, for example, a label or product insert approved by the U.S. Food and Drug Administration for a prescription drug. In some embodiments, a composition containing the compounds provided herein, formulated on a suitable pharmaceutical carrier, is prepared, placed in a suitable container, and labeled for the treatment of an indication.

[0147] As described above, the compounds and compositions of this disclosure will find usefulness in a wide range of protein kinase-mediated diseases and conditions (e.g., kinase-mediated diseases and conditions). Such diseases may include, but are not limited to, the following as examples: cancer, e.g., lung cancer, NSCLC (non-small cell lung cancer), oat cell carcinoma, bone cancer, pancreatic cancer, skin cancer, dermatofibrosarcoma protuberans, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, gynecological tumors (e.g., uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, or vulvar cancer), Hodgkin's disease, hepatocellular carcinoma, esophageal cancer, small intestine cancer, endocrine cancers (e.g., thyroid cancer, pancreatic cancer, parathyroid cancer, or adrenal cancer), soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer (in particular, hormone resistance **Psychiatric leukemia, chronic or acute leukemia, pediatric solid tumors, hypereosinophilia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer (e.g., renal cell carcinoma, renal pelvis cancer), pediatric malignancies, neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axial tumor, medulloblastoma, brainstem glioma, or pituitary adenoma), Barrett's esophagus (precancerous syndrome), neoplastic skin diseases, psoriasis, mycosis fungoides, and benign prostatic hyperplasia, diabetes-related diseases (e.g., diabetic retinopathy, retinal ischemia, and retinal neovascularization), cirrhosis, angiogenesis (e.g., cardiovascular disease and arteriosclerosis), immune diseases (e.g., autoimmune diseases), and kidney disease.**

[0148] In some embodiments, the pharmaceutical composition comprises the above-mentioned compounds and pharmaceutically acceptable carriers (e.g., any auxiliary agents, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers) which are approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock.

[0149] In one embodiment, a pharmaceutical composition is disclosed comprising a compound of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2) and an additional therapeutic agent.

[0150] In one embodiment, a pharmaceutical composition is disclosed comprising a compound of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2), or a compound of formula (I), (IA) to (ID), (IA-1), (IA-2), (IB-1), or (IB-2) and an additional therapeutic agent used to treat diseases associated with mutations in human epidermal growth factor receptor 2 (ErbB2).

[0151] In one embodiment, a method for treating a disease associated with ErbB2 mutations includes administering a compound of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2), or a pharmaceutical composition containing a compound of formula (I), (IA)-(ID), (IA-1), (IA-2), (IB-1), or (IB-2), to a subject in need. In one embodiment, the subject is an animal. In some embodiments, the subject is a human. In some embodiments, the disease associated with ErbB2 mutations is cancer. For example, cancers associated with ErbB2 mutations include lung cancer, glioma, esophageal cancer, liver cancer, gastric cancer, uterine cancer, cervical cancer, biliary tract cancer, skin cancer, head and neck cancer, salivary gland cancer, breast cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer. In some embodiments, the cancer associated with ErbB2 mutations is lung cancer. In some embodiments, cancer associated with ErbB2 mutations is glioma. In some embodiments, cancer associated with ErbB2 mutations is esophageal cancer. In some embodiments, cancer associated with ErbB2 mutations is liver cancer. In some embodiments, cancer associated with ErbB2 mutations is gastric cancer. In some embodiments, cancer associated with ErbB2 mutations is uterine cancer. In some embodiments, cancer associated with ErbB2 mutations is cervical cancer. In some embodiments, cancer associated with ErbB2 mutations is biliary tract cancer. In some embodiments, cancer associated with ErbB2 mutations is skin cancer. In some embodiments, cancer associated with ErbB2 mutations is head and neck cancer. In some embodiments, cancer associated with ErbB2 mutations is salivary gland cancer. In some embodiments, cancer associated with ErbB2 mutations is breast cancer. In some embodiments, cancer associated with ErbB2 mutations is pancreatic cancer. In some embodiments, cancer associated with ErbB2 mutations is colorectal cancer. In some embodiments, the cancer associated with the ErbB2 mutation is kidney cancer. In some embodiments, the cancer associated with the ErbB2 mutation is bladder cancer. In some embodiments, the cancer associated with the ErbB2 mutation is prostate cancer. In certain embodiments, the cancer is non-small cell lung cancer.

[0152] IV. Preparation method Methods for preparing the above compounds and compositions are described below and / or are known in the art.

[0153] Those skilled in the art will understand that in the processes described herein, the functional groups of intermediate compounds may need to be protected with suitable protecting groups. Such functional groups include hydroxy, amino, mercapto, and carboxylic acids. Suitable protecting groups for hydroxyl groups include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, and benzyl. Suitable protecting groups for amino, amidino, and guanidino groups include t-butoxycarbonyl and benzyloxycarbonyl. Suitable protecting groups for mercapto groups include -C(O)-R'' (wherein R'' is alkyl, aryl, or arylalkyl), p-methoxybenzyl, and trityl. Suitable protecting groups for carboxylic acids include alkyl, aryl, or arylalkyl esters. Protecting groups are known to those skilled in the art and can be added or removed according to the standard methods described herein. The use of protecting groups is detailed below: Green, TWand PGMWutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As those skilled in the art will understand, the protecting group may be a polymer resin (e.g., Wang resin, Rink resin, or 2-chlorotrityl chloride resin).

[0154] Furthermore, while such protected derivatives of the compounds of the present invention may not possess pharmacological activity on their own, those skilled in the art will understand that they may be administered to mammals and subsequently metabolized in the body to form pharmacologically active compounds of the present invention. Therefore, such derivatives are sometimes referred to as "prodrugs." All prodrugs of the compounds of the present invention are included within the scope of the present invention.

[0155] Furthermore, all compounds of the present invention, existing in the form of free bases or acids, can be converted to their pharmaceutically acceptable salts by treatment with a suitable inorganic or organic base or acid using methods known to those skilled in the art. Salts of the compounds of the present invention can be converted to the form of free bases or acids by standard methods. [Examples]

[0156] The following sections describe the abbreviations used in the examples and include examples for preparing intermediate compounds I1-I178 (Examples 1-88) and examples for preparing compounds 1-414 (Examples 89-104).

[0157] Abbreviation: sat.: saturation aq.: water-based TEA: Triethylamine DIPEA: N,N-diisopropylethylamine MeCN: Acetonitrile TFA: 2,2,2-trifluoroacetic acid FA: Formic acid DCM: Dichloromethane Pd / C: Palladium-supported carbon PET: Petroleum ether DMF: N,N-dimethylformamide IPA: Isopropyl alcohol EtOH: Ethanol MeOH: methanol n-BuOH: Butane-1-ol Quant.: Quantitative HATU:2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) K2CO3: Potassium carbonate Cs2CO3: Cesium Carbonate Na2SO4: Sodium sulfate MgSO4: Magnesium sulfate DMF-DMA: N,N-dimethylformamide dimethylacetal Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Xanthophos:4,5-bis(diphenylphosphin)-9,9-dimethylxanthene MsOH: Methanesulfonic acid LCMS: Liquid Chromatography Mass Spectrometry æ:ethyl acetate THF: Tetrahydrofuran MeI: Methyl iodide KOAc: Potassium acetate DMSO: Dimethyl sulfoxide HPLC: High-Performance Liquid Chromatography CuCN: Copper(I) cyanide

[0158] Synthesis of intermediate compounds Example 1 (I1) 1-Methyl-1H-benzo[d][1,2,3]triazole-5-ol [ka] Step A. 4-Methoxy-N-methyl-2-nitroaniline. Two parallel batches contained, respectively, a solution of 1-fluoro-4-methoxy-2-nitrobenzene (45.0 g, 0.26 mol) and methylamine hydrochloride (81.7 g, 1.21 mol) in MeCN (800 mL). DIPEA (229 mL, 1.31 mol) was added, and the reaction mixture was stirred at 80°C for 12 hours. The mixture was concentrated under vacuum, and the resulting residue was diluted with water (1 L) and extracted with RINKAN (1 L × 3). The organic layers were combined, washed with water (3 ×) and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The two batches were combined to obtain 4-methoxy-N-methyl-2-nitroaniline (93.6 g, yield 98%) as a red solid. LCMS (MM-ES + APCI, Pos): m / z 183.3 (M + H).

[0159] Step B. 4-Methoxy-N 1-Methylbenzene-1,2-diamine. To a solution of 4-methoxy-N-methyl-2-nitroaniline (30.0 g, 165 mmol) in MeOH (400 mL), Pd / C (8.76 g, 8.23 ​​mmol, 10 wt%) was added and the mixture was stirred at 25°C for 1 hour under H2 (3.4 atm). The mixture was filtered through diatomaceous earth and the solid was rinsed with MeOH (1 L). The filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography (10%~15% Â / PET) to obtain 4-methoxy-N 1 Methylbenzene-1,2-diamine (18.0 g, 72% yield) was obtained as a brown solid. LC-MS (MM-ES+APCI,Pos): m / z 153.5 (M+H).

[0160] Step C. 5-Methoxy-1-methyl-1H-benzo[d][1,2,3]triazole. 4-Methoxy-N 1 To a solution of methylbenzene-1,2-diamine (17.0 g, 112 mmol) in EtOH (200 mL), tert-butylnitrite (15.9 mL, 134 mmol) and MsOH (15.9 mL, 223 mmol) were added dropwise at 0°C. The mixture was stirred at 25°C for 1 hour and then concentrated under vacuum. The resulting residue was quenched by the slow addition of an additional saturated NaHCO3 aqueous solution (1 L), and the product was extracted with 3% MeOH / DCM (1 L x 5). The combined organic layers were washed with brine (1 L x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (10%-15% siRNA / PET) to obtain 5-methoxy-1-methylbenzotriazole (14.9 g, yield 82%) as a brown solid. LCMS(MM-ES+APCI,Pos):m / z164.5(M+H).

[0161] Step D. 1-Methyl-1H-benzo[d][1,2,3]triazole-5-ol. To a solution of 5-methoxy-1-methylbenzotriazole (14.9 g, 91.3 mmol) in DCM (200 mL), BBr3 (13.2 mL, 137 mmol) was added at 0°C. The mixture was heated to 25°C, stirred for 2 hours, and quenched with water (200 mL). The mixture was neutralized with NaHCO3 (pH 7) and extracted with DCM (200 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 1-methylbenzotriazole-5-ol (11.9 g, yield 87%) as a brown solid. LCMS (MM-ES+APCI,Pos): m / z 150.1 (M+H).

[0162] Example 2 (I65) 1-Ethyl-1H-benzo[d][1,2,3]triazole-5-ol [ka] Steps A-D. 1-ethyl-1H-benzo[d][1,2,3]triazole-5-ol. Prepared according to Example 1 using ethamine hydrochloride instead of methylamine hydrochloride, 1-ethyl-1H-benzo[d][1,2,3]triazole-5-ol (1.60 g, yield 57%) was obtained as a brown solid. LCMS(MM-ES+APCI,Pos): m / z 164.3(M+H).

[0163] Example 3 (I2) 7-Fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-ol [ka] Step A. 4-Bromo-2-fluoro-N-methyl-6-nitroaniline. To a solution of 4-bromo-2-fluoro-6-nitroaniline (25.0 g, 106 mmol) in THF (250 mL), NaH (5.11 g, 127 mmol, 60 wt%) was added under N2 conditions at 0°C. The mixture was heated to 25°C for 30 minutes, and MeI (9.93 mL, 160 mmol) was added. The reaction mixture was stirred at 25°C for 30 minutes and then at 60°C for 5 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (50 L) and extracted with siRNA (100 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-bromo-2-fluoro-N-methyl-6-nitroaniline (38.4 g, quantitative yield) as a brown solid. LCMS(MM-ES+APCI,Pos):m / z249.0(M+H).

[0164] Step B. 4-Bromo-6-Fluoro-N 1 -Methylbenzene-1,2-diamine. 4-Bromo-2-fluoro-N-methyl-6-nitroaniline (38.4 g, 77.1 mmol) was dissolved in EtOH (200 mL) / H2O (100 mL), to which NH4Cl (41.2 g, 771 mmol) and iron powder (21.5 g, 385 mmol) were added. The mixture was stirred at 80°C for 2 hours, cooled to 25°C, and filtered. Water (50 mL) was added to the filtrate, and the product was extracted with ethylbenzene (500 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (15% ethylbenzene / PET) to obtain 4-bromo-6-fluoro-N 1 Methylbenzene-1,2-diamine (14.0 g, 68% yield) was obtained as a brown oily substance. LC-MS (MM-ES+APCI,Pos): m / z 219.0 (M+H).

[0165] Step C. 5-Bromo-7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole. 4-Bromo-6-fluoro-N 1Sodium nitrite (1.13 g, 16.4 mmol) was added to a solution of methylbenzene-1,2-diamine (3.00 g, 13.7 mmol) in HCl (10 mL, 12 M) / water (5 mL) at 0°C. The mixture was stirred at 25°C for 1 hour and neutralized with NaHCO3 (pH 7). After dilution with water (50 mL), the product was extracted with RINKAN (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-bromo-7-fluoro-1-methylbenzotriazole (3.11 g, yield 31%) as a brown oil. LCMS (MM-ES+APCI,Pos): m / z 230.0 (M+H).

[0166] Step D. (7-Fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)boronic acid. To a solution of 5-bromo-7-fluoro-1-methylbenzotriazole (1.00 g, 4.35 mmol) in 1,4-dioxane (20 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.66 g, 6.52 mmol), KOAc (1.28 g, 13.0 mmol), and Pd(dppf)Cl2 (318 mg, 0.44 mmol) were added. The mixture was stirred at 100°C for 2 hours under N2. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue, which was purified by preparative HPLC (30%-35% MeCN / 0.2% FA aqueous solution). After lyophilization, (7-fluoro-1-methyl-benzotriazole-5-yl)boronic acid (100 mg, yield 9%) was obtained as a gray solid. LC-MS (MM-ES+APCI,Pos): m / z 196.2 (M+H).

[0167] Step E. 7-Fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-ol. To a solution of (7-fluoro-1-methylbenzotriazole-5-yl)boronic acid (100 mg, 0.51 mmol) in MeCN (1 mL), H2O2 (148 μL, 1.54 mmol, 30 wt%) was added at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction product was quenched with aqueous sodium sulfite solution (30 mL) and extracted with RINKAN (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 7-fluoro-1-methyl-benzotriazole-5-ol (170 mg, quantitative yield) as gray. LCMS (MM-ES+APCI,Pos): m / z 167.8 (M+H).

[0168] Example 3 (I66) 1-(methyl-d3)-1H-benzo[d][1,2,3]triazole-5-ol [ka] Step A. 4-Bromo-N-(methyl-d3)-2-nitroaniline. Methyl-D3-amine hydrochloride (93.8 g, 1.33 mol) was added to a solution of 4-bromo-1-fluoro-2-nitrobenzene (195 g, 0.89 mol) and Cs2CO3 (289 g, 1.77 mol) in DMF (2 L). The reaction mixture was heated at 80°C for 1 hour. The mixture was poured into water (6 L), stirred for 1 hour, and filtered. The solid was collected and vacuum-dried to obtain 4-bromo-N-(methyl-d3)-2-nitroaniline (203 g, yield 96%) as a red solid.

[0169] Step B. 4-Bromo-N1-(methyl-d3)benzene-1,2-diamine. A solution of 4-bromo-N-(methyl-d3)-2-nitroaniline (170 g, 0.73 mol), iron (122 g, 2.18 mol), and NH4Cl (117 g, 2.18 mol) in EtOH (1.7 L) / water (0.34 L) was heated at 80°C for 3 hours. The reaction mixture was cooled to 30°C, filtered through Celite, and washed with EtOH (0.85 L). After vacuum concentration, the mixture was made basic (pH 9) with NaOH (2 M) aqueous solution and extracted with SiO2 (2 × 850 mL). The combined organic matter was dried over MgSO4, filtered, and vacuum concentrated to obtain 4-bromo-N1-(methyl-d3)benzene-1,2-diamine (146 g, yield 85%).

[0170] Step C. 5-Bromo-1-(methyl-d3)-1H-benzo[d][1,2,3]triazole. 237 mL of 4-bromo-N1-(methyl-d3)benzene-1,2-diamine was dissolved in 237 mL of water, to which concentrated HCl (16 mL, 528 mmol) was added. The reaction mixture was cooled to 0°C, and 237 mL of NaNO2 (10.9 g, 159 mmol) was added in water. The reaction mixture was made basic (pH 9) with 2 M NaOH solution and extracted with DCM (3 × 75 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (10% to 35% Â1 / PET) to obtain 5-bromo-1-(methyl-d3)-1H-benzo[d][1,2,3]triazole (12.7 g, yield 35%) as a brown solid.

[0171] Step D. 1-(methyl-d3)-1H-benzo[d][1,2,3]triazole-5-ol. 5-bromo-1-(methyl-d3)-1H-benzo[d][1,2,3]triazole (2.00 g, 9.30 mmol) was added to a solution of Pd2(dba)3 (0.85 g, 0.93 mmol), tBuXPhos (0.79 g, 1.86 mmol), and KOH (2.97 g, 53.0 mmol) in 1,4-dioxane (40 mL) / water (8 mL). The reaction mixture was heated at 85 °C for 2 hours and then cooled to ambient temperature. The mixture was acidified with aqueous HCl (pH 5) and extracted with RINKAN (4 × 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was purified by silica gel column chromatography (10% to 35% siRNA / PET), and then further purified by slurry (1:2 siRNA:heptane) to obtain 1-(methyl-d3)-1H-benzo[d][1,2,3]triazole-5-ol (200 mg, yield 12%) as a brown solid.

[0172] Example 4 (I67) 7-Methoxy-1-methyl-1H-benzo[d][1,2,3]triazole-5-ol [ka] Step A. 5-bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole. 5-bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole (1.00 g, 4.13 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.15 g, 12.4 mmol), and KOAc (1.22 g, 12.4 mmol) were dissolved in 1,4-dioxane (20 mL) and Pd(dppf)Cl2 (302 mg, 0.41 mmol). The reaction mixture was purged with N2 and stirred at 100°C for 2 hours. The mixture was filtered through Celite and eluted with siRNA (50 mL). The filtrate was vacuum concentrated, and the residue was purified by silica gel column chromatography (0% to 100% siRNA / PET) to obtain 7-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole (1.40 g, quantitative yield) as an off-white solid. LCMS (MM-ES+APCI,Pos): m / z 290.2 (M+H).

[0173] Step B. 7-Methoxy-1-methyl-1H-benzo[d][1,2,3]triazole-5-ol. 7-Methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole (1.30 g, 4.50 mmol) was dissolved in THF (20 mL) / water (4 mL) and NaBO3 hydrate (1.73 mL, 8.99 mmol) was added. The mixture was stirred at 25°C for 12 hours. The suspension was filtered and eluted with MeOH (150 mL). The filtrate was concentrated under vacuum, and the residue was pulverized by slurring in siRNA (15 mL) and water (15 mL) at 25°C for 0.5 hours. After filtration, the solid was vacuum-dried to obtain 7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole-5-ol 3 (1.60 g, quantitative yield) as an off-white solid. LCMS(MM-ES+APCI,Pos): m / z 180.1(M+H).

[0174] Example 5 (I68) 6-Fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-ol [ka] Steps A-C. 5-bromo-6-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole. Using 4-bromo-5-fluoro-2-nitroaniline instead of 4-bromo-2-fluoro-6-nitroaniline, preparation was carried out according to Example 3 to obtain 5-bromo-6-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole (580 mg, 51% yield in 3 steps) as a brown solid. LCMS (MM-ES+APCI,Pos): m / z 229.8 (M+H).

[0175] Steps D-E: 6-Fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-ol. Using 5-bromo-6-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole instead of 5-bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole, preparation was carried out according to steps A-B of Example 4 to obtain 6-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-ol (450 mg, 88% yield in 2 steps) as a gray solid. LCMS(MM-ES+APCI,Pos): m / z 168.1(M+H).

[0176] Intermediates I68 to I71 in Table 11 below were prepared according to steps A to E of Example 5. [Table 11]

[0177] Example 6 (I72) 7-Fluoro-1,6-dimethyl-1H-benzo[d][1,2,3]triazole-5-ol [ka] Step A. 2-Fluoro-N,3-dimethyl-6-nitroaniline. K2CO3 (7.98 g, 57.8 mmol) was added to a solution of 2,3-difluoro-1-methyl-4-nitrobenzene (10.0 g, 57.8 mmol) and methamine hydrochloride (5.85 g, 86.7 mmol) in DMF (130 mL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (300 mL), the resulting precipitate was filtered, and rinsed with water (250 mL). The solid was vacuum-dried and pulverized in 10% siRNA / PET (110 mL) for 10 minutes. Filtration and drying yielded 2-fluoro-N,3-dimethyl-6-nitroaniline (5.6 g, yield 52%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 185.1 (M+H).

[0178] Step B. 4-Bromo-2-fluoro-N,3-dimethyl-6-nitroaniline. 5.36 g (30.1 mmol) of 2-fluoro-N,3-dimethyl-6-nitroaniline (5.6 g, 30.1 mmol) was dissolved in MeCN (50 mL), to which NBS (5.36 g, 30.1 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction was quenched with water (30 mL), and the product was extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-bromo-2-fluoro-N,3-dimethyl-6-nitroaniline (5.1 g, yield 64%) as a red solid. LCMS (MM-ES+APCI,Pos): m / z 263.0, 265.0 (M+H).

[0179] Steps C to F: 7-Fluoro-1,6-dimethyl-1H-benzo[d][1,2,3]triazole-5-ol. Using 4-bromo-2-fluoro-N,3-dimethyl-6-nitroaniline instead of 4-bromo-5-fluoro-2-nitroaniline, preparation was carried out according to steps B to E of Example 4 to obtain 7-fluoro-1,6-dimethyl-1H-benzo[d][1,2,3]triazole-5-ol (765 mg, yield 74%) as a brown solid. LCMS (MM-ES+APCI,Pos): m / z 182.3 (M+H).

[0180] Example 7 (I73) 6-Fluoro-1,7-dimethyl-1H-benzo[d][1,2,3]triazole-5-ol [ka] Steps A-F: 6-Fluoro-1,7-dimethyl-1H-benzo[d][1,2,3]triazole-5-ol. Using 1,3-difluoro-2-methyl-4-nitrobenzene instead of 2,3-difluoro-1-methyl-4-nitrobenzene, preparation was carried out according to steps A-F of Example 6 to obtain 6-fluoro-1,7-dimethyl-1H-benzo[d][1,2,3]triazole-5-ol (2.2 g, yield 52%) as a brown solid. LCMS(MM-ES+APCI,Pos): m / z 182.0(M+H).

[0181] Example 8 (I74) 4-((3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-yl)oxy)-3-methylaniline [ka] Step A. 5-Bromo-N,6-dimethyl-3-nitropyridine-2-amine. 5-bromo-2-chloro-6-methyl-3-nitropyridine (4.90 g, 19.5 mmol) and methaneamine hydrochloride (2.63 g, 39.0 mmol) were dissolved in acetonitrile (70 mL), to which DIPEA (13.6 mL, 77.9 mmol) was added. The mixture was stirred at 50°C for 12 hours. The reaction product was quenched with water and extracted with RINKAN (200 mL x 3). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-bromo-N,6-dimethyl-3-nitropyridine-2-amine (5.37 g, quantitative yield) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 245.8, 247.8 (M+H).

[0182] Step B. 5-Bromo-N2,6-dimethylpyridine-2,3-diamine. To a solution of 5-bromo-N,6-dimethyl-3-nitropyridine-2-amine (5.37 g, 21.8 mmol) in EtOH (60 mL) / water (20 mL), NH4Cl (11.6 g, 218 mmol) and Fe powder (8.53 g, 153 mmol) were added. The mixture was stirred at 80°C for 2 hours. The reaction product was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned into saturated NaHCO3 aqueous solution (200 mL) and  (200 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-bromo-N2,6-dimethylpyridine-2,3-diamine (4.48 g, yield 95%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z216.0,218.0(M+H).

[0183] Step C. 6-Bromo-3,5-dimethyl-3H-imidazo[4,5-b]pyridine. A solution of 5-bromo-N2,6-dimethylpyridine-2,3-diamine 3 (4.48 g, 20.7 mmol) in trimethoxymethane (50 mL) was stirred at 110°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was partitioned into NaHCO3 aqueous solution (100 mL) and ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0%~100% ethyl acetate / PET) to obtain 6-bromo-3,5-dimethylimidazo[4,5-b]pyridine (3.72 g, yield 79%) as a pink solid. LCMS (MM-ES+APCI,Pos): m / z 226.1 (M+H).

[0184] Steps D-E: 3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-ol. Using 6-bromo-3,5-dimethyl-3H-imidazo[4,5-b]pyridine instead of 5-bromo-6-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole, preparation was carried out according to steps D-E of Example 4 to obtain 3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-ol (2.9 g, yield 72%) as an off-white solid. LCMS(MM-ES+APCI,Pos): m / z 164.0(M+H).

[0185] Example 9 (I75) 3-methyl-3H-[1,2,3]triazolo[4,5-c]pyridine-6-ol [ka] Step A. 6-Chloro-N3-methylpyridine-3,4-diamine. 5-bromo-2-chloropyridine-4-amine (2.00 g, 9.64 mmol), methamine hydrochloride (6.51 g, 96.4 mmol), and 1-(2-pyridyl)ethanone oxime (0.53 g, 3.86 mmol) were dissolved in 1-methylpyrrolidine-2-one (30 mL), to which K2CO3 (6.66 g, 48.2 mmol) and CuI (0.37 g, 1.93 mmol) were added. The reaction mixture was purged with N2 and heated in a sealed tube at 130°C for 12 hours. The mixture was cooled to ambient temperature, diluted with water (200 mL), and extracted with RINKAN (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0%-15% toluene / PET) to obtain 6-chloro-N3-methylpyridine-3,4-diamine (1.70 g, yield 38%) as a yellow oil. LCMS (MM-ES+APCI,Pos): m / z 158.1 (M+H).

[0186] Step B. 6-Chloro-3-methyl-3H-[1,2,3]triazolo[4,5-c]pyridine. A flask containing 6-chloro-N3-methylpyridine-3,4-diamine (1.70 g, 10.8 mmol) was placed under N2 and cooled to 0°C. A solution of H2SO4 (1.61 mL, 30.2 mmol) in water (30 mL) was added, followed by a solution of NaNO2 (1.49 g, 21.6 mmol) in water (20 mL). The mixture was stirred at 0°C for 1 hour. The reaction product was neutralized with saturated NH4HCO3 aqueous solution and extracted with RINKAN (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (0% to 50% Â1 / PET) to obtain 6-chloro-3-methyltriazolo[4,5-c]pyridine (530 mg, yield 27%) as a red solid. LCMS (MM-ES+APCI,Pos): m / z 169.2 (M+H).

[0187] Step C. (3-methyl-3H-[1,2,3]triazolo[4,5-c]pyridine-6-yl)boronic acid. To a solution of 6-chloro-3-methyl-triazolo[4,5-c]pyridine 4 (530 mg, 3.14 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.40 g, 9.43 mmol) in 1,4-dioxane (10 mL), KOAc (617 mg, 6.29 mmol), SPhos (258 mg, 0.63 mmol), and Pd2(dba)3 (287 mg, 0.31 mmol) were added. The reaction mixture was purged with N2 and heated at 100°C for 12 hours. The mixture was concentrated under vacuum to obtain (3-methyltriazolo[4,5-c]pyridine-6-yl)boronic acid (500 mg, yield 89%). LC-MS (MM-ES+APCI,Pos): m / z 178.9 (M+H).

[0188] Step D. 3-Methyl-3H-[1,2,3]triazolo[4,5-c]pyridine-6-ol. Sodium borate tetrahydrate (1.08 mL, 5.62 mmol) was added to a solution of (3-methyltriazolo[4,5-c]pyridine-6-yl)boronic acid (500 mg, 2.81 mmol) in THF (10 mL) / water (5 mL). The reaction mixture was stirred at 50°C for 1 hour. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (0.1% NH4OH aqueous solution) and lyophilized to obtain 3-methyltriazolo[4,5-c]pyridine-6-ol 6 (400 mg, yield 95%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 152.1 (M+H).

[0189] Example 10 (I3) 4-((7-fluoro-1-methyl-1H-benzo[d]imidazole-5-yl)oxy)-3-methylaniline [ka] Step A. 5-bromo-7-fluoro-1-methyl-1H-benzo[d]imidazole formate. 4-bromo-6-fluoro-N 1 Trimethoxymethane (1.20 mL, 10.9 mmol) was added to a solution of methylbenzene-1,2-diamine (2.40 g, 10.9 mmol) in formic acid (20 mL). The mixture was stirred at 100°C for 1 hour and then concentrated under vacuum to obtain 5-bromo-7-fluoro-1-methyl-1H-benzo[d]imidazole formate (2.00 g, 67%) as a yellow oil. LCMS (MM-ES+APCI,Pos): m / z 228.7,230.7 (M+H-FA).

[0190] Step B. tert-butyl(4-((7-fluoro-1-methyl-1H-benzo[d]imidazole-5-yl)oxy)-3-methylphenyl)carbamate. To a DMSO (20 mL) solution of 5-bromo-7-fluoro-1-methyl-1H-benzo[d]imidazole formate (2.00 g, 8.73 mmol) and tert-butyl N-(4-hydroxy-3-methylphenyl)carbamate (1.95 g, 8.73 mmol), CuI (0.67 g, 3.49 mmol), pyridine-2-carboxylic acid (0.43 g, 3.49 mmol), and K2CO3 (3.62 g, 26.2 mmol) were added. The reaction mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The mixture was filtered, concentrated under reduced pressure, and purified by preparative HPLC (30%-65% MeCN / 0.05% FA aqueous solution) to obtain tert-butyl(4-((7-fluoro-1-methyl-1H-benzo[d]imidazole-5-yl)oxy)-3-methylphenyl)carbamate (1.40 g, yield 40%) as a dark brown solid. LC-MS (MM-ES+APCI,Pos): m / z 372.1(M+H).

[0191] Step C. 4-((7-fluoro-1-methyl-1H-benzo[d]imidazole-5-yl)oxy)-3-methylaniline hydrochloride. To a solution of tert-butyl(4-((7-fluoro-1-methyl-1H-benzo[d]imidazole-5-yl)oxy)-3-methylphenyl)carbamate (1.40 g, 3.77 mmol) in MeOH (5 mL), HCl (4 M in 1,4-dioxane, 20.3 mL, 81.2 mmol) was added. The mixture was stirred for 2 hours and then concentrated under vacuum to obtain 4-(7-fluoro-1-methylbenzimidazole-5-yl)oxy-3-methylaniline hydrochloride (1.00 g, yield 86%) as a dark brown solid. LCMS (MM-ES+APCI,Pos): m / z 272.0 (M+H-HCl).

[0192] Example 11 (I76) 7-Fluoro-1-methyl-1H-benzo[d]imidazole-5-ol [ka] Step A. 7-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole. 1,4-dioxane (200 mL) was added at 25°C to a flask containing 5-bromo-7-fluoro-1-methylbenzimidazole (7.0 g, 29 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (11 g, 44 mmol), KOAc (5.8 g, 59 mmol), and Pd(dppf)Cl2 (1.1 g, 1.5 mmol). The mixture was purged with N2 and heated at 90°C for 2 hours. The reaction mixture was gradually quenched with water (200 mL), and the aqueous layer mixture was extracted with RINKAN (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0%~20% RINKAN / PET) to obtain 7-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole (7.6 g, yield 74%) as a brown solid. LCMS (MM-ES+APCI,Pos): m / z 276.8 (M+H).

[0193] Step B. 7-Fluoro-1-methyl-1H-benzo[d]imidazole-5-ol. 7-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole (7.3 g, 21 mmol) was dissolved in MeCN (60 mL) / water (60 mL) and Oxon (6.4 g, 10 mmol) was added. The mixture was heated at 50 °C for 3 hours. The reaction was gradually quenched with water (200 mL), and the aqueous mixture was extracted with RINKAN (100 mL x 3). The combined organic layers were washed with saturated Na2SO3 (300 mL) aqueous solution and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0%-5% MeOH / DCM) to obtain 7-fluoro-1-methyl-benzimidazole-5-ol (3.2 g, 85% yield) as a gray solid. LC-MS (MM-ES+APCI,Pos): m / z 167.0 (M+H).

[0194] Example 12 (I4) 1-(difluoromethyl)-1H-benzo[d][1,2,3]triazole-5-ol [ka] Step A. 5-Methoxy-1H-benzo[d][1,2,3]triazole. 4-Methoxy-N 1 Using 4-methoxybenzene-1,2-diamine instead of methylbenzene-1,2-diamine, 5-methoxy-1H-benzotriazole (5.03 g, 48% yield) was prepared according to step C of Example 1 to obtain a yellow solid. LCMS(MM-ES+APCI,Pos): m / z 150.3(M+H).

[0195] Step B. 1-(difluoromethyl)-5-methoxy-1H-benzo[d][1,2,3]triazole. To a solution of 5-methoxy-1H-benzotriazole (5.27 g, 35.3 mmol) in DMF (50 mL), sodium chlorodifluoroacetate (10.8 g, 70.7 mmol) and Cs2CO3 (23.0 g, 70.7 mmol) were added. The reaction mixture was stirred at 80°C for 1 hour, diluted with water (400 mL), and extracted with RINKAN (100 mL x 4). The combined organic layer was washed with brine (200 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(difluoromethyl)-5-methoxybenzotriazole (6.49 g, yield 73%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 200.1 (M+H).

[0196] Step C. 1-(difluoromethyl)-1H-benzo[d][1,2,3]triazole-5-ol. Using 1-(difluoromethyl)-5-methoxybenzotriazole instead of 5-methoxy-1-methylbenzotriazole, preparation was carried out according to Step D of Example 1 to obtain 1-(difluoromethyl)benzotriazole-5-ol (6.12 g, yield 89%) as a brown solid. LCMS(MM-ES+APCI,Pos): m / z 186.2(M+H).

[0197] Example 13 (I5) 1-(difluoromethyl)-1H-benzo[d]imidazole-5-ol [ka] 1-(difluoromethyl)-1H-benzo[d]imidazole-5-ol. Using 5-methoxy-1H-benzotriazole instead of 5-methoxy-1H-benzo[d]imidazole (3.00 g, 20.25 mmol), 1-(difluoromethyl)benzimidazole-5-ol (2.04 g, 81% yield) was prepared according to steps B-C of Example 12 to obtain a white solid. LCMS(MM-ES+APCI,Pos): m / z 185.1(M+H).

[0198] Example 14 (I77) 1-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole-5-ol [ka] Step A. 5-Methoxy-1-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole. Two parallel batches each contained a solution of 5-methoxy-1H-benzotriazole (250 mg, 1.68 mmol), 3,3-dimethyl-1-(trifluoromethyl)-1,2-benzoiodoxol (830 mg, 2.51 mmol), and 1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (47.1 mg, 0.17 mmol) in CS2 (10 mL). The mixtures were stirred at 60°C for 1 hour and then concentrated under vacuum. The two batches were combined and purified by silica gel column chromatography (0% to 20% siRNA in PET) to obtain 5-methoxy-1-(trifluoromethyl)benzotriazole (120 mg, yield 15%) as a pale yellow solid. LCMS(MM-ES+APCI,Pos):m / z218.0(M+H).

[0199] Step B. 1-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole-5-ol. Using 5-methoxy-1-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole instead of 5-methoxy-1-methylbenzotriazole, preparation was carried out according to Step D of Example 1 to obtain 1-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole-5-ol (150 mg, yield 67%) as a pale yellow solid. LCMS(MM-ES+APCI,Pos): m / z 204.0(M+H).

[0200] Example 15 (I78) 3-(difluoromethyl)-3H-imidazo[4,5-b]pyridine-6-ol [ka] Step A. 6-Bromo-3-(difluoromethyl)-3H-imidazo[4,5-b]pyridine. 6-Bromo-3H-imidazo[4,5-b]pyridine (22.0 g, 111 mmol) and 2-chloro-2,2-difluoroacetate sodium (25.4 g, 167 mmol) were dissolved in DMF (300 mL), to which Cs2CO3 (72.4 g, 222 mmol) was added. The reaction mixture was stirred at 80°C for 2 hours. The mixture was partitioned into Depositphotos (500 mL) and water (500 mL). The aqueous phase was extracted with Depositphotos (500 mL x 2), the combined organic phase was washed with brine (500 mL x 2), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0% to 100% Âx / PET) to obtain 6-bromo-3-(difluoromethyl)-3H-imidazo[4,5-b]pyridine (3.00 g, yield 11%) as a pale yellow solid. LCMS (MM-ES+APCI,Pos): m / z 247.9 (M+H).

[0201] Steps B-C: 3-(difluoromethyl)-3H-imidazo[4,5-b]pyridine-6-ol. Using 6-bromo-3-(difluoromethyl)-3H-imidazo[4,5-b]pyridine instead of 5-bromo-7-methoxy-1-methyl-1H-benzo[d][1,2,3]triazole, preparation was carried out according to steps A-B of Example 4 to obtain 3-(difluoromethyl)-3H-imidazo[4,5-b]pyridine-6-ol (1.63 g, yield 67%) as a white solid. LCMS(MM-ES+APCI,Pos): m / z 186.2(M+H).

[0202] Example 16 (I79) 2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-ol [ka] Step A. 2-Imino-4-methoxypyridine-1(2H)-amine. O-(mesitylsulfonyl)hydroxylamine trifluoroacetate (8.30 g, 25.2 mmol) was added to a solution of 4-methoxypyridine-2-amine (2.00 g, 16.1 mmol) in DCM (30 mL). The mixture was stirred at 25°C for 12 hours. The reaction product was filtered, and the filtered solid was vacuum-dried to obtain 2-imino-4-methoxypyridine-1(2H)-amine (2.00 g, yield 89%) as a white solid. LCMS (MM-ES+APCI,Pos): m / z 140.2 (M+H).

[0203] Step B. 7-Methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine. To a solution of 2-imino-4-methoxypyridine-1(2H)-amine (2.00 g, 14.4 mmol) in pyridine (20 mL), acetyl chloride (2.04 mL, 28.7 mmol) was added. The mixture was stirred at 100 °C for 12 hours. The reaction product was cooled to ambient temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (0%~35% ethyl acetate / PET) to obtain 7-Methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (0.73 g, yield 31%) as a pale yellow solid. LCMS(MM-ES+APCI,Pos):m / z164.2(M+H).

[0204] Step C. 2-Methyl-[1,2,4]triazolo[1,5-a]pyridine-7-ol. A sealed tube containing 7-methoxy-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (930 mg, 5.70 mmol) and HBr (33% in AcOH, 10 mL) was stirred at 100°C for 24 hours. The mixture was vacuum concentrated, and the residue was diluted with saturated NaHCO3 (100 mL) aqueous solution. The aqueous mixture was extracted with RINKAN (30 mL x 3), and the aqueous phase was freeze-dried to obtain 2-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-ol (610 mg, yield 72%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 150.2 (M+H).

[0205] Example 17 (I80) 6-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-ol [ka] Step A. 5-Bromo-4-methoxypyridine-2-amine. NBS (21.5 g, 121 mmol) was added to a solution of 4-methoxypyridine-2-amine (15.0 g, 121 mmol) in MeCN (400 mL). The reaction mixture was stirred at 20°C for 3 hours. The mixture was concentrated under vacuum, and the residue was partitioned into H2O (100 mL) and  (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-bromo-4-methoxypyridine-2-amine (21.0 g, yield 85%) as a brown solid. LCMS (MM-ES+APCI,Pos): m / z 203.2, 205.2 (M+H).

[0206] Step B. (E)-N'-(5-bromo-4-methoxypyridine-2-yl)-N,N-dimethylformimidamide. 5-bromo-4-methoxypyridine-2-amine (20.0 g, 98.5 mmol) was dissolved in MeOH (200 mL) and DMF-DMA (15.7 mL, 1118 mmol) was added. The reaction mixture was stirred at 75°C for 3 hours. The mixture was concentrated under reduced pressure to obtain N'-(5-bromo-4-methoxy-2-pyridyl)-N,N-dimethylformamidine (21.0 g, yield 83%) as a brown oil. LCMS (MM-ES+APCI,Pos): m / z 258.2,260.2 (M+H).

[0207] Step C. (E)-N'-(5-bromo-4-methoxypyridin-2-yl)-N-hydroxyformimidamide. Hydroxylamine hydrochloride (11.3 g, 163 mmol) was added to a solution of N'-(5-bromo-4-methoxy-2-pyridyl)-N,N-dimethylformamidine (21.0 g, 81.4 mmol) in MeOH (220 mL). The reaction mixture was stirred at 70°C for 1 hour. The mixture was filtered, and the filtered solid was washed with MeOH (20 mL). The filtered solid was vacuum dried. N'-(5-bromo-4-methoxy-2-pyridyl)-N-hydroxyformamidine (17.8 g, 88% yield) was obtained as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 246.2, 248.2 (M+H).

[0208] Step D. 6-Bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine. To a solution of N'-(5-bromo-4-methoxy-2-pyridyl)-N-hydroxyformamidine (17.8 g, 71.3 mmol) in THF (200 mL), anhydrous trifluoroacetic acid (12.9 mL, 92.7 mmol) was added. The mixture was stirred at 20°C for 12 hours. The reaction product was quenched with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0%~65% ethyl acetate / PET) to obtain 6-bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine (3.0 g, yield 18%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z228.2,230.2(M+H).

[0209] Step E. 7-Methoxy-6-methyl-[1,2,4]triazolo[1,5-a]pyridine. To a solution of 6-bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine (3.0 g, 13.2 mmol) in 1,4-dioxane (30 mL) / water (6 mL), dioxane (30 mL) and H2O (6 mL) were added, followed by the addition of Pd(dppf)Cl2 (0.96 g, 1.32 mmol), K2CO3 (5.45 g, 39.5 mmol), and methylboronic acid (1.57 g, 26.3 mmol). The mixture was purged with N2 and stirred at 110°C for 2 hours. The reaction product was quenched with water (20 mL) and extracted with RINKAN (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0%-65% Âx / PET) to obtain 7-methoxy-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (900 mg, yield 27%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 164.4 (M+H).

[0210] Step F. 6-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-ol. Pyridine hydrochloride (7.71 g, 66.7 mmol) was added to a solution of 7-methoxy-6-methyl-[1,2,4]triazolo[1,5-a]pyridine (850 mg, 3.33 mmol). The mixture was purged with N2 and heated at 145°C for 2 hours. The reaction mixture was cooled to ambient temperature, quenched with saturated NH4Cl aqueous solution (20 mL), and extracted with RINKAN (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-methyl-[1,2,4]triazolo[1,5-a]pyridine-7-ol (380 mg, yield 77%) as a white solid. LCMS(MM-ES+APCI,Pos):m / z150.4(M+H).

[0211] Example 18 (I81) Imidazō[1,2-b]pyridazine-7-ol [ka] Step A. Tert-butyl(5-methoxypyridazin-3-yl)carbamate. Two parallel batches contained 3-chloro-5-methoxypyridazin (5.0 g, 35 mmol) and tert-butylcarbamate (8.10 g, 69 mmol) in 1,4-dioxane (100 mL). Xanthophos (2.0 g, 3.5 mmol), Cs2CO3 (22.5 g, 69 mmol), and Pd(OAc)2 (0.78 g, 3.5 mmol) were added, and the mixture was purged with N2. The reaction mixture was heated at 90°C for 5 hours. The mixture was diluted with water (100 mL) and extracted with RINKAN (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid was purified by silica gel column chromatography (1% to 50% Â1 / PET), and the batches were combined to obtain tert-butyl N-(5-methoxypyridazin-3-yl)carbamate (10.64 g, yield 68%) as a white solid. LC-MS (MM-ES+APCI,Pos): m / z 226.1 (M+H).

[0212] Step B. 5-Methoxypyridazine-3-amine. To a solution of tert-butyl N-(5-methoxypyridazine-3-yl)carbamate (10.64 g, 47.2 mmol) in DCM (50 mL), TFA (53.2 mL) was added. The reaction mixture was stirred at 25°C for 4 hours. The mixture was concentrated under vacuum and combined with another batch (12.96 g, 57.5 mmol). The mixture was gradually diluted with water (200 mL) and neutralized with saturated NaHCO3 aqueous solution (pH = 7-8). The aqueous solution was extracted with 25% IPA / DCM (150 mL x 20), the combined organic layer was washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain 5-methoxypyridazine-3-amine (9.34 g, yield 71%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z126.1(M+H).

[0213] Step C. 7-Methoxyimidazo[1,2-b]pyridazine. 2-chloroacetaldehyde (13.7 mL, 212 mmol) was added to a solution of 5-methoxypyridazine-3-amine (3.79 g, 30.3 mmol) in IPA (70 mL). The reaction mixture was heated to 80°C and stirred for 20 hours. A second batch of 5-methoxypyridazine-3-amine (5.55 g, 44.4 mmol) and 2-chloroacetaldehyde (20 mL, 310 mmol) in IPA (80 mL) was stirred at 80°C for 16 hours. The two batches were combined and the mixture was concentrated under reduced pressure. The crude residue was purified by grinding in  (20 mL) at 25°C for 1 hour. The solid product was obtained by filtration and then vacuum-dried to yield 7-methoxyimidazo[1,2-b]pyridazine 14 (12.0 g, quantitative yield) as a brown solid. LC-MS (MM-ES+APCI,Pos): m / z 150.1 (M+H).

[0214] Step D. Imidazon[1,2-b]pyridazine-7-ol. Two parallel batches containing 7-methoxyimidazo[1,2-b]pyridazine (6.0 g, 40.2 mmol) and DCE (120 mL) were cooled to 0°C. BBr3 (27.1 mL, 282 mmol) was added dropwise, and the mixture was heated at 80°C for 6 hours. The reaction mixture was gradually quenched with ice water (50 mL) and concentrated under vacuum. The residue was diluted with 30% IPA / DCM (120 mL) and stirred for 30 minutes. The suspension was filtered and washed with 30% IPA / DCM (20 mL). The filtrate was concentrated under reduced pressure, and the crude residue was purified by grinding in 30% IPA / DCM (80 mL). A solid product was obtained by filtration. The filtrate was concentrated, water was added, and the mixture was freeze-dried to obtain an additional solid product. Combining the two batches yielded imidazo[1,2-b]pyridazine-7-ol (10.0 g, 92% yield) as a brown solid. LC-MS (MM-ES+APCI,Pos): m / z 136.1 (M+H).

[0215] Example 19 (I82) 4-Bromo-2-fluoro-3-(methyl-d3)aniline [ka] Step A. 2-Fluoro-1-(methyl-d3)-3-nitrobenzene. A solution of 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.5 g, 54.3 mmol), CsF (28.9 g, 190 mmol), and Pd(Amphos)Cl2 (1.92 g, 2.71 mmol) in DMF (167 mL) / water (102 mL) was purged with N2. CD3I (6.8 mL, 109 mmol) was added, and the reaction mixture was heated at 45 °C for 2 hours. The mixture was diluted with water (45 mL) and extracted with ELISA (2 × 75 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude substance was purified by silica gel column chromatography (10% siRNA / heptane) to obtain 2-fluoro-1-(methyl-d3)-3-nitrobenzene (6.77 g, yield 78%) as a yellow solid.

[0216] Step B. 2-Fluoro-3-(methyl-d3)aniline. To a solution of 2-fluoro-1-(methyl-d3)-3-nitrobenzene (6.80 g, 43.0 mmol) in EtOH (102 mL) / water (34 mL), Fe powder (7.20 g, 129 mmol) and NH4Cl (6.90 g, 129 mmol) were added. The mixture was stirred at 80°C for 2 hours and then cooled to 30°C. The suspension was filtered and rinsed with EtOH (35 mL). The filtrate was concentrated under reduced pressure, diluted with water (35 mL), and extracted with ELISA (2 x 70 mL). The combined organic matter was washed with brine, dried over MgSO4, filtered, and concentrated to obtain 2-fluoro-3-(methyl-d3)aniline (7.0 g, yield 88%) as a pale yellow oil.

[0217] Step C. 4-Bromo-2-fluoro-3-(methyl-d3)aniline. A solution of 2-fluoro-3-(methyl-d3)aniline (4.56 g, 35.6 mmol) in MeCN (23 mL) was placed under an N2 atmosphere and cooled to -20°C. A solution of NBS (6.33 g, 35.6 mmol) in MeCN (46 mL) was added dropwise. The mixture was stirred at -20°C for 5 minutes, quenched with saturated NaHSO3 (23 mL), and extracted with MTBE (9 mL). The organic phase was concentrated to dryness, and the residue was redissolved in MTBE (46 mL). The organic mixture was washed with 10% NaOH (23 mL) and brine (23 mL), dried over MgSO4, and filtered. After concentration, the residue was purified by slurrying with heptane (14 mL) over 2 hours at -20°C. The solution was filtered and vacuum-dried to obtain 4-bromo-2-fluoro-3-(methyl-d3)aniline (3.9 g, 53% yield) as a pink solid. LC-MS (MM-ES+APCI,Pos): m / z 207.0, 209.0 (M+H).

[0218] Example 20 (I6) 2,3-dimethyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxyaniline [ka] Step A. 5-(2,3-dimethyl-4-nitrophenoxy)-1-methyl-1H-benzo[d][1,2,3]triazole. To a solution of 1-fluoro-2,3-dimethyl-4-nitrobenzene (500 mg, 2.96 mmol) in DMF (10 mL), Cs2CO3 (1.93 g, 5.91 mmol) and 1-methylbenzotriazole-5-ol (371 mg, 2.36 mmol) were added. The mixture was stirred at 50°C for 2 hours, diluted with water (10 mL), and extracted with  (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (5%~25%  / PET) to obtain 5-(2,3-dimethyl-4-nitrophenoxy)-1-methylbenzotriazole (800 mg, quant.) as a brown oil. LCMS(MM-ES+APCI,Pos):m / z299.1(M+H).

[0219] Step B. 2,3-Dimethyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxyaniline. To a solution of 5-(2,3-dimethyl-4-nitrophenoxy)-1-methylbenzotriazole (800 mg, 2.47 mmol) in EtOH (10 mL) / water (5 mL), Fe powder (551 mg, 9.87 mmol) and NH4Cl (528 mg, 9.87 mmol) were added. The mixture was stirred at 85°C for 1 hour and then cooled to ambient temperature. The suspension was filtered and rinsed with EtOH (10 mL). The filtrate was concentrated under reduced pressure to obtain 2,3-dimethyl-4-(1-methylbenzotriazole-5-yl)oxyaniline (500 mg, yield 69%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 269.0 (M+H).

[0220] Intermediates I7-I23 and I83-I102 in Table 2 below were prepared according to steps A-B of Example 20. Step A can be carried out using Cs2CO3 or K2CO3 as the base and DMF or MeCN as the solvent. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0221] Example 21 (I24) 3-Methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline [ka] Step A. 1-Methyl-5-(2-methyl-4-nitrophenoxy)-1H-benzo[d][1,2,3]triazole. 1-Methyl-1H-benzo[d][1,2,3]triazole-5-ol (14.6 g, 98.3 mmol), 1-fluoro-2-methyl-4-nitrobenzene (15.3 g, 98.3 mmol), and K2CO3 (27.2 g, 196.6 mmol) were placed in DMF (164 mL, 98.3 mmol) and heated at 90°C for 40 minutes under N2. The reaction mixture was cooled to ambient temperature, diluted with 250 mL of water and ice, stirred for 30 minutes, and filtered. The beige solid was rinsed with water and vacuum-dried to obtain 1-methyl-5-(2-methyl-4-nitrophenoxy)-1H-benzo[d][1,2,3]triazole (27.9 g, 98% yield). LCMS(MM-ES+APCI,Pos):m / z285.1(M+H).

[0222] Step B. 3-Methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline. A flask containing 1-methyl-5-(2-methyl-4-nitrophenoxy)-1H-benzo[d][1,2,3]triazole (1.00 g, 3.52 mmol) and Pd / C (749 mg, 0.35 mmol, 5 wt%) was sealed and purged with N2. MeOH (13 mL) and ammonium formate (1.11 g, 17.6 mmol) were added, and the reaction mixture was stirred for 1 hour. The mixture was filtered through diatomaceous earth, eluted with methanol, and the filtrate was concentrated under vacuum to obtain 3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline (833 mg, yield 93%) as an off-white powder. LCMS(MM-ES+APCI,Pos):m / z255.2(M+H).

[0223] Example 22 (I25) N-(2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidine-4-amine [ka] Step A. 6-(5-methoxy-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole. A solution of 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (0.969 g, 5.23 mmol), 1-methyl-1H-benzo[d]imidazole-6-ol (775 mg, 5.23 mmol), Cs2CO3 (2.05 g, 6.28 mmol), and IPA (10.0 mL) was heated at 85°C for 3 hours. The mixture was filtered and concentrated under vacuum. The crude substance was purified by silica gel chromatography (0% to 100% siRNA / hexane) to obtain 6-(5-methoxy-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (1.10 g, yield 66%). LCMS(MM-ES+APCI,Pos):m / z314.1(M+H).

[0224] Step B: 2-Methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazole-5-yl)oxy)aniline. 5-(5-methoxy-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole (950 mg, 3.03 mmol) and 5% Pd / Al2O3 (645 mg, 303 μmol) were suspended in MeOH (15.2 mL) and sparged with H2 gas for 10 minutes. The reaction mixture was sealed and stirred at 25°C for 16 hours under H2 (1 atm), then filtered to obtain 2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazole-5-yl)oxy)aniline (453 mg, yield 53%). LCMS (MM-ES+APCI, Pos): m / z 284.1 (M+H).

[0225] Example 23 (I26) 2,3,6-Trifluoro-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxyaniline [ka] Step A. 1-Methyl-5-(2,3,5-trifluoro-4-nitrophenoxy)-1H-benzo[d][1,2,3]triazole. 1,2,3,5-tetrafluoro-4-nitrobenzene (500 mg, 2.56 mmol), 1-methyl-1H-benzo[d][1,2,3]triazole-5-ol (382 mg, 2.56 mmol), and tetrabutylammonium bisulfate (87 mg, 0.26 mmol) were dissolved in DCM (12.8 mL), to which NaOH (2 M aqueous solution, 1.3 mL) was added. The reaction mixture was stirred at 23°C for 16 hours. The solution was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography to obtain 1-methyl-5-(2,3,5-trifluoro-4-nitrophenoxy)-1H-benzo[d][1,2,3]triazole (143 mg, 17%). LCMS(MM-ES+APCI,Pos): m / z 325.0(M+H).

[0226] Step B. 2,3,6-trifluoro-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline. H2 was spurged into a methanol (4.4 mL) slurry of 1-methyl-5-(2,3,5-trifluoro-4-nitrophenoxy)-1H-benzo[d][1,2,3]triazole (143 mg, 0.44 mmol) and Pd / C (141 mg, 0.13 mmol, 10 wt%) for 10 minutes. The reaction mixture was sealed and stirred at 23°C for 17.5 hours under an H2 (1 atm) atmosphere. The reaction mixture was filtered through Celite and the pad was washed with MeOH (15 mL). The filtrate was concentrated under vacuum to obtain 2,3,6-trifluoro-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxyaniline (125 mg, 96%) as an off-white solid. LC-MS (MM-ES+APCI,Pos): m / z 295.1 (M+H).

[0227] Example 24 (I27) 2,6-Difluoro-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxyaniline [ka] 2,6-difluoro-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline. Using 1,3,5-trifluoro-2-nitrobenzene instead of 1,2,3,5-tetrafluoro-4-nitrobenzene, 2,6-difluoro-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline (56 mg, 11%) was prepared according to steps A-B of Example 23. LCMS(MM-ES+APCI,Pos):m / z 277.1(M+H).

[0228] Example 25 (I28) 2-Fluoro-3-methoxy-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline [ka] Step A. 1-Bromo-3,5-difluoro-4-methoxy-2-nitrobenzene. A solution of 5-bromo-1,3-difluoro-2-methoxybenzene (4.0 g, 17.9 mmol) in H2SO4 (30 mL) was cooled to 0°C, and KNO3 (2.18 g, 21.5 mmol) was added gradually. The mixture was stirred at 25°C for 1 hour, and then gradually poured into H2O (100 mL) at 0°C. The aqueous solution was neutralized with NaHCO3 (pH 7), and the product was extracted with RINKAN (100 mL x 3). The combined organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-bromo-3,5-difluoro-4-methoxy-2-nitrobenzene (4.2 g, yield 88%) as a yellow oil.

[0229] Step B. 5-(5-bromo-3-fluoro-2-methoxy-4-nitrophenoxy)-1-methyl-1H-benzo[d][1,2,3]triazole. 1-bromo-3,5-difluoro-4-methoxy-2-nitrobenzene (2.00 g, 7.46 mmol) and 1-methylbenzotriazole-5-ol (0.67 g, 4.48 mmol) were dissolved in DMF (20 mL), to which K2CO3 (2.06 g, 14.9 mmol) was added. The mixture was stirred at 80°C for 1 hour, diluted with water (50 mL), and extracted with siRNA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude oily substance was purified by preparative HPLC to obtain 5-(5-bromo-3-fluoro-2-methoxy-4-nitrophenoxy)-1-methylbenzotriazole (450 mg, 1.13 mmol, yield 25%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 397.0, 398.9 (M+H).

[0230] Step C. 2-Fluoro-3-methoxy-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxyaniline. 10% Pd / C (200 mg, 25 μmol) was added to a solution of 5-(5-bromo-3-fluoro-2-methoxy-4-nitrophenoxy)-1-methylbenzotriazole (200 mg, 0.50 mmol) in THF (50 mL). The flask was evacuated and filled with H2 three times. The mixture was stirred at 25°C for 2 hours under an H2 (3 atm) atmosphere, and the suspension was filtered through a Celite pad and eluted with MeOH (50 mL). The crude substance was purified by preparative TLC (10% MeOH / DCM) to obtain 2-fluoro-3-methoxy-4-(1-methylbenzotriazole-5-yl)oxyaniline (50 mg, yield 34%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z289.0(M+H)

[0231] Example 26 (I103) 3-Chloro-5-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline [ka] Step A. 5-(2-bromo-6-chloro-4-nitrophenoxy)-1-methyl-1H-benzo[d][1,2,3]triazole. 1-bromo-3-chloro-2-fluoro-5-nitrobenzene (200 mg, 0.79 mmol) and 1-methylbenzotriazole-5-ol (117 mg, 0.79 mmol) were dissolved in DMF (2.5 mL), to which Cs2CO3 (512 mg, 1.57 mmol) was added. The reaction mixture was stirred at 25°C for 1.5 hours. The mixture was diluted with water, the layers were separated, and the aqueous phase was extracted with  (8 mL × 3). The combined organic layers were washed with brine (6 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 5-(2-bromo-6-chloro-4-nitrophenoxy)-1-methylbenzotriazole (290 mg, yield 94%) as a brown solid. LCMS(MM-ES+APCI,Pos):m / z383.0,384.9(M+H).

[0232] Step B. 3-Bromo-5-chloro-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline. NH4Cl (238 mg, 4.45 mmol) was added to a solution of 5-(2-bromo-6-chloro-4-nitrophenoxy)-1-methylbenzotriazole (290 mg, 0.74 mmol) in EtOH (6 mL) / water (2 mL). The mixture was heated to 60°C and Fe (207 mg, 3.70 mmol) was added. The reaction mixture was stirred at 80°C for 1 hour, diluted with MeOH (20 mL), and filtered through Celite. The filtrate was concentrated under reduced pressure. The crude product was diluted with water (20 mL) and extracted with siRNA (12 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-bromo-5-chloro-4-(1-methylbenzotriazol-5-yl)oxyaniline 4 (255 mg, yield 93%) as a brown oily substance. LCMS(MM-ES+APCI,Pos): m / z 353.0, 355.0 (M+H).

[0233] Step C. 3-Chloro-5-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxyaniline. 3-bromo-5-chloro-4-(1-methylbenzotriazole-5-yl)oxyaniline (255 mg, 0.69 mmol) and methylboronic acid (41 mg, 0.69 mmol) were dissolved in 1,4-dioxane (3 mL) / water (0.3 mL). K2CO3 (191 mg, 1.38 mmol) and Pd(dppf)Cl2 (51 mg, 69 μmol) were added. The reaction mixture was purged with N2 and stirred at 100°C for 3 hours. The mixture was transferred to a separatory funnel, diluted with water (15 mL), and extracted with  (8 mL × 3). The combined organic layers were washed with brine (6 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (25%-50%  / PET) to obtain the product 3-chloro-5-methyl-4-(1-methylbenzotriazol-5-yl)oxyaniline (115 mg, yield 55%) as a brown solid. LCMS (MM-ES+APCI,Pos): m / z 289.2 (M+H).

[0234] Example 27 (I104) 2-Fluoro-6-methoxy-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxyaniline [ka] Step A: 2-Bromo-1,3-difluoro-5-methoxy-4-nitrobenzene. To an ice-cold DCM (80 mL) solution of 2-bromo-1,3-difluoro-5-methoxybenzene (8.00 g, 35.9 mmol), fuming HNO3 (8.99 mL, 199 mmol) was added dropwise at 0°C under an N2 atmosphere. The mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was diluted with ice water (200 mL) and made basic with saturated NaHCO3 aqueous solution (pH=8). The product was extracted with DCM (60 mL x 3), the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0%~4% Â / PET) to obtain 2-bromo-1,3-difluoro-5-methoxy-4-nitrobenzene (9.0 g, yield 94%) as a white solid.

[0235] Steps B-D: 2-Fluoro-6-methoxy-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline. Using 2-bromo-1,3-difluoro-5-methoxy-4-nitrobenzene instead of 1-bromo-3-chloro-2-fluoro-5-nitrobenzene, preparation was carried out according to steps A-C of Example 26 to obtain 2-fluoro-6-methoxy-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline (180 mg, yield 64%) as a brown solid. LCMS(MM-ES+APCI,Pos): m / z 302.8(M+H).

[0236] Example 28 (I105) 2-Fluoro-4-((7-Fluoro-1-methyl-1H-benzo[d]imidazole-5-yl)oxy)-6-methoxy-3-methylaniline [ka] Steps A-D: 2-Fluoro-4-((7-Fluoro-1-methyl-1H-benzo[d]imidazole-5-yl)oxy)-6-methoxy-3-methylaniline. Using 7-Fluoro-1-methyl-1H-benzo[d]imidazole-5-ol instead of 1-methylbenzotriazole-5-ol, preparation was carried out according to steps A-D of Example 27 to obtain 2-Fluoro-4-((7-Fluoro-1-methyl-1H-benzo[d]imidazole-5-yl)oxy)-6-methoxy-3-methylaniline (225 mg, yield 45%) as a yellow solid. LCMS(MM-ES+APCI,Pos): m / z 320.0(M+H).

[0237] Example 29 (I106) 3-Fluoro-5-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline [ka] Step A. 5-(2-bromo-6-fluoro-4-nitrophenoxy)-1-methyl-1H-benzo[d][1,2,3]triazole. 200 mg, 0.84 mmol of 1-bromo-2,3-difluoro-5-nitrobenzene and 1-methylbenzotriazole-5-ol (139 mg, 0.84 mmol) were dissolved in DMF (8 mL), to which 290 mg, 2.10 mmol of K2CO3 was added. The reaction mixture was stirred at 80°C for 1 hour and diluted with water (100 mL). The mixture was transferred to a separatory funnel, and the aqueous mixture was extracted with RINKAN (100 mL x 2). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-50% Â1 / PET and 2% MeOH / DCM) to obtain 5-(2-bromo-6-fluoro-4-nitrophenoxy)-1-methylbenzotriazole (1.55 g, 70% yield) as a brown solid. LCMS (MM-ES+APCI,Pos): m / z 367.0, 368.9 (M+H).

[0238] Step B.5-(2-bromo-6-fluoro-4-nitrophenoxy)-1-methylbenzotriazole (300 mg, 0.80 mmol) and methylboronic acid (57 mg, 0.96 mmol) were dissolved in 1,4-dioxane (5 mL) / H2O (1 mL). Pd(dppf)Cl2 (58 mg, 80 μmol) and K2CO3 (275 mg, 1.99 mmol) were added. The reaction mixture was purged with N2, stirred at 90°C for 2 hours, and quenched with H2O (100 mL). The two-phase mixture was separated, and the aqueous layer was extracted with RINKAN (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-50% Âx / PET) to obtain 5-(2-fluoro-6-methyl-4-nitrophenoxy)-1-methylbenzotriazole (300 mg, 23% yield) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 303.0 (M+H).

[0239] Step C. 230 mg, 0.71 mmol of 5-(2-fluoro-6-methyl-4-nitrophenoxy)-1-methylbenzotriazole was dissolved in EtOH (2 mL) / H2O (2 mL). Fe (157 mg, 2.81 mmol) and NH4Cl (151 mg, 2.82 mmol) were added. The mixture was stirred at 60°C for 1 hour, and the suspension was filtered and eluted with EtOH (20 mL). The filtrate was concentrated under vacuum to obtain 3-fluoro-5-methyl-4-(1-methylbenzotriazole-5-yl)oxyaniline (360 mg, quantitative yield) as an off-white solid. LCMS (MM-ES+APCI,Pos): m / z 273.1 (M+H).

[0240] Example 30 (I107) 2,5-Difluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline [ka] Steps A-C: 2,5-difluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline. Using 3-bromo-1,2,4-trifluoro-5-nitrobenzene instead of 1-bromo-2,3-difluoro-5-nitrobenzene, preparation was carried out according to steps A-C of Example 29 to obtain 2,5-difluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline (1.60 g, yield 77%) as a pink solid. LCMS(MM-ES+APCI,Pos): m / z 291.1(M+H).

[0241] Example 31 (I108) 2-Fluoro-4-((7-Fluoro-1-methyl-1H-benzo[d]imidazole-5-yl)oxy)-3-methylaniline [ka] Step A. 2-Fluoro-4-((7-Fluoro-1-methyl-1H-benzo[d]imidazole-5-yl)oxy)-3-methylaniline. At 25°C, DMSO (15 mL) was added to a flask containing 7-Fluoro-1-methylbenzimidazole-5-ol (772 mg, 4.29 mmol), 2-Fluoro-4-iodo-3-methylaniline (1 g, 3.57 mmol), CuI (204 mg, 1.07 mmol), picolinic acid (88 mg, 0.72 mmol), and K3PO4 (1.52 g, 7.14 mmol). The mixture was purged with N2 and heated at 80°C for 16 hours. The reaction product was quenched with H2O (50 mL), and the aqueous layer mixture was extracted with RINKAN (30 mL x 3). The combined organic layers were washed with water (150 mL) and brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0%~75% Â / PET) to obtain 2-fluoro-4-(7-fluoro-1-methylbenzimidazole-5-yl)oxy-3-methylaniline (500 mg, yield 45%) as a pink solid. LCMS (MM-ES+APCI,Pos): m / z 290.2 (M+H).

[0242] Intermediates I108 to I115 in Table 12 below were prepared according to step A of Example 31. [Table 12]

[0243] Example 32 (I116) 3-Ethyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxyaniline [ka] Step A. 5-(2-bromo-4-nitrophenoxy)-1-methyl-1H-benzo[d][1,2,3]triazole. To a solution of 2-bromo-1-fluoro-4-nitrobenzene (1.00 g, 4.55 mmol) in DMF (10 mL), K2CO3 (1.26 g, 9.09 mmol) and 1-methylbenzotriazole-5-ol (0.68 g, 4.55 mmol) were added. The mixture was stirred at 25°C for 2 hours. The reaction product was quenched with H2O (50 mL) and extracted with  (50 mL x 3). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0% to 25%  / PET) to obtain 5-(2-bromo-4-nitrophenoxy)-1-methylbenzotriazole 3 (800 mg, 50% yield) as a brown solid. LC-MS (MM-ES+APCI,Pos): m / z 349.0, 351.0 (M+H).

[0244] Step B. 1-Methyl-5-(4-nitro-2-vinylphenoxy)-1H-benzo[d][1,2,3]triazole. To a solution of 5-(2-bromo-4-nitrophenoxy)-1-methylbenzotriazole (700 mg, 2.00 mmol) in 1,4-dioxane (10 mL) / water (2 mL), Pd(dppf)Cl2 (145 mg, 0.20 mmol), Na2CO3 (425 mg, 4.01 mmol), and potassium vinyltrifluoroborate (322 mg, 2.41 mmol) were added. The reaction mixture was stirred at 110 °C for 2 hours. The mixture was concentrated under vacuum, and the crude residue was purified by silica gel column chromatography (0%~25% Â / PET) to obtain 1-methyl-5-(4-nitro-2-vinylphenoxy)benzotriazole (500 mg, yield 79%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z297.2(M+H).

[0245] Step C. 3-Ethyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxyaniline. 10% Pd / C (1 g) was added to a MeOH solution of 1-methyl-5-(4-nitro-2-vinylphenoxy)benzotriazole (500 mg, 1.57 mmol). The mixture was degassed and purged three times with H2. The reaction mixture was stirred at 20°C for 30 minutes, filtered through Celite, and eluted with MeOH (30 mL). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (1%~30% Â1 / PET) to obtain 3-ethyl-4-(1-methylbenzotriazole-5-yl)oxyaniline 5 (230 mg, yield 52%) as a colorless oil. LCMS (MM-ES+APCI,Pos): m / z 269.3 (M+H).

[0246] Example 33 (I117) 4-([1,2,4]triazolo[1,5-c]pyrimidine-7-yloxy)-3-methylaniline [ka] Step A. 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-c]pyrimidine. A solution of 2-methyl-4-nitrophenol (5.94 g, 38.8 mmol), 7-chloro-[1,2,4]triazolo[1,5-c]pyrimidine (5.00 g, 32.3 mmol), and K2CO3 (11.2 g, 80.9 mmol) in MeCN (50 mL) was heated at 80°C for 3 hours. The mixture was concentrated under vacuum, diluted with water (50 mL), and extracted with DCM (25 mL). The organic phase was washed with 2 M NaOH (25 mL) aqueous solution, dried over anhydrous MgSO4, and filtered. The product was concentrated to dryness to obtain 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-c]pyrimidine (2.87 g, 31% yield) as a yellow solid.

[0247] Step B. 4-([1,2,4]triazolo[1,5-c]pyrimidine-7-yloxy)-3-methylaniline. 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-c]pyrimidine (2.00 g, 7.37 mmol) was dissolved in EtOH (30 mL) / water (10 mL) and Fe (1.24 g, 22.1 mmol) and NH4Cl (1.97 g, 36.9 mmol) were added. The reaction mixture was heated at 60 °C for 3 hours and then cooled to ambient temperature. The mixture was filtered through Celite, washed with EtOH (10 mL), and volatile substances were removed by vacuum. Water (20 mL) was added, the product was extracted with SiO2 (10 mL x 3), and the combined organic matter was concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (25%-60% ethyl acetate / heptane) to obtain 4-([1,2,4]triazolo[1,5-c]pyrimidine-7-yloxy)-3-methylaniline (0.92 g, yield 51%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 242.3 (M+H).

[0248] Example 34 (I29) N-(4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidine-4-amine [ka] Step AN-(4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidine-4-amine. 4-(7-fluoro-1-methylbenzotriazole-5-yl)oxy-3-methylaniline (130 mg, 0.48 mmol) and 4-chloro-6-methylsulfanylpyrimido[5,4-d]pyrimidine (203 mg, 0.96 mmol) were dissolved in IPA (5 mL) and DIPEA (250 μL, 1.43 mmol) was added. The mixture was stirred at 25°C for 12 hours and concentrated under reduced pressure. The residue was pulverized in MeCN (5 mL) at 25°C for 30 minutes. By filtration, N-[4-(7-fluoro-1-methylbenzotriazole-5-yl)oxy-3-methylphenyl]-6-methylsulfanylpyrimide[5,4-d]pyrimidine-4-amine (190 mg, yield 84%) was obtained as a gray solid. LC-MS (MM-ES+APCI,Pos): m / z 449.2 (M+H).

[0249] Step BN-(4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)-6-(methylsulfinyl)pyrimide[5,4-d]pyrimidine-4-amine. Oxon (242 mg, 1.44 mmol) was added to a solution of N-[4-(7-fluoro-1-methylbenzotriazole-5-yl)oxy-3-methylphenyl]-6-methylsulfanylpyrimide[5,4-d]pyrimidine-4-amine (270 mg, 0.60 mmol) in MeCN (3 mL) / H2O (3 mL). The reaction mixture was stirred at 50 °C for 1.5 hours, diluted with saturated NaHCO3 aqueous solution (15 mL), and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium 2SO4, filtered, and vacuum concentrated to obtain N-[4-(7-fluoro-1-methylbenzotriazole-5-yl)oxy-3-methylphenyl]-6-methylsulfinylpyrimide[5,4-d]pyrimidine-4-amine (190 mg, yield 68%) as a yellow gum. LC-MS(MM-ES+APCI,Pos): m / z 465.1(M+H).

[0250] Intermediates I29-I46 and I118-I144 in Table 3 below were prepared according to steps A-B of Example 34. Step A can be carried out using DIPEA, TEA, or Cs2CO3 as the base. Depending on the substrate, either a sulfoxide or a sulfone was separated. Both oxidation states are effective in subsequent reactions. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7]

[0251] Example 35 (I47) N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidine-4-amine [ka] Step AN-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidine-4-amine. 3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline (21.0 g, 82.6 mmol) and 8-chloro-2-(methylthio)pyrimido[5,4-d]pyrimidine (26.3 g, 124 mmol) were dissolved in DMF (413 mL), to which TEA (13.8 mL, 99.1 mmol) was added. The reaction mixture was heated at 45°C for 2.5 hours, cooled to 0°C, and water (500 mL) was added. After stirring for 15 minutes, the mixture was filtered, and the solid was rinsed with water. The solid was collected and vacuum-dried at 40°C to obtain N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidine-4-amine (33.6 g, 95% yield). LC-MS(MM-ES+APCI,Pos): m / z 431.2(M+H).

[0252] Step B: N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidine-4-amine. A solution of N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidine-4-amine (51.9 g, 121 mmol) in DCM (603 mL) was cooled to 0°C. A solution of mCPBA (29.1 g, 127 mmol, 75 wt%) in DCM (300 mL) was gradually added over 2 hours. The ice bath was removed and the reaction mixture was stirred at 25°C for 30 minutes. Sodium thiosulfate (1 M, 1 L) was gradually added and the reaction mixture was stirred for 10 minutes. Methanol (300 mL) was gradually added to dissolve the solid, and the layers were separated. The organic matter was diluted with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered, and concentrated to obtain N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidine-4-amine (47.8 g, yield 89%). LCMS(MM-ES+APCI,Pos): m / z 447.2(M+H).

[0253] Example 36 (I48) N-(2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidine-4-amine [ka] Step AN-(2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidine-4-amine. 2-fluoro-3-methyl-4-(1-methylbenzimidazole-5-yl)oxyaniline (250 mg, 0.92 mmol) and 4-chloro-6-methylsulfanylpyrimido[5,4-d]pyrimidine (600 mg, 2.82 mmol) were dissolved in n-BuOH (5 mL), to which TFA (0.21 mL, 2.83 mmol) was added. The mixture was stirred at 80°C for 2 hours and then concentrated under vacuum. The crude substance was purified by preparative silica gel TLC (10% MeOH / DCM) to obtain N-[2-fluoro-3-methyl-4-(1-methylbenzimidazole-5-yl)oxyphenyl]-6-methylsulfanylpyrimide[5,4-d]pyrimidine-4-amine (210 mg, yield 51%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 448.1 (M+H).

[0254] Step BN-(2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazole-5-yl)oxy)phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidine-4-amine. Prepared according to step B of Example 34, N-[2-fluoro-3-methyl-4-(1-methylbenzimidazole-5-yl)oxyphenyl]-6-methylsulfinylpyrimido[5,4-d]pyrimidine-4-amine was used instead of N-[4-(7-fluoro-1-methylbenzotriazole-5-yl)oxyphenyl]-6-methylsulfinylpyrimido[5,4-d]pyrimidine-4-amine to obtain N-[2-fluoro-3-methyl-4-(1-methylbenzimidazole-5-yl)oxyphenyl]-6-methylsulfinylpyrimido[5,4-d]pyrimidine-4-amine (150 mg, yield 72%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z 464.0(M+H).

[0255] Intermediates I48-I50 and I145-I148 in Table 4 below were prepared according to steps A-B of Example 36. [Table 4]

[0256] Example 37 (I51) 6-Chloro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine [ka] 4,6-Dichloropyrido[3,2-d]pyrimidine (2.36 g, 11.8 mmol) and 3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline (3.00 g, 11.8 mmol) were suspended in IPA (29.5 mL) and heated at 85°C for 40 minutes. The reaction mixture was cooled to ambient temperature, the slurry was vacuum filtered, and the precipitate was washed with MTBE. The filtrate was vacuum concentrated, and the solid was washed with MTBE. The two solids were combined to obtain 6-chloro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (5.16 g, quantitative yield) as a yellow fine powder. LCMS(MM-ES+APCI,Pos):m / z418.1(M+H).

[0257] Example 38 (I52) 6-Chloro-N-(2-fluoro-4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)pyrido[3,2-d]pyrimidine-4-amine [ka] Step A. 6-Chloro-N-(2-fluoro-4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)pyrido[3,2-d]pyrimidine-4-amine. 4,6-dichloropyrido[3,2-d]pyrimidine (55 mg, 0.28 mmol) and 2-fluoro-4-(7-fluoro-1-methylbenzotriazole-5-yl)oxy-3-methylaniline (80 mg, 0.28 mmol) were dissolved in IPA (5 mL), to which DIPEA (0.14 mL, 0.83 mmol) was added. The mixture was stirred at 80°C for 1 hour and then concentrated under vacuum. The crude substance was purified by slurring in HCl (5 mL) at 25°C for 10 minutes. After filtration, the solid was dried to obtain 6-chloro-N-[2-fluoro-4-(7-fluoro-1-methylbenzotriazol-5-yl)oxy-3-methylphenyl]pyrido[3,2-d]pyrimidine-4-amine (135 mg, yield 79%) as a yellow solid. LCMS(MM-ES+APCI,Pos): m / z 454.3(M+H).

[0258] Intermediates I52 and I149-I164 in Table 13 below were prepared according to step A of Example 38. [Table 13-1] [Table 13-2] [Table 13-3]

[0259] Example 39 (I53) 6-Chloro-N-(2,3-difluoro-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine [ka] 6-Chloro-N-(2,3-difluoro-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine. 2,3-difluoro-4-(1-methylbenzotriazole-5-yl)oxyaniline (140 mg, 0.51 mmol) and 4,6-dichloropyrido[3,2-d]pyrimidine (101 mg, 0.51 mmol) were dissolved in n-BuOH (5 mL), to which TFA (38 μL, 0.51 mmol) was added. The mixture was stirred at 100 °C for 1 hour and then vacuum concentrated. The residue was diluted with water (5 mL), made basic with saturated NaHCO3 (5 mL) aqueous solution, and extracted with ELISA (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and vacuum concentrated. The crude product was purified by silica gel column chromatography (15% Â15%) to obtain 6-chloro-N-[2,3-difluoro-4-(1-methylbenzotriazol-5-yl)oxyphenyl]pyrido[3,2-d]pyrimidine-4-amine (128 mg, yield 55%) as a yellow oil. LCMS (MM-ES+APCI,Pos): m / z 440.0 (M+H).

[0260] Intermediates I53 and I165-I172 in Table 14 below were prepared according to step A of Example 39. [Table 14-1] [Table 14-2]

[0261] Example 40 (I173) 6-Fluoro-N-(2-Fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine [ka] Step A. 6-chloro-N-(2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine. KF (93.3 mg, 1.61 mmol) and DIPEA (0.28 mL, 1.61 mmol) were added to a solution of 6-chloro-N-[2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]pyrido[3,2-d]pyrimidine-4-amine (140 mg, 0.32 mmol) in DMSO (6 mL). The reaction mixture was stirred at 100 °C for 4 hours. The mixture was concentrated under reduced pressure to obtain 6-fluoro-N-[2-fluoro-3-methyl-4-(1-methylbenzotriazol-5-yl)oxyphenyl]pyrido[3,2-d]pyramide in-4-amine 7 (200 mg, quantitative yield) as a pale yellow oil. LCMS(MM-ES+APCI,Pos): m / z 420.1(M+H).

[0262] Example 41 (I54) tert-butyl4-(4-chloropyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate [ka] Step A. tert-butyl 4-(6-carbamoyl-5-nitropyridine-2-yl)piperazine-1-carboxylate. To a solution of 6-chloro-3-nitropyridine-2-carboxamide (1.00 g, 4.96 mmol) in DMSO (30 mL), DIPEA (2.59 mL, 14.9 mmol) and tert-butylpiperazine-1-carboxylate (1.39 g, 7.44 mmol) were added. The mixture was stirred at 90°C for 1 hour, quenched with H2O (100 mL), and extracted with siRNA (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 4-(6-carbamoyl-5-nitro-2-pyridyl)piperazine-1-carboxylate (2.0 g, quantitative yield) as a white solid. LCMS(MM-ES+APCI,Pos):m / z352.0(M+H).

[0263] Step B. tert-butyl 4-(5-amino-6-carbamoylpyridin-2-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(6-carbamoyl-5-nitro-2-pyridyl)piperazine-1-carboxylate (1.8 g, 5.12 mmol) in EtOH (20 mL) / H2O (10 mL), Fe powder (1.14 g, 20.5 mmol) and NH4Cl (1.10 g, 20.5 mmol) were added. The mixture was stirred at 80°C for 1 hour. The suspension was filtered, and the filtrate solid was washed with MeOH (20 mL). The filtrate was concentrated under vacuum to obtain tert-butyl 4-(5-amino-6-carbamoyl-2-pyridyl)piperazine-1-carboxylate 4 (1.8 g, quantitatively) as a gray solid. LCMS(MM-ES+APCI,Pos):m / z322.1(M+H).

[0264] Step C. tert-butyl 4-(8-hydroxypyrimido[5,4-d]pyrimidine-2-yl)piperazine-1-carboxylate. A solution of tert-butyl 4-(5-amino-6-carbamoyl-2-pyridyl)piperazine-1-carboxylate (1.7 g, 5.29 mmol) in CH(OEt)3 (20 mL) was heated at 100 °C for 2 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (25%~35% ethyl acetate / PET) to obtain tert-butyl 4-(4-hydroxypyrimido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate (1.1 g, yield 60%) as a brown solid. LCMS(MM-ES+APCI,Pos):m / z332.1(M+H).

[0265] Step D. tert-butyl 4-(8-chloropyrimido[5,4-d]pyrimidine-2-yl)piperazine-1-carboxylate. A solution of tert-butyl 4-(4-hydroxypyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate (527 mg, 1.51 mmol) in toluene (10 mL) was cooled to 0°C, and POCl3 (0.18 mL, 1.96 mmol) and DIPEA (1.31 mL, 7.54 mmol) were added. The mixture was stirred at 80°C for 2 hours and then concentrated under vacuum to obtain tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate (800 mg, quantitatively) as a brown oily substance. LCMS (MM-ES+APCI,Pos): m / z 350.0 (M+H).

[0266] Example 42 (I55) tert-butyl3-(4-chloropyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate [ka] tert-butyl 3-(4-chloropyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate. Using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate instead of tert-butylpiperazine-1-carboxylate, preparation was carried out according to steps A-D of Example 41 to obtain tert-butyl 3-(4-chloropyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (350 mg, quantitative yield) as a black oily substance. LCMS(MM-ES+APCI,Pos):m / z 362.0(M+H).

[0267] Example 43 (I56) tert-butyl6-(4-chloropyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate [ka] tert-butyl 6-(4-chloropyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate. Using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate instead of tert-butylpiperazine-1-carboxylate, preparation was carried out according to steps A-D of Example 41 to obtain tert-butyl 6-(4-chloropyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (420 mg, quantitative yield) as a brown oily substance. LCMS(MM-ES+APCI,Pos):m / z 362.0(M+H).

[0268] Example 44 (I57) tert-butyl 4-(4-chloro-5-fluoropyrido[3,4-d]pyrimidine-6-yl)piperazine-1-carboxylate [ka] Step A. tert-butyl 4-(5-bromo-3-fluoropyridine-2-yl)piperazine-1-carboxylate. To a solution of 5-bromo-2,3-difluoropyridine (10.0 g, 51.6 mmol) in DMF (100 mL), K2CO3 (9.26 g, 67.0 mmol) and tert-butylpiperazine-1-carboxylate (9.60 g, 51.6 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours, gradually quenched with water (100 mL), and extracted with siRNA (100 mL x 3). The combined organic layer was washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude oily substance was purified by silica gel column chromatography (1% to 30% toluene / PET) to obtain tert-butyl 4-(5-bromo-3-fluoro-2-pyridyl)piperazine-1-carboxylate (11 g, yield 59%) as a white solid. LCMS (MM-ES+APCI,Pos): m / z 304.1(M+H- t Bu).

[0269] Step B. 5-Bromo-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluoroisonicotinic acid. A solution of tert-butyl 4-(5-bromo-3-fluoro-2-pyridyl)piperazin-1-carboxylate (10.0 g, 27.8 mmol) in THF (30 mL) was cooled to -78°C. LDA (2 M in THF, 20.8 mL, 41.6 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. Solid CO2 (1.22 g, 27.8 mmol) was added, and stirring was continued at -78°C for 2 hours. The mixture was gradually quenched with saturated NH4Cl (50 mL) aqueous solution, warmed to 25°C, and extracted with RINKAN (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude oily substance was purified by silica gel column chromatography (0%~90% toluene / PET) to obtain 5-bromo-2-(4-tert-butoxycarbonylpiperazin-1-yl)-3-fluoropyridine-4-carboxylic acid (8.0 g, yield 71%) as a yellow oily substance. LCMS(MM-ES+APCI,Pos):m / z348.0(M+H- t Bu).

[0270] Step C. tert-butyl 4-(5-bromo-3-fluoro-4-(methoxycarbonyl)pyridine-2-yl)piperazine-1-carboxylate. To a solution of 5-bromo-2-(4-tert-butoxycarbonylpiperazine-1-yl)-3-fluoropyridine-4-carboxylic acid (8.0 g, 19.8 mmol) in DMF (80 mL), K2CO3 (5.47 g, 39.6 mmol) and MeI (6.16 mL, 99.0 mmol) were added. The mixture was stirred at 20°C for 2 hours, quenched with water (30 mL), and extracted with RINKAN (40 mL x 3). The combined organic layers were washed with water (100 mL x 2) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude oily substance was purified by silica gel column chromatography (1%-20% toluene / PET) to obtain tert-butyl 4-(5-bromo-3-fluoro-4-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate (6.0 g, yield 72%) as a yellow oily substance. LCMS (MM-ES+APCI,Pos): m / z 364.1(M+H- t Bu).

[0271] Step D. tert-butyl 4-(5-((diphenylmethylene)amino)-3-fluoro-4-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate. A solution of tert-butyl 4-(5-bromo-3-fluoro-4-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate (5.0 g, 12.0 mmol) in 1,4-dioxane (50 mL) was purged with N2. Pd2(dba)3 (1.09 g, 1.20 mmol), xanthophos (1.04 g, 1.79 mmol), Cs2CO3 (9.74 g, 30.0 mmol), and diphenylmethanymine (2.41 mL, 14.4 mmol) were added, and the mixture was heated at 100 °C for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with toluene (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude solid was purified by silica gel column chromatography (1% to 50% toluene / PET) to obtain tert-butyl 4-[5-(benzhydrideneamino)-3-fluoro-4-methoxycarbonyl-2-pyridyl]piperazine-1-carboxylate (5.8 g, yield 94%) as a yellow solid. LC-MS (MM-ES+APCI, Pos): m / z 519.5 (M+H).

[0272] Step E. tert-butyl 4-(5-amino-3-fluoro-4-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-[5-(benzhydrideneamino)-3-fluoro-4-methoxycarbonyl-2-pyridyl]piperazine-1-carboxylate (5.8 g, 11.2 mmol) in MeOH (20 mL) / water (20 mL), 2 M HCl (11.2 mL, 22.4 mmol) was added. The mixture was stirred at 20°C for 2 hours, neutralized with saturated NaHCO3 (200 mL) aqueous solution (pH 7), and extracted with siRNA (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (1% to 50% toluene / PET) to obtain tert-butyl 4-(5-amino-3-fluoro-4-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate (3.1 g, yield 78%) as a yellow oil. LCMS (MM-ES+APCI,Pos): m / z 355.2 (M+H).

[0273] Step F. tert-butyl 4-(5-fluoro-4-hydroxypyrido[3,4-d]pyrimidine-6-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(5-amino-3-fluoro-4-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate (3.0 g, 8.47 mmol) in 2-methoxyethanol (30 mL), NaOAc (2.08 g, 25.4 mmol) and formamidine hydrochloride (2.73 g, 33.9 mmol) were added. The mixture was stirred at 110°C for 2 hours, quenched with water (30 mL), and extracted with ELISA (40 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude oily substance was purified by silica gel column chromatography (1% to 50% toluene / PET) to obtain tert-butyl 4-(5-fluoro-4-hydroxypyrido[3,4-d]pyrimidine-6-yl)piperazine-1-carboxylate (1.9 g, yield 64%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 294.0 (M+H- t Bu).

[0274] Step G. tert-butyl 4-(4-chloro-5-fluoropyrido[3,4-d]pyrimidine-6-yl)piperazine-1-carboxylate. To a PhMe (20 mL) solution of tert-butyl 4-(5-fluoro-4-hydroxypyrido[3,4-d]pyrimidine-6-yl)piperazine-1-carboxylate (1.8 g, 5.15 mmol), DIPEA (4.5 mL, 25.8 mmol) and POCl3 (0.58 mL, 6.18 mmol) were added. The mixture was stirred at 100°C for 2 hours, quenched with saturated NaHCO3 (30 mL) aqueous solution, and extracted with ELISA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude solid was purified by silica gel column chromatography (1% to 50% toluene / PET) to obtain tert-butyl 4-(4-chloro-5-fluoropyrido[3,4-d]pyrimidine-6-yl)piperazine-1-carboxylate (1.10 g, yield 58%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 368.2 (M+H).

[0275] Example 45 (I58) tert-butyl 4-(4-chloro-7-methoxypyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate [ka] Step A. 2,6-Dibromo-3-methoxy-5-nitropyridine. Nitric acid (32.9 mL, 732 mmol) was added dropwise to ice-cold sulfuric acid (30 mL), followed by the gradual addition of 2,6-dibromo-3-methoxypyridine (7.50 g, 28.1 mmol). The mixture was stirred at 0°C for 20 minutes, at 10°C for 10 minutes, and at 60°C for 2.5 hours. The reaction mixture was gradually poured into ice water (200 mL), the yellow precipitate was collected, washed with water (800 mL), and vacuum-dried to obtain 2,6-dibromo-3-methoxy-5-nitropyridine (3.32 g, yield 36%) as a pale yellow solid. LCMS (MM-ES+APCI,Pos): m / z 312.6 (M+H).

[0276] Step B. tert-butyl 4-(6-bromo-3-methoxy-5-nitropyridine-2-yl)piperazine-1-carboxylate. To a solution of 2,6-dibromo-3-methoxy-5-nitropyridine (1.00 g, 3.21 mmol) in DMF (20 mL), K2CO3 (1.33 g, 9.62 mmol) and tert-butylpiperazine-1-carboxylate (597 mg, 3.21 mmol) were added. The mixture was stirred at 25°C for 1 hour, diluted with water (50 mL), and extracted with siRNA (40 mL x 2). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain tert-butyl 4-(6-bromo-3-methoxy-5-nitro-2-pyridyl)piperazine-1-carboxylate (1.70 g, yield 88%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z439.0(M+Na + ).

[0277] Step C. tert-butyl 4-(6-cyano-3-methoxy-5-nitropyridine-2-yl)piperazine-1-carboxylate. CuCN (438 mg, 4.89 mmol) was added to a solution of tert-butyl 4-(6-bromo-3-methoxy-5-nitro-2-pyridyl)piperazine-1-carboxylate (1.70 g, 4.07 mmol) in DMF (40 mL). The mixture was stirred at 100 °C for 1 hour, diluted with water (60 mL), and extracted with siRNA (50 mL x 2). The combined organic layers were washed with brine (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain tert-butyl 4-(6-cyano-3-methoxy-5-nitro-2-pyridyl)piperazine-1-carboxylate (1.22 g, yield 68%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z386.0(M+Na + ).

[0278] Step D. tert-butyl 4-(5-amino-6-carbamoyl-3-methoxypyridine-2-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(6-cyano-3-methoxy-5-nitro-2-pyridyl)piperazine-1-carboxylate (1.22 g, 3.36 mmol) in EtOH (30 mL) / water (10 mL), Fe powder (937 mg, 16.8 mmol) and NH4Cl (1.80 g, 33.6 mmol) were added. The mixture was stirred at 80°C for 1 hour and filtered. The filtrate was concentrated under vacuum, diluted with water (40 mL), and extracted with siRNA (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl 4-(5-amino-6-carbamoyl-3-methoxy-2-pyridyl)piperazine-1-carboxylate (1.14 g, yield 73%) as a brown solid. LCMS(MM-ES+APCI,Pos): m / z 352.1(M+H).

[0279] Step E. tert-butyl 4-(4-hydroxy-7-methoxypyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate. A solution of tert-butyl 4-(5-amino-6-carbamoyl-3-methoxy-2-pyridyl)piperazine-1-carboxylate (1.14 g, 3.24 mmol) in CH(OEt)3 (15 mL) was heated to 100°C and stirred for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (5%~10% MeOH / DCM) to obtain tert-butyl 4-(4-hydroxy-7-methoxypyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate (350 mg, yield 27%) as a brown solid. LCMS (MM-ES+APCI,Pos): m / z 362.3 (M+H).

[0280] Step F. tert-butyl 4-(4-chloro-7-methoxypyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate hydrochloride. To a solution of tert-butyl 4-(4-hydroxy-7-methoxypyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate (145 mg, 0.40 mmol) in toluene (1 mL), DIPEA (0.28 mL, 1.60 mmol) and POCl3 (0.37 mL, 4.01 mmol) were added. The reaction mixture was stirred at 90°C for 1 hour and then concentrated under vacuum to obtain tert-butyl 4-(4-chloro-7-methoxypyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate hydrochloride (167 mg, quantitative yield) as a brown solid. LCMS(MM-ES+APCI,Pos):m / z380.3(M+H-HCl).

[0281] Example 46 (I59) 1-(4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)propa-2-en-1-one [ka] Step A: tert-butyl 4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazine-1-carboxylate. DIPEA (3.98 mL, 22.8 mmol) was added to a solution of N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidine-4-amine (5.10 g, 11.4 mmol) and tert-butylpiperazine-1-carboxylate (4.26 g, 22.8 mmol) in 1,4-dioxane (62 mL). The reaction mixture was heated at 80 °C for 2 hours and then concentrated under vacuum. The solid was purified by silica gel column chromatography (0% to 100% siRNA / DCM) to obtain tert-butyl 4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazine-1-carboxylate (6.41 g, 99% yield). LCMS (MM-ES+APCI,Pos): m / z 569.3 (M+H).

[0282] Step BN-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazine-1-yl)pyrimido[5,4-d]pyrimidine-4-amine. To a solution of tert-butyl4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazine-1-carboxylate (48.1 g, 84.6 mmol) in DCM (423 mL), TFA (65.2 mL, 846 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 hours and then concentrated under vacuum. The mixture was dissolved in 20% MeOH / DCM and neutralized with 1 M NaOH (pH 7). The layers were separated, and the organic layer was washed with saturated NaHCO3 aqueous solution (2×) and brine. The organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The crude material was purified using silica gel column chromatography (0%~20% MeOH / DCM) to obtain N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4-amine (35.2 g, yield 89%). LCMS (MM-ES+APCI,Pos): m / z 469.3 (M+H).

[0283] Alternative step: BN-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazine-1-yl)pyrimido[5,4-d]pyrimidine-4-amine hydrochloride. To an ice-cold DCM (10 mL) solution of tert-butyl 4-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]piperazine-1-carboxylate (410 mg, 0.72 mmol), HCl (4 M in HCl, 4 mL, 16 mmol) was added. The mixture was stirred at 0°C for 1 hour and then concentrated under vacuum to obtain N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazine-1-ylpyrimido[5,4-d]pyrimidine-4-amine hydrochloride (435 mg, quantitative yield) as a yellow solid. LCMS(MM-ES+APCI,Pos): m / z 469.1(M+H).

[0284] Example 47 (I60) (E)-4-(3-fluoroazetidine-1-yl)buta-2-enoic acid [ka] Step A. (E)-4-(3-fluoroazetidine-1-yl)buta-2-enoic acid. 3-fluoroazetidine hydrochloride (500 mg, 4.48 mmol) and (E)-4-bromobuta-2-enoic acid (740 mg, 4.48 mmol) were dissolved in DMF (10 mL), to which DIPEA (3.12 mL, 7.93 mmol) was added dropwise at 25°C. The mixture was heated to 60°C, stirred for 1 hour, and then vacuum concentrated to obtain (E)-4-(3-fluoroazetidine-1-yl)buta-2-enoic acid (945 mg, quantitatively) as a yellow oily substance. LCMS (MM-ES+APCI,Neg): m / z 158.2 (MH) + ).

[0285] Example 48 (I61) 1-(4-hydroxypiperidine-1-yl)propa-2-en-1-one [ka] Step A. 1-(4-hydroxypiperidine-1-yl)propa-2-en-1-one. At 0°C, 27.5 mL (198 mmol) of piperidine-4-ol (10.0 g, 98.9 mmol) was mixed with 15 mL of DCM solution, to which TEA (27.5 mL, 198 mmol) and acryloyl chloride (8.1 mL, 98.9 mmol) were added. The reaction mixture was stirred under N2 at 0°C for 2 hours and then at 25°C for 12 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (20% MeCN / 0.05% NH4OH aqueous solution) to obtain 1-(4-hydroxypiperidine-1-yl)propa-2-en-1-one (5.5 g, yield 32%) as a yellow oil. LCMS (MM-ES+APCI,Pos): m / z 156.2 (M+H).

[0286] Example 49 (I174) 1-(3-hydroxypyrrolidine-1-yl)propa-2-en-1-one [ka] Step A. 1-(3-hydroxypyrrolidine-1-yl)propa-2-en-1-one. Prepared according to Example 48, piperidine-4-ol was replaced with pyrrolidine-3-ol to obtain 1-(3-hydroxypyrrolidine-1-yl)propa-2-en-1-one (1.02 g, yield 52%) as a white solid. LCMS(MM-ES+APCI,Pos):m / z283.2(2xM+H).

[0287] Example 50 (I62) 1-(3-(methylamino)azetidine-1-yl)propa-2-en-1-one 2,2,2-trifluoroacetate [ka] Step A. tert-butyl(1-acryloylazetidine-3-yl)(methyl)carbamate. To a solution of tert-butyl N-(azetidine-3-yl)-N-methylcarbamate hydrochloride (300 mg, 1.35 mmol) in THF (5 mL), saturated NaHCO3 aqueous solution (0.15 mL, 4.04 mmol) was added. After addition, the mixture was cooled to 0°C, and propa-2-enoyl chloride (0.22 mL, 2.69 mmol) was added dropwise. The reaction mixture was stirred at 20°C for 0.5 hours and gradually quenched with saturated aqueous solution. Diluted with NaHCO3 (10 mL) aqueous solution. The mixture was extracted with DCM (15 mL x 3), the combined organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain tert-butyl N-methyl-N-(1-propa-2-enoylazetidine-3-yl)carbamate (300 mg, yield 93%) as a pale yellow oil.

[0288] Step B. 1-(3-(methylamino)azetidine-1-yl)propa-2-en-1-one 2,2,2-trifluoroacetate. To a solution of tert-butyl N-methyl-N-(1-propa-2-enoylazetidine-3-yl)carbamate (300 mg, 1.25 mmol) in DCM (3 mL), TFA (1.00 mL, 13.5 mmol) was added. The mixture was stirred at 20°C for 0.5 hours and then concentrated under vacuum to obtain 1-[3-(methylamino)azetidine-1-yl]propa-2-en-1-one 2,2,2-trifluoroacetate (300 mg, 1.18 mmol, yield 95%) as a pale yellow oil. LCMS (MM-ES+APCI,Pos): m / z 141.0 (M+H-TFA).

[0289] Example 51 (I63) (E)-4-(pyrrolidine-1-yl)buta-2-enoic acid [ka] Step A. (E)-4-(pyrrolidine-1-yl)buta-2-enoic acid. DIPEA (1.38 mL, 7.95 mmol) was added to a solution of pyrrolidine (0.33 mL, 3.97 mmol) and (E)-4-bromopropa-2-enoic acid (400 mg, 2.65 mmol) in DMF (10 mL). The mixture was heated to 60°C, stirred for 1 hour, and then concentrated under vacuum to obtain (E)-4-pyrrolidine-1-ylbuta-2-enoic acid (1.4 g, quantitative yield) as a yellow oil. LCMS (MM-ES+APCI,Neg): m / z 154.2 (MH) + ).

[0290] Example 52 (I64) (E)-4-hydroxybuta-2-enoic acid [ka] Step A. (E)-4-Hydroxybuta-2-enoic acid. (E)-4-Bromobuta-2-enoic acid (300 mg, 1.82 mmol) was added to a solution of KOH (408 mg, 7.27 mmol) in H2O (4 mL). The mixture was heated to 60 °C, stirred for 1 hour, and then concentrated under vacuum to obtain (E)-4-Hydroxybuta-2-enoic acid (510 mg, quantitative yield) as a white solid. LCMS (MM-ES+APCI,Neg): m / z 101.1 (MH + ).

[0291] Example 53 (I175) (E)-4-fluorobuta-2-enoic acid [ka] Step A. Ethyl(E)-4-fluorobuta-2-enoate. To a solution of AgF (986 mg, 7.77 mmol) in MeCN (10 mL), a solution of ethyl(E)-4-bromobuta-2-enoate (0.36 mL, 2.59 mmol) in MeCN (6 mL) was added. The vial was purged with N2, and the reaction mixture was stirred in the dark at 25°C for 24 hours. The mixture was filtered, and the filtrate solid was washed with DCM (20 mL). The filtrate was concentrated under vacuum to obtain ethyl(E)-4-fluorobuta-2-enoate 7 (340 mg, yield 99%) as a brown oil.

[0292] Step B. (E)-4-fluorobuta-2-enoic acid. LiOH·H2O (286 mg, 6.81 mmol) was added to a solution of ethyl (E)-4-fluorobuta-2-enoate 7 (300 mg, 2.27 mmol) in THF (3 mL) / water (3 mL). The reaction mixture was stirred at 25°C for 2.5 hours. The mixture was acidified to pH=4 with 1 M HCl (15 mL). The aqueous mixture was extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum to obtain (E)-4-fluorobuta-2-enoic acid 5 (60 mg, yield 25%) as a yellow oil. (MM-ES+APCI,Neg):m / z103.0(M-H+).

[0293] Example 54 (I176) tert-butyl(2S,3S)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate [ka] Step A. tert-butyl(2S,3S)-2-methyl-3-((4-nitrophenyl)sulfonamide)pyrrolidine-1-carboxylate. At 0°C, tert-butyl(2S,3S)-3-amino-2-methylpyrrolidine-1-carboxylate (430 mg, 2.15 mmol) was dissolved in THF (5 mL), to which TEA (0.80 mL, 5.75 mmol) and 2-nitrobenzenesulfonyl chloride (550 mg, 2.48 mmol) were sequentially added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was poured into water (30 mL) and extracted with  (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl(2S,3S)-2-methyl-3-[(2-nitrophenyl)sulfonylamino]pyrrolidine-1-carboxylate (1.20 g, quantitative yield) as a yellow oil. LCMS(MM-ES+APCI,Pos): m / z 285.9(M+H-Boc).

[0294] Step B: tert-butyl(2S,3S)-2-methyl-3-((N-methyl-4-nitrophenyl)sulfonamide)pyrrolidine-1-carboxylate. To a solution of tert-butyl(2S,3S)-2-methyl-3-[(2-nitrophenyl)sulfonylamino]pyrrolidine-1-carboxylate (600 mg, 1.56 mmol) in DMF (6 mL), K2CO3 (500 mg, 3.62 mmol) and MeI (0.15 mL, 2.41 mmol) were added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was poured into water (30 mL) and extracted with Â(30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl(2S,3S)-2-methyl-3-[methyl-(2-nitrophenyl)sulfonylamino]pyrrolidine-1-carboxylate 4 (710 mg, quantitative yield) as a yellow oil. LCMS(MM-ES+APCI,Pos): m / z 299.8(M+H-Boc).

[0295] Step C. tert-butyl(2S,3S)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate. To a solution of tert-butyl(2S,3S)-2-methyl-3-[methyl-(2-nitrophenyl)sulfonylamino]pyrrolidine-1-carboxylate (700 mg, 1.75 mmol) in MeCN (5 mL), K2CO3 (700 mg, 5.06 mmol) and 2-fluorobenzenethiol (0.38 mL, 3.55 mmol) were added. The reaction mixture was stirred at 20°C for 2 hours. The mixture was poured into water (20 mL) and extracted with RINKAN (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (1%-20% MeOH / DCM) to obtain tert-butyl(2S,3S)-2-methyl-3-(methylamino)pyrrolidine-1-carboxylate (340 mg, yield 82%) as a yellow oil. LCMS(MM-ES+APCI,Pos):m / z159.1(M+H- t Bu).

[0296] Intermediates I176 to I178 in Table 15 below were prepared according to steps A to C of Example 54. [Table 15]

[0297] The synthesis of compounds of formula (I), (IA)~(ID), (IA-1), (IA-2), (IB-1), or (IB-2) is described below.

[0298] Example 55 (R)-1-(2-methyl-4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)propa-2-en-1-one (compound 1) [ka] Step A: tert-butyl(R)-2-methyl-4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazine-1-carboxylate. DIPEA (45 mg, 0.35 mmol) was added to a solution of N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-methylsulfinylpyrimido[5,4-d]pyrimidine-4-amine (80 mg, 0.14 mmol) and tert-butyl(R)-2-methylpiperazine-1-carboxylate (42 mg, 0.21 mmol) in IPA (1.5 mL). The mixture was stirred at 80°C for 16 hours and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10% to 100% siRNA / PET) to obtain tert-butyl(R)-2-methyl-4-[4-[3-methyl-4-(1-methylbenzotriazol-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]piperazine-1-carboxylate (40 mg, yield 41%) as a yellow oil. LCMS (MM-ES+APCI,Pos): m / z 583.3 (M+H).

[0299] Step B: (R)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(3-methylpiperazine-1-yl)pyrimido[5,4-d]pyrimidine-4-amine hydrochloride. To a solution of tert-butyl(R)-2-methyl-4-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]piperazine-1-carboxylate (35 mg, 50 μmol) in DCM (1 mL), HCl (4 M in 1,4-dioxane, 1 mL, 4.0 mmol) was added. The mixture was stirred at 25°C for 1 hour and then concentrated under reduced pressure to obtain (R)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(3-methylpiperazine-1-yl)pyrimido[5,4-d]pyrimidine-4-amine hydrochloride (40 mg, quantitative yield) as a yellow oily substance. LCMS(MM-ES+APCI,Pos):m / z 483.3(M+H-HCl).

[0300] Step C: (R)-1-(2-methyl-4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)propa-2-en-1-one. (R)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(3-methylpiperazin-1-yl)pyrimido[5,4-d]pyrimidine-4-amine hydrochloride (30 mg, 58 μmol) was dissolved in DMF (1 mL) and TEA (16 μL, 116 μmol) was added. The mixture was cooled to 0°C and acryloyl chloride (4.7 μL, 58 μmol) was added dropwise. The reaction mixture was heated to 25°C, stirred for 0.5 hours, quenched with saturated NaHCO3 (0.2 mL) aqueous solution, and filtered. The filtrate was vacuum concentrated, and the residue was purified by preparative HPLC (30%~60% MeCN / 0.05% NH4HCO3 aqueous solution). Freeze-drying yielded (R)-1-(2-methyl-4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)propa-2-en-1-one (10 mg, yield 25%) as a white solid. LC-MS (MM-ES+APCI,Pos): m / z 537.1(M+H).

[0301] Compounds 1-49 and 111-195 in Table 4 below were prepared according to steps A-C of Example 55.

[0302] Step A can be carried out using IPA, DMF, DMSO, or 1,4-dioxane as the solvent. Boc deprotection (Step B) can similarly be achieved using HCl (4M in 1,4-dioxane or SiO) or TFA. Step C can use DMF or DCM interchangeably as the solvent. Purification options include C18 preparative HPLC, silica gel chromatography, and / or preparative TLC. [Table 4-1] Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 [Table 4-19] [Table 4-20] [Table 4-21] [Table 4-22] [Table 4-23] Compounds 196-208 in Table 16 below were prepared as a racemic mixture according to steps A-C of Example 55. The enantiomers were separated using chiral supercritical fluid chromatography (SFC). [Table 16-1] [Table 16-2] [Table 16-3]

[0303] Example 56 2-Fluoro-1-(5-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)propa-2-en-1-one (compound 50) [ka] Step A: tert-butyl 5-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate. Using tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate instead of tert-butyl-2-methylpiperazine-1-carboxylate, preparation was carried out according to step A of Example 55 to obtain tert-butyl 5-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (44.8 mg, yield 80%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z595.3(M+H).

[0304] Step B.6-(2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine. Instead of tert-butyl(R)-2-methyl-4-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]piperazine-1-carboxylate, use tert-butyl5-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine Using (-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate, preparation was carried out according to step B of Example 55 to obtain 6-(2,5-diazabicyclo[2.2.2]octane-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine (38.1 mg, quantitative yield). LCMS(MM-ES+APCI,Pos):m / z 495.3(M+H).

[0305] Step C: 2-Fluoro-1-(5-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)propa-2-en-1-one. 6-(2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine (38.4 mg, 0.078 mmol), 2-fluoroacrylic acid (15.4 mg, 0.171 mmol), DIPEA (0.07 mL, 0.4 mmol), and HATU (65.0 mg, 0.171 mmol) were diluted with DMF (1 mL). The reaction mixture was stirred at room temperature for 1 hour, then partitioned into 20% MeOH / DCM (20 mL) and brine, and extracted with 20% MeOH / DCM (5 × 10 mL). The combined organic layer was washed with brine (3 × 10 mL), dried over anhydrous MgSO4, and concentrated under vacuum. The crude residue was purified by silica gel chromatography (0%-20% MeOH / DCM) to obtain 2-fluoro-1-(5-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)propa-2-en-1-one (21.3 mg, yield 46%). LCMS (MM-ES+APCI,Pos): m / z 567.3 (M+H).

[0306] Compounds 50-59 in Table 5 below were prepared according to Example 56. *The racemic mixture was separated by SFC. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0307] Example 57 1-(3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)propa-2-en-1-one (compound 60) [ka] Step A: tert-butyl3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate. N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(methylsulfonyl)pyrimido[5,4-d]pyrimidine-4-amine (200 mg, 0.43 mmol) and 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (171 mg, 0.86 mmol) were dissolved in DMF (2.1 mL) and K2CO3 (120 mg, 0.86 mmol) was added. The mixture was stirred at 90°C for 4 hours, diluted with MeOH, and filtered. The filtrate was concentrated under vacuum and purified by preparative HPLC (5%-95% MeCN / 0.1% TFA aqueous solution). The purified product was neutralized with saturated NaHCO3 aqueous solution and extracted with 4:1 DCM:IPA to obtain tert-butyl 3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate (34 mg, yield 14%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z 581.4(M+H).

[0308] Step B: 6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine. To a solution of tert-butyl3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate (34 mg, 59 μmol) in DCM (1 mL), TFA (1 mL, 13 mmol) was added. The mixture was stirred at 25°C for 2 hours and then concentrated under reduced pressure. The residue was dissolved in a 4:1 DCM:IPA solution and washed with saturated NaHCO3 (50 mL x 2) aqueous solution and brine (50 mL x 1). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (5%-95% MeCN / 0.1% TFA aqueous solution). The product was neutralized with saturated NaHCO3 aqueous solution and extracted with a 4:1 DCM:IPA solution to obtain 6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine (15 mg, 53%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 481.2(M+H).

[0309] Step C.1-(3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)propa-2-en-1-one. 6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine (15 mg, 31 μmol) was dissolved in DCM (0.2 mL) and TEA (8.7 μL, 62 μmol) was added. The mixture was cooled to -78°C, and acryloyl chloride (5.6 μL, 69 μmol) was added dropwise. The reaction mixture was heated to 25°C, stirred for 0.5 hours, and quenched with saturated aqueous solution. The mixture was diluted with NaHCO3 (0.2 mL) aqueous solution. The reaction mixture was diluted with additional saturated NaHCO3 aqueous solution and extracted with 4:1 DCM:IPA (50 mL x 2). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (5%-95% MeCN / 0.1% TFA aqueous solution). The product was neutralized with saturated NaHCO3 aqueous solution and extracted with 4:1 DCM:IPA to obtain 1-(3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)propa-2-en-1-one (6.9 mg, 41%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z535.3(M+H).

[0310] Compounds 60-66 in Table 6 below were synthesized according to Example 57. Step A can be carried out using K2CO3 or DIPEA as a base and DMF, DMSO, or IPA as a solvent. [Table 6-1] [Table 6-2] [Table 6-3]

[0311] Example 58 N-(2-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2-azaspiro[3,3]heptan-6-yl)acrylamide (compound 225) [ka] Step A: tert-butyl(2-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2-azaspiro[3,3]heptan-6-yl)carbamate. DIPEA (0.82 mL, 4.71 mmol) was added to a solution of tert-butyl N-(2-azaspiro[3,3]heptan-6-yl)carbamate (200 mg, 0.94 mmol) and N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-methylsulfinylpyrimido[5,4-d]pyrimidine-4-amine (421 mg, 0.94 mmol) in IPA (10 mL). The reaction mixture was heated at 80°C for 15 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50%-100% toluene / PET) to obtain tert-butyl N-[2-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]-2-azaspiro[3.3]heptan-6-yl]carbamate (328 mg, yield 59%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 595.6 (M+H).

[0312] Step B. 6-(6-amino-2-azaspiro[3.3]heptan-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine. To a 10 mL solution of tert-butyl N-[2-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]-2-azaspiro[3.3]heptan-6-yl]carbamate (318 mg, 0.53 mmol) in DCM (10 mL), TFA (4 mL) was added. The mixture was stirred at 20°C for 20 minutes and then concentrated under vacuum. The residue was dissolved in water (6 mL), neutralized with saturated NaHCO3 aqueous solution (pH=7), and extracted with siRNA (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-(6-amino-2-azaspiro[3.3]heptan-2-yl)-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]pyrimido[5,4-d]pyrimidine-4-amine 4 (130 mg, 262.87 μmol, yield 49.16%) as a yellow solid, which was used in the next step without further purification.

[0313] Example 59 1-(6-(8-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-1,6-diazaspiro[3,3]heptan-1-yl)propa-2-en-1-one (compound 67) [ka] Step A. tert-butyl 1-acryloyl-1,6-diazaspiro[3.3]heptane-6-carboxylate. At 25°C, 0.12 mL of TEA (0.83 mmol) was added to a 2 mL solution of tert-butyl 1,6-diazaspiro[3.3]heptane-6-carboxylate oxalate (80 mg, 0.28 mmol) in DCM (2 mL). The reaction mixture was cooled to -40°C, and propa-2-enoyl chloride (23 μL, 0.28 mmol) was added. The mixture was stirred for 1 hour. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (0.1 mL), extracted with DCM (10 mL x 3), and the combined organic layer was dried over anhydrous Na2SO4. The mixture was then filtered and concentrated under reduced pressure to obtain tert-butyl1-propa-2-enoyl-1,6-diazaspiro[3.3]heptane-6-carboxylate (60 mg, yield 86%) as a pale yellow oil. LCMS (MM-ES+APCI,Pos): m / z 253.1 (M+H).

[0314] Step B. 1-(1,6-diazaspiro[3.3]heptan-1-yl)propa-2-en-1-one 2,2,2-trifluoroacetate. To a solution of tert-butyl 1-propa-2-enoyl-1,6-diazaspiro[3.3]heptan-6-carboxylate (60 mg, 0.24 mmol) in DCM (1 mL), TFA (18 μL, 0.24 mmol) was added. The mixture was stirred at 25°C for 1 hour and then concentrated under vacuum to obtain 1-(1,6-diazaspiro[3.3]heptan-1-yl)propa-2-en-1-one 2,2,2-trifluoroacetate (62 mg, quantitative yield) as a pale yellow oil. LCMS (MM-ES+APCI,Pos): m / z 153.1 (M+H-TFA).

[0315] Step C. 1-(6-(8-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-1,6-diazaspiro[3,3]heptan-1-yl)propa-2-en-1-one. DIPEA (42 mg, 0.32 mmol) was added to a solution of N-[2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-methylsulfinylpyrimido[5,4-d]pyrimidine-4-amine (50 mg, 0.11 mmol) and 1-(1,6-diazaspiro[3.3]heptan-1-yl)propa-2-en-1-one 2,2,2-trifluoroacetate (62 mg, 0.23 mmol) in IPA (3 mL). The mixture was stirred at 80°C for 2 hours and then concentrated under vacuum. The crude substance was purified by preparative HPLC (25%-55% MeCN / 0.08% NH4HCO3 aqueous solution) to obtain 1-[6-[4-[2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]-1,6-diazaspiro[3,3]heptan-1-yl]propa-2-en-1-one (13 mg, yield 22%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 553.2 (M+H).

[0316] Compounds 67, 68, and 226-230 in Table 17 below were synthesized according to steps A-C of Example 59. *The racemic mixture was separated by SFC. [Table 17-1] [Table 17-2]

[0317] Example 60 (R)-2-fluoro-1-(4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2-(trifluoromethyl)piperazine-1-yl)propa-2-en-1-one (compound 231) [ka] Step A. tert-butyl(R)-4-(2-fluoroacryloyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a solution of tert-butyl(3R)-3-(trifluoromethyl)piperazine-1-carboxylate (100 mg, 0.39 mmol) in DCM (2 mL), DIPEA (0.21 mL, 1.18 mmol) and 2-fluoropropa-2-enoyl chloride (43 mg, 0.39 mmol) were added. The mixture was stirred at 25°C for 1 hour. The reaction product was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (25% Âxy / PET) to obtain tert-butyl(3R)-4-(2-fluoropropa-2-enoyl)-3-(trifluoromethyl)piperazine-1-carboxylate 3 (122 mg, 95% yield) as a white solid. LCMS(MM-ES+APCI,Pos):m / z271.1(M+H- t Bu).

[0318] Step B. (R)-2-fluoro-1-(2-(trifluoromethyl)piperazin-1-yl)propa-2-en-1-one. A solution of tert-butyl(3R)-4-(2-fluoropropa-2-enoyl)-3-(trifluoromethyl)piperazin-1-carboxylate (120 mg, 0.37 mmol) in DCM (2 mL) / TFA (1 mL) was stirred at 25°C for 30 minutes. The mixture was concentrated under reduced pressure to obtain 2-fluoro-1-[(2R)-2-(trifluoromethyl)piperazin-1-yl]propa-2-en-1-one trifluoroacetate (100 mg, yield 79%) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 227.0 (M+H).

[0319] Step C: (R)-2-fluoro-1-(4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2-(trifluoromethyl)piperazine-1-yl)propa-2-en-1-one. 6-Chloro-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]pyrimido[5,4-d]pyrimidine-4-amine (163 mg, 0.36 mmol) and 2-fluoro-1-[(2R)-2-(trifluoromethyl)piperazin-1-yl]propa-2-en-1-one trifluoroacetate (81 mg, 0.24 mmol) were dissolved in IPA (5 mL), to which DIPEA (0.19 mL, 1.07 mmol) and KF (42 mg, 0.72 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure, diluted with water (20 mL), and extracted with RINKAN (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (38%-68% MeCN / 0.08% NH4HCO3 aqueous solution) to obtain 2-fluoro-1-[(2R)-4-[4-[3-methyl-4-(1-methylbenzotriazol-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]-2-(trifluoromethyl)piperazin-1-yl]propa-2-en-1-one (55.2 mg, yield 24%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 609.3(M+H).

[0320] Example 61 1-(3-((8-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)(methyl)amino)azetidine-1-yl)propa-2-en-1-one (compound 69) [ka] Step A. 1-(3-((8-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)(methyl)amino)azetidine-1-yl)propa-2-en-1-one. Instead of 1-(1,6-diazaspiro[3.3]heptan-1-yl)propa-2-en-1-one 2,2,2-trifluoroacetate, 1-[3-(methylamino)azetidine-1-yl]propa-2-en-1-one 2,2,2-trifluoroacetate was used to prepare 1-[3-[[4-[2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]-methyl-amino]azetidine-1-yl]propa-2-en-1-one (8 mg, yield 5%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z541.2(M+H).

[0321] Example 62 N-methyl-N-(2-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2-azaspiro[3,3]heptan-6-yl)acrylamide (compound 232) [ka] Step A. tert-butyl 6-(methylamino)-2-azaspiro[3.3]heptane-2-carboxylate. To a solution of methanamine hydrochloride (160 mg, 2.37 mmol) and TEA (0.49 mL, 3.55 mmol) in MeOH (10 mL), AcOH (7 μL, 0.12 mmol), tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.18 mmol), and NaBH3CN (223 mg, 3.55 mmol) were added. The mixture was stirred at 20°C for 2 hours. The reaction product was quenched with water (20 mL) and extracted with RINKAN (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl 6-(methylamino)-2-azaspiro[3.3]heptane-2-carboxylate 2 (215 mg, yield 80%) as a white solid. LC-MS (MM-ES+APCI,Pos): m / z 227.4 (M+H).

[0322] Step B ~ Step DN-methyl-N-(2-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2-azaspiro[3,3]heptan-6-yl)acrylamide. Using tert-butyl 6-(methylamino)-2-azaspiro[3.3]heptan-2-carboxylate instead of tert-butyl 1,6-diazaspiro[3.3]heptan-6-carboxylate, preparation was carried out according to steps A-C of Example 59 to obtain N-methyl-N-(2-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-2-azaspiro[3.3]heptan-6-yl)acrylamide (15 mg, yield 12%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z563.4(M+H).

[0323] Example 63 (E)-1-(4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)-4-(1H-pyrazole-1-yl)buta-2-en-1-one (compound 233) [ka] Step A. (E)-4-bromobuta-2-enoyl chloride. Oxalyl dichloride (0.12 mL, 1.33 mmol) was added to a solution of (E)-4-bromobuta-2-enoic acid 4 (200 mg, 1.21 mmol) in DCM (4 mL). The mixture was cooled to 0°C and DMF (1 drop) was added. The mixture was heated to 20°C and stirred for 2 hours. A solution of (E)-4-bromobuta-2-enoyl chloride 2 (222.36 mg, crude) in DCM (4 mL) was obtained as a brown liquid and used as is in Step B.

[0324] Step B: (E)-4-chloro-1-(4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)buta-2-en-1-one. DIPEA (86 μL, 0.50 mmol) was added to a solution of N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazin-1-ylpyrimido[5,4-d]pyrimidine-4-amine hydrochloride (100 mg, 0.20 mmol) in DCM (1 mL). The mixture was cooled to 0°C and (E)-4-bromobuta-2-enoyl chloride (73 mg, 0.40 mmol) was added dropwise. The reaction mixture was heated to ambient temperature, stirred for 2 hours, and then concentrated under vacuum. The residue was purified by preparative silica gel TLC (5% MeOH / DCM) to obtain (E)-4-chloro-1-[4-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]piperazin-1-yl]buta-2-en-1-one (22 mg, yield 19%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 571.2 (M+H).

[0325] Step C. A solution of 1H-pyrazole (4.7 mg, 68 μmol) in THF (0.5 mL) was cooled to 0°C, and NaH (2.7 mg, 68 μmol, 60% w / w) was added. The mixture was warmed to ambient temperature and stirred for 30 minutes. (E)-4-chloro-1-[4-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidi-n-6-yl]piperazin-1-yl]buta-2-en-1-one (20.4 mg, 34 μmol) was added, and the mixture was stirred for another 30 minutes. The reaction mixture was quenched with saturated saline. NH4Cl (0.2 mL) was added, the mixture was diluted with water, and extracted with RINKAN (2 mL × 3). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified twice by preparative HPLC (30%-60% MeCN / 0.08% NH4HCO3 aqueous solution), and then lyophilized to obtain (E)-1-[4-[4-[3-methyl-4-(1-methylbenzotriazol-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]piperazin-1-yl]-4-pyrazole-1-ylbuta-2-en-1-one (2.7 mg, yield 12%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 603.4(M+H).

[0326] Example 64 1-(4-(8-((4-(Imidazoz[1,2-b]pyridazine-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)propa-2-en-1-one (compound 234) [ka] Step A. 6-Chloro-N-(4-(imidazo[1,2-b]pyridazine-7-yloxy)-3-methylphenyl)pyrimido[5,4-d]pyrimidine-4-amine. A mixture of 4-imidazo[1,2-b]pyridazine-7-yloxy-3-methylaniline (85 mg, 0.35 mmol) and 4,6-dichloropyrimido[5,4-d]pyrimidine (78 mg, 0.39 mmol) in IPA was stirred at 30°C for 1 hour. The reaction product was concentrated under vacuum to obtain 6-Chloro-N-(4-imidazo[1,2-b]pyridazine-7-yloxy-3-methylphenyl)pyrimido[5,4-d]pyrimidine-4-amine 3 (135 mg, yield 95%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 405.2 (M+H).

[0327] Steps B to D. 1-(4-(8-((4-(Imidazoz[1,2-b]pyridazine-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)propa-2-en-1-one. Using 6-chloro-N-(4-(imidazo[1,2-b]pyridazin-7-yloxy)-3-methylphenyl)pyrido[5,4-d]pyrimidine-4-amine instead of N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-methylsulfinylpyrimido[5,4-d]pyrimidine-4-amine, 1-(4-(8-((4-(imidazo[1,2-b]pyridazin-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)propa-2-en-1-one (24.5 mg, yield 20%) was obtained as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z509.3(M+H).

[0328] Compounds 234-237 in Table 18 below were synthesized according to steps A-D of Example 64. [Table 18]

[0329] Example 65 (R)-1'-(8-((4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3-methylene-[1,3'-bipyrrolidine]-2-one (compound 238) [ka] Step A. tert-butyl(S)-3-(4-chlorobutanamide)pyrrolidine-1-carboxylate. To a solution of tert-butyl(3S)-3-aminopyrrolidine-1-carboxylate (3.50 g, 18.8 mmol) in DCM (30 mL), TEA (2.62 mL, 18.8 mmol) was added. The solution was cooled to 0°C, and 4-chlorobutanoyl chloride (2.10 mL, 18.8 mmol) was added. The mixture was stirred at 25°C for 3 hours. The reaction product was quenched with water (120 mL), filtered through Celite, and eluted with toluene (60 mL). The two-phase mixture was separated, and the aqueous layer was extracted with toluene (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (1% to 30% toluene / PET) to obtain tert-butyl(3S)-3-(4-chlorobutanoylamino)pyrrolidine-1-carboxylate (4.70 g, yield 72%) as a white solid. LCMS(MM-ES+APCI,Pos):m / z235.3(M+H- t Bu).

[0330] Step B. tert-butyl(S)-2-oxo-[1,3'-bipyrrolidine]-1'-carboxylate. At 0°C, tert-butyl(3S)-3-(4-chlorobutanoylamino)pyrrolidine-1-carboxylate 3 (4.70 g, 13.5 mmol) was added little by little to a solution of THF (80 mL) with NaH (0.57 g, 14.1 mmol, 60% w / w). The mixture was stirred at 0°C for 30 minutes and then at 80°C for 2 hours. The reaction product was quenched with saturated NH4Cl (30 mL) aqueous solution, diluted with water (60 mL), and extracted with RINKAN (50 mL x 3). The organic layers were combined, washed with water (50 mL x 2) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel column chromatography (1%-20% toluene / PET) to obtain tert-butyl(3S)-3-(2-oxopyrrolidine-1-yl)pyrrolidine-1-carboxylate (1.56 g, yield 46%) as a pale yellow oil. LCMS (MM-ES+APCI,Pos): m / z 199.3(M+H- t Bu).

[0331] Step C. 1'-(tert-butyl)3-ethyl(3'S)-2-oxo-[1,3'-bipyrrolidine]-1',3-dicarboxylate. To a solution of tert-butyl(3S)-3-(2-oxopyrrolidine-1-yl)pyrrolidine-1-carboxylate 4 (1.40 g, 5.45 mmol) in THF (24 mL), LiHMDS (1 M, 10.9 mL, 10.9 mmol) was added at -70°C under an N2 atmosphere. The mixture was stirred at -70°C for 1 hour, and diethyl carbonate (1.32 mL, 10.9 mmol) in THF (2.4 mL) was added, and the solution was warmed to ambient temperature over 2 hours. The reaction product was quenched with brine (30 mL) and extracted with ELISA (50 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (1% to 50% Âxy / PET) to obtain ethyl 1-[(3S)-1-tert-butoxycarbonylpyrrolidine-3-yl]-2-oxopyrrolidine-3-carboxylate (1.25 g, yield 70%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z271.3(M+H- t Bu).

[0332] Step D. (3'S)-1'-(tert-butoxycarbonyl)-2-oxo-[1,3'-bipyrrolidine]-3-carboxylic acid. NaOH (0.12 g, 3.06 mmol) was added to a solution of ethyl 1-[(3S)-1-tert-butoxycarbonylpyrrolidine-3-yl]-2-oxopyrrolidine-3-carboxylate (1.00 g, 3.06 mmol) in MeOH (8 mL) / water (8 mL). The mixture was stirred at 25 °C for 3 hours. The reaction product was diluted with water (50 mL), the suspension was filtered through Celite, and eluted with ELISA. The layers were separated, and the aqueous layer was extracted with ELISA (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-[(3S)-1-tert-butoxycarbonylpyrrolidine-3-yl]-2-oxopyrrolidine-3-carboxylic acid (575 mg, yield 53%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z243.3(M+H- tBu).

[0333] Step E. tert-butyl(S)-3-methylene-2-oxo-[1,3'-bipyrrolidine]-1'-carboxylate. 1-[(3S)-1-tert-butoxycarbonylpyrrolidine-3-yl]-2-oxopyrrolidine-3-carboxylic acid (600 mg, 2.01 mmol) was dissolved in 14 mL of ethyl acetate (CHO)n (154 mg, 3.02 mmol). The mixture was cooled to 0°C and Et2NH (0.25 mL, 2.41 mmol) was added. The reaction mixture was heated to 50°C for 3 hours. The mixture was diluted with water (80 mL), filtered through Celite, and eluted with ethyl acetate (50 mL). The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (1% to 50% Â1 / PET) to obtain tert-butyl(3S)-3-(3-methylene-2-oxopyrrolidine-1-yl)pyrrolidine-1-carboxylate (400 mg, yield 72%) as a white solid. LCMS(MM-ES+APCI,Pos):m / z211.3(M+H- t Bu).

[0334] Step F. (S)-3-methylene-[1,3'-bipyrrolidine]-2-ontrifluoroacetate. To a solution of tert-butyl(3S)-3-(3-methylene-2-oxopyrrolidine-1-yl)pyrrolidine-1-carboxylate (400 mg, 1.44 mmol) in DCM (6 mL), TFA (1.93 mL) was added. The reaction mixture was stirred at 20°C for 2 hours. The mixture was concentrated under vacuum to obtain 3-methylene-1-[(3S)-pyrrolidine-3-yl]pyrrolidine-2-ontrifluoroacetate (400 mg, 99% yield) as a pale yellow oil. LCMS (MM-ES+APCI,Pos): m / z 167.1 (M+H).

[0335] Step G.(R)-1'-(8-((4-(([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3-methylene-[1,3'-bipyrrolidine]-2-one. To a solution of 3-methylene-1-[(3S)-pyrrolidine-3-yl]pyrrolidine-2-ontrifluoroacetate (200 mg, 0.71 mmol) in IPA (10 mL), DIPEA (0.93 mL, 5.35 mmol) and 6-methylsulfinyl-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)phenyl]pyrimido[5,4-d]pyrimidine-4-amine (154 mg, 0.34 mmol) were added. The reaction mixture was heated to 80°C and stirred for 2 hours. The mixture was diluted with water (30 mL) and extracted with RINKAN (25 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (25%-55% MeCN / 0.05% NH4OH aqueous solution) and lyophilized to obtain 3-methylene-1-[(3R)-1-[4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)anilino]pyrimido[5,4-d]pyrimidine-6-yl]pyrrolidine-3-yl]pyrrolidine-2-one (12 mg, yield 6%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 535.2(M+H).

[0336] Compounds 238-241 in Table 19 below were synthesized according to steps A-G of Example 65. [Table 19]

[0337] Example 66 1-(6-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.1.0]hexane-3-yl)propa-2-en-1-one (compound 242) [ka] Step A: tert-butyl 6-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.1.0]hexane-3-carboxylate. DIPEA (75 μL, 0.43 mmol) was added to a DMSO (1.5 mL) solution of N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-methylsulfonyl-pyrimido[5,4-d]pyrimidine-4-amine (100 mg, 0.22 mmol) and tert-butyl 3,6-diazabicyclo[3.1.0]hexane-3-carboxylate (39.8 mg, 0.22 mmol). The mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with toluene (5 mL x 4). The combined organic layer was washed with brine (5 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This was purified by silica gel column chromatography (0%~10% MeOH / DCM) to obtain tert-butyl 6-[4-[3-methyl-4-(1-methylbenzotriazol-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.0]hexane-3-carboxylate (89.0 mg, yield 48%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 567.5 (M+H).

[0338] Step B. 6-(3,6-diazabicyclo[3.1.0]hexane-6-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine. A DCM solution of tert-butyl6-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.0]hexane-3-carboxylate (89.0 mg, 0.10 mmol) and 2,6-dimethylpyridine (72 μL, 0.62 mmol) was cooled to 0°C. TMSOTf (0.11 mL, 0.59 mmol) was added, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with 10% MeOH / DCM (4 mL x 3). The combined organic layer was washed with brine (4 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (10% MeOH / DCM) to obtain 6-(3,6-diazabicyclo[3.1.0]hexane-6-yl)-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]pyrimido[5,4-d]pyrimidine-4-amine (40.0 mg, yield 71%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 467.3 (M+H).

[0339] Step C. 1-(6-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.1.0]hexane-3-yl)propa-2-en-1-one. 6-(3,6-diazabicyclo[3.1.0]hexane-6-yl)-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]pyrimido[5,4-d]pyrimidine-4-amine (40.0 mg, 74 μmol) was dissolved in DCM (2 mL) and TEA (31 μL, 221 μmol) was added. The mixture was cooled to 0°C, and a solution of propa-2-enoyl chloride (6.0 μL, 74 μmol) in DCM (0.5 mL) was gradually added. The reaction mixture was stirred at 0°C for 1 hour and then concentrated under vacuum. MeOH (1 mL) and DMF (0.5 mL) were added to the crude residue, and the suspension was filtered. The filtrate was purified by preparative HPLC (20%-40% MeCN / 0.01% NH4OH aqueous solution), and lyophilized to obtain 1-[6-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.0]hexane-3-yl]propa-2-en-1-one (7.1 mg, yield 18%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z521.3(M+H).

[0340] Example 67 cis-1-((1r,5s)-3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.2.0]heptan-6-yl)propa-2-en-1-one (compound 243) [ka] Step A. Cis-tert-butyl(1r,5s)-3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.2.0]heptan-6-carboxylate. Using cis-tert-butyl(1r,5s)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate instead of tert-butyl3,6-diazabicyclo[3.1.0]hexane-3-carboxylate, preparation was carried out according to step A of Example 66 to obtain cis-tert-butyl(1r,5s)-3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (100 mg, yield 75%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z581.3(M+H).

[0341] Step B. To a DCM solution of cis-6-((1s,5s)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine, tert-butylcis-(1r,5s)-3-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrimido[5,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.2.0]heptan-6-carboxylate (90 mg, 0.16 mmol), ZnBr2 (349 mg, 1.55 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours. The mixture was added to water (10 mL), the suspension was filtered, and the filtrate was washed with SiO2 (20 mL). The solid was vacuum-dried to obtain cis-6-((1s,5s)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine (60.0 mg, yield 59%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z481.1(M+H).

[0342] Step C: cis-1-((1r,5s)-3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.2.0]heptan-6-yl)propa-2-en-1-one. Instead of 6-(3,6-diazabicyclo[3.1.0]hexane-6-yl)-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]pyrimido[5,4-d]pyrimidine-4-amine, use cis-6-((1s,5s)-3,6-diazabicyclo[3.2.0]heptan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4 Using -d]pyrimidine-4-amine, preparation was carried out according to step C of Example 66 to obtain cis-1-((1r,5s)-3-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)-3,6-diazabicyclo[3.2.0]heptan-6-yl)propa-2-en-1-one (4.2 mg, yield 21%) as a yellow solid.

[0343] Example 68 1-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propa-2-en-1-one (compound 70) [ka] Step A. tert-butyl 3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A solution of 6-chloro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (100 mg, 0.24 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (102 mg, 0.48 mmol), and Cs2CO3 (234 mg, 3 equivalents, 0.72 mmol) in DMSO (0.80 mL) was stirred at 95°C for 16 hours and at 120°C for 15 hours. The reaction mixture was cooled to 25°C, diluted with ELISA, and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography (0-20% MeOH in DCM) to obtain tert-butyl 3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (38.6 mg, 27%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 594.3 (M+H).

[0344] Step B.6-(3,8-diazabicyclo[3.2.1]octane-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine. tert-butyl3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (38.6 mg, 0.65 mmol) was dissolved in DCM (0.65 mL) and TFA (0.10 mL) was added. The reaction mixture was stirred for 1 hour, quenched with saturated NaHCO3 aqueous solution, and extracted with 4:1 CHCl3:IPA. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum to obtain 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (31.3 mg, 97%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z 494.3(M+H).

[0345] Step C. 1-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propa-2-en-1-one. At -78°C, 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (31 mg, 0.63 mmol) and TEA (18 μL, 0.13 mmol) were dissolved in DCM (0.80 mL), to which acryloyl chloride (5.6 μL, 0.70 mmol) was added. The reaction mixture was stirred at this temperature for 20 minutes, quenched with saturated NaHCO3 aqueous solution, and extracted with DCM (3×). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by preparative HPLC (5-100% MeCN / 0.1% TFA aqueous solution). The product was neutralized with saturated NaHCO3 aqueous solution and extracted with 20% MeOH / DCM to obtain 1-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propa-2-en-1-one (22.7 mg, 65%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 548.3 (M+H).

[0346] Compounds 70-82 and 244-340 in Table 7 below were synthesized according to Example 68. Step A can be carried out in DMF or DMSO using an inorganic base or a tertiary amine base. When microwave heating is used, the reaction time is shortened. Boc deprotection (Step B) can be carried out using HCl (4 M in 1,4-dioxane or 2 M in SiO) or TFA. In Step C, both DCM and THF are acceptable as solvents. [Table 7-1] Table 7-2 Table 7-3 Table 7-4 Table 7-5 Table 7-6 Table 7-7 Table 7-8 Table 7-9 Table 7-10 Table 7-11 Table 7-12 Table 7-13 Table 7-14 Table 7-15 Table 7-16 Table 7-17 Table 7-18

[0347] Compounds 335-340 in Table 20 below were prepared as a racemic mixture according to steps A-C of Example 68. The enantiomers were separated using chiral supercritical fluid chromatography (SFC). [Table 20]

[0348] Example 69 N-((3R,4R)-1-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-4-methylpiperidine-3-yl)acrylamide (compound 341) [ka] Step A. tert-butyl(3R,4R)-3-acrylamido-4-methylpiperidine-1-carboxylate. To a solution of tert-butyl(3R,4R)-3-amino-4-methylpiperidine-1-carboxylate (120 mg, 0.56 mmol) and TEA (0.24 mL, 1.72 mmol) in DCM (1 mL), propa-2-enoyl chloride (90 μL, 1.11 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude residue was purified by preparative TLC (50% siRNA / PET) to obtain tert-butyl(3R,4R)-4-methyl-3-(propa-2-enoylamino)piperidine-1-carboxylate 3 (113 mg, yield 75%) as a pale yellow solid. LCMS(MM-ES+APCI,Pos):m / z169.3(M+H- t Bu).

[0349] Step BN-((3R,4R)-4-methylpiperidine-3-yl)acrylamide trifluoroacetate. A solution of tert-butyl(3R,4R)-4-methyl-3-(propa-2-enoylamino)piperidine-1-carboxylate (100 mg, 0.37 mmol) in DCM (2 mL) / TFA (1 mL) was stirred at 25°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain N-[(3R,4R)-4-methyl-3-piperidyl]propa-2-enamide trifluoroacetate (150 mg, quantitative yield) as a yellow oil. LCMS (MM-ES+APCI,Pos): m / z 168.9 (M+H).

[0350] Step CN-((3R,4R)-1-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-4-methylpiperidine-3-yl)acrylamide. To a DMSO (3 mL) solution of N-[(3R,4R)-4-methyl-3-piperidyl]propa-2-enamide trifluoroacetate (100 mg, 0.35 mmol) and 6-chloro-N-[2-fluoro-3-methyl-4-(1-methylbenzotriazol-5-yl)oxyphenyl]pyrido[3,2-d]pyrimidine-4-amine (150 mg, 0.29 mmol), KF (42 mg, 0.72 mmol) and DIPEA (0.24 mL, 1.37 mmol) were added. The reaction mixture was heated at 140 °C for 1 hour. The mixture was filtered, and the filtrate was purified by preparative HPLC (37%-67% MeCN / 0.08% NH4HCO3 aqueous solution), lyophilized, and obtained N-[(3R,4R)-1-[4-[2-fluoro-3-methyl-4-(1-methylbenzotriazol-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]-4-methyl-3-piperidyl]prop-2-enamide (81.5 mg, yield 40%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 568.3 (M+H).

[0351] Compounds 341-350 in Table 21 below were synthesized according to steps A-C of Example 69. *The racemic mixture was separated by SFC. [Table 21-1] [Table 21-2]

[0352] Example 70 1-((2R,4S)-2-methyl-4-(methyl(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)amino)pyrrolidine-1-yl)prop-2-en-1-one (compound 351) [ka] Step A. tert-butyl((3S,5R)-1-acryloyl-5-methylpyrrolidine-3-yl)carbamate. Using tert-butyl((3S,5R)-5-methylpyrrolidine-3-yl)carbamate instead of tert-butyl((3R,4R)-3-amino-4-methylpiperidine-1-carboxylate), the mixture was prepared according to Step A of Example 69 to obtain tert-butyl((3S,5R)-1-acryloyl-5-methylpyrrolidine-3-yl)carbamate (120 mg, yield 95%) as a colorless oil.

[0353] Step B. tert-butyl((3S,5R)-1-acryloyl-5-methylpyrrolidine-3-yl)(methyl)carbamate. At 0°C, 120 mg, 0.47 mmol of tert-butyl N-[(3S,5R)-5-methyl-1-propa-2-enoylpyrrolidine-3-yl]carbamate was dissolved in 5 mL of THF, to which NaH (28 mg, 0.71 mmol, 60% w / w) and iodomethane (59 μL, 0.94 mmol) were added. The mixture was stirred at 25°C for 0.5 hours. The reaction product was quenched with saturated NH4Cl aqueous solution (10 mL) and extracted with ₹ (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (100% siRNA) to obtain tert-butyl N-methyl-N-[(3S,5R)-5-methyl-1-propa-2-enoyl-pyrrolidine-3-yl]carbamate (110 mg, yield 87%) as a yellow oily substance.

[0354] Steps C-D. 1-((2R,4S)-2-methyl-4-(methyl(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)amino)pyrrolidine-1-yl)propa-2-en-1-one. Prepared according to steps B-C of Example 69, using tert-butyl((3S,5R)-1-acryloyl-5-methylpyrrolidine-3-yl)(methyl)carbamate instead of tert-butyl(3R,4R)-3-acrylamido-4-methylpiperidine-1-carboxylate. LCMS(MM-ES+APCI,Pos):m / z550.2(M+H).

[0355] Example 71 1-((2R,5S)-5-((4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)(methyl)amino)-2-methylpiperidine-1-yl)prop-2-en-1-one (compound 352) [ka] Steps A-D. 1-((2R,5S)-5-((4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)(methyl)amino)-2-methylpiperidine-1-yl)propa-2-en-1-one. Replace tert-butyl((3S,6R)-6-methylpiperidine-3-yl)carbamate with tert-butyl((3S,5R)-5-methylpyrrolidine-3-yl)carbamate, and replace 6-chloro-N-[2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl)pyrido[3,2-d]pyrimidine-4-amine with 6-fluoro-N-(2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d Using pyrimidine-4-amine, preparations were made according to steps A to D of Example 70 to obtain 1-((2R,5S)-5-((4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)(methyl)amino)-2-methylpiperidine-1-yl)propa-2-en-1-one (38.8 mg, (yield 14%)) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z582.4(M+H).

[0356] Example 72 (S)-2-(1-acryloyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile (compound 83) [ka] Step A. tert-butyl(S)-2-(cyanomethyl)-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate. A solution of 6-chloro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (20 mg, 48 μmol), tert-butyl(S)-2-(cyanomethyl)piperazine-1-carboxylate (13 mg, 57 μmol), Cs2CO3 (31 mg, 96 μmol), and dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II) (9 mg, 10 μmol) in 1,4-dioxane (0.24 mL) was heated at 90°C for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography (0-10% MeOH in DCM) to obtain tert-butyl(S)-2-(cyanomethyl)-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate (9.0 mg, 31%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 607.3(M+H).

[0357] Step B. (S)-2-(4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile. tert-butyl3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate is replaced with tert-butyl(S)-2-(cyanomethyl)-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl) (S)-2-(4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazine-2-yl)acetonitrile (11.3 mg, 64%) was prepared using oxy)phenyl)amino)pyrimidine-6-yl)piperazine-2-yl)acetonitrile (11.3 mg, 64%) as a yellow solid. LCMS(MM-ES+APCI,Pos): m / z 507.3(M+H).

[0358] Step C. (S)-2-(1-acryloyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile. 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine instead of (S)-2-(4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d] (S)-2-(1-acryloyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile (3.9 mg, 31%) was prepared using pyrimidine-6-yl)piperazin-2-yl)acetonitrile according to step C of Example 68. LCMS(MM-ES+APCI,Pos):m / z561.3(M+H).

[0359] Compounds 83, 353-357 in Table 22 below were synthesized according to steps A-C of Example 72. [Table 22]

[0360] Example 73 (R)-2-(1-acryloyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile (compound 84) [ka] (R)-2-(1-acryloyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile. Using tert-butyl(R)-2-(cyanomethyl)piperazine-1-carboxylate instead of tert-butyl(S)-2-(cyanomethyl)piperazine-1-carboxylate, preparation was carried out according to steps A-C of Example 72 to obtain (R)-2-(1-acryloyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazine-2-yl)acetonitrile (11.20 mg, 19%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z561.3(M+H).

[0361] Example 74 (S)-2-(1-(2-fluoroacryloyl)-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile (compound 85) [ka] Step A. (S)-2-(1-(2-fluoroacryloyl)-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile. (S)-2-(4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile (60.0 mg, 0.12 mmol), 2-fluoroacrylic acid (24 mg, 0.26 mmol), and HATU (99 mg, 0.26 mmol) were dissolved in DMF (1.2 mL) and DIPEA (0.10 mL, 0.59 mmol) was added. The reaction mixture was stirred for 1.5 hours, diluted with 25% IPA / CHCl3, and washed with H2O. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by preparative HPLC (5%-100% MeCN / 0.1% TFA aqueous solution). The product was neutralized with saturated NaHCO3 aqueous solution and extracted with 25% IPA / CHCl3 to obtain (S)-2-(1-(2-fluoroacryloyl)-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile (29.43 mg, 43%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 579.3(M+H).

[0362] Example 75 (R)-2-(1-(2-fluoroacryloyl)-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile (compound 86) [ka] (R)-2-(1-(2-fluoroacryloyl)-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile (S)-2-(4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile instead of (R)-2-(4-(4-((3-methyl-4 (R)-2-(1-(2-fluoroacryloyl)-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile was prepared according to step A of Example 74 to obtain (R)-2-(1-(2-fluoroacryloyl)-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-2-yl)acetonitrile (37.7 mg, 47%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z579.3(M+H).

[0363] Example 76 2-Fluoro-1-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propa-2-en-1-one (compound 87) [ka] Step A. DIPEA (42 μL, 0.24 mmol) was added to a 1,4-dioxane (1.0 mL) slurry of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. 6-chloro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (40 mg, 0.01 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (31 mg, 0.14 mmol). The reaction mixture was heated to 110°C and stirred for 2 hours. DMSO (1 mL) was added, and the reaction mixture was heated at 140°C for 14 hours. The mixture was diluted with water (10 mL), extracted with 20% MeOH / DCM (10 mL x 6), dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0%~20% MeOH / DCM) to obtain tert-butyl 3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (38 mg, yield 67%). LCMS (MM-ES+APCI,Pos): m / z 594.4(M+H).

[0364] Step B.6-(3,8-diazabicyclo[3.2.1]octane-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine. tert-butyl3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate is replaced with tert-butyl3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)py Using lido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, preparation was carried out according to step B of Example 68 to obtain 6-(3,8-diazabicyclo[3.2.1]octane-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (13.9 mg, yield 45%). LCMS(MM-ES+APCI,Pos):m / z494.3(M+H).

[0365] Step C. 2-Fluoro-1-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propa-2-en-1-one. 6-(2,5-diazabicyclo[2.2.2]octan-2-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrimido[5,4-d]pyrimidine-4-amine is replaced with 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl Using pyrimido[3,2-d]pyrimidine-4-amine, preparation was carried out according to step C of Example 56 to obtain 2-fluoro-1-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)propa-2-en-1-one (8.7 mg, yield 52%). LCMS(MM-ES+APCI,Pos):m / z566.3(M+H).

[0366] Compounds 87, 88, and 358-369 in Table 23 below were synthesized according to steps A-C of Example 76. [Table 23-1] [Table 23-2] [Table 23-3]

[0367] Example 77 1-(2,2-dimethyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (compound 89) [ka] Step A. 6-(3,3-dimethylpiperazine-1-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine. A mixture of 6-chloro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (100 mg, 0.24 mmol), tert-butyl 2,2-dimethylpiperazine-1-carboxylate (103 mg, 0.48 mmol), and Cs2CO3 (234 mg, 0.72 mmol) in DMF (0.8 mL) was heated at 110°C for 18 hours. The reaction mixture was diluted with ELISA and washed with H2O and brine. The organic phase was dried with Na2SO4, filtered, and vacuum concentrated. The crude residue was purified by silica gel chromatography (0%-20% MeOH / DCM) to obtain 6-(3,3-dimethylpiperazin-1-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (8.6 mg, 7%). LC-MS (MM-ES+APCI,Pos): m / z 496.3(M+H).

[0368] Step B: 1-(2,2-dimethyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one. At 0°C, 6-(3,3-dimethylpiperazin-1-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (8.6 mg, 17 μmol) and TEA (5 μL, 35 μmol) were dissolved in DCM (0.17 mL) and acryloyl chloride (0.2 M in DCM, 0.10 mL, 20 μmol). The reaction mixture was stirred for 10 minutes, quenched with saturated NaHCO3 aqueous solution, and extracted by DCM. The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (5%-100% MeCN / 0.1% TFA aqueous solution). The product was neutralized with saturated NaHCO3 aqueous solution and extracted with 20% MeOH in DCM to obtain 1-(2,2-dimethyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (5.7 mg, 59%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 550.3 (M+H).

[0369] Example 78 (S)-1-(3-methyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one 2,2,2-trifluoroacetate (compound 90) [ka] Step A. (S)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(2-methylpiperazine-1-yl)pyrido[3,2-d]pyrimidine-4-amine. 6-chloro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (50 mg, 0.12 mmol), tert-butyl(S)-3-methylpiperazine-1-carboxylate (96 mg, 0.48 mmol), and Cs2CO3 (39 mg, 0.12 mmol) were dissolved in DMSO (1.1 mL). The reaction mixture was stirred at 115°C for 2 hours and at 150°C for 16 hours. The mixture was concentrated under vacuum and purified by silica gel chromatography (0%-20% MeOH / DCM) to obtain tert-butyl(S)-3-methyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate (60 mg, 77% yield). LCMS (MM-ES+APCI,Pos): m / z 482.3(M+H).

[0370] Step B. (S)-1-(3-methyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one 2,2,2-trifluoroacetate. 6-(3,3-dimethylpiperazine-1-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (25 mg, 52 μmol) instead of (S)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(2-methylpiperazine-1-yl)pyrido[3,2- Using [d]pyrimidine-4-amine (25 mg, 52 μmol), (S)-1-(3-methyl-4-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one 2,2,2-trifluoroacetate (8.5 mg, yield 24%). LCMS(MM-ES+APCI,Pos):m / z536.3(M+H).

[0371] Example 79 1-(4-(4-((2-fluoro-4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (compound 91) [ka] Step A: tert-butyl 4-(4-((2-fluoro-4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate. 6-chloro-N-[2-fluoro-4-(7-fluoro-1-methylbenzotriazole-5-yl)oxy-3-methylphenyl]pyrido[3,2-d]pyrimidine-4-amine (95 mg, 0.21 mmol) and tert-butylpiperazine-1-carboxylate (39 mg, 0.21 mmol) were dissolved in DMF (5 mL), to which DIPEA (0.11 mL, 0.63 mmol) was added. The mixture was stirred at 120 °C for 6 hours, diluted with water (10 mL), and extracted with ELISA (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium 2SO4, filtered, and vacuum concentrated to obtain tert-butyl 4-[4-[2-fluoro-4-(7-fluoro-1-methylbenzotriazol-5-yl)oxy-3-methylanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate (92 mg, yield 73%) as a yellow oil. LCMS(MM-ES+APCI,Pos): m / z 604.4(M+H).

[0372] Step BN-(2-fluoro-4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)-6-(piperazine-1-yl)pyrido[3,2-d]pyrimidine-4-amine 2,2,2-trifluoroacetate. tert-butyl 3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate is replaced with tert-butyl 4-[4-[2-fluoro-4-(7-fluoro-1-methyl-benzotriazole-5-yl)oxy-3-methyl- Using [nirino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate, preparation was carried out according to step B of Example 68 to obtain N-[2-fluoro-4-(7-fluoro-1-methylbenzotriazole-5-yl)oxy-3-methylphenyl]-6-piperazine-1-yl-pyrido[3,2-d]pyrimidine-4-amine 2,2,2-trifluoroacetate (94 mg, quantitative yield) as a yellow oily substance. LCMS(MM-ES+APCI,Pos):m / z504.2(M+H-TFA).

[0373] Step C.1-(4-(4-((2-fluoro-4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)prop-2-en-1-one. 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine instead of N-[2-fluoro-4-(7-fluoro-1-methyl-benzotriazole-5-yl)oxy-3-methylphenyl]-6-piperazin-1-yl-pyrido[3,2-d]pyrim Using din-4-amine 2,2,2-trifluoroacetate (76 mg, 0.12 mmol), preparation was carried out according to step C of Example 68 to obtain 1-[4-[4-[2-fluoro-4-(7-fluoro-1-methylbenzotriazol-5-yl)oxy-3-methylanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazin-1-yl]propa-2-en-1-one (4.7 mg, yield 7%) as an off-white solid. LCMS(MM-ES+APCI,Pos):m / z558.3(M+H).

[0374] Example 80 1-(4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)propa-2-en-1-one (compound 92) [ka] Step A: tert-butyl 4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate (310 mg, 0.88 mmol) in IPA (5 mL), 3-methyl-4-(1-methylbenzotriazole-5-yl)oxyaniline (152 mg, 0.59 mmol) was added. The mixture was stirred at 80°C for 2 hours, quenched with H2O (10 mL), and extracted with ELISA (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (45%-75% MeCN / 10 mM NH4HCO3 aqueous solution) to obtain tert-butyl 4-[4-[3-methyl-4-(1-methylbenzotriazol-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate (150 mg, yield 43%) as a white solid. LC-MS (MM-ES+APCI,Pos): m / z 568.1 (M+H).

[0375] Step BN-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazine-1-yl)pyrimido[5,4-d]pyrimidine-4-amine 2,2,2-trifluoroacetate. To a solution of tert-butyl 4-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate (140 mg, 0.24 mmol) in DCM (2 mL), TFA (2 mL, 27.0 mmol) was added. The mixture was stirred at 25°C for 1 hour and then concentrated under vacuum to obtain N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazine-1-ylpyrido[3,2-d]pyrimidine-4-amine 2,2,2-trifluoroacetate (140 mg, quantitative yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 468.1 (M+H-TFA).

[0376] Step C. 1-(4-(8-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrimido[5,4-d]pyrimidine-2-yl)piperazin-1-yl)propa-2-en-1-one. A solution of N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazin-1-ylpyrido[3,2-d]pyrimidine-4-amine 2,2,2-trifluoroacetate (140 mg, 0.24 mmol) in DCM (3 mL) was purged with N2 and cooled to -40°C. TEA (101 μL, 0.72 mmol) and propa-2-enoyl chloride (24 μL, 0.29 mmol) were added dropwise, and the mixture was stirred at -40°C for 1 hour. The reaction mixture was quenched with saturated NaHCO3 (5 mL) aqueous solution and extracted with RINKAN (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by preparative HPLC (25%~55% MeCN / 10 mM NH4HCO3 aqueous solution) to obtain 1-[4-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazin-1-yl]propa-2-en-1-one (50 mg, yield 39%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 522.1 (M+H).

[0377] Compounds 92 and 370-372 in Table 24 below were synthesized according to steps A-C of Example 80. [Table 24]

[0378] Example 81 1-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)propa-2-en-1-one (compound 93) [ka] 1-(3-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)propa-2-en-1-one. Using tert-butyl 3-(4-chloropyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate instead of tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptan-6-carboxylate, preparation was carried out according to steps A-C of Example 80 to obtain 1-[3-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]propa-2-en-1-one (22 mg, yield 6%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z534.4(M+H).

[0379] Example 82 1-(4-(4-((2-fluoro-5-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (compound 94) [ka] Step AN-(2-fluoro-5-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidine-4-amine. Using 2-fluoro-5-methyl-4-(1-methylbenzotriazole-5-yl)oxyaniline instead of 3-methyl-4-(1-methylbenzotriazole-5-yl)oxyaniline, preparation was carried out according to Step A of Example 80 to obtain N-[2-fluoro-5-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazin-1-ylpyrido[3,2-d]pyrimidine-4-amine (150 mg, 77%) as a pale yellow solid. LCMS(MM-ES+APCI,Pos):m / z486.2(M+H).

[0380] Step B. 1-(4-(4-((2-fluoro-5-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one. Instead of tert-butyl4-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate, N-[2-fluoro-5-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazine-1-yl-pyrido[3,2-d]pyrimidine-4-amine was used to prepare 1-[4-[4-[2-fluoro-5-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-yl]propa-2-en-1-one (70 mg, yield 46%) as a white solid. LCMS(MM-ES+APCI,Pos):m / z 540.3(M+H).

[0381] Example 83 1-(4-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (compound 95) [ka] Step A: tert-butyl 4-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate. 2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyaniline (100 mg, 0.37 mmol) was dissolved in IPA (6 mL), to which DIPEA (0.19 mL, 1.10 mmol) and tert-butyl 4-(4-chloropyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate (193 mg, 0.55 mmol) were added. The reaction mixture was stirred at 90°C for 2 hours, diluted with water (20 mL), and extracted with 10% MeOH / DCM (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude solid was purified by silica gel column chromatography (0%-75% toluene / PET) to obtain tert-butyl 4-[4-[2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate (100 mg, yield 35%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 586.3 (M+H).

[0382] Step B: N-(2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazine-1-yl)pyrido[3,2-d]pyrimidine-4-amine hydrochloride. To a solution of tert-butyl 4-[4-[2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate (100 mg, 0.13 mmol) in DCM (2.5 mL), HCl (4 M in 1,4-dioxane, 2.5 mL, 10 mmol) was added. The mixture was stirred at 25°C for 1 hour and then concentrated under vacuum to obtain N-[2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazine-1-ylpyrido[3,2-d]pyrimidine-4-amine hydrochloride (105 mg, quantitatively) as a yellow solid. LCMS(MM-ES+APCI,Pos): m / z 486.2(M+H-HCl).

[0383] Step C. 1-(4-(4-((2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one. DIPEA (0.10 mL, 0.57 mmol) was added to a solution of N-[2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazin-1-ylpyrido[3,2-d]pyrimidine-4-amine hydrochloride (100 mg, 0.19 mmol) in DMF (8 mL). The solution was cooled to -50°C, and propa-2-enoyl chloride (16 μL, 0.19 mmol) in DMF (0.5 mL) was added dropwise. The mixture was stirred at -50°C for 1 hour and quenched with saturated aqueous solution. It was diluted with NaHCO3 (0.5 mL) aqueous solution. The crude substance was purified by preparative HPLC (24%-54% MeCN / 0.08% NH4HCO3 aqueous solution) to obtain 1-[4-[4-[2-fluoro-3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazin-1-yl]propa-2-en-1-one (49 mg, yield 46%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 540.3 (M+H).

[0384] Example 84 1-(6-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)propa-2-en-1-one (compound 96) [ka] Step A: tert-butyl 6-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate. To a solution of tert-butyl 6-(4-chloropyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (410 mg, 1.13 mmol) in IPA (3 mL), 3-methyl-4-(1-methylbenzotriazole-5-yl)oxyaniline (288 mg, 1.13 mmol) and DIPEA (0.59 mL, 3.40 mmol) were added. The mixture was stirred at 80°C for 8 hours and then concentrated under vacuum. The crude residue was purified by silica gel column chromatography (5%-10% MeOH / DCM) to obtain tert-butyl 6-[4-[3-methyl-4-(1-methylbenzotriazol-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-carboxylate (140 mg, yield 21%) as a white solid. LCMS (MM-ES+APCI,Pos): m / z 580.3(M+H).

[0385] Step B. 6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine. To a solution of tert-butyl6-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-carboxylate (120 mg, 0.21 mmol) in DCM (2 mL), TFA (2 mL, 27 mmol) was added. The mixture was stirred at 25°C for 1 hour, gradually quenched with saturated NaHCO3 (10 mL) aqueous solution, and extracted with SiO2 (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (10% MeOH / DCM) to obtain 6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]pyrido[3,2-d]pyrimidine-4-amine (60 mg, yield 58%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 480.1 (M+H).

[0386] Step C. 1-(6-(4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)propa-2-en-1-one. A solution of 6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]pyrido[3,2-d]pyrimidine-4-amine (50 mg, 0.10 mmol) in DCM (2 mL) was placed under N2 and cooled to 0°C. TEA (42 μL, 0.30 mmol) and propa-2-enoyl chloride (9.8 μL, 0.12 mmol) were added dropwise. The mixture was stirred at 0°C for 1 hour, quenched with saturated NaHCO3 aqueous solution (10 mL), and extracted with siRNA (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (27%~57% MeCN / 0.08% NH4HCO3 aqueous solution) to obtain 1-[6-[4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]propa-2-en-1-one (12 mg, yield 22%) as a white solid. LCMS(MM-ES+APCI,Pos):m / z534.2(M+H).

[0387] Example 85 1-(4-(4-((4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (compound 97) [ka] Step A. 4-Chloro-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidine. A solution of tert-butyl 4-(4-hydroxypyrido[3,2-d]pyrimidine-6-yl)piperazin-1-carboxylate (120 mg, 0.36 mmol) in toluene (1.2 mL) was heated at ambient temperature with DIPEA (0.13 mL, 0.72 mmol) and POCl3 (0.34 mL, 3.62 mmol). The mixture was heated to 100°C, stirred for 1 hour, and concentrated under reduced pressure to obtain 4-chloro-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidine (90 mg, 20% purity) as a brown solid. LCMS (MM-ES+APCI,Pos): m / z 250.0 (M+H).

[0388] Step BN-(4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidine-4-amine. 4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylaniline (56 mg, 0.21 mmol) was added to a solution of 4-chloro-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidine (86 mg, 0.34 mmol) in IPA (2.0 mL). The reaction mixture was stirred at 80°C for 1 hour and then concentrated under vacuum. The residue was diluted with water (50 mL), made basic with saturated NaHCO3 aqueous solution (pH 8), and extracted with DCM (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (1%-40% MeOH / DCM) to obtain N-(4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidine-4-amine (70 mg, 60% yield) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 486.4(M+H).

[0389] Step C. 1-(4-(4-((4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one. N-(4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)-6-(piperazin-1-yl)pyrido[3,2-d]pyrimidine-4-amine (50 mg, 0.10 mmol) was dissolved in DCM (1.0 mL) and TEA (43 μL, 0.31 mmol) was added. The mixture was cooled to 0°C and propa-2-enoyl chloride (8 μL, 0.10 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 0.5 hours and then concentrated under vacuum. The crude solid was purified by preparative HPLC (30%-60% MeCN / 10mM NH4HCO3 aqueous solution) to obtain 1-(4-(4-((4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (12 mg, yield 19%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 540.3 (M+H).

[0390] Example 86 1-(4-(7-Methoxy-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (compound 98) [ka] Step A. 7-Methoxy-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazine-1-yl)pyrido[3,2-d]pyrimidine-4-amine. 3-methyl-4-(1-methylbenzotriazole-5-yl)oxyaniline (58 mg, 0.23 mmol) was added to a solution of tert-butyl 4-(4-chloro-7-methoxypyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate hydrochloride (157 mg, 0.38 mmol) in IPA (2 mL). The reaction mixture was stirred at 80°C for 1 hour and neutralized with saturated NaHCO3 aqueous solution (pH 7). The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (20%-30% MeOH / DCM) to obtain 7-methoxy-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazine-1-ylpyrido[3,2-d]pyrimidine-4-amine (125 mg, quantitative yield) as a yellow oil. LCMS (MM-ES+APCI,Pos): m / z 498.3 (M+H).

[0391] Step B. 1-(4-(7-Methoxy-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one. 7-Methoxy-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazin-1-yl-pyrido[3,2-d]pyrimidine-4-amine (125 mg, 0.25 mmol) was dissolved in DCM (15 mL) and TEA (0.10 mL, 0.75 mmol) was added. The reaction mixture was cooled to 0°C and propa-2-enoyl chloride (41 μL, 0.50 mmol) was added. After stirring at 0°C for 30 minutes, the mixture was concentrated under vacuum. The crude residue was purified by preparative HPLC (28%-58% MeCN / 10mM NH4HCO3 aqueous solution) to obtain 1-[4-[7-methoxy-4-[3-methyl-4-(1-methylbenzotriazol-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazin-1-yl]propa-2-en-1-one (38.5 mg, yield 28%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 552.2 (M+H).

[0392] Example 87 1-(4-(4-((2-fluoro-4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)amino)-7-methoxypyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (compound 99) [ka] 1-(4-(4-((2-fluoro-4-((7-fluoro-1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)-3-methylphenyl)amino)-7-methoxypyrido[3,2,d]pyrimidine-6-yl)piperazine-1-yl)propa-2-en-1-one. Using 2-fluoro-4-(7-fluoro-1-methylbenzotriazol-5-yl)oxy-3-methylaniline instead of 3-methyl-4-(1-methylbenzotriazol-5-yl)oxyaniline, preparation was carried out according to steps A and B of Example 86 to obtain 1-[4-[4-[2-fluoro-4-(7-fluoro-1-methylbenzotriazol-5-yl)oxy-3-methylanilino]-7-methoxypyrido[3,2-d]pyrimidine-6-yl]piperazin-1-yl]propa-2-en-1-one (6.5 mg, yield 6%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z588.3(M+H).

[0393] Example 88 1-(4-(7-fluoro-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (compound 373) [ka] Step A. Methyl 3-amino-5-fluoropicolinate. To a solution of 2-bromo-5-fluoropyridine-3-amine (2.0 g, 10.5 mmol) in MeOH (50 mL), Pd(dppf)Cl2 (0.38 g, 0.52 mmol) and TEA (2.91 mL, 20.9 mmol) were added. The suspension was degassed under vacuum and purged several times with CO. The mixture was heated at 60°C for 48 hours under CO (50 psi). The suspension was filtered through a Celite pad and eluted with MeOH (50 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (3%-33% MeCN / 0.05% NH4HCO3 aqueous solution). Methyl 3-amino-5-fluoropyridine-2-carboxylate (650 mg, yield 36%) was obtained as a white solid by lyophilization. LCMS(MM-ES+APCI,Pos):m / z171.2(M+H).

[0394] Step B. Methyl 3-amino-6-bromo-5-fluoropicolinate. NBS (690 mg, 3.88 mmol) was added to a solution of methyl 3-amino-5-fluoropyridine-2-carboxylate (550 mg, 3.23 mmol) in MeCN (10 mL). The mixture was stirred at 25°C for 2 hours. The reaction product was diluted with water (30 mL) and extracted with  (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (20%-25%  / PET) to obtain methyl 3-amino-6-bromo-5-fluoropyridine-2-carboxylate (750 mg, 92% yield) as a white solid. LCMS (MM-ES+APCI,Pos): m / z 249.0, 251.0 (M+H).

[0395] Step C. 3-Amino-6-Bromo-5-Fluoropicorine. NaOH (192 mg, 4.80 mmol) was added to a solution of methyl 3-amino-6-bromo-5-fluoropyridine-2-carboxylate (300 mg, 1.19 mmol) in THF (2 mL) / water (0.4 mL). The reaction mixture was stirred at 60°C for 5 hours. The mixture was diluted with water (10 mL), acidified with 1 M HCl (pH=4), and extracted with ₹ (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-amino-6-bromo-5-fluoropicolinic acid (230 mg, yield 82%) as a gray solid. LCMS (MM-ES+APCI,Pos): m / z 234.9, 236.9 (M+H).

[0396] Step D. 6-Bromo-7-Fluoropyrido[3,2-d]pyrimidine-4-ol. Formamidine acetate (200 mg, 1.92 mmol) was added to a solution of 3-amino-6-bromo-5-fluoropicolinic acid (210 mg, 0.89 mmol) in EtOH (3 mL). The reaction mixture was heated in a microwave at 120°C for 2 hours. The mixture was diluted with water (10 mL) and extracted with RINKAN (10 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-bromo-7-fluoropyrido[3,2-d]pyrimidine-4-ol (205 mg, yield 94%) as a gray solid. LC-MS (MM-ES+APCI,Pos): m / z 244.0, 246.0 (M+H).

[0397] Step E. 6-Bromo-4-chloro-7-fluoropyrido[3,2-d]pyrimidine. 6-bromo-7-fluoropyrido[3,2-d]pyrimidine-4-ol (150 mg, 0.61 mmol) was dissolved in PhMe (3 mL), to which POCl3 (0.12 mL, 1.24 mmol) and DIPEA (0.54 mL, 3.09 mmol) were added at 0°C. The reaction mixture was heated at 110°C for 2 hours. The mixture was concentrated under reduced pressure, the crude product was dissolved in HCl (10 mL), and saturated NaHCO3 aqueous solution (5 mL) was added. The layers were separated, and the aqueous layer was extracted with HCl (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-bromo-4-chloro-7-fluoropyrido[3,2-d]pyrimidine (180 mg, quantitative yield) as a yellow solid.

[0398] Step F. 6-bromo-7-fluoro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine. 3-methyl-4-(1-methylbenzotriazole-5-yl)oxyaniline (160 mg, 0.63 mmol) was added to a solution of 6-bromo-4-chloro-7-fluoropyrido[3,2-d]pyrimidine (160 mg, 0.61 mmol) in IPA (4 mL). The reaction mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (10 mL) and extracted with RINKAN (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (50%-65% Âxy / PET) to obtain 6-bromo-7-fluoro-N-[3-methyl-4-(1-methylbenzotriazol-5-yl)oxyphenyl]pyrido[3,2-d]pyrimidine-4-amine (170 mg, 40% yield) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 480.0, 482.0 (M+H).

[0399] Step G. tert-butyl 4-(7-fluoro-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate. A mixture of tert-butylpiperazine-1-carboxylate (122 mg, 0.66 mmol), 6-bromo-7-fluoro-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]pyrido[3,2-d]pyrimidine-4-amine (150 mg, 0.22 mmol), RuPhos Pd G3 (20 mg, 24 μmol), and Cs2CO3 (210 mg, 0.64 mmol) in 1,4-dioxane (3 mL) was degassed and purged with N2. The reaction mixture was heated at 100°C for 2.5 hours under N2. The mixture was diluted with water (5 mL) and extracted with RINKAN (10 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (5% MeOH / DCM) to obtain tert-butyl 4-[7-fluoro-4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate (64 mg, yield 33%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 586.3 (M+H).

[0400] Step H.7-Fluoro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazine-1-yl)pyrido[3,2-d]pyrimidine-4-amine. To a solution of tert-butyl 4-[7-fluoro-4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate (60 mg, 68 μmol) in DCM (1 mL), TFA (1 mL) was added. The reaction mixture was stirred at 25°C for 2 hours and then concentrated under vacuum. The mixture was diluted with saturated NaHCO3 aqueous solution (5 mL) and extracted with ELISA (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (10% MeOH / DCM) to obtain 7-fluoro-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazine-1-ylpyrido[3,2-d]pyrimidine-4-amine (31 mg, 92% yield) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 486.2 (M+H).

[0401] Step I. 1-(4-(7-fluoro-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one. A mixture of 7-fluoro-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]-6-piperazin-1-ylpyrido[3,2-d]pyrimidine-4-amine (28 mg, 57 μmol) and TEA (28 μL, 198 μmol) in DCM (2 mL) was purged with N2 and cooled to 0°C. Propa-2-enoyl chloride (5.4 μL, 66 μmol) was added dropwise, and the reaction mixture was stirred at 0°C for 1 hour. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted with toluene (10 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (7%-10% MeOH / DCM) to obtain 1-[4-[7-fluoro-4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazin-1-yl]propa-2-en-1-one (24 mg, yield 75%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 540.3 (M+H).

[0402] Example 89 1-(4-(7-methyl-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (compound 374) [ka] Steps A-D: 6-bromo-7-methylpyrido[3,2-d]pyrimidine-4-ol. Using 2-bromo-5-methyl-3-nitropyridine instead of 2-bromo-5-fluoropyridine-3-amine, 6-bromo-7-methylpyrido[3,2-d]pyrimidine-4-ol (200 mg, quantitative yield) was prepared according to steps A-D of Example 88 to obtain a white solid. LCMS (MM-ES+APCI,Pos): m / z 239.8,241.8 (M+H).

[0403] Step E. 4,6-Dichloro-7-methylpyrido[3,2-d]pyrimidine. To a solution of 6-bromo-7-methylpyrido[3,2-d]pyrimidine-4-ol (120 mg, 0.50 mmol) in SOCl2 (5 mL), DMF (4 μL, 0.05 mmol) was added. The mixture was heated at 90°C for 2 hours and then concentrated under vacuum to obtain 4,6-dichloro-7-methylpyrido[3,2-d]pyrimidine (160 mg, quantitative yield) as a yellow oily substance. LCMS (MM-ES+APCI,Pos): m / z 214.1 (M+H).

[0404] Step F. 6-chloro-7-methyl-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine. Prepared according to Step F of Example 88, using 4,6-dichloro-7-methylpyrido[3,2-d]pyrimidine instead of 6-bromo-4-chloro-7-fluoropyrido[3,2-d]pyrimidine, 6-chloro-7-methyl-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)pyrido[3,2-d]pyrimidine-4-amine (120 mg, yield 35%) was obtained as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z432.2(M+H).

[0405] Step G. tert-butyl 4-(7-methyl-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazine-1-carboxylate. A mixture of 6-chloro-7-methyl-N-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyphenyl]pyrido[3,2-d]pyrimidine-4-amine (60 mg, 0.12 mmol), tert-butylpiperazine-1-carboxylate (330 mg, 1.77 mmol), and DIPEA (64 μL, 0.37 mmol) in DMSO (2 mL) was microwaved at 150°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with SiO2 (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (10% MeOH / DCM) to obtain tert-butyl 4-[7-methyl-4-[3-methyl-4-(1-methylbenzotriazol-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate (40 mg, yield 53%) as a yellow solid. LC-MS (MM-ES+APCI,Pos): m / z 582.4 (M+H).

[0406] Steps H to I. 1-(4-(7-methyl-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one. Using tert-butyl4-[7-fluoro-4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,2-d]pyrimidine-6-yl]piperazine-1-carboxylate instead, preparations were made according to steps H to I of Example 88 to obtain 1-(4-(7-methyl-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidine-6-yl)piperazine-1-yl)propa-2-en-1-one (7 mg, yield 25%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z536.3(M+H).

[0407] Example 90 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)amino)-5-fluoropyrido[3,4-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (compound 100) [ka] Step A: tert-butyl 4-(4-((4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)amino)-5-fluoropyrido[3,4-d]pyrimidine-6-yl)piperazine-1-carboxylate. DIPEA (0.11 mL, 0.61 mmol) and 3-methyl-4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)aniline (49.0 mg, 0.20 mmol) were added to a solution of tert-butyl 4-(4-chloro-5-fluoropyrido[3,4-d]pyrimidine-6-yl)piperazine-1-carboxylate (90 mg, 0.24 mmol) in IPA (10 mL). The mixture was stirred at 80°C for 2 hours, quenched with water (30 mL), and extracted with toluene (40 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude oil was purified by silica gel column chromatography (1%-30% toluene / PET) to obtain tert-butyl 4-[5-fluoro-4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)anilino]pyrido[3,4-d]pyrimidine-6-yl]piperazine-1-carboxylate (110 mg, yield 96%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 572.4 (M+H).

[0408] Step BN-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-5-fluoro-6-(piperazin-1-yl)pyrido[3,4-d]pyrimidine-4-amine 2,2,2-trifluoroacetate. To a solution of tert-butyl 4-[5-fluoro-4-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)anilino]pyrido[3,4-d]pyrimidine-6-yl]piperazin-1-carboxylate (110 mg, 0.19 mmol) in DCM (5 mL), TFA (5 mL, 67.3 mmol) was added. The mixture was stirred at 20°C for 2 hours and then concentrated under vacuum to obtain 5-fluoro-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)phenyl]-6-piperazine-1-ylpyrido[3,4-d]pyrimidine-4-amine 2,2,2-trifluoroacetate (90 mg, yield 81%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z 472.2(M+H-TFA).

[0409] Step C.1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)amino)-5-fluoropyrido[3,4-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one. 5-Fluoro-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)phenyl]-6-piperazin-1-yl-pyrido[3,4-d]pyrimidine-4-amine 2,2,2-trifluoroacetate (85 mg, 0.15 mmol) was dissolved in DCM (3 mL) and DIPEA (94 μL, 0.54 mmol) was added. The mixture was cooled to -78°C, propa-2-enoyl chloride (15 μL, 0.18 mmol) was added dropwise, and the reaction was stirred at -78°C for 5 minutes. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under vacuum. The crude solid was purified by preparative HPLC (20%-59% MeCN / 0.05% NH4OH aqueous solution) to obtain 1-(4-(4-((4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)amino)-5-fluoropyrido[3,4-d]pyrimidine-6-yl)piperazin-1-yl)propa-2-en-1-one (38 mg, yield 40%) as a yellow solid. LCMS(MM-ES+APCI,Pos):m / z526.3(M+H).

[0410] Compounds 100-103 in Table 8 were prepared according to steps A-C of Example 90. [Table 8]

[0411] Example 91 1-(4-(5-fluoro-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)quinazoline-6-yl)piperazine-1-yl)propa-2-en-1-one (compound 104) [ka] Step A. N'-(4-bromo-2-cyano-3-fluorophenyl)-N,N-dimethylformimidamide. DMF-DMA (0.49 mL, 3.72 mmol) was added to a solution of 6-amino-3-bromo-2-fluorobenzonitrile (400 mg, 1.86 mmol) in 1,4-dioxane (4 mL). The mixture was heated to 75°C, stirred for 30 minutes, and then concentrated under vacuum to obtain N'-(4-bromo-2-cyano-3-fluorophenyl)-N,N-dimethylformimidamide (500 mg, 96% yield) as a red solid. LC-MS (MM-ES+APCI,Pos): m / z 270.0 (M+H).

[0412] Step B. 6-Bromo-5-fluoro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)quinazoline-4-amine. 3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)aniline (274 mg, 1.07 mmol) was added to a solution of N'-(4-bromo-2-cyano-3-fluorophenyl)-N,N-dimethylformimidamide (300 mg, 1.07 mmol) in AcOH (12 mL). The mixture was heated to 85°C, stirred for 2 hours, and quenched with saturated NaHCO3 aqueous solution. This reaction product was combined with another batch (50 mg, 0.17 mmol), and the suspension was filtered. The filtered solid was washed with water (3 mL), and the solid was vacuum-dried to obtain 6-bromo-5-fluoro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)quinazoline-4-amine (415 mg, yield 70%) as an off-white solid. LC-MS (MM-ES+APCI,Pos): m / z 479.0 (M+H).

[0413] Step C. tert-butyl 4-(5-fluoro-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)quinazoline-6-yl)piperazine-1-carboxylate. 6-bromo-5-fluoro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)quinazoline-4-amine (175 mg, 0.36 mmol) and tert-butylpiperazine-1-carboxylate (201 mg, 1.08 mmol) were dissolved in 1,4-dioxane (5 mL) and Cs2CO3 (352 mg, 1.08 mmol), Pd2(dba)3 (33 mg, 36 μmol), and Xantphos (42 mg, 72 μmol) were added. The mixture was heated to 100°C, stirred for 4 hours, and quenched with water (5 mL). This batch was combined with another quenched batch (200 mg, 0.42 mmol). The aqueous mixture was extracted with toluene (5 mL x 3), the combined organic layer was washed with brine (10 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude oil was purified by silica gel column chromatography (0%~80% toluene / PET) to obtain tert-butyl 4-(5-fluoro-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)quinazoline-6-yl)piperazine-1-carboxylate (390 mg, yield 86%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 585.4(M+H).

[0414] Step D. 5-Fluoro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazin-1-yl)quinazoline-4-amine hydrochloride. A solution of tert-butyl 4-(5-fluoro-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)quinazoline-6-yl)piperazin-1-carboxylate (150 mg, 0.23 mmol) in DCM (1 mL) was cooled to 0°C, and then HCl (4 M in HCl, 1 mL, 4.0 mmol) was added dropwise. The mixture was stirred at 0°C for 0.5 hours and then concentrated under vacuum to obtain 5-fluoro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazin-1-yl)quinazoline-4-amine hydrochloride (113 mg, yield 94%) as a yellow solid. LCMS(MM-ES+APCI,Pos): m / z 485.3(M+H-HCl).

[0415] Step E. 1-(4-(5-fluoro-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)quinazolin-6-yl)piperazin-1-yl)propa-2-en-1-one. Two batches performed in parallel contained a DCM (2 mL) solution of 5-fluoro-N-(3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)-6-(piperazin-1-yl)quinazolin-4-amine (50 mg, 91 μmol) and DIPEA (79 μL, 453 μmol), respectively. The solutions were cooled to -78°C and propa-2-enoyl chloride (7.4 μL, 91 μmol) was added dropwise. The mixture was stirred at -78°C for 5 minutes, quenched with saturated NaHCO3 (5 mL) aqueous solution, and extracted with DCM (5 mL x 3). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (24%~44% MeCN / 2.25% TFA aqueous solution), and the two batches were combined to obtain 1-(4-(5-fluoro-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)quinazoline-6-yl)piperazin-1-yl)propa-2-en-1-one (34 mg, yield 35%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 539.3(M+H).

[0416] Example 92 1-(4-(5-Methoxy-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)quinazoline-6-yl)piperazine-1-yl)propa-2-en-1-one (compound 105) [ka] Step A. tert-butyl 4-(5-methoxy-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)quinazolin-6-yl)piperazine-1-carboxylate. NaOMe (9.2 mg, 0.17 mmol) was added to a solution of tert-butyl 4-[5-fluoro-4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,4-d]pyrimidine-6-yl]piperazine-1-carboxylate (100 mg, 0.17 mmol) in MeOH (5 mL). The mixture was heated at 70°C for 2 hours and then concentrated under vacuum. The crude substance was purified by silica gel column chromatography (1% to 50% toluene / PET) to obtain tert-butyl 4-[5-methoxy-4-[3-methyl-4-(1-methylbenzotriazol-5-yl)oxyanilino]pyrido[3,4-d]pyrimidine-6-yl]piperazine-1-carboxylate (80 mg, yield 78%) as a yellow solid. LCMS (MM-ES+APCI,Pos): m / z 598.5 (M+H).

[0417] Step B. 1-(4-(5-methoxy-4-((3-methyl-4-((1-methyl-1H-benzo[d][1,2,3]triazole-5-yl)oxy)phenyl)amino)quinazolin-6-yl)piperazin-1-yl)propa-2-en-1-one. To a solution of tert-butyl 4-[5-methoxy-4-[3-methyl-4-(1-methylbenzotriazole-5-yl)oxyanilino]pyrido[3,4-d]pyrimidine-6-yl]piperazin-1-carboxylate (70 mg, 0.12 mmol) in DCM (3 mL), TFA (3 mL, 40.4 mmol) was added. The mixture was stirred at 20°C for 2 hours and then concentrated under vacuum. The crude residue was suspended in DCM (5 mL) and cooled to -78°C. DIPEA (53 μL, 0.30 mmol) and propa-2-enoyl chloride (8.2 μL, 0.10 mmol) were added. The mixture was stirred at -78°C for 5 minutes, quenched with water (10 mL), and extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine...

Claims

1. Compounds having the structure of formula (I) below: 【Chemistry 299】 Alternatively, stereoisomers of the compound, tautomers of the compound, or pharmaceutically acceptable salts thereof (in the formula, X １ CR １ or N, X ２ CR ２ or N, Y １ CR ４ or N, Y ２ CR ５ａ or N, Y ３ is C or N, Y ４ CR ６ Or NR ６ And, Y ５ CR ７ , O, or NR ７ And, Y ６ is C or N, R １ , R ２ , R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ４ , R ５ａ , R ５ｂ , and R ７ These are H, Halo, and C, respectively, independently. １ -C ３ Alkyl, C １ -C ３ Haloalkyl, or C １ -C ３ It is heteroalkyl, R ６ H, C １ -C ３ Alkyl, C １ -C ３ Alkyl deuterated, or C １ -C ３ It is a haloalkyl, R ８ and R ９ However, each is independent of H or C １ -C ３ It is alkyl, Z １ is, -NR ９ -, -O-, -S-, or direct bond, Z ２ is, -NR ９ - or direct bond, L is C １ -C ４ Alkyl, C ３ -C ８ Cycloalkyl, C ３ -C ８ Heterocycloalkyl, condensed heterodicyclic, bridging heterodicyclic, heterospirocyclic, or directly bonded, E is an α,β-unsaturated carbonyl or C ２ -C ４ It is an alkyne-conjugated carbonyl, [Chemical 300] Each of these can be a single or double bond, provided the valence allows it.

2. The compound is one of the structures of the following formulas (IA) to (ID): 【Chemical 301-1】 【Chemical 301-2】 Alternatively, the compound according to claim 1, comprising a stereoisomer of the compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

3. Y ５ However, N is Y ３ The compound according to any one of claims 1 to 2, wherein C is present.

4. The aforementioned compound has one of the following structures: (IA-1) to (IB-1): 【Chemical 302】 Alternatively, the compound according to any one of claims 1 to 3, comprising a stereoisomer of the compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

5. Y ５ However, CR ７ Y ３ However, C is R ７ The compound according to any one of claims 1 to 2, wherein H is present.

6. The compound is one of the structures of the following formulas (IA-2) to (IB-2): 【Chemical 303】 Alternatively, the compound according to claim 5, comprising a stereoisomer of the compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

7. R ６ However, C １ -C ３ The compound according to any one of claims 1 to 6, wherein it is a haloalkyl compound.

8. R ６ However, C １ The compound according to any one of claims 1 to 7, wherein it is a haloalkyl compound.

9. R ６ However, CHF ２ or CF ３ The compound according to any one of claims 1 to 8.

10. Z １ and Z ２ The compound according to any one of claims 1 to 9, wherein each of them is directly bonded.

11. Z １ However, -NR ９ -, -O-, or -S-, Z ２ The compound according to any one of claims 1 to 10, wherein the bond is direct.

12. Z １ However, it is a direct bond, Z ２ However, -NR ９ - The compound according to any one of claims 1 to 11.

13. Z １ and Z ２ However, each of them is -NR ９ - The compound according to any one of claims 1 to 12.

14. R ９ However, H or CH ３ The compound according to any one of claims 1 to 13.

15. R １ 、R ２ 、R ３ａ 、R ３ｂ 、R ３ｃ 、R ３ｄ 、R ４ 、R ５ａ 、R ５ｂ 、and R ７ are each independently H, halo, C １ alkyl, C １ -C ２ haloalkyl, or C １ -C ３ heteroalkyl, the compound according to any one of claims 1 to 14.

16. R １ , R ２ , R ３ａ , R ３ｂ , R ３ｃ , R ３ｄ , R ４ , R ５ａ , R ５ｂ , and R ７ However, each is independent of H, F, Cl, and CH. ３ ,CH ２ CF ３ CF ３ CHF ２ ,CH ２ OCH ３ CD ３ , OCHF ２ OCF ３ , or OCH ３ The compound according to any one of claims 1 to 15.

17. R １ and R ２ However, each is independent of H, F, and CH. ３ , or OCH ３ The compound according to any one of claims 1 to 16.

18. R ３ａ , R ３ｂ , R ３ｃ , and R ３ｄ However, H and CH are independent of each other. ３ , OCH ３ ,CH ２ OCH ３ , OCHF ２ OCF ３ A compound according to any one of claims 1 to 17, wherein the compound is F or Cl.

19. R ４ However, H, F, CH ３ ,CH ２ OCH ３ , or CH ２ CF ３ The compound according to any one of claims 1 to 18.

20. R ５ａ and R ５ｂ However, H and CH are independent of each other. ３ , F, or OCH ３ The compound according to any one of claims 1 to 19.

21. R ７ However, H or CH ３ The compound according to any one of claims 1 to 20.

22. R ８ However, H or CH ３ The compound according to any one of claims 1 to 21.

23. L's C ３ -C ８ The compound according to any one of claims 1 to 22, wherein the heterocycloalkyl, the condensed heterodicycle, the bridged heterodicycle, and the heterospiro ring each have 1 to 3 nitrogen atoms.

24. L's C ３ -C ８ The compound according to any one of claims 1 to 23, wherein the heterocycloalkyl, the condensed heterodicycle, the crosslinked heterodicycle, and the heterospiro ring each have one to two nitrogen atoms.

25. L's C ３ -C ８ The compound according to any one of claims 1 to 24, wherein the heterocycloalkyl, the condensed heterodicycle, the crosslinked heterodicycle, and the heterospiro ring are unsaturated heterocycles.

26. L's C ３ -C ８ The compound according to any one of claims 1 to 25, wherein the heterocycloalkyl is azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1,2-diadinane, 1,3-diadinane, 1,4-diadinane, azapan, diazepan, or azocan.

27. The compound according to any one of claims 1 to 26, wherein the condensed heterodicycle of L is 3-azabicyclo[3.1.0]heptane, 2,5-diazabicyclo[4.2.0]octane, octahydropyrrolo[3.4.c]pyrrole, octahydropyrrolo[3.4.b]pyrrole, octahydro-1H-pyrrolo[3.4.c]pyridine, decahydro-2,6-naphthyridine, 2,5-diazabicyclo[4.1.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, or 3,6-diazabicyclo[3.1.0]hexane.

28. The compound according to any one of claims 1 to 27, wherein the crosslinked heterobiring of L is 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane, 8-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, 3-oxa-9-azabicyclo[3.3.1]nonanane, 3-oxa-9-azabicyclo[3.3.1]nonan-6-ene, 9-azabicyclo[3.3.1]nonan-2-ene, 8-azabicyclo[3.2.1]octa-2-ene, or 3,6-diazabicyclo[3.1.1]heptane.

29. The compound according to any one of claims 1 to 28, wherein the heterospiro ring of L is 2,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5]nonane, 2,8-diazaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 4,8-diazaspiro[2.5]octane, 5,9-diazaspiro[3.5]nonane, 6,10-diazaspiro[4.5]decane, or 1,5-diazaspiro[5.5]undecane.

30. L's C ３ -C ８ The heterocycloalkyl group, the condensed heterodicyclic group, the crosslinked heterodicyclic ring, and the heterospiro ring are further composed of deuterium, halo, and C. １ -C ６ Alkyl, or C １ -C ６ A compound according to any one of claims 1 to 29, which is substituted with a heteroalkyl group.

31. L's C ３ -C ８ The heterocycloalkyl, the condensed heterodicycle, the crosslinked heterodicycle, and the heterospiro ring are further composed of deuterium, halo, and C. １ -C ３ Alkyl, or C １ -C ３ A compound according to any one of claims 1 to 30, which is substituted with a heteroalkyl group.

32. L's C ３ -C ８ The heterocycloalkyl, the condensed heterodicycle, the crosslinked heterodicycle, and the heterospirocycle are further -D, -F, and -CH ３ , -CF ３ ,-CHF ２ ien-CH ２ F, -CH ２ CHF ２ ien-CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ OH, -CH ２ OCH ３ , 【Chemical 304】 or -CH ２ A compound according to any one of claims 1 to 31, which is substituted with CCN.

33. L's C ３ -C ８ The compound according to any one of claims 1 to 32, wherein the heterocycloalkyl, the condensed heterodicycle, the crosslinked heterodicycle, and the heterospiro ring are monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or octasubstituted.

34. L is C ２ -C ４ Alkyl or C ４ -C ５ A compound according to any one of claims 1 to 33, wherein it is a cycloalkyl compound.

35. L's C １ -C ４ Alkyl is -(CH ２ ) ２ - or -CH ２ C (CH ３ ) ２ The compound according to any one of claims 1 to 34.

36. L's C ３ -C ８ Cycloalkyl, 【Chemical 305】 And * is Z ２ A compound according to any one of claims 1 to 35, indicating the position of binding to the compound.

37. The compound according to any one of claims 1 to 36, wherein L has one of the following structures: 【Chemical Engineering 306-1】 【Chemical Engineering 306-2】 (In the formula, * represents Z) ２ (This indicates the position of the connection with [the other element].)

38. E's α,β-unsaturated carbonyl or C ２ -C ４ Alkyne conjugated carbonyls are further, halo, C １ -C ３ Alkyl, C １ -C ３ Alkylhalogen, C １ -C ６ Heteroalkyl, -(CH ２ ) ｎ C ３ -C ７ The compound according to any one of claims 1 to 37, wherein it is substituted with a heterocycloalkyl group or a combination thereof, and n is an integer from 1 to 3.

39. The compound according to any one of claims 1 to 38, wherein the α,β-unsaturated carbonyl of E has one of the following structures: 【Chemical 307】

40. Said C ２ -C ４ Alkyne conjugated carbonyl, C ２ Alkyne conjugated carbonyl or C ３ The compound according to any one of claims 1 to 39, which is an alkyne-conjugated carbonyl.

41. Said C ２ -C ４ The compound according to any one of claims 1 to 40, wherein the alkyne-conjugated carbonyl has the following structure: 【Chemical 308】

42. The compound according to any one of claims 1 to 41, wherein E has one of the following structures: 【Chemical 309】

43. The compound according to claim 1, wherein the compound has one of the following structures: 【Chemical 310-1】 【Chemical 310-2】 【Chemical 310-3】 【Chemical 310-4】 【Chemical 310-5】 【Chemical 310-6】 【Chemical 310-7】 【Chemical 310-8】 【Chemical 310-9】 【Chemical 310-10】 【Chemical Engineering 310-11】 【Chemical 310-12】 【Chemistry 310-13】 【Chemical 310-14】 【Chemical 310-15】 【Chemical 310-16】 【Chemical Engineering 310-17】 【Chemical 310-18】 【Chemical Engineering 310-19】 【Chemical 310-20】 【Chemical Engineering 310-21】 【Chemical Engineering 310-22】 【Chemical Engineering 310-23】 【Chemical 310-24】 【Chemical 310-25】 【Chemical Engineering 310-26】 【Chemical Engineering 310-27】 【Chemical 310-28】

44. A pharmaceutical composition comprising the compound described in claim 1 and an additional therapeutic agent.

45. A compound according to any one of claims 1 to 43 or a pharmaceutical composition according to claim 44, used for the treatment of diseases associated with mutations in human epidermal growth factor receptor 2 (ErbB2).

46. A method for treating a disease associated with ErbB2 mutation, comprising administering a compound according to any one of claims 1 to 43 or a pharmaceutical composition according to claim 45 to a subject in need thereof.

47. The method according to claim 46, wherein the subject is an animal.

48. The method according to any one of claims 46 to 47, wherein the subject is a human.

49. The method according to any one of claims 46 to 48, wherein the disease associated with the ErbB2 mutation is cancer.

50. The method according to any one of claims 46 to 49, wherein the cancer is lung cancer, glioma, esophageal cancer, liver cancer, stomach cancer, uterine cancer, cervical cancer, biliary tract cancer, skin cancer, head and neck cancer, salivary gland cancer, breast cancer, pancreatic cancer, colorectal cancer, kidney cancer, bladder cancer, or prostate cancer.

51. The method according to any one of claims 46 to 50, wherein the cancer is non-small cell lung cancer.

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