RU2783706C1 - Compounds with condensed rings - Google Patents

Abstract

FIELD: organic chemistry; pharmaceutics.

SUBSTANCE: group of inventions relates to the field of organic chemistry and pharmaceutics; it is aimed at the treatment of a disorder mediated by mutation K-Ras G12C. A compound of the formula (II), or its pharmaceutically acceptable salt, or isomer is disclosed, where R₂ is NH₂; R₃ is H; R₄ is H or C_1-6 alkyl; R₅ is CF₃; R₇ is selected from a group consisting of H, cyano, and halogen; each of R₈ and R₉ is independently selected from a group consisting of H, C_1-6 alkyl, C_1-6 halogenalkyl, C_1-6 hydroxyalkyl, cyano, and halogen; where C_1-6 alkyl is optionally substituted with one substitute selected from a group consisting of: methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), a leaving group of alkyl- or arylsulfonate, C_1-6 alkanoylamino, C_1-6 alkoxy, C_1-6 alkylamino, C_1-6 alkylsulfonylamino, C_6-12 dialkylamino, and C_1-6 halogenalkoxy; X is piperazinyl optionally substituted with 1-4 substitutes, where each substitute is independently selected from a group consisting of cyano, C_1-6 alkyl, C_1-6 cyanoalkyl, and C_1-6 halogenalkyl; Y (see cl.1), U is C(R_6a), where R_6a is H; V is C(R_6b), where R_6b is H or halogen; W is C(R_6c), where R_6c is H or halogen; and n is 0. In addition, a compound of the formula (IV), as well as specific compounds and their pharmaceutically acceptable salts are disclosed. A pharmaceutical composition for regulation of activity of mutant protein K-Ras G12C is disclosed, containing an effective number of the above-mentioned compounds, as well as the use of these compounds in the production of a drug for inhibition of proliferation of a cell population having mutant protein K-Ras G12C and for the treatment of cancer mediated by mutation K-Ras G12C.

EFFECT: group of inventions provides effective inhibition of proteins Ras.

58 cl, 4 tbl, 98 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority over international application serial number PCT/CN 2018/114788 filed November 9, 2018, the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates to fused ring compounds of formula (I), as further detailed herein, which are used to inhibit Ras proteins such as K-Ras, H-Ras and N-Ras, as well as compositions, containing these compounds and methods of treatment by their introduction.

BACKGROUND OF THE INVENTION

[0003] Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch for central growth signaling pathways. In response to extracellular signals, Ras changes from a GDP-bound (Ras ^GDF ) to a GTP-bound (Ras ^GTP )) state, which is catalyzed by guanine nucleotide exchange factors (GEF), namely, the SOS1 protein. Active Ras ( ^GTP ) mediates a variety of growth-promoting functions through direct interactions with effectors including Raf, PI3K, and the guanine nucleotide dissociation promoter Ral. The characteristic GTPase activity of Ras then hydrolyzes GTP to GDP with termination of Ras signaling. The GTPase activity of Ras can be further accelerated through its interactions with GTPase-activating proteins (GAPs), including the tumor suppressor neurofibromin 1.

[0004] Mutant Ras has reduced GTPase activity, which prolongs the existence of its activated conformation, thereby promoting Ras-dependent signaling and survival or growth of cancer cells. A mutation in Ras that affects its ability to interact with GAP or convert GTP back to GDP would prolong the activation of the protein and therefore prolong the signal to the cell telling it to keep growing and dividing. Because these signals lead to cell growth and division, overactive RAS signaling can eventually lead to cancer. Mutations in any of the three major isoforms of the RAS gene (H-Ras, N-Ras, or K-Ras) are common events in human oncogenesis. Among the three isoforms of Ras (K, N, and H), K-Ras is the most frequently mutated.

[0005] The most common K-Ras mutations occur at residues G12 and G13 in the P-loop and at residue Q61. G12C is a common mutation in the K-Ras gene (glycine-12 to cysteine). G12D and G13D are other frequent mutations. Ras mutations in cancer are associated with poor prognosis. Inactivation of oncogenic Ras in mice leads to a decrease in the size of tumors. Thus, in a broad sense, Ras is considered an oncological target of exceptional importance.

BRIEF DESCRIPTION OF THE INVENTION

[0006] In one aspect, the present disclosure is directed to a compound of formula (1):

or a pharmaceutically acceptable salt thereof; where

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X, Y, U, V, W and n are described in this document.

[0007] Another aspect of the disclosure includes a compound of formula (II):

or a pharmaceutically acceptable salt thereof;

where R ₂ , R ₃ , R ₄ , R ₅ , R ₇ , R ₈ , R ₉ , X, Y, U, V, W and n are described in this document.

[0008] A compound of formula (III) is also disclosed:

or a pharmaceutically acceptable salt thereof;

where R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , X, Y, U, V, W and n are described in this document.

[0009] In another aspect, the present disclosure is directed to a compound of formula (IV):

or a pharmaceutically acceptable salt thereof;

where R ₁ , R ₁₁ , X, Y, U, V, W and n are described in this document.

[0010] Also provided is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] Another aspect includes a method of treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0012] Another aspect includes a method for regulating the activity of a K-Ras G12C mutant protein, comprising reacting the mutant protein with a compound of the invention or a pharmaceutically acceptable salt thereof.

[0013] Another aspect includes a method of treating a disorder mediated by a K-Ras G12C mutation in an individual in need thereof, comprising determining whether the individual has the mutation; and if it is determined that the individual has the mutation, administering to the individual a therapeutically effective amount of the pharmaceutical composition of the invention.

[0014] Another aspect includes a method of inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The term "halogen" or "halo" refers to F, Cl, Br, or I. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl.

[0016] the Term "alkyl" refers to a saturated monovalent hydrocarbon radical with a linear or branched chain. In one example, the alkyl radical has from one to eighteen carbon atoms (C _1-18 ). In other examples, the alkyl radical is C _1-12 , C _1-10 , C _1-8 , C _1-6 , C _1-5 , C _1-4 or C _1-3 . Examples of alkyl groups include methyl (Me, -CH ₃ ), ethyl (Et, CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, CH ₂ CH ₂ CH ₃ ), 2-propyl (and-Pr , and-propyl, -CH (CH3) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (and-Bu, and- butyl, CH ₂ CH (CH ₃ ) ₂ ), 2-butyl (c-Bu, s-butyl, CH (CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, t-butyl , -C (CH ₃ ) ₃ ), 1-pentyl (t-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₃ ), 3 -pentyl (-CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ ) CH (CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH (CH ₃ )CH ₂ CH ₃ ), 1-hexyl (CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH (CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH (CH ₃ ) CH ₂ CH (CH ₃ ) 2), 3-methyl-3-pentyl (-C (CH ₃ ) (CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C( CH ₃ ) ₃ , 1-heptyl and 1-octyl.

[0017] The term "amino" refers to -NH ₂ .

[0018] The term "alkylamino" refers to NH alkyl.

[0019] The term "dialkylamino" refers to -N(alkyl)2.

[0020] The term "oxo" refers to =O.

[0021] The term "carboxy" refers to -C(=O)OH.

[0022] The term "carbamoyl" refers to -C(=O)NH ₂ .

[0023] The term "alkanoyl" refers to -C(=O)-alkyl.

[0024] The term "hydroxyalkanoyl" refers to -C(=O)-hydroxyalkyl.

[0025] The term "alkanoylamino" refers to -NH-C(=O)-alkyl.

[0026] The term "alkoxy" refers to -O-alkyl.

[0027] The term "alkoxyalkyl" refers to alkyl substituted with one alkoxy substituent.

[0028] The term "dialkylamino cyclopropyl" refers to cyclopropyl substituted with one dialkylamino substituent.

[0029] The term "alkylsulfanyl" refers to S(=O) alkyl.

[0030] The term "alkylsulfonyl" refers to -S(=O) ₂ -alkyl.

[0031] The term "alkylsulfonylamino" refers to -NH-S(=O) ₂ -alkyl.

[0032] The term "alkylthio" refers to -S-alkyl.

[0033] The term "haloalkylthio" refers to -S-haloalkyl.

[0034] The term "aminoalkyl" refers to alkyl substituted with one amino substituent.

[0035] The term "carbamoylalkyl" refers to alkyl substituted with one carbamoyl substituent.

[0036] The term "carboxyalkyl" refers to alkyl substituted with one carboxy substituent.

[0037] The terms "cyano" or "nitrile" refer to -C=N or -CN.

[0038] The term "cyanoalkyl" refers to alkyl substituted with one cyano substituent.

[0039] The term "haloalkoxy" refers to -O-haloalkyl.

[0040] The term "heterocyclylamino" refers to -NH- heterocyclyl.

[0041] The term "hydroxy" refers to -OH.

[0042] The term "hydroxyalkyl" refers to alkyl substituted with one hydroxy substituent.

[0043] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon double bond and includes radicals having "cis" and "trans" orientations, or alternatively "E" and "Z"-orientations. In one example, the alkenyl radical has two to eighteen carbon atoms (C _2-18 )— In other examples, the alkenyl radical is C _2-12 , C2-10, C _2-8 , C _2-6 or C _2-3 . Examples include, but are not limited to, ethenyl or vinyl (-CH=CH ₂ ), prop-1-enyl (-CH=CHCH ₃ ), prop-2-enyl (-CH ₂ CH=CH ₂ ), 2-methylprop -1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2 -enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

[0044] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon triple bond. In one example, the alkynyl radical has two to eighteen carbon atoms (C _2-18 )— In other examples, the alkynyl radical is C _2-12 , C _2-10 , C _2-8 , C _2-6 or C _2-3 . Examples include, but are not limited to, ethynyl (-C=CH), prop-1-ynyl (C≡CCH ₃ ), prop-2-ynyl (propargyl, -CH ₂ C=CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.

[0045] The term "alkylene" refers to a saturated, branched or straight chain hydrocarbon group having two monovalent radical centers obtained by removing two hydrogen atoms from one or two different carbon atoms of the parent alkane. In one example, a divalent alkylene group has from one to eighteen carbon atoms (C _1-18 ). In other examples, the divalent alkylene group is C _1-12 , C _1-10 , C _1-8 , C _1-6 , C _1-5 , C _1-4 or C _1-3 . Examples of alkylene groups include (-CH ₂ -), 1,1-ethyl (-CH(CH ₃ )-), (1,2-ethyl (-CH ₂ CH ₂ -), 1,1-propyl (-CH( CH ₂ CH ₃ -), 2,2-propyl (-C (CH ₃ ) ₂ -), 1,2-propyl (-CH (CH ₃ ) CH ₂ -), 1,3-propyl (CH ₂ CH ₂ CH ₂ ), 1,1-dimethylethyl-1,2-yl (-C(CH ₃ ) ₂ CH ₂ -), 1,4-butyl (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. .

[0046] the Term "aryl" refers to a carbocyclic aromatic group, fused with one or more groups or not, having the specified number of carbon atoms, or if the number is not specified, up to 14 carbon atoms. One example includes aryl groups having 6-14 carbon atoms. Another example includes aryl groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthacenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like. (See, for example, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13th edition, Table 7-2 [1985]). A particular aryl is phenyl.

[0047] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyl embraces mono-, bi-, tricyclic, spiro and bridged saturated ring systems. In one example, the cycloalkyl group has from 3-12 carbon atoms (C _3-12 ). In other examples, cycloalkyl is C _3-7 , C _3-8 , C _3-10 or C _5-10 . In other examples, the cycloalkyl group, as a monocycle, is C _3-8 , C _3-6 or C _5-6 . In another example, the cycloalkyl group, as bicycle, is C ₇ -C ₁₂ . In another example, the cycloalkyl group, as a spiro system, is C _5-12 . Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Typical configurations of bicyclic cycloalkyls having 7-12 ring atoms include, but are not limited to, [4.4], [4.5], [5.5], [5.6], or [6.6] ring systems . Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Examples of spirocycloalkyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane.

[0048] The term "cycloalkenyl" refers to a non-aromatic, hydrocarbon ring group with at least one carbon-carbon double bond. Cycloalkenyl encompasses mono-, bi-, tricyclic, spiro or bridged saturated ring systems. Examples of monocyclic cycloalkenyls include 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3- enyl and cyclohexadienyl. Typical configurations of bicyclic cycloalkenyls having 7-12 ring atoms include, but are not limited to, [4.4], [4.5], [5.5], [5.6], or [6.6] ring systems . Exemplary bridged bicyclic cycloalkenyls include, but are not limited to, bicyclo[2.2.1]heptene, bicyclo[2.2.2]octene, and bicyclo[3.2.2]nonene. Examples of spirocycloalkenyls include spiro[2.2]pentene, spiro[2.3]hexene, spiro[2.4]heptene, spiro[2.5]octene, and spiro[4.5]decene.

[0049] The terms "heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl" or "heterocyclo" are used interchangeably and refer to any mono-, bi-, tricyclic, spiro or bridged, saturated, partially saturated or unsaturated, a non-aromatic ring system having 3-20 ring atoms, where the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl contains 3-11 ring atoms ("members") and includes monocycles, bicycles, tricycles, spiro and bridged ring systems, where the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In other examples, heterocyclyl contains 4-10 or 5-10 ring atoms. In one example, a heterocyclyl contains 1-4 heteroatoms. In one example, a heterocyclyl contains 1-3 heteroatoms. In another example, heterocyclyl includes 3-7 membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4-6 membered monocycles having 12, 13 or 14 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6 membered monocycles. In some embodiments, the heterocycloalkyl contains at least one nitrogen atom. In one example, the heterocyclyl group contains 0 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (eg NO, SO, SO ₂ ) and the nitrogen heteroatom may optionally be quaternized (eg [NR4] ⁺ Cl ^- , [NR4] ⁺ OH ^- ). Examples of heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thientanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl , tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanil, thiazinanil, thioxanyl, homopiperazinyl, homopiperidinium, azepanil, oxepanil, thiepanyl, oxazepanyl-diazepanyl, 1-oxazepinyl, , diazepinyl, thiazepinyl, thiazepanil, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinoyl, 1,1-dioxoisothiazolyl, oxazolidinoyl, imidazolidinoyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5 ,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinium l, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, tiapiranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2- azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[ 4.5]decan-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl.

[0050] The term "methylheterocyclyl" refers to a heterocyclyl substituted with a methyl group.

[0051] The term "heteroaryl" refers to any mono-, bi-, or tricyclic aromatic ring system containing 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur, and, in an exemplary embodiment, at least one heteroatom is nitrogen . See, for example, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13th edition, Table 7-2 [1985]. Included in this definition are any bicyclic groups in which any of the above heteroaryl rings are fused to an aryl ring, where the aryl ring or heteroaryl ring is bonded to the rest of the molecule. In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups, where one or more ring atoms are nitrogen, sulfur or oxygen. Examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5- b]pyridazinyl, imidazol[1,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indazolyl and indolyl.

[0052] In specific embodiments, a heterocyclyl group or a heteroaryl group is attached at the carbon atom of the heterocyclyl group or heteroaryl group. By way of example, carbon-linked heterocyclyl groups include bonding configurations at position 2, 3, 4, 5 or 6 of the pyridine ring, position 3, 4, 5 or 6 of the pyridazine ring, position 2, 4, 5 or 6 of the pyrimidine ring, position 2 , 3, 5 or 6 rings of pyrazine, position 2, 3, 4 or 5 of the ring of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4 or 5 of the ring of oxazole, imidazole or thiazole, position 3, 4 or 5 of the ring isoxazole, pyrazole or isothiazole, position 2 or 3 of the aziridine ring, position 2, 3 or 4 of the azetidine ring, position 2, 3, 4, 5, 6, 7 or 8 of the quinoline ring, or position 1, 3, 4, 5, 6, 7 or 8 isoquinoline rings.

[0053] In certain embodiments, the implementation of the heterocyclyl group or heteroaryl group is N-attached. By way of example, nitrogen-bonded heterocyclyl or heteroaryl groups include 1-position binding configurations of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2- pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, the 2-position of isoindole or isoindoline, the 4-position of morpholine, and the 9-position of carbazole or β-carboline.

[0054] "Fused" refers to any ring structure described herein that shares one or more atoms (eg, carbon or nitrogen atoms) with an existing ring structure in the compounds of the invention.

[0055] The term "acyl" refers to a carbonyl containing a substituent represented by the formula -C(=O)-R, in which R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, where alkyl, cycloalkyl, aryl or heterocyclyl as defined herein. Acyl groups include alkanoyl (eg acetyl), aroyl (eg benzoyl) and heteroaroyl (eg pyridinoyl).

[0056] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms have been replaced by a halogen. Examples of haloalkyls include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0057] The terms "compound(s) of the invention" and "compound(s) of the present invention" and the like, unless otherwise indicated, include compounds of formula (I), formula (II), formula (III), formulas (IV), formulas (Ia)-(Ik), and the compounds listed in the tables herein, including their stereoisomers (including atropisomers), geometric isomers, tautomers, isotopes, and salts (eg, pharmaceutically acceptable salts).

[0058] The term "optionally substituted", unless otherwise indicated, means that the group may be unsubstituted or substituted with one or more (for example, 0, 1, 2, 3, 4, or 5 or more, or any range derived from these values) by the substituents listed for this group, in which these substituents may be the same or different. In an embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents. In another embodiment, the optionally substituted group has 5 substituents.

которая пересекает связь в химической структуре, указывает точку присоединения атома, с которым волнистая связь соединена в химической структуре, с остальной молекулой или с остальным фрагментом молекулы.[0059] In the context of this document, the wavy line

which crosses a bond in a chemical structure indicates the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the rest of the molecule or to the rest of the molecule.

[0060] In certain embodiments, divalent groups are described generally without specific bond configurations. It is understood that the general description is intended to include both communication configurations unless otherwise indicated. For example, in the group R ¹ -R ² -R ³ if the group R ² is described as -CH ₂ C(O)-, it is clear that this group can be linked as R ¹ -CH ₂ C(O) -R ³ , and R ¹ -C(O)CH ₂ -R ³ unless otherwise indicated.

[0061] The term "pharmaceutically acceptable" refers to molecular substances and compositions that do not cause an adverse, allergic or other undesirable reaction when administered to an animal, such as, for example, a human, as the case may be.

[0062] The compounds of the invention may be in the form of a salt, such as a pharmaceutically acceptable salt. "Pharmaceutical acceptable salts" includes both acid addition salts and base addition salts. A "pharmaceutically acceptable acid addition salt" refers to salts that retain the biological effectiveness and properties of free bases and that are not biologically or otherwise undesirable formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid. , phosphoric acid and p. t., and organic acids can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0063] The term "pharmaceutically acceptable base addition salts" includes those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Particular base addition salts are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimetamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperisine, piperidine, N-ethylpiperidine, polyamine resins, etc. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline and caffeine.

[0064] In some embodiments, the salt is selected from hydrochloride, hydrobromide, trifluoroacetate, phosphate, sulfate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g. 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2- sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylene sulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylene sulfonate), napsylate (2-naphthalenesulfonate), camsylate (camphor-10-sulfonate, for example, salt (lS) - (+) -10-k amphorsulfonic acid), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylen-2-sulfonate), and pamoic (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3 '-dicarboxylate).

[0065] A "sterile" formulation is aseptic or free of live microorganisms and their spores.

[0066] The term "stereoisomer" refers to compounds that have an identical chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers, and the like.

[0067] the Term "chiral" refers to molecules that have the property of mismatch when superimposed with a mirror image, while the term "achiral" refers to molecules that match when superimposed on a mirror image.

[0068] The term "diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have excellent physical properties, such as melting points, boiling points, spectral properties, and biological activity. Mixtures of diastereomers can be separated using high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0069] The term "enantiomers" refers to two stereoisomers of a compound that are not superimposed mirror images of each other.

[0070] The stereochemical definitions and notations used herein are generally in accordance with S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, ie. they have the ability to rotate the plane of plane polarized light. When describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are used to indicate the direction of rotation of plane polarized light by the connection, while (-) or 1 means that the connection is left-handed. Connection with a prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Also, a specific stereoisomer may be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A mixture of enantiomers in a ratio of 50:50 is called a racemic mixture or racemate, which can occur in a chemical reaction or process where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric compounds with no optical activity.

[0071] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible when passing through a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions during proton transfer, such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversions during the rearrangement of some of the bonding electrons.

[0072] "Atropisomers" are stereoisomers that result from steric hindrance of rotation around a single bond, where energy differences due to steric strain or other factors create a barrier to rotation that is high enough to allow individual conformers to be isolated.

[0073] Certain compounds of the invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. "Solvate" refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. Certain compounds of the invention may exist in several crystalline or amorphous forms. In general, all physical forms are intended to be included within the scope of the present invention. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0074] "Metabolite" refers to a product formed through metabolism in the body of a particular compound or its salt. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

[0075] Metabolite products are typically identified by obtaining a radiolabeled (e.g., ¹⁴ C or ³ H) isotope of a compound of the invention administered at a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal, such as rat, mouse, guinea pig, monkey, or human, waiting long enough for metabolism to occur (generally about 30 seconds to 30 hours) and excreting metabolic products from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies capable of binding epitopes remaining in the metabolite). The structures of the metabolites are determined in the conventional manner, for example by MS, LC/MS or NMR analysis. In general, metabolite assays are performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolite products, provided they do not occur in vivo, are useful in a diagnostic assay for therapeutic dosing of the compounds of the invention.

[0076] The invention described herein includes isotopically labeled compounds of the present invention that are identical to those listed herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. All isotopes of any particular atom or element indicated are intended to be within the scope of the compounds of the invention and their uses. Typical isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ² H, ³ H, ¹¹ C, 13 C, ¹⁴ C, ¹³ N , ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I. Certain isotopically labeled compounds ^of the present invention ( ^e.g. ) are applicable in the analysis of tissue distribution of the compound and/or substrate. Tritiated isotopes ( ³ H) and isotopes of carbon-14 (/14C) are applicable due to their ease of production and detection. In addition, substitution with heavier isotopes such as deuterium (i.e. ² H) may provide certain therapeutic advantages as a result of greater metabolic stability (eg, increased in vivo half-life or reduced dosages required) and therefore may be preferred. in some circumstances. Substitution with positron emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C and ¹⁸ F is useful in positron emission tomography (PET) studies to study substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared following procedures similar to those described herein in the Examples section below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0077] In the context of this document, the term "amino-protecting group" refers to a derivative of the groups commonly used to block or protect the amino group when carrying out reactions in other functional groups of the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, and imines, as well as many derivatives of N-heteroatoms, which can be removed to restore the desired amino group. Specific amino protecting groups are Pmb (p-methoxybenzyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), and Cbz (carbobenzyloxy). Additional examples of these groups can be found in T. W. Greene and P. G. M. Wuts, "Protecting Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, Inc., 1999. The term "protected amino" refers to an amino group substituted with one of the above amino protecting groups.

[0078] In the context of this document, the term "carboxy-protecting group" refers to those groups that are stable under the conditions of subsequent reaction(s) at other positions of the molecule, which can be removed at the appropriate point without destroying the rest of the molecule, with obtaining a deprotected carboxy group. Examples of carboxy protecting groups include ester groups and heterocyclyl groups. Ester derivatives of the carboxylic acid group can be used to block or protect the carboxylic acid group when carrying out reactions on other functional groups of the compound. Examples of such ester groups include substituted arylalkyl, including substituted benzyls such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl or substituted alkyl esters such as methyl, ethyl, t-butyl allyl or t-amyl , triphenylmethyl (trityl), 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4''-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as tert-butyl thioester, silyl esters , such as trimethylsilyl, tert-butyldimethylsilyl esters, phenacyl, 2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl , cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl and the like. Another example of carboxy protecting groups are heterocyclyl groups such as 1,3-oxazolinyl. Additional examples of these groups can be found in T. W. Greene and P. G. M. Wuts, "Protecting Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, Inc., 1999. The term "protected carboxy" refers to a carboxy group substituted with one of the above carboxy protecting groups.

[0079] The compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers, and mixtures thereof. In the synthesis of compounds, racemates, diastereomers or enantiomers can be used as starting materials or as intermediates. Mixtures of specific diastereomeric compounds can be separated or enriched for one or more specific diastereomers by chromatography or crystallization techniques. Likewise, enantiomeric mixtures can be separated or enriched enantiomerically using the same techniques or others known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R- or S-configuration, and both of these configurations are included in the scope of the invention.

[0080] In the structures illustrated herein, unless the stereochemistry of any particular chiral atom is indicated, all stereoisomers are contemplated and included as compounds of the invention. Where stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is indicated and defined as such. Unless otherwise indicated, solid wedges or dotted lines are assumed to be relative stereochemistry.

[0081] Another aspect includes prodrugs of the compounds of the invention, including known amino-protecting and carboxy-protecting groups, which under physiological conditions are separated, for example, hydrolyzed, to obtain the compounds of the present invention.

[0082] The term "prodrug" refers to a precursor or derivative form of a pharmaceutically active substance that is less effective for the patient than the parent drug and is subject to enzymatic or hydrolytic activation or conversion to the more active parent form. See, for example, Wilman, "Prodrugs in Cancer Chemotherapy" Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al., "Prodrugs: A Chemical Approach to Targeted Drug Delivery," Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press (1985). Prodrugs include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid modified prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs preparations containing optionally substituted phenoxyacetamide prodrugs or containing optionally substituted phenylacetamide prodrugs and 5-fluorocytosine and 5-fluorouridine prodrugs.

[0083] A particular class of prodrugs are compounds in which the nitrogen atom in the amino-, amidino-, aminoalkyleneamino-, iminoalkyleneamino-, or guanidino group is replaced by a hydroxy group, -CO-R, -CO-OR or -CO-O-R-O-CO-R, where R is a monovalent or divalent group, for example, alkyl, alkylene or aryl, or a group having the formula -C(O-O-CP1P2 haloalkyl, where P1 and P2 are the same or different and represent hydrogen, alkyl, alkoxy, cyano , halogen, alkyl, or aryl.In a specific embodiment, the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the invention.Prodrugs can be prepared by reacting a compound of the present invention with an activated group, such as acyl groups, to bond, for example, the atom nitrogen in conjunction with an exemplary carbonyl or activated acyl group Examples of activated carbonyl compounds are those containing a leaving group linked to with a carbonyl group, and include, for example, acyl halides, acylamines, acyl pyridinium salts, acyl alkoxides, acyl phenoxides such as p-nitrophenoxy acyl, dinitro phenoxy acyl, fluorophenoxy acyl, and difluorophenoxy acyl. The reactions are generally carried out in inert solvents at temperatures such as from about -78 to about 50°C. The reactions can also be carried out in the presence of an inorganic base such as potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, trimethylamine, triethylamine, triethanolamine, and the like.

[0084] Additional types of prodrugs are also covered. For example, the free carboxyl group of a compound of the invention can be derivatized as an amide or alkyl ester. As another example, compounds of the invention containing free hydroxyl groups can be derivatized as prodrugs by converting the hydroxyl group to a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as described in Fleisher, D. et al. , (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Also included are carbamate prodrugs of hydroxy and amino groups, as are carbonate prodrugs, sulfonate esters, and sulfate esters of hydroxy groups. Also covered is the derivatization of hydroxy groups such as (acyloxy)methyl and (acyloxy)ethyl esters, where the acyl group may be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional moieties, or where the acyl the group is an amino acid ester as described above. Prodrugs of this type are described in J. Med. Chem., (1996), 39:10. More specific examples include substitution of a hydrogen atom in the alcohol group with a group such as (C _1-6 )alkanoyloxymethyl, 1-((C _1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C _1-6 )alkanoyloxy) ethyl, (C _1-6 )alkoxycarbonyloxymethyl, N-(C _1-6 )alkoxycarbonylaminomethyl, succinoyl, (C _1-6 )alkanoyl, alpha-amino(C _1-4 )alkanoyl, arylacyl, and alpha-aminoacyl or alpha-aminoacyl -alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from L-amino acids of natural origin, P(O)(OH) ₂ , -P(O)(O(C _1-6 )alkyl) ₂ or glycosyl (radical, resulting from the removal of the hydroxyl group of the hemiacetal form of the carbohydrate).

[0085] The term "leaving group" refers to the portion of the first reactant in the chemical reaction that is displaced from the first reactant in the chemical reaction. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxy and sulfonyloxy groups. Examples of sulfonyloxy groups include, but are not limited to, alkyl sulfonyloxy groups (eg, methylsulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)) and arylsulfonyloxy groups (eg, p-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylate group)).

[0086] "Subject", "individual" or "patient" is a vertebrate. In certain embodiments, the implementation of the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human. In embodiments involving administering a compound to a patient, the patient will typically need it.

[0087] The terms "inhibition" and "decrease", or any variation of these terms, include any measurable reduction or complete inhibition to obtain the desired result. For example, the reduction may be about, no more than about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60 %, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derived from these values, reduction in activity from normal.

[0088] "A therapeutically effective amount" means an amount of a compound of the present invention, such as a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, which (i) treats or prevents a particular disease, condition, or disorder, or (ii) relieves, alleviates, or eliminates one or more symptoms of a particular disease, condition, or disorder, and optionally (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described in this document. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the size of the tumor; inhibit (ie, to some extent slow down and preferably stop) the infiltration of cancer cells into peripheral organs; inhibit (ie, to some extent slow down and preferably stop) tumor metastasis; inhibit tumor growth to some extent; or alleviate to some extent one or more of the symptoms associated with cancer. Where a drug may prevent the growth or kill existing cancer cells, it may be cytostatic or cytotoxic. In the case of cancer therapy, efficacy can be determined, for example, by evaluating the time to disease progression (TRT) or determining the response rate (FR).

[0089] "Treatment" (and variations thereof, such as "treating" or "treating") refers to clinical intervention to alter the natural course of disease in the individual or cell being treated, and can be done both prophylactically and during clinical pathology. The desired effects of treatment include preventing the onset or reappearance of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, stabilizing (i.e., not worsening) the state of the disease, reducing the rate of progression of the disease, attenuating or temporarily alleviating the state of the disease, prolonging survival by compared with expected survival in the absence of treatment and improved prognosis. In some embodiments, the compounds of the invention are used to delay the progression of a disease or disorder, or to slow the progression of a disease or disorder. Those in need of treatment include those who already have the condition or disorder, as well as those who are predisposed to the condition or disorder (eg, due to a genetic mutation), or those in whom the condition or disorder needs to be prevented.

[0090] "Therapeutic effect" in the context of the use of this term in this document covers the therapeutic benefit and/or prophylactic benefit, as described above. A prophylactic effect includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, arresting, or reversing the progression of a disease or condition, or any combination thereof.

[0091] In the context of this document, the expressions "co-administration", "administered in combination with" and their grammatical equivalents cover the administration of two or more agents to an animal, including humans, in such a way that both agents and / or their metabolites are present in the subject's body at the same time . Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in compositions in which both agents are present.

[0092] The terms "antagonist" and "inhibitor" are used interchangeably and refer to a compound having the ability to inhibit the biological function of a target protein by inhibiting the activity or expression of a protein such as K-Ras, H-Ras, or N-Ras G12C. Accordingly, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Although the preferred antagonists of this document specifically interact (eg, bind) to the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is also explicitly included in this definition. The preferred biological activity inhibited by the antagonist is associated with tumor development, growth or spread.

[0093] As used herein, the term "agonist" refers to a compound having the ability to initiate or enhance the biological function of a target protein by inhibiting the activity or expression of the target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target polypeptide. Although the preferred agonists of this document specifically interact (eg, bind) to the target, compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is also explicitly included in this definition.

[0094] The terms "cancer" and "cancerous", "neoplasm" and "tumor", as well as similar terms, refer to a physiological condition or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" contains one or more cancer cells. Examples of cancers include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (eg, epithelial squamous cell carcinoma) and lung cancer, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma. Other cancers include skin cancer, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral cavity cancer, pharyngeal cancer (oral), lip cancer, tongue cancer, oropharyngeal cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular cancer, gastric cancer, cancer gastrointestinal tract, small intestine cancer, colon cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary system cancer , bile duct cancer, thyroid cancer, papillary cancer, liver cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, testicular cancer, vulvar cancer, abdominal cavity cancer, anal cancer, penile cancer, bone cancer, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system cancer, brain cancer, head and neck cancer, Hodgkin's lymphoma and related metastases. Examples of neoplastic disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, myelofibrosis such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

[0095] A "chemotherapeutic agent" is an agent useful in the treatment of a given disorder, such as cancer or inflammatory disorders. Examples of chemotherapeutic agents are well known in the art and include examples as described in US Application Publication No. 2010/0048557, incorporated herein by reference. In addition, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of the chemotherapeutic agents, as well as combinations of two or more of them.

[0096] Unless otherwise indicated, structures depicted herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I, respectively. Isotopically labeled compounds (eg, labeled with ³ H and ¹⁴ C) are useful in the analysis of tissue distribution of the compound or substrate. Tritiated isotopes (ie ³ H) and carbon-14 isotopes (ie ¹⁴ C) are useful due to their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium (ie, ² H) may provide certain therapeutic advantages as a result of greater metabolic stability (eg, increased in vivo half-life or reduced dosages required). In some embodiments, in the compounds of the invention, one or more carbon atoms are replaced with ¹³ C- or ¹⁴ C-rich carbons. Substitution with positron emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C and ¹⁸ F is useful in positron emission tomography (PET) studies to study substrate receptor occupancy. Isotopically labeled compounds can generally be prepared following procedures similar to those described herein in the Schemes or Example sections by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0097] It is expressly provided that any limitation discussed in relation to one embodiment of the invention may be applicable to another embodiment of the invention. In addition, any compound or composition of the invention can be used in any method of the invention, and any method of the invention can be used to prepare or use any compound or composition of the invention.

[0098] The use of the term "or" means "and/or", unless it is clearly indicated that it refers only to alternatives or alternatives are mutually exclusive, although the invention supports a definition that refers to the only alternatives and "and/or ".

[0099] Throughout this application, the term "about" is used to indicate that the value includes the standard deviation of the error for the device or method used to determine the value.

[0100] In the context of this document, the singular means one or more, unless explicitly stated otherwise. In the context of this document, "other" means at least the second or more.

[0101] The headings used herein are for ordering purposes only.

RAS INHIBITORS

[0102] In one aspect, the invention provides compounds that are capable of selectively binding and/or modulating a K-Ras, H-Ras, or N-Ras protein with a G12C, G12D, or G13D mutation.

[0103] As noted, one aspect of the invention includes a compound of formula (I):

or a pharmaceutically acceptable salt thereof; where

R ₁ is an electrophilic fragment capable of forming a covalent bond with the cysteine residue at position 12 of the K-Ras G12C mutant protein;

R ₂ is selected from the group consisting of H, OH, NH ₂ , halogen, C _1-6 alkyl a, C _1-6 halo alkyl a, cyclopropyl and -NHR, where R is selected from the group consisting of C _1-6 alkyl , C _1-6 alkokei, C _1-6 alkanoyl, C _1-6 hydroxyalkanoyl, C _1-6 cyanoalkyl, C _1-6 alkylamino, -(C _1-6 alkylenyl) NH (CH ₃ ) - (C _1-6 alkylenyl)N(CH ₃ ) ₂ and -(C _1-3 alkylenyl)(3-7 membered heterocyclyl a);

each of R ₃ and R ₄ is independently selected from the group consisting of Η, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio , C _1-6 haloalkylthio, C _1-6 alkylamino and cyclopropyl;

R ₅ is selected from the group consisting of H, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, C _1-6 haloalkylthio , C _1-6 alkylamino and C _3-7 cycloalkyl,

where at least one of R ₂ , R ₃ , R ₄ and R ₅ is different from H; or

R ₂ and R ₃ , R ₃ and R ₄ , or R ₄ and R ₅ , together with the atoms to which each is bonded, form C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-14 aryl or 5-10 membered heteroaryl; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy ;

X is selected from the group consisting of NH2, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _3-7 cycloalkyl , 4-7-membered heterocyclyl and 4-7-membered heterocyclylamino; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl , C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 4-7 membered heterocyclyl; where two geminal substituents can be taken together to form C _3-7 spirocycloalkyl or 4-7 membered spiroheterocyclyl;

Υ is selected from the group consisting of -LY ₁ or Υ ₁ ;

Υ ₁ is selected from the group consisting of Η, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl , which is optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 dialkylamino, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _6-14 aryl substituted with C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 membered heteroaryl, 4- 10-membered heterocyclyl, 4-10-membered heterocyclyl substituted with methyl, hydroxy and oxo;

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy;

L is selected from the group consisting of a bond, O, S and N(L ^a );

L ^a is selected from the group consisting of hydrogen and C _1-3 alkyl;

U is C(R _6a );

V is C(R _6b );

W is C(R _6c ) or N;

each of R _6a , R _6b and R _6c is independently selected from the group consisting of H, OH, NH ₂ , halo, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _{1 -6} alkyl substituted with 4-10 membered heterocyclyl substituent, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _1-6 haloalkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 α-membered heteroaryl and 4-10-membered heterocyclyl; and

n is selected from the group consisting of 0, 1 and 2.

[0104] According to some embodiments of a compound of formula (I) or a pharmaceutically acceptable salt thereof, R ¹ is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the K-Ras G12C mutant protein.

[0105] According to some embodiments of a compound of formula (I) or a pharmaceutically acceptable salt thereof, R ¹ is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the H-Ras G12C mutant protein.

[0106] According to some embodiments of a compound of formula (I) or a pharmaceutically acceptable salt thereof, R ¹ is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the N-Ras G12C mutant protein.

[0107] In the above definition of R ¹ , an electrophilic moiety capable of forming a covalent bond with a cysteine residue is determined using K-Ras G12C alkylation studies and time-resolved homogeneous fluorescence (HRF) analysis. The G12C mutation of the K-Ras gene is an amino acid change from glycine to cysteine in the 12th amino acid. Compounds in accordance with the present invention were detected by HPLF analysis and K-Ras G12C alkylation assay, as further detailed herein below, after which NMR spectroscopy was used to confirm the specificity with which the molecule was attached to G12C.

[0108] In another aspect, the invention includes a compound of formula (II):

or a pharmaceutically acceptable salt thereof; where

R ₂ is selected from the group consisting of H, OH, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyclopropyl and -NHR, where R is selected from the group consisting of C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkanoyl, C _1-6 hydroxyalkanoyl, C _1-6 cyanoalkyl, C _1-6 alkylamino, -(C _1-6 alkylenyl)]NH(CH ₃ )-(C _1-6 alkylenyl) N(CH ₃ ) ₂ and -(C _1-3 alkylenyl)(3-7 membered heterocyclyl);

each of R ₃ and R ₄ is independently selected from the group consisting of Η, NH ₂ , halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio , C _1-6 haloalkylthio, C _1-6 alkylamino and cyclopropyl;

R ₅ is selected from the group consisting of Η, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkokei, C _1-6 haloalkoxy, C _1-6 alkylthio, C _1-6 haloalkylthio , C _1-6 alkylamino and C _3-7 cycloalkyl,

where at least one of R ₂ , R ₃ , R ₄ and R ₅ is different from H; or

R ₂ and R ₃ , R ₃ and R ₄ , or R ₄ and R ₅ , together with the atoms to which each is bonded, form C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-14 aryl or 5-10 membered heteroaryl; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkokei, and C _1-3 haloalkoxy ;

R ₇ is selected from the group consisting of H, cyano and halo; and each of R ₈ and R ₉ is independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, cyano and halogen; where C _1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), an alkyl or arylsulfonate leaving group, C _1-6 alkanoylamino, C _1-6 alkokei, C _1-6 alkylamino, C _1-6 alkylsulfonylamino, C _6-12 dialkylamino and C _1-6 haloalkoxy;

or

R ₇ and R ₈ together form a triple bond between the carbon atoms to which they are attached, or R ₇ and R ₈ together with the carbon atoms to which they are each attached, form a C _3-7 cycloalkenyl optionally substituted with one or two substituents - halogens; and R ₉ is selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, cyano and halogen; where C _1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: C _1-6 alkanoylamino, C _1-6 alkokei, C _1-6 alkylamino, C _1-6 alkylsulfonylamino, C _6-12 dialkylamino and C _{1 -6} haloalkoxy;

X is selected from the group consisting of ΝΗ ₂ , C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _3-7 cycloalkyl, 4-7 membered heterocyclyl and 4-7 membered heterocyclylamino; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl , C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 4-7 membered heterocyclyl; where two geminal substituents can be taken together to form C _3-7 spirocycloalkyl or 4-7 membered spiroheterocyclyl;

Υ is selected from the group consisting of -LY ₁ or Υ ₁ ;

Υ ₁ is selected from the group consisting of Η, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl , which is optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 dialkylamino substituent, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _6-14 aryl substituted with C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocyclyl, 4-10-membered heterocyclyl substituted with methyl, hydroxy and oxo;

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy;

L is selected from the group consisting of a bond, O, S and N(L ^a );

L ^a is selected from the group consisting of hydrogen and C _1-3 alkyl;

U is C(R _6a );

V is C(R _6b );

W is C(R _6c ) or N;

each of R _6a , R _6b and R _6c is independently selected from the group consisting of H, OH, NH ₂ , halo, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _{1 -6} alkyl substituted with 4-10 membered heterocyclyl substituent, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _1-6 haloalkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 α-membered heteroaryl and 4-10-membered heterocyclyl; and

n is selected from the group consisting of 0, 1 and 2.

[0109] In another aspect, the invention includes a compound of formula (III):

or a pharmaceutically acceptable salt thereof; where

R ₂ is selected from the group consisting of H, OH, ΝΗ ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyclopropyl and -NHR, where R is selected from the group consisting of C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkanoyl, C _1-6 hydroxyalkanoyl, C _1-6 cyanoalkyl, C _1-6 alkylamino, -(C _1-6 alkylenyl)NH(CH ₃ )-(C _1-6 alkylenyl)] N(CH ₃ ) ₂ and -(C _1-3 alkylenyl)(3-7 membered heterocyclyl);

each of R ₃ and R ₄ is independently selected from the group consisting of Η, NH ₂ , halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio , C _1-6 haloalkylthio, C _1-6 alkylamino and cyclopropyl;

R ₅ is selected from the group consisting of Η, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, C _1-6 haloalkylthio , C _1-6 alkylamino and C _3-7 cycloalkyl,

where at least one of R ₂ , R ₃ , R ₄ and R ₅ is different from H; or

R ₂ and R ₃ , R ₃ and R ₄ , or R ₄ and R ₅ , together with the atoms to which each is bonded, form C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-14 aryl or 5-10 membered heteroaryl; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy ;

R ₁₀ is selected from the group consisting of R _10a and -C(O)-R _10a ;

R _10a is selected from the group consisting of oxiranil and aziridinyl;

X is selected from the group consisting of NH ₂ , C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _3-7 cycloalkyl, 4-7 membered heterocyclyl and 4-7 membered heterocyclylamino; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl , C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 4-7 membered heterocyclyl; where two geminal substituents can be taken together to form C _3-7 spirocycloalkyl or 4-7 membered spiroheterocyclyl;

Y is selected from the group consisting of -LY ₁ or Y ₁ ;

Y ₁ is selected from the group consisting of H, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl , which is optionally substituted with 1-4 substituents Y ₁ a, C _1-6 alkyl substituted with C _1-6 dialkylamino substituent, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl , C _1-6 alkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _6-14 aryl substituted with C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, 4-10 membered heterocyclyl substituted with methyl, hydroxy and oxo; each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy;

L is selected from the group consisting of a bond, O, S and N(L ^a );

L ^a is selected from the group consisting of hydrogen and C _1-3 alkyl;

U is C(R _6a );

V is C(R _6b );

W is C(R _6c ) or N;

each of R _6a , R _6b and R _6c is independently selected from the group consisting of H, OH, NH ₂ , halo, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _{1 -6} alkyl substituted with 4-10 membered heterocyclyl substituent, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _1-6 haloalkylthio, C _1-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 α-membered heteroaryl and 4-10-membered heterocyclyl; and

n is selected from the group consisting of 0, 1 and 2.

[0110] According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₂ is selected from the group consisting of NH ₂ and NHR; a R is C _1-6 alkyl.

[0111] According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₂ is NH ₂ . In one embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₂ is -NHR, where R is C _1-6 alkyl or C _1-6 alkoxy. In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₂ is -NHR, where R is C(O)CH ₃ , C(O)CH ₂ OH, CH(CH ₃ ) ₂ , CH ₂ CN or CH ₃ .

[0112] According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₃ and R ₄ are independently selected from the group consisting of H, halo, C _{1- 6} alkyl, C _1-6 haloalkyl and cyclopropyl. In one embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₃ is C _1-3 alkyl (e.g., methyl or ethyl) or C _1-3 haloalkyl (e.g., -CF ₃ or -CH ₂ CF ₃ ). In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₃ is hydrogen. In one embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₄ is hydrogen, halogen, C _1-3 alkyl, C _1-3 haloalkyl, or cyclopropyl. In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₄ is hydrogen or halogen. In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₄ is C _1-3 alkyl (eg, methyl or ethyl). In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₄ is methyl. In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₄ is —CF ₃ . In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₄ is hydrogen.

[0113] According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₅ is selected from the group consisting of H, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkylamino and C3-7 cycloalkyl. In one embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₅ is C _1-6 haloalkyl. In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₅ is C _1-3 haloalkyl. In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₅ is C _1-3 alkyl. In one embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₅ is C _1-3 haloalkoxy. In yet another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₅ is H, CH ₃ , CHF ₂ , CF ₃ , OCF ₃ , CH ₂ CF ₃ , halogen or cyclopropyl. In yet another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₅ is CF ₃ .

[0114] In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₅ is CF ₃ and R ₂ is NH ₂ .

[0115] In another embodiment, a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₂ is NH ₂ , R ₄ is C _1-3 alkyl, and R ₅ is is CF ₃ .

[0116] According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₅ is cyclopropyl.

[0117] According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, at least two of R ₂ , R ₃ , R ₄ and R ₅ are different from H .

[0118] According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, at least three of R ₂ , R ₃ , R ₄ and R ₅ are different from H .

[0119] According to some embodiments, a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₄ and R ₅ , together with the atoms to which each is bonded, form C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-14 aryl or 5-10 membered heteroaryl; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy .

[0120] According to some embodiments, a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₄ and R ₅ , together with the atoms to which each is bonded, form C _6-14 aryl which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _{1 -3} haloalkoxy.

[0121] According to some embodiments, a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R ₄ and R ₅ , together with the atoms to which each is bonded, form C ₆ aryl which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, and C _1-3 haloalkoxy. According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, C ₆ aryl is unsubstituted. According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, C ₆ aryl is substituted with 1-4 substituents, where each substituent is independently halogen.

[0122] According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, Y is -LY ₁ . In one embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, L is O or N(La). In another embodiment, a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, L is O. In one embodiment, a compound of formula (I), formula (II), or formula (III) , or a pharmaceutically acceptable salt thereof, Y ₁ is C _2-6 alkenyl, C _1-6 alkyl, or C _1-6 alkyl substituted with a 4-10 membered heterocyclyl or methyl heterocyclyl substituent. In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, Y ₁ is C _1-6 alkyl or C _1-6 alkyl substituted with 4-10 membered heterocyclyl or methylheterocyclyl substituent. In yet another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, Y ₁ is C _1-6 alkyl substituted with a 4-10 membered heterocyclyl or methyl heterocyclyl substituent. In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, Y ₁ is C _1-6 alkyl substituted with a 4-10 membered heterocyclyl or d-methylheterocyclyl substituent, wherein the heterocyclyl or the methylheterocyclyl substituent contains at least 1 nitrogen atom. In one embodiment, the heterocyclyl or methylheterocyclyl substituent is a pyrrolidinyl moiety. In one embodiment, the pyrrolidinyl is substituted with F. In one embodiment, the heterocyclyl and methylheterocyclyl moiety are each independently optionally substituted with 1-3 substituents selected from the group consisting of OH, NH ₂ , halo, cyano, C _1-6 alkyl, C _{1- 6} carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, or C _1-6 hydroxyalkyl.

В одном варианте осуществления Y представляет собой

В другом варианте осуществления соединения формулы (I), формулы (II) или формулы (III), или его фармацевтически приемлемой соли, Y представляет собой

Еще в одном другом варианте осуществления соединения формулы (I), формулы (II) или формулы (III), или его фармацевтически приемлемой соли, Y представляет собой

Еще в одном другом варианте осуществления соединения формулы (I), формулы (II) или формулы (III), или его фармацевтически приемлемой соли, Y представляет собой

[0123] In one embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, Y is

In one embodiment, Y is

In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, Y is

In yet another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, Y is

In yet another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, Y is

[0124] According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R _6a is hydrogen, halogen, or C _1-3 alkyl. According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R _6b is hydrogen, halo, C _1-3 alkyl, C _1-3 haloalkyl, C _{1 -3} alkoxy or cyclopropyl. In one embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R _6b is hydrogen, halogen, or C _1-3 haloalkyl. In another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R _6b is halo or C _1-3 haloalkyl. In another embodiment, R _6b is halo (eg, Cl or F). In yet another embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R _6b is Cl. In another embodiment, R _6b is CF ₃ or CHF ₂ . According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R _6c is hydrogen or halogen. In one embodiment of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, R _6c is hydrogen. In one embodiment, R _6c is halo. In one embodiment, the compounds of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, R _6b and R _3c are independently halogen. In another embodiment, R _ab is halogen and R _6c is hydrogen.

[0125] This document also provides compounds of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein:

X представляет собой

R₂ представляет собой NH₂; R₃ представляет собой водород; R₄ представляет собой водород или C_1-3 метил; a R₅ представляет собой CF₃.Y represents

X represents

R ₂ is NH ₂ ; R ₃ is hydrogen; R ₄ is hydrogen or C _1-3 methyl; a R ₅ is CF ₃ .

[0126] According to some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, the compound is selected from the group consisting of compounds in Table 1 shown below, or a pharmaceutically acceptable salt thereof. salt.

Table 1 Exemplary compounds of the present invention. Salts of such compounds are also contemplated. See the examples section for the preparation of such compounds. Compounds for which preparation details are not explicitly described in the examples can be prepared by modifying preparation details for other compounds provided herein using methods generally known in the art.

[0127] In another embodiment, in accordance with some embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof:

R ₂ is selected from the group consisting of H, OH, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyclopropyl and -NHR, where R is selected from the group consisting of linear C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 hydroxyalkanoyl, C _1-6 cyanoalkyl, C _1-6 alkylamino, -(C ₁ - ₆ alkylenyl)]NH(CH ₃ )-(C _1-6 alkylenyl )]N(CH ₃ ) ₂ and -(C _1-3 alkylenyl)(3-7 membered heterocyclyl);

each of R ₃ and R ₄ is independently selected from the group consisting of H, NH ₂ , halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio , C _1-6 haloalkylthio and C _1-6 alkylamino;

R ₅ is selected from the group consisting of H, Cl, Br, I, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, C _1-6 haloalkylthio, C _1-6 alkylamino and C _3-7 cycloalkyl,

where at least two of R ₂ , R ₃ , R ₄ and R ₅ are different from H; or

R ₂ and R ₃ , R ₃ and R ₄ , or R ₄ and R ₅ , together with the atoms to which each is bonded, form C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl or C _6-14 aryl; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 haloalkoxy;

X is selected from the group consisting of NH ₂ , C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _3-7 cycloalkyl, 4-7 membered heterocyclyl and 4-7 membered heterocyclylamino; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl , C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 4-7 membered heterocyclyl; where two geminal substituents can be taken together to form C _3-7 spirocycloalkyl or 4-7 membered spiroheterocyclyl;

Y is selected from the group consisting of -LY ₁ or Y ₁ ;

Y ₁ is selected from the group consisting of H, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl , which is optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 dialkylamino substituent, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _6-14 aryl substituted with C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocyclyl, 4-10-membered heterocyclyl substituted with methyl, hydroxy and oxo;

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkyl;

L is selected from the group consisting of a bond, O, S and N(L ^a );

L ^a is selected from the group consisting of hydrogen and C _1-3 alkyl;

U is C(R _6a );

V is C(R _6b );

W is C(R _6c ) or N;

each of R _6a , R _6b and R _6c is independently selected from the group consisting of H, OH, NH ₂ , halo, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _{1 -6} alkyl substituted with 4-10 membered heterocyclyl substituent, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _1-6 haloalkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 α-membered heteroaryl and 4-10-membered heterocyclyl; and

n is selected from the group consisting of 0, 1 and 2.

[0128] It should be understood that, in accordance with embodiments of a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, when one of R ₂ and R ₃ , R ₃ and R ₄ , or R ₄ and R ₅ , together with the atoms to which they are each attached, form a ring, substituents which do not form a ring are defined above for formula (I).

[0129] In another aspect, the invention includes a compound of formula (IV):

or a pharmaceutically acceptable salt thereof;

where

R ₁ is an electrophilic fragment capable of forming a covalent bond with the cysteine residue at position 12 of the K-Ras G12C mutant protein;

X is selected from the group consisting of NH ₂ , C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _3-7 cycloalkyl, 4-7 membered heterocyclyl and 4-7 membered heterocyclylamino; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl , C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 4-7 membered heterocyclyl; where two geminal substituents can be taken together to form C _3-7 spirocycloalkyl or 4-7 membered spiroheterocyclyl;

Y is selected from the group consisting of -LY ₁ or Y ₁ ;

Y ₁ is selected from the group consisting of H, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl , which is optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 dialkylamino, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _6-14 aryl substituted with C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocyclyl, 4-10-membered heterocyclyl substituted with methyl, hydroxy and oxo;

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkyl;

L is selected from the group consisting of a bond, O, S and N(L ^a );

L ^a is selected from the group consisting of hydrogen and C _1-3 alkyl;

U is C(R _6a );

V is C(R _6b );

W is C(R _6c ) or N;

each of R _6a , R _6b and R _6c is independently selected from the group consisting of H, OH, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _{1 -6} alkyl substituted with 4-10 membered heterocyclyl substituent, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _1-6 haloalkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 α-membered heteroaryl and 4-10-membered heterocyclyl;

n is selected from the group consisting of 0, 1 and 2; and

R ₁₁ is selected from the group consisting of:

[0130] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is Y ₁ and Y ₁ is selected from the group consisting of from H, C _1-6 alkyl and C _1-6 haloalkyl.

[0131] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y ₁ is H.

[0132] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is -LY ₁ ; L is selected from the group consisting of O and N(L ^a ); L ^a is H; and Y ₁ is selected from the group consisting of C _1-6 alkyl, C _1-6 alkyl substituted with a methyl heterocyclyl substituent, and C _1-6 alkyl substituted with a C _1-6 dialkylamino substituent.

[0133] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y ₁ is monocyclic aryl or monocyclic heteroaryl.

[0134] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is -LY ₁ ; L is selected from the group consisting of O and N(L ^a ); L ^a is H; Y ₁ is selected from the group consisting of C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl which is optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 substituent dialkylamino, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, and 4-10 membered heterocyclyl substituted with methyl; and each Y ₁ a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo , hydroxy, NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy.

[0135] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is -LY ₁ ; L is N(L ^a ); L ^a is H; a Y ₁ is C _1-6 alkyl or C _1-6 alkyl substituted with C _1-6 dialkylamino substituent.

[0136] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is -LY ₁ ; L is O; Y ₁ is selected from the group consisting of C _1-6 alkyl substituted with 4-10 membered heterocyclyl which is optionally substituted with 1-4 substituents Y _1a , C _1-6 alkyl substituted with C _1-6 substituent dialkylamino, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, and 4-1 0-membered heterocyclyl substituted with methyl; and each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy, NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy.

[0137] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is -LY ₁ ; L is selected from the group consisting of O and N(L ^a ); L ^a is H; Y ₁ is C _1-6 alkyl substituted with a 4-10 membered methyl heterocyclyl substituent.

[0138] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is selected from the group consisting of:

и

and

[0139] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is:

или

or

В другом варианте осуществления соединения формулы (I), формулы (II), формулы (III) или формулы (IV), или его фармацевтически приемлемой соли, Y представляет собой

Еще в одном другом варианте осуществления соединения формулы (I), формулы (II), формулы (III) или формулы (IV), или его фармацевтически приемлемой соли, Y представляет собой

Еще в одном другом варианте осуществления соединения формулы (I), формулы (II), формулы (III) или формулы (IV), или его фармацевтически приемлемой соли, Y представляет собой

[0140] In one embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is

In another embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is

In yet another embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is

In yet another embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, Y is

[0141] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, R _6a is H.

[0142] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, R _6b is selected from the group consisting of H, halo, C _{1 -6} alkoxy, C _1-6 alkylsulfonyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, C _1-6 haloalkylthio, and 4-10 membered heterocyclyl.

[0143] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, R _6b is selected from the group consisting of H, halo, C _{1 -3} haloalkyl.

[0144] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, W is C(R _6c ) and R _6c is selected from group consisting of H and halogen.

[0145] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, W is C(R _6c ) and R _6c is halogen.

[0146] According to some embodiments of a compound of formula (I), formula (II), formula (III), formula (IV), or a pharmaceutically acceptable salt thereof, R _6a , R _6b and R _6c are independently selected from the group consisting of from monocyclic aryl and monocyclic heteroaryl.

[0147] According to some embodiments of a compound of formula (I), formula (II), formula (III), formula (IV), or a pharmaceutically acceptable salt thereof, X is C3-7 cycloalkyl, 4-7 membered heterocyclyl or 4-7 membered heterocyclylamino; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 haloalkyl and 4-7 membered heterocyclyl. In one embodiment of a compound of formula (I), formula (II), formula (III), formula (IV), or a pharmaceutically acceptable salt thereof, X is C _3-7 cycloalkyl or 4-7 membered heterocyclyl, each of which optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, C _1-6 alkyl and C _1-6 haloalkyl. In another embodiment of a compound of formula (I), formula (II), formula (III), formula (IV), or a pharmaceutically acceptable salt thereof, X is a piperazinyl or azetidinyl moiety, each optionally substituted with 1-4 substituents, wherein each substituent is independently selected from the group consisting of OH, NH ₂ , halo, cyano, C _1-6 alkyl and C _1-6 haloalkyl. In yet another embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, X is a piperazinyl moiety optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of halogen, cyano, C _1-3 alkyl and C _1-3 haloalkyl.

[0148] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, X is a 4-7 membered heterocyclyl.

[0149] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, X is a 4-10 membered heterocyclyl substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of cyano, C _1-6 alkyl, C _1-6 cyanoalkyl and C _1-6 haloalkyl.

[0150] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, X is selected from the group consisting of:

и

and

[0151] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, X is selected from the group consisting of:

и

and

[0152] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, X is selected from the group consisting of:

и

and

или

[0153] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, X is

or

[0154] In another embodiment of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, X is

[0155] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, X is

[0156] According to some embodiments of a compound of formula (IV) or a pharmaceutically acceptable salt thereof, R ₁₁ is

или

or

[0157] According to some embodiments of a compound of formula (IV) or a pharmaceutically acceptable salt thereof, R ₁₁ is:

,

или

,

or

[0158] According to some embodiments of a compound of formula (IV) or a pharmaceutically acceptable salt thereof, R ₁₁ is

[0159] According to some embodiments of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, n is 0.

[0160] According to some embodiments of a compound of formula (I) or formula (IV), or a pharmaceutically acceptable salt thereof, R ₁ is selected from the group consisting of:

и

and

where:

R ₁₂ is selected from the group consisting of C _1-6 alkanoyl, C _1-6 alkyl and C _1-6 alkylsulfonyl;

R ₁₃ is selected from the group consisting of H, C _1-6 alkyl and C _1-6 haloalkyl;

R _13a is halogen; and

R ₁₄ is halogen.

[0161] According to some embodiments of a compound of formula (I) or formula (IV), or a pharmaceutically acceptable salt thereof, R ₁ is selected from the group consisting of:

и

and

или

[0162] According to some embodiments of a compound of formula (I) or formula (IV), or a pharmaceutically acceptable salt thereof, R ₁ is

or

[0163] According to some embodiments of a compound of formula (I) or formula (IV), or a pharmaceutically acceptable salt thereof, R ₁ is

[0164] According to some embodiments of a compound of formula (I) or formula (IV), or a pharmaceutically acceptable salt thereof, R ₁ is

[0165] According to some embodiments of a compound of formula (I) or formula (IV), or a pharmaceutically acceptable salt thereof, R ₁ is

[0166] According to some embodiments of a compound of formula (II), or a pharmaceutically acceptable salt thereof, R ₇ is selected from the group consisting of H, cyano, and halo; and each of R ₈ and R ₉ is independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, cyano and halogen; where C _1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), an alkyl or arylsulfonate leaving group, C _1-6 alkanoylamino, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylsulfonylamino, C _6-12 dialkylamino and C _1-6 halogen alkoxy.

[0167] According to some embodiments of a compound of formula (II), or a pharmaceutically acceptable salt thereof, R ₇ and R ₈ together form a triple bond between the carbon atoms to which they are attached, or R ₇ and R ₈ together with the carbon atoms, with with which each of them is bound, form C _3-7 cycloalkenyl, optionally substituted with one or two halogen substituents; and R ₉ is selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, cyano and halogen; where C _1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: C _1-6 alkanoylamino, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylsulfonylamino, C _6-12 dialkylamino and C _{1 -6} halogen alkoxy.

[0168] According to some embodiments of a compound of formula (II), or a pharmaceutically acceptable salt thereof, R ₇ , R ₈ and R ₉ are each H.

[0169] According to some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt thereof, R ₁₀ is C(O)-R _10a and R _10a is oxiranil.

[0170] According to some embodiments of a compound of formula (III) or a pharmaceutically acceptable salt thereof, R ₁₀ is C(O)-R _10a and R _10a is aziridinyl.

[0171] According to some embodiments of formula (I), the compound has the formula selected from the group consisting of:

и

and

or a pharmaceutically acceptable salt thereof.

или

В одном варианте осуществления соединения формулы (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik) или (Il), или его фармацевтически приемлемой соли, Y представляет собой

. В одном варианте осуществления соединения формулы (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik) или (Il), или его фармацевтически приемлемой соли, Y представляет собой

. В одном варианте осуществления соединения формулы (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik) или (Il), или его фармацевтически приемлемой соли, Y представляет собой

. Еще в одном другом варианте осуществления соединения формулы (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik) или (Il), или его фармацевтически приемлемой соли, Y представляет собой

.[0172] In one embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik), or ( Il), or a pharmaceutically acceptable salt thereof, Y is

or

In one embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik) or (Il), or a pharmaceutically acceptable salt thereof, Y is

. In one embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik) or (Il), or a pharmaceutically acceptable salt thereof, Y is

. In one embodiment, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik) or (Il), or a pharmaceutically acceptable salt thereof, Y is

. In yet another embodiment, the compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), (Ik) or (Il ), or a pharmaceutically acceptable salt thereof, Y is

.

[0173] According to some embodiments of a compound of formula (I), the compound is of formula (Ia) or (Ic), or a pharmaceutically acceptable salt thereof.

[0174] According to some embodiments of a compound of formula (I), the compound is of formula (Ib) or (II), or a pharmaceutically acceptable salt thereof.

[0175] According to some embodiments of a compound of formula (I), the compound has formula (1a), or a pharmaceutically acceptable salt thereof.

[0176] According to some embodiments of a compound of formula (I), the compound is of formula (Ib), or a pharmaceutically acceptable salt thereof.

[0177] According to some embodiments of a compound of formula (I), the compound is of formula (Ic), or a pharmaceutically acceptable salt thereof.

[0178] According to some embodiments of a compound of formula (I), the compound has formula (II), or a pharmaceutically acceptable salt thereof.

[0179] According to some embodiments of a compound of formula (IV) or a pharmaceutically acceptable salt thereof, the compound is selected from the group consisting of:

and

or a pharmaceutically acceptable salt thereof.

[0180] According to some embodiments of a compound of formula (IV), the compound comprises a compound of formula (IVa), (IVb), (IVd), or (IVg), or a pharmaceutically acceptable salt thereof. According to some embodiments of a compound of formula (IV), the compound comprises a compound of formula (IVa) or (IVb), or a pharmaceutically acceptable salt thereof. According to some embodiments of a compound of formula (IV), the compound comprises a compound of formula (IVd) or (IVg), or a pharmaceutically acceptable salt thereof.

[0181] In one embodiment of a compound of formula (I), (II), (III) or (IV), the compound is a compound, or a pharmaceutically acceptable salt thereof, as set forth in Table 1 herein.

[0182] In another embodiment of a compound of formula (I), (II), (III) or (IV), the compound is a compound corresponding to compound 9, compound 17a, compound 17b, compound 18a, compound 18b, compound 19, compound 44, compound 83a, compound 83b, compound 83c, compound 83d, or compound 69, or a pharmaceutically acceptable salt thereof.

[0183] In one embodiment, the compound is compound 9. In one embodiment, the compound is compound 17a. In one embodiment, the compound is compound 17b. In one embodiment, the compound is compound 18a. In one embodiment, the compound is compound 18b. In one embodiment, the compound is compound 19. In one embodiment, the compound is compound 83a. In one embodiment, the compound is compound 83b. In one embodiment, the compound is compound 83c. In one embodiment, the compound is compound 83d. In one embodiment, the compound is compound 69.

[0184] According to some embodiments of formula (I), the compound is selected from the group consisting of compounds 1, 5, 7-10, 13-15, 17a, 17b, 18a, 18b, 19-33, 35, 40- 41, 43-45, 46a, 46b, 47-58, 59a, 59b, 60-61, 62a, 62b, 63a, 63b, 64a, 64b, 65, 66, 67a, 67b, 68a, 68b, 69-74, 75a, 75b, 76, 77, 78a, 78b, 79a, 79b, 80, 81a, 81b, 82a, 82b, 83a, 83b, 83c, 83d, 84a, 84b and 85-97 of Table 1, or its pharmaceutically acceptable salt. According to other embodiments of formula (I), the compound is selected from the group consisting of compounds 1, 5, 7-10, 13-15, 17a, 17b, 18a, 18b, 19-33, 35, 40-41, 43 -45, 46a, 46b and 47-54 of Table 1, or a pharmaceutically acceptable salt thereof. According to another embodiment of formula (I), the compound is selected from the group consisting of compounds 55-58, 59a, 59b, 60-61, 62a, 62b, 63a, 63b, 64a, 64b, 65, 66, 67a, 67b , 68a, 68b, 69-74, 75a, 75b, 76, 77, 78a, 78b, 79a, 79b, 80, 81a, 81b, 82a, 82b, 83a, 83b, 83c, 83d, 84a, 84b and 85- 97 of Table 1, or a pharmaceutically acceptable salt thereof.

[0185] Compounds of the invention (for example, compounds of formula (I), (II), (III) or (IV)) or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers and other stereoisometric forms which are defined, in terms of absolute stereochemistry, as (R)- or (S)- or as (D)- or (L)- for amino acids. Thus, embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (b)-isomers can be obtained using chiral synthons or chiral reagents, or separated using conventional techniques, for example , chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or decomposition of a racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0186] Embodiments of the present invention include all variants of rotamers and conformationally constrained states of the compound of the invention. Also included are atropisomers, which are stereoisomers resulting from steric hindrance of rotation around a single bond, when energy differences due to steric strain or other factors create a barrier to rotation that is high enough to allow individual conformers to be isolated. By way of example, some compounds of the invention may exist as mixtures of atropisomers or purified or enriched to a single atropisomer.

[0187] In some embodiments, the compound of formula (I) is a mixture of atropisomers. In other embodiments, the compound of formula (I) is a substantially purified atropisomer. In some embodiments, the compound of formula (I) is a substantially purified R-atropisomer. In some other embodiments, the compound of formula (I) is a substantially purified R-atropisomer.

SYNTHESIS OF RAS INHIBITORS

[0188] the Compounds of the present invention can be obtained in a number of ways, depicted in the illustrative synthesis reaction schemes shown and described below. Starting materials and reagents used in the preparation of these compounds are generally either available from commercial suppliers such as Aldrich Chemical Co. or prepared by methods known to those skilled in the art following the procedures given in references such as Fieser and Fieser's. Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vol. 1-40. The following synthetic reaction schemes are merely illustrative of some of the ways in which the compounds of the present invention can be synthesized, and various modifications of these synthetic reaction schemes may be made or contemplated by those skilled in the art with reference to the invention set forth herein.

[0189] For illustrative purposes, the reaction schemes below show synthetic routes for the compounds of the invention, as well as major intermediates. For a more detailed description of the individual reaction steps, see the example section below. Those skilled in the art will recognize that other synthetic routes may be used. Although some specific starting materials and reagents are illustrated in the schemes and discussed below, they can be replaced with other starting materials and reagents to provide a variety of derivatives or reaction conditions. In addition, many of the compounds obtained by the methods described below can be further modified in light of this invention using conventional chemistry methods well known to those skilled in the art.

[0190] Starting materials and intermediates of synthetic reaction schemes can be isolated and purified as needed using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0191] Unless otherwise indicated, the reactions described herein are preferably carried out under an inert atmosphere at atmospheric pressure over a reaction temperature range of from about -78°C to about 150°C, more preferably from about 0°C to about 125°C, and most preferably and conveniently at room temperature (or ambient temperature) or at about 20°C.

[0192] Some of the compounds in the following diagrams are illustrated with generic substituents; however, the person skilled in the art will immediately understand that the nature of the substituents can be varied to obtain various compounds provided in this invention. In addition, the reaction conditions are illustrative and alternative conditions are well known. The reaction sequences in the following examples are not intended to limit the scope of the invention as set forth in the claims.

[0193] Specialists in the art will be clear that the described chemical reactions can be easily adapted to obtain other compounds of the present invention. For example, the synthesis of non-exemplary compounds of the invention can be successfully carried out by modifications that are obvious to those skilled in the art, for example, by suitable protection of interfering groups, by using other suitable reagents known in the art other than those described, or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be understood as having applicability to the preparation of other compounds of the invention.

RAS INHIBITOR TREATMENT METHODS AND THEIR USE

[0194] The compounds of the present invention are useful as Ras inhibitors. In one aspect, the compounds of the present invention are useful as K-Ras inhibitors. In another aspect, the compounds of the present invention are useful as N-Ras inhibitors. In another aspect, the compounds of the present invention are useful as H-Ras inhibitors. Accordingly, in one embodiment, a method is provided for contacting a cell, such as an ex vivo cell, with a compound of the present invention, or a pharmaceutically acceptable salt thereof, to inhibit Ras activity (e.g., K-Ras, H-Ras, and/or N-Ras activities). ) in a cage. It should be understood that the therapeutic methods described herein may further include, in some embodiments, determining the presence or absence of a G12 Ras mutation prior to administering a compound described herein or a pharmaceutically acceptable salt thereof.

[0195] Further provided is a method for preventing, treating, or ameliorating a disease or condition susceptible to Ras inhibition (e.g., K-Ras, H-Ras, and/or N-Ras) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to of the present invention or a pharmaceutically acceptable salt thereof.

[0196] In one aspect, the present invention provides a method of preventing, treating, or ameliorating a disease or condition susceptible to K-Ras inhibition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0197] In one aspect, the present invention relates to a method of preventing, treating, or ameliorating a disease or condition susceptible to H-Ras inhibition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0198] In one aspect, the present invention relates to a method of preventing, treating, or ameliorating a disease or condition susceptible to N-Ras inhibition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0199] Also provided is a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0200] Also provided is a method for inhibiting Ras (e.g., K-Ras, H-Ras, and/or N-Ras) in a patient in need of therapy, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0201] In one aspect, the present invention provides a method for inhibiting K-Ras in a patient in need of therapy, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0202] In one aspect, the present invention relates to a method of inhibiting H-Ras in a patient in need of therapy, comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0203] In one aspect, the present invention provides a method for inhibiting N-Ras in a patient in need of therapy, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0204] Also provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Compounds of the invention, including pharmaceutical compositions containing such compounds, can be used with the methods described herein.

[0205] In embodiments, the present invention provides a method for inhibiting Ras-mediated cell signaling, comprising contacting a cell with a therapeutically effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof. Inhibition of Ras-mediated signaling can be assessed and demonstrated by a number of methods known in the art. Non-limiting examples include demonstrating (a) a decrease in the GTPase activity of Ras; (b) reducing the binding affinity of GTP or increasing the binding affinity of GDP; (c) increasing Kdiss. GTP or Kdiss reduction. GDP; (d) reducing the levels of signaling molecules after the Ras pathway, such as reducing the level of pMEK; and/or (e) reducing the binding of the Ras complex to downstream signaling molecules, including but not limited to Raf. Kits and commercially available assays can be used to determine one or more of the above.

[0206] Embodiments also provide methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, conditions associated with a G12C K-Ras mutation, a G12C H-Ras mutation, and/or a G12C N- Ras (eg cancer).

[0207] In some embodiments, a method is provided for treating a disorder in a subject in need thereof, said method comprising determining whether the subject has a G12C mutation in K-Ras, H-Ras, or N-Ras, and if the subject is determined to have the mutation G12C in K-Ras, H-Ras or N-Ras, administering to the subject a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof.

[0208] Mutations of G12C in K-Ras, H-Ras, or N-Ras have also been identified in hematological malignancies (eg, cancers that affect the blood, bone marrow, and/or lymph nodes). Accordingly, some embodiments relate to administering a described compound of the present invention, or a pharmaceutically acceptable salt thereof (eg, in the form of a pharmaceutical composition), to a patient in need of treatment for a hematologic malignancy. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the present compounds can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small cell lymphocytic lymphoma (MLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (OMOL) and/or other leukemias. In other embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are useful in the treatment of lymphomas such as all subtypes of Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0209] Determining whether a tumor or cancer contains a G12C mutation in K-Ras, H-Ras, or N-Ras can be performed by evaluating the nucleotide sequence encoding a K-Ras, H-Ras, or N-Ras protein by evaluating the amino acid sequence K-Ras, H-Ras, or N-Ras protein, or by characterizing a putative K-Ras, H-Ras, or N-Ras mutant protein. Wild type human K-Ras (eg accession number NP203524), H-Ras (eg accession number NP001123914) and N-Ras (eg accession number NP002515) sequences are known in the art.

[0210] Methods for detecting a mutation in a K-Ras, H-Ras, or N-Ras nucleotide sequence are known to those skilled in the art. These methods include, but are not limited to, restriction fragment length polymorphism analysis by polymerase chain reaction (PCR-RFLP), single-strand conformational polymorphism analysis by polymerase chain reaction (PCR-PSCR), real-time PCR analysis, PCR sequencing, mutant allele specific PCR amplification (CAMA) assay, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high resolution melt assay, and microarray assay. In some embodiments, samples are evaluated for G12C mutations in K-Ras, H-Ras, or N-Ras by real-time PCR. Real-time PCR uses fluorescent probes specific for the G12C mutation in K-Ras, H-Ras, or N-Ras. If the mutation is present, the probe binds and fluorescence is detected. In some embodiments, a G12C mutation in K-Ras, H-Ras, or N-Ras is identified using direct sequencing of specific regions (e.g., exon 2 and/or exon 3) in a K-Ras, H-Ras, or N-Ras gene. . This technique allows you to identify all possible mutations in the sequenced region.

[0211] Methods for detecting a mutation in a K-Ras, H-Ras, or N-Ras protein are known to those skilled in the art. These methods include, but are not limited to, detection of mutant K-Ras, H-Ras, or N-Ras with a binding agent (eg, antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing. Various samples can be used in methods for determining whether a tumor or cancer contains a G12C mutation in K-Ras, H-Ras, or N-Ras. In some embodiments, the sample is obtained from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor/cancerous sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed and paraffin-embedded sample. In some embodiments, the sample is processed to obtain a cell lysate. In some embodiments, the sample is processed to obtain DNA or RNA.

[0212] Embodiments also relate to a method of treating a hyperproliferative disorder in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the method relates to the treatment of cancer, such as acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, broechial tumors, Burkitt's lymphoma, carcinoid tumor, embryonic tumors, germ cell tumor, primary lymphoma, cervical cancer uterus, childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS ), embryonic tumors, CNS cancer, endometrial cancer, ependymoma, cancer esophagus, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous bone histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor , hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and mouth cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, latent-onset metastatic squamous cell carcinoma of the neck, median carcinoma, oropharyngeal cancer, multiple endocrine neoplasm syndrome, multiple myeloma/plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, multiples Malignant myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous bone histiocytoma and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer , skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymus cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, uncommon childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and virus-induced p ak. In some embodiments, said method relates to the treatment of a noncancerous hyperproliferative disorder, such as benign skin hyperplasia (eg, psoriasis), restenosis, or benign prostatic hyperplasia (BPH).

[0213] In certain specific embodiments, the invention relates to methods for treating lung cancers, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition containing them). In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung carcinoma, or large cell lung carcinoma. In other embodiments, the lung cancer is small cell lung cancer. Other cancers to be treated with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors, and undifferentiated carcinomas.

[0214] In some embodiments, the invention provides methods for inhibiting the activity of K-Ras, H-Ras, or N-Ras with G12C in a cell by contacting said cell with an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, sufficient to inhibit the activity K-Ras, H-Ras or N-Ras with G12C in the specified cell. In some embodiments, the invention provides methods for inhibiting K-Ras, H-Ras, or N-Ras activity with G12C in a tissue by contacting said tissue with an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, sufficient to inhibit K-Ras activity. , H-Ras or N-Ras with G12C in the specified tissue. In some embodiments, the invention provides methods for inhibiting K-Ras, H-Ras, or N-Ras activity with G12C in an organism by contacting said organism with an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, sufficient to inhibit K-Ras activity. , H-Ras or N-Ras with G12C in the specified organism. In some embodiments, the invention provides methods for inhibiting K-Ras, H-Ras, or N-Ras activity with G12C in an animal by contacting said animal with an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, sufficient to inhibit K-Ras activity. , H-Ras or N-Ras with G12C in the indicated animal. In some embodiments, the invention provides methods for inhibiting K-Ras, H-Ras, or N-Ras activity with G12C in a mammal by contacting said mammal with an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, sufficient to inhibit K-Ras activity. , H-Ras or N-Ras with G12C in the indicated mammal. In some embodiments, the invention provides methods for inhibiting K-Ras, H-Ras, or N-Ras activity with G12C in a human by contacting said human with an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, sufficient to inhibit K-Ras activity. , H-Ras or N-Ras with G12C in the indicated individual. In other embodiments, the present invention provides methods for treating a disease mediated by G12C K-Ras, H-Ras, or N-Ras activity in a subject in need of such treatment.

[0215] In some embodiments, the invention provides methods for treating cancer comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention. In some embodiments, the individual is a human. In some embodiments, administration is by the oral route. In some embodiments, administration is by injection. In some embodiments, the cancer is mediated by a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutation. In some embodiments, the cancer is mediated by a K-Ras G12C mutation. In some embodiments, the cancer is hemoblastosis, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma.

[0216] In some embodiments, the invention provides methods for regulating the activity of a mutant protein selected from the group consisting of K-Ras G12C, H-Ras G12C, and N-Ras G12C, comprising reacting the mutant protein with a compound of the present invention or a pharmaceutical formulation thereof. acceptable salt.

[0217] In some embodiments, the invention provides methods for inhibiting the proliferation of a cell population, comprising contacting the cell population with a compound of the present invention, or a pharmaceutically acceptable salt thereof. In some embodiments, proliferation inhibition is defined as a reduction in cell viability of a cell population.

[0218] In some embodiments, the invention provides methods for treating a disorder mediated by a mutation selected from the group consisting of K-Ras G12C, H-Ras G12C, and N-Ras G12C in an individual in need thereof, comprising determining whether the individual has mutation and, if the individual is determined to have the mutation, administering to the individual a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention. In some embodiments, the implementation of the violation is mediated by the mutation K-Ras G12C. In some embodiments, the disorder is cancer. In some embodiments, the cancer is hemoblastosis, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma.

[0219] In some embodiments, the invention provides methods for producing a labeled K-Ras G12C, H-Ras G12C, or N-Ras G12C mutant protein, comprising reacting the K-Ras G12C, H-Ras G12C, or N-Ras G12C mutant protein with a compound of the present invention, or a pharmaceutically acceptable salt thereof, to result in a labeled K-Ras G12C, H-Ras G12C or N-Ras G12C mutant protein.

[0220] In some embodiments, the invention provides methods for inhibiting tumor metastases, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0221] In some embodiments, the invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In some embodiments, the drug is formulated for oral administration. In some embodiments, the drug is formulated for injection. In some embodiments, the cancer is mediated by a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutation. In some embodiments, the cancer is mediated by a K-Ras G12C mutation. In some embodiments, the cancer is mediated by an H-Ras G12C mutation. In some embodiments, the cancer is mediated by an N-Ras G12C mutation. In some embodiments, the cancer is hemoblastosis, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastases.

[0222] In some embodiments, the invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition of the present invention for use in a method of therapeutic treatment of a human or animal body. In some embodiments, the invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition of the present invention for use in a method of treating cancer. In some embodiments, the cancer is mediated by a K-Ras G12C, H-Ras G12C, or N-Ras G12C mutation. In some embodiments, the cancer is mediated by a K-Ras G12C mutation. In some embodiments, the cancer is mediated by an H-Ras G12C mutation. In some embodiments, the cancer is mediated by an N-Ras G12C mutation. In some embodiments, the cancer is hemoblastosis, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the invention provides a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition of the present invention for use in a method for inhibiting tumor metastases.

[0223] Also provided herein are methods of treating lung cancer in a patient with lung cancer, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition containing him/her). In one embodiment, the lung cancer is non-small cell lung carcinoma (NSCLC). NSLCL can be, for example, adenocarcinoma, squamous cell carcinoma of the lung, or large cell carcinoma of the lung. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is glandular tumors, carcinoid tumors, or undifferentiated carcinomas. The lung cancer may be stage I or II lung cancer. In one embodiment, the lung cancer is stage III or IV lung cancer. Methods provided herein include administering the compound as lL therapy. In one embodiment, the lung cancer contains the G12C KRas mutation.

[0224] In addition, provided herein are methods for treating pancreatic cancer in a patient with pancreatic cancer, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the patient has previously been treated with radiation therapy and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is stage 0, I, or II cancer. In another embodiment, the pancreatic cancer is stage III or stage IV cancer. In one embodiment, the pancreatic cancer contains the G12C KRas mutation.

[0225] In addition, provided herein are methods for treating colon cancer in a patient with colon cancer, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the colon cancer is stage I or II cancer. In another embodiment, the colon cancer is stage III or stage IV cancer. In one embodiment, the colon cancer contains the G12C KRas mutation.

[0226] Also provided herein are methods for treating cancer mediated by the G12C KRas tumor agnostic mutation. In one embodiment of such methods, the method includes:

a. determining the absence or presence of a G12C KRas mutation in a sample taken from a patient with suspected diagnosed cancer; and

b. administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0227] In one embodiment of such methods, the patient is diagnosed with the cancer described herein. In another embodiment of such methods, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is taken prior to the administration of any therapy. In another such embodiment, the sample is taken prior to administration of a compound described herein, or a pharmaceutically acceptable salt thereof, and after administration of another chemotherapeutic agent. In another embodiment of such methods, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered as suggested herein (eg, orally).

DOSAGE AND ADMINISTRATION

[0228] The present invention provides pharmaceutical compositions or medicaments comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. .

[0229] Therefore, one embodiment includes a pharmaceutical composition containing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. An additional embodiment includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.

[0230] In one example, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the desired purity can be prepared by mixing with physiologically acceptable excipients, i.e. excipients that are non-toxic to recipients in the dosages and concentrations used, in the form of a dosage form at ambient temperature and at an appropriate pH. The pH of the formulation depends primarily on the particular application and concentration of the compound, but is typically in the range of about 3 to about 8. In one example, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is formulated in an acetate buffer at pH 5. In another embodiment, implementation of the connection of the present invention or its pharmaceutically acceptable salt are sterile. The compound of the present invention, or a pharmaceutically acceptable salt thereof, may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0231] The compositions are formulated, dosed and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular patient being treated, the clinical condition of the individual patient, the cause of the disorder, site of delivery of the agent, route of administration, schedule of administration, and other factors known to practitioners. The "therapeutically effective amount" of a compound of the present invention, or a pharmaceutically acceptable salt thereof, administered will be based on such factors and is the minimum amount necessary to inhibit K-Ras, H-Ras and/or N-Ras activity. Typically, such an amount may be below the amount that is toxic to normal cells or the patient as a whole.

[0232] The pharmaceutical composition (or composition) for use can be packaged in a number of ways depending on the method used to administer the drug. In general, the dispensing article comprises a container containing a pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident device to prevent inadvertent access to the contents. container. In addition, the container may have a label describing the contents of the container. The label may also contain appropriate warnings.

[0233] Sustained release formulations can be obtained. Suitable sustained release formulations include semi-permeable matrices of solid hydrophobic polymers containing a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, which are in the form of molded articles such as films or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g. poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene vinyl acetate, degradable copolymers of lactic acid and glycolic acids such as LUPRON DEPOT™ (injectable microspheres consisting of a copolymer of lactic acid and glycolic acid and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0234] The dose for treating human patients may be in the range of about 0.01 mg to about 1000 mg of a compound of the present invention, or a pharmaceutically acceptable salt thereof. For example, in the treatment of adults, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that are used in some embodiments. Typical dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. The dose may be administered once daily (r/s), twice daily (d/s), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxic factors can influence the dosage and administration schedule. When administered orally, the pill, capsule or tablet can be taken once a day or more often for a certain period of time. The scheme can be repeated over a number of cycles of therapy.

[0235] A therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, may be administered by any suitable route, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, as well as, if necessary, local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal or subcutaneous administration.

[0236] A therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, may be administered in any convenient administration form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, plasters, etc. Such compositions may contain conventional pharmaceutical ingredients such as diluents, carriers, pH modifiers, sweeteners, bulking agents and additional active agents.

[0237] A typical formulation is prepared by mixing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and an excipient. Suitable excipients include carriers (eg microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (eg sodium dodecyl sulfate, polyoxysorbitan oleate), binders (eg polyvinylpyrrolidone), synthetic and natural polymers (eg, albumin), stabilizers (eg, antioxidants, eg, ascorbic acid), colorants (eg, inorganic pigments, eg, iron oxides), and flavor and/or odor correctors, and are well known to those skilled in the art and described in detail. , for example, in Ansel, H. C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, R. C, Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. Formulations may also contain one or more buffers, surfactants, lubricants, suspending agents, preservatives, coating agents, glidants, processing aids, sweeteners , flavoring agents, flavoring agents, diluents, or other known additives to provide a good appearance of a drug (ie, a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (ie, a drug).

[0238] In certain embodiments, oral pharmaceutical preparations are prepared by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules after adding, if necessary, suitable auxiliary ingredients for the production of tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrants are optionally added. Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0239] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coatings. In specific embodiments, concentrated sugar solutions are used to coat the dosage form. The sugar solutions optionally contain additional components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes and/or pigments are also optionally added to the coatings for identification purposes. In addition, dyes and/or pigments are optionally used to indicate different combinations of active compound doses.

[0240] In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated in other oral dosage forms. Oral dosage forms include hard capsules made from gelatin, as well as soft, sealed capsules made from gelatin and a plasticizer such as glycerol or sorbitol. In specific embodiments, hard capsules may contain the active ingredients in admixture with one or more excipients. Fillers include, by way of example only, lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In other embodiments, soft capsules contain one or more active compounds that are dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more of fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers are optionally added.

[0241] In other embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges or gels. In other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (eg, in ampoules) or in multi-dose containers. Preservatives are optionally added to formulations for injection. In other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Parenteral injectable formulations optionally contain adjuvants such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical compositions for parenteral administration contain aqueous solutions of the active compounds in water-soluble form, in additional embodiments, suspensions of the compound of the present invention, or a pharmaceutically acceptable salt thereof, are prepared as appropriate oily injection suspensions. Suitable lipophilic diluents or carriers for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, the implementation of aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compounds to ensure that highly concentrated solutions are obtained. Alternatively, the active ingredient may be in the form of a powder for mixing with a suitable vehicle, such as sterile, pyrogen-free water, prior to use.

[0242] In certain embodiments, the pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable excipients and ingredients that facilitate the processing of the active compounds into formulations that can be used for pharmaceutical purposes. The proper composition depends on the chosen route of administration. Optionally, any suitable pharmaceutically acceptable techniques and excipients are used. Pharmaceutical compositions containing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, are manufactured in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, panning, elutriating, emulsifying, encapsulating, encapsulating, or compressing methods.

[0243] Pharmaceutical compositions contain at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof described herein as an active ingredient. The active ingredient is in free acid or free base form, or in the form of a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds provided herein. In addition, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. It is assumed that the solvated forms presented in this document, the compounds are also described in this document. In addition, the pharmaceutical compositions optionally contain other medical or pharmaceutical agents, excipients such as preservative, stabilizing, wetting or emulsifying agents, solubilizing agents, salts for regulating osmotic pressure, buffers and/or other therapeutically relevant substances.

[0244] Methods for preparing compositions containing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, as described herein, include mixing a compound of the present invention, or a pharmaceutically acceptable salt thereof, with one or more inert, pharmaceutically acceptable excipients to form a solid , semi-solid or liquid substance. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions containing a compound, or a solution containing liposomes, micelles, or nanoparticles containing a compound described herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The form of the pharmaceutical compositions described herein includes liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to use, or emulsions. These compositions also optionally contain minor amounts of non-toxic adjuvants such as wetting or emulsifying agents, pH buffering agents, and the like.

[0245] In some embodiments, a pharmaceutical composition containing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, is illustratively in the form of a liquid in which the agents are in solution, in suspension, or both. Typically, when the composition is administered as a solution or suspension, the first part of the agent is in solution and the second part of the agent is in particulate form, in suspension in a liquid matrix. In some embodiments, the implementation of the liquid composition includes a gel composition. In other embodiments, the liquid composition is aqueous.

[0246] In certain embodiments, the aqueous suspensions used contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulose-based polymers, such as hydroxypropylmethylcellulose, and water-soluble polymers, such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain a mucoadhesive polymer selected from, for example, carboxymethyl cellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate, and dextran.

[0247] Suitable pharmaceutical compositions also optionally contain solubilizing agents to aid in the solubility of a compound of the present invention or a pharmaceutically acceptable salt thereof. The term "solubilizing agent" generally includes agents that result in the formation of a micellar solution or a true solution of the agent. Certain acceptable non-ionic excipients, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmologically acceptable glycols, polyglycols, such as polyethylene glycol 400, or glycol ethers.

[0248] In addition, applicable pharmaceutical compositions optionally contain one or more pH-adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount necessary to maintain the pH of the composition within an acceptable range.

[0249] In addition, applicable compositions also optionally contain one or more salts in an amount necessary to bring the osmolality of the composition to an acceptable range. Such salts include those containing sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0250] Other applicable pharmaceutical compositions optionally contain one or more preservatives to inhibit the activity of microorganisms. Suitable preservatives include mercury containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0251] Other applicable compositions contain one or more surfactants to improve physical stability or for other purposes. Suitable surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, for example octoxynol 10, octoxynol 40.

[0252] Other applicable compositions contain one or more antioxidants to improve, if necessary, chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulphite.

[0253] In certain embodiments, aqueous suspension based compositions are packaged in single dose non-resealable containers. Alternatively, multi-dose, resealable containers are used, in which case the composition typically contains a preservative.

[0254] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or excipients applicable in the context of this document. 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, such as semi-permeable matrices of solid hydrophobic polymers containing a therapeutic agent. Various sustained release materials are applicable within the context of this document. In some embodiments, the slow release capsules provide a release of the compounds for several weeks to more than 100 days.

[0255] The invention further provides veterinary compositions comprising at least one active ingredient as defined above with a veterinary adjuvant. Veterinary excipients are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials that are otherwise inert or veterinary acceptable and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other route desired.

COMBINATION THERAPY

[0256] The compounds of the present invention or their pharmaceutically acceptable salts can be used alone or in combination with other therapeutic agents for the treatment of the disease or disorder described herein. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activity to the compound of the present invention, or a pharmaceutically acceptable salt thereof, such that they do not interfere with each other. Combination therapy can provide "synergism" and be "synergistic", i.e. the effect achieved by the combined use of active ingredients exceeds the sum of the effects obtained as a result of the use of these compounds separately.

[0257] Combination therapy can be used as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered over two or more administrations. Combination administration includes co-administration using separate formulations or a single pharmaceutical formulation and sequential administration in any order, and it is preferable that there is a period of time when both (or all) active agents simultaneously exhibit their biological activity.

[0258] Thus, the combination therapy in accordance with the present invention includes the introduction of the compounds of the present invention or its pharmaceutically acceptable salt and the use of at least one other method of treatment. The amounts of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and other(their) pharmaceutically active(s) agent(s) and the relative time of administration are chosen to achieve the desired combined therapeutic effect.

[0259] In various embodiments of this method, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met-kinase inhibitor , an SRC kinase family inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal regulated kinase (ERK) inhibitor, a topoisomerase inhibitor (such as irinotecan, or such as etoposide, or such as docetaxel), a taxane (such as an agent that exerts exposure to microtubules, including paclitaxel and docetaxel), an antimetabolite (such as 5-FU or such as gemcitabine), or an alkylating agent (such as cisplatin or such cyclophosphamide), or a taxane.

[0260] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor such as erlotinib or such as afatinib. In some embodiments, the additional therapeutic agent is iressa. In some embodiments, the additional therapeutic agent is a monoclonal antibody such as cetuximab (Erbitux) or panitumumab (Vectibix). In some embodiments, the GFR inhibitor is a dual or pan-HER inhibitor. In other embodiments, the additional therapeutic agent is a phosphatidylinositol 3-kinase (PI3K) inhibitor such as GDC-0941, MLN1117, BYL719 (Alpelisib), or VKM120 (Buparlisib). GDC-0941 refers to 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine or its salt (for example, bismesylate salt).

[0261] In other embodiments, the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor. For example, in some embodiments, the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541. In other embodiments, the additional therapeutic agent is IGOSI-906 (linzitinib), BMS-754807, or in other embodiments, the additional therapeutic agent is an IGF1R-specific neutralizing monoclonal antibody such as AMG-479 (ganitumab), CP-751,871 ( figitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (robatumumab).

[0262] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor. In some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, lestaurtinib, momelotinib, pacritinib, ruxolitinib, or TG101348.

[0263] In some other embodiments, the additional therapeutic agent is an anti-glypican 3 antibody. In some embodiments, the anti-glypican 3 antibody is corituzumab.

[0264] In some other embodiments, the additional therapeutic agent is an antibody drug conjugate (ADC). In some embodiments, the ADC is polatuzumab vedotin, RG7986, RG7882, RG6109, or R07172369.

[0265] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist. In some embodiments, the MDM2 antagonist is idazanutlin.

[0266] In some other embodiments, the additional therapeutic agent is an anti-CD40 agonist antibody. In some embodiments, the CD40 agonist antibody is selicrelumab (RG7876).

[0267] In some other embodiments, the additional therapeutic agent is a bispecific antibody. In some embodiments, the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP-DR5), RG6160, RG6026, ERY974, or anti-HER2/CD3.

[0268] In some other embodiments, the additional therapeutic agent is a targeted immunocytokine. In some embodiments, the targeted immunocytokine is RG7813 or RG7461.

[0269] In some other embodiments, the additional therapeutic agent is an antibody that targets colony stimulating factor 1 receptor (CSF-1R). In some embodiments, the anti-CSF-1R antibody is emactuzumab.

[0270] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine. In some embodiments, the personalized cancer vaccine is RG6180.

[0271] In some other embodiments, the additional therapeutic agent is a BET (bromodomain and extraterminal family) (BRD2/3/4/T) protein inhibitor. In some embodiments, the BET inhibitor is RG6146.

[0272] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT. In some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0273] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor degrader (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545).

[0274] In some other embodiments, the additional therapeutic agent is a MET kinase inhibitor, such as crizotinib, tivantinib, AMG337, cabozantinib, or foretinib. In other embodiments, the additional therapeutic agent is an anti-MET neutralizing monoclinal antibody, such as onartuzumab.

[0275] In other embodiments, the additional therapeutic agent is an inhibitor of the SRC family of non-receptor tyrosine kinases. For example, in some embodiments, the additional therapeutic agent is a subfamily inhibitor of the SRC family of non-receptor tyrosine kinases. Exemplary inhibitors in this direction include dasatinib. Other examples along these lines include ponatinib, saracatinib, and bosutinib.

[0276] In other embodiments, the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is trametinib, selumetinib, Cotellic® (cobimetinib), PD0325901, or RO5126766. In other embodiments, the MEK inhibitor is GSK-1120212, also known as trametinib.

[0277] In other embodiments, the additional therapeutic agent is an extracellular signal regulated kinase (ERK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is SCH722984 or GDC-0994.

[0278] In other embodiments, the protein kinase inhibitor is tazelisib, ipatasertib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, afatinib, axitinib, bevacizumab, bosutinib, cetuximab, crizotinib, dasatinib, erlotinib , fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, ruxolitinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, or vemurafenib. In other embodiments, the additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is irinotecan. In other embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include taxol and docetaxel.

[0279] In addition to the above additional therapeutic agents, other chemotherapeutic agents currently known in the art can be used with the compounds of the invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormonal agents, angiogenesis inhibitors, and antiandrogens.

[0280] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Glivec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as many other chemotherapeutic agents. . Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (Cytoxan™); alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbokwon, meturedopa and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphasine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterin, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carcinophyllin, Casodex™, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin , esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, cinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprin, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enocytabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; adrenal depressants such as aminoglutethimide, mitotane, trilostane; a folic acid supplement such as frolinic acid; aceglatone; aldofosfamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraksat; defofamine; demecolcin; diaziquon; elfornitine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pyrarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide K; razoxane; sisofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; hacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes such as paclitaxel (Taxol™, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (Taxotere™; Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamycins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included as suitable chemotherapeutic cell conditioners are antihormonal agents whose action is to regulate or inhibit the action of hormones on tumors, such as antiestrogen, including, for example, tamoxifen (Nolvadex™, raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen , trioxifene, keoxifene, LY 117018, onapristone and toremifene (Fareston); antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbin; novantrone; teniposide; daunomycin; aminopterin; Xeloda®; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000 and difluoromethylornithine (DMFO).If necessary, the compounds or pharmaceutical compositions of the present invention can be used in combination with the usual prop researched anticancer drugs such as Herceptin®, Avastin®, Gazyvara®, Tecentriq®, Alecensa®, Perjeta®, Venclexta™, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, Avicin, Abagovomab, Acridine carboxamide, adecatumumab, 17-N-allyamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafid, anthracendione, anti-CD22 immunotoxins, antineoplastic agents, antitumor herbs, apaziquone, atiprimod, azathioprine, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, butionine sulfoximine, CBV (chemotherapy), caliculin, non-cell cycle specific antineoplastic agents, dichloroacetic acid, discodermolide, elsamitrucin, enocytabine, epothilone, eribulin, everolimus, exatecan, ferginolind, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, lanquidar, larotaxel, lenalidomide, lucanton, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitor, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, stanford V, swinesonine, thalaporfin, tarikvidar, tegafur -uracil, temodar, tezetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxcitabine, uramustine, vadimesan, vinflunine, ZD6126 or zosuquidar.

[0281] The exact method of administering the compound and the additional therapeutic agent will be apparent to those skilled in the art. In some exemplary embodiments, the compound and the additional therapeutic agent are co-administered. In other embodiments, the compound and the additional therapeutic agent are administered separately.

[0282] In some embodiments, the compound and the additional therapeutic agent are administered with the second agent simultaneously or separately. Such combination administration may include simultaneous administration of the two agents in a single dosage form, simultaneous administration in separate dosage forms, and separate administration. This means that the compound and any of the additional therapeutic agents described herein can be mixed together in a single dosage form and administered simultaneously. Alternatively, the compound and any of the additional therapeutic agents described herein may be administered simultaneously, with both agents in separate formulations. In another alternative, you can enter the connection, and immediately after it - any of the additional therapeutic agents described in this document, or vice versa. In some embodiments of a particular administration protocol, the compound and any of the additional therapeutic agents described herein are administered at intervals of several minutes, or several hours, or several days.

FINISHED GOODS

[0283] In another embodiment, a finished product or "kit" containing materials used to treat the diseases and disorders described above is provided. In one embodiment, the kit contains a container containing a compound of the present invention or a pharmaceutically acceptable salt thereof. The kit may further include a label or package insert on or associated with it. The term "package insert" is used to refer to instructions commonly included in commercial packages of therapeutic products that contain information about the indications, use, dosage, administration, contraindications and/or warnings regarding the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container can be made from a number of materials such as glass or plastic. The container may contain a compound of the present invention, or a pharmaceutically acceptable salt or formulation thereof, that is effective for treating a medical condition and may have a sterile inlet (for example, the container may be an intravenous solution sachet or a vial having a pierceable stopper). hypodermic needle for injection). At least one active ingredient in the composition is a compound of the present invention or a pharmaceutically acceptable salt thereof. Alternatively or additionally, the finished article may further comprise a second container containing a pharmaceutical diluent such as bacteriostatic water for injection (BVDI), phosphate buffered saline, Ringer's solution, or dextrose solution. It may also contain other materials required from a commercial and user point of view, including other buffers, diluents, filters, needles and syringes.

[0284] In another embodiment, the kits are suitable for delivering solid oral forms of a compound of the present invention, or a pharmaceutically acceptable salt thereof, such as tablets or capsules. Such a kit may contain a number of unit dosages. An example of such a kit is the "blister pack". Blister packs are well known in the packaging industry and are widely used in the packaging of pharmaceutical unit dosage forms.

ADDITIONAL IMPLEMENTATION OPTIONS

[0285] Additional embodiments are given below.

[0286] Embodiment 1: Compound of Formula (I):

or a pharmaceutically acceptable salt thereof; where

R ₁ is a chtectrophilic fragment capable of forming a covalent bond with the cysteine residue at position 12 of the K-Ras G12C mutant protein;

R ₂ is selected from the group consisting of H, OH, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyclopropyl and -NHR, where R is selected from the group consisting of C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkanoyl, C _1-6 hydroxyalkanoyl, C _1-6 cyanoalkyl C _1-6 alkylamino, - (C _1-6 alkylenyl) NH (CH ₃ ) - (C _1-6 alkylenyl) N [ (CH ₃ ) ₂ and -(C _1-3 alkylenyl)(3-7 membered heterocyclyl);

each of R ₃ and R ₄ is independently selected from the group consisting of H, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio , C _1-6 haloalkylthio, C _1-6 alkylamino and cyclopropyl;

R ₅ is selected from the group consisting of H, NH ₂ , halogen, C _1-6 alkyl, C _-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, C _1-6 haloalkylthio, C _1-6 alkylamino and C _3-7 cycloalkyl,

where at least one of R ₂ , R ₃ , R ₄ and R ₅ is different from H; or

R ₂ and R ₃ , R ₃ and R ₄ , or R ₄ and R ₅ , together with the atoms to which each is bonded, form C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-14 aryl or 5-10 membered heteroaryl; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy ;

X is selected from the group consisting of NH ₂ , C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _3-7 cycloalkyl, 4-7 membered heterocyclyl and 4-7 membered heterocyclylamino; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl , C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 4-7 membered heterocyclyl; where two geminal substituents can be taken together to form C _3-7 spirocycloalkyl or 4-7 membered spiroheterocyclyl;

Y is selected from the group consisting of -LY ₁ or Y ₁ ;

Y ₁ is selected from the group consisting of H, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl , which is optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 dialkylamino substituent, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _6-14 aryl substituted with C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocyclyl, 4-10-membered heterocyclyl substituted with methyl, hydroxy and oxo;

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy;

L is selected from the group consisting of a bond, O, S and N(L ^a );

L ^a is selected from the group consisting of hydrogen and C _1-3 alkyl;

U is C(R _6a );

V is C(R _cb );

W is C(R _6c ) or N;

each of R _6a , R _6b and R _6c is independently selected from the group consisting of H, OH, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _{1 -6} alkyl substituted with 4-10 membered heterocyclyl substituent, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _1-6 haloalkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 α-membered heteroaryl and 4-10-membered heterocyclyl; and

n is selected from the group consisting of 0, 1 and 2.

[0287] Embodiment 2: The compound of Embodiment 1 having formula (II):

or a pharmaceutically acceptable salt thereof;

where

R ₂ is selected from the group consisting of H, OH, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyclopropyl and -NHR, where R is selected from the group consisting of C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkanoyl, C _1-6 hydroxyalkanoyl, C _1-6 cyanoalkyl, C _1-6 alkylamino, - (C _1-6 alkylenyl) NH (CH ₃ ) - (C _1-6 alkyllenyl) N (CH ₃ ) ₂ and -(C _1-3 alkylenyl)(3-7 membered heterocyclyl);

each of R ₃ and R ₄ is independently selected from the group consisting of H, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio , C _1-6 haloalkylthio, C _1-6 alkylamino and cyclopropyl;

R ₅ is selected from the group consisting of H, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, C _1-6 haloalkylthio , C _1-6 alkylamino and C _3-7 cycloalkyl,

where at least one of R ₂ , R ₃ , R ₄ and R ₅ is different from H; or

R ₂ and R ₃ , R ₃ and R ₄ , or R ₄ and R ₅ , together with the atoms to which each is bonded, form C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-14 aryl or 5-10 membered heteroaryl; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy ;

R ₇ is selected from the group consisting of H, cyano and halo; and each of R ₈ and R ₉ is independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, cyano and halogen; where C _1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), an alkyl or arylsulfonate leaving group, C _1-6 alkanoylamino, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylsulfonylamino, C _6-12 dialkylamino and C _1-6 haloalkoxy;

or

R ₇ and R ₈ together form a triple bond between the carbon atoms to which they are attached, or R ₇ and Rs together with the carbon atoms to which they are each attached form a C _3-7 cycloalkenyl optionally substituted with one or two halogen substituents ; and R ₉ is selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, cyano and halogen; where C _1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: C _1-6 alkanoylamino, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylsulfonylamino, C _6-12 dialkylamino and C _{1 -6} haloalkoxy;

X is selected from the group consisting of NH ₂ , C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _3-7 cycloalkyl, 4-7 membered heterocyclyl and 4-7 membered heterocyclylamino;

each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl , C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 4-7 membered heterocyclyl; where two geminal substituents can be taken together to form C _3-7 spirocycloalkyl or 4-7 membered spiroheterocyclyl;

Y is selected from the group consisting of -LY ₁ or Y ₁ ;

Y ₁ is selected from the group consisting of H, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl , which is optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 dialkylamino substituent, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _6-14 aryl substituted with C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocyclyl, 4-10-membered heterocyclyl substituted with methyl, hydroxy and oxo;

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy;

L is selected from the group consisting of a bond, O, S and N(L ^a );

L ^a is selected from the group consisting of hydrogen and C _1-3 alkyl;

U is C(R _6a );

V is C(R _6b );

W is C(R _6c ) or N;

each of R _6a , R _6b and R _6c is independently selected from the group consisting of H, OH, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _{1 -6} alkyl substituted with 4-10 membered heterocyclyl substituent, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _1-6 haloalkylthio, C _1-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 α-membered heteroaryl and 4-10-membered heterocyclyl; and

n is selected from the group consisting of 0, 1 and 2.

[0288] Embodiment 3: The compound of Embodiment 1 having formula (III):

or a pharmaceutically acceptable salt thereof; where

R ₂ is selected from the group consisting of H, OH, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyclopropyl and -NHR, where R is selected from the group consisting of C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkanoyl, C _1-6 hydroxyalkanoyl, C _1-6 cyanoalkyl, C _1-6 alkylamino, - (C _1-6 alkylenyl) NH (CH ₃ ) - (C _1-6 alkylenyl) N (CH ₃ ) ₂ and -(C _1-3 alkylenyl)(3-7 membered heterocyclyl);

each of R ₃ and R ₄ is independently selected from the group consisting of H, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio , C _1-6 haloalkylthio, C _1-6 alkylamino and cyclopropyl;

R ₅ is selected from the group consisting of H, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, C _1-6 haloalkylthio , C _1-6 alkylamino and C _3-7 cycloalkyl,

where at least one of R ₂ , R ₃ , R ₄ and R ₅ is different from H; or

R ₂ and R ₃ , R ₃ and R ₄ , or R ₄ and R ₅ , together with the atoms to which each is bonded, form C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C _6-14 aryl or 5-10 membered heteroaryl; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy ;

R ₁₀ is selected from the group consisting of R _10a and -C(O)-R _10a ;

R _10a is selected from the group consisting of oxiranil and aziridinyl;

X is selected from the group consisting of NH ₂ , C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _3-7 cycloalkyl, 4-7 membered heterocyclyl and 4-7 membered heterocyclylamino; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl , C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 4-7 membered heterocyclyl; where two geminal substituents can be taken together to form C _3-7 spirocycloalkyl or 4-7 membered spiroheterocyclyl;

Y is selected from the group consisting of -LY ₁ or Y ₁ ;

Y ₁ is selected from the group consisting of H, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl , which is optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 dialkylamino substituent, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _6-14 aryl substituted with C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocyclyl, 4-10-membered heterocyclyl substituted with methyl, hydroxy and oxo;

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy;

L is selected from the group consisting of a bond, O, S and N(L ^a );

L ^a is selected from the group consisting of hydrogen and C _1-3 alkyl;

U is C(R _6a );

V is C(R _6b );

W is C(R _6c ) or N;

each of R _6a , R _6b and R _6c is independently selected from the group consisting of H, OH, NH ₂ , halogen, cyano, carbamoyl, C _1-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _{1 -6} alkyl substituted with 4-10 membered heterocyclyl substituent, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _1-6 haloalkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 α-membered heteroaryl and 4-10-membered heterocyclyl; and

n is selected from the group consisting of 0, 1 and 2.

[0289] Embodiment 4: The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from the group consisting of NH ₂ and -NHR; a R is C _1-6 alkyl.

[0290] Embodiment 5: The compound of any one of Embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein R ₂ is NH ₂ .

[0291] Embodiment 6: The compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R ₃ and R ₄ are independently selected from the group consisting of H, halo, C _1-6 alkyl, C _1-6 haloalkyl and cyclopropyl.

[0292] Embodiment 7: The compound of any one of Embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein R ₅ is selected from the group consisting of H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6} haloalkoxy, C _1-6 alkylamino and C _3-7 cycloalkyl.

[0293] Embodiment 8: The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is C _1-3 haloalkyl.

[0294] Embodiment 9: The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein R ₅ is CF ₃ and R ₂ is NH ₂ .

[0295] Embodiment 10: The compound of any one of Embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein R ₅ is cyclopropyl.

[0296] Embodiment 11: The compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein R ₄ and R ₅ , together with the atoms to which each is bonded, form a C _3-7 cycloalkyl, 3- 7-membered heterocycloalkyl, C _6-14 aryl or 5-10 membered heteroaryl; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy .

[0297] Embodiment 12: The compound of Embodiment 11, or a pharmaceutically acceptable salt thereof, wherein R ₄ and R ₅ , together with the atoms to which each is bonded, form a C _6-14 aryl that is optionally substituted with 1-4 substituents where each substituent is independently selected from the group consisting of OH, NH ₂ , halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, and C _1-3 haloalkoxy.

[0298] Embodiment 13: The compound of Embodiment 12, or a pharmaceutically acceptable salt thereof, wherein R ₄ and R ₅ , together with the atoms to which each is bonded, form a C ₆ aryl that is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, and C _1-3 haloalkoxy.

[0299] Embodiment 14: The compound of Embodiment 13, or a pharmaceutically acceptable salt thereof, wherein C ₆ aryl is unsubstituted.

[0300] Embodiment 15: The compound of Embodiment 13, or a pharmaceutically acceptable salt thereof, wherein C ₆ aryl is substituted with 1-4 substituents, where each substituent is independently halogen.

[0301] Embodiment 16: The compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein:

R ₂ is selected from the group consisting of H, OH, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyclopropyl and -NHR, where R is selected from the group consisting of linear C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 hydroxyalkanoyl, C _1-6 cyanoalkyl, C _1-6 alkylamino, -(C _1-6 alkylenyl) NH (CH ₃ )-(C _1-6 alkylenyl) N(CH ₃ ) ₂ and -(C _1-3 alkylenyl)(3-7 membered heterocyclyl);

each of R ₃ and R ₄ is independently selected from the group consisting of H, NH ₂ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio , C _1-6 haloalkylthio and C _1-6 alkylamino;

R ₅ is selected from the group consisting of H, Cl, Br, I, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, C _1-6 haloalkylthio, C _1-6 alkylamino and C _3-7 cycloalkyl,

where at least two of R ₂ , R ₃ , R ₄ and R ₅ are different from H; or

R ₂ and R ₃ , R ₃ and R ₄ , or R ₄ and R ₅ , together with the atoms to which each is bonded, form C _3-7 cycloalkyl, 3-7 membered heterocycloalkyl or C _6-14 aryl; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, C _1-3 alkyl, C _1-3 haloalkyl and C _1-3 haloalkoxy;

X is selected from the group consisting of NH ₂ , C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _3-7 cycloalkyl, 4-7 membered heterocyclyl and 4-7 membered heterocyclylamino; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl , C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 4-7 membered heterocyclyl; where two geminal substituents can be taken together to form C _3-7 spirocycloalkyl or 4-7 membered spiroheterocyclyl;

Y is selected from the group consisting of -LY ₁ or Y ₁ ;

Y ₁ is selected from the group consisting of H, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl , which is optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 dialkylamino substituent, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _6-14 aryl substituted with C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 membered heteroaryl, 4 -10-membered heterocyclyl, 4-10-membered heterocyclyl substituted with methyl, hydroxy and oxo;

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy;

L is selected from the group consisting of a bond, O, S and N(L ^a );

L ^a is selected from the group consisting of hydrogen and C _1-3 alkyl;

U is C(R _6a );

V is C(R _6b );

W is C(R _6c ) or N;

each of R _6a , R _6b and R _6c is independently selected from the group consisting of H, OH, NH ₂ , halogen, cyano, carbamoyl, C _1-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _{1 -6} alkyl substituted with 4-10 membered heterocyclyl substituent, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _1-6 haloalkylthio, C _1-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 α-membered heteroaryl and 4-10-membered heterocyclyl; and

n is selected from the group consisting of 0, 1 and 2.

[0302] Embodiment 17: Compound of formula (I) having formula (IV):

or a pharmaceutically acceptable salt thereof;

where

R ₁ is an electrophilic fragment capable of forming a covalent bond with the cysteine residue at position 12 of the K-Ras G12C mutant protein;

X is selected from the group consisting of NH ₂ , C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _3-7 cycloalkyl, 4-7 membered heterocyclyl and 4-7 membered heterocyclylamino; each of which is optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of OH, NH ₂ , halogen, cyano, carboxy, carbamoyl, C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and 4-7 membered heterocyclyl; where two geminal substituents can be taken together to form C _3-7 spirocycloalkyl or 4-7 membered spiroheterocyclyl;

Y is selected from the group consisting of LY ₁ or Y ₁ ;

Y ₁ is selected from the group consisting of H, NH ₂ , halogen, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl , optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 dialkylamino substituent, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _6-14 aryl substituted with C _1-6 alkyl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _{1 -6} carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 membered heteroaryl, 4- 10-membered heterocyclyl, 4-10-membered heterocyclyl substituted with methyl, hydroxy and oxo;

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkoxy;

L is selected from the group consisting of a bond, O, S and N(L ^a );

L ^a is selected from the group consisting of hydrogen and C _1-3 alkyl;

U is C(R _6a );

V is C(R _6b );

W is C(R _6c ) or N;

each of R _6a , R _6b and R _6c is independently selected from the group consisting of H, OH, NH ₂ , halo, cyano, carbamoyl, C _2-6 alkenyl, C _1-6 alkoxy, C _1-6 alkyl, C _{1 -6} alkyl substituted with 4-10 membered heterocyclyl substituent, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, C _1-6 alkylthio, C _1-6 haloalkylthio, C _2-6 alkynyl, C _1-6 alkylamino, C _6-14 aryl, C _1-6 aminoalkyl, C _1-6 carbamoylalkyl, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _3-7 cycloalkyl, C _1-6 haloalkoxy, C _1-6 haloalkyl, 5-10 α-membered heteroaryl and 4-10-membered heterocyclyl;

n is selected from the group consisting of 0, 1 and 2; and

R ₁₁ is selected from the group consisting of:

[0303] Embodiment 18: The compound of any one of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein Y is Y ₁ and Y ₁ is selected from the group consisting of H, C _1-6 alkyl, and C _{1- 6} haloalkyl.

[0304] Embodiment 19: The compound of any one of Embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein:

Y is -LY ₁ ;

L is selected from the group consisting of O and N(L ^a );

L ^a is H; and

Y ₁ is selected from the group consisting of C _1-6 alkyl, C _1-6 alkyl substituted with 4-10 membered heterocyclyl which is optionally substituted with 1-4 Y _1a substituents, C _1-6 alkyl substituted with C _1-6 substituent dialkylamino, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, and 4-10 membered heterocyclyl substituted with methyl; and

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy.

[0305] Embodiment 20: The compound of Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein L is N(L ^a ), L ^a is H, and Y ₁ is C _1-6 alkyl or C _1-6 alkyl , substituted with a C _1-6 dialkylamino substituent.

[0306] Embodiment 21: The compound of Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein:

L is O;

Y ₁ is selected from the group consisting of C _1-6 alkyl substituted with 4-10 membered heterocyclyl which is optionally substituted with 1-4 substituents Y _1a , C _1-6 alkyl substituted with C _1-6 substituent dialkylamino, C _1-6 alkyl substituted with C _1-6 dialkylaminocyclopropyl, C _3-7 cycloalkyl substituted with C _1-6 dialkylamino, and 4-10 membered heterocyclyl substituted with methyl; and

each Y _1a is independently selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclyl, C _1-6 alkoxyC _1-6 alkyl, C _1-6 haloalkyl, oxo, hydroxy , NH ₂ , cyano, C _1-6 carboxyalkyl, C _1-6 cyanoalkyl, C _1-6 hydroxyalkyl and C _1-6 haloalkoxy.

[0307] Embodiment 22: The compound of Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein Y ₁ is C _1-6 alkyl substituted with a 4-10 membered methyl heterocyclyl substituent.

[0308] Embodiment 23: The compound of Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of:

[0309] Embodiment 24: The compound of Embodiment 23, or a pharmaceutically acceptable salt thereof, wherein Y is

[0310] Embodiment 25: The compound of any one of Embodiments 17-24, or a pharmaceutically acceptable salt thereof, wherein R ₁₁ is

[0311] Embodiment 26: The compound of any one of Embodiments 17-25, or a pharmaceutically acceptable salt thereof, wherein R ₁₁ is

[0312] Embodiment 27: The compound of any one of Embodiments 17-25, or a pharmaceutically acceptable salt thereof, wherein R ₁₁ is

[0313] Embodiment 28: The compound of any one of Embodiments 1-27, or a pharmaceutically acceptable salt thereof, wherein R _6a is H.

[0314] Embodiment 29: The compound of any one of Embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein R _6b is selected from the group consisting of H, halo, C _1-6 alkoxy, C _1-6 alkylsulfonyl, C _{1 -6} haloalkyl, C _3-7 cycloalkyl, C _1-6 haloalkylthio and 4-10 membered heterocyclyl.

[0315] Embodiment 30: The compound of any one of Embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein R _6b is hydrogen, halogen, or C _1-3 haloalkyl.

[0316] Embodiment 31: The compound of any one of Embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein W is C(R _6c ) and R _6c is hydrogen or halogen.

[0317] Embodiment 32: The compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein W is C(R _6c ) and R _6c is halogen.

[0318] Embodiment 33: The compound of any one of Embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein X is a 4-7 membered heterocyclyl.

[0319] Embodiment 34: The compound of any one of Embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein X is a 4-7 membered heterocyclyl substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of cyano, C _1-6 alkyl, C _1-6 cyanoalkyl and C _1-6 haloalkyl.

[0320] Embodiment 35: The compound of any one of Embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of:

[0321] Embodiment 36: The compound of any one of Embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of:

[0322] Embodiment 37: The compound of any one of Embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of:

[0323] Embodiment 38: The compound of any one of Embodiments 1-32, or a pharmaceutically acceptable salt thereof, wherein X is

[0324] Embodiment 39: The compound of any one of Embodiments 1-38, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0325] Embodiment 40: The compound of Embodiment 1 or 17, or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of:

where:

R ₁₂ is selected from the group consisting of C _1-6 alkanoyl, C _1-6 alkyl and C _1-6 alkylsulfonyl;

R ₁₃ is selected from the group consisting of H, C _1-6 alkyl and C _1-6 haloalkyl;

R _13a is halogen; and

R ₁₄ is halogen.

[0326] Embodiment 41: The compound of Embodiment 40, or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from the group consisting of:

[0327] Embodiment 42: The compound of Embodiment 41, or a pharmaceutically acceptable salt thereof, wherein R ¹ is

[0328] Embodiment 43: The compound of Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R ₇ is selected from the group consisting of H, cyano, and halo; and each of R ₈ and R ₉ is independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, cyano and halogen; where C _1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), an alkyl or arylsulfonate leaving group, C _1-6 alkanoylamino, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylsulfonylamino, C _6-12 dialkylamino and C _1-6 haloalkoxy.

[0329] Embodiment 44: The compound of Embodiment 1 or 17, or a pharmaceutically acceptable salt thereof, having the formula selected from the group consisting of:

or their pharmaceutically acceptable salt.

[0330] Embodiment 45: The compound of Embodiment 44, or a pharmaceutically acceptable salt thereof, having a formula selected from the group consisting of formula (Ib) or (Il).

[0331] Embodiment 46: The compound of any one of Embodiments 17-41, wherein the compound of formula (IV) has the formula selected from the group consisting of:

or their pharmaceutically acceptable salt.

[0332] Embodiment 47: The compound of Embodiment 46, wherein the compound of formula (IV) comprises a compound of formula (IVa), (IVb), (IVd), or (IVg), or a pharmaceutically acceptable salt thereof.

[0333] Embodiment 48: The compound of Embodiment 46, wherein the compound of formula (IV) comprises a compound of formula (IVa) or (IVb), or a pharmaceutically acceptable salt thereof.

[0334] Embodiment 49: The compound of Embodiment 46, wherein the compound of formula (IV) comprises a compound of formula (IVd) or (IVg), or a pharmaceutically acceptable salt thereof.

[0335] Embodiment 50: The compound of Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R ₇ and R ₈ together form a triple bond between the carbon atoms to which they are attached, or R ₇ and R ₈ together with the carbon atoms to which each is linked to form a C _3-7 cycloalkenyl optionally substituted with one or two halogen substituents; and R ₉ is selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, cyano and halogen; where C _1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: C _1-6 alkanoylamino, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylsulfonylamino, C _6-12 dialkylamino and C _{1 -6} haloalkoxy.

[0336] Embodiment 51: The compound of Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R ₇ , R ₈ , and R ₉ are each H.

[0337] Embodiment 52: A compound or a pharmaceutically acceptable salt thereof from Table 1.

[0338] Embodiment 53: A pharmaceutical composition comprising a compound according to any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0339] Embodiment 54: The pharmaceutical composition of Embodiment 53, wherein the pharmaceutical composition is formulated for oral administration.

[0340] Embodiment 55: The pharmaceutical composition of Embodiment 53, wherein the pharmaceutical composition is formulated for injection.

[0341] Embodiment 56: A method of treating cancer, comprising administering to an individual in need a therapeutically effective amount of a compound of any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 53-55.

[0342] Embodiment 57: The method of Embodiment 56, wherein the individual is a human.

[0343] Embodiment 58: The method of Embodiment 55 or 56 wherein administration is by oral route.

[0344] Embodiment 59: The method of Embodiment 55 or 56, wherein the administration is by injection.

[0345] Embodiment 60: The method of any one of embodiments 56-59, wherein the cancer is mediated by a K-Ras G12C mutation.

[0346] Embodiment 61: The method of any one of embodiments 56-60, wherein the cancer is hemoblastosis, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0347] Embodiment 62: The method of any one of Embodiments 56-61, wherein the cancer is lung adenocarcinoma.

[0348] Embodiment 63: A method for regulating the activity of a K-Ras G12C mutant protein, said method comprising reacting the mutant protein with a compound of any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof.

[0349] Embodiment 64: A method of inhibiting the proliferation of a cell population, comprising contacting the cell population with a compound of any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof.

[0350] Embodiment 65: The method of Embodiment 64, wherein inhibition of proliferation is defined as a decrease in cell viability of a cell population.

[0351] Embodiment 66: A method of treating a disorder mediated by a K-Ras G12C mutation in an individual in need thereof, comprising:

determining whether an individual has a mutation; and

if the individual is determined to have the mutation, administering to the individual a therapeutically effective amount of a compound according to any one of embodiments 1-52 or a pharmaceutically acceptable salt or pharmaceutical composition thereof according to any one of embodiments 53-55.

[0352] Embodiment 67: The method of Embodiment 66, wherein the disorder is cancer.

[0353] Embodiment 68: The method of Embodiment 67, wherein the cancer is hemoblastosis, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0354] Embodiment 69: The method of Embodiment 66, wherein the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer.

[0355] Embodiment 70: The method of any one of Embodiments 66-69, wherein the cancer is lung adenocarcinoma.

[0356] Embodiment 71: A method for producing a labeled K-Ras G12C mutant protein, comprising reacting the K-Ras G12C mutant protein with a labeled compound according to any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof, to produce a labeled K-Ras mutant protein. Ras G12C.

[0357] Embodiment 72: A method of inhibiting tumor metastasis, comprising administering to a subject in need a therapeutically effective amount of a compound of any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 53-55.

[0358] Embodiment 73: Use of the compound of any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0359] Embodiment 74: The use of Embodiment 73 wherein the drug is formulated for oral administration.

[0360] Embodiment 75: The use of Embodiment 73 wherein the drug is formulated for injection.

[0361] Embodiment 76: The use of any one of Embodiments 73-75, wherein the cancer is mediated by a K-Ras G12C mutation.

[0362] Embodiment 77: The use of any one of Embodiments 73-76, wherein the cancer is hemoblastosis, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0363] Embodiment 78: The use of any one of Embodiments 73-76, wherein the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer.

[0364] Embodiment 79: The use of any one of Embodiments 73-78, wherein the cancer is lung adenocarcinoma.

[0365] Embodiment 80: Use of the compound of any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastases.

[0366] Embodiment 81: The compound of any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 53-55, for use in a method of therapeutic treatment of a human or animal body.

[0367] Embodiment 82: The compound of any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 53-55, for use in a method of treating cancer.

[0368] Embodiment 83: The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition of Embodiment 82, wherein the cancer is mediated by a K-Ras G12C mutation.

[0369] Embodiment 84: The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition of Embodiment 82 or 83, wherein the cancer is hemoblastosis, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

[0370] Embodiment 85: The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition of Embodiment 82 or 83, wherein the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer.

[0371] Embodiment 86: The compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition of any one of Embodiments 82-85, wherein the cancer is a lung adenocarcinoma.

[0372] Embodiment 87: The compound of any one of Embodiments 1-52, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of Embodiments 53-55, for use in a method for inhibiting tumor metastases.

EXAMPLES

[0373] The following examples illustrate the preparation and biological evaluation of compounds within the scope of the invention. These following examples and preparations are provided to enable those skilled in the art to more clearly understand and practice the present invention. They are not to be taken as limiting the scope of the invention, but only as illustrating and representing it.

[0374] The following abbreviations are used in the examples:

ACN - acetonitrile

Ac ₂ O - acetylacetate

BINAP - (+/-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

Vos ₂ O - di-tert-butyl dicarbonate

BOP - (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

CH ₃ Ti (O _i -Pr) ₃ - methyltitanium (IV) triisophosphate

DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE - 1,2-dichloroethane

DXM - dichloromethane

DIEA or DIPEA - N,N-diisopropylethylamine

DMA - N,N-dimethylacetamide

DMAC - N,N-dimethylacetamide

DMAP - 4-dimethylaminopyridine

DMF - N,N-dimethylformamide

DMSO - dimethyl sulfoxide

EA - ethyl acetate

EtOAc - ethyl acetate

EtOH - ethanol

HATU - 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HFIP - hexafluoroisopropanol

HOAc - acetic acid

iPrOAc - isopropyl acetate

KF - potassium fluoride

KOAc - potassium acetate

DAL - lithium diisopropylamide

LiHMDS - lithium bis(trimethylsilyl)amide

LCMS-a

mCPBA - 3-chloroperoxybenzoic acid

MeCN - acetonitrile

MeI - iodomethane

MeOH - methanol

MeONa - sodium methoxide or sodium methanolate

MTBE - methyl tert-butyl ether

MB - microwave

NaBH(OAc) ₃ - sodium triacetoxyborohydride

NIS - N-iodosuccinimide

P (Su) ₃ or PCu ₃ - tricyclohexylphosphine

P(t-Bu) ₃ HBF ₄ - tri-tert-butylphosphonium tetrafluoroborate

Pd/C - palladium on carbon

Pd ₂ (dba) ₃ - tris (dibenzylideneacetone) dipalladium (0)

Pd ₂ (dba) ₃ CHCl ₃ - tris (dibenzylideneacetone) dipalladium (0) chloroform

Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ - [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) or dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II), in complex with dichloromethane

Pd (PPh ₃ ) ₄ - tetrakis (triphenylphosphine) palladium (0)

Pd (PPh ₃ ) ₂ Cl ₂ - bis (triphenylphosphine) palladium (II) chloride

PE - petroleum ether

PMBCl - 4-methoxybenzyl chloride

pTsA - p-toluenesulfonic acid

k. t. - room temperature

Sn ₂ (n-Bu) ₆ - hexabutylditin

TBSCl - tert-butyldimethylsilyl chloride or tert-butyldimethylchlorosilane

[Rh(COD)Cl] ₂ - dimer of chlorine(1,5-cyclooctadiene)rhodium (I)

TEA - triethylamine

TFA - trifluoroacetic acid or 2,2,2-trifluoroacetic acid

THF - tetrahydrofuran

THP or THP - tetrahydropyran

TsOH - p-toluenesulfonic acid

Connection examples

Intermediate 1: tert-Butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate

[0375] The intermediate tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate was prepared according to the following synthesis scheme:

Stage 1: 7-bromo-4,6-dichloroquinazoline

[0376] To a solution of 7-bromo-6-chloro-3,4-dihydroquinazolin-4-one (330 g, 1.28 mol) in thionyl chloride (4.0 L) was added N,N-dimethylformamide (4 ml) . The mixture was stirred for 12 hours at 80°C. Upon completion, the resulting mixture was concentrated in vacuo to give 7-bromo-4,6-dichloroquinazoline (350 g, crude) as a yellow solid. LCMS (ESI, m/z): 277.1 [M+H] ⁺ .

Step 2: tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate

[0377] A solution of 7-bromo-4,6-dichloroquinazoline (330 g, 1.20 mol), tert-butyl piperazine-1-carboxylate (340 g, 1.80 mol, 1.50 equiv.) and DIPEL (586 ml, 3.60 mol) in 1,4-dioxane (3.0 L) was stirred for 60 min at 110°C. Upon completion, the solids were collected by filtration, washed with PE (500 ml) and water (500 ml), and then dried to give tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (446 g, 87.4%) as a light yellow solid.

[0378] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 3.76 (dd, J=6.2, 3.7 Hz, 4H), 3.65 (dd, J=6.4, 3.8 Hz, 4H), 1.50 (s, 9H). LCMS (ESI, m/z): 429.2 [M+H] ⁺ .

Intermediate 2: 2((2R)-5-methylpiperizin-2-yl)acetonitrile

[0379] Intermediate 2((2R)-5-methylpiperizin-2-yl)acetonitrile was prepared according to the following reaction scheme:

Step 1: tert-butyl (2-((4-methoxybenzyl)amino)propyl)carbamate

[0380] To a solution of tert-butyl N-(2-aminopropyl)carbamate (8.3 g, 47.6 mmol) and p-anisaldehyde (5.8 ml, 47.6 mmol) in 1,2-dichloroethane (175 ml) sodium triacetoxyborohydride (15 g, 71.5 mmol) was added. The reaction system was stirred at room temperature for 18 hours. The reaction was diluted with DCM, then washed with sat. _{Na2CO3 .} The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was dried by flash chromatography on silica (eluting with iPrOAc/Hep) to give t-butyl (2-((4-methoxybenzyl)amino)propyl)carbamate (10.2 g, 71%). LCMS (ESI, m/z): 295.5 [M+H] ⁺ .

Step 2: tert-butyl (E)-(2-((3-cyanoallyl)(4-methoxybenzyl)amino)propyl)carbamate

[0381] A solution of tert-butyl (2-((4-methoxybenzyl)amino)propyl)carbamate (2.9 g, 9.8 mmol), (E)-4-brobut-2-ennitrile (1.2 mg, 8.22 mmol) and sodium carbonate (2.8 g, 26.3 mmol) in ethanol (30 ml) were stirred at 50° C. for 18 hours. The reaction was concentrated, then diluted in EtOAc. The organic layer was washed with water. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was dried by flash chromatography on silica (eluting with iPrOAc/Hep) then (eluting with MeOH/DCM)) to give t-butyl (E)-(2-((3-cyanoallyl)(4-methoxybenzyl )amino)propyl)carbamate. LCMS (ESI, m/z): 360.6 [M+H] ⁺ .

Step 3: 2-((2R)-4-(4-methoxybenzyl)-5-methylpiperazin-2-yl)acetonitrile and 2-((2S)-4-(4-methoxybenzyl)-5-methylpiperazin-2-yl )acetonitrile

[0382] A solution of tert-butyl (E)-(2-((3-cyanoallyl)(4-methoxybenzyl)amino)propyl)carbamate (2.3 g, 6.4 mmol) in 5% trifluoroacetic acid in hexafluoro-2 -propanol (75 ml, 49.3 mmol) was stirred at RT. within 18 hours. The reaction was concentrated, then 1,4-dioxane (80 ml) and triethylamine (5.75 ml, 41.1 mmol) were added. The reaction system was stirred at room temperature for 60 minutes. The crude product was concentrated and purified by HPLC (NH ₄ OH 5-50%) to give 2-((2R)-4-(4-methoxybenzyl)-5-methylpiperazin-2-yl)acetonitrile as HPLC peak 1 (1. 05 g, 49%) and 2-((2S)-4-(4-methoxybenzyl)-5-methylpiperazin-2-yl)acetonitrile as HPLC peak 2 (0.76 g, 35%). Stereochemistry was randomly assigned. LCMS (ESI, m/z): 260.1 [M+H] ⁺ .

Step 4: 2-((2R)-5-methylpiperazin-2-yl)acetonitrile and 2-((2S)-5-methylpiperazin-2-yl)acetonitrile

[0383] Trifluoroacetic acid (17.5 ml , 231.3 mmol). The reaction system was stirred at 50°C for 48 hours. The reaction was concentrated and the crude product was taken to the next step. LCMS (ESI, m/z): 140.1 [M+H] ⁺ .

Intermediate 3: tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine -1-carboxylate

[0384] Tert-butyl compound 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine -1-carboxylate was obtained in accordance with the following synthesis scheme:

Stage 1: 2-amino-4-bromo-5-chloro-benzamide

[0385] A solution of 2-amino-4-bromo-5-chlorobenzoic acid (10.0 g, 39.92 mmol), N,N-diisopropylethylamine (15.45 g, 119.77 mmol) and ammonium chloride (6, 41 g, 119.77 mmol) in N,N-dimethylformamide (50 ml) was stirred at room temperature for 5 minutes. Then HATU (18.22 g, 47.91 mmol) was added and stirred at room temperature for 2 hours. After completion, the reaction was quenched with water. The reaction system was filtered and the filter cake was collected and dried in vacuo to give 2-amino-4-bromo-5-chloro-benzamide (8 g, 32.0 mmol, 80.3% yield) as a yellow solid. LCMS (ESI, m/z): 248.9 [M+H] ⁺ .

Stage 2: 7-bromo-2,6-dichloro-quinazolin-4-ol

[0386] To a solution of 2-amino-4-bromo-5-chloro-benzamide (20.0 g, 80.16 mmol) in 1,4-dioxane (100 ml) was then added thiophosgene (20.3 g, 176 52 mmol) dropwise with stirring. The resulting solution was stirred for 1 hour at room temperature, then stirred for 1 hour at 105°C. Upon completion, the resulting solution was concentrated in vacuo. The organic layer was washed with diethyl ether to give 7-bromo-2,6-dichloro-quinazolin-4-ol (20 g, 68.043 mmol, 84.9% yield) as a brown solid. LCMS (ESI, m/z): 292.9 [M+H] ⁺ .

Step 3: tert-butyl 4-(7-6rom-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate

[0387] A solution of 7-bromo-2,6-dichloro-quinazolin-4-ol (15.0 g, 51.03 mmol), methanesulfonic anhydride (35.6 g, 204.11 mmol) and N,N- diisopropylethylamine (26.3 g, 203.88 mmol) in dichloromethane (200 ml) was stirred at 25° C. for 0.5 hour. Then tert-butyl 1-piperazinecarboxylate (14.2 g, 76.24 mmol) and N,N-diisopropylethylamine (13.2 g, 102.33 mmol) were added and stirred at 25° C. for 2 hours. Upon completion, the resulting solution was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/6) to give tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate ( 13 g, 28.13 mmol, 55.1% yield as a yellow solid. LCMS (ESI, m/z): 461.0 [M+H] ⁺ .

Step 4: tert-Butyl 4-(7-bromo-6-chloro-2-fluoro-quinazolin-4-yl)piperazine-1-carboxylate

[0388] A solution of tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazin-1-carboxylate (15.6 g, 33.75 mmol) and KF (40.0 g, 688.47 mmol) in dimethyl sulfoxide (100 ml) was stirred at 140° C. for 4 hours. Upon completion, the reaction system was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (3/1) to give tert-butyl 4-(7-bromo-6-chloro-2-fluoro-quinazolin-4-yl)piperazin-1- carboxylate (10 g, 22.44 mmol, 66.5% yield) as a yellow solid. LCMS (ESI, m/z): 445.0 [M+H] ⁺ .

Step 5: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate

[0389] In nitrogen, a solution of tert-butyl 4-(7-bromo-6-chloro-2-fluoro-quinazolin-4-yl)piperazin-1-carboxylate (50.0 g, 104.66 mmol), (6 -(bis(4-methoxyphenyl)amino)pyridin-2-yl)boronic acid (90.0g, 229.44mmol), potassium phosphate (45.0g, 212.26mmol) and 1,1'-bis (diphenylphosphino)ferrocene-palladium(II)dichloride (11.5 g, 15.73 mmol) in tetrahydrofuran (1.5 L) and water (300 ml) was stirred at 65° C. for 3 hours. Upon completion, the resulting solution was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/6) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)pyridin-2-yl)-6 -chloro-2-fluoroquinazolin-4-yl)piperazin-1-carboxylate (52 g, 69.77 mmol, 66.7% yield) as a yellow solid. LCMS (ESI, m/z): 713.3 [M+H] ⁺ .

Step 6: tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodopyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate

[0390] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin-1-carboxylate (9 .61 g, 12.9 mmol), N-iodosuccinimide (14.45 g, 64.49 mmol) and p-toluenesulfonic acid (0.09 g, 0.52 mmol) in acetonitrile (180 ml) were stirred at 25° C within 24 hours. Upon completion, the resulting solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/7) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodopyridin-2-yl )-6-Chloro-2-fluoroquinazolin-4-yl)piperazin-1-carboxylate (7.71 g, 8.85 mmol, 68.6% yield) as a yellow solid. LCMS (ESI, m/z): 839.2 [M+H] ⁺ .

Step 7: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate

[0391] To a solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodopyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin-1 -carboxylate (15.35 g, 17.62 mmol) and copper(I) iodide (40.17 g, 21.144 mmol) in N,N-dimethylacetamide (380 ml) were added methyl 2,2-difluoro-2 -(fluorosulfonyl)acetate (84.63 g, 440.51 mmol) and stirred at 90° C. for 6 hours. Upon completion, the resulting solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/5) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridine- 2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin-1-carboxylate (11.8 g, 14.51 mmol, 82.3% yield) as a yellow solid. LCMS (ESI, m/z): 781.3 [M+H] ⁺ .

Intermediate 4: tert-Butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate

[0392] The compound tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazin-1-carboxylate was prepared according to the following synthesis scheme:

Stage 1: 7-bromo-6-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0393] In a 3000 ml round bottom flask were placed 2-amino-4-bromo-5-chlorobenzoic acid (200 g, 0.8 mol) and urea (720 g, 12 mol). The resulting solution was stirred at 160° C. for 12 hours. The mixture was cooled to 80° C. and quenched with water, then heated under reflux for 5-10 minutes. The mixture was cooled to room temperature with the formation of a precipitate. The solids were collected by filtration and washed with H ₂ O and dried in an oven to give 200 g (90%) of crude 7-bromo-6-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione in form of a yellow solid. The crude material was taken to the next step without further purification.

Stage 2: 7-bromo-2,4,6-trichloroquinazoline

[0394] A solution of 7-bromo-6-chloro-1,2,3,4-tetrahydroquinazolin-2,4-dione (200 g, 0.72 mol) and N,N-dimethylaniline (264 g, 2.16 mol ) in POCl ₃ (750 ml) was stirred at 120°C for 8 hours and concentrated in vacuo, and taken to the next step without further purification.

Step 3: tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazine-1-carboxylate (Intermediate 4)

[0395] A solution of 7-bromo-2,4,6-trichloroquinazoline (200 g, 0.64 mol), tert-butyl piperazine-1-carboxylate (178 g, 0.92 mol) and DIEA (3 equiv.) in 1,4-dioxane (2000 ml) was stirred at 25°C for 8 hours. The resulting solution was diluted with 2000 ml of water, then extracted with 3×3000 ml of ethyl acetate. The combined organic layer was washed with brine (1×100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a silica gel column, eluting with ethyl acetate/petroleum ether (1:10) to give 126 g (43%) tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazin- 1-carboxylate as a yellow solid.

[0396] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20-8.14 (m, 1H), 8.16-8.10 (m, 1H), 3.95-3.87 (m, 4H), 3.60-3.52 (m, 4H ), 1.44 (s, 9Н). LCMS (ESI, m/z): 461.1 [M+H] ⁺ .

Intermediate 5: tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0397] The compound tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (Intermediate 5) was prepared according to the protocol presented for Intermediate compound 4, except that in Step 3 tert-butyl (S)-3-methylpiperazine-1-carboxylate was used instead of tert-butyl piperazine-1-carboxylate.

Example 1: 1-[4-[7-(3-Amino-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0398] The compound 1-[4-[7-(3-Amino-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one was prepared according to with the following synthesis scheme:

Step 1: tert-butyl 4-(6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazine-1-carboxylate

[0399] To a solution of tert-butyl 4-(7-bromo-6-chloroquinazolin-4-yl)piperazin-1-carboxylate (550 mg, 1.29 mmol) and bis(pinacolato)diboron (733 mg, 2.83 mmol) in 1,4-dioxane (25.0 mL) were added potassium acetate (189.3 mg, 0.121 mL, 1.929 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (95.0 mg, 0.129 mmol). The reaction system was degassed, then heated at 85°C for 18 hours. The reaction system was filtered through celite, concentrated, and the crude product was purified by flash chromatography on silica (eluting with MeOH/DCM) to give tert-butyl 4-( 6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazine-1-carboxylate (514mg, 84%). LCMS shows the mass of boronic acid. LCMS (ESI, m/z): 393.1 [M+H] ⁺ .

Step 2: tert-butyl 4-(7-(3-aminoisoquinolin-1-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate

[0400] 1-Bromoisoquinoline-3-amine solution (196 mg, 0.85 mmol), tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (270 mg, 0.57 mmol), cesium carbonate (371 mg, 1.14 mmol) and [1,1'-bis(diphenylphosphino)ferrocene ]dichloropalladium(II) dichloromethane adduct (47 mg, 0.057 mmol) in acetonitrile (6 ml) and water (3 ml, 157.8 mmol) was degassed. The reaction system was heated at 90°C for 5 hours. The reaction system was filtered through celite and the crude product was purified by flash chromatography on silica (eluting with MeOH/DCM) to give 235 mg tert-butyl 4-(7-( 3-aminoisoquinolin-1-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate as a yellow solid. LCMS (ESI, m/z): 491.2 [M+H] ⁺ .

Step 3: 1-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinoline-3-amine

[0401] To a solution of tert-butyl 4-[7-(3-amino-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-carboxylate (235 mg, 0.48 mmol) in 1, 4-dioxane (2.0 ml) was added hydrochloric acid (4 mol/l) in 1,4-dioxane (1.2 ml, 4.8 mmol). The reaction system was stirred at room temperature. for 18 hours. The reaction was concentrated to give 136 mg of crude 1-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinolin-3-amine. The crude product was used for the next step without purification. LCMS (ESI, m/z): 391.1 [M+H] ⁺ .

Step 4: 1-[4-[7-(3-Amino-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0402] To a solution of 1-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinolin-3-amine (136 mg, 0.35 mmol) and acrylic acid (0.026 ml, 0. 3 83 mmol) in N,N-dimethylformamide (3.5 ml) were added N,N-diisopropylethylamine (0.30 ml, 1.74 mmol) and HATU (203 mg, 0.52 mmol). The reaction system was stirred at room temperature. within 15 min. The reaction was quenched with water and extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by flash chromatography on silica (eluting with MeOH/DCM), then applied to reverse phase HPLC to give 8 mg of 1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloroquinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one as a white solid.

[0403] Example 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.21 (s, 1H), 7.84 (s, 1H), 7.63 (dd, J=8.5, 1.0 Hz , 1Н), 7.47 (ddd, J=8.3, 6.6, 1.2 Hz, 1Н), 7.25 (dq, J=8.5, 0.9 Hz, 1Н), 7.07 (ddd, J=8.5, 6.7, 1.2 Hz, 1Н), 6.85 (dd, J=16.7, 10.4 Hz, 1H), 6.75 (d, J=0.9 Hz, 1H), 6.18 (dd, J=16.7, 2.4 Hz, 1H), 6.10 (s, 2H), 5.75 (dd , J=10.4, 2.4 Hz, 1Н), 4.01-3.73 (m, 8Н). LCMS (ESI, m/z): 445.1 [M+H] ⁺ .

Example 2: 1-[4-[6-chloro-7-(3-methyl-2-pyridyl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0404] The procedure is the same as Example 1, except that in Step 2 of Example 2, commercially available 2-bromo-3-methylpyridine was used instead of 1-bromoisoquinoline-3-amine as an alternative reagent

[0405] Example 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.51 (ddd, J=4.8, 1.6, 0.7 Hz, 1H), 8.19 (s, 1H), 7.81 (ddd, J=7.8, 1.7, 0.8 Hz, 1H), 7.76 (s, 1H), 7.42 (dd, J=7.7, 4.7 Hz, 1H), 6.84 (dd, J=16.7, 10.4 Hz, 1H), 6.18 (dd, J=16.7, 2.4 Hz, 1H), 5.74 (dd, J=10.4, 2.4 Hz, 1H), 3.95-3.75 (m, 8H), 2.14 (d, J=0.8 Hz, 3H). LCMS (ESI, m/z): 394.1 [M+H] ⁺ .

Example 3: 1-[4-[7-(6-Amino-1,7-naphthyridin-8-yl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1 -he

[0406] The procedure is the same as Example 1, except that in Step 2 of Example 3, commercially available 8-bromo-1,7-naphthyridine-6-amine was used instead of 1-bromoisoquinoline-3-amine as alternative reagent

[0407] Example 3: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.44 (dd, J=4.0, 1.6 Hz, 1H), 8.14 (s, 1H) , 8.07 (dd, J=8.6, 1.6 Hz, 1H), 7.84 (s, 1H), 7.44 (dd, J=8.5, 4.0 Hz, 1H), 6.84 (dd, J=16.7, 10.5 Hz, 1H), 6.75 (s, 1H), 6.32 (s, 2H), 6.18 (dd, J=16.7, 2.4 Hz, 1H), 5.75 (dd, J=10.5, 2.3 Hz, 1H), 3.85 (d, J=43.6 Hz , 8H). LCMS (ESI, m/z): 446.1 [M+H] ⁺ .

Example 4: 1-[4-[7-(3-Amino-2,6-naphthyridin-1-yl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1 -he

[0408] The procedure is the same as Example 1, except that in Step 2 of Example 4, commercially available 1-bromo-2,6-naphthyridine-3-amine was used instead of 1-bromoisoquinoline-3-amine as alternative reagent

[0409] Example 4: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (d, J=1.1 Hz, 1H), 8.71 (s, 1H), 8.23 (s, 1H), 8.09 (d, J =5.9 Hz, 1H), 7.89 (s, 1H), 7.09 (dt, J=5.9, 1.1 Hz, 1H), 6.88 (t, J=1.1 Hz, 1H), 6.87-6.79 (m, 1H), 6.49 (s, 2H), 6.18 (dd, J=16.7, 2.4 Hz, 1H), 5.75 (dd, J=10.4, 2.4 Hz, 1H), 3.99-3.74 (m, 8H). LCMS (ESI, m/z): 446.1 [M+H] ⁺ .

Example 5: 1-[4-[7-(3-Amino-5-chloro-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0410] The procedure is the same as Example 1, except that in Step 2 of Example 5, commercially available 1-bromo-5-chloro-isoquinoline-3-amine was used in place of 1-bromoisoquinoline-3-amine as alternative reagent

[0411] Example 5: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.22 (s, 1H), 7.88 (s, 1H), 7.67 (dd, J=7.4, 1.1 Hz , 1H), 7.25 (dt, J=8.5, 1.0 Hz, 1H), 7.03 (dd, J=8.5, 7.3 Hz, 1H), 6.98 (d, J=1.0 Hz, 1H), 6.85 (dd, J= 16.7, 10.5 Hz, 1H), 6.49 (s, 2H), 6.18 (dd, J=16.7, 2.4 Hz, 1H), 5.75 (dd, J=10.5, 2.4 Hz, 1H), 3.99-3.75 (m, 8H ). LCMS (ESI, m/z): 479.1 [M+H] ⁺ .

Example 6: 1-[4-[7-(3-Amino-6-methoxy-1-isoquinolyl)-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0412] The procedure is the same as Example 1, except that in Step 2 of Example 6, commercially available 1-bromo-6-methoxyisoquinoline-3-amine was used in place of 1-bromoisoquinoline-3-amine as an alternative reagent

[0413] Example 6: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.19 (s, 1H), 7.80 (s, 1H), 7.14 (d, J=9.2 Hz, 1H ), 6.98 (d, J=2.4 Hz, 1H), 6.84 (dd, J=16.7, 10.5 Hz, 1H), 6.74-6.63 (m, 2H), 6.18 (dd, J=16.7, 2.4 Hz, 1H) , 6.03 (s, 2Н), 5.75 (dd, J=10.4, 2.4 Hz, 1H), 3.78-3.99 (m, 11Н). LCMS (ESI, m/z): 475.1 [M+H] ⁺ .

Example 7: (S)-1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1 -he

[0414] Compound (S)-1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en- 1-it was obtained in accordance with the following synthesis scheme

Step 1: 1-(tributylstannyl)isoquinoline-3-amine

[0415] To a solution of 1-bromoisoquinoline-3-amine (500 mg, 2.17 mmol), bis(tributyltin) (1.21 ml, 2.39 mmol), tris(dibenzylideneacetone) dipalladium(0) (205 mg, 0.217 mmol), tricyclohekeylphosphine (122 mg, 0.435 mmol) and lithium chloride (460 mg, 10.9 mmol) in 1,4-dioxane (10 ml) were degassed. The reaction system was stirred at 115° C. for 18 hours. The reaction was filtered through celite. The crude product was used in the next step. LCMS (ESI, m/z): 434.1 [M+H] ⁺ .

Step 2: tert-butyl 4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)pyrerazine-1-carboxylate

[0416] 1-tributylethane annlysoquinolin-3-amine solution (300 mg, 0.693 mmol), tert-butyl 4-(7-bromo-6-chloro-8-fluoro-quinazolin-4-yl) piperazine-1-carboxylate (617 mg, 1.39 mmol), tetrakis(triphenylphosphine)palladium(0) (80.0 mg, 0.069 mmol), copper iodide (39.6 mg, 0.21 mmol) and lithium chloride (124 mg, 2.77 mmol ) in N,N-dimethylformamide (14 ml) was degassed. The reaction system was heated at 150° C. for 15 min under microwave. The reaction system was filtered through celite and concentrated. The crude product was concentrated and purified by flash chromatography on silica (eluting with MeOH/DCM) to give t-butyl 4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4- yl)piperazine-1-carboxylate (94 mg, 27%). LCMS (ESI, m/z): 444.9 [M+H] ⁺ .

Step 3: 1-(6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinoline-3-amine

[0417] To a solution of tert-butyl 4-[7-(3-amino-1-isoquinolyl)-6-chloro-8-fluoro-quinazolin-4-yl]piperazin-1-carboxylate (410 mg, 0.806 mmol) in 1,4-dioxane (3.0 ml) was added hydrochloric acid (4 mol/l) in 1,4-dioxane (2.0 ml, 8.1 mmol). The reaction system was stirred at room temperature. for 18 hours. The reaction was concentrated to give 329 mg of crude 1-(6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)isoquinolin-3-amine. The crude product was used for the next step without purification. LCMS (ESI, m/z): 409.1 [M+H] ⁺ .

Step 4: (S)-1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1 -he

[0418] To a solution of 1-(6-chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl)isoquinolin-3-amine (329 mg, 0.805 mmol) and N,N-diisopropylethylamine (0 .70 ml, 4.02 mmol) in dichloromethane (8.0 ml) were added acrylic acid (0.061 ml, 0.885 mmol) and HATU (468.3 mg, 1.21 mmol) at 0°C. The reaction system was stirred at 0°C for 10 min. The reaction was quenched with water and extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by flash chromatography on silica (eluting with MeOH/DCM) to give 1-(4-(7-(3-aminoisolinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin- 1-yl)prop-2-en-1-one, then submitted to chiral SFC purification to obtain 30.6 mg of (S)-1-(4-(7-(3-aminoisoquinolin-1-yl)-6 -chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one as a white solid (8.2% yield).

[0419] Example 7: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 8.08 (d, J=1.5 Hz, 1H), 7.65 (dt, J=8.7, 0.9 Hz, 1H ), 7.49 (ddd, J=8.3, 6.7, 1.2 Hz, 1H), 7.25 (dt, J=8.6, 1.0 Hz, 1H), 7.09 (ddd, J=8.5, 6.7, 1.1 Hz, 1H), 6.84 (dd, J=16.7, 10.4 Hz, 1H), 6.79 (d, J=0.9 Hz, 1H), 6.24-6.08 (m, 3H), 5.75 (dd, J=10.4, 2.4 Hz, 1H), 4.04- 3.90 (m, 4H), 3.90-3.74 (m, 4H). LCMS (ESI, m/z): 463.1 [M+H] ⁺ .

Example 8: (R)-1-(4-(7-(3-aminoisolinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1 -he

[0420] Chiral branch of 1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one gave example 8.

[0421] Example 8: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 8.08 (d, J=1.5 Hz, 1H), 7.65 (dt, J=8.5, 0.9 Hz, 1H ), 7.49 (ddd, J=8.3, 6.7, 1.2 Hz, 1H), 7.25 (dt, J=8.6, 1.0 Hz, 1H), 7.09 (ddd, J=8.5, 6.7, 1.2 Hz, 1H), 6.84 (dd, J=16.7, 10.5 Hz, 1H), 6.80-6.76 (m, 1H), 6.23-6.10 (m, 3H), 5.75 (dd, J=10.5, 2.4 Hz, 1H), 4.05-3.90 (m , 4Н), 3.82 (d, J=29.0 Hz, 4Н). LCMS (ESI, m/z): 463.1 [M+H] ⁺ .

Example 9: (S)-1-(4-(7-(6-Amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one

[0422] The procedure is the same as Example 7, except that in Step 1 of Example 9, commercially available 6-chloro-5-(trifluoromethyl)pyridine-2-amine was used instead of 1-bromoisoquinoline-3-amine in as an alternative reagent

[0423] Example 9: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.00 (s, 2H), 6.82 (dd, J=16.7, 10.4 Hz, 1H), 6.69-6.61 (m, 1H), 6.17 (dd, J=16.7, 2.4 Hz, 1H), 5.74 (dd, J= 10.4, 2.4 Hz, 1H), 3.92 (t, J=5.2 Hz, 4H), 3.84 (s, 2H), 3.77 (s, 2H). LCMS (ESI, m/z): 481.1 [M+H] ⁺ .

Example 10: (R)-1-(4-(7-(6-Amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl) prop-2-en-1-one

[0424] The procedure is the same as Example 7, except that in Step 1 of Example 10, commercially available 6-chloro-5-(trifluoromethyl)pyridine-2-amine was used instead of 1-bromoisoquinoline-3-amine in as an alternative reagent.

[0425] Example 10: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.00 (s, 2H), 6.82 (dd, J=16.7, 10.4 Hz, 1H), 6.69-6.61 (m, 1H), 6.17 (dd, J=16.7, 2.4 Hz, 1H), 5.74 (dd, J= 10.4, 2.4 Hz, 1H), 3.91 (dd, J=6.5, 4.0 Hz, 4H), 3.84 (s, 2H), 3.77 (s, 2H). LCMS (ESI, m/z): 481.1 [M+H] ⁺ .

Example 11: 1-(4-(7-(6-Amino-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1 -he

[0426] Compound 1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en- 1-it was obtained in accordance with the following synthesis scheme:

Step 1: 2-(5-fluoro-4-methylpyridin-2-yl)isoindoline-1,3-dione

[0427] A solution of 2-amino-5-fluoro-4-picoline (500 mg, 3.77 mmol) and phthalic anhydride (836 mg, 5.65 mmol) in acetic acid (9.5 ml) was heated at 90°C within 18 hours the Reaction was quenched sat. sodium bicarbonate, then extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by flash silica chromatography (eluting with iPrOAc/Hep) to give 2-(5-fluoro-4-methylpyridin-2-yl)isoindoli-1,3-dione (834 mg, 86.5% ). LCMS (ESI, m/z): 257.1 [M+H] ⁺ .

Step 2: 2-(6-chloro-5-fluoro-4-methylpyridin-2-yl)isoindoline-1,3-dione

[0428] 3-Chloroperoxybenzoic acid (1, 30 g, 7.53 mmol). The reaction system was stirred at room temperature. within 18 hours the Reaction was extinguished with a saturated aqueous solution of Na ₂ S ₂ O ₃ and was extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator to give 2-(1,3-dioxoisoindolin-2-yl)-5-fluoro-4-methylpyridine 1-oxide (945 mg, 92.3%).

[0429] A solution of 2-(1,3-dioxoisoindolin-2-yl)-5-fluoro-4-methylpyridine 1-oxide (550 mg, 2.02 mmol) in phosphorus oxychloride (5.0 ml, 50.51 mmol ) was heated to 80° C. for 2 hours. The reaction was quenched with ice water and sat. NaHCO ₃ , then extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by flash silica chromatography (eluting with iPrOAc/Hep) to give 2-(6-chloro-5-fluoro-4-methylpyridin-2-yl)isoindoline-1,3-dione (234 mg, 39 ,eight%). LCMS (ESI, m/z): 290.9 [M+H] ⁺ .

Step 3: 6-chloro-5-fluoro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine

[0430] A solution of 2-(6-chloro-5-fluoro-4-methylpyridin-2-yl)isoindoline-1,3-dione (633 mg, 2.18 mmol) in ammonia (7 mol/l) in methanol 3 1 ml) was stirred at 45° C. for 5 hours. The solid was filtered to give 136 mg of crude 6-chloro-5-fluoro-4-methylpyridine-2-amine. The crude product was used for the next step without purification. LCMS (ESI, m/z): 161.1 [M+H] ⁺ .

[0431] Sodium hydride was added to a solution of 6-chloro-5-fluoro-4-methyl-pyridine-2-amine (250 mg, 1.56 mmol) in N,N-dimethylacetamide (6.0 ml) at 0°C. (60 wt%) in oil (75.0 mg, 1.87 mmol). The reaction was stirred at 0°C for 30 min, then 4-methoxybenzyl chloride (0.24 ml, 1.71 mmol) was added dropwise. The reaction system was stirred at RT for 18 hours. The reaction was quenched with water and extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by flash silica chromatography (eluting with iPrOAc/Hep) to give 6-chloro-5-fluoro-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (521 mg, 83.4%. LCMS (ESI, m/z): 401.9 [M+H] ⁺ .

Step 4: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-carboxylate

[0432] A suspension of tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (250 mg, 0.527 mmol) 6-chloro-5-fluoro-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine (190.0 mg, 0.474 mmol), bis(triphenylphosphine)palladium(ii ) dichloride (37.3 mg, 0.053 mmol) and potassium fluoride (92 mg, 1.58 mmol) in acetonitrile (5.0 ml) and water (1.0 ml) were degassed. The reaction system was heated in microwaves at 125°C for 30 min. The reaction was filtered through celite. The crude product was purified by flash chromatography on silica (eluting with MeOH/DCM) to give t-butyl. 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-carboxylate (145 mg, 38 6%). LCMS (ESI, m/z): 657.1 [M+H] ⁺ .

Step 5: 6-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)-5-fluoro-4-methylpyridin-2-amine

[0433] To the mpem-butyl solution. 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-carboxylate (200 mg, 0.280 mmol ) in dichloromethane (3.0 ml) trifluoroacetic acid (0.106 ml, 1.40 mmol) was added. The reaction system was stirred at room temperature. within 18 hours the Reaction was concentrated and diluted in EtOAc. The solution was washed with sat. _NaHC03 . The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator to obtain 105 mg of crude 6-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)-5-fluoro-4-methylpyridine- 2-amines. The crude product was used for the next step without purification. LCMS (ESI, m/z): 373.1 [M+H] ⁺ .

Step 6: 1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1 -he

[0434] To a solution of 6-(6-chloro-4-piperazin-1-yl-quinazolin-7-yl)-5-fluoro-4-methyl-pyridin-2-amine (210 mg, 0.563 mmol) and N, N-diisopropylethylamine (0.50 ml, 2.82 mmol) in dichloromethane (5.5 ml) was added acrylic acid (0.042 ml, 0.620 mmol) and HATU (328 mg, 0.845 mmol) at 0°C. The reaction system was stirred at 0°C for 10 min. The reaction was quenched with water and extracted with HtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by flash chromatography on silica (eluting with MeOH/DCM), then applied to reverse phase HPLC to give 1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl )-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (54.1 mg, 20.7%).

[0435] Example 11: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (s, 1H), 8.14 (s, 1H), 7.81 (s, 1H), 6.83 (dd, J=16.7, 10.4 Hz , 1H), 6.45 (dd, J=4.7, 1.0 Hz, 1 H), 6.17 (dd, J=16.7, 2.4 Hz, 1 H), 5.93 (s, 2H), 5.74 (dd, J=10.4, 2.4 Hz, 1H), 3.91-3.73 (m, 8H), 2.21 (dd, J=1.7, 0.9 Hz, 3H). LCMS (ESI, m/z): 427.1 [M+H] ⁺ .

Example 12: (R)-1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3 -methylbutyl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0436] Compound (R)-1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-2-((2-fluoro-3-hydroxy- 3-methylbutyl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one was obtained according to the following synthesis scheme:

Step 1: tert-butyl (R)-4-(7-bromo-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazine-1-carboxylate

[0437] To a solution of tert-butyl 4-(7-bromo-2,6-dichloro-quinazolin-4-yl)piperazin-1-carboxylate (Intermediate 4) (500 mg, 1.08 mmol) and (3R) N,N-diisopropylethylamine (1.90 ml, 10.8 mmol). The reaction system was stirred at 65° C. for 18 hours. The reaction was concentrated and the crude product was purified by flash chromatography on silica (eluting with MeOH/DCM) to give tert-butyl (R)-4-(7-bromo- 6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazine-1-carboxylate (558mg, 94.3%). LCMS (ESI, m/z): 548.1 [M+H] ⁺ .

Step 2: tert-butyl (R)-4-(6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazine-1-carboxylate

[0438] To a solution of tert-butyl (R)-4-(7-bromo-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazin-1 -carboxylate (100 mg, 0.183 mmol) and bis(pinacolato)diboron (142 mg, 0.549 mmol) in 1,4-dioxane (3.5 ml) were added potassium acetate complex (54 mg, 0.548 mmol) and 1.1' -bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride (9.0 mg, 0.0091 mmol). The reaction system was degassed, then stirred at 125° C. for 1 hour. The reaction was filtered through celite and concentrated to give 108 mg of crude tert-butyl (R)-4-(6-chloro-2-((2-fluoro-3- hydroxy-3-methylbutyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazine-1-carboxylate. The crude material was used for the next step without purification. LCMS (ESI, m/z): 595.1 [M+H] ⁺ .

Step 3: (R)-2-((6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl )amino)quinazolin-7-yl)-5-fluoro-4-methylpyridin-2-yl)carbamoyl)benzoic acid

[0439] A solution of tert-butyl (R)-4-(6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazin-1-carboxylate (108 mg, 0.182 mmol), 2-(6-chloro-5-fluoro-4-methyl-2-pyridyl) isoindoline-1,3-dione (74.0 mg, 0.255 mmol), bis(triphenylphosphine)palladium(II) dichloride (13.0 mg, 0.01-82 mmol) and potassium fluoride (42.0 mg, 0.727 mmol) in acetonitrile (2.0 ml) and water (0.5 ml) was degassed. The reaction system was heated in microwaves at 125°C for 30 min. The reaction was filtered through celite. The crude product was purified by flash chromatography on silica (eluting with MeOH/DCM) to give (R)-2-((6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro- 2-((2-Fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-7-yl)-5-fluoro-4-methylpyridin-2-yl)carbamoyl)benzoic acid (38mg, 28.2%) . LCMS (ESI, m/z): 741.1 [M+H] ⁺ .

Step 4: (R)-4-((7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-4-(piperazin-1-yl)quinazolin-2-yl) amino)-3-fluoro-2-methylbutan-2-ol

[0440] To a solution of (R)-2-((6-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3 -methylbutyl)amino)quinazolin-7-yl)-5-fluoro-4-methylpyridin-2-yl)carbamoyl)benzoic acid (270 mg, 0.365 mmol) and N,N-diisopropylethylamine (0.32 ml, 1.80 mmol) in dichloromethane (3.5 ml) was added HATU (212.0 mg, 0.547 mmol). The reaction system was stirred at room temperature. within 18 hours the reaction was quenched with water and was extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by flash chromatography on silica (eluting with MeOH/DCM) to give t-butyl. 4-[6-chloro-7-[6-(1,3-dioxoisoindolin-2-yl)-3-fluoro-4-methyl-2-pyridyl]-2-[[(2R)-2-fluoro-3 -hydroxy-3-methyl-butyl]amino]quinazolin-4-yl]piperazine-1-carboxylate (151 mg, 57.3%). LCMS (ESI, m/z): 723.1 [M+H] ⁺ .

[0441] A solution of tert-butyl 4-[6-chloro-7-[6-(1,3-dioxoisoindolin-2-yl)-3-fluoro-4-methyl-2-pyridyl]-2-[[(2R )-2-fluoro-3-hydroxy-3-methyl-butyl]amino]quinazolin-4-yl]piperazin-1-carboxylate (190 mg, 0.263 mmol) in ammonia (7 mol/l) in methanol (1.90 ml, 13.2 mmol) was stirred at 45° C. for 2 hours. The reaction was concentrated and the crude product was taken to the next step without further purification.

[0442] To a solution of tert-butyl 4-[7-(6-amino-3-fluoro-4-methyl-2-pyridyl)-6-chloro-2-[[(2R)-2-fluoro-3-hydroxy -3-methyl-butyl]amino]quinazolin-4-yl]piperazin-1-carboxylate (156 mg, 0.263 mmol) in 1,4-dioxane (1.0 ml) was added hydrochloric acid (4 mol/l) in 1 ,4-dioxane (0.65 ml, 2.63 mmol). The reaction system was stirred at room temperature. over 18 hours. The reaction was concentrated to give 129 mg of crude (R)-4-((7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-4-(piperazin-1 -yl)quinazolin-2-yl)amino)-3-fluoro-2-methylbutan-2-ol. The crude product was used for the next step without purification. LCMS (ESI, m/z): 493.1 [M+H] ⁺ .

Step 5: (R)-1-(4-(7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3 -methylbutyl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0443] To a solution of (R)-4-((7-(6-amino-3-fluoro-4-methylpyridin-2-yl)-6-chloro-4-(piperazin-1-yl)quinazolin-2- yl)amino)-3-fluoro-2-methylbutan-2-ol (129 mg, 0.262 mmol) and N,N-diisopropylethylamine (0.23 ml, 1.31 mmol) in dichloromethane 2.5 ml) acrylic acid was added (0.020 ml, 0.290 mmol) and HATU (153 mg, 0.393 mmol) at 0°C. The reaction system was stirred at 0°C for 10 min. The reaction was quenched with water and extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by flash chromatography on silica (eluting with MeOH/DCM), then applied to reverse phase HPLC to give (R)-1-(4-(7-(6-amino-3-fluoro-4-methylpyridine -2-yl)-6-chloro-2-((2-fluoro-3-hydroxy-3-methylbutyl)amino)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one ( 25 mg, 17.3%).

[0444] Example 12: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.84 (s, 1H), 7.25 (d, J=58.3 Hz, 2H), 6.84 (dd, J=16.7, 10.5 Hz, 1H ), 6.41 (dd, J=4.7, 1.0 Hz, 1H), 6.16 (dd, J=16.7, 2.4 Hz, 1H), 5.88 (s, 2H), 5.73 (dd, J=10.4, 2.4 Hz, 1H) , 4.77 (s, 1H), 4.36 (s, 1H), 3.90-3.59 (m, 10H), 2.19 (dd, J=1.7, 0.8 Hz, 3H), 1.20-1.09 (m, 6H). LCMS (ESI, m/z): 526.2 [M+H] ⁺ .

Example 13 1-(4-(7-(6-amino-3,4-dimethylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0445] The procedure is the same as Example 11, except that in Step 1 of Example 12, commercially available 4,5-dimethylpyridine-2-amine was used instead of 2-amino-5-fluoro-4-picoline as alternative reagent.

[0446] Example 13: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (s, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 6.83 (dd, J=16.7, 10.5 Hz , 1H), 6.40-6.36 (m, 1H), 6.17 (dd, J=16.7, 2.4 Hz, 1H), 5.79-5.69 (m, 3H), 3.90-3.74 (m, 8H), 2.18 (d, J =0.8 Hz, 3H), 1.83 (s, 3H). LCMS (ESI, m/z): 423.1 [M+H] ⁺ .

Example 14: 1-(4-(7-(6-Amino-3-chloro-4-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1 -he

[0447] The procedure is the same as Example 11, except that in Step 1 of Example 13, commercially available 2-amino-5-chloro-4-picoline was used instead of 2-amino-5-fluoro-4-picoline as an alternative reagent.

[0448] Example 14: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (s, 1H), 8.14 (s, 1H), 7.72 (s, 1H), 6.83 (dd, J=16.7, 10.5 Hz , 1Н), 6.51 (d, J=0.9 Hz, 1H), 6.23-6.14 (m, 3Н), 5.74 (dd, J=10.4, 2.4 Hz, 1Н), 3.83 (dd, J=39.2, 5.3 Hz, 8Н), 2.28 (d, J=0.7 Hz, 3Н). LCMS (ESI, m/z): 443.1 [M+H] ⁺ .

Example 15 1-(4-(7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: tert-butyl 4-(7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate

[0449] In nitrogen, a solution of tert-butyl 4-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate (2.5 g , 5.2 mmol), 6-bromo-5-methylpyridin-2-amine complex (1 g, 5.3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride (432 mg, 0.52 mmol), sodium hydroxide (430 mg, 10.75 mmol) in 1,4-dioxane (15 ml) and water (2 ml) was stirred for 2 h at 100°C. Upon completion, the solution was diluted with water (30 ml) and extracted with ethyl acetate (3×50 ml) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with dichloromethane/methanol (10/1) to give 1.6 g (67%) tert-butyl 4-[7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin- 4-yl]piperazin-1-carboxylate (1.6 g, 3.5 mmol, 67% yield) as a yellow oil. LC-MS: (ESI, m/z): 455.2 [M+H] ⁺

Step 2: 6-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)-5-methylpyridin-2-amine

[0450] tert-Butyl 4-[7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-carboxylate solution (1.5 g, 3.29 mmol) and trifluoroacetic acid (1.12 g, 9.82 mmol) in dichloromethane (20 ml) was stirred for 3 h at 25°C. Upon completion, the resulting mixture was concentrated in vacuo to give 1.8 g (crude) of 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-methylpyridin-2-amine in as a brown oil, which was used for the next step without purification. LC-MS: (ESI, m/z): 355.1 [M+H] ⁺

Step 3: 1-[4-[7-(6-Amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0451] 6-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-methylpyridin-2-amine solution (600 mg, 1.69 mmol), prop-2-enoic acid (140 mg, 1.94 mmol), HATU (1.3 g, 3.41 mmol), N,N-diisopropylethylamine (877 mg, 6.78 mmol) in dichloromethane (20 ml) was stirred for 2 h at 25 °C. Upon completion, the solution was quenched with water (5 ml), diluted with dichloromethane (50 ml) and washed with brine (3×10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was further isolated by preparative HPLC under the following conditions, column: CHIRALPAK IE, 2*25 cm, 5 µm; mobile phase A: MTBE (10 mM NH ₃ -methanol)-HPLC; mobile phase B: methanol-HPLC; flow rate: 20 ml/min; gradient: 15V to 15V in 27 min; 220/254 nm; RT1:17.672; RT2:23.294 to give 1-[4-[7-(6-amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (20.2 mg, 0.048 mmol, 3% yield) as a white solid. LC-MS: (ESI, m/z): 409.1 [M+H] ⁺

[0452] Example 15: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 8.68 (s, 1H), 8.23 (s, 1H), 7.76 (s, 1H), 7.48 (dd, J= 8.4, 0.4 Hz, 1H), 6.88-6.81 (m, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.29 (dd, J=16.8, 2.0 Hz, 1H), 5.83 (dd, J= 10.8, 2.0 Hz, 1 H), 4.02 (s, 4H), 3.94 (s, 4H), 2.00 (s, 3H).

Example 16 N-(6-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]-5-methylpyridin-2-yl)acetamide

Synthetic way

Step 1: N-(6-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]-5-methylpyridin-2-yl)acetamide

[0453] 1-[4-[7-(6-Amino-3-methylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one solution ( 300 mg, 0.73 mmol), acetyl acetate (112 mg, 1.09 mmol), triethylamine (221 mg, 2.18 mmol) in dichloromethane (20 ml) was stirred for 9 h at 25°C. Upon completion, the solution was quenched with water (5 ml), diluted with dichloromethane (50 ml) and washed with brine (3×10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was further isolated by preparative HPLC under the following conditions, column: CHIRALPAK IE, 2*25 cm, 5 µm; mobile phase A: MTBE (10 mM NH ₃ -methanol)-HPLC, mobile phase B: methanol-HPLC; flow rate: 20 ml/min; gradient: 15 V to 15 V in 27 min; 220/254 nm; RT1:17.672; RT2:23.294 to give N-(6-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]-5-methylpyridin-2-yl)acetamide ( 10.2 mg, 0.023 mmol, 3% yield as a white solid. LC-MS: (ESI, m/z): 451.2 [M+H] ⁺

[0454] Example 16: ¹ H NMR (400 MHz, Methanol-d ₄ ), ppm) δ 8.68 (s, 1H), 8.22 (s, 1H), 8.13-8.08 (m, 1H), 7.76-7.74 (m , 2Н), 6.86-6.79 (m, 1Н), 6.27 (dd, J=16.8, 2.0 Hz, 1Н), 5.80 (dd, J=14.4, 2.0 Hz, 1Н), 4.00 (s, 4Н), 3.92 ( s, 4Н), 2.16 (s, 3Н), 2.13 (s, 3Н).

Examples 17a and 17b: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro- 2-(((S)-1-methylpyrrolidin-2-yl)methokei)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 17a) and 1-( (S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 17b)

Synthetic way

Step 1: 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine

[0455] Sodium hydride (19.0 g, 792 mmol) was added slowly at 0 °C and stirred at 25°C for 1 hour. Then, 4-methoxybenzyl chloride (56.0 g, 359 mmol) was added to the reaction system and stirred at 25° C. for 2 hours. Upon completion, the reaction system was quenched with saturated ammonium chloride solution (500 ml) and diluted with ethyl acetate (2.5 l). The mixture was washed with brine (5×500 ml) and the organic layers were combined, dried with Na ₂ SO ₄ , evaporated in vacuo. The residue was loaded onto a silica gel column eluting with petroleum ether/ethyl acetate (15%) to give 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (60 g, 140 mmol, 87.5 yield %) as an off-white solid. LCMS: (ESI, m/z): 427.1 [M+H] ⁺ .

Step 2: N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-pyridine-2-amine

[0456] In nitrogen, 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridine-2-amine solution (35.0 g, 82 mmol), hexabutylditin (143.0 g , 247 mmol), tris(dibenzylideneacetone) dipalladium (7.53 g, 8.2 mmol), tricyclohexyl phosphine (4.6 g, 16.4 mmol) and lithium chloride (17.3 g, 412 mmol) in 1, 4-dioxane (220 ml) was stirred at 110°C for 5 hours. Upon completion, the reaction system was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (1/1) to give N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-pyridine-2-amine ( 45 g, 71 mmol, 86.2% yield as red oil. LCMS: (ESI, m/z): 639.3 [M+H] ⁺ .

Stage 3: 2-amino-4-bromo-5-chloro-3-fluoro-benzoic acid

[0457] A solution of 2-amino-4-bromo-3-fluoro-benzoic acid (100.0 g, 427 mmol) and N-chlorosuccinimide (66.0 g, 494 mmol) in N,N-dimethylformamide (1 L) stirred at 80°C for 2 hours. Upon completion, the system was poured into water (2.0 L), a large amount of solids was precipitated. Then, the solids were collected after filtration. The solids were washed with hot water (1 L). Then, the solids were dried under an infrared lamp to give 2-amino-4-bromo-5-chloro-3-fluoro-bezoic acid (100 g, 373 mmol, 87.2% yield) as an off-white solid. LCMS: (ESI, m/z): 265.9 [M-H] ⁺ .

Step 4: 7-bromo-6-chloro-8-fluoroquinazolin-2,4(1H,3H)-dione

[0458] A solution of 2-amino-4-bromo-5-chloro-3-fluoro-benzoic acid (120.0 g, 447 mmol) in urea (806.0 g, 13.4 mol) was stirred at 200°C in within 1.5 hours. Upon completion, the reaction system was cooled to 80°C and water (1.5 L) was added to the system with stirring over 20 minutes. After filtration, the solids were collected and washed with hot water (1 L). Then, the solids were dried under an infrared lamp to give 7-bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione (120 g, 409 mmol, 91.5% yield) as light brown solid. LCMS: (ESI, m/z): 290.9 [M-H] ⁺ .

Step 5: tert-butyl (3S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0459] A solution of 7-bromo-6-chloro-8-fluoro-quinazolin-2,4-diol (65.0 g, 222 mmol) and DMF (500.0 mg, 6.85 mmol) in POCl ₃ (1 0 L) was stirred at 110° C. for 60 hours. After the starting material was thoroughly stirred, the resulting mixture was concentrated in vacuo. Then, 1,4-dioxane (1.0 L), N,N-diisopropylethylamine (286.0 g, 2217 mmol) and tert-butyl (3S)-3-methyl-1-piperazinecarboxylate (90.0 g, 449 mmol) was added to the reaction system and stirred at 25°C for 1 hour. After completion, the solvent was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (20%) to give t-butyl (3S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)- 3-methylpiperazine-1-carboxylate (65 g, 132 mmol, 59.4% yield) as a yellow solid. LCMS: (ESI, m/z): 493.0 [M+H] ⁺ .

Step 6: tert-butyl (3S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0460] A mixture of tert-butyl (3S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (30.0 g, 61 mmol) and potassium fluoride (71.0 g, 1224 mmol) in N,N-dimethylacetamide (300 ml) was stirred at 120°C for 18 hours. After completion, the reaction system was cooled to room temperature. Then, ethyl acetate (1.5 L) was added to the system and the mixture was washed with water (3×500 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (20%) to give t-butyl (3S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)- 3-methylpiperazine-1-carboxylate (23 g, 48 mmol, 79.3% yield) as a yellow solid. LCMS: (ESI, m/z): 477.0 [M+H] ⁺ .

Step 7: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl )-3-methylpiperazine-1-carboxylate

[0461] In nitrogen, a solution of tert-butyl (3S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (23.0 g, 48 mmol), N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-pyridin-2-amine (62.0 g, 97 mmol), tetrakis(triphenylphosphine)palladium (11.2 g , 9.7 mmol), copper iodide (2.8 g, 15 mmol) and lithium chloride (5.0 g, 119 mmol) in 1,4-dioxane (320 ml) were stirred at 120°C for 16 hours. Upon completion, the reaction system was diluted with water (100 ml) and extracted with ethyl acetate (100 ml). Then the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (30%) to give t-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridine-2- yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (18.5 g, 25 mmol, 51.6% yield) as a yellow solid. LCMS: (ESI, m/z): 745.3 [M+H] ⁺ .

Step 8: tert-Butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazoline -4-yl)-3-methylpiperazin-1-carboxylate

[0462] A solution of tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4- yl)-3-methylpiperazine-1-carboxylate (18.5 g, 25 mmol), p-toluenesulfonic acid (171.0 mg, 0.99 mmol) and N-iodosuccinimide (28.0 g, 125 mmol) in N ,N-dimethylformamide (350 ml) was stirred at 25°C for 5 hours. Upon completion, the reaction system was diluted with ethyl acetate (1.5 L) and washed with saturated sodium thiosulfate solution (4×350 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (25%) to give t-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo- 4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (16 g, 18.4 mmol, 74% yield) as a yellow solid. LCMS: (ESI, m/z): 871.2 [M+H] ⁺ .

Step 9: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2, 8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0463] Under nitrogen, a solution of tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2 ,8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (16.0 g, 18.4 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (88.3 g, 460 mmol) and copper iodide (42.0 g, 221 mmol) in N,N-dimethylformamide (400 ml) were stirred at 90° C. for 18 hours. Upon completion, the reaction system was diluted with ethyl acetate (2.0 L) and washed with brine (4×350 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo.

The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (30%) to give t-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl- 3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (12.2 g, 15 mmol, 81.7% yield) in form of a yellow solid. LCMS: (ESI, m/z): 813.3 [M+H] ⁺ .

Step 10: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8- fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0464] To a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (4.32 g, 37.5 mmol) in tetrahydrofuran (300 ml) was slowly added sodium hydride (2.1 g, 87.5 mmol ) at 0°C and stirred for 1 h at 25°C. Then, tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2.8 -difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (12.2 g, 15 mmol) was added to the reaction system and stirred at 25° C. for 1 hour. Upon completion, the reaction system was quenched with methanol (50 ml). Then, the mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (6/94) to give t-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino )-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl) -3-methylpiperazine-1-carboxylate (8.6 g, 9.5 mmol, 63.1% yield) as a brown solid. LCMS: (ESI, m/z): 908.4 [M+H] ⁺ .

Step 11: 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin- 7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0465] tert-Butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8 solution -fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-caboxylate (8.6 g, 9.5 mmol) in trifluoroacetic acid ( 100 ml) was stirred at 50°C for 4 hours. Upon completion, the reaction system was concentrated in vacuo. The residue was diluted with dichloromethane (50 ml) and the pH was adjusted to pH=9 with N,N-diisopropylethylamine. After concentration in vacuo, the residue was purified by reverse phase chromatography directly under the following conditions: Column, C18 silica gel; mobile phase, A: water, B:ACN, V% (5% ~ 40% in 30 min); Detector, UV 254 nm to give 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl) methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (3.5 g, 6.17 mmol, 65.1% yield) as a yellow solid. LCMS: (ESI, m/z): 568.2 [M+H] ⁺ .

Step 12: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 17a) and 1-((S )-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperzin-1-yl)prop-2-en-1-one (Example 17b)

[0466] To a solution of 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy) quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (2.5 g, 4.4 mmol) and N,N-diisopropylethylamine (2.9 g, 22.5 mmol) in dichloromethane (120 ml) was added acryloyl chloride (359.0 mg, 3.97 mmol) at -78°C and stirred at -78°C for 25 min. The reaction was quenched with water and extracted with dichloromethane. The organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography directly under the following conditions: Column, C18 silica gel; mobile phase, A: water, B:ACN, V% (5% ~ 60% in 30 min); Detector, UV 254 nm to give 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[ [(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one (1.3 g, 2.09 mmol, 47.5% yield) as a brown solid. A mixture of diastereoisomers was separated by preparative chiral HPLC under the following conditions: Column, CHFRALPAK IC-3 0.46*5 cm 3 µm; mobile phase, (hexane: dichloromethane=3:1) (0.1% DEA): EtOH=50:50; Detector, 254 nm; Flow, 1.0 ml/min; Temperature: 25° C. to give 657.7 mg of 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6- chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 17a) as a white solid and 352.1 mg of 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6 -chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one ( Example 17b) as a white solid.

[0467] Example 17a: LC-MS: (ESI, m/z): 622.2 [M+H] ⁺ , ¹ H NMR: (400 MHz, CDCl ₃ , ppm) δ 7.64 (s, 1H) , 6.70-6.55 (m, 1H), 6.48 (m, 1H), 6.42-6.35 (m, 1H), 5.82-5.75 (m, 1H), 4.90-4.79 (m, 2H), 4.78-4.40 (m, 3Н), 4.35-4.28 (m, 1Н), 4.18-4.00 (m, 1Н), 3.99-3.76 (m, 1Н), 3.72-3.45 (m, 2Н), 3.31-2.98 (m, 2Н), 2.81- 2.70 (m, 1H), 2.55-2.45 (m, 6H), 2.35-2.25 (m, 1H), 2.11-2.01 (m, 1H), 1.95-1.72 (m, 3H), 1.36-1.34 (m, 3H ).

[0468] Example 17b: LC-MS: (ESI, m/z): 622.2 [M+H] ⁺ , ¹ H NMR: (400 MHz, CDCl ₃ , ppm) δ 7.63 (u, 1H) , 6.70-6.55 (m, 1H), 6.50 (s, 1H), 6.42-6.35 (m, 1H), 5.82-5.75 (m, 1H), 4.85-4.70 (m, 2H), 4.78-4.68 (m, 2Н), 4.65-4.55 (m, 1Н), 4.50-4.40 (m, 1Н), 4.30-4.10 (m, 1Н), 4.05-3.75 (m, 1Н), 3.80-3.76 (m, 2Н), 3.25- 3.08 (m, 2H), 2.85-2.75 (m, 1H), 2.60-2.45 (m, 6H), 2.40-2.25 (m, 1H), 2.15-2.05 (m, 1H), 1.95-1.72 (m, 3H ), 1.45-1.32 (m, 3H).

Examples 18a and 18b: (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro- 8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-fluorobutyl-2-en-1-one and (E)-1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2 -(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-fluorobut-2-en-1-one

Synthetic way

[0469] To a solution of 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methyl-pyrrolidin-2-yl]methoxy ]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (500mg, 0.88mmol), HATU (401mg, 1.06mmol) and N,N-diisopropyl)thylamine (228 mg, 0.96 mmol) in dichloromethane (25 ml) was added (E)-4-fluorobut-2-enoic acid (100 mg, 3.97 mmol) at 25° C. and the mixture solution was stirred for 0. 5 hours After completion, the reaction was quenched with water and extracted with dichloromethane. The organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography directly under the following conditions: Column, C1 8 silica gel; mobile phase, A: water, B:ACN, V% (5% ~ 60% in 30 min); Detector, UV 254 nm to give a mixture of (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6 -chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-fluorobut-2-en-1 -one and (E)-1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8- fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-fluorobut-2-en-1-one (130 mg , 0.20 mmol, 23% yield as a white solid. The mixture of diastereoisomers was separated by preparative chiral HPLC under the following conditions: Column: CHIRAL Cellulose-SB, Column size: 0.46*10 cm; 3 µm, Mobile phase hexane: EtOH=50:50, Flow: 1.0 ml/min, Temperature: 25° C. to give 32 mg of (E)-1-((S)-4-((R)-7 -(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin- 4-yl)-3-methylpiperazin-1-yl)-4-fluorobut-2-en-1-one as a white solid and 29.9 mg of (E)-1-((S)-4-(( (S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl )methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-fluorobut-2-en-1-one as a white solid.

[0470] Example 18a: LC-MS: (ESI, m/z): 654.2 [M+H] ⁺ , ¹ H NMR: (400 MHz, DMSO-d ₆ , ppm) δ 7.82 (s, 1H), 6.85 (s, 2H), 6.83-6.68 (m. 2H), 6.50 (s, 1H), 5.20 (d, J=2.8 Hz, 1H), 5.08 (d, J=2.8 Hz, 1H), 4.75 (s, 1H), 4.41-4.23 (m, 2H), 4.19-3.94 (m, 3H), 3.73-3.65 (m, 1H), 3.43-3.07 (m, 2H), 2.96-2.93 (m, 1H ), 2.60-2.50 (m, 1H), 2.37-2.36 (m, 6H), 2.18 (dd, J=16.4, 8.0 Hz, 1H), 1.99-1.90 (m, 1H), 1.72-1.59 (m, 3H ), 1.27 (t, J=6.8 Hz, 3H).

[0471] Example 18b: LC-MS: (ESI, m/z): 654.2 [M+H] ⁺ , ¹ H NMR: (400 MHz, DMSO-d ₆ , ppm) δ 7.80 (s, 1H), 6.85 (s, 2H), 6.83-6.68 (m, 2H), 6.50 (s, 1H), 5.20 (d, J=2.8 Hz, 1H), 5.08 (d, J=2.8 Hz, 1H), 4.71 (s, 1Н), 4.39-4.23 (m, 2Н), 4.20-3.93 (m, 3Н), 3.70-3.60 (m, 1Н), 3.51-3.09 (m, 2Н), 2.96-2.93 (m, 1Н ), 2.60-2.52 (m, 1H), 2.37-2.36 (m, 6H), 2.18 (dd, J=16.4, 8.0 Hz, 1H), 1.99-1.90 (m, 1H), 1.72-1.59 (m, 3H ), 1.30 (t, J=8.0 Hz, 3H).

Example 19: 1-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3 -methylpiperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl] piperazine-1-carboxylate

[0472] In nitrogen, a solution of N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-pyridin-2-amine (4.0 g, 6.27 mmol) and tert-butyl 4 -[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]piperazin-1-carboxylate (2 .31 g, 5.02 mmol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.63 mmol), lithium chloride (0.66 g, 15.69 mmol) and copper iodide (0.12 g, 0 .63 mmol) in 1,4-dioxane (100 ml) was stirred at 120° C. for 3 hours. Upon completion, the solution was diluted with water (200 ml) and extracted with ethyl acetate (3×50 ml). Then the organic layers were combined and dried over anhydrous sodium sulfate. The organic layers were concentrated in vacuo and the residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/20) to give t-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl] amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]piperazin-1-carboxylate (1.1 g, 1.54 mmol, 24.6% yield) as yellow oil. LC-MS: (ESI, m/z): 713.3 [M+H] ⁺

Step 2: tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-iodo-4-methyl-2-pyridyl]-6-chloro-8- fluoro-quinazolin-4-pl]-3-methyl-piperazine-1-carboxylate

[0473] 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl tert-butyl solution ]piperazine-1-carboxylate (2 g, 3 mmol) and N-iodosuccinimide (1 g, 3.00 mmol) in acetonitrile (200 ml) were stirred at 50°C for 4 hours. Upon completion, the solution was diluted with water (30 ml) and extracted with ethyl acetate (4×50 ml) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/20) to give t-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]- 3-iodo-4-methyl-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate (1.3 g, 1.55 mmol, 656 yield .5%) as a yellow oil. LC-MS: (ESI, m/z): 839.2 [M+H] ⁺

Step 3: tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro- 8-fluoro-quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate

[0474] Under nitrogen, a solution of tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl] -6-chloro-8-fluoro-quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate (0.1 g, 0.12 mmol), (1,10-phenanthroline) (trifluoromethyl) copper (I ) (0.73 g, 2.34 mmol) and copper iodide (0.45 g, 2.34 mmol) in N,N-dimethylformamide (5 ml) were stirred at 50° C. for 5 hours. Upon completion, the solution was diluted with water (30 ml) and extracted with ethyl acetate (4×350 ml) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/5) to give t-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]- 4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate (60 mg, 0.075 mmol, 64.4 yield %) as a yellow solid. LC-MS: (ESI, m/z): 781.3 [M+H] ⁺

Step 4: 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0475] tert-Butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro solution -8-fluoro-quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate (0.1 g, 0.13 mmol) in trifluoroacetic acid (5.0 ml) was stirred at 50° C. for 3 hours . Upon completion, the solution was diluted with water (30 ml) and extracted with ethyl acetate (3×50 ml) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (1/9) to give 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7 -yl]-4-methyl-5-(trifluoromethyl)pyridine-2-amine (40 mg, 0.08 mmol, 69.9% yield) as a yellow oil. LC-MS: (ESI, m/z): 441.1 [M+H] ⁺

Step 5: 1-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3 -methylpiperazin-1-yl)prop-2-en-1-one

[0476] A solution of 6-[6-chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2- amine (0.04 g, 0.09 mmol) and HATU (0.07 g, 0.18 mmol), N,N-diisopropylethylamine (0.03 g, 0.26 mmol) in dichloromethane (3 ml) was stirred at -78°C for 0.5 hour. Then added acrylic acid (0.01 g, 0.13 mmol) and stirred at -78°C for 4 hours. Upon completion, the solution was diluted with water (30 ml) and extracted with ethyl acetate (3×50 ml) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was further isolated by preparative HPLC under the following conditions, column: CHIRALPAK IE, 2*25 cm, 5 µm; mobile phase A: MTBE(10 mM NH ₃ - methanol)--HPLC; mobile phase B: methanol--HPLC; flow rate: 20 ml/min; gradient: 15 V to 15 V in 27 min; 220/254 nm; RT1:17.672; RT2:23.294 to give 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-quinazolin-4-yl ]-3-methyl-piperazin-1-yl]prop-2-en-1-one (10 mg, 0.019 mmol, 22.3% yield) as a white solid. LC-MS: (ESI, m/z): 509.1 [M+H] ⁺

[0477] Example 19: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 8.67 (s, 1H), 7.92 (s, 1H), 6.89-6.82 (m, 1H), 6.62 (s, 1H), 6.32-6.26 (m, 1H), 5.83-5.80 (m, 1H), 4.56-4.39 (m, 1H), 4.38-4.30 (m, 1H), 4.20-4.02 (m, 1H), 3.80- 3.52 (m, 2H), 3.33-3.30 (m, 1H), 3.22-3.13 (m, 1H), 2.45 (s, 3H), 1.42 (d, J=1.6 Hz, 3H).

Example 20: 1-[4-[7-[6-Amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidin-1-yl)quinazolin-4-yl]piperazin-1-yl]prop- 2-en-1-he

Synthetic way

Step 1: tert-butyl 4-[6-(azetidin-1-yl)-7-bromo-quinazolin-4-yl]piperazine-1-carboxylate

[0478] In nitrogen, a solution of tert-butyl 4-(7-bromo-6-iodo-quinazolin-4-yl)piperazin-1-carboxylate (5.5 g, 10.59 mmol), azetidine (1.2 g , 21.19 mmol), tris(dibenzylideneacetone) dipalladium (609.15 mg, 1.06 mmol), xanthos (1.22 g, 2.12 mmol) and cesium carbonate (6.9 g, 21.19 mmol) in 1,4-dioxane (20 ml) was stirred at 80°C for 2 hours. Upon completion, the solution was diluted with ethyl acetate (200 ml) and washed with brine (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (45/55) to give mpem-butyl 4-[6-(azetidin-1-yl)-7-bromo-quinazolin-4-yl]piperazin- 1-carboxylate (1.0 g, 2.24 mmol, 21.1% yield) as a yellow solid. LC-MS: (ESI, m/z): 448.1 [M+H] ⁺

Step 2: tert-butyl 4-[6-(azetidin-1-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl] piperazine-1-carboxylate

[0479] Under nitrogen, a solution of tert-butyl 4-[6-(azetidin-1-yl)-7-bromo-quinazolin-4-yl]piperazin-1-carboxylate (1.0 g, 2.23 mmol), bis (pinacolato) diboron (5.66 g, 22.3 mmol), dichloromethane complex of 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride (182.0 mg, 0.22 mmol) and potassium acetate ( 437.15 mg, 4.46 mmol) in 1,4-dioxane (15 ml) was stirred at 80° C. for 3 hours. Upon completion, the solution was diluted with dichloromethane (100 ml). After completion, the filtrate was concentrated under reduced pressure. The residue was diluted with petroleum ether (100 ml). After filtration, the filter cake was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/1) to give t-butyl 4-[6-(azetidin-1-yl)-7-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate (500 mg, 1.01 mmol, 45.3% yield) as a yellow solid. LC-MS: (ESI, m/z): 496.3 [M+H] ⁺

Stage 3; mpem-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidin-1-yl)quinazolin-4-yl]piperazine-1-carboxylate

[0480] In nitrogen, a solution of tert-butyl 4-[6-(azetidin-1-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin- 4-yl]piperazin-1-carboxylate (500.0 mg, 1.01 mmol), 6-bromo-5-(trifluoromethyl)pyridin-2-amine (243.24 mg, 1.01 mmol), bis(triphenylphosphine )palladium(II) chloride (70.85 mg, 0.10 mmol) and potassium fluoride (117.07 mg, 2.02 mmol) in acetonitrile (10 ml) and water (2 ml) were stirred at 80°C for 2 hours. Upon completion, the solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (3/97) to give t-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidine- 1-yl)quinazolin-4-yl]piperazin-1-carboxylate (280 mg, 0.53 mmol, 52.4% yield) as a yellow solid. LC-MS: (ESI, m/z): 530.2 [M+H] ⁺

Step 4: 6-[6-(azetidin-1-yl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine

[0481] A solution of tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidin-1-yl)quinazolin-4-yl]piperazin-1-carboxylate (200 .0 mg, 0.38 mmol) and silica gel (1.0 g) in toluene (20 ml) were stirred at 110° C. for 12 hours. Upon completion, the solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (1/9) to give 6-[6-(azetidin-1-yl)-4-piperazin-1-yl-quinazolin-7-yl]-5 -(trifluoromethyl)pyridine-2-amine (150 mg, 0.35 mmol, 92.5% yield) as a yellow solid. LC-MS: (ESI, m/z): 430.2 [M+H] ⁺

Step 5: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidin-1-yl)quinazolin-4-yl]piperazin-1-yl]prop- 2-en-1-he

[0482] 6-[6-(azetidin-1-yl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine solution (150.0 mg, 0. 35 mmol), acrylic acid (25.17 mg, 0.35 mmol), HATU (159.37 mg, 0.42 mmol) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) in dichloromethane (10 ml ) was stirred at 25° C. for 1 hour. Upon completion, the solution was diluted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with acetonitrile/water (1/1) to give 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(azetidine- 1-yl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (5.9 mg, 3.5% yield) as a yellow solid. LC-MS: (ESI, m/z): 484.2 [M+H] ⁺

[0483] Example 20: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 8.50 (s, 1H), 7.83 (d,J=9.0 Hz, 1H), 7.54 (s, 1H), 6.91 -6.82 (m, 1H), 6.75-6.70 (m, 2H), 6.30 (dd, J=16.8, 2.0 Hz, 1H), 5.83 (dd, J=10.6, 2.0 Hz, 1H), 3.99-3.81 (m , 8Н), 3.78-3.61 (m, 4Н), 2.29-2.19 (m, 2Н).

Example 21 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-(1,1-difluoroethyl)quinazolin-4-yl)piperazin-1-yl)prop -2-en-1-he

Synthetic way

Step 1: tert-butyl 4-(6-acetyl-7-bromoquinazolin-4-yl)piperazine-1-carboxylate

[0484] In nitrogen, a solution of mpem-butyl 4-(7-bromo-6-iodo-quinazolin-4-yl)piperazin-1-carboxylate (1.8 g, 3.47 mmol), tributyl(1-ethoxyvinyl) tin (2.5 g, 6.93 mmol), bis(triphenylphosphine)palladium(II) chloride (243.4 mg, 0.35 mmol) in 1,4-dioxane (40 ml) was stirred at 65°C for 30 hours. After completion, hydrochloric acid (40 ml, 2 M) was added to the solution, stirred at 25° C. for 0.5 hour. The solvent was then concentrated in vacuo. The residue was diluted with water (40 ml) and the pH of the resulting solution was adjusted to pH=9 with potassium carbonate. Then di-tert-butyl dicarbonate (1.67 g, 7.61 mmol) was added and the solution was stirred at 25° C. for 2 hours. Upon completion, the solution was extracted with ethyl acetate (100 ml) and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase elution with acetonitrile/water (1:1) to give tert-butyl 4-(6-acetyl-7-bromoquinazolin-4-yl)piperazin-1-carboxylate (1.0 g, 2.30 mmol, 66.3% yield) as a yellow oil. LC-MS: (ESI, m/z): 435.1, 437.1 [M+H] ⁺ .

Step 2: tert-butyl 4-[7-bromo-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazine-1-carboxylate

[0485] A solution of tert-butyl 4-(6-acetyl-7-bromoquinazolin-4-yl)piperazin-1-carboxylate (1.2 g, 2.8 mmol), diethylaminosulfur trifluoride (3.6 ml, 27.6 mmol) in chloroform (30 ml) was stirred at 25°C for 36 hours. Upon completion, the solution was quenched with water (5 ml) and concentrated in vacuo. The residue was purified by elution on a reverse phase column with acetonitrile/water (5/1) to give tert-butyl 4-[7-bromo-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazin-1-carboxylate (570 mg, 1.2 mmol, 45.2% yield) as a light brown solid. LC-MS: (ESI, m/z): 457.1, 459.1 [M+H] ⁺ .

Step 3: tert-butyl 4-[6-(1,1-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl] piperazine-1-carboxylate

[0486] Under nitrogen, a solution of tert-butyl 4-[7-bromo-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazin-1-carboxylate (550.0 mg, 1.2 mmol), bis (pinacolato) diboron (1.5 g, 6.0 mmol), dichloromethane complex 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride (88.0 mg, 0.1 mmol), potassium acetate ( 353.6 mg, 3.6 mmol) in toluene (20.0 ml) was stirred at 95° C. for 4 hours. Upon completion, the solution was concentrated in vacuo. The residue was purified by reverse phase elution with acetonitrile/water (4/1) to give tert-butyl 4-[6-(1,1-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (350.0 mg, 0.7 mmol, 57.7% yield) as a light yellow oil. LC-MS: (ESI, m/z): 505.3 [M+H] ⁺ .

Step 4: tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazine-1-carboxylate

[0487] In nitrogen, a solution of tert-butyl 4-[6-(1,1-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin- 4-yl]piperazin-1-carboxylate (350.0 mg, 0.7 mmol), 6-bromo-5-(trifluoromethyl)pyridin-2-amine (167.2 mg, 0.7 mmol), potassium carbonate ( 287.3 mg, 2.1 mmol) and

bis(triphenylphosphine)palladium(II) chloride (48.7 mg, 0.1 mmol) in acetonitrile (20 ml) and water (2 ml) were stirred for 4 h at 95°C. Upon completion, the solution was concentrated in vacuo. The residue was purified with reverse phase acetonitrile/water (6:1) to give tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(1,1-difluoroethyl)quinazoline- 4-yl]piperazin-1-carboxylate (170 mg, 0.3 mmol, 45.5% yield) as light brown oil. LC-MS: (ESI, m/z): 539.2 [M+H] ⁺ .

Step 5: 6-[6-(1,1-difluoroethyl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine

[0488] A solution of tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazin-1-carboxylate (160 .0 mg, 0.3 mmol) in dichloromethane (10 ml) and trifluoroacetic acid (2 ml) were stirred at 25° C. for 3 hours. Upon completion, the solution was concentrated in vacuo to give 6-[6-(1,1-difluoroethyl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine (crude 170 mg ) as a light brown oil, which was used for the next step without purification. LC-MS: (ESI, m/z): 439.2 [M+H] ⁺

Step 6: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-(1,1-difluoroethyl)quinazolin-4-yl]piperazin-1-yl]prop- 2-en-1-he

[0489] Solution (6-[6-(1,1-difluoroethyl)-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine (160.0 mg, 0 .4 mmol), HATU (346.9 mg, 0.9 mmol), acrylic acid (52.6 mg, 0.7 mmol) and N,N-diisopropylethylamine (235.4 mg, 1.8 mmol) in dichloromethane (10 ml) was stirred at -78°C for 1.0 h After completion, the solution was quenched with water (5 ml) The resulting solution was extracted with dichloromethane (3×20 ml) and the organic layers were combined The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo The residue was purified by reverse phase elution with acetonitrile/water (6/1) to give 100 mg of the crude product The crude product was then purified by preparative HPLC to give 1-(4-(7-(6 -amino-3-(trifluoromethyl)pyridin-2-yl)-6-(1,1-difluoroethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (22.1 mg , 0.04 mmol, 12.3% yield) as an off-white solid LC-MS: (ESI, m/z): 493.2 [M+H] ⁺ .

[0490] Example 21: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 8.69 (s, 1H), 8.26 (s, 1H), 7.78 (d, J=7.2 Hz, 1 H), 7.67 (s, 1H), 6.84 (dd, J=16.8, 10.4 Hz, 1H), 6.67 (d,J=8.8 Hz, 1H), 6.29 (dd, J=16.8, 2.0 Hz, 1H), 5.82 ( dd, J=10.4, 2.0 Hz, 1H), 4.15-4.00 (m, 4H), 3.99-3.86 (m, 4H), 2.02 (dd, J=19.2, 18.4 Hz, 3H).

Example 22 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-1-prop-2-enoyl-piperidin-4 -carbonitrile

Synthetic way

Stage 1: 7-bromo-4,6-dichloroquinazoline

[0491] A solution of 7-bromo-6-chloro-3H-quinazolin-4-one (50 g, 38.5 mmol), N,N-dimethylformamide (1.0 ml) in thionyl chloride (500 ml, 192.7 mmol) was stirred at 80°C for 3 hours. Upon completion, the solution was concentrated in vacuo. The residue was then purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/10) to give 7-bromo-4,6-dichloro-quinazoline (26 g, 98% yield) as a white solid.

Step 2: 7 tert-butyl 4-(7-bromo-6-chloro-quinazolin-4-yl)-4-cyano-piperidine-1-carboxylate

[0492] In nitrogen, to a solution of 1-Boc-4-cyanopiperidine (18.9 g, 90.0 mmol) and 7-bromo-4,6-dichloro-quinazoline (5.0 g, 18.0 mmol) in dry toluene (100 ml) was added TMPMgCl⋅LiCl (54.0 ml, 54.0 mmol, 1.0 M in THF) at -78°C over 0.5 h. After completion, the solution was quenched with water (50 ml ) and extracted with ethyl acetate (3×100 ml) and the organic layers combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/petroleum ether (1/2) to give the crude product. The crude material was then repurified by reverse phase chromatography eluting with acetonitrile/water (7/3) to give tert-butyl 4-(7-bromo-6-chloro-quinazolin-4-yl)-4-cyano-piperidin-1- carboxylate (1.6 g, 3.5 mmol, 19.7% yield). LC-MS: (ESI, m/z): 451.0 [M+H] ⁺

Step 3: tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-4-cyano-piperi din-1-carboxylate

[0493] Under nitrogen, a solution of tert-butyl 4-(7-bromo-6-chloro-quinazolin-4-yl)-4-cyano-piperidine-1-carboxylate (1.0 g, 2.2 mmol), bis (pinacolato)diboron (2.8 g, 11.1 mmol), dichloromethane complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (310.4 mg, 0.4 mmol) and potassium acetate (650 .8 mg, 6.6 mmol) in 1,4-dioxane (30 ml) was stirred at 110° C. for 2 hours. Upon completion, the solution was diluted with water (30 ml) and extracted with dichloromethane (3×50 ml) and combined organic layers. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography eluting with acetonitrile/water (7/3) to give tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)quinazolin-4-yl]-4-cyano-piperidine-1-carboxylate (300 mg, 0.6 mmol, 27.2% yield) as off-white solid, LC-MS: (ESI, m /z): 499.2 [M+H] ⁺ .

Step 4: tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-4-cyano-piperidin-1- carboxylate

[0494] In nitrogen, a solution of tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-4 -cyano-piperidine-1-carboxylate (200.0 mg, 0.48 mmol), 6-bromo-4-methyl-5-(trifluoromethyl) pyridine-2-amine (134.7 mg, 0.5 mmol), bis(triphenylphosphine)palladium(II) chloride (33.7 mg, 0.05 mmol), potassium fluoride (83.5 mg, 1.4 mmol) in acetonitrile (10 ml) and water (1 ml) were stirred at 80° C within 1 hour. Upon completion, the solution was diluted with water (20 ml) and extracted with dichloromethane (3×50 ml) and combined organic layers. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column eluting with petroleum ether/ethyl acetate (2/1) to give tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro -quinazolin-4-yl]-4-cyano-piperidine-1-carboxylate (140 mg, 0.26 mmol, 53.3% yield) as a white solid. LC-MS: (ESI, m/z): 547.2 [M+H] ⁺ .

Step 5: 4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl)piperidine-4-carbonitrile 2,2,2-trifluoroacetate

[0495] 4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-4-cyano-piperidin-1 tert-butyl solution -carboxylate (140.0 mg, 0.26 mmol) in dichloromethane (5 ml) and trifluoroacetic acid (0.5 ml) was stirred at 25°C for 3 hours. Upon completion, the solution was concentrated in vacuo to give 150 mg of crude product, which was used for the next step without purification. LC-MS: (ESI, m/z): 447.1 [M+H] ⁺ .

Step 6: 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-1-prop-2-enoyl-piperidine-4 -carbonitrile

[0496] Acrylic acid solution (32.3 mg, 0.5 mmol), HATU (85.1 mg, 0.2 mmol), N,N-diisopropylethylamine (86.6 mg, 0.7 mmol) and 4- (7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl)piperidine-4-carbonitrile 2,2,2-trifluoroacetate in dichloromethane (5 ml) stirred at 25°C for 20 min. Upon completion, the solution was quenched with water (30 ml) and extracted with dichloromethane (3×30 ml) and combined organic layers. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (1/49) to give the crude product. The crude material was then purified by reverse phase elution with acetonitrile/water (6/1) to give 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazoline-4 -yl]-1-prop-2-enoyl-piperidine-4-carbonitrile (2.1 mg, 0.0042 mmol, 1.9% yield) as a white solid. LC-MS: (ESI, m/z): 501.1 [M+H] ⁺ .

[0497] Example 22 ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 9.34 (s, 1H), 8.87 (s, 1H), 8.02 (s, 1H), 6.91-6.87 (m, 1H ), 6.63 (s, 1Н), 6.27 (dd, J=16.8, 2.0 Hz, 1Н), 5.82 (dd, J=10.8, 2.0 Hz, 1Н), 4.82-4.78 (m, 1Н), 4.65(m, 1Н), 4.44-4.35 (m, 1Н), 3.81-3.72 (m, 1Н), 3.40-3.35 (m, 1Н), 2.69-2.60 (m, 2Н), 2.48 (s, 3Н), 2.45-2.35 ( m, 1H).

Example 23 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-1-(cyclobutene-1-carbonyl)piperazin- 2-carbonitrile

Synthetic way

Stage 1: cyclobutene-1-carbonyl chloride

[0498] A solution of cyclobutene-1-carboxylic acid (300.0 mg, 3.1 mmol), N,N-dimethylformamide (22.3 mg, 0.3 mmol) in dichloromethane (20 ml) was stirred at 0°C in within 0.5 hours. Then oxalic acid chloride (582.3 mg, 4.6 mmol) was added and stirred at 0° C. for 3 hours. After completion, the solution was concentrated in vacuo to give 350 mg of crude product, which was directly used for the next step.

Step 2: 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-1-(cyclobutene-1-carbonyl)piperazin- 2-carbonitrile

[0499] 4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin-2-carbonitrile solution (150.0 mg, 0.3 mmol) and triethylamine (507.4 mg, 5.0 mmol) in dichloromethane (25 ml) were stirred at 25°C for 0.5 hour. Then cyclobutene-1-carbonyl chloride (195.2 mg, crude) was added and stirred at 25° C. for 16 hours. The reaction was quenched with methanol. Upon completion, the solution was concentrated in vacuo. The residue was purified by preparative HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column 30*150 mm, 5 µm; Phase L: Water (10 mmol/l NH ₄ HCO ₃ ), Phase B: ACN. flow rate: 60 ml/min, RT: 6.15 min to give 4-[7-[6-amino-4-methyl- 3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-1-(cyclobutene-1-carbonyl)piperazine-2-carbonitrile (50.6 mg, 0.0958 mmol, yield 28, 6%) as a light yellow solid. LC-MS: (ESI, m/z): 528.1 [M+H] ⁺ .

[0500] Example 23 ¹ H NMR (300 MHz, CDCl ₃ , ppm) δ 8.88 (s, 1H), 8.15 (d, J=12.3 Hz, 1H), 7.91 (s, 1H), 6.69 (d, J=0.9 Hz, 1H), 6.51 (s, 1H), 5.82 (s, 1H), 4.85 (s, 2H), 4.47 (dd, J=13.8, 7.8 Hz, 2H), 4.28 (d, J=12.9 Hz, 1H), 3.88 (s, 1H), 3.40 (t, J=15.8 Hz, 1H), 3.32-3.14 (m, 1H), 2.94 (s, 2H), 2.66-2.57 (m, 2H), 2.51 (s, 3H).

Example 24 4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-1-(oxiran-2-carbonyl)piperazin- 2-carbonitrile

Synthetic way

Step 1: tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazine-1-carboxylate

[0501] Under nitrogen, a solution of tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin- 1-carboxylate (4.3 mg, 9.0 mmol), 6-chloro-4-methyl-5-(trifluoromethyl)pyridine-2-amine (1.5 mg, 7.2 mmol), bis(triphenylphosphine)palladium (II) chloride (504.1 mg, 0.7 mmol), potassium chloride (1.6 mg, 26.9 mmol) in acetonitrile (15 ml) and water (1.5 ml) were stirred at 100°C for 18 hours. Upon completion, the solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (10/1) to give t-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]- 6-chloro-quinazolin-4-yl]piperazine-1-carboxylate (2.8 g, 5.4 mmol, 59.8% yield) as a light brown solid. LC-MS: (ESI, m/z): 523.2 [M+H] ⁺ .

Step 2: 7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-ol

[0502] A solution of tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin-1-carboxylate (2, 5 g, 4.8 mmol), sodium hydroxide (573.7 mg, 14.3 mmol) in ethanol (30 ml) and water (10 ml) were stirred at 40°C for 16 hours. Upon completion, the solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/1) to give 7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazoline- 4-ol (1.5 g, 4.2 mmol, 88.5% yield) as a light yellow solid. LC-MS: (ESI, m/z): 355.0 [M+H] ⁺ .

Step 3: 4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazine-2-carbonitrile

[0503] Piperazine-2-carbonitrile dihydrochloride solution (3.6 mg, 19.7 mmol), 7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazoline- 4-ol (1.4 g, 4.0 mmol), BOP (1.0 g, 23.7 mmol), N,N-diisopropylethylamine (5.1 g, 39.5 mmol) in dichloromethane (50 ml) stirred at 25°C for 18 hours. Upon completion, the solution was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (10/1) to give 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro- quinazolin-4-yl]piperazin-2-carbonitrile (950 mg, 2.1 mmol, 53.7% yield) as a yellow solid. LC-MS: (ESI, m/z): 448.1 [M+H] ⁺ .

Step 4: 4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-1-(oxiran-2-carbonyl)piperazin- 2-carbonitrile

[0504] 4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin-2-carbonitrile solution (300.0 mg, 0.7 mmol), oxirane-2-carboxylic acid (88.5 mg, 1.0 mmol), BOP (592.6 mg, 1.3 mmol), N,N-diisopropylethylamine (432.1 mg, 3, 4 mmol) in N,N-dimethylformamide (20 ml) was stirred at 25°C for 24 hours. Upon completion, the solution was quenched with water (40 ml) and extracted with dichloromethane (3×100 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (10/1) to give 220 mg of crude product. The crude product was purified by preparative HPLC under the following conditions: Column, X Bridge C18, 19*150 mm, 5 µm; mobile phase A: Water/0.05%NH ₄ HCO ₃ , mobile phase B: ACN; (terms); Detector, UV 254 nm. 4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-1-(oxiran-2-carbonyl)piperazine-2-carbonitrile (10.6 mg, 0.02 mmol, 3.1% yield) as a white solid. LC-MS: (ESI, m/z): 518.1 [M+H] ⁺ .

[0505] Example 24: ¹ H NMR (300 MHz, CDCl ₃ , ppm) δ 8.90 (s, 1H), 8.21-8.09 (m, 1H), 7.91 (s, 1H), 6.50 (s, 1H), 5.85 -5.75 (m, 1H), 4.82 (s, 2H), 4.47-4.21 (m, 3H), 4.05-3.95 (m, 1H), 3.73 (t, J=3.4 Hz, 1H), 3.59-3.09 (m , 4H), 2.51 (s, 3H).

Example 25: 1-[4-[7-[6-Amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-2-(trifluoromethyl)piperazin-1-yl]prop -2-en-1-he

Synthetic way

Step 1: 1-[4-[7-[6-Amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-2-(trifluoromethyl)piperazin-1-yl]prop -2-en-1-he

[0506] 6-[6-Chloro-4-[3-(trifluoromethyl)piperazin-1-yl]quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine solution (200.0 mg, 0. 4 mmol) and acryloyl chloride (45.6 mg, 0.5 mmol), pyridine (0.07 ml, 0.8 mmol) in N,N-dimethylformamide (3 ml) were stirred at 0°C for 3 hours. Upon completion, the solution was quenched with water (10 ml) and extracted with dichloromethane (3×20 ml). The combined organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (1/10) to give 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazoline -4-yl]-2-(trifluoromethyl)piperazin-1-yl]prop-2-en-1-one (19.4 mg, 0.04 mmol, 8.7% yield) as a white solid. LC-MS: (ESI, m/z): 531.1 [M+H] ⁺ .

[0507] Example 25: ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.73 (s, 1H), 8.10 (s, 1H), 7.86-7.75 (m, 2H), 6.96 (s, 2Н), 6.93-6.88 (m, 1Н), 6.63 (d, 0.9 Hz, 1Н), 6.27 (t, J=12 Hz, 1H), 5.90-5.80 (m, 1H), 5.50-5.38 (m, 1H ), 4.55-4.20 (m, 3H), 3.90-3.68 (m, 2H), 3.56-3.40 (m, 1H).

Example 26 1-(4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)-2-fluoroprop -2-en-1-he

Synthetic way

Step 1: 1-(4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)-2-fluoroprop -2-en-1-he

[0508] 6-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine solution (240.0 mg, 0.6 mmol), 2-fluoroprop-2-enoic acid (60 mg, 0.7 mmol), HATU (260 mg, 0.7 mmol), N,N-diisopropylethylamine (150 mg, 1.2 mmol) in dichloromethane (10 ml) was stirred for 30 min at -78°C. Upon completion, the solution was quenched with water (20 ml) and extracted with dichloromethane (3×30 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10/1) to give 108 mg (38%) of 1-(4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl ]-6-chloroquinazolin-4-yl]piperazin-1-yl)-2-fluoroprop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 495.1 [M+H] ⁺ .

[0509] Example 26: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 8.68 (s, 1H), 8.18 (s, 1H), 7.71 (s, 1H), 6.61 (s, 1H) , 5.38-5.32 (dd, J=18.8, 3.6 Hz, 1H), 5.29-5.25 (dd, J=13.2, 4.0 Hz, 1H), 4.09-3.96 (m, 4H), 3.92 (s, 4H), 2.47 (s, 3H).

Example 27 1-[4-[7-(3-Amino-8-fluoro-1-isoquinolyl)-6-chloro-8-fluoro-quinazolin-4-yl]piperazin-1-yl]prop-2-ene -1-he

Synthetic way

Step 1: tert-butyl 4-(6-chloro-8-fluoro-7-(tributylstannyl)quinazolin-4-yl)piperazine-1-carboxylate

[0510] In nitrogen, a solution of tert-butyl 4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-carboxylate (2.0 g, 4.5 mmol), hexabutylditin (5, 2 g, 9.0 mmol), tris(dibenzylideneacetone) dipalladium (413 mg, 0.45 mmol), tricyclohexyl phosphine (230 mg, 0.9 mmol) and lithium chloride (565 mg, 13.5 mmol) in 1, 4-dioxane (20 ml) was stirred at 110°C for 5 hours. Upon completion, the reaction system was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (10/1) to give tert-butyl 4-(6-chloro-8-fluoro-7-(tributylstannyl)quinazolin-4-yl)piperazin-1 -carooxylate (1.5 g, 2.3 mmol) as a red oil. LC-MS: (ESI, m/z): 657.2 [M+H] ⁺ .

Step 2: tert-butyl 4-(7-(3-amino-8-fluoroisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)pyrerazine-1-carboxylate

[0511] In nitrogen, a solution of tert-butyl 4-(6-chloro-8-fluoro-7-(tributylstannyl)quinazolin-4-yl)piperazin-1-carboxylate (500 mg, 0.76 mmol), 1-bromo -8-fluoroisoquinoline-3-amine (183 mg, 0.76 mmol), tetrakis(triphenylphosphine)palladium (88 mg, 0.076 mmol), copper iodide (14.4 mg, 0.076 mmol) and lithium chloride (96 g, 2 .28 mmol) in 1,4-dioxane (5 ml) was stirred at 120° C. for 16 hours. Upon completion, the reaction system was diluted with water (10 ml) and extracted with ethyl acetate (3×20 ml). Then the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (2/1) to give tert-butyl 4-(7-(3-amino-8-fluoroisoquinolin-1-yl)-6-chloro-8- fluoroquinazolin-4-yl)pyrerazine-1-carboxylate (40 mg, 0.076 mmol, 10% yield) as a yellow solid. LC-MS: (ESI, m/z): 527.2 [M+H] ⁺ .

Step 3: 1-(6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)-8-fluoroisoquinolin-3-amine

[0512] tert-Butyl 4-(7-(3-amino-8-fluoroisoquinolin-1-yl)-6-chloro-8-fluoroquinazolin-4-yl)pyrerazine-1-carboxylate solution (60 mg, 0.1 mmol), trifluoroacetic acid (1.0 ml) in dichloromethane (5.0 ml) was stirred for 30 min at 25°C. Upon completion, the solution was concentrated in vacuo. The residue was then diluted with dichloromethane (10 ml) and the pH of the resulting solution was adjusted to pH=8 with N,N-diisopropylethylamine and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10/1) to give 30 mg of 1-(6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)-8-fluoroisoquinolin- 3-amine as a white solid. LC-MS: (ESI, m/z): 427.1 [M+H] ⁺ .

Step 4: 1-[4-[7-(3-Amino-8-fluoro-1-isoquinolyl)-6-chloro-8-fluoro-quinazolin-4-yl]piperazin-1-yl]prop-2-ene -1-he

[0513] 1-(6-Chloro-8-fluoro-4-piperazin-1-yl-quinazolin-7-yl)-8-fluoro-isoquinoline-3-amine solution (30.0 mg, 0.07 mmol) , acrylic acid (5.1 mg, 0.07 mmol), N,N-diisopropylethylamine (18.1 mg, 0.14 mmol) and HATU (32.1 mg, 0.08 mmol) in dichloromethane (2 ml) stirred at -78°C for 30 min. Upon completion, the reaction was quenched with water (20 ml) and extracted with ethyl acetate (3×50 ml). The solvent was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (4/96) to give 50 mg of crude material. The crude product was then further purified by preparative HPLC under the following conditions to give 1-[4-[7-(3-amino-8-fluoro-1-isoquinolyl)-6-chloro-8-fluoro-quinazolin-4-yl] piperazin-1-yl]prop-2-en-1-one (4.2 mg, 0.0087 mmol, 12.4% yield) as a white solid.

[0514] Preparative HPLC Column Conditions: XBridge Prep CI8 OBD Column, 5 µm, 19*150 mm; mobile phase A: Water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 20 ml/min; gradient: 35% B to 49% B in 7 min; 254/220 nm; Rt: 5.68 min

[0515] Example 27: LC-MS: (ESI, m/z): 481.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6, ppm) δ 8.71 (s, 1H), 8.04 (s, 1H), 7.51-7.45 (m, 2H), 6.87-6.80 (m, 3H), 6.41 ( d, J=5.2 Hz, 2H), 6.18 (d, J=16.4, 2.0 Hz, 1H), 5.75(dd, J=10.4, 2.4 Hz, 1H), 3.94-3.77 (m, 8H).

Example 28 1-[4-[7-[6-Amino-3-(trifluoromethyl)-2-pyridyl]-6-methylsulfonyl-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1 -he

Synthetic way

Step 1: tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-methylsulfonyl-quinazolin-4-yl]piperazine-1-carboxylate

[0516] In nitrogen, a solution of tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin-1-carboxylate (1.0 g, 1.96 mmol), sodium methanesulfinate (810.3 mg, 7.86 mmol) and copper(1) iodide (74.8 mg, 0.39 mmol) in dimethyl sulfoxide (20 ml) were stirred for 10 hours at 80°C. Upon completion, the reaction system was diluted with water (100 ml) and extracted with ethyl acetate (3×150 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (4/96) to give tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-methylsulfonylquinazoline -4-yl]piperazin-1-carboxylate (250 mg, 0.45 mmol, 23% yield) as a yellow solid. LC-MS: (ESI, m/z): 553.2 [M+H] ⁺

Step 2: 6-(6-methylsulfonyl-4-piperazin-1-yl-quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine

[0517] A solution of tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-methylsulfonyl-quinazolin-4-yl]piperazin-1-carboxylate (240.0 mg, 0 .43 mmol) and trifluoroacetic acid (1 ml) in dichloromethane (5 ml) were stirred at 25° C. for 1 hour. Upon completion, the resulting solution was concentrated in vacuo. The residue was diluted with dichloromethane (5 ml) and the pH of the resulting solution was adjusted to pH=9 with N,N-diisopropylethylamine. After concentration in vacuo, the residue was purified by reverse phase column eluting with water/acetonitrile (62/38) to give 6-(6-methylsulfonyl-4-piperazin-1-yl-quinazolin-7-yl)-5-( trifluoromethyl)pyridine-2-amine (150 mg, 0.33 mmol, 76.3% yield) as a yellow solid. LC-MS: (ESI, m/z): 453.1 [M+H] ⁺

Step 3: 1-[4-[7-[6-Amino-3-(trifluoromethyl)-2-pyridyl]-6-methylsulfonyl-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1 -he

[0518] 6-(6-Methylsulfonyl-4-piperazin-1-yl-quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine solution (140.0 mg, 0.31 mmol), HATU ( 141.2 mg, 0.37 mmol), acrylic acid (22.3 mg, 0.31 mmol) and N,N-diisopropylethylamine (0.11 ml, 0.62 mmol) in dichloromethane (5 ml) were stirred at - 78°C for 1 hour. Upon completion, the reaction was quenched with water (20 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a reverse phase column eluting with water/acetonitrile (75/25) to give 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-methylsulfonyl-quinazoline- 4-yl]piperazin-1-yl]prop-2-en-1-one (20.5 mg, 0.0405 mmol, 13.1% yield) as a white solid. LC-MS: (ESI, m/z): 507.1 [M+H] ⁺ .

[0519] Example 28: ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.74 (s, 1H), 8.68 (s, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.66 (s, 1H), 6.89 (s, 2H), 6.86-6.80 (m, 1H), 6.60 (d, J=8.1 Hz, 1H), 6.19 (dd, J=16.8, 2.4 Hz, 1H), 5.75 ( dd, J=10.5, 2.4 Hz, 1H), 4.05 (m, 4H), 3.86-3.72 (m, 4H), 3.42 (s, 3H).

Example 29 1-[4-[7-[6-Amino-3-(trifluoromethyl)-2-pyridyl]-6-cyclopropyl-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1 -he

Synthetic way

1-[4-[7-[6-Amino-3-(trifluoromethyl)-2-pyridyl]-6-cyclopropyl-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0520] 6-(6-Cyclopropyl-4-piperazin-1-yl-quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine solution (50.0 mg, 0.12 mmol), acrylic acid (8.7 mg, 0.12 mmol), HATU (45.87 mg, 0.12 mmol), N,N-diisopropylethylamine (15.6 mg, 0.12 mmol) in dichloromethane (10 mL) was stirred for 20 min at -78°C. Upon completion, the solution was quenched with water (20 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with dichloromethane/methanol (4/96) to give the crude product. The crude product was then purified by reverse phase chromatography eluting with water/acetonitrile (3/2) to give 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-cyclopropyl-quinazoline- 4-yl]piperazin-1-yl]prop-2-en-1-one (2.8 mg, 0.006 mmol, 5% yield) as a white solid. LC-MS: (ESI, m/z): 469.2 [M+H] ⁺ .

[0521] Example 29: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 8.62 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.63 (d, J=11.4 Hz , 2Н), 6.85 (dd, J=16.8, 10.6 Hz, 1Н), 6.71 (d, J=9.0 Hz, 1Н), 6.29 (dd, J=16.8, 2.0 Hz, 1Н), 5.82 (dd, J= 10.6, 1.9 Hz, 1H), 3.94 (s, 8H), 1.82 (t, J=5.8 Hz, 1H), 0.97-0.83 (m, 3H), 0.71 (d, J=5.6 Hz, 1H).

Example 30: 1-(4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-(trifluoromethyl)quinazolin-4-yl]piperazin-1 -yl)prop-2-en-1-one

Synthetic way

Step 1: 7-bromo-6-chloro-2-(trifluoromethyl)quinazolin-4(3H)-one

[0522] To a solution of 2-amino-4-bromo-5-chlorobenzoic acid (10 g, 39.9 mmol) in a mixture of chloroform (100 ml) and N,N-diisopropylethylamine (7.5 ml) at 0°C was added trifluoroacetic anhydride (84 g, 399.2 mmol). After completion of the addition, the reaction system was heated to reflux, where it was stirred for 3 hours. The reaction system was then cooled to room temperature and concentrated to give crude material. The crude material was diluted in chloroform (100 ml) saturated with ammonium gas and then stirred for 2 hours at room temperature. Upon completion, the mixture was concentrated in vacuo and the resulting solid was washed with water (100 ml). After filtration, the filter cake was collected and recrystallized from toluene to give 2.1 g (16%) of 7-bromo-6-chloro-2-(trifluoromethyl)quinazolin-4(3H)-one as a yellow solid. LC-MS: (ESI, m/z): 326.9 [M+H] ⁺ .

Step 2: tert-butyl 4-(7-bromo-6-chloro-2-(trifluoromethyl)quinazolin-4-yl)piperazine-1-carboxylate

[0523] 7-Bromo-6-chloro-2-(trifluoromethyl)quinazolin-4(3H)-one solution (4.0 g, 12.2 mmol, 1.00 equiv), t-butyl piperazin-1- carboxylate (4.6 g, 24.4 mmol), BOP (8.1 g, 18.3 mmol) and N,N-diisopropylethylamine (4.7 g, 36.5 mmol) in chloroform (100 ml) were stirred in for 15 h at 80°C. Upon completion, the solution was concentrated in vacuo. The residue was purified using a silica gel column with ethyl acetate/petroleum ether (1/2) hashing to give 5.2 g (85%) tert-butyl 4-(7-bromo-6-chloro-2-(trifluoromethyl)quinazoline-4- yl)piperazine-1-carboxylate as a light yellow solid. LC-MS: (ESI, m/z): 495.0 [M+H] ⁺ .

Step 3: tert-butyl 4-(6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)quinazolin-4-yl) piperazine-1-carboxylate

[0524] Under nitrogen, a solution of tert-butyl 4-(7-bromo-6-chloro-2-(trifluoromethyl)quinazolin-4-yl)piperazin-1-carboxylate (3.0 g, 6.0 mmol), bis (pinacolato) diboron (7.6 g, 30.3 mmol), dichloromethane complex of 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride (490.2 mg, 0.6 mmol) and potassium acetate ( 1.8 g, 18.0 mmol) in 1,4-dioxane (50 ml) was stirred at 80° C. for 2 hours. Upon completion, the resulting solution was diluted with dichloromethane (50 ml) and filtered. The filter was collected and concentrated in vacuo. The solid was washed with petroleum ether (3*30 ml) and collected by filtration to give 2.0 crude (80% pure) tert-butyl 4-(6-chloro-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)quinazolin-4-yl)piperazine-1-carboxylate as an off-white solid. LC-MS: (ESI, m/z): 543.2 [M+H] ⁺ .

Step 4: tert-Butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-(trifluoromethyl)quinazolin-4-yl]piperazin-1 -carboxylate

[0525] In nitrogen, a solution of tert-butyl 4-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)quinazolin-4-yl]piperazin-1- carboxylate (1.0 g crude, 80% pure, 1.5 mmol), 6-chloro-4-methyl-5-(trifluoromethyl)pyridine-2-amine (300 mg, 1.4 mmol), bis(triphenylphosphine) palladium(II) chloride (50 mg, 0.07 mmol), potassium fluoride (250 mg, 4.3 mmol) in acetonitrile (4 ml) and water (1 ml) were stirred for 30 min at 100°C. Upon completion, the resulting solution was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). Then, the organic layers were combined, washed with brine (3×20 ml) and dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified with a silica gel column eluting with ethyl acetate/petroleum ether (1/2) to give 400 mg (46%) tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridine-2 -yl]-6-chloro-2-(trifluoromethyl)quinazolin-4-yl]piperazine-1-carboxylate as an off-white solid. LC-MS: (ESI, m/z): 591.2 [M+H] ⁺ .

Step 5: 6-[6-chloro-4-(piperazin-1-yl)-2-(trifluoromethyl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridine-2-amine

[0526] A solution of tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-(trifluoromethyl)quinazolin-4-yl]piperazin- 1-carboxylate (490 mg, 0.8 mmol) in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) were stirred for 30 min at 25°C. Upon completion, the resulting solution was concentrated in vacuo. The residue was diluted with dichloromethane (5 ml) and the pH of the resulting solution was adjusted to pH=9 with N,N-diisopropylethylamine. After concentration in vacuo, the residue was purified with a silica gel column eluting with dichloromethane/methanol (85/15) to give 230 mg (57%) of 6-[6-chloro-4-(piperazin-1-yl)-2-(trifluoromethyl )quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine as a light brown solid. LC-MS: (ESI, m/z): 491.1 [M+H] ⁺ .

Step 6: 1-(4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-(trifluoromethyl)quinazolin-4-yl]piperazin-1 -yl)prop-2-en-1-one

[0527] 6-[6-Chloro-4-(piperazin-1-yl)-2-(trifluoromethyl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine solution (210 mg , 0.4 mmol), prop-2-enoic acid (40 mg, 0.6 mmol), HATU (200 mg, 0.5 mmol) and N,N-diisopropylethylamine (300 mg, 2.3 mmol) in dichloromethane (5 ml) was stirred for 30 min at -78°C. Upon completion, the solution was quenched with water (20 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. Then, the residue was purified by reverse phase chromatography eluting with water/acetonitrile (3/2) to give 49.6 mg (21%) of 1-(4-[7-[6-amino-4-methyl-3-(trifluoromethyl) pyridin-2-yl]-6-chloro-2-(trifluoromethyl)quinazolin-4-yl]piperazin-1-yl)prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 545.1 [M+H] ⁺ .

[0528] Example 30: ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.24 (s, 1H), 7.78 (s, 1H), 6.85-6.78 (m, 3H), 6.49 (s, 1Н), 6.22-6.15 (m, 1Н), 5.78-5.72 (m, 1Н), 4.08-4.00 (m, 4Н), 3.88-3.70 (m, 4Н), 2.37 (s, 3Н).

Example 31: 1-(4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-(methylamino)quinazolin-4-yl]piperazin-1 -yl)prop-2-en-1-one

Synthetic way

Step 1: tert-butyl 4-[7-bromo-6-chloro-2-(methylamino)quinazolin-4-yl]piperazine-1-carboxylate

[0529] tert-Butyl 4-(7-bromo-2,6-dichloroquinazolin-4-yl)piperazin-1-carboxylate solution (3 g, 6.5 mmol), methylamine hydrochloride (900 mg, 13.3 mmol) , potassium carbonate (2.3 g, 16.6 mmol), N,N-dimethylacetamide (60 ml) was stirred for 12 h at 100°C. Upon completion, the solution was diluted with water (150 ml) and extracted with ethyl acetate (3×150 ml). Then, the organic layers were combined and washed with saline (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with dichloromethane/methanol (10/1) to give 1.5 g (51%) tert-butyl 4-[7-bromo-6-chloro-2-(methylamino)quinazolin-4-yl] piperazine-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 456.1 [M+H] ⁺ .

Step 2: tert-butyl 4-[6-chloro-2-(methylamino)-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate

[0530] In nitrogen, a solution of tert-butyl 4-[7-bromo-6-chloro-2-(methylamino)quinazolin-4-yl]piperazin-1-carboxylate (500 mg, 1.1 mmol), bis(pinacolato ) diboron (1.4 g, 5.5 mmol), potassium acetate (323.1 mg, 3.3 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (89.8 mg, 0.1 mmol) in 1,4-dioxane (20 ml) was irradiated with microwave irradiation for 2 h at 80°C. Upon completion, the resulting solution was diluted with dichloromethane (20 ml and filtered. The filter was collected and concentrated in vacuo. The solid was washed with petroleum ether (3×30 ml) and collected by filtering 600 mg (crude) tert-butyl 4-(6- chloro-2-(methylamino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazin-1-carboxylate LC-MS: ( ESI, m/z): 504.2 [M+H] ⁺ .

Step 3: tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-(methylamino)quinazolin-4-yl]piperazin-1 -carboxylate

[0531] Under nitrogen, a solution of tert-butyl 4-(6-chloro-2-(methylamino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin- 4-yl)piperazin-1-carboxylate (500 mg, 1.0 mmol), bis(triphenylphosphine)palladium(II) chloride (69.8 mg, 0.1 mmol), potassium fluoride (115.5 mg, 2, 0 mmol) and 6-chloro-4-methyl-5-(trifluoromethyl)pyridine-2-amine (229.9 mg, 1.1 mmol) in acetonitrile (10 ml) and water (2 ml) were stirred for 1 h at 110°C. Upon completion, the resulting solution was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). Then, the organic layers were combined, washed with brine (3×20 ml) and dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10/1) to give 300 mg (55%) tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl ]-6-chloro-2-(methylamino)quinazolin-4-yl]piperazine-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 552.2 [M+H] ⁺ .

Step 4: 7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-7^r-methyl-4-(piperazin-1-yl)quinazolin-2-amine

[0532] A solution of tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-(methylamino)quinazolin-4-yl]piperazin- 1-carboxylate (110 mg, 0.2 mmol) in dichloromethane (5 ml) and trifluoroacetic acid (1 ml) were stirred for 30 min at 25°C. Upon completion, the resulting solution was concentrated in vacuo to give 110 mg (crude) 7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-N-methyl-4- (piperazin-1-yl)quinazolin-2-amine as a dark red solid, which was used for the next step without purification. LC-MS: (ESI, m/z): 452.1 [M+H] ⁺ .

Step 5: 1-(4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-(methylamino)quinazolin-4-yl]piperazin-1 -yl)prop-2-en-1-one

[0533] 7-[6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-N-methyl-4-(piperazin-1-yl)quinazolin-2-amine solution ( 110 mg crude), prop-2-enoic acid (17.5 mg, 0.2 mmol), HATU (92.6 mg, 0.2 mmol) and N,N-diisopropylethylamine (125.6 mg, 1.0 mmol) in dichloromethane (10 ml) was stirred for 30 min at -78°C. Upon completion, the solution was quenched with water (20 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10/1) to give the crude product. The crude product was then purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C18 OBD Column, 5 µm, 19*150 mm; mobile phase A: Water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: 15% B to 58% B in 7 min; 254/220 nm; Rt: 6.15 min to give 32.8 mg (27%) 1-(4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2 -(methylamino)quinazolin-4-yl]piperazin-1-yl)prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 506.2 [M+H] ⁺ .

[0534] Example 31: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 8.16 (s, 1H), 7.59-7.25 (m, 1H), 6.79 (dd, J=16.8, 10.5 Hz, 1Н), 6.65 (s, 1Н), 6.30 (dd, J=16.5, 1.8 Hz, 1Н), 5.82 (dd, J=10.8, 2.1 Hz, 1Н), 4.27 (s, 4Н), 3.94 (s, 4Н ), 3.09 (s, 3Н), 2.45 (s, 3Н).

Example 32: 1-(4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-methylquinazolin-4-yl]piperazin-1-yl) prop-2-en-1-one

Synthetic way

Step 1: 7-bromo-6-chloro-2-methyl-3,4-dihydroquinazolin-4-one

[0535] A solution of 2-amino-4-bromo-5-chlorobenzoic acid (10 g, 39.9 mmol) and acetyl acetate (50 ml) were stirred for 3 hours at 130°C. After completion, the resulting solution was concentrated. Then, the residue was diluted in chloroform (100 ml) saturated with ammonium gas, and then stirred for 2 hours at 80°C. Upon completion, the resulting solution was concentrated in vacuo and the resulting solid was washed with water (100 ml). After filtration, the filter cake was collected and recrystallized from toluene to give 8.4 g (77%) of 7-bromo-6-chloro-2-methyl-3,4-dihydroquinazolin-4-one as a yellow solid. LC-MS: (ESI, m/z): 272.9 [M+H] ⁺ .

Step 2: tert-butyl 4-(7-bromo-6-chloro-2-methylquinazolin-4-yl)piperazine-1-carboxylate

[0536] 7-Bromo-6-chloro-2-methyl-3,4-dihydroquinazolin-4-one solution (1 g, 3.66 mmol), tert-butyl piperazine-1-carboxylate (1.37 g, 7 .36 mmol), BOP (2.45 g, 5.54 mmol) and N,N-diisopropylethylamine (1.8 ml, 10.89 mmol) in chloroform (30 ml) were stirred for 15 hours at 8°C. Upon completion, the solution was concentrated in vacuo. The residue was purified with a silica gel column eluting with ethyl acetate/petroleum ether (1/2) to give 850 mg (53%) tert-butyl 4-(7-bromo-6-chloro-2-methylquinazolin-4-yl)piperazin-1 -carboxylate as a light yellow solid. LC-MS: (ESI, m/z): 441.1 [M+H] ⁺ .

Step 3: tert-butyl 4-[6-chloro-2-methyl-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate

[0537] Under nitrogen, a solution of tert-butyl 4-(7-bromo-6-chloro-2-methylquinazolin-4-yl)piperazin-1-carboxylate (2 g, 4.5 mmol), bis(pinacolato)diboron ( 3.3 g, 13.0 mmol), potassium acetate (1.3 g, 13.6 mmol, 3.0 equiv.) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex ( 196 mg, 0.24 mmol) in 1,4-dioxane (30 ml) was stirred for 12 hours at 80°C. Upon completion, the resulting solution was diluted with dichloromethane (30 ml) and filtered. The filter was collected and concentrated in vacuo. The solid was washed with petroleum ether (3 x 30 mL) and collected by filtration to give 1.9 g of crude (85% pure) tert-butyl 4-[6-chloro-2-methyl-7-(tetramethyl-1,3, 2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate as a brown solid. LC-MS: (ESI, m/z): 489.2 [M+H] ⁺ .

Step 4: tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-methylquinazolin-4-yl]piperazine-1-carboxylate

[0538] In nitrogen, a solution of tert-butyl 4-[6-chloro-2-methyl-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate ( 1 g, 2.1 mmol), 6-chloro-4-methyl-5-(trifluoromethyl) pyridine-2-amine (430 mg, 2.04 mmol), bis(triphenylphosphine) palladium(II) chloride (144 mg, 0.2 mmol) and potassium fluoride (195 mg, 3.4 mmol) in acetonitrile (20 ml) and water (4 ml) were stirred for 1 h at 100°C. After completion, the resulting solution was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). Then, the organic layers were combined, washed with brine (3×30 ml) and dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified with a silica gel column eluting with dichloromethane/methanol (20/1) to give 460 mg (42%) tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridine-2- yl]-6-chloro-2-methylquinazolin-4-yl]piperazine-1-carboxylate as a light yellow solid. LC-MS: (ESI, m/z): 537.2 [M+H] ⁺ .

Step 5: 6-[6-chloro-2-methyl-4-(piperazin-1-yl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0539] tert-Butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-methylquinazolin-4-yl]piperazin-1-carboxylate solution (350 mg, 0.65 mmol) in trifluoroacetic acid (3 ml) and dichloromethane (10 ml) was stirred for 30 min at room temperature. Upon completion, the resulting solution was concentrated in vacuo to give 700 mg (crude) of 6-[6-chloro-2-methyl-4-(piperazin-1-yl)quinazolin-7-yl]-4-methyl-5- (trifluoromethyl)pyridine-2-amine as a brown solid. LC-MS: (ESI, m/z): 431.1 [M+H] ⁺ .

Step 6: 1-(4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-methylquinazolin-4-yl]piperazin-1-yl) prop-2-en-1-one

[0540] 6-[6-Chloro-2-methyl-4-(piperazin-1-yl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine solution (285 mg, crude ), prop-2-enoic acid (94 mg, 1.30 mmol), HATU (370 mg, 1.0 mmol) and N,N-diisopropylethylamine (2 ml) in dichloromethane (15 ml) were stirred for 30 min at -78°C. Upon completion, the solution was quenched with water (20 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column eluting with dichloromethane/methanol (20/1) to give the crude product. The crude product was purified by preparative HPLC under the following conditions: column: X Bridge C18, 19*150 mm, 5 µm; mobile phase A: Water/0.05% TFA; mobile phase B: ACN; flow rate: 20 ml/min; gradient: 30%B to 70%B in 10 min; 254 nm to give 79.2 mg (12%) 1-(4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-methylquinazolin-4 -yl]piperazin-1-yl)prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 491.1 [M+H] ⁺

[0541] Example 32: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 8.12 (s, 1H), 7.62 (s, 1H), 6.84 (dd, J=16.8, 10.6 Hz, 1H) , 6.64-6.57 (m, 1Н), 6.29 (dd, J=16.8, 2.0 Hz, 1Н), 5.82 (dd, J=10.6, 2.0 Hz, 1Н), 3.98-3.89 (m, 8Н), 2.63 (s , 3Н), 2.46 (s, 3Н).

Example 33: 1-(4-[7-[6-Amino-3-methyl-4-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2- en-1-he

Synthetic way

Step 1: 1-(4-[7-[6-Amino-3-methyl-4-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2- en-1-he

[0542] 6-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-methyl-4-(trifluoromethyl)pyridin-2-amine solution (290.0 mg, 0.7 mmol), HATU (312.9 mg, 0.8 mmol), N,N-diisopropylethylamine (177.3 mg, 1.4 mmol), prop-2-enoic acid (49.4 mg, 0.7 mmol) in dichloromethane (10 ml) was stirred for 1 h at -78°C. Upon completion, the solution was quenched with water (20 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase column eluting with acetonitrile/water (3/7) to give 50.8 mg (16%) 1-(4-[7-[6-amino-3-methyl-4-(trifluoromethyl)pyridine -2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 411.1 [M+H] ⁺ .

[0543] Example 33: ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) 8.68 (s, 1H), 8.17 (s, 1H), 7.76 (s, 1H), 6.89-6.70 (m, 2H ), 6.50 (s, 2Н), 6.21-6.15 (m, 1Н), 5.78-5.72 (m, 1Н), 3.88-3.78 (m, 8Н), 1.99 (s, 3Н)

Example 34: 1-(4-(7-(6-Amino-4-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one

Synthetic way

Stage 1: 2,6-dichloro-4-cyclopropylpyridine

[0544] In nitrogen, to a solution of 2,6-dichloro-4-iodopyridine (3.6 g, 13.2 mmol), tetrakis(triphenylphosphine)palladium (1.5 g, 1.3 mmol) in dry THF (30 ml) was added a solution of bromine(cyclopropyl)zinc (26.4 ml, 26.4 mmol, 1.0 M in THF), then the solution was stirred for 1 h at 25°C. Upon completion, the solution was quenched with water (20 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product, the residue was loaded onto a silica gel column eluting with petroleum ether/ethyl acetate (10/1) to give 2.2 g (79%) of 2,6-dichloro-4-cyclopropylpyridine as an orange solid. LC-MS: (ESI, m/z): 188.0 [M+H] ⁺ .

Stage 2: 6-chloro-4-cyclopropylpyridin-2-amine

[0545] In nitrogen, 2,6-dichloro-4-cyclopropylpyridine solution (1.2 g, 6.4 mmol), diphenylmethanimine (1.16 g, 6.4 mmol), tris(dibenzylideneacetone) dipalladium complex chloroform (662 mg, 0.64 mmol), xanthos (370 mg, 0.64 mmol), cesium carbonate (4.2 g, 12.8 mmol) in 1,4-dioxane (25 ml) was stirred for 2 h at 90° FROM. Upon completion, the solution was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The organic layers were collected, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was diluted with hydrogen chloride (10 ml, 3M in 1,4-dioxane) and stirred for 1 h at 25°C. Upon completion, the solution was concentrated in vacuo. Then, the residue was diluted with dichloromethane (50 ml) and the pH of the resulting solution was adjusted to pH - 9 N,N-diisopropylethylamine. The resulting solution was then concentrated in vacuo and the residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1/3) to give 690 mg (64%) of 6-chloro-4-cyclopropylpyridin-2-amine as a white solid . LC-MS: (ESI, m/z): 169.0 [M+H] ⁺ .

Stage 3: 6-chloro-4-cyclopropyl-5-iodopyridine-2-amine

[0546] A solution of 6-chloro-4-cyclopropylpyridin-2-amine (690 mg, 4.1 mmol), N-iodosuccinimide (1.2 g, 5.3 mmol) in acetonitrile (10 ml) was stirred for 1 hour at 50°C. Upon completion, the solution was diluted with saturated sodium thiosulfate (50 ml) and extracted with ethyl acetate (4×50 ml). Then the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/4) to give 950 mg (79%) of 6-chloro-4-cyclopropyl-5-iodopyridin-2-amine as a brown solid. LC-MS: (ESI, m/z): 294.9 [M+H] ⁺ .

Step 4: 6-chloro-4-cyclopropyl-5-iodo-N,N-bis(4-methoxybenzyl)pyridine-2-amine

[0547] 6-Chloro-4-cyclopropyl-5-iodopyridin-2-amine solution (690 mg, 2.3 mmol), potassium carbonate (1.3 g, 9.4 mmol), 1-(chloromethyl)-4 -methoxybenzene (1.5 g, 9.6 mmol), potassium iodide (200 mg, 1.2 mmol) in N,N-dimethylformamide (5 ml) was stirred for 2 h at 110°C. Upon completion, the solution was diluted with water (25 ml) and extracted with ethyl acetate (3×30 ml). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (3/97) to give 1.2 g (96%) of 6-chloro-4-cyclopropyl-5-iodo-N,N-bis[(4-methoxyphenyl)methyl ]pyridine-2-amine as a colorless oil. LC-MS: (ESI, m/z): 535.1 [M+H] ⁺ .

Step 5: 6-chloro-4-cyclopropyl-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridine-2-amine

[0548] Under nitrogen, 6-chloro-4-cyclopropyl-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]pyridine-2-amine solution (1.2 g, 2.2 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (960 mg, 4.9 mmol) and copper iodide (880 mg, 4.621 mmol) in N,N-dimethylformamide (10 ml) were stirred for 1 h at 100°C . Upon completion, the solution was diluted with water (25 ml) and extracted with ethyl acetate (3×30 ml). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (3/97) to give 1.0 g (93%) of 6-chloro-4-cyclopropyl-N,N-bis[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)pyridine-2-amine as a light yellow oil. LCMS: (ESI, m/z): 477.1 [M+H] ⁺ .

Step 6: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin- 1-carboxylate

[0549] Under nitrogen, a solution of tert-butyl 4-(6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazin- 1-carboxylate (500 mg, 1.05 mmol), 6-chloro-4-cyclopropyl-N,N-bis[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyridine-2-amine (553 mg, 1 .16 mmol), bis(triphenylphosphine)palladium(II) chloride (77.2 mg, 0.1 mmol) and potassium fluoride (122 mg, 2.1 mmol) in acetonitrile (10 ml) and water (1 ml) were stirred for 30 min at 100°C. Upon completion, the resulting solution was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). Then, the organic layers were combined, washed with brine (3×20 ml) and dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified with a silica gel column eluting with ethyl acetate/petroleum ether (1/2) to give 491 mg (59%) tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-cyclopropyl- 3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate as an off-white solid. LC-MS: (ESI, m/z): 789.3 [M+H] ⁺ .

Step 7: 6-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl)-4-cyclopropyl-5-(trifluoromethyl)pyridin-2-amine

[0550] tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl)piperazine solution -1-carboxylate (491 mg, 0.62 mmol) in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) were stirred for 30 min at 25°C. Upon completion, the resulting solution was concentrated in vacuo. The residue was diluted with dichloromethane (5 ml) and the pH of the resulting solution was adjusted to pH=9 with N,N-diisopropylethylamine. After concentration in vacuo, the residue was purified with a silica gel column eluting with dichloromethane/methanol (83/17) to give 205 mg (74%) of 6-(6-chloro-4-(piperazin-1-yl)quinazolin-7-yl )-4-cyclopropyl-5-(trifluoromethyl)pyridine-2-amine as a light brown solid. LC-MS: (ESI, m/z): 449.1 [M+H] ⁺ .

Step 8: 1-(4-(7-(6-amino-4-cyclopropyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one

[0551] 6-(6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl)-4-cyclopropyl-5-(trifluoromethyl)pyridin-2-amine solution (205 mg, 0.46 mmol) , prop-2-enoic acid (33 mg, 0.46 mmol), HATU (210 mg, 0.55 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol) in dichloromethane (10 ml) were stirred in for 30 min at -78°C. Upon completion, the solution was quenched with water (30 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. Then, the residue was purified by reverse phase chromatography eluting with water/acetonitrile (3/2) to give 49.6 mg (21%) of 1-(4-[7-[6-amino-4-methyl-3-(trifluoromethyl) pyridin-2-yl]-6-chloro-2-(trifluoromethyl)quinazolin-4-yl]piperazin-1-yl)prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 503.1 [M+H] ⁺ .

[0552] Example 34: ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 8.75 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 6.75-6.65 (m, 1H) , 6.42-6.37 (m, 1H), 6.22 (s, 1H), 5.81 (dd, J=7.2, 2.4 Hz, 1H), 4.98 (s, 1H), 4.05-3.80 (m, 8H), 2.19 (s , 1Н), 1.25 (s, 1Н), 1.14–1.07 (m, 2Н), 0.88 (s, 2Н).

Example 35: 1-(4-[7-[6-Amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2-en-1- he

Synthetic way

Step 1: tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-carboxylate

[0553] 6-Chloro-5-(trifluoromethyl)pyridine-2-amine solution (400.0 mg, 2.04 mmol), t-butyl 4-[6-chloro-7-(tetramethyl-1,3,2 -dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (1.00 g, 2.11 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (164 .1 mg, 0.20 mmol) and K ₃ PO ₄ (848.0 mg, 3.99 mmol) in 1,4-dioxane (8 ml) and water (0.5 ml) were stirred for 60 min at 100 °C. Upon completion, the resulting solution was concentrated, diluted with dichloromethane (150 ml), washed with water (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column eluting with dichloromethane/methanol (20/1) to give 200.0 mg (19%) tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl] -6-chloroquinazolin-4-yl]piperazine-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 509.2 [M+H] ⁺

Step 2: 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine

[0554] A solution of tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-carboxylate (500.0 mg, 0. 98 mmol) in trifluoroacetic acid (3 ml) and dichloromethane (10 ml) was stirred for 60 min at room temperature. After completion, the resulting solution was concentrated. This gave 600.0 mg (crude) 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine as a brown oil. LC-MS: (ESI, m/z): 409.1 [M+H] ⁺

Step 3: 1-(4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2-en-1- he

[0555] Prop-2-enoic acid solution (10.0 mg, 0.14 mmol), 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-(trifluoromethyl) pyridine-2-amine (60.0 mg, 0.15 mmol), HATU (56.0 mg, 0.15 mmol) and N,N-diisopropylethylamine (1 ml, 5.69 mmol) in dichloromethane (5 ml) stirred for 30 min at room temperature. Upon completion, the resulting solution was concentrated and diluted with dichloromethane (150 ml), washed with brine (40 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a silica gel column eluting with dichloromethane/methanol (20/1). The product was obtained by HPLC under the following conditions: column: X Bridge C18, 19*150 mm, 5 µm; mobile phase A: water/0.05% TFA; mobile phase B: ACN; flow rate: 20 ml/min; gradient: 30% B to 70% B in 10 min; 254 nm. This gave 9.7 mg (15%) 1-(4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop -2-en-1-one as a white solid. LC-MS (ESI, m/z): 463.1 [M+H] ⁺

[0556] Example 35: ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.68 (s, 1H), 8.14 (s, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.72 (s, 1H), 6.95 (s, 2H), 6.84 (dd, J=16.5, 10.2 Hz, 1H), 6.62 (d, J=9.0 Hz, 1H), 6.18 (dd, J=16.8, 2.4 Hz, 1H), 5.75 (dd, J=10.5, 2.4 Hz, 1H), 3.87-3.79 (m, 8H).

Example 36 N-(1-(4-(4-acryloylpiperazin-1-yl)-6-chloroquinazolin-7-yl)isoquinolin-3-yl)cyclopropanecarboxamide

Synthetic way

Step 1: N-(1-(4-(4-acryloylpiperazin-1-yl)-6-chloroquinazolin-7-yl)isoquinolin-3-yl)cyclopropanecarboxamide

[0557] To a solution of 1-(4-(7-(3-aminoisoquinolin-1-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (160 mg, 0.36 mmol), pyridine (57 mg, 0.72 mmol) in dichloromethane (10 ml) was added cyclopropanecarbonyl chloride (41 mg, 0.4 mmol), then the solution was stirred for 30 min at 25°C. Upon completion, the resulting solution was quenched with water (30 ml), extracted with dichloromethane (3×30 ml), washed with brine (3×10 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (20/1) to give the crude product. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge Shield R.P18 OBD Column, 5 µm, 19*150 mm; mobile phase, Water (0.05% NH3 water) and ACN (10% ACN to 45% in 10 min); Detector, UV 254/220 nm. This gave 53.9 mg (29.3%) of N-(1-(4-(4-acryloylpiperazin-1-yl)-6-chloroquinazolin-7-yl)isoquinolin-3-yl)cyclopropanecarboxamide as a white solid . LC-MS: (ESI, m/z): 513.2 [M+H] ⁺ .

[0558] Example 36: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 8.71 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.95-7.92 (m, 2Н), 7.74-7.69(m, 1Н), 7.55 (d, J=8.4 Hz, 1Н), 7.47-7.42 (m, 1Н), 6.85 (dd, J=16.8, 10.8 Hz, 1Н), 6.30 (dd , J=16.8, 1.8 Hz, 1H), 5.83 (dd, J=10.6, 1.9 Hz, 1H), 4.08-4.04 (m, 4H), 3.98-3.92 (m, 4H), 1.95-1.92 (m, 1H ), 1.05–1.01 (m, 2Н), 0.94–0.89 (m, 2Н).

Example 37 N-(1-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]isoquinolin-3-yl)-2-hydroxyacetamide

Synthetic way

Step 1: N-(1-bromoisoquinolin-3-yl)-2-chloroacetamide

[0559] To a solution of 1-bromoisoquinoline-3-amine (200.0 mg, 0.9 mmol) and pyridine (100.0 mg, 1.3 mmol) in dichloromethane (5 ml) was added 2-chloroacetyl chloride (150, 0 mg, 1.3 mmol). The resulting solution was stirred for 30 min at 0° C. and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with ethyl acetate/petroleum ether (5/1) to give 210.0 mg (78%) of N-(1-bromoisoquinolin-3-yl)-2-chloroacetamide as a light yellow solid. LC-MS: (ESI, m/z): 299.0 [M+H] ⁺

Step 2: 2-((1-bromoisoquinolin-3-yl)amino)-2-oxoethyl acetate

[0560] A solution of N-(1-bromoisoquinolin-3-yl)-2-chloroacetamide (150.0 mg, 0.50 mmol) and potassium acetate (75.0 mg, 0.76 mmol) in N,N-dimethyl amide forms (5 ml) was stirred for 2 h at 100°C. Upon completion, the resulting solution was cooled to room temperature and diluted with water (50 ml). After filtration, the solids were collected and dried in vacuo to give 120 mg (66%) of 2-((1-bromoisoquinolin-3-yl)amino)-2-oxoethyl acetate as a white solid. LC-MS: (ESI, m/z): 323.0 [M+H] ⁺ .

Step 3: tert-butyl 4-[6-chloro-7-[3-(2-hydroxyacetamido)isoquinolin-1-yl]quinazolin-4-yl]piperazin-1-carboxylate

[0561] In nitrogen, a solution of 2-((1-bromoisoquinolin-3-yl)amino)-2-oxoethyl acetate (150.0 mg, 0.46 mmol), tert-butyl 4-[6-chloro-7-( tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate (250.0 mg, 0.53 mmol), dichloromethane complex 1,1'-bis(diphenylphosphino)ferrocene- palladium(II) dichloride (75.0 mg, 0.10 mmol) and cesium carbonate (400.0 mg, 1.20 mmol) in water (1 ml) and acetonitrile (5 ml) were stirred for 30 min at 80° FROM. Upon completion, the resulting solution was concentrated, diluted with 150 ml dichloromethane, washed with water (3×80 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column eluting with dichloromethane/methanol (20/1) to give 200.0 mg (78%) tert-butyl 4-[6-chloro-7-[3-(2-hydroxyacetamido)isoquinoline-1- yl]quinazolin-4-yl]piperazine-1-carboxylate as a light yellow solid. LC-MS: (ESI, m/z): 549.2 [M+H] ⁺

Step 4: N-[1-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]isoquinolin-3-yl]-2-hydroxyacetamide

[0562] tert-Butyl 4-[6-chloro-7-[3-(2-hydroxyacetamido)isoquinolin-1-yl]quinazolin-4-yl]piperazin-1-carboxylate solution (200.0 mg, 0.36 mmol) in dichloromethane (5 ml) and trifluoroacetic acid (3 ml) were stirred for 1 h at 25°C. Upon completion, the solution was concentrated in vacuo. The residue was then diluted with dichloromethane (20 ml), the pH of the resulting solution was adjusted to pH=8 with N,N-diisopropylethylamine and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (85/15) to give 100.0 mg (61%) N-[1-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl] isoquinolin-3-yl]-2-hydroxyacetamide as a light yellow solid. LC-MS: (ESI, m/z): 449.1 [M+H] ⁺ .

Step 5: N-(1-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]isoquinolin-3-yl)-2-hydroxyacetamide

[0563] To a solution of N-[1-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]isoquinolin-3-yl]-2-hydroxyacetamide (50.0 mg, 0.10 mmol ) and N,N-diisopropylethylamine (1 ml) in THF (5 ml) was added prop-2-enoyl chloride (11.0 mg, 0.10 mmol) and stirred for 30 min at -78°C. Upon completion, the solution was quenched with water (30 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: Column, XBridge Shield RP1 8 OBD Column, 5 µm, 19*150 mm; mobile phase, Water (0.05% NH3 water) and ACN (20% ACN to 45% in 7 min). This gave 6.0 mg (11%) N-(1-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]isoquinolin-3-yl) -2-hydroxyacetamide as a white solid. LC-MS: (ESI, m/z): 503.2 [M+H] ⁺ .

[0564] Example 37: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm): δ 8.71 (d, J=4.6 Hz, 2H), 8.33 (s, 1H), 8.01 (d, J=8.4 Hz, 1Н), 7.95 (s, 1Н), 7.80-7.74 (m, 1Н), 7.60-7.57 (m, 1Н), 7.53-7.47 (m, 1Н), 6.86 (dd, J=16.8, 10.6 Hz, 1Н), 6.31 (dd, J=16.8, 1.9 Hz, 1Н), 5.84 (dd, J=10.6, 2.0 Hz, 1Н), 4.23 (s, 2Н), 4.10-4.06 (m, 4Н), 3.99-3.94 (m, 4H).

Example 38: 1-[4-(6-chloro-7-[3-[(propan-2-yl)amino]isolinolin-1-yl]quinazolin-4-yl)piperazin-1-yl]prop-2- en-1-he

Synthetic way

Step 1: tert-butyl 4-(6-chloro-7-[3-[(propan-2-yl)amino]isoquinolin-1-yl]quinazolin-4-yl)piperazine-1-carboxylate

[0565] tert-Butyl 4-[7-(3-aminoisoquinolin-1-yl)-6-chloroquinazolin-4-yl]piperazin-1-carboxylate solution (400.0 mg, 0.82 mmol), AcOH (1 ml, 17.45 mmol), propan-2-one (60.0 mg, 1.00 mmol) in dichloromethane (5 ml) NaBH(OAc) ₃ (500 mg, 2.4 mmol) was added and stirred for 2 h at 25°C. Upon completion, the resulting solution was diluted with dichloromethane (150 ml), washed with water (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column eluting with dichloromethane/methanol (20/1) to give 350 mg (81%) tert-butyl 4-(6-chloro-7-[3-[(propan-2-yl)amino]isoquinoline -1-yl]quinazolin-4-yl)piperazin-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 533.2 [M+H] ⁺

Step 2: 1-[6-chloro-4-(pipepazin-1-yl)quinazolin-7-yl]-N-(propan-2-yl)isoquinolin-3-amine

[0566] A solution of tert-butyl 4-(6-chloro-7-[3-[(propan-2-yl)amino]isoquinolin-1-yl]quinazolin-4-yl)piperazin-1-carboxylate (350.0 mg, 0.66 mmol) in TFA (2 ml) and dichloromethane (10 ml) was stirred for 1 h at 25°C. Upon completion, the solution was concentrated in vacuo. The residue was then diluted with dichloromethane (10 ml) and the pH of the resulting solution was adjusted to pH=8 with N,N-diisopropylethylamine and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (85/15) to give 230.0 mg (81%) 1-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-N- (propan-2-yl)isoquinoline-3-amine as a yellow solid. LC-MS: (ESI, m/z): 433.2 [M+H] ⁺

Step 3: 1-[4-(6-chloro-7-[3-[(propan-2-yl)amino]isoquinolin-1-yl]quinazolin-4-yl)piperazin-1-yl]prop-2- en-1-he

[0567] To a solution of 1-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-N-(propan-2-yl)isoquinolin-3-amine (200.0 mg, 0. 46 mmol) in THF (5 ml) was added N,N-diisopropylethylamine (120.0 mg, 0.93 mmol) and prop-2-eonyl chloride (42.0 mg, 0.46 mmol), stirred for 60 min at -78°C. Upon completion, the solution was quenched with water (30 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with dichloromethane/methanol (10:1). The product was purified by preparative HPLC under the following conditions: Column, XBridge Shield RP18 OBD Column, 5 µm, 19*150 mm; mobile phase, Water (0.05% NH3 water) and ACN (28.0% ACN to 70.0% in 7 min); Detector, UV 220 nm. This gave 10.3 mg (4.6%) 1-[4-(6-chloro-7-[3-[(propan-2-yl)amino]isoquinolin-1-yl]quinazolin-4-yl)piperazine -1-yl]prop-2-en-1-one as a yellow solid. LC-MS: (ESI, m/z): 487.2 [M+H] ⁺

[0568] Example 38: ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 8.80 (s, 1H), 8.18-8.06 (s, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.52 -7.47 (m, 1H), 7.35-7.33 (m, 1H), 7.13-7.11 (m, 1H), 6.66-6.59 (m, 2H), 6.39 (dd, J=16.8, 1.8 Hz, 1H), 5.80 (dd, J=10.5, 1.8 Hz, 1H), 3.95-3.82 (m, 9H), 1.35-1.34 (m, 6H).

Example 39 2-[(1-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]isoquinolin-3-yl)amino]acetonitrile

Step 1: tert-butyl N-(1-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]isoquinolin-3-yl)-N-( cyanomethyl)carbamate

[0569] Under nitrogen, [6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]boronic acid solution (200.0 mg, 0.58 mmol), tert-butyl N-(1-bromoisoquinolin-3-yl)-N-(cyanomethyl)carbamate (167.0 mg, 0.46 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex dichloride (47.0 mg, 0.06 mmol) and cesium carbonate (373.0 mg, 1.14 mmol) in acetonitrile (5 ml) were irradiated with microwave radiation for 1.5 h at 80°C. Upon completion, the resulting solution was diluted with dichloromethane (150 ml), washed with water (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a silica gel column eluting with dichloromethane/methanol (20/1) to give 150 mg (45%) tert-butyl N-(1-[6-chloro-4-[4-(prop-2-enoyl)piperazine -1-yl]quinazolin-7-yl]isoquinolin-3-yl)-N-(cyanomethyl)carbamate as a yellow solid. LC-MS: (ESI, m/z): 584.2 [M+H] ⁺

Step 2: 2-[(1-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]isoquinolin-3-yl)amino]acetonitrile

[0570] A solution of tert-butyl N-(1-[6-chloro-4-[4-(prop-2-enoyl)piperazin-1-yl]quinazolin-7-yl]isoquinolin-3-yl)-N- (cyanomethyl)carbamate (200.0 mg, 0.34 mmol) and silica gel (205.0 mg, 3.41 mmol) in toluene (3 ml) were stirred for 2 h at 80°C. Upon completion, the resulting solution was concentrated in vacuo. The residue was applied to a silica gel column eluting with methanol/dichloromethane (1/10) to give 15.7 mg (9%) of 2-[(1-[6-chloro-4-[4-(prop-2-enoyl)piperazine- 1-yl]quinazolin-7-yl]isoquinolin-3-yl)amino]acetonitrile as a yellow solid. LC-MS: (ESI, m/z): 484.2 [M+H] ⁺

[0571] Example 39: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 8.71 (s, 1H), 8.31 (s, 1H), 7.93 (s, 1H), 7.77 (d, J= 8.4 1c, 1H), 7.58 (ddd, J=8.3, 6.7, 1.2 Hz, 1H), 7.45-7.42 (m, 1H), 7.23 (ddd, J=8.4, 6.8, 1.2 Hz, 1 H), 7.03 ( s, 1H), 6.86 (dd, J=16.8, 10.6 Hz, 1H), 6.31 (dd, J=16.8, 1.9 Hz, 1H), 5.84 (dd, J=10.6, 1.9 Hz, 1H), 4.44 (d , J=1.9 Hz, 2H), 4.09-4.06 (m, 4H), 3.97-3.95 (m, 4H).

Example 40: 1-(4-[7-[6-Amino-3-(trifluoromethoxy)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2-en-1- he

Synthetic way

Step 1: 3-(Bromodifluoromethoxy)-2-chloro-6-iodopyridine

[0572] To a solution of 2-chloro-6-iodopyridin-3-ol (2.0 g, 7.8 mmol) in N,N-dimethylformamide (15 ml) was added sodium hydride (1.0 g, 41.7 mmol ) followed by stirring a solution of dibromodifluoromethane (5.0 g, 23.8 mmol) in N,N-dimethylformamide (10 ml) for 3 hours at 25°C. Upon completion, the resulting solution was quenched by adding water (50 ml), extracted with dichloromethane (100 ml x 3), washed with water (100 ml x 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column and purified eluting with petroleum ether to give 1.8 g (60%) of 3-(bromodifluoromethoxy)-2-chloro-6-iodopyridine as a light yellow oil. LC-MS: (ESI, m/z): 383.8 [M+H] ⁺

Stage 2: 2-chloro-6-iodo-3-(trifluoromethoxy)pyridine

[0573] In nitrogen, to a solution of 3-(bromodifluoromethoxy)-2-chloro-6-iodopyridine (1.8 g, 4.7 mmol) in dichloromethane (10 ml) was added silver tetrafluoroborate (2.00 g, 10.30 mmol) and stirred for 16 h at -78°C. The solids were filtered off and the filtrate was concentrated in vacuo to give 1.0 g (crude) 2-chloro-6-iodo-3-(trifluoromethoxy)pyridine as a light yellow oil. LC-MS: (ESI, m/z): 323.9 [M+H] ⁺

Step 3: N-(6-chloro-5-(trifluoromethoxy)pyridin-2-yl)acetamide

[0574] In nitrogen, 2-chloro-6-iodo-3-(trifluoromethoxy)pyridine solution (500.0 mg, 1.50 mmol), acetamide (100.0 mg, 1.7 mmol), adduct

tris(dibenzylideneacetone) dipalladium-chloroform (80.0 mg, 0.1 mmol), xanthos (90.0 mg, 0.2 mmol) and cesium carbonate (1.0 g, 3.1 mmol) in 1.4- dioxane (5 ml) was stirred for 20 min at 50°C. Upon completion, the resulting solution was diluted with ethyl acetate (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (93/7) to give 300.0 mg (76%) of N-[6-chloro-5-(trifluoromethoxy)pyridin-2-yl]acetamide as light brown solid. LC-MS: (ESI, m/z): 255.0 [M+H] ⁺ .

Step 4: tert-butyl 4-[6-chloro-7-[6-acetamido-3-(trifluoromethoxy)pyridin-2-yl]quinazolin-4-yl]piperazin-1-carboxylate

[0575] In nitrogen, a solution of N-[6-chloro-5-(trifluoromethoxy)pyridin-2-yl)acetamide (200.0 mg, 0.79 mmol), tert-butyl 4-[6-chloro-7- (tetramethyl-1,3,2-dioxaborolan-2-yl) quinazolin-4-yl] piperazine-1-carboxylate (400.0 mg, 0.84 mmol), bis (triphenylphosphine) palladium (II) chloride (40, 0 mg, 0.06 mmol) and potassium fluoride (100.0 mg, 1.70 mmol) in acetonitrile (5 ml) and water (1 ml) were stirred for 20 min at 80°C. Upon completion, the resulting solution was diluted with:) tyl acetate (200 ml), washed with water (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane/methanol (97/3) quenching to give 420 mg (94%) tert-butyl 4-[6-chloro-7-[6-acetamido-3-(trifluoromethoxy)pyridin-2-yl ]quinazolin-4-yl]piperazine-1-carboxylate as a light yellow solid. LC-MS: (ESI, m/z): 567.2 [M+H] ⁺ .

Step 5: 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-(trifluoromethokei)pyridine-2-amine

[0576] 4-[6-Chloro-7-[6-acetamido-3-(trifluoromethokei)pyridin-2-yl]quinazolin-4-yl]piperazin-1-carboxylate solution (400.0 mg, 0.70 mmol ) in hydrochloric acid (5 ml, 3 M in methanol) was stirred for 2 hours at room temperature. Upon completion, the resulting solution was concentrated in vacuo. The residue was diluted with water (2 ml) and the pH of the resulting solution was adjusted to pH=10 with a solution saturated with potassium carbonate. Then, the mixture was extracted with n-butanol (60 ml x 3) and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (9:1) to give 150.0 mg (50%) of 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5- (trifluoromethoxy)pyridine-2-amine as a light yellow solid. LC-MS: (ESI, m/z): 425.1 [M+H] ⁺ .

Step 6: 1-(4-[7-[6-amino-3-(trifluoromethoxy)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2-en-1- he

[0577] 6-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-(trifluoromethoxy)pyridine-2-amine solution (100.0 mg, 0.24 mmol), HATU (150.0 mg, 0.39 mmol), prop-2-enoic acid (20.0 mg, 0.28 mmol) and N,N-diisopropylethylamine (100.0 mg, 0.80 mmol) in dichloromethane (10 ml) was stirred for 30 min at 25°C. Upon completion, the solution was quenched with water (20 ml) and extracted with dichloromethane (3×30 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (20/1) to give 68.0 mg (60%) 1-(4-[7-[6-amino-3-(trifluoromethoxy)pyridin-2-yl]- 6-chloroquinazolin-4-yl]piperazin-1-yl)propoen-1-one as a white solid. LC-MS: (ESI, m/z): 479.1 [M+H] ⁺ .

[0578] Example 40: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 8.68 (s, 1H), 8.22 (s, 1H), 7.85 (s, 1H), 7.64-7.55 (m, 1H), 6.84 (dd, J=16.8, 10.6 Hz, 1H), 6.74 (d, J=9.1 Hz, 1H), 6.29 (dd, J=16.8, 2.0 Hz, 1H), 5.82 (dd, J=10.7 , 2.0 Hz, 1H), 4.04–4.00 (m, 4H), 3.95–3.92 (m, 4H).

Example 41: 1-(4-[7-[6-Amino-3-(difluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2-en-1- he

Synthetic way

Step 1: 2,6-dichloro-3-(difluoromethyl)pyridine

[0579] To a solution of 2,6-dichloropyridine-3-carbaldehyde (20.00 g, 113.64 mmol) in dichloromethane (100 ml) was added diethylaminosulfur trifluoride (55.27 g, 342.86 mmol) and stirred for 60 min at 0°C. After completion, the reaction was quenched by adding 400 ml of an aqueous solution saturated with sodium carbonate, extracted with dichloromethane (200 ml × 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1:10) to give 15.7 g (70%) of 2,6-dichloro-3-(difluoromethyl)pyridine as a colorless oil. LC-MS: (ESI, m/z): 198.0 [M+H] ⁺ .

Stage 2: 6-chloro-5-(difluoromethyl)-N-[(4-methoxyphenyl)methyl]pyridine-2-amine

[0580] A solution of (4-methoxyphenyl)methanamine (459.0 mg, 3.35 mmol) and 2,6-dichloro-3-(difluoromethyl)pyridine (600.0 mg, 3.03 mmol) in n-butanol ( 5 ml) was stirred for 60 min at 100°C. Upon completion, the resulting solution was concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/5) to give 100.0 mg (10%) of 6-chloro-5-(difluoromethyl)-N-[(4-methoxyphenyl)methyl]pyridine-2- amine as a yellow solid. LC-MS: (ESI, m/z): 299.1 [M+H] ⁺ .

Step 3: tert-butyl 4-[6-chloro-7-[3-(difluoromethyl)-6-[[(4-methoxyphenyl)methyl]amino]pyridin-2-yl]quinazolin-4-yl]piperazin-1 -carboxylate

[0581] In nitrogen, a solution of 6-chloro-5-(difluoromethyl)-N-[(4-methoxyphenyl)methyl]pyridine-2-amine (300.0 mg, 1.00 mmol), potassium fluoride (116.2 mg, 2.00 mmol), tert-butyl 4-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate (568.0 mg, 1.20 mmol) and bis(triphenylphosphine)palladium(II) chloride (70.7 mg, 0.10 mmol) in acetonitrile (5 ml) and water (1 ml) were stirred for 60 min at 110°C. The resulting mixture was concentrated in vacuo, diluted with ethyl acetate (200 ml), washed with brine (50 ml x 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/5) to give 280.0 mg (46%) tert-butyl 4-[6-chloro-7-[3-(difluoromethyl)-6-[[( 4-Methoxyphenyl)methyl]amino]pyridin-2-yl]quinazolin-4-yl]piperazine-1-carboxylate as a white solid. LC-MS: (ESI, m/z): 6 11.2 [M+H] ⁺ .

Step 4: 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-(difluoromethyl)pyridin-2-amine

[0582] A solution of tert-butyl 4-[6-chloro-7-[3-(difluoromethyl)-6-[[(4-methoxyphenyl)methyl]amino]pyridin-2-yl]quinazolin-4-yl]piperazin- 1-carboxylate (280.0 mg, 0.46 mmol) in dichloromethane (2 ml) and trifluoroacetic acid (2 ml) were stirred for 60 min at 40°C. Upon completion, the resulting solution was concentrated in vacuo. The residue was diluted with water (2 ml) and the pH of the resulting solution was adjusted to pH=10 with a solution saturated with potassium carbonate. Then, the mixture was extracted with ethyl acetate (50 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/5) to give 150.0 mg (84%) of 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5 -(difluoromethyl)pyridine-2-amine as a white solid. LC-MS: (ESI, m/z): 391.1 [M+H] ⁺

Step 5: 1-(4-[7-[6-amino-3-(difluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2-en-1- he

[0583] 6-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-(difluoromethyl)pyridin-2-amine solution (100.0 mg, 0.26 mmol), N ,N-diisopropylethylamine (33.0 mg, 0.26 mmol), HATU (97.44 mg, 0.26 mmol) and prop-2-enoic acid (18.48 mg, 0.26 mmol) in dichloromethane (5 ml) was stirred for 60 min at 0°C. Upon completion, the solution was quenched with water (30 ml) and extracted with dichloromethane (3×50 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with methanol/dichloromethane (1/10) to give the crude product. Then, the crude product was purified by reverse phase column eluting with acetonitrile/water (3/7) to give 3.2 mg (3%) of 1-(4-[7-[6-amino-3-(difluoromethyl)pyridine-2 -yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 445.1 [M+H] ⁺

[0584] Example 41: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 8.68 (s, 1H), 8.22 (s, 1H), 7.81-7.78 (m, 2H), 6.87-6.73 ( m, 2H), 6.53-6.16 (m, 2H), 5.81 (dd,./=10.6, 1.9 Hz, 1H), 4.03-3.99 (m, 4H), 3.93-3.91 (m, 4H).

Example 42: 1-[4-[7-(6-Amino-3-methanesulfonylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Synthetic way

Step 1: 2,6-dichloro-3-(methylsulfanyl)pyridine

[0585] Under nitrogen, to a solution of 2,6-dichloropyridine (10.00 g, 67.57 mmol) in tetrahydrofuran (200 ml) was slowly added n-butyllithium (35.0 ml, 81.96 mmol, 2.5 M solution in hexane) and stirred for 1 h at -78°C. Then, (methylsulfanyl)methane (6.50 g, 69.00 mmol) was added slowly at -78° C. and stirred for 5 hours at room temperature. Upon completion, the resulting solution was quenched with a solution saturated with ammonium chloride, concentrated in vacuo, diluted with dichloromethane (200 ml), washed with water (80 ml × 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/5) to give 5.0 g (38%) of 2,6-dichloro-3-(methylsulfanyl)pyridine as a yellow oil. LC-MS: (ESI, m/z): 194.0 [M+H] ⁺ .

Stage 2: 2,6-dichloro-3-methanesulfonylpyridine

[0586] To a solution of 2,6-dichloro-3-(methylsulfanyl)pyridine (1.00 g, 5.15 mmol) in dichloromethane (10 ml) was added l/-chloro-peroxybenzoic acid (3.50 g, 20. 28 mmol), stirred for 12 hours at room temperature. Upon completion, the resulting mixture was quenched with a solution saturated with sodium sulfite (40 ml) and extracted with dichloromethane (80 ml x 3). Then the organic layers were collected and dried over anhydrous sodium sulfate, and concentrated in vacuo. This gave 1.6 g (crude) 2,6-dichloro-3-methanesulfonylpyridine as a yellow solid. LC-MS: (ESI, m/z): 225.9 [M+H] ⁺ .

Stage 3: 6-chloro-5-methanesulfonylpyridine-2-amine

[0587] In ammonia, a solution of 2,6-dichloro-3-methanesulfonylpyridine (1.80 g, 7.96 mmol) in n-butanol (20 ml) was stirred for 1 hour at 90°C. The resulting mixture was concentrated in vacuo to give 1.50 g (crude) of 6-chloro-5-methanesulfonylpyridin-2-amine as a yellow solid. LC-MS: (ESI, m/z): 207.0 [M+H] ⁺ .

Step 4: tert-Butyl 4-[7-(6-amino-3-methanesulfonylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-carboxylate

[0588] In nitrogen, a solution of tert-butyl 4-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate (400.0 mg , 0.84 mmol), 6-chloro-5-methanesulfonylpyridin-2-amine (200.0 mg, 0.97 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (80.0 mg, 0.10 mmol) and sodium carbonate (200.0 mg, 1.89 mmol) in dioxane (10 ml) and water (2 ml) were stirred for 1 h at 100°C. Upon completion, the resulting mixture was diluted with dichloromethane (100 ml), washed with brine (30 ml x 3). Then, the organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (96/4) to give 250 mg (57%) tert-butyl 4-[7-(6-amino-3-methanesulfonylpyridin-2-yl)-6-chloroquinazolin-4 -yl]piperazine-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 519.2 [M+H] ⁺ .

Step 5: 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-methanesulfonylpyridin-2-amine

[0589] tert-Butyl 4-[7-(6-amino-3-methanesulfonylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-carboxylate solution (240.0 mg, 0.46 mmol) in dichloromethane (10 ml) and trifluoroacetic acid (3 ml) was stirred for 2 h at room temperature. Upon completion, the resulting mixture was concentrated in vacuo. This gave 200 mg (crude) 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-methanesulfonylpyridin-2-amine as a yellow oil. LC-MS: (ESI, m/z): 419.1 [M+H] ⁺ .

Step 6: 1-[4-[7-(6-Amino-3-methanesulfonylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0590] 6-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-methanesulfonylpyridin-2-amine solution (100.0 mg crude), HATU (110.0 mg, 0 .29 mmol), prop-2-enoic acid (20.0 mg, 0.28 mmol) and N,N-diisopropylethylamine (60 mg, 0.46 mmol) in dichloromethane (5 ml) were stirred for 30 min at room temperature. temperature. Upon completion, the reaction was quenched with water (20 ml) and extracted with dichloromethane (3×30 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10/1) to give 40 mg of crude product. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge Shield RP18 OBD Column, 5 µm, 19*150 mm; mobile phase, Water (0.05% NH ₃ water) and ACN (28.0% ACN to 70.0% in 7 min); Detector, UV 220 nm. This gave 2.6 mg (2%) 1-[4-[7-(6-Amino-3-methanesulfonylpyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2- en-1-one as a white solid. LC-MS: (ESI, m/z): 473.1 [M+H] ⁺ .

[0591] Example 42:^oneH NMR (300 MHz, Methanol-d_four, ppm) δ 8.68 (s, 1H), 8.17 (s, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.84 (s, 1H), 6.84 (dd, J=16.8, 10.6 Hz, 1H ), 6.76 (d, J=9.0 Hz, 1H), 6.29 (dd, J=16.8, 2.0 Hz, 1H), 5.82 (dd, J=10.6, 2.0 Hz, 1H), 4.05-3.92 (m, 8H) , 2.99 (s, 3H).

Example 43: 1-(4-[7-[6-Amino-3-(2,2,2-trifluoroethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop- 2-en-1-he

Synthetic way

Stage 1: 3-(bromomethyl)-2,6-dichloropyridine

[0592] A solution of 2,6-dichloro-3-methylpyridine (3.00 g, 18.52 mmol), 2,2'-azobis(isobutyronitrile) (300.0 mg, 1.83 mmol) and N-bromosuccinimide ( 3.50 g, 19.44 mmol) in 1,2-dichloroethane (20 ml) was stirred for 12 h at 80°C. Upon completion, the resulting mixture was diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with petroleum ether/ethyl acetate (10/1) to give 2.5 g (56%) of 3-(bromomethyl)-2,6-dichloropyridine as a white solid. LC-MS: (ESI, m/z): 239.9 [M+H] ⁺ .

Step 2: 2,6-dichloro-3-(2,2,2-trifluoroethyl)pyridine

[0593] Under nitrogen, 3-(bromomethyl)-2,6-dichloropyridine solution (1.00 g, 4.15 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (1.00 g, 5 .21 mmol) and copper iodide (79.05 mg, 0.42 mmol) in N,N-dimethylformamide (15 ml) were stirred for 2 h at 110°C. Upon completion, the resulting mixture was diluted with dichloromethane (100 ml), washed with brine (20 ml x 3). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with petroleum ether:ethyl acetate (50:1) to give 560.0 mg (59%) of 2,6-dichloro-3-(2,2,2-trifluoroethyl)pyridine as a yellow oil. LC-MS: (ESI, m/z): 230.0 [M+H] ⁺ .

Step 3: tert-butyl N-[6-chloro-5-(2,2,2-trifluoroethyl)pyridin-2-yl]carbamate

[0594] In nitrogen, 2,6-dichloro-3-(2,2,2-trifluoroethyl)pyridine solution (560.0 mg, 2.44 mmol), tert-butyl carbamate (570.4 mg, 4.87 mmol), adduct of tris(dibenzylideneacetone)dipalladium-chloroform (126.0 mg, 0.12 mmol), xanthos (140.9 mg, 0.24 mmol) and cesium carbonate (1.59 g, 4.87 mmol) in 1,4-dioxane (20 ml) was stirred for 1 h at 110°C. Upon completion, the resulting mixture was diluted with ethyl acetate (200 ml), washed with brine (80 ml × 3). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with petroleum ether/ethyl acetate (50/1) to give 230.0 mg (30%) tert-butyl N-[6-chloro-5-(2,2,2-trifluoroethyl)pyridine-2 -yl]carbamate as a white solid. LC-MS: (ESI, m/z): 311.1 [M+H] ⁺ .

Step 4: tert-butyl 4-[7-(6-[[(tert-butoxy)carbonyl]amino]-3-(2,2,2-trifluoroethyl)pyridin-2-yl)-6-chloroquinazolin-4- yl]piperazine-1-carboxylate

[0595] Under nitrogen, tert-butyl N-[6-chloro-5-(2,2,2-trifluoroethyl)pyridin-2-yl]carbamate solution (200.0 mg, 0.64 mmol), tert-butyl 4-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate (305.6mg, 0.64mmol), bis(triphenylphosphine )palladium(II) chloride (49.7 mg, 0.07 mmol) and potassium fluoride (112.2 mg, 1.93 mmol) in acetonitrile (10 mL) and water (1 mL) were stirred for 30 min at 110°C. Upon completion, the resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (20/1) to give 200.0 mg (50%) tert-butyl 4-[7-(6-[[(tert-butoxy)carbonyl]amino]-3- (2,2,2-trifluoroethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl]piperazine-1-carboxylate as a yellow oil. LC-MS: (ESI, m/z): 623.2 [M+H] ⁺ .

Step 5: 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-(2,2,2-trifluoroethyl)pyridin-2-amine

[0596] 4-[7-(6-[[(tert-butoxy)carbonyl]amino]-3-(2,2,2-trifluoroethyl)pyridin-2-yl)-6-chloroquinazolin-4 tert-butyl solution -yl]piperazin-1-carboxylate (100.0 mg, 0.16 mmol) in trifluoroacetic acid (2 ml) and dichloromethane (10 ml) was stirred for 2 h at 25°C. Upon completion, the resulting mixture was concentrated in vacuo to give 100 mg (crude) 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-(2,2,2-trifluoroethyl )pyridine-2-amine as a yellow oil. LC-MS: (ESI, m/z): 423.1 [M+H] ⁺ .

Step 6: 1-(4-[7-[6-amino-3-(2,2,2-trifluoroethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop- 2-en-1-he

[0597] 6-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-5-(2,2,2-trifluoroethyl)pyridin-2-amine solution (60.0 mg crude) , prop-2-enoic acid (10.2 mg, 0.14 mmol), HATU (64.7 mg, 0.17 mmol) and N,N-diisopropylethylamine (36.7 mg, 0.28 mmol) in dichloromethane (4 ml) was stirred for 30 min at -78°C. Upon completion, the solution was quenched with water (20 ml) and extracted with dichloromethane (3×20 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10/1) to give 22.0 mg (33%) 1-(4-[7-[6-amino-3-(2,2,2-trifluoroethyl)pyridine -2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2-en-1-one as a white solid. LC-MS: (PER, m/z): 477.1 [M+H] ⁺ .

[0598] Example 43: ¹ H NMR (300 MHz, CDCl ₃ , ppm) δ 8.80 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.62 (d, J=9.0 Hz , 1H), 6.70 (d, J=8.6 Hz, 1H), 6.64 (dd, J=16.8, 10.5 Hz, 1H), 6.40 (dd, J=16.8, 1.9 Hz, 1H), 5.80 (dd, J= 10.5, 1.9 Hz, 1H), 5.12 (brs, 2H), 3.94–3.85 (m, 8H), 3.34–2.99 (m, 2H).

Example 44: 1-(4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2- en-1-one

Synthetic way

Step 1: tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-carboxylate

[0599] Under nitrogen, 6-chloro-4-methyl-5-(trifluoromethyl)pyridine-2-amine solution (2.00 g, 9.50 mmol), tert-butyl 4-[6-chloro-7-( tetramethyl 1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate (5.40 g, 11.42 mmol), bis(triphenylphosphine)palladium(II) chloride (666.6 mg, 0.95 mmol) and potassium fluoride (1.60 g, 28.50 mmol) in acetonitrile (50 ml) and water (5 ml) were stirred for 30 min at 100°C. Upon completion, the solids were filtered off. The resulting mixture was diluted with dichloromethane (200 ml), washed with brine (80 ml x 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with dichloromethane/methanol (10/1) to give 3.1 g (62%) tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridine-2 -yl]-6-chloroquinazolin-4-yl]piperazine-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 523.2 [M+H] ⁺ .

Step 2: 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0600] A solution of tert-butyl 4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-carboxylate (4.00 g, 7.67 mmol) in trifluoroacetic acid (20 ml) and dichloromethane (100 ml) was stirred for 1 h at 25°C. Upon completion, the resulting mixture was concentrated in vacuo to give 4.10 g (crude) of 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl )pyridine-2-amine as a yellow oil. ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 8.70 (s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 6.61 (s, 1H), 3.95-3.81 (m , 4H), 3.10-3.00 (t, 4H), 2.46 (s, 3H) LC-MS (ESI, m/z): 423.1 [M+H] ⁺ .

Step 3: 1-(4-[7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2- en-1-one

[0601] 6-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine solution (3.00 g, 7.10 mmol), prop-2-enoic acid (600.3 mg, 8.33 mmol), HATU (4.20 mg, 11.05 mmol) and A^-diisopropylethylamine (4.60 g, 35.47 mmol) in dichloromethane (50 ml) was stirred for 30 min at -78°C. Upon completion, the solution was quenched with water (50 ml) and extracted with dichloromethane (3×80 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (20/1) to give the crude product. Then, the crude product was purified by reverse phase chromatography (acetonitrile 0-40/0.1% ammonium bicarbonate in water) to give 2.1 g (62%) 1-(4-[7-[6-amino-4-methyl -3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-yl)prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 477.1 [M+H] ⁺

[0602] Example 44: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) e 8.67 (s, 1H), 8.18 (s, 1H), 7.71 (s, 1H), 6.84 (dd, J= 16.8, 10.6 Hz, 1H), 6.61 (m, 1H), 6.29 (dd, J=16.8, 2.0 Hz, 1H), 5.82 (dd, J=10.6, 2.0 Hz, 1H), 4.03-3.91 (m, 8H ), 2.48-2.46 (m, 3H).

Example 45: 1-(4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-[[2-(dimethylamino)ethyl]amino]quinazolin-4-yl ]piperazin-1-yl) prop-2-en-1-one.trifluoroacetic acid salt

Synthetic way

Step 1: tert-butyl 4-(7-bromo-6-chloro-2-[[-2-(dimethylamino)ethyl]amino]quinazolin-4-yl)piperazine-1-carboxylate

[0603] tert-Butyl 4-(7-bromo-2,6-dichloroquinazolin-4-yl)piperazin-1-carboxylate solution (4.00 g, 8.65 mmol), N,N-diisopropylethylamine (2.20 g, 17.38 mmol) and (2-aminoethyl)diamethylamine (3.80 g, 43.40 mmol) in 2-propanol (10 ml) were stirred for 3 days at 25°C. Upon completion, the resulting mixture was concentrated in vacuo to give 2.70 g (crude) tert-butyl 4-(7-bromo-6-chloro-2-[[-2-(dimethylamino)ethyl]amino]quinazoline-4 -yl)piperazine-1-carboxylate as a solid. LC-MS: (ESI, m/z): 513.1 [M+H] ⁺ .

Step 2: tert-butyl 4-(7-bromo-2-[[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino]-6-chloroquinazolin-4-yl)piperazine-1-carboxylate

[0604] tert-Butyl 4-(7-bromo-6-chloro-2-[[-2-(dimethylamino)ethyl]amino]quinazolin-4-yl)piperazin-1-carboxylate solution (2.70 g crude) , di-tert-butyl dicarbonate (1.70 g, 7.88 mmol) N,N-diisopropylethylamine (1.40 g, 10.52 mmol) in dichloromethane (10 ml) was stirred for 1 h at 25°C. Upon completion, the resulting mixture was diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with dichloromethane/methanol (10/1) to give 1.50 mg (46%) tert-butyl 4-(7-bromo-2-[[(tert-butoxy)carbonyl][2-( dimethylamino)ethyl]amino]-6-chloroquinazolin-4-yl)piperazine-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 613.2 [M+H] ⁺ .

Step 3: tert-butyl 4-(2-[[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino]-6-chloro-7-(tetramethyl-1,3,2-dioxaborolane-2- yl)quinazolin-4-yl)piperazine-1-carboxylate

[0605] In nitrogen, a solution of tert-butyl 4-(7-bromo-2-[[(trem-butoxy)carbonyl][2-(dimethylamino)ethyl]amino]-6-chloroquinazolin-4-yl)piperazin-1 -carboxylate (500.0 mg, 0.81 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane ( 1.00 g, 4.08 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (66.7 mg, 0.09 mmol), potassium acetate (240.2 mg, 2.45 mmol) in 1,4-dioxane (10 ml) was irradiated with microwave irradiation for 2 h at 80°C. Upon completion, the resulting mixture was diluted with dichloromethane (200 ml) and washed with brine (80 ml×3). Then, the organic layer was collected and dried over anhydrous sodium sulfate, and concentrated in vacuo to give 480 mg (crude) tert-butyl 4-(2-[[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino] -6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)piperazine-1-carboxylate as a dark red solid. LC-MS: (ESI, m/z): 661.4 [M+H] ⁺ .

Step 4: tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-2-[[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino]- 6-chloroquinazolin-4-yl]piperazine-1-carboxylate

[0606] Under nitrogen, a solution of tert-butyl 4-(2-[[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino]-6-chloro-7-(tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-4-yl)piperazin-1-carboxylate (500.0 mg, 0.76 mmol), potassium fluoride (88.0 mg, 1.52 mmol), bis(triphenylphosphine)palladium(II ) chloride (53.18 mg, 0.08 mmol) and 6-chloro-5-(trifluoromethyl)pyridine-2-amine (178.0 mg, 0.91 mmol) in acetonitrile (10 ml) and water (2 ml ) was stirred for 60 min at 110°C. Upon completion, the resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10:1) to give 200.0 mg (38%) tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]- 2-[[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino]-6-chloroquinazolin-4-yl]piperazine-1-carboxylate as a black solid. LC-MS: (ESI, m/z): 695.3 [M+H] ⁺

Step 5: 6-(6-chloro-2-[[2-(dimethylamino)ethyl]amino]-4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine

[0607] 4-[7-[6-Amino-3-(trifluoromethyl)pyridin-2-yl]-2-[[(tert-butoxy)carbonyl][2-(dimethylamino)ethyl]amino] solution -6-chloroquinazolin-4-yl]piperazin-1-carboxylate (200.0 mg, 0.29 mmol) in dichloromethane (8 ml) and trifluoroacetic acid (2 ml) was stirred for 30 min at 25°C. Upon completion, the resulting mixture was concentrated in vacuo to give 200.0 mg (crude) 6-(6-chloro-2-[[2-(dimethylamino)ethyl]amino]-4-(piperazin-1-yl)quinazoline -7-yl)-5-(trifluoromethyl)pyridin-2-amine. LC-MS: (ESI, m/z): 495.2 [M+H] ⁺ .

Step 6: 1-(4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2-[[2-(dimethylamino)ethyl]amino]quinazolin-4-yl ]piperazin-1-yl)prop-2-en-1-one; trifluoroacetic acid salt

[0608] 6-(6-Chloro-2-[[2-(dimethylamino)ethyl]amino]-4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2- solution amine (150.0 mg, 0.30 mmol), HATU (138.4 mg, 0.36 mmol), N,N-diisopropylethylamine (469.8 mg, 3.63 mmol) and prop-2-enoic acid (21.9 mg, 0.30 mmol) in dichloromethane (10 ml) was stirred for 30 min at -78°C. Upon completion, the reaction was quenched with water (60 ml), extracted with dichloromethane (100 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10/1) to give the crude product. The crude product was then purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C 18 OBD Column, 5 µm, 19*150 mm; mobile phase A: Water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: 15% B to 26% B in 7 min; 254/220 nm; RT: 5.92 min to give 22.5 mg (11%) 1-(4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-2- [[2-(dimethylamino)ethyl]amino]quinazolin-4-yl]piperazin-1-yl)prop-2-en-1-one; trifluoroacetic acid as a white solid. LC-MS: (ESI. m/z): 549.2 [M+H] ⁺ .

[0609] Example 45: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 8.22 (s, 1H), 7.85 (d, J - 9.0 Hz; 1H); 7.56 (s. 1H); 6.84-6.75 (m. 2H); 6.31 (dd; J=16.8. 1.9 Hz; 1H). 5.84 (dd. J - 10.6, 1.9 Hz, 1H). 4.31 (brs. 1H), 4.04-3.92 (m. 6H). 3.49 (t, J - 5.9 Hz; 2H). 2.99(s, 6H).

Example 46a: (2S)-4-[7-[6-amnino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazine -2-carbonitrile

Example 46b: (2R)-4-[7-[6-Amino-3-(trifluoromethyl)pipyridin-2-yl]-6-chloroquinazolin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazine -2-carbonitrile

Synthetic way

Step 1: 7-[6-Amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-3,4-dihydroquinazolin-4-one

[0610] A solution of tert-butyl 4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-1-carboxylate (500.0 mg, 0. 98 mmol) and sodium hydroxide (80.0 mg, 2.00 mmol) in ethanol (10 ml) and water (1 ml) were stirred for 2 h at 80°C. Upon completion, the pH of the resulting solution was adjusted to pH=7.0 with hydrochloric acid in 1,4-dioxane solution, concentrated in vacuo. The residue was purified with a silica gel column eluting with dichloromethane/methanol (10:1) to give 150.0 mg (45%) of 7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-3 ,4-dihydroquinazolin-4-one as a white solid. LC-MS: (ESI, m/z): 341.0 [M+H] ⁺ .

Step 2: 4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-2-carbonitrile

[0611] Piperazin-2-carbonitrile solution (94.0 mg, 0.85 mmol), 7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-3,4-dihydroquinazolin-4- she (150.0 mg, 0.44 mmol), BOP (234.0 mg, 0.53 mmol) and N,N-diisopropylethylamine (0.4 ml, 2.42 mmol) in dichloromethane (10 ml) were stirred in for 12 hours at room temperature. Upon completion, the resulting solution was concentrated and diluted with dichloromethane (150 ml), washed with brine (50 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column eluting with dichloromethane/methanol (10/1) to give 70.0 mg (37%) of 4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6- chlorquinazolin-4-yl]piperazine-2-carbonitrile as a white solid. LC-MS: (ESI, m/z): 434.1 [M+H] ⁺ .

Step 3: (2S)-4-[7-[6-Amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazine -2-carbonitriles

(2R)-4-[7-[6-Amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2- carbonitrile

[0612] 4-[7-[6-Amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]piperazin-2-carbonitrile solution (70.0 mg, 0.16 mmol) , 2-fluoroprop-2-enoic acid (15.0 mg, 0.17 mmol), BOP (85.0 mg, 0.19 mmol) and J-diisopropylethylamine (62.0 mg, 0.48 mmol) in dichloromethane (5 ml) was stirred for 60 min at room temperature. Upon completion, the reaction was quenched with water (20 ml) and extracted with dichloromethane (3×30 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column eluting with dichloromethane/methanol (10:1) to give the crude product. Then the crude product was obtained using preparative HPLC with the following conditions: column: X Bridge C18, 19*150 mm, 5 μm; mobile phase A: Water/0.05% TFA; mobile phase B: ACN; flow rate: 20 ml/min; gradient: 30% B to 70% B in 10 min; 254 nm. The product was purified by chiral preparative HPLC with the following conditions (Prep-HPLC-009): Column, CHIRAL ART Cellulose-SB, 2*25 cm, 5 µm; mobile phase, hexane--HPLC and ethanol-HPLC (retention 40% ethanol--HPLC for 10 min); Detector, UV 220/254 nm. This gave 5.6 mg (7%) of (2S)-4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]-1-(2- fluoroprop-2-enoyl)piperazine-2-carbonitrile (presumably) as a white solid. LC-MS (ESI, m/z): 506.1 [M+H] ⁺ and 6.0 mg (7%) (2R)-4-[7-[6-amino-3-(trifluoromethyl)pyridine- 2-yl]-6-chloroquinazolin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-carbonitrile (presumably) as a white solid. LC-MS: (ESI, m/z): 506.1 [M+H] ⁺

[0613] Example 46a: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 8.79 (s, 1H), 8.31 (d,J=1.8 Hz, 1H), 7.85-7.83 (m, 2H) , 6.74 (dd, J=8.9, 0.9 Hz, 1H), 5.67 (brs, 1H), 5.55 (dd, J=4.0, 1.3 Hz, 1H), 5.45-5.40 (m, 1H), 4.71 (dq, J =14.1, 2.3 Hz, 1H), 4.52-4.47 (m, 1H), 4.38-4.34 (m, 1H), 3.83 (brs, 1H), 3.72 (ddd, J=13.9, 10.2, 3.6 Hz, 1H), 3.54-3.43 (m, 1H).

[0614] Example 46b: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 8.79 (s, 1H), 8.31 (d,J=1.8 Hz, 1H), 7.85-7.83 (m, 2H) , 6.74 (dd, J=8.9, 0.9 Hz, 1H), 5.67 (brs, 1H), 5.55 (dd, J=4.0, 1.3 Hz, 1H), 5.45-5.40 (m, 1H), 4.71 (dq, J =14.1, 2.3 Hz, 1H), 4.52-4.47 (m, 1H), 4.38-4.34 (m, 1H), 3.83 (brs, 1H), 3.72 (ddd, J=13.9, 10.2, 3.6 Hz, 1H), 3.54-3.43 (m, 1H).

Example 47 1-[4-[7-(6-Amino-3-cyclopropylpyridin-2-yl)-6-methoxyquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Step 1: tert-butyl 4-(7-bromo-6-methoxyquinazolin-4-yl)piperazine-1-carboxylate

[0615] 7-Bromo-6-methoxy-3,4-dihydroquinazolin-4-one solution (5.00 g, 19.60 mmol), tert-butyl piperazine-1-carboxylate (7.30 g, 39.19 mmol), BOP (17.30 g, 39.21 mmol) and N,N-diisopropylethylamine (5.07 g, 39.23 mmol) in acetonitrile (120 ml) were stirred for 4 hours at 25°C. Upon completion, the resulting mixture was concentrated in vacuo and diluted with ethyl acetate (150 ml), washed with brine (40 ml x 3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with petroleum ether/ethyl acetate (1/1). This gave 5.00 g (60%) tert-butyl 4-(7-bromo-6-methoxyquinazolin-4-yl)piperazine-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 506.1 [M+H] ⁺ .

Step 2: tert-Butyl 4-[6-methoxy-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazine-1-carboxylate

[0616] In nitrogen, a solution of tert-butyl 4-(7-bromo-6-methoxyquinazolin-4-yl)piperazin-1-carboxylate (2.00 g, 4.73 mmol), 4,4,5,5- tetramethyl-2-(tetramethyl-1,3,2-diocaborolan-2-yl)-1,3,2-dioxaborolane (4.80 g, 18.90 mmol), 1,1'-bis(diphenylphosphino)ferrocen- palladium(II) dichloride (139.3 mg, 0.24 mmol), potassium acetate (927.4 mg, 9.45 mmol) in 1,4-dioxane (100 ml) was stirred for 2 h at 80°C. Upon completion, the resulting solution was concentrated and diluted with ethyl acetate (150 ml), washed with brine (40 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10/1). This gave 700.0 mg (31%) tert-butyl 4-[6-methoxy-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate as yellow solid. LC-MS: (ESI, m/z): 471.3 [M+H] ⁺ .

Step 3: tert-butyl 4-[7-(6-amino-3-cyclopropylpyridin-2-yl)-6-methoxyquinazolin-4-yl]piperazin-1-carboxylate

[0617] In nitrogen, a solution of tert-butyl 4-[6-methoxy-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate (200.0 mg , 0.43 mmol), 6-chloro-5-cyclopropylpyridin-2-amine (71.6 mg, 0.43 mmol), Pd ₂ (dba) ₃ (19.5 mg, 0.02 mmol), tricyclohexyl phosphine (12.0 mg, 0.04 mmol) and potassium carbonate (117.5 mg, 0.85 mmol) in dioxane (5 ml) and water (1 ml) were stirred for 30 min at 110°C. Upon completion, the resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (20/1). This gave 100.0 mg (49%) tert-butyl 4-[7-(6-amino-3-cyclopropylpyridin-2-yl)-6-methoxyquinazolin-4-yl]piperazin-1-carboxylate as off-white oils. LC-MS: (ESI, m/z): 477.3 [M+H] ⁺ .

Step 4: 5-cyclopropyl-6-[6-methoxy-4-(piperazin-1-yl)quinazolin-7-yl]pyridine-2-amine

[0618] tert-Butyl 4-[7-(6-amino-3-cyclopropylpyridin-2-yl)-6-methoxyquinazolin-4-yl]piperazin-1-carboxylate solution (100.0 mg, 0.21 mmol) in trifluoroacetic acid (2 ml) and dichloromethane (10 ml) were stirred for 1 h at 25°C. Upon completion, the resulting mixture was concentrated in vacuo. This gave 100 mg (crude) 5-cyclopropyl-6-[6-methoxy-4-(piperazin-1-yl)quinazolin-7-yl]pyridin-2-amine as a yellow oil. LC-MS: (ESI, m/z): 377.2 [M+H] ⁺

Step 5: 1-[4-[7-(6-Amino-3-cyclopropylpyridin-2-yl)-6-methokeiquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0619] 5-Cyclopropyl-6-[6-methoxy-4-(piperazin-1-yl)quinazolin-7-yl]pyridin-2-amine solution (50.0 mg, 0.13 mmol), prop-2 -enoic acid (10.0 mg, 0.14 mmol), HATU (60.6 mg, 0.16 mmol) and N,N-diisopropylethylamine (20.6 mg, 0.16 mmol) in dichloromethane (5 ml) stirred for 1 h at -78°C. Upon completion, the resulting solution was quenched (1 ml) and diluted with dichloromethane (150 ml), washed with brine (40 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10/1). This gave 19.6 mg (34%) 1-[4-[7-(6-amino-3-cyclopropylpyridin-2-yl)-6-methoxyquinazolin-4-yl]piperazin-1-yl]prop-2- en-1-one as a white solid. LC-MS: (ESI, m/z): 431.2 [M+H] ⁺ .

[0620] Example 47: ¹ H NMR (300 MHz, chloroform-d) δ 8.77 (s, 1H), 7.91 (s, 1H), 7.22-7.18 (m, 2H), 6.66 (dd, J=16.8, 10.5 Hz, 1H), 6.56 (d, J=8.5 Hz, 1H), 6.38 (dd, J=16.8, 1.9 Hz, 1H), 5.79 (dd, J=10.5, 1.9 Hz, 1H), 4.65 (brs, 2H ), 3.92-3.78 (m, 11Н), 1.65-1.55 (m, 1Н), 0.69-0.66 (m, 2Н), 0.55-0.49 (m, 2Н).

Example 48 1-[4-[7-(3-Amino-8-fluoroisoquinolin-1-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Synthetic way

Step 1: Methyl 2-cyano-2-(2-cyano-3-fluorophenyl)acetate

[0621] A solution of 2,6-difluorobenzonitrile (10.00 g, 71.89 mmol), methyl 2-cyanoacetate (7.50 g, 75.69 mmol) and potassium carbonate (20.00 g, 144.71 mmol) in DMSO (50 ml) was stirred for 12 h at room temperature. Upon completion, the resulting solution was diluted with water (100 ml). Solids were collected by filtration. This gave 11.5 g (73%) methyl 2-cyano-2-(2-cyano-3-fluorophenyl)acetate as a yellow solid. LC-MS: (ESI, m/z): 219.0 [M+H] ⁺

Step 2: 2-(cyanomethyl)-6-fluorobenzonitrile

[0622] A solution of methyl 2-cyano-2-(2-cyano-3-fluorophenyl)acetate (1.00 g, 4.58 mmol) in DMSO (8 ml) and a solution of hydrogen chloride (6M) (2 ml) were stirred within 12 hours at 70°C. Upon completion, the pH of the resulting solution was adjusted to pH=9.0 with sodium carbonate solution. Solids were collected by filtration. This gave 700.0 mg (95%) of 2-(cyanomethyl)-6-fluorobenzonitrile as a gray solid. LC-MS: (ESI, m/z): 161.0 [M+H] ⁺ .

Stage 3: 1-bromo-8-fluoroisoquinoline-3-amine

[0623] A solution of 2-(cyanomethyl)-6-fluorobenzonitrile (3.00 g, 18.73 mmol) in HBr/AcOH (40%) (15 ml) was stirred for 30 min at 0°C. Upon completion, the pH of the resulting solution was adjusted to pH=8.0 with an aqueous solution saturated with sodium carbonate. Solids were collected by filtration. This gave 1.70 g (38%) of 1-bromo-8-fluoroisoquinoline-3-amine as a light yellow solid. LC-MS: (ESI, m/z): 241.0 [M+H] ⁺ .

Step 4: tert-butyl 4-[7-(3-amino-8-fluoroisoquinolin-1-yl)-6-chloroquinazolin-4-yl]piperazin-1-carboxylate

[0624] Suspension of 4-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate (1.2 g, 2.48 mmol) , 1-bromo-8-fluoroisoquinoline-3-amine (600.0 mg, 2.49 mmol), Pd(dppf)Cl ₂ (183.0 mg, 0.25 mmol) and K ₃ PO ₄ (1.00 g, 4.71 mmol) in acetonitrile (10 ml) and water (0.2 ml) were stirred for 60 min at 100°C. Upon completion, the resulting solution was concentrated and diluted with ethyl acetate (250 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column eluting with dichloromethane/methanol (10/1) to give 200.0 mg (9%) tert-butyl 4-[7-(3-amino-8-fluoroisoquinolin-1-yl)-6- chlorquinazolin-4-yl]piperazine-1-carboxylate as a brown solid. LC-MS: (PER, m/z): 509.2 [M+H] ⁺ .

Step 5: 1-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-8-fluoroisoquinolin-3-amine

[0625] tert-Butyl 4-[7-(3-amino-8-fluoroisoquinolin-1-yl)-6-chloroquinazolin-4-yl]piperazin-1-carboxylate solution (200.0 mg, 0.39 mmol) in trifluoroacetic acid (2 ml) and dichloromethane (6 ml) was stirred for 60 min at room temperature. Upon completion, the resulting solution was concentrated in vacuo. This gave 300 mg (crude) 1-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-8-fluoroisoquinolin-3-amine as a brown oil. LC-MS: (ESI, m/z): 409.2 [M+H] ⁺ .

Step 6: 1-[4-[7-(3-amino-8-fluoroisoquinolin-1-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0626] 1-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-8-fluoroisoquinolin-3-amine solution (100.0 mg crude), prop-2-enoic acid (53 0 mg, 0.73 mmol), HATU (109.0 mg, 0.29 mmol) and N,N-diisopropylethylamine (155.0 mg, 1.20 mmol) in dichloromethane (5 mL) were stirred for 30 min. at -78°C. Upon completion, the resulting solution was quenched with water (1 ml), diluted with dichloromethane (150 ml), washed with brine (40 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: column: X Bridge C18, 19*150 mm, 5 µm; mobile phase Λ: Water/0.05% TFL, mobile phase B: LCN; flow rate: 20 ml/min; gradient: 30% B to 70% B in 10 min; 254 nm. This gave 9.1 mg (8%) 1-[4-[7-(3-Amino-8-fluoroisoquinolin-1-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2- en-1-one as a light yellow solid. LC-MS: (ESI, m/z): 463.1 [M+H] ⁺ .

[0627] Example 48: ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.69 (s, 1H), 8.14 (s, 1H), 7.83 (s, 1H), 7.49-7.40 (m, 2Н), 6.89-6.76 (m, 3Н), 6.35 (s, 2Н), 6.18 (dd, 3=16.7, 2.4 Hz, 1Н), 5.75 (dd, 3=10.4, 2.4 Hz, 1Н), 3.88 (brs , 6Н), 3.79 (brs, 2Н).

Example 49 1-[4-[7-(3-Amino-7-fluoroisoquinolin-1-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Synthetic way

Step 1: 1-[4-[7-(3-Amino-7-fluoroisoquinolin-1-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0628] 1-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-7-fluoroisoquinolin-3-amine solution (100.0 mg, 0.24 mmol), HATU (111, 6 mg, 0.29 mmol), N,N-diisopropylethylamine (63.2 mg, 0.49 mmol) and prop-2-enoic acid (17.6 mg, 0.25 mmol) in dichloromethane (5 ml) were stirred for 30 min at room temperature. Upon completion, the reaction was quenched with water (1 ml), diluted with dichloromethane (150 ml), washed with brine (40 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: column: X Bridge C18, 19*150 mm, 5 µm; mobile phase A: Water/0.05% TFA; mobile phase B: ACN; flow rate: 20 ml/min; gradient: 30% B to 70% B in 10 min; 254 nm. This gave 3.8 mg (3%) 1-[4-[7-(3-amino-7-fluoroisoquinolin-1-yl)-6-chloroquinazolin-4-yl]piperazin-1-yl]prop-2- en-1-one as a yellow solid. LC-MS: (ESI, m/z): 463.1 [M+H] ⁺ .

[0629] Example 49: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 8.70 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.73 (dd, J= 9.2, 5.4 Hz, 1H), 7.42-7.35 (m, 1H), 6.99-6.93 (m, 2H), 6.85 (dd, J=16.8, 10.6 Hz, 1H), 6.29 (dd, J=16.8, 1.9 Hz , 1Н), 5.82 (dd, J=10.6, 2.0 Hz, 1Н), 4.09-4.04 (m, 4Н), 3.96-3.93(m, 4Н).

Example 50: 1-(3-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]azetidin-1-yl)prop-2-en-1- he

Synthetic way

Step 1: tert-butyl 3-(7-bromo-6-chloroquinazolin-4-yl)azetidine-1-carboxylate

[0630] In nitrogen, a solution of 7-bromo-4,6-dichloroquinazoline (6.00 g, 21.59 mmol), [1-[(tert-butoxy)carbonyl]azetidin-3-yl](iodine)zinc ( 30 ml, 15.49 mmol), adduct of tris(dibenzylideneacetone) dipalladium-chloroform (998.0 mg, 0.96 mmol) and tri-2-furylphosphine (500.0 mg, 2.15 mmol) in N,N- dimethylformamide (30 ml) was stirred for 30 min at room temperature. Upon completion, the resulting solution was diluted with water (100 ml), extracted with ethyl acetate (100 ml×3), washed with brine (100 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/5) to give 3.3 g (42%) tert-butyl 3-(7-bromo-6-chloroquinazolin-4-yl)azetidine-1-carboxylate in as a light yellow solid. LC-MS: (PER, m/z): 398.0 [M+H] ⁺ .

Step 2: tert-butyl 3-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]azetidine-1-carboxylate

[0631] In nitrogen, a solution of tert-butyl 3-(7-bromo-6-chloroquinazolin-4-yl)azetidine-1-carboxylate (2.00 g, 5.02 mmol), 1,1'-bis(diphenylphosphino )ferrocene-palladium(II) dichloride (400.6 mg, 0.55 mmol), potassium acetate (1.48 g, 15.08 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.88 g, 15.28 mmol) in 1,4-dioxane (30 ml) was stirred for 2 h at 80°C. Upon completion, the resulting solution was concentrated in vacuo, diluted with dichloromethane (150 ml). After filtration, the filtrate was collected, concentrated in vacuo, washed with petroleum ether (10 ml×3). This gave 1.4 g (crude) tert-butyl 3-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]azetidine-1-carboxylate as brown solid. LC-MS: (ESI, m/z): 446.2 [M+H] ⁺ .

Step 3: tert-butyl 3-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]azetidine-1-carboxylate

[0632] In nitrogen, a solution of tert-butyl 3-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]azetidine-1-carboxylate (1.40 g , 3.14 mmol), bis (triphenylphosphine) palladium (II) chloride (220.5 mg, 0.31 mmol), potassium fluoride (380.0 mg, 6.54 mmol) and 6-chloro-5- (trifluoromethyl )pyridine-2-amine (620.0 mg, 3.15 mmol) in acetonitrile (20 ml) and water (5 ml) were stirred for 60 min at 110°C. Upon completion, the resulting solution was diluted with ethyl acetate (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10/1). This gave 600.0 mg (40%) tert-butyl 3-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]azetidine-1-carbokeylate as dark red solid. LC-MS: (ESI, m/z): 480.1 [M+H] ⁺ .

Step 4: 6-[4-(azetidin-3-yl)-6-chloroquinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine

[0633] A solution of tert-butyl 3-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]azetidine-1-carbokeylate (300.0 mg, 0. 63 mmol) in trifluoroacetic acid (5 ml) and dichloromethane (15 ml) were stirred for 20 min at 25°C. Upon completion, the resulting solution was concentrated in vacuo. This gave 320 mg (crude) 6-[4-(azetidin-3-yl)-6-chloroquinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine as a dark red solid. LC-MS: (ESI, m/z): 3:80.1 [M+H] ⁺ .

Step 5: 1-(3-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]azetidin-1-yl)prop-2-en-1- he

[0634] 6-[4-(azetidin-3-yl)-6-chloroquinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine solution (300.0 mg, 0.79 mmol), HATU ( 300.8 mg, 0.79 mmol), N,N-diisopropylethylamine (408.4 mg, 3.16 mmol) and prop-2-enoic acid (57.0 mg, 0.79 mmol) in dichloromethane (15 ml ) was stirred for 60 min at -78°C. Upon completion, the resulting solution was quenched with water (1 ml), diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with dichloromethane/methanol (10:1). The crude product was then purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column 30×150 mm, 5 µm; mobile phase A: water (10 mmol/l NH4HCO3), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 20% B to 50% B in 7 min; 254/220 nm; Rt: 6.62 min to give 141.2 mg (41%) 1-(3-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]azetidine -1-yl)prop-2-en-1-one as a white solid. LC-MS: (PER, m/z): 434.1 [M+H] ⁺ .

[0635] Example 50: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) 3 9.33 (s, 1H), 8.33 (s, 1H), 7.98 (s, 1H), 7.82 (d, J= 8.9 Hz, 1H), 6.73 (dd, J=9.0, 1.1 Hz, 1H), 6.47-6.38 (m, 1H), 6.29 (dd, J=17.0, 2.1 Hz, 1H), 5.78 (ddd, J=10.2 , 2.3, 1.0 Hz, 1H), 5.00–4.88 (m, 2H), 4.84–4.76 (m, 1H), 4.64–4.50 (m, 2H).

Example 51 1-[4-[7-[6-Amino-3-(2,2,2-trifluoroethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop -2-en-1-he

Synthetic way

Step 1: tert-butyl N-[6-chloro-5-(2,2,2-trifluoroethyl)-2-pyridyl]carbamate

[0636] A solution of 6-chloro-5-(2,2,2-trifluoroethyl)pyridine-2-carboxylic acid (300.0 mg, 1.25 mmol), diphenylphosphoryl azide (0.27 ml, 1.25 mmol) and triethylamine (0.17 ml, 1.25 mmol) in 2-methyl-1-propanol (10 ml) was stirred at 85°C for 2 hours. After completion, the solvent was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (90/10) to give tert-butyl N-[6-chloro-5-(2,2,2-trifluoroethyl)-2-pyridyl]carbamate ( 100.0 mg, 0.32 mmol, 25.7% yield) as a yellow oil. LC-MS: (ESI, m/z): 311.1 [M+H] ⁺ .

Step 2: tert-butyl 4-[7-[6-(tert-butoxycarbonylamino)-3-(2,2,2-trifluoroethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin-1 -carboxylate

[0637] Under nitrogen, a solution of tert-butyl 4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin- 1-carboxylate (183.4 mg, 0.39 mmol), tert-butyl N-[6-chloro-5-(2,2,2-trifluoroethyl)-2-pyridyl]carbamate (100.0 mg, 0 .32 mmol), bis(triphenylphosphine)palladium(m)dichloride (22.7 mg, 0.03 mmol) and potassium fluoride (56.0 mg, 0.97 mmol) in acetonitrile (3 ml) and water (0. 5 ml) was stirred at 110°C for 20 min. Upon completion, the resulting solution was diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel qut with dichloromethane/methanol (95/5) to give t-butyl 4-[7-[6-(t-butoxycarbonylamino)-3-(2,2,2-trifluoroethyl)- 2-pyridyl]-6-chloro-quinazolin-4-yl]-piperazine-1-carboxylate (80 mg, 0.13 mmol, 39.9% yield) as a solid. LC-MS: (ESI, m/z): 623.1 [M+H] ⁺ .

Step 3: 6-(6-chloro-4-piperazin-1-yl-quinazolin-7-yl)-5-(2,2,2-trifluoroethyl)pyridine-2-amine

[0638] A solution of tert-butyl 4-[7-[6-(tert-butoxycarbonylamino)-3-(2,2,2-trifluoroethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin- 1-carbokeylate (50.0 mg, 0.08 mmol) in TFA (2 ml) and dichloromethane (10 ml) were stirred at 25° C. for 3 hours. Upon completion, the solvent was concentrated in vacuo. The material was taken to the next stage without additional purification. LC-MS: (ESI, m/z): 423.1 [M+H] ⁺ .

Step 4: 1-[4-[7-[6-Amino-3-(2,2,2-trifluoroethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop -2-en-1-he

[0639] 6-(6-Chloro-4-piperazin-1-yl-quinazolin-7-yl)-5-(2,2,2-trifluoroethyl)pyridine-2-amine solution (50.0 mg, 0.12 mmol ), acrylic acid (8.5 mg, 0.12 mmol), HATU (54.0 mg, 0.14 mmol) and N,N-diisopropylethylamine (22.9 mg, 0.18 mmol) in dichloromethane (5 ml ) was stirred at -78°C for 30 min. Upon completion, the resulting solution was quenched with water (1 ml), diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography quipped with dichloromethane/methanol (95/5) to give 1-[4-[7-[6-amino-3-(2,2,2-trifluoroethyl)-2-pyridyl] -6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (7.6 mg, 13.5% yield) as a white solid. LC-MS: (ESI, m/z): 477.1 [M+H] ⁺ .

[0640] Example 51: ¹ H NMR (300 MHz, Methanol-d ₄ , ppm) δ 8.68 (s, 1H), 8.24 (s, 1H), 7.80 (s, 1H), 7.62 (d, J= 8.6 Hz, 1H), 6.84 (dd, J=16.8, 10.6 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.29 (dd, J=16.8, 2.0 Hz, 1H), 5.82 {66, J=10.6, 2.0 Hz, 1Н), 4.06-4.01 (m, 4Н), 3.98-3.93 (m, 4Н), 3.43-3.36 (m, 1Н), 3.16-3.00 (m, 1Н).

Example 52: 1-[4-[7-[6-Amino-4-ethyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2 -en-1-he

Synthetic way

Stage 1: 2,6-dichloro-4-ethylpyridine

[0641] In nitrogen, 2,6-dichloro-4-iodopyridine solution (10.00 g, 36.51 mmol), triethylborane (36.0 ml, 36.00 mmol), 1,1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride (2.67 g, 3.65 mmol) and potassium carbonate (10.00 g, 72.36 mmol) in N,N-dimethylformamide (80 ml) were stirred for 60 min at 80° C. Upon completion, the resulting solution was diluted with water (100 ml), extracted with ethyl acetate (150 ml×3), washed with brine (150 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with ethyl acetate/petroleum ether (3/97) to give 6.3 g (98%) of 2,6-dichloro-4-ethylpyridine as a solid. LC-MS: (PER, m/z): 176.0 [M+H] ⁺

Step 2: tert-butyl N-(6-chloro-4-ethylpyridin-2-yl)carbamate

[0642] 2,6-Dichloro-4-ethylpyridine solution (3.00 g, 17.04 mmol), tert-butyl carbamate (2.20 g, 18.78 mmol), tris(dibenzylideneacetone) dipalladium chloroform adduct ( 880.0 mg, 0.85 mmol), xanthos (985.0 mg, 1.70 mmol) and cesium carbonate (11.00 g, 33.76 mmol) in 1,4-dioxane (50 ml) were stirred for 60 min at 90°C. Upon completion, the resulting solution was concentrated in vacuo, diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/10). This gave 3.3 g (69%) of tert-butyl N-(6-chloro-4-ethylpyridin-2-yl)carbamate as a solid. LC-MS (ESI, m/z): 257.1 [M+H] ⁺ .

Stage 3: 6-chloro-4-ethylpyridine-2-amine

[0643] A solution of tert-butyl N-(6-chloro-4-ethylpyridin-2-yl)carbamate (3.00 g, 11.68 mmol) in trifluoroacetic acid (20 ml) and dichloromethane (70 ml) was stirred for 60 min at 25°C. After completion, the resulting solution was concentrated in vacuo, diluted with water (30 ml), the pH of the resulting solution was adjusted to pH=7.0 with an aqueous solution saturated with sodium carbonate, extracted with ethyl acetate (100 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/3) to give 1.52 g (83%) of 6-chloro-4-ethylpyridine-2-amine as a solid. LC-MS: (ESI, m/z): 157.0 [M+H] ⁺ .

Stage 4: 6-chloro-4-ethyl-5-iodopyridine-2-amine

[0644] A solution of 6-chloro-4-ethylpyridin-2-amine (1.50 g, 9.58 mmol) and NIS (2.16 g, 9.60 mmol) in acetonitrile (70 ml) was stirred for 2 hours at 25 °C Upon completion, the resulting solution was concentrated in vacuo, diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with ethyl acetate/petroleum ether (1/10) to give 1.73 g (64%) of 6-chloro-4-ethyl-5-iodopyridine-2-amine as a solid. LC-MS: (ESI, m/z): 282.9 [M+H] ⁺ .

Step 5: 6-chloro-4-ethyl-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]pyridine-2-amine

[0645] A solution of 6-chloro-4-ethyl-5-iodopyridine-2-amine (1.05 g, 3.72 mmol), 1-(chloromethyl)-4-methoxybenzene (1.75 g, 11.17 mmol ) and sodium hydride (270.0 mg, 11.25 mmol) in N,N-dimethylformamide (15.00 ml) was stirred for 60 min at 25°C. Upon completion, the resulting solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (100 ml×3), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/10) to give 1.10 g (57%) of 6-chloro-4-ethyl-5-iodo-N,N-bis[(4-methoxyphenyl)methyl ]pyridine-2-amine as a solid. LC-MS: (ESI, m/z): 523.1 [M+H] ⁺ .

Step 6: 6-chloro-4-ethyl-N,N-bis[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyridine-2-amine

[0646] 6-Chloro-4-ethyl-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]pyridine-2-amine solution (1.20 g, 2.30 mmol), copper(I) iodide ) (0.87 g, 4.60 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.58 ml, 4.59 mmol) in N,N-dimethylformamide (10 ml) were stirred at 90 °C for 2 hours. Upon completion, the resulting solution was diluted with water (50 ml), extracted with ethyl acetate (100 ml×3), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with ethyl acetate/petroleum ether (1/10) to give 0.70 g (70%) of 6-chloro-4-ethyl-N,N-bis[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)pyridine-2-amine. LC-MS: (ESI, m/z): 465.1 [M+H] ⁺

Step 7: 6-chloro-4-ethyl-5-(trifluoromethyl)pyridine-2-amine

[0647] A solution of 6-chloro-4-ethyl-N,N-bis[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)pyridine-2-amine (1.20 g, 2.58 mmol) in dichloromethane ( 10 ml) and trifluoroacetic acid (10 ml) were stirred at 40°C for 2 hours. Upon completion, the resulting solution was concentrated in vacuo, diluted with water (50 ml), the pH of the resulting solution was adjusted to pH=8 with an aqueous solution saturated with sodium carbonate, extracted with ethyl acetate (100 ml×3), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (1/10) to give 0.59 g (89.6%) of 6-chloro-4-ethyl-5-(trifluoromethyl)pyridine-2-amine . LC-MS: (ESI, m/z): 225.0 [M+H] ⁺ .

Step 8: tert-Butyl 4-[7-[6-amino-4-ethyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazine-1-carboxylate

[0648] In nitrogen, a solution of 6-chloro-4-ethyl-5-(trifluoromethyl)pyridine-2-amine (560.0 mg, 2.49 mmol), tert-butyl 4-[6-chloro-7-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate (1.42 g, 2.99 mmol), bis(triphenylphosphine)palladium(II ) dichloride (175.5 mg, 0.25 mmol) and potassium fluoride (289.7 mg, 4.99 mmol) in acetonitrile (10 ml) and water (2 ml) were stirred at 90°C for 1 hour. Upon completion, the resulting solution was concentrated in vacuo, diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (1/20) to give 250.0 mg (18.7%) tert-butyl 4-[7-[6-amino-4-ethyl-3- (trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazine-1-carboxylate. LC-MS: (ESI, m/z): 537.2 [M+H] ⁺ .

Step 9: 6-(6-chloro-4-piperazin-1-yl-quinazolin-7-yl)-4-ethyl-5-(trifluoromethyl)pyridine-2-amine

[0649] A solution of tert-butyl 4-[7-[6-amino-4-ethyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin-1-carboxylate (250, 0 mg, 0.47 mmol) in dichloromethane (10 ml) and trifluoroacetic acid (2 ml) were stirred at 25°C for 0.5 hour. Upon completion, the resulting solution was concentrated in vacuo, diluted with water (50 ml), the pH of the resulting solution was adjusted to pH=8 with an aqueous solution saturated with sodium carbonate, extracted with ethyl acetate (100 ml×3), washed with brine ( 80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (1/5) to give 142.0 mg (70%) of 6-(6-chloro-4-piperazin-1-yl-quinazolin-7-yl) -4-ethyl-5-(trifluoromethyl)pyridine-2-amine. LC-MS: (ESI, m/z): 437.1 [M+H] ⁺

Step 10: 1-[4-[7-[6-Amino-4-ethyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolpn-4-yl]piperazin-1-yl]prop-2 -en-1-he

[0650] 6-(6-Chloro-4-piperazin-1-yl-quinazolin-7-yl)-4-ethyl-5-(trifluoromethyl)pyridin-2-amine solution (21 1.0 mg, 0.48 mmol), acrylic acid (0.05 ml, 0.72 mmol), N,N-diisopropylethylamine (1.0 ml, 5.74 mmol) and HATU (220.4 mg, 0.58 mmol) in dichloromethane (7 ml) was stirred at -78°C for 0.5 hours. Upon completion, the resulting solution was diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (10/1) to give 48.4 mg (20.1%) of 1-[4-[7-[6-amino-4-ethyl-3- (trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one. LC-MS: (ESI, m/z): 491.1 [M+H] ⁺

[0651] Example 52: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) 6 8.67 (s, 1H), 8.11 (s, 1H), 7.65 (s, 1H), 6.88-6.81 (m, 3Н), 6.54 (s, 1Н), 6.18 (dd, J=16.7, 2.4 Hz, 1Н), 5.75 (dd, J=10.4, 2.4 Hz, 1Н), 3.86 (brs, 7Н), 3.78 (brs, 1Н ), 2.74-2.68 (m, 2Н), 1.24 (t, J=7.4 Hz, 3Н).

Example 53 1-(4-[6-chloro-7-[6-(methylamino)-3-(trifluoromethyl)pyridin-2-yl]quinazolin-4-yl]piperazin-1-yl)prop-2-ene -1-he

Synthetic way

Step 1: tert-butyl N-[(tert-butoxy)carbonyl]-N-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]carbamate

[0652] 6-Chloro-5-(trifluoromethyl)pyridine-2-amine solution (1.04 g, 5.29 mmol), di-tert-butyl dicarbonate (2.30 g, 10.54 mmol), triethylamine ( 1.55 g, 15.32 mmol) and 4-dimethylaminopyridine (70 mg, 0.57 mmol) in dichloromethane (6 ml) were stirred for 120 min at 60°C. Upon completion, the resulting solution was diluted with ethyl acetate (200 ml), washed with water (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with petroleum ether/ethyl acetate (0-20%) to give 1.37 g (65%) t-butyl N-[(t-butoxy)carbonyl]-N-[6-chloro-5- (trifluoromethyl)pyridin-2-yl]carbamate as a solid. LC-MS: (ESI, m/z): 397.1 [M+H] ⁺

Step 2: tert-butyl N-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]carbamate

[0653] A solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]carbamate (1.37 g, 3.45 mmol) and sodium hydroxide ( 848.0 mg, 21.20 mmol) in water (7 ml) and tetrahydrofuran (7 ml) were stirred for 120 min at 70°C. Upon completion, the pH of the resulting solution was adjusted to pH=7.0 with HCl/1,4-dioxane, diluted with ethyl acetate (200 ml), washed with water (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo . The residue was applied to a silica gel column eluting with petroleum ether/ethyl acetate (0~30%) to give 523.0 mg (70%) tert-butyl N-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]carbamate in the form of a solid. LC-MS: (ESI, m/z): 297.1 [M+H] ⁺

Step 3: tert-butyl N-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-methylcarbamate

[0654] To a solution of tert-butyl N-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]carbamate (1.00 g, 3.37 mmol) in N,N-dimethylformamide (11 ml) was added sodium hydride (206.0 mg, 8.58 mmol), stirred for 5 min at 0°C. Then, iodomethane (1.00 g, 7.04 mmol) was added and stirred for 30 min at 0°C. Upon completion, the resulting solution was quenched with saturated ammonium chloride solution, extracted (80 ml×3), washed (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with petroleum ether/ethyl acetate (0-30%) to give 1.00 g (95%) t-butyl N-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]-N -methylcarbamate as a solid. LC-MS: (ESI, m/z): 311.1 [M+H] ⁺ .

Step 4: tert-butyl 4-[7-(6-[[(tert-butoxy)carbonyl](methyl)amino]-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl]piperazine -1-carboxylate

[0655] In nitrogen, a solution of tert-butyl N-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-methylcarbamate (200.0 mg, 0.64 mmol), tert-butyl 4-[ 6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]piperazin-1-carboxylate (360.0 mg, 0.76 mmol), bis(triphenylphosphine)palladium( II) chloride (45.0 mg, 0.064 mmol) and potassium fluoride (120.0 mg, 2.07 mmol) in acetonitrile (3 ml) and water (0.6 ml) were stirred for 30 min at 80°C. Upon completion, the resulting solution was diluted with ethyl acetate (200 ml), washed with water (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (0~10%) to give 380 mg (95%) tert-butyl 4-[7-(6-[[(tert-butoxy)carbonyl](methyl)amino]- 3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl]piperazin-1-carbokeylate as a solid. LC-MS: (ESI, m/z): 623.2 [M+H] ⁺

Step 5: 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-N-methyl-5-(trifluoromethyl)pyridin-2-amine

[0656] Solution tert-butyl 4-[7-(6-[[(tert-butoxy)carbonyl](methyl)amino]-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4-yl] piperazine-1-carboxylate (380.0 mg, 0.61 mmol) in trifluoroacetic acid (3 ml) and dichloromethane (10 ml) were stirred for 30 min at 25°C. Upon completion, the resulting solution was concentrated in vacuo to give 450.0 mg (crude) of 6-[6-chloro-4-(piperazin-1-yl)quinazolin-7-yl]-N-methyl-5-(trifluoromethyl )pyridine-2-amine as a brown oil. LC-MS: (ESI, m/z): 523.2 [M+H] ⁺

Step 6: 1-(4-[6-chloro-7-[6-(methylamino)-3-(trifluoromethyl)pyridin-2-yl]quinazolin-4-yl]piperazin-1-yl)prop-2-ene -1-he

[0657] 6-[6-Chloro-4-(piperazin-1-yl)quinazolin-7-yl]-N-methyl-5-(trifluoromethyl)pyridin-2-amine solution (420.0 mg, 0.99 mmol), prop-2-enoic acid (97.0 mg, 1.35 mmol), HATU (410.0 mg, 1.08 mmol) and N,N-diisopropylethylamine (1 ml, 6.05 mmol) in dichloromethane (10 ml) was stirred for 30 min at -78°C. Upon completion, the resulting solution was quenched with water (1 ml), diluted with dichloromethane (200 ml), washed with water (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with dichloromethane/methanol (0-10%) to give 40.1 mg (8%) of 1-(4-[6-chloro-7-[6-(methylamino)-3-(trifluoromethyl) pyridin-2-yl]quinazolin-4-yl]piperazin-1-yl)prop-2-en-1-one as a solid. LC-MS: (ESI, m/z): 477.1 [M+H] ⁺ .

[0658] Example 53: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) 6 8.68 (s, 1H), 8.20 (s, 1H), 7.80-7.76 (m, 2H), 6.85 (dd, J=16.8, 10.6Hz, 1H), 6.65 (dd, J=9.0, 0.9Hz, 1H), 6.30 (dd, J=16.8, 1.9Hz, 1H), 5.83 (dd, J=10.6, 2.0Hz, 1H ), 4.03–4.01 (m, 4H), 3.96–3.91 (m, 4H), 2.91 (s, 3H).

Example 54 1-[(3S)-4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]-3-methylpiperazin-1-yl]prop -2-en-1-he

Synthetic way

Stage 1: 7-bromo-4,6-dichloroquinazoline

[0659] N,N-dimethylformamide (0.2 ml) and stirred for 3 h at 90°C. Upon completion, the resulting solution was concentrated in vacuo. This gave 11.00 g (crude) 7-bromo-4,6-dichloroquinazoline as a white solid. LC-MS: (PER, m/z): 276.9 [M+H] ⁺

Step 2: tert-butyl (3S)-4-(7-bromo-6-chloroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0660] A solution of 7-bromo-4,6-dichloroquinazoline (10.00 g, 35.98 mmol), tert-butyl (3S)-3-methylpiperazine-1-carboxylate (10.90 g, 54.424 mmol) and N ,N-diisopropylethylamine (9.3 g, 71.96 mmol) in 1,4-dioxane (50 ml) was stirred for 1 h at 90°C. Upon completion, the resulting solution was concentrated in vacuo, diluted with dichloromethane (300 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (20/1) to give 10.00 g (63%) tert-butyl (3S)-4-(7-bromo-6-chloroquinazolin-4-yl )-3-methylpiperazine-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 441.1 [M+H] ⁺

Step 3: tert-butyl (3S)-4-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-3-methylpiperazin-1-carboxylate

Under nitrogen, a solution of tert-butyl (3S)-4-(7-bromo-6-chloroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (1.00 g, 2.26 mmol), 4.4, 5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.73 g, 6.81 mmol), dichloromethane complex 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloride (186.0 mg, 0.23 mmol) and potassium acetate (450 mg, 4.585 mmol) in 1,4-dioxane (8 ml) was stirred for 1 h at 90° C. Upon completion, the resulting solution was diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to reverse phase with water:acetonitrile (5%~60%). This gave 1.2 g (36%) tert-butyl (3S)-4-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-3- methylpiperazine-1-carboxylate as a white solid. LC-MS: (ESI, m/z): 489.2 [M+H] ⁺

Step 4: tert-butyl (3S)-4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]-3-methylpiperazin-1-carboxylate

[0661] In nitrogen, a solution of tert-butyl (3S)-4-[6-chloro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-3-methylpiperazin-1 -carboxylate (800.0 mg, 1.64 mmol), 6-chloro-5-(trifluoromethyl)pyridine-2-amine (257.0 mg, 1.31 mmol), bis(triphenylphosphine)palladium(II) chloride ( 115.0 mg, 0.16 mmol) and potassium fluoride (190.0 mg, 3.27 mmol) in acetonitrile (6 ml) and water (1 ml) were stirred for 1 h at 110°C. Upon completion, the resulting solution was diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with methanol/dichloromethane (1/20) to give 80.0 mg (9%) tert-butyl (3S)-4-[7-[6-amino-3-(trifluoromethyl)pyridine-2 -yl]-6-chloroquinazolin-4-yl]-3-methylpiperazin-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 523.2 [M+H] ⁺

Step 5: 6-[6-chloro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine

[0662] A solution of tert-butyl (3S)-4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]-3-methylpiperazin-1-carboxylate ( 100.0 mg, 0.19 mmol) in trifluoroacetic acid (1 ml) and dichloromethane (3 ml) were stirred for 1 h at room temperature. After completion, the resulting solution was concentrated in vacuo, diluted with water (50 ml), the pH of the resulting solution was adjusted to pH=8 with an aqueous solution saturated with sodium carbonate, extracted with ethyl acetate (100 ml×3), dried over anhydrous sulfate sodium and concentrated in vacuo. This gave 90 mg (crude) 6-[6-chloro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine as a gray solid substances. LC-MS: (ESI, m/z): 423.1 [M+H] ⁺

Step 6: 1-[(3S)-4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]-3-methylpiperazin-1-yl]prop -2-en-1-he

[0663] 6-[6-Chloro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine solution (200.0 mg, 0 .47 mmol), prop-2-enoic acid (41.0 mg, 0.57 mmol), HATU (270.0 mg, 0.71 mmol) and N,N-diisopropylethylamine (122.0 mg, 0.94 mmol) in dichloromethane (5 ml) was stirred for 30 min at -78°C. Upon completion, the resulting solution was quenched with water (1 ml), diluted with dichloromethane (200 ml), washed with brine (80 ml×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with dichloromethane/methanol (20/1). The product was obtained by preparative HPLC under the following conditions: column: X Bridge C18, 19*150 mm, 5 µm; mobile phase A: Water/0.05% TFA; mobile phase B: ACN; flow rate: 20 ml/min; gradient: 30% B to 70% B in 10 min; 254 nm. This gave 30.5 mg (14%) 1-[(3S)-4-[7-[6-amino-3-(trifluoromethyl)pyridin-2-yl]-6-chloroquinazolin-4-yl]-3- methylpiperazin-1-yl]prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 477.1 [M+H] ⁺ .

[0664] Example 54: ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 8.69 (s, 1H), 8.12 (s, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.77 (s, 1H), 6.92-6.80 (m, 1H), 6.74 (dd, J=8.9, 0.8 Hz, 1H), 6.31 (dd, J=16.9, 5.7 Hz, 1H), 5.84 (dd, J=10.7 , 1.9 Hz, 1Н), 4.59-4.41 (m, 1Н), 4.34-4.29 (m, 1Н), 4.23-4.05 (m, 1Н), 3.85-3.60 (m, 2Н), 3.39-3.37 (m, 1Н ), 3.26-3.19 (m, 1Н), 1.44 (d, J=6.8 Hz, 3Н).

Example 55: 2-[4-|7-|6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)-1-methylpyrrolidin-2-yl ]methoxy[quinazolin-4-yl]1-(2-fluoronron-2-spoil)piperazin-2-yl]acetonitrile

Synthetic way

Step 1: tert-butyl 4-(7-6rom-2,6-dichloroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0665] N,N-diisopropylethylamine (1.00 ml, 6 .00 mmol) and 2-piperazine-2-placetonitrile dihydrochloride (300 mg; 1.50 mmol). The reaction system was stirred at 60°C for 1 hour. The reaction system was cooled to rt, then 4-dimethylaminopyridine (37.5 mg; 0.303 mmol) and di-tert-butyl dicarbonate (1022 mg, 4.54 mmol) were added. The reaction system was stirred at room temperature. within 18 hours. The reaction was quenched with water and extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by flash chromatography on silica (eluting with MeOH/DCM) to give tert-butyl 4-(7-bromo-2,6-dichloroquinazolin-4-yl)-2-(cyanomethyl)piperazin-1- carboxylate (562 mg, 74%). LCMS (ESI, m/z): 501.9 [M+H] ⁺ .

Step 2: tert-butyl 4-(7-bromo-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazin-1 -carboxylate

[0666] To a solution of [(2S)-1-methylpyrrolidin-2-yl]methanol (0.334 ml, 2.70 mmol) in tetrahydrofuran (18 ml) was added sodium hydride (60 wt.%) in oil (108 mg, 2 .70 mmol) at room temperature, then stirred for 20 minutes. The reaction was cooled to 0°C and a solution of tert-butyl 4-(7-bromo-2,6-dichloroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (450 mg, 0.90 mmol) in tetrahydrofuran (3 ml). The reaction system was allowed to warm to room temperature and stirred for 1 hour. The reaction system was quenched with water and extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by flash chromatography on silica (eluting with MeOH/DCM) to give t-butyl 4-(7-bromo-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl) methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (224 mg, 43%). LC-MS (ESI, m/z): 579.1 [M+H] ⁺ .

Step 3: tert-butyl 4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0667] To a solution of tert-butyl 4-(7-bromo-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine -1-carboxylate (220 mg, 0.379 mmol) and bis(pinacolato)diboron (147 mg, 0.570 mmol) in 1,4-dioxane (7.0 ml) were added potassium acetate (55.9 mg, 0.570 mmol) and dichloromethane [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (2S, 0 mg, 0.038 mmol). The reaction system was degassed, then heated at 95° C. for 2 hours. The reaction was filtered through celite, concentrated to give tert-butyl 4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate. The crude product was transferred to the next step. LCMS (ESI, m/z): 545.1 [M+H] ⁺ (LCMS indicates the mass of boronic acid).

Step 4: tert-butyl 4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0668] A suspension of tert-butyl 4-(6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (240mg, 0.383mmol), 6-bromo-4-methyl-5-(trifluoromethyl)pyridine-2- amine (195.0 mg, 0.766 mmol), bis(triphenylphosphine)palladium(II) dichloride (27.0 mg, 0.038 mmol), potassium fluoride (223 mg, 3.83 mmol) in 1,4-dioxane (7, 0 ml) and water (3.5 ml) was degassed. The reaction system was heated with microwaves at 125° C. for 25 minutes. The reaction was filtered through celite. The crude product was purified by flash chromatography on silica (eluting with MeOH/DCM) to give t-butyl 4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6 -chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (112 mg, 43%). LCMS (ESI, m/z): 675.4 [M+H] ⁺ .

Step 5: 2-(4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1-methylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile

[0669] A solution of tert-butyl 4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1-methylpyrrolidin-2 -yl)methoxy)quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (112 mg, 0.166 mmol) in 5% trifluoroacetic acid in hexafluoroisopropanol (2.509 ml, 1.66 mmol) was stirred at rt . within 4 hours. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The reaction was concentrated and the crude product was purified by HPLC to give 2-(4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S )-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile (50 mg, 52%). LCMS (ESI, m/z): 575.2 [M+H] ⁺ .

Step 6: 2-[4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)-1-methylpyrrolidin-2-yl ]methoxy]quinazolin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

[0670] To a solution of 2-(4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1-methylpyrrolidin- 2-yl)methoxy)quinazolin-4-yl)piperazin-2-yl)acetonitrile (60mg, 0.10mmol), 2-fluoroprop-2-enoyloxysodium (14mg, 0.13mmol) and N,N- Diisopropylethylamine (0.09 ml, 0.52 mmol) in N,N-dimethylformamide (2.0 ml) was added HATU (83.5 mg, 0.21 mmol) at 0° C. and stirred for 20 minutes. The reaction was quenched with water and extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered and concentrated using a rotary vacuum evaporator. The crude product was purified by HPLC FA 5-50% 15 min to give 2-[4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[ [(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (34 mg, 50%).

[0671] Example 55: ¹ H NMR (400 MHz, DMSO-d6) δ 8.17 - 8.06 (m, 1H), 7.42 (d, J=3.2 Hz, 1H), 6.77 (d, J=2.9 Hz, 2H) , 6.46 (s, 1Н), 5.48-5.18 (m, 2Н), 4.86 (s, 1H), 4.36 (dt, J=11.3, 5.7 Hz, 1H), 4.21 (qd, J=10.4, 9.0, 6.0 Hz , 3H), 3.11 - 2.93 (m, 2H), 2.63 (s, 1H), 2.40 - 2.34 (m, 6H), 2.23 (q, J=8.4 Hz, 2H), 2.02 -1.88 (m, 1H), 1.67 (tdd, J=16.1, 9.6, 4.8 Hz, 3H). LCMS (ESI, m/z): 647.3 [M+H] ⁺ .

Example 56: 2-[4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R)-4-fluoro-1 -methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

[0672] Example 56 was prepared according to the same protocol as Example 55, except that in Step 2 of Example 56 ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol was used in place of [(2S)-1-methylpyrrolidin-2-yl]methanol as an alternative reagent.

[0673] Example 56: ¹ H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J=3.9 Hz, 1H), 7.43 (d, J=3.1 Hz, 1H), 6.77 (d, J=2.8 Hz , 2Н), 6.46 (s, 1Н), 5.41 (dd, J=18.0, 4.1 Hz, 1H), 5.37-5.08 (m, 2Н), 4.39 (ddd, J=11.5, 7.6, 4.7 Hz, 1Н), 4.25 (ddq, J=24.9, 12.6, 5.3 Hz, 3H), 2.92 (dd, J=10.2, 5.3 Hz, 2Н), 2.40 (s, 3H), 2.38 - 2.33 (m, 3H), 2.22 - 2.04 ( m, 1Н), 1.91 (dddd, J=33.6, 14.8, 9.8, 5.9 Hz, 1Н). LCMS (ESI, m/z): 665.3 [M+H] ⁺ .

Example 57: 1-[4-[7-[6-Amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)-1-methylpyrrolidin-2-yl ]methoxy]quinazolin-4-yl]-2-(fluoromethyl)piperazin-1-yl]-2-fluoro-prop-2-en-1-one

[0674] Example 57 was prepared according to the same protocol as Example 55, except that in Step 1 of Example 57, tert-butyl 2-(fluoromethyl)piperazine-1-carboxylate hydrochloride was used instead of 2-piperazine-2- ylacetonitrile dihydrochloride as an alternative reagent.

[0675] Example 57: ¹ H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=1.5 Hz, 1H), 7.42 (d, J=1.7 Hz, 1H), 6.78 (d, J=2.9 Hz , 2Н), 6.46 (s, 1Н), 5.43 - 5.18 (m, 2Н), 4.74 (d, J=43.0 Hz, 3H), 4.43 - 4.12 (m, 5Н), 2.99 - 2.93 (m, 1H), 2.63 - 2.53 (m, 1H), 2.36 (s, 6H), 2.18 (q, J=8.6 Hz, 1H), 2.01 - 1.89 (m, 1H), 1.74 - 1.56 (m, 4H). LCMS (ESI, m/z): 640.3 [M+H] ⁺ .

Example 58: 2-[(2R)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R)-4 -fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-1-(2-fluoroprop-2-enoyl)-5-methyl-piperazin-2-yl]acetonitrile:

[0676] Example 58 was prepared according to the same protocol as Example 55 except that in Step 1 of Example 58, 2-((2R)-5-methylpiperazin-2-yl)acetonitrile (Intermediate 2) was used instead of 2-piperazin-2-ylacetonitrile dihydrochloride, and in Step 2 of Example 58, instead of [(2S)-1-methylpyrrolidin-2-yl]methanol, ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl ) methanol as an alternative reagent.

[0677] Example 58: ¹ H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J=10.5 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.77 (s, 2H), 6.46 (d, J=1.5 Hz, 1H), 5.49 - 4.92 (m, 4H), 4.64 (s, 1H), 4.38 (dt, J=10.6, 5.1 Hz, 1H), 4.34 - 4.22 (m, 1H), 4.21 - 3.93 (m, 2H), 3.71 (d, J=29.2 Hz, 2H), 3.53 - 3.37 (m, 2H), 3.07 - 2.84 (m, 2H), 2.40 (dd, J=2.4, 1.1 Hz, 4H), 2.38 - 2.34 (m, 3H), 2.13 (ddd, J=25.1, 10.7, 4.0 Hz, 1H), 2.02 -1.80 (m, 1H), 1.15 (d, J=8.5 Hz, 3H). LCMS (ESI, m/z): 679.3 [M+H] ⁺ .

Examples 59a and 59b: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(( (S)-1-methylinrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-mstylinperain-1-yl)prop-2-en-1-one (Example 59a ) and 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((S) -1-methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylinperazin-1-yl)pron-2-en-1-one (Example 59b)

Synthetic way

Step 1: 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid

[0678] A solution of 2-amino-4-bromo-3-fluorobenzoic acid (31.0 g, 132.47 mmol) and N-iodosuccinimide (32.86 g, 146.05 mmol) in N,N-dimethylformamide (100 ml) was stirred at 80°C for 2 hours. LC-MS showed the formation of the desired product. The resulting solution was diluted with water (2 L), filtered, and the solids were collected and washed with water to give 2-amino-4-bromo-3-fluoro-5-iodo-benzoic acid (45 g, 125.03 mmol, 94 .4% yield) as a yellow solid. LC-MS: (ESI, m/z): 357.9 [M+H] ⁺

Step 2: 7-bromo-8-fluoro-6-iodoquinazoline-2,4(1H,3H)-dione

[0679] A solution of urea (352.0 g, 5860.8 mmol) and 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (44.0 g, 122.25 mmol) was stirred at 200°C in within 1 hour. LC-MS showed the formation of the desired product. The reaction was cooled to 80°C and further diluted with water. After filtration, the solids were collected and washed with water (-50°C) to give 7-bromo-8-fluoro-6-iodoquinazoline-2,4(1H,3H)-dione (45 g, 116.9 mmol, 95 6% yield) as a yellow solid. LC-MS: (ESI, m/z): 382.8 [M+H] ⁺

Step 3: 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline

[0680] A solution of 7-bromo-8-fluoro-6-iodoquinazoline-2,4(1H,3H)-dione (1.0 g, 2.6 mmol) and N,N-dimethylaniline (0.99 ml, 7 .79 mmol) in phosphorus oxychloride (10 ml, 107.28 mmol) was stirred at 80° C. for 2 hours. After completion, the crude product was used directly in the next step.

Step 4: tert-butyl (S)-4-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0681] A solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (2.2 g, 5.22 mmol) and N,N-diisopropylethylamine (4.58 ml, 26.31 mmol) in 1,4-dioxane (20 ml) was stirred at 25°C for 2 minutes. tert-Butyl (3S)-3-methyl-1-piperazinecarboxylate (3.1 g, 15.48 mmol) was added and stirred at 25° C. for 1 hour. Upon completion, the reaction was concentrated in vacuo and the residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (85:15) to give tert-butyl (S)-4-(7-bromo-2-chloro-8- fluoro-6-iodhinazolin-4-yl)-3-methylpiperazin-1-carboxylate (700 mg, 1.1953 mmol, 22.9% yield) as a yellow solid. LCMS: (ESI, m/z): 584.9 [M+H] ⁺

Step 5: tert-butyl (S)-4-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0682] tert-Butyl (S)-4-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3-methylpiperazin-1-carboxylate solution (5.0 g, 8. 54 mmol) and potassium fluoride (2.5 g, 43.03 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 120° C. for 2 hours. Upon completion, the solution was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (9:1) to give tert-butyl (S)-4-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl) -3-methylpiperazine-1-carboxylate (3.1 g, 5.4 mmol, 63.8% yield) as a yellow solid. LCMS: (ESI, m/z): 569.0 [M+H] ⁺

Step 6: tert-butyl (S)-4-(7-bromo-2,8-difluoro-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0683] Under nitrogen, a solution of tert-butyl (S)-4-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (1.0 g, 1 .76 mmol), copper(1) iodide (3400 mg, 17.85 mmol) and silver(I) trifluoromethanethiolate (1.1 g, 5.26 mmol) in N,N-dimethylformamide (10 ml) were stirred at 90° C for 2 hours in microwave. Upon completion, the residue was purified by C18 gel flash chromatography eluting with methanol/water (97:3) to give t-butyl (S)-4-(7-bromo-2,8-difluoro-6-(( trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate. LC-MS: (ESI, m/z): 543.1 [M+H] ⁺

Step 7: tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-2,8-difluoro-6-((trifluoromethyl)thio )quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0684] Under nitrogen, a solution of tert-butyl (S)-4-(7-bromo-2,8-difluoro-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate ( 2.0 g, 3.68 mmol), N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-6-tributylstannyl-pyridine-2-amine (3.5 g, 5.49 mmol), tetrakis (triphenylphosphine) palladium (0) (2.1 g, 1.82 mmol), copper (I) iodide (400 mg, 2.1 mmol) and lithium chloride (400.0 mg, 9.22 mmol) in 1 ,4-dioxane (20 ml) was added and stirred at 90°C for 16 hours. After completion, the reaction was filtered, the filtrate was diluted with ethyl acetate and washed with water. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (80:20) to give tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridine -2-yl)-2,8-difluoro-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (1.6 g, 1.9 mmol, 53.6% yield ) as a yellow oil. LC-MS: (ESI, m/z): 811.3 [M+H] ⁺

Step 8: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-2,8-difluoro-6-( (trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0685] tert-Butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-2,8-difluoro-6-((trifluoromethyl) solution thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (3.7 g, 4.56 mmol), N-iodosuccinimide (1.25 g, 5.59 mmol) and p-toluenesulfonic acid monohydrate (44 0 mg, 0.23 mmol) in N,N-dimethylformamide (20 ml) was stirred at 25° C. for 1 hour. Upon completion, the solution was diluted with ethyl acetate, transferred to a sorting funnel and washed with water. The organic layer was combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (75:25) to give t-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodine -4-methylpyridin-2-yl)-2,8-difluoro-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (1.1 g, 1.1 mmol, 25 .7% yield) as a yellow oil. LC-MS: (ESI, m/z): 937.1 [M+H] ⁺

Step 9: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,8-difluoro- 6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0686] In nitrogen, a solution of tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-2,8-difluoro -6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (200.0 mg, 0.21 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1000 0 mg, 5.21 mmol) and copper(I) iodide (404 mg, 2.12 mmol) in N,N-dimethylacetamide (10 ml) were added and stirred at 90° C. for 2 hours. After completion, the reaction was filtered, the filtrate was concentrated under reduced pressure and diluted with ethyl acetate and washed with water. The organic layer was combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (80:20) to give t-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl -3-(trifluoromethyl)pyridin-2-yl)-2,8-difluoro-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (160 mg, 0.18 mmol, 85.3% yield) as a yellow oil. LC-MS: (ESI, m/z): 879.2 [M+H] ⁺

Step 10: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2- (((S)-1-methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0687] A solution of sodium hydride (165.0 mg, 4.12 mmol) in tetrahydrofuran (50 ml) was stirred at 25° C. for 5 minutes. N-methyl-1-prolinol (412.5 mg, 3.58 mmol) was added and stirred at 25° C. for 10 minutes. Then, tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,8-difluoro- 6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (1650.0 mg, 1.88 mmol) and stirred at 25°C for 10 minutes. Upon completion, the reaction was concentrated to give crude tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8 -fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (1.5 g, 1.54 mmol, 82% yield), which was used directly in the next step without purification. LC-MS: (ESI, m/z): 974.4 [M+H] ⁺ .

Step 11: 6-(8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl )thio)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0688] tert-Butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2 solution -(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (1.3 g, 1.33 mmol ) in 2,2,2-trifluoroacetic acid (20 ml) was stirred at 60°C for 16 hours. After completion, the reaction was concentrated. The residue was purified by silica gel flash chromatography eluting with methanol/water (25/75) and (60/40) to give 6-(8-fluoro-4-((S)-2-methylpiperazin-1-yl)- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (410 mg, 0.6 mmol, 48.5% yield) as a yellow oil. LC-MS: (ESI, m/z): 634.2 [M+H] ⁺

Step 12: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((S )-1-methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 59a) and 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 59b)

[0689] A solution of N,N-diisopropylethylamine (288.0 mg, 2.23 mmol) and 6-(8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2(((S) -1-methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)inazolin-7-yl)-4-methyl-5-trifluoromethyl)pyridin-2-amine (720.0 mg, 1.14 mmol ) in dichloromethane (50 ml) was stirred at -78°C for 5 minutes. Then acryloyl chloride (108.0 mg, 1.19 mmol) was added and the reaction was stirred at -78° C. for 30 minutes. Upon completion, the reaction was quenched with methanol and diluted with dichloromethane. The resulting mixture was poured into a sorting funnel and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by C18 gel flash chromatography eluting with acetonitrile/water (65:35) to give the crude product. The crude product was purified by preparative HPLC - Column: Xselect CSH OBD Column 30*150 mm 5 µm, n; mobile phase A: Water (0.1% FA), mobile phase B: ACN; flow rate: 60 ml/min. The crude product was purified by chiral preparative HPLC - Column: CHIRALPAK IC, 2*25 cm, 5 µm; mobile phase A:hexane:DCM=3:1(10 mM NH ₃ -MeOH)--HPLC, mobile phase B:EtOH--HPLC; flow rate: 15 ml/min; to give 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((S) -1-methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one as a white solid and 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)-6-((trifluoromethyl)thio)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (44.5 mg, 0, 06 mmol, 5.7% yield) as a white solid.

[0690] Example 59a: LC-MS: (ESI, m/z): 688.2 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO, ppm) δ 8.12 (d, J=21 Hz, 1H ), 6.84 (s, 3H), 6.50 (s, 1H), 6.18 (d, J=36.0 Hz, 1H), 5.75 (dd, J=2.4, 10.2 Hz, 1H), 4.75-4.63 (m, 1H) , 4.47-4.00 (m, 5Н), 3.67-3.55 (m, 2Н), 3.25-3.16 (m, 1H), 3.02-2.92 (m, 1Н), 2.66-2.55 (m, 1H), 2.38 (s, 6Н), 2.25-2.15 (m, 1H), 2.02-1.85 (m, 1Н), 1.75-1.55 (m, 3Н), 1.45-1.26 (m, 3Н). Chiral HPLC: CHIRALPAK IC-3 (0.46*5 cm; 3 µm); detection at 254 nm; n-hexane / dichloromethane = 3/1 (0.1% diethylamine); flow rate=1.0 ml/min; Hold time: 0.9 min (faster peak).

[0691] Example 59b: LC-MS: (ESI. m/z): 688.2 [M+H] ^{+ 1} H NMR (300 MHz. DMSO, ppm) δ 8.13 (s, 1H), 6.92-6.84 ( m, 3Н), 6.51 (s, 1Н), 6.20 (d, J = 30.0 Hz, 1H). 5.75 (dd, J = 2.4.10.2 Hz, 1H), 4.75 (s. 1H), 4.45-4.35 (m, 1H), 4.30-3.90 (m, 4H), 3.80-3.55 (m, 2H), 3.28- 3.04 (m, 1H), 3.01-2.90 (m, 1H), 2.65-2.55 (m, 1H), 2.43-2.31 (m, 6H), 2.23-2.11 (m, 1H), 2.04-1.87 (m, 1H ), 1.75–1.55 (m, 3Н), 1.34 (d, J = 6.6 Hz. 3H). Chiral HPLC: CHIRALPAK IC-3 (0.46*5 cm; 3 µm): detection at 254 nm; n-hexane/dichloromethane - 3/1 (0.1% diethylamine): flow rate - 1.0 ml/min; Retention time: 1.8 min (slower peak).

Example 60: 1-[(3S,5S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl[-6-chloro-quinazolin-4-yl]-3, 5-dimethyl-piperazin-1-yl]prop-2-en-1-one

Synthetic way

Ethane I: tert-butyl (3S,5S)-4-(7-bromo-6-chloro-quinazolin-4-yl)-3,5-dimethyl-piperazil-1-carboxylate

[0692] 7-Bromo-4,6-dichloro-quinazoline mixture (see Example 22, Step 1) (1.0 g, 3.6 mmol), t-butyl (3S,5S)-3,5-dimethylpiperazine -1-carboxylate (1.1 g, 5.4 mmol) and sodium carbonate (1.1 g, 10.7 mmol) in dimethyl sulfoxide (10 ml) were stirred at 60° C. for 16 hours. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (9:1) to give t-butyl (3S,5S)-4-(7-bromo-6-chloro-quinazolin-4-yl)-3 ,5-dimethyl-piperazine-1-carboxylate (0.50 g, 1.0 mmol, 30.5% yield) as a yellow oil. LC-MS: (ESI, m/z): 455.1 [M+H] ⁺

Step 2: tert-butyl (3S,5S)-4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl] -3,5-dimethyl-piperazine-1-carboxylate

[0693] Under nitrogen, a solution of tert-butyl (3S,5S)-4-(7-bromo-6-chloro-quinazolin-4-yl)-3,5-dimethyl-piperazine-1-carboxylate (900.0 mg , 1.9 mmol), bis(pinacolato)diboron (5.0 g, 19.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (144.3 mg, 0. 20 mmol) and potassium acetate (387.0 mg, 3.9 mmol) in 1,4-dioxane (90 ml) were stirred at 80°C for 1 hour. Upon completion, the reaction was filtered and the resulting solid was washed with hexane. The crude product was directly used in the next step. LC-MS: (ESI, m/z): 503.3 [M+H] ⁺

Step 3: tert-butyl (3S,5S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-3, 5-dimethyl-piperazine-1-carboxylate

[0694] tert-Butyl (3S,5S)-4-[6-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl solution ]-3,5-dimethyl-piperazine-1-carboxylate (1.0 g, 1.9 mmol), 6-bromo-4-methyl-5-(trifluoromethyl) pyridine-2-amine (1.0 g, 3 .9 mmol), potassium fluoride (230.6 mg, 3.9 mmol) and bis(triphenylphosphine)palladium(II) chloride (139.4 mg, 0.2 mmol) in acetonitrile (10 ml) and water (2 ml ) was stirred at 80°C for 1 hour under nitrogen. After completion, the reaction was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The mixture was concentrated and the residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (20:1) to give t-butyl (3S,5S)-4-[7-[6-amino-4-methyl-3-( trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-3,5-dimethyl-piperazine-1-carboxylate (300 mg, 0.5 mmol, 27.4% yield) as a brown solid . LC-MS: (ESI, m/z): 551.2 [M+H] ⁺

Step 4: 1-[(3S,5S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]-3, 5-dimethyl-piperazin-1-yl]prop-2-en-1-one

[0695] To a solution of tert-butyl (3S,5S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazolin-4-yl]- 3,5-dimethyl-piperazine-1-carboxylate (300.0 mg, 0.5 mmol) in dichloromethane (6 ml) trifluoroacetic acid (1.2 ml, 15.7 mmol) was added. The reaction was stirred at 25°C for 30 minutes and concentrated. The resulting mixture was diluted with dichloromethane (6 ml) and N,N-diisopropylethylamine (343.3 mg, 2.6 mmol) was added thereto. Acryloyl chloride (48.1 mg, 0.5 mmol) was added at -78°C and the reaction was stirred for 30 minutes. After completion, the reaction was concentrated and the residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (20/1) to give a crude solid. The crude product was purified by preparative HPLC to give 1-[(3S,5S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-quinazoline-4 -yl]-3,5-dimethyl-piperazin-1-yl]prop-2-en-1-one (90.1 mg, 0.18 mmol, 33.5% yield) as a white solid. The crude product was purified by preparative HPLC - Column: XBridge Prep C18 OBD Column 19×150 mm 5 µm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 ml/min.

[0696] Example 60: ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 8.97 (d, J=4.9 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.79 (d, J=5.3 Hz, 1H), 6.97 - 6.71 (m, 3H), 6.55 - 6.46 (m, 1H), 6.20 (dd, J=16.7, 2.4 Hz, 1H), 5.75 (dd, J=10.4, 2.4 Hz , 1H), 4.15 - 3.89 (m, 4H), 3.65 (s, 2H), 2.38 (d, J=2.5 Hz, 3H), 1.01 (d, J=6.4 Hz, 6H). LC-MS: (ESI, m/z): 505.1 [M+H] ⁺

Example 61: 1-((S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: tert-butyl (S)-4-(7-bromo-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin- 1-carboxylate

[0697] Sodium hydride (1.01 g, 42.00 mmol) was added to a solution of (S)-(1-methylpyrrolidin-2-yl) methanol (4.84 g, 42.00 mmol) in N,N-dimethylformamide (40 ml) and stirred at 0°C for 5 minutes. Then, tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (Intermediate 5) (10.00 g, 21.00 mmol ) and the resulting mixture was stirred at 0°C for 1 hour. Upon completion, the reaction was quenched with aqueous ammonium chloride, diluted with water, extracted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified using a silica gel column eluting with dichloromethane/methanol (20:1) to give tert-butyl (S)-4-(7-bromo-6-chloro-2-(((S)-1-methylpyrrolidine-2- yl)methoxy)hipazolip-4-yl)-3-methylinperazin-1-carboxylate (10.50 g, 17.98 mmol, 85.6% yield) as a yellow oil. LC-MS: (ESI, m/z): 556.4 [M+H] ⁺

Step 2: 4-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline -7-ylboronic acid

[0698] tert-Butyl (S)-4-(7-bromo-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine solution -1-carboxylate (2.00 g, 3.60 mmol), bis(pinacolato)diboron (2.75 g, 10.81 mmol), potassium acetate (1.06 g, 10.81 mmol) and dichloromethane complex [ 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.27 g, 0.36 mmol) in 1,4-dioxane (15 ml) was stirred at 80° C. for 2 hours under nitrogen. Upon completion, the resulting solution was concentrated, diluted with dichloromethane and filtered. The filtrate was concentrated in vacuo to give 4-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl) methoxy)quinazolin-7-ylboronic acid (3.00 g, crude) as a black oil. The crude product was directly used in the next step. LC-MS: (ESI, m/z): 520.2 [M+H] ⁺

Step 3: tert-butyl (S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0699] 4-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy) solution quinazolin-7-ylboronic acid (2.20 g, 2.12 mmol), 6-bromo-4-methyl-5-(trifluoromethyl)pyridine-2-amine (0.54 g, 2.12 mmol), potassium fluoride (0.25 g, 4.23 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.15 g, 0.21 mmol) in a mixed solvent of acetonitrile (35 ml) and water (7 ml) were stirred at 80° C for 2 hours in nitrogen. Upon completion, the resulting solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified with a silica gel column eluting with dichloromethane/methanol (10:1) to give tert-butyl (S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl) -6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (0.50 g, 0.72 mmol, 34, 2% yield) as a brown solid. LC-MS: (ESI, m/z): 650.3 [M+H] ⁺

Step 4: 1-((S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

[0700] A solution of tert-butyl (S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (0.30 g, 0.46 mmol) and trifluoroacetic acid (0.6 ml, 7.79 mmol) in dichloromethane (3 ml) was stirred at 25°C for 1 hour. Upon completion, the reaction system was concentrated, diluted with dichloromethane, adjusted to pH>7 with N,N-diisopropylethylamine. Then acryloyl chloride (0.03 g, 0.37 mmol) was added and the reaction was stirred at -78° C. for 1 hour. Upon completion, the resulting solution was diluted with water, extracted with dichloromethane, dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC to give 1-((S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(( (S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (28.7 mg, 0.05 mmol, 15 , 1% yield) as a white solid. LCMS: (ESI, m/z): 604.2 [M+H] ⁺ . Prep HPLC Conditions: Column: XBridge Prep C18 OBD Column; mobile phase, A: water, B: acetonitrile, V% (from 33% to 50% in 7 min); detector, UV 254 nm

[0701] Example 61: ¹ H NMR (300 MHz, DMSO-d6, ppm) δ 7.94 (d, J=3.9 Hz, 1H), 7.41 (s, 1H), 6.95 - 6.72 (m, 3H), 6.47 (s, 1H), 6.18 (d, J=18.3 Hz, 1H), 5.75 (d, J=10.5, 2.4 Hz, 1H), 4.70 (s, 1H), 4.46 - 4.31 (m, 2H), 4.31 - 3.92 (m, 4H), 3.73 - 3.51 (m, 2H), 3.01 - 2.91 (m, 1H), 2.64 - 2.53 (m, 1H), 2.36 (s, 6H), 2.25 -2.12 (m, 1H) , 2.00 - 1.90 (m, 1H), 1.77 - 1.56 (m, 3H), 1.26 (d,J=6.0 Hz, 3H).

Examples 62a and 62b: 1-((S)-4-((R)-6-chloro-8-fluoro-7-(4-methyl-6-(methylamino)-3-(trifluoromethyl)pyridin-2-yl )-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 62a) and 1 -((S)-4-((S)-6-chloro-8-fluoro-7-(4-methyl-6-(methylamino)-3-(trifluoromethyl)pyridin-2-yl)-2-(( (S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 62b) (2 atropisomers)

Synthetic way

Ethane 1: tert-butyl (S)-4-(6-chloro-2,8-difluoro-7-(6-((4-methoxybenzyl)(methyl)amino)-4-methylpiperazin-2-yl)quinazolin- 4-yl)-3-methylpiperazin-1-carboxylate

[0702] N-[(4-methoxyphenyl)methyl]-N,4-dimethyl-6-tributylethanetannyl-pyridin-2-amine solution (5.5 g, 10.35 mmol). tert-butyl (3S)-4-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)-3-methyl-piperazin-1-carboxylate (2.47 g, 5.17 mmol ), tetrakis(triphenylphosphine)palladium (1.2 ml, 1.03 mmol). copper iodide (296.1 ml, 1.55 mmol) and lithium chloride (548.4 ml, 12.94 mmol) in 1,4-dioxane (100 ml) were stirred overnight at 150° C. under nitrogen. The reaction was concentrated and the residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (7/3) to give t-butyl (S)-4-(6-chloro-2,8-difluoro-7-(6- ((4-methoxybenzyl)(methyl)amino)-4-methylpyridin-2-yl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (2.2 g, 3.48 mmol, 67.2% yield ) as a yellow solid. LCMS: (ESI, m/z): 639.3 [M+H] ⁺

Step 2: tert-butyl (3S)-4-(6-chloro-2,8-difluoro-7-(3-iodo-6-((4-methoxybenzyl)(methyl)amino)-4-methylpyridine-2- yl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0703] tert-Butyl (S)-4-(6-chloro-2,8-difluoro-7-(6-((4-methoxybenzyl)(methyl)amino)-4-methylpyridin-2-yl)quinazoline solution -4-yl)-3-methylpiperazin-1-carboxylate (2.22 g, 3.48 mmol), N-iodosuccinimide (1.57 g, 6.96 mmol) and p-toluenesulfonic acid (129.5 mg, 0.75 mmol) was dissolved in N,N-dimethylformamide (100 ml) and stirred overnight at room temperature. The reaction system was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (75/25) to give tert-butyl (3S)-4-(6-chloro-2,8-difluoro-7-(3-iodo-6 -((4-methoxybenzyl)(methyl)amino)-4-methylpyridin-2-yl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (1.53 g, 2.00 mmol, 57.5% yield) as a yellow solid. LCMS: (ESI, m/z): 765.1 [M+H] ⁺ .

Step 3: tert-butyl (3S)-4-(6-chloro-2,8-difluoro-7-(6-((4-methoxybenzyl)(methyl)amino)-4-methyl-3-(trifluoromethyl)pyridine -2-yl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0704] Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate solution (4.39 g, 22.85 mmol), t-butyl (3S)-4-(6-chloro-2,8-difluoro-7 -(3-iodo-6-((4-methoxybenzyl)(methyl)amino)-4-methylpyridin-2-yl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (3.5 g, 4, 57 mmol) and copper iodide (870.0 mg, 4.57 mmol) in N,N-dimethylformamide (70 ml) were stirred for 6 hours at 90° C. under nitrogen. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (75/25) to give tert-butyl (3S)-4-(6-chloro-2,8-difluoro-7-(6-((4 -methoxybenzyl)(methyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (2.5 g, 3.54 mmol, 77 .5% yield) as a yellow solid. LCMS: (ESI, m/z): 707.3 [M+H] ⁺ .

Step 4: tert-butyl (3S)-4-(6-chloro-8-fluoro-7-(6-((4-methoxybenzyl)(methyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2 -yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0705] To a solution of N-methyl-1-prolinol (70 mg, 0.57 mmol) in tetrahydrofuran (3 ml) was added sodium hydride (23 mg, 0.57 mmol, 60% dispersion in mineral oil) at 0°C . The reaction was stirred for 0.5 hour. To the resulting mixture was added tert-butyl (3S)-4-(6-chloro-2,8-difluoro-7-(6-((4-methoxybenzyl)(methyl)amino)-4-methyl-3-( trifluoromethyl)pyridin-2-yl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (0.2 g, 0.28 mmol) and the reaction was stirred at room temperature for an additional 0.5 hour. The reaction was quenched with water and extracted with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (30%) to give t-butyl (3S)-4-(6-chloro-8-fluoro-7-(6-((4-methoxybenzyl) (methyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine -1-carboxylate (100 mg, 0.12 mmol, 44.1% yield) as a yellow solid. LCMS (ESI, m/z): 802.1 [M+H] ⁺ .

Step 5: 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin- 7-yl)-N,4-dimethyl-5-(trifluoromethyl)pyridine-2-amine

[0706] A solution of tert-butyl (3S)-4-(6-chloro-8-fluoro-7-(6-((4-methoxybenzyl)(methyl)amino)-4-methyl-3-(trifluoromethyl)pyridine- 2-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (2.1 g, 2.66 mmol) in trifluoroacetic acid (40 ml) was stirred at 50°C for 2 hours. The reaction solution was concentrated and the residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (2/10) to give 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl )-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-N,4-dimethyl-5-(trifluoromethyl)pyridin-2-amine (1.2 g, 2 .11 mmol, 79.3% yield) as a yellow solid. LCMS (ESI, m/z): 582.1 [M+H] ⁺ .

Step 6: 1-((S)-4-((R)-6-chloro-8-fluoro-7-(4-methyl-6-(methylamino)-3-(trifluoromethyl)pyridin-2-yl)- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 62a) and 1-( (S)-4-((S)-6-chloro-8-fluoro-7-(4-methyl-6-(methylamino)-3-(trifluoromethyl)pyridin-2-yl)-2-(((S )-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 62b) (2 atropisomers)

[0707] 6-(6-Chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline solution -7-yl)-N,4-dimethyl-5-(trifluoromethyl)pyridine-2-amine (400.0 mg, 0.69 mmol) and N,N-diisopropylethylamine (177.3 mg, 1.37 mmol) in dichloromethane (10 ml) was cooled to -78°C. Acryloyl chloride (62 mg, 0.69 mmol) was added to the reaction, and the mixture was stirred at -78° C. for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was isolated by preparative HPLC - CHIRAL ART Cellulose-SB column, 2*25 cm, 5 µm; mobile phase, hexane - HPLC and ethanol-HPLC (exposure 40% ethanol - HPLC for 10 min); detector, UV 220/254 nm) to give the title compounds. The stereochemistry of the title compounds was assigned based on activity.

[0708] Example 62a: 1-((S)-4-((R)-6-chloro-8-fluoro-7-(4-methyl-6-(methylamino)-3-(trifluoromethyl)pyridine-2- yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (70.9 mg , 0.11 mmol, 16.2% yield, white solid). ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 7.84 (d,J=1.7 Hz, 1H), 6.93 - 6.76 (m, 1H), 6.53 (s, 1H), 6.31 (d, J =16.8 Hz, 1H), 5.87 - 5.79 (m, 1H), 4.59 - 4.38 (m, 3H), 4.28 - 4.22 (m, 2H), 4.20 - 4.15 (m, 2H), 4.05 (d, J=14.1 Hz, 1H), 3.76 - 3.72 (m, 1H), 3.61 (s, 1H), 3.40 (s, 3H), 3.23 - 3.20 (m, 1H), 3.15 - 3.08 (m, 3H), 2.89 (s, 3H), 2.81 - 2.73 (m, 1H), 2.54 - 2.50 (m, 1H), 2.49 - 2.44 (m, 3H), 1.43 (s, 3H).

[0709] Example 62b: 1-((S)-4-((S)-6-chloro-8-fluoro-7-(4-methyl-6-(methylamino)-3-(trifluoromethyl)pyridine-2- yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (65.1 mg , 0.10 mmol, 14.9% yield, white solid). ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 7.84 (d, J=1.7 Hz, 1H), 6.85 (d, J=10.7 Hz, 1H), 6.53 (s, 1H), 6.31 (d, J= 17.5 Hz, 1H), 5.83 (d, J=10.6 Hz, 1H), 4.51-4.48 (m, 3H), 4.31 (d, J=13.9 Hz, 2H), 4.05 (d, J=13.2 Hz, 1H) , 3.76 (d, J=14.0 Hz, 2H), 3.18 - 3.09 (m, 1H), 2.88 (s, 4H), 2.56 (s, 4H), 2.46 (s, 3H), 2.45 - 2.34 (m, 2H ), 1.92 - 1.73 (m, 3H), 1.45 (d, J=6.8 Hz, 3H). LC-MS: (ESI, m/z): 636.1 [M+H] ⁺ .

Examples 63a and 63b: 1-((S)-4-((R)-7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine -2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 63a) and 1-((S)-4-((S)- 7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1 -yl)prop-2-en-1-one (Example 63b)

Synthetic way

Step 1: tert-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)- 3-methylpiperazine-1-carboxylate

[0710] A solution of N-methyl-1-prolinol (3.5 g; 30.39 mmol) and potassium carbonate (5.6 g, 40.58 mmol) in dimethyl sulfoxide (2.0 ml) was stirred at 90°C for 0 .5 hours. Then, tert-butyl (S)-4-(7-bromo-6-chloro-2.8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (10.0 g, 20.24 mmol) was added and stirred at 90°C for 1 hour. Upon completion, the reaction system was diluted with water. The resulting solution was extracted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (94:6) to give t-butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-(((S) -1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylinperazin-1-carboxylate (6.5 g, 11.3 mmol, 56.1% yield) as a yellow oil. LC-MS: (ESI. m/z): 572.1 [M+H] ⁺

Step 2: tert-butyl (S)-4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(tributylethanenyl)quinazolin-4-yl )-3-methylpiperazine-1-carboxylate

[0711] tert-Butyl (S)-4-(7-bromo-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl) solution -3-methylpiperazine-1-carboxylate (1.0 g, 1.75 mmol), hexabutylditin (2.9 g, 8.85 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (181.0 mg, 0.1700 mmol), tricyclohexylphosphine (100.0 mg, 0.3600 mmol) and lithium chloride (189.0 mg, 4.35 mmol) in 1,4-dioxane (100 ml) were stirred at 105°C for 2 hours under nitrogen . Upon completion, the reaction system was diluted with dichloromethane. The resulting solution was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by C18 gel flash chromatography eluting with methanol/water (19:1) to give t-butyl (S)-4-(6-chloro-8-fluoro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)-7-(tributylstannyl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (340 mg, 0.4 mmol, 24.9% yield) as a brown solid. LC-MS: (ESI, m/z): 784.3 [M+H] ⁺

Step 3: tert-butyl (3S)-4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy )quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0712] A solution of tert-butyl (S)-4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-7-(tributylstannyl)quinazolin-4- yl)-3-methylpiperazine-1-carboxylate (212.5 mg, 0.27 mmol), 1-bromoisoquinoline-3-amine (50.0 mg, 0.2200 mmol), tetrakis(triphenylphosphine)palladium(0) ( 130.0 mg, 0.1100 mmol), copper(I) iodide (22.5 mg, 0.1200 mmol) and lithium chloride (22.5 mg, 0.5200 mmol) in N,N-dimethylformamide (5 ml ) was stirred at 90° C. for 1 hour under nitrogen. Upon completion, the solution was concentrated and the residue was purified by C18 gel flash chromatography eluting with methanol/water (97:3) to give t-butyl (3S)-4-(7-(3-aminoisoquinolin-1-yl) -6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (100 mg, 0.15 mmol, 70.1% yield) as a yellow solid. LC-MS: (ESI, m/z): 636.2 [M+H] ⁺

Step 4: 1-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin- 7-yl)isoquinoline-3-amine

[0713] tert-Butyl (3S)-4-(7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl) solution methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (600.0 mg, 0.94 mmol) in dichloromethane (20 ml) and trifluoroacetic acid (10 ml, 129.8 mmol) were stirred at 25°C within 1 hour. After completion, the reaction was concentrated and the residue was purified by C18 gel flash chromatography eluting with methanol/water (40:60) to give 1-(6-chloro-8-fluoro-4-((S)-2- methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)isoquinolin-3-amine (410 mg, 0.76 mmol, 81.1% yield ) as a yellow solid. LC-MS: (ESI, m/z): 536.2 [M+H] ⁺

Step 5: 1-((S)-4-((R)-7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2 -yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 63a) and 1-((S)-4-((S)-7- (3-aminoisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl )prop-2-en-1-one (Example 63b)

[0714] 1-(6-Chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazoline solution -7-yl)isoquinoline-3-amine (410.0 mg, 0.76 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.77 mmol) in dichloromethane (10 ml) were stirred at -78°C within 5 minutes. Then acryloyl chloride (76.0 mg, 0.84 mmol) was added and stirred at -78° C. for 30 minutes. After completion, the reaction was quenched with water and the reaction was concentrated. The residue was purified by C18 gel flash chromatography eluting with methanol/water (9:1) and further purified by preparative HPLC - Column: Xcelect CSH F-pheny OBD Column 19*250 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: methanol; flow rate: 25 ml/min. The product was purified using a chiral preparative HPLC column: CHIRALPAK IC, 3*25 cm, 5 µm; mobile phase A: hexane:DCM=3:1 (10 mM NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 18 ml/min. The residue was freeze-dried to give 1-((S)-4-((R)-7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 63) (39.7 mg, 0.06 mmol, 8.8 % yield) as a yellow solid and 1-((S)-4-((S)-7-(3-aminoisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S) -1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 63b) (47.0 mg, 0.079 mmol, 10, 4% yield) as a yellow solid.

[0715] Example 63a: LC-MS: (ESI, m/z): 590.2 [M+H] ⁺ , ¹ H NMR (300 MHz, CDCl ₃ , ppm) δ 7.74 (s, 1H), 7.64 ( d, J=8.4 Hz, 1H), 7.54-7.49 (m, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.28-7.15 (m, 1H), 6.88 (s, 1H), 6.69-6.55 (m, 1H), 6.39 (dd,J=1.8, 16.5 Hz, 1H), 5.79 (dd, J=1.8, 10.5 Hz, 1H), 4.90-4.70 (m, 1H), 4.67-4.50 (m, 3H ), 4.39-4.27(m, 1Н), 4.23-4.11 (m, 1H), 4.05-3.85 (m, 1Н), 3.72-3.41 (m, 2Н), 3.40-2.95 (m, 2Н), 2.82-2.75 (m, 1H), 2.52(s, 3H), 2.42-1.95 (m, 3H), 1.95-1.69 (m, 3H), 1.50-1.25 (m, 3H). Chiral HPLC: CHIRALPAK IG-3 (0.46*5 cm; 3 µm); detection at 254 nm; (p-hexane / dichloromethane = 1/1) (0.1% diethylamine) / ethanol = 1/1; flow rate=1.0 ml/min; Hold time: 1.5 min (faster peak).

[0716] Example 63b: LC-MS: (ESI, m/z): 590.2 [M+H] ⁺ , ¹ H NMR (300 MHz, CDCl ₃ , ppm) δ 7.73 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.55-7.50 (m, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.21-7.18 (m, 1H), 6.89 (s, 1H), 6.78 -6.50 (m, 1H), 6.40 (dd, J=2.l, 16.8 Hz, 1H), 5.80 (d,J=11.1 Hz, 1H), 4.80-4.67 (m, 1H), 4.65-4.45 (m , 3H), 4.45-4.32(m, 1Н), 4.32-4.17 (m, 1Н), 4.12-3.75 (m, 1Н), 3.78-3.43 (m, 2Н), 3.30-3.00 (m, 2Н), 2.97 -2.70 (m, 1H), 2.55(s, 3H), 2.45-2.30 (m, 1H), 2.17-2.03 (m, 1H), 1.99-1.66 (m, 4H), 1.54-1.35 (m, 3H) . Chiral HPLC: CHIRALPAK IG-3 (0.46*5 cm; 3 µm); detection at 254 nm; (p-hexane / dichloromethane = 1/1) (0.1% diethylamine) / ethanol = 1/1; flow rate=1.0 ml/min; Hold time: 2.5 min (slower peak).

Examples 64a and 64b: (S)-5-((((S)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(6-amino-4-methyl-3 -(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one (Example 64a) and (S)-5-(((( R)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro- 8-fluoroquinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one (Example 64b) (2 atropisomers)

Synthetic way

Step 1: (5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-one

[0717] A solution of (5S)-5-(hydroxymethyl)-2-pyrrolidinol (15.0 g, 130.29 mmol), imidazole (17.74 g, 260.58 mmol) and tert-butyl dimethylsilyl chloride (29, 31 g, 195.43 mmol) in dichloromethane (300 ml) was stirred at 25°C for 1 hour. After completion, the reaction was concentrated and the residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (97/3) to give 25 g (83.6%) of (5S)-5-[[t-butyl(dimethyl)silyl ]hydroxymethyl]pyrrolidin-2-one as a colorless oil. LC-MS: (ESI, m/z): 230.1 [M+H] ⁺

Step 2: (5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-pyrrolidin-2-one

[0718] Sodium hydride (10 99 g, 274.64 mmol, 60% dispersion in mineral oil) was stirred at 25° C. for 10 minutes. Iodomethane (22.29 g, 156.94 mmol) was then added and stirred at 25° C. for 1 hour. Upon completion, the resulting solution was quenched with water and the mixture was concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (20/1) to give 10 g (52.4%) of (5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-1- methyl-pyrrolidin-2-one as a colorless oil. LC-MS: (ESI, m/z): 244.1 [M+H] ⁺

Step 3: (5S)-5-(hydroxymethyl)-1-methyl-pyrrolidin-2-one

[0719] A solution of (5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-pyrrolidin-2-one (1.06 g, 4.35 mmol) in HCl/dioxane (30 ml , 4.35 mmol) was stirred at 25°C for 2 hours. After completion, the reaction was concentrated, the pH was adjusted to 7~8 with aqueous sodium bicarbonate. The reaction was concentrated and the resulting mixture was purified by silica gel flash chromatography eluting with dichloromethane/methanol (95/5) to give 550 mg (97.8%) of (5S)-5-(hydroxymethyl)-1-methyl-pyrrolidine -2-it is in the form of yellow oil. LC-MS: (ESI, m/z): 130.1 [M+H] ⁺

Step 4: tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro- 8-fluoro-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate

[0720] A solution of (5S)-5-(hydroxymethyl)-1-methyl-pyrrolidin-2-one (0.54 g, 4.18 mmol) in tetrahydrofuran (8 ml) was added sodium hydride (292.65 mg, 7 .32 mmol, 60% dispersion in mineral oil) at 0°C and stirred at 25°C for 1 hour. Then, tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro- 2,8-difluoro-quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate (see Step 9 of Example 17a/17b) (1.7 g, 2.09 mmol) and stirred at 25°C in within 1 hour. Upon completion, the reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (95/5) to give 1.676 g (86.9%) tert-butyl (3S)-4-[7-[6-[bis[(4- methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S)-1-methyl-5-oxo-pyrrolidine-2- yl]methoxy]quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 922.3 [M+H] ⁺

Step 5: (5S)-5-[[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-4-[(2S)-2- methylpiperazin-1-yl]quinazolin-2-yl]oxymethyl]-1-methyl-pyrrolidin-2-one

[0721] tert-Butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl[amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro solution -8-fluoro-2-[[(2S)-1-methyl-5-oxo-pyrrolidin-2-yl[methoxy]quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate (1.63 g , 1.77 mmol) in trifluoroacetic acid (8 ml) was stirred at 50°C for 24 hours. After completion, the reaction was concentrated. The pH was adjusted to 8 with N,N-dinzopropylethylamine. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: acetonitrile, V% (5%~70% in 30 minutes); detector, UV 254 nm yielding 785 mg (76.1%) (5S)-5-[[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8 -fluoro-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-2-yl[oxymethyl]-1-methyl-pyrrolidin-2-one as a light yellow solid. LC-MS: (ESI, m/z): 582.2 [M+H] ⁺

Step 6: (S)-5-((((S)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(6-amino-4-methyl-3-( trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one (Example 64a) and (S)-5-((((R) -4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8- fluoroquinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one (Example 64b) (2 athroisomers)

[0722] To a solution of (5S)-5-[[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridine]-6-chloro-8-fluoro-4-[(2S)- 2-methylpiperazin-1-yl]quinazolin-2-yl]oxymethyl]-1-methyl-pyrrolidin-2-one (463.0 mg, 0.80 mmol) and N,N-dinzopropylethylamine (513.13 mg, 3 .98 mmol) in dichloromethane (12 ml) was added acryloyl chloride (57.6 mg, 0.6400 mmol) at -78°C and stirred at -78°C for 1 hour. Upon completion, the reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: acetonitrile, V% (5%~70% in 30 min); detector, UV 254 nm to give 251 mg of crude product as a white solid. A mixture of diastereoisomers was separated using preparative chiral HPLC - Column, CHIRALPAK IE-3 0.46*5 cm 3 μm; mobile phase, (Hexane : dichloromethane = 3:1) (0.1% DEA) : EtOH = 50:50; detector, 254 nm; Flow, 1.0 ml/min; Temperature: 25° C. to give 96.5 mg (19.1%) of (S)-5-((((S)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)- 7-(6-Amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one as white solids and 95.1 mg (18.8%) of (S)-5-((((R)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(6 -amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoroquinazolin-2-yl)oxy)methyl)-1-methylpyrrolidin-2-one as a white solid. LC-MS: (ESI, m/z): 636.2 [M+H] ⁺

[0723] Example 64a: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 7.85 (d, J=1.6 Hz, 1H), 6.92-6.77 (m, 1H), 6.62 (s, 1H) , 6.30 (dd, J=16.8, 3.2 Hz, 1H), 5.82 (dd, J=10.8, 8.8 Hz, 1H), 4.82-4.78 (m, 1H), 4.52-4.48 (m, 2H), 4.31-4.28 (m, 1H), 4.28-4.01 (m, 2H), 3.87-3.52 (m, 2H), 3.40-3.44 (m, 1H), 3.32-3.17 (m, 1H), 2.92 (s, 3H), 2.61 -2.58 (m, 1H), 2.46 (d, J=1.2 Hz, 3H), 2.37-2.27 (m, 2H), 2.10-2.05 (m, 1H), 1.43 (d, J=6.8 Hz, 3H). LC-MS: (ESI, m/z): 636.2 [M+H] ⁺ chiral HPLC: CHIRALPAK IE-3 (0.46*5 cm; 3 µm); detection at 254 nm; (hexane: DCM=3:1) (0.1% DEA)/EtOH=50/50; flow rate = 1 ml/min; hold time: 1.74 min (faster peak).

[0724] Example 64b: ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 7.85 (d, J=1.6 Hz, 1H), 6.92-6.77 (m, 1H), 6.62 (s, 1H) , 6.30 (dd, J=16.8, 3.2 Hz, 1H), 5.81 (dd, J=10.8, 8.8 Hz, 1H), 4.85-4.77 (m, 1H), 4.53-4.49 (m, 2H), 4.31-4.28 (m, 1H), 4.28-4.01 (m, 2H), 3.87-3.52 (m, 2H), 3.36-3.34 (m, 1H), 3.30-3.17 (m, 1H), 2.92 (s, 3H), 2.61 -2.58 (m, 1H), 2.46 (d, J=1.2 Hz, 3H), 2.37-2.27 (m, 2H), 2.11-2.05 (m, 1H), 1.43 (d, J=6.8 Hz, 3H). LCMS: (ESI, m/z): 636.2 [M+H] ⁺ chiral HPLC: CHIRALPAK IE-3 (0.46*5 cm; 3 µm); detection at 254 nm; (hexane: DCM=3:1) (0.1% DEA)/EtOH=50/50; flow rate = 1 ml/min; hold time: 3.48 min (slower peak).

Example 65: (E)-1-((S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S )-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1yl)-4,4-difluorobut-2-en-1-one

Synthetic way

[0725] A solution of tert-butyl (S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (see Ethane 3, Example 61) (0.29 g, 0.53 mmol) and trifluoroacetic acid (0.6 ml, 7.79 mmol) in dichloromethane (3 ml) was stirred at 25°C for 1 hour. Upon completion, the reaction system was concentrated. The resulting mixture was re-diluted in dichloromethane (3 mL) and N,N-dinzopropylethylamine (0.18 mL, 1.05 mmol), (E)-4,4-difluorobut-2-enoic acid (0.07 g ,; 0.58 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.26 g, 0.69 mmol). The mixture was stirred at 25°C for 1 hour. Upon completion, the resulting solution was diluted with water, extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The residue was purified with a silica gel column eluting with dichloromethane/methanol (10/1) to give the product. The crude product was purified by preparative HPLC to give 23 mg of (E)-1-((S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6- chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4,4-difluorobut-2-en-1-one in form of a white solid. LCMS: (ESI, m/z): 654.3 [M+H] ⁺ . Preparative HPLC conditions: Column: XBridge Shield RP18 OBD Column; mobile phase, A: water, B: acetonitrile, V% (40%~62% in 7 min); detector, UV 220 nm.

[0726] Example 65: ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 7.94 (t, J=7.2 Hz, 1H), 7.41 (s, 1H), 7.23-7.08 (m, 1H), 6.78 (s, 2H), 6.69-6.62 (m, 1H), 6.53-6.45 (m, 1H), 4.84-4.63 (m, 1H), 4.43-4.22 (m, 2H), 4.19-3.98 (m, 3H ), 3.98-3.80 (m, 1H), 3.78-3.42 (m, 2H), 3.28-3.08 (m, 1H), 2.97-2.92 (m, 1H), 2.63-2.55 (m, 1H), 2.41-2.33 (m, 6H), 2.18 (q, J=8.4 Hz, 1H), 2.01-1.92 (m, 1H), 1.73-1.58 (m, 3H), 1.35-1.23 (m, 3H).

Example 66: 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[2-(dimethylamino)cyclopentoxy]quinazoline -4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one

Synthetic way

Step 1: 2-(dimethylamino)cyclonsilan-1-ol

[0727] Formic acid (10 ml) was added to a solution of 2-aminocyclone-1-al (5.0 g, 49.4 mmol) at room temperature under nitrogen. Formaldehyde (2.8 g) was added and the reaction was stirred at 100° C. for 2 hours. The reaction was cooled to room temperature, diluted with water, and the pH of the solution was adjusted to 9 with sodium bicarbonate. The resulting mixture was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-(dimethylamino)cyclonsilan-1-ol (5 g, crude) as a yellow oil, which was used for the next step without purification. LC-MS: (ESI, m/z): 129.2 [M+H] ⁺ .

Step 2: tert-butyl (3S)-4-(7-bromo-6-chloro-2-((2-(dimethylamino)cyclonesityl)oxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0728] Sodium hydride (584 mg, 14.6 mmol, 60% dispersion in mineral oil) at room temperature. The resulting solution was stirred for 30 min at room temperature. Then, tert-butyl (3S)-4-(7-bromo-2,6-dichloro-quinazolin-4-yl)-3-methyl-piperazin-1-carboxylate (Intermediate 5) (2.0 g, 4.2 mmol) and stirred at 40°C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. Then, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with ethyl acetate/petroleum ether (1/8) to give tert-butyl (3S)-4-(7-bromo-6-chloro-2-((2-(dimethylamino)cyclopentyl )oxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (2 g, 3.52 mmol, 83% yield) as a yellow solid. LCMS: (ESI, m/z): 568.9 [M+H] ⁺ .

Step 3: tert-butyl (3S)-4-(6-chloro-2-((2-(dimethylamino)cyclopentyl)oxy)-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0729] A solution of tert-butyl (3S)-4-(7-bromo-6-chloro-2-((2-(dimethylamino)cyclopentyl)oxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate ( 2.0 g, 3.52 mmol), bis (pinacolato) diboron (8.0 g, 31.3 mmol), dichloro[1,1-bis (diphenylphosphino) ferrocene] palladium (II) (256 mg, 0. 35 mmol) and potassium acetate (1400 mg, 10.9 mmol) in 1,4-dioxane (20 ml) were stirred at 80° C. for 2 hours under nitrogen. The reaction system was diluted with ethyl acetate (100 ml) and washed with water (3×100 ml) to give tert-butyl (3S)-4-(6-chloro-2-((2-(dimethylamino)cyclopentyl)oxy)-7-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (1 g, 1.6 mmol, 5.2% yield ) as a yellow solid. LC-MS: (ESI, m/z): 616.0 [M+H] ⁺ .

Step 4: tert-butyl (3S)-4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((2-(dimethylamino)cyclopentyl)oxy)quinazoline -4-yl)-3-methylpiperazin-1-carboxylate

[0730] A solution of tert-butyl (3S)-4-(6-chloro-2-((2-(dimethylamino)cyclopentyl)oxy)-7-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (1000 mg, 1.8 mmol), 6-bromo-4-methyl-5-(trifluoromethyl)pyridine-2-amine ( 500 mg, 1.9 mmol), Pd(PPh3)2Cl2 (120 mg, 0.2 mmol) and potassium fluoride (300 mg, 6.5 mmol) in acetonitrile (10 ml) and water (1 ml) were stirred at 80 °C for 3 hours in nitrogen. The reaction system was diluted with dichloromethane (50 ml). The mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with methyl alcohol/dichloromethane (1:13) to give t-butyl (3S)-4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl) -6-chloro-2-((2-(dimethylamino)cyclopentyl)oxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (200 mg, 0.2 mmol, 14.5% yield) as yellow solid. LC-MS: (ESI, m/z): 650.1 [M+H] ⁺

Step 5: 6-[6-chloro-2-[2-(dimethylamino)cyclopentoxy]-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl-5-( trifluoromethyl)pyridine-2-amine

[0731] tert-Butyl (3S)-4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((2-(dimethylamino)cyclopentyl)oxy) solution quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (200 mg, 0.3 mmol) in 2,2,2-trifluoroacetic acid (5 ml) and dichloromethane (20 ml) were stirred at room temperature for 1 hour . The solvent was concentrated in vacuo to give 6-[6-chloro-2-[2-(dimethylamino)cyclopentoxy]-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl- 5-(trifluoromethyl)pyridine-2-amine (150 mg, 0.3 mmol, 79.5% yield) as a yellow solid. LC-MS: (ESI, m/z): 564.1 [M+H] ⁺

Step 6: 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[2-(dimethylamino)cyclopentoxy]quinazoline -4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one

[0732] 6-[6-Chloro-2-[2-(dimethylamino)cyclopentoxy]-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl-5- solution (trifluoromethyl)pyridine-2-amine (250 mg, 0.4 mmol) in dichloromethane (5 ml) and DIEA (171 mg, 1.3 mmol) acryloyl chloride (32 mg, 0.3 mmol) was added at -78° C and for 1 hour. The solvent was concentrated in vacuo. The residue was purified by preparative HPLC to give 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[2-( dimethylamino)cyclonesynthoxy]quinazolin-4-yl]-3-methyl-piperazin-1-yl]|pron-2-on-1-one (32 mg, 0.1 mmol, 11.6% yield) as a white solid substances.

[0733] Example 66: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 7.93 (s, 1H), 7.42 (d, J-3.4 Hz; 1H); 6.89 6.80 (m, 1H), 6.77 (s, 2H), 6.46 (s, 1H), 6.19 (d, J-16.4 Hz, 1H), 5.75 (dd, J-10.4, 2.4 Hz, 1H), 5.40 ( s, 1H), 4.70 (s, 1H), 4.40 4.19 (m, 1H), 4.15-3.89 (m, 2H), 3.62-3.40 (m, 2H), 3.25-3.05 (m, 2H), 2.40-2.25 (m, 8H), 2.13 1.97 (m, 3H), 1.68 1.52 (s, 4H), 1.39 1.25 (m, 3H). LC-MS: (ESI, m/z): 618.2 [M+H] ⁺

Examples 67a and 67b: 1-((S)-4-((R)-7-(3-amino-4-fluoroisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S) -1-methylpyrrolidin-2-yl)methoxy)quinazolin-4yl)-3-methylpiperaznin-1-yl)prop-2-en-1-one (Example 67a) and 1-((S)-4-((S )-7-(3-amino-4-fluoroisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl) -3-methylpiperazin-1-yl)prop-2-en-1-one (Example 67b) (2 atronisomers)

Synthetic way

Step 1: tert-butyl (3S)-4-(7-(3-acetamido-4-fluoroisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2 -yl)methoxy)quinazolin-4-yl)-3-methylpiperazil-1-carboxylate

[0734] A solution of tert-butyl (S)-4-(6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxin)-7-(tributylethanyl)quinazolin-4- yl)-3-methylpiperazine-1-carboxylate (see Example 63a/63b, Step 2) (138.0 mg, 0.18 mmol), N-(1-bromo-4-fluoro-3-isoquinolyl)acetamide ( 50.0 mg, 0.18 mmol), tetraxis (triphenylphosphine) palladium (0) (102.0 mg, 0.09 mmol), copper (I) iodide (17.0 mg, 0.09 mmol) and lithium chloride (19.0 mg, 0.4400 mmol) in N,N-dimethylformamide (2 ml) was stirred at 105° C. for 16 hours under nitrogen. After completion, the reaction was filtered, the filtrate was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (92:8) to give tert-butyl (3S)-4-(7-(3-acetamido-4-fluoroisoquinolin-1-yl)-6-chloro -8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (60 mg, 0.08 mmol, 48.8% output) as a yellow oil. LC-MS: (ESI, m/z): 696.3 [M+H] ⁺

Step 2: N-(1-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy )quinazolin-7-yl)-4-fluoroisoquinolin-3-yl)acetamide

[0735] A solution of tert-butyl (3S)-4-(7-(3-acetamido-4-fluoroisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin- 2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (800.0 mg, 1.15 mmol) in 2,2,2-trifluoroacetic acid (10 ml) and dichloromethane (10 ml) stirred at 25°C for 1 hour. Upon completion, the reaction was concentrated and the resulting residue was purified by C18 gel flash chromatography eluting with methanol/water (3:7) to give N-(1-(6-chloro-8-fluoro-4-(( S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-fluoroisoquinolin-3-yl)acetamide (500 mg, 0.83 mmol, 73% yield) as a yellow solid. LC-MS: (ESI, m/z): 596.2 [M+H] ⁺

Step 3: 1-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin- 7-yl)-4-fluoroisoquinoline-3-amine

[0736] N-(1-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpiperolidin-2-yl) solution methoxy)quinazolin-7-yl)-4-fluoroisoquinolin-3-yl)acetamide (400.0 mg, 0.67 mmol) in methyl alcohol (20 ml) and hydrochloric acid (1 ml, 10 mmol) were stirred at 25° C within 16 hours. Upon completion, the solution was concentrated in vacuo. Crude product 1-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7 -yl)-4-fluoroisoquinoline-3-amine (350 mg, 0.63 mmol, 94.1% yield) was used directly in the next step without purification. LC-MS: (ESI, m/z): 554.3 [M+H] ⁺

Step 4: 1-((S)-4-((R)-7-(3-amino-4-fluoroisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1 -mestylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 67a) and 1-((S)-4-((S )-7-(3-amino-4-fluoroisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl) -3-methylpiperazin-1-yl)prop-2-en-1-one (Example 67b) (2 atronisomers)

[0737] A solution of 1-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S-1-methylpyrrolidin-2-yl)methoxy)quinazolin- 7-yl)-4-fluoroisoquinoline-3-amine (220.0 mg, 0.4000 mmol) and N,N-dinzopropylethylamine (1 ml, 5.74 mmol) in dichloromethane (20 ml) were stirred at -78°C for 5 minutes Acrylonyl chloride (36.0 mg, 0.4000 mmol) was then added and the reaction was stirred at -78° C. for an additional 30 minutes The reaction was concentrated and the residue was purified by C18 gel flash chromatography eluting with acetonitrile /water (7:3) to give the crude product The product was purified by chiral preparative HPLC - Column: CHIRALPAK IC, 2*25 cm, 5 µm, mobile phase A: hexagan: DCM - 1:1 (10 mM NH3-MeOH ) - HPLC, mobile phase B:EtOH - HPLC, flow rate: 17 ml/min to give 1-((S)-4-((R)-7-(3-amino-4-fluoroisoquinolin-1-yl) -6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1- she (36.9 mg, 0.060 mmol, 15.3% yield) as a white solid th substance and 1-((S)-4-((S)-7-(3-amino-4-fluoroisoquinolin-1-yl)-6-chloro-8-fluoro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (41.4 mg, 0.068 mmol, 17.1% yield) as white solid.

[0738] Example 67a: LC-MS: (ESI, m/z): 608.2 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO, ppm) δ 8.01-7.74 (m, 2H), 7.73 -7.60 (m, 1H), 7.40-7.30 (m, 1H), 7.25-7.17 (m, 1H), 6.75-7.00 (m, 1H), 6.33 (s, 2H), 6.22-6.09 (m, 1H) , 5.74 (dd, J=2.4, 10.5 Hz, 1H), 4.80 (s, 1H), 4.42-3.95 (m, 5H), 3.87-3.37 (m, 2H), 3.29-3.02 (m, 1H), 2.98 -2.83 (m, 1H), 2.68-2.54 (m, 1H), 2.32 (s, 3H), 2.19-2.09 (m, 1H), 2.00-1.85 (m, 1H), 1.70-1.52 (m, 3H) , 1.38-1.25 (m, 3H). Chiral HPLC: CHIRALPAK IC-3 (0.46*5 cm; 3 µm); detection at 254 nm; (n-hexane / dichloromethane = 1/1) (0.1% diethylamine) / ethanol = 1/1; flow rate = 1.0 ml/min; Hold time: 1.4 min (faster peak).

[0739] Example 67b: LC-MS: (ESI, m/z): 608.2 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO, ppm) δ 8.05-7.75 (m, 2H), 7.73 -7.53 (m, 1H), 7.51-7.30 (m, 1H), 7.27-7.10 (m, 1H), 7.00-6.6.63 (m, 1H), 6.33 (s, 2H), 6.22-6.15 (d, J=21, 1H), 5.74 (dd, J=2.4, 10.5 Hz, 1H), 4.80 (s, 1H), 4.42-3.95 (m, 5H), 3.87-3.37 (m, 2H), 3.29-3.02 ( m, 1H), 2.98-2.83 (m, 1H), 2.68-2.54 (m, 1H), 2.32 (s, 3H), 2.19-2.09 (m, 1H), 2.01-1.87 (m, 1H), 1.80- 1.53 (m, 3H), 1.33-1.17 (m, 3H). Chiral HPLC: CHIRALPAK IC-3 (0.46*5 cm; 3 µm); detection at 254 nm; (n-hexane / dichloromethane = 1/1) (0.1% diethylamine) / ethanol = 1/1; flow rate = 1.0 ml/min; Hold time: 2.4 min (slower peak).

Examples 68a and 68b: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoroprop-2-en-1-one (Example 68a) and 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((( S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoroprop-2-en-1-one (Example 68b) (2 atropisomers)

Synthetic way

[0740] 6-[6-Chloro-8-fluoro-4-[(2S)-2-methylpiperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinzoline solution -7-yl]-4-methyl-5-(trifluoromethyl)pyridine-2-amine (see Step II, Example 17) (450.0 mg, 0.79 mmol), 2-fluoroacrylic acid (64.21 mg , 0.71 mmol), HATU (451.85 mg, 1.19 mmol) and N,N-dinzopropylethylamine (408.8 mg, 3.17 mmol) in dichloromethane (4 ml) were stirred at 25°C for 1 hours. After completion, the reaction was diluted with dichloromethane and washed with water. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: acetonitrile, V% (5%~70% in 30 min); detector, UV 254 nm yielding 150 mg 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2 -[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazin-1-yl]-2-fluoro-prop-2-en-1-one as white solid. The crude product was purified directly by preparative HPLC - Column, XBridge Prep C18 OBD Column 19*15 mm, 5 µm, C-0013; mobile phase, A: 10 mmol HCOOH in water, B: ACN and B% (51%~73% in 7 mi); detector, UV 254 nm to give the crude product (130 mg) as a white solid. The diastersoisomer mixture was separated by preparative chiral HPLC - Column, CHIRALPAK IC-3 0.45*5 cm 3 µm; mobile phase, (hexane:dichloromethane = 3:1) (0.1% DEA) : EtOH = 50:50; detector, 254 nm; Flow, 1.0 ml/min; Temperature: 25°C to give 32 mg (6.3%) 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl )-6-chloro-8-fluoro-2-(((8)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoroprop-2- en-1-one (at 1.01 min) as a white solid and 48 mg (9.5%) 1-((S)-4-((S)-7-(6-amino-4-methyl -3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin- 1-yl)-2-fluoroprop-2-en-1-one (at 1.41 min) as a white solid. LC-MS: (ESI, m/z): 640.2 [M+H] ⁺

[0741] Example 68a: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 7.81 (s, 1H), 6.85 (s, 2H), 6.49 (s, 1H), 5.37-5.20 (m, 2Н), 4.76 (s, 1H), 4.39 (dd, J=10.8, 6.0 Hz, 1H), 4.18-4.11 (m, 3Н), 4.11-3.93 (m, 1H), 3.91-3.69 (m, 2Н) , 3.20-3.03 (m, 1H), 2.96-2.92 (m, 1H), 2.60-2.57 (m, 1H), 2.37-2.35 (m, 6H), 2.19-2.14 (m, 1H), 1.96-1.92 ( m, 1H), 1.70-1.62 (m, 3H), 1.28 (d, J=6.8 Hz, 3H). LC-MS: (ESI, m/z): 640.2 [M+H] ⁺ chiral HPLC CHIRALPAK IC-3 (0.46*5 cm; 3 µm); detection at 254 nm; (hexane: DCM=3:1) (0.1% DEA)/EtOH=50/50; flow rate = 1 ml/min; hold time: 1.00 min (faster peak).

[0742] Example 68b: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 7.79 (s, 1H), 6.84 (s, 2H), 6.49 (s, 1H), 5.37-5.19 (m, 2Н), 4.73 (s, 1Н), 4.37 (dd, J=10.8, 6.0 Hz, 1H), 4.18-4.01 (m, 3Н), 4.01-3.79 (m, 1H), 3.79-3.66 (m, 2Н) , 3.31-3.03 (m, 1H), 2.96-2.92 (m, 1H), 2.59-2.56 (m, 1H), 2.37-2.35 (m, 6H), 2.18-2.14 (m, 1H), 1.97-1.93 ( m, 1H), 1.70-1.62 (m, 3H), 1.31 (d, J=6.8 Hz, 3H). LC-MS: (ESI, m/z): 640.2 [M+H] ⁺ chiral HPLC CHIRALPAK IC-3 (0.46*5 cm; 3 µm); detection at 254 nm; (hexane: DCM=3:1) (0.1% DEA)/EtOH=50/50; flow rate = 1 ml/min; hold time: 1.41 min (slower peak).

Example 69: 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S, 4R)-4-fluoro-l-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one

Synthetic way

Step 1: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8- fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0743] A solution of [(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (300 mg, 2.2 mmol) in tetrahydrofuran (20 ml) was added sodium hydride (206 mg, 1. 9 mmol) at room temperature. The resulting solution was stirred for 30 min at room temperature. Then, tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro- 2,8-difluoro-quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate (see Step 9 of Example 17a/17b) (1.6 g, 1.9 mmol) and stirred at room temperature for additional 1 hour. The reaction was quenched with water. The resulting solution was extracted with ethyl acetate (3×100 ml) and the organic layers combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (30%) to give t-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl- 3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl) -3-methylpiperazine-1-carboxylate (900 mg, 0.8 mmol, 44.4% yield) as a yellow solid. LC-MS: (ESI, m/z): 926.4 [M+H] ⁺

Step 2: 1-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S, 4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one

[0744] tert-Butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8 solution -fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (900 mg, 0.9 mmol) in 2,2,2-trifluoroacetic acid (10 ml) was stirred at 50°C for 5 hours. The reaction was concentrated to give 6-[6-chloro-8-fluoro-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-[(2S)-2 -methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (500 mg, 0.7 mmol, 79% yield) as a yellow solid. Then, to a solution of 6-[6-chloro-8-fluoro-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-[(2S)-2 -methylpiperazin-1-yl]quinazolin-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (500 mg, 0.7 mmol) and N,N-diisopropylethylamine (1.2 g, 2 .7 mmol) in dichloromethane (30 ml) was added acryloyl chloride (70 mg, 0.7 mmol) at -78°C. The resulting solution was stirred for 1 hour at -78°C, extinguished with water and was extracted with dichloromethane (3×100 ml). The organic layers were combined and concentrated and the residue was purified by preparative HPLC - Column, CHIRALPAK IC-3 0.46*5 cm 3 μm; mobile phase, (hexane : DCM = 3:1) (0.1% DEA) : EtOH = 50:50; detector, 254 nm; Flow, 1.0 ml/min; temperature: 25° C. to give l-[(3S)-4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[ [(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazin-1-yl]prop-2-en-1-one ( 53 mg, 0.1 mmol, 9.5% yield) (in 1.058 min) as a white solid. LC-MS: (ESI, m/z): 640.2 [M+H] ⁺

[0745] Example 69: ¹ H NMR (400 MHz, DMS0-d ₆ , ppm) δ 7.80 (s, 1H), 6.85 (s, 3H), 6.50 (s, 1H), 6.25-6.12 (m, 1Н), 5.74 (dd, J=10.4, 2.4 Hz, 1Н), 5.19 (d, J=56.6 Hz, 1Н), 4.71 (s, 1H), 4.51-4.19 (m, 3Н), 4.19-3.91 (m , 2Н), 3.61 (d, J=12.3 Hz, 2Н), 3.45 (m, J=25.6, 11.5, 5.3 Hz, 1H), 3.25-3.02 (m, 1Н), 2.93 (dd, J=10.1, 5.3 Hz, 1H), 2.42-2.34 (m, 7H), 2.24-2.05 (m, 1H), 1.92 (m, J=33.7, 14.9, 10.0, 6.0 Hz, 1H), 1.30 (d, J=6.6 Hz, 3H).

Example 70: (S)-1-(4-(7-(6-Amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylpyrrolidin-2-yl)methoxy) quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1- methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate

[0746] To a solution of N-methyl-1-prolinol (45.0 mg, 0.39 mmol) in tetrahydrofuran (5 ml) was added sodium hydride (22.0 mg, 0.54 mmol, 60% dispersion in mineral oil) and the mixture stirred at 25°C for 5 minutes. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (200.0 mg, 0.26 mmol) and stirred at 25°C for 1 hour. The reaction solution was quenched with water and extracted with ethyl acetate. Then, the organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with net ether/ethyl acetate (7/3) to give tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-( trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (210 mg, 0.24 mmol, 93.4 % exit). LC-MS: (ESI, m/z): 862.2 [M+H] ⁺

Step 2: (S)-6-(6-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl) pyridine-2-amine

[0747] A solution of tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1 -methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (200.0 mg, 0.2300 mmol) in trifluoroacetic acid (5 ml) was stirred at 50° C. for 2 hours. After completion, the solvent was concentrated in vacuo. The residue was purified by C18 gel flash chromatography eluting with acetonitrile/water (7/3) to give (S)-6-(6-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)-4 -(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine (90 mg, 0.17 mmol, 74.3% yield) as a yellow oil. LC-MS: (ESI, m/z): 522.2 [M+H] ⁺

Step 3: (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylpyrrolidin-2-yl)methoxy) quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0748] A solution of (5)-6-(6-chloro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl )pyridine-2-amine (100.0 mg, 0.19 mmol) and N,N-diisopropylethylamine (1.0 ml, 5.74 mmol) in dichloromethane (10 ml) were stirred at -78°C for 5 minutes . Then acryloyl chloride (17.0 mg, 0.19 mmol) was added and stirred at -78° C. for 30 minutes. After completion, the solvent was concentrated in vacuo. The crude product was purified by preparative HPLC to give (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylpyrrolidin- 2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (19.3 mg, 0.034 mmol, 17.5% yield) as a white solid. LC-MS: (ESI, m/z): 576.2 [M+H] ⁺

[0749] Example 70: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 8.04 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.46 (s, 1H), 6.90 (s, 2H), 6.82 (dd, J=10.0, 16.4 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H), 6.17 (dd, J=2.4, 16.8 Hz, 1H), 5.74 (dd, J=2.0, 10.4 Hz, 1H), 4.36-4.33 (m, 1H), 4.19-4.15 (m, 1H), 3.85-3.77 (m, 8H), 2.96-2.95 (m, 1H), 2.68-2.65 ( s, 1H), 2.35 (s, 3H), 2.19-2.13 (m, 1H), 1.97-1.88 (m, 1H), 1.68-1.60 (m, 3H). LC-MS: (ESI, m/z): 576.2 [M+H] ⁺ .

Example 71: 1-(4-(7-(6-Amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((2S,4R)-4-ethoxy-1-methylpyrrolidin- 2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: ((2S,4R)-4-ethoxy-1-methylpyrrolidin-2-yl)methanol

[0750] A solution of (2S,4R)-1-tert-butoxycarbonyl-4-ethoxy-pyrrolidine-2-carboxylic acid (600.0 mg, 2.31 mmol) in tetrahydrofuran (10 ml) was stirred at room temperature for 5 minutes. Then lithium aluminum hydride (352.0 mg, 9.26 mmol) was added and stirred at 25° C. for 6 hours. The reaction was quenched with water and extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give ((2S,4R)-4-ethoxy-1-methylpyrrolidin-2-yl)methanol (150 mg, crude) as a yellow oil. LC-MS: (ESI, m/z): 160.1 [M+H] ⁺

Step 2: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((2S,4R)- 4-ethoxy-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0751] Sodium hydride (21.6 mg , 0.54 mmol, 60% dispersion in mineral oil) and the mixture was stirred at 25° C. for 30 minutes. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (200.0 mg, 0.26 mmol) and stirred at 25° C. for 6 hours. The reaction was quenched with water and extracted with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (4/1) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridine- 2-yl)-6-chloro-2-(((2S,4R)-4-ethoxy-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (160 mg, 0, 18 mmol, 67.7% yield) as a yellow solid. LC-MS: (ESI, m/z): 906.4 [M+H] ⁺

Step 3: 6-(6-chloro-2-(((2S,4R)-4-ethoxy-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl) -5-(trifluoromethyl)pyridine-2-amine

[0752] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((2S,4R) -4-ethoxy-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (150.0 mg, 0.17 mmol) in trifluoroacetic acid (20 ml) was stirred at 50°C in within 6 hours. The reaction was concentrated and the residue was purified by C18 flash chromatography eluting with acetonitrile/water (7/3) to give 6-(6-chloro-2-(((2S,4R)-4-ethoxy-1-methylpyrrolidine-2- yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine (80 mg, 0.14 mmol, 85.4% yield) as dirty white solid. LC-MS: (ESI, m/z): 566.2 [M+H] ⁺

Step 4: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((2S,4R)-4-ethoxy-1-methylpyrrolidin- 2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0753] 6-(6-Chloro-2-(((28.4K)-4-ethoxy-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl solution )-5-(trifluoromethyl)pyridine-2-amine (70.1 mg, 0.12 mmol) and N,N-diisopropylethylamine (48.1 mg, 0.37 mmol) in dichloromethane (10 ml) were stirred at -78 °C for 5 minutes. Then, acryloyl chloride (12.0 mg, 0.13 mmol) was added dropwise to the reaction system and stirred at -78°C for 30 minutes. Upon completion, the reaction was quenched with water and concentrated. The residue was purified by preparative HPLC to give 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((2S,4R)-4-ethoxy -1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (32.9 mg, 0.053 mmol, 42.9% yield) as white solid.

[0754] Example 71: ¹ H NMR (300 MHz, methanol-d ₄ , ppm) δ 8.09 (s, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.54 (s, 1H), 6.89 -6.77 (m, 1H), 6.71-6.66 (m, 1H), 6.31-6.25 (m, 1H), 5.86-5.75 (m, 1H), 4.52-4.48 (m, 2H), 4.10 (s, 1H) , 3.98 (s, 4Н), 3.93 (s, 4Н), 3.56-3.36 (m, 3Н), 3.17 (s, 1Н), 2.60 (s, 3Н), 2.56-2.47 (m, 1Н), 2.12 (s , 1H), 2.00 (d, J-8.2 Hz, 1H), 1.18 (t, J-7.0 Hz, 3H). LC-MS: (ESI, m/z): 620.3 [M+H] ⁺ .

Example 72: (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((4-methyl-4-azaspiro[2.4] -gentan-5-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: (S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-4-azaspiro[2.4]gentane

[0755] Solution (S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-methylpyrrolidin-2-one (see Step 2 of Examples 64a and 64b) (3.0 g, 12.32 mmol) in tetrahydrofuran (40 ml) was added CH ₃ Ti(Oi-Pr) ₃ (13.96 g, 49.3 mmol) at 25° C. under nitrogen. The resulting solution was stirred for 0.5 hours. Ethylmagnesium bromide (13.14 g, 98.6 mmol) was added at 0° C. and stirred at 25° C. for 6 hours. Upon completion, the solution was quenched with water and extracted with dichloromethane. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with petroleum ether/ethyl acetate (7/1) to give (S)-5-(((t-butyldimethylsilyl)oxy)methyl)-4-methyl-4-azaspiro[2,4]heptane ( 1.5 g, 5.87 mmol, 47.6% yield) as a yellow oil. LC-MS: (ESI, m/z): 256.2 [M+H] ⁺

Step 2: (S)-(4-methyl-4-azaspiro[2.4]heptan-5-yl)methanol

[0756] A solution of (S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-4-azaspiro[2.4]heptane (1.4 g, 5.48 mmol) in HCl/1.4 -dioxane (20 ml) was stirred at 50°C for 6 hours. Upon completion, the solution was quenched with water and extracted with dichloromethane. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column eluting with petroleum ether/ethyl acetate (5/1) to give (S)-(4-methyl-4-azaspiro[2.4]heptan-5-yl)methanol (300 mg, 2.12 mmol, 38 .8% yield) as a yellow oil. LC-MS: (ESI, m/z): 142.1 [M+H] ⁺

Step 3: tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((4- methyl-4-azaspiro[2.4]heptan-5-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0757] A solution of (S)-(4-methyl-4-azaspiro[2.4]heptan-5-yl)methanol (148.0 mg, 1.05 mmol) and sodium hydride (60%) (50.0 mg, 2.08 mmol) in tetrahydrofuran (10 ml) was stirred at 25° C. for 0.5 hour. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (200.0 mg, 0.26 mmol) and stirred at 25° C. for 6 hours. Upon completion, the solution was quenched with water and extracted with dichloromethane. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluting with petroleum ether/ethyl acetate (8/1) to give tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridine- 2-yl)-6-chloro-2-((4-methyl-4-azaspiro[2.4]heptan-5-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (96 mg, 0.11 mmol , 41.5% yield) as a yellow solid. LC-MS: (ESI, m/z): 888.5 [M+H] ⁺

Step 4: (S)-6-(6-chloro-2-((4-methyl-4-azaspiro[2.4]heptan-5-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7- yl)-5-(trifluoromethyl)pyridine-2-amine

[0758] A solution of tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((4 -methyl-4-azaspiro[2.4]heptan-5-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (80.0 mg, 0.09 mmol) in 2,2,2-trifluoroacetic acid (10 ml) was stirred at 50°C for 5 hours. Upon completion, the solution was quenched with water and extracted with dichloromethane. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column eluting with dichloromethane/methanol (7/1) to give (S)-6-(6-chloro-2-((4-methyl-4-azaspiro[2.4]heptan-5-yl)methoxy) -4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridin-2-amine (40 mg, 0.073 mmol, 81.1% yield). LC-MS: (ESI, m/z): 548.2 [M+H] ⁺

Step 5: (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((4-methyl-4-azaspiro[2.4] heptan-5-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0759] Solution (S)-6-(6-chloro-2-((4-methyl-4-azaspiro[2.4]heptan-5-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7 -yl)-5-(trifluoromethyl)pyridine-2-amine (30.0 mg, 0.05 mmol) and N,N-diisopropylethylamine (22.0 mg, 0.17 mmol) in dichloromethane (10 ml) were stirred at -78°C for 5 minutes. Then acryloyl chloride (5.0 mg, 0.06 mmol) was added and stirred at -78° C. for 0.5 hour. Upon completion, the solution was quenched with water and extracted with dichloromethane. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((4-methyl-4 -azaspiro[2.4]heptan-5-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (10.8 mg, 0.018 mmol, 32.8% yield) in form of a white solid. LC-MS: (ESI, m/z): 602.3 [M+H] ⁺ . Preparative HPLC conditions: Column: XBridge Shield RP18 OBD Column; mobile phase, A: water, B: acetonitrile, V% (40%~62% in 7 min); detector, UV 220 nm.

[0760] Example 72: ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 7.89 (s, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.68 (s, 1H), 6.72-6.50 (m, 2H), 6.48-6.23 (m, 1H), 5.89-5.68 (m, 1H), 5.03-4.82 (m, 2H), 4.56 (s, 1H), 4.34 (s, 1H), 4.02-3.73 (m, 8Н), 3.17 (s, 1Н), 2.24 (s, 3H), 2.20-2.11 (m, 1H), 2.01-1.89 (m, 1Н), 1.89-1.72 (m, 2Н), 0.91 (s , 1Н), 0.67 (s, 1Н), 0.52 (s, 1Н), 0.31 (s, 1Н).

Example 73: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((4,4-difluoro-1,2-dimethylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: 1-(tert-butyl) 2-methyl 4,4-difluoro-2-methylpyrrolidine-1,2-dicarboxylate

[0761] A solution of 1-butyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (3.0 g, 11.31 mmol) and lithium dinzopropylamide (6.8 ml, 13.57 mmol, 2M in tetrahydrofuran) in tetrahydrofuran (25 ml) was stirred at -78°C for 0.5 hour under nitrogen. Iodomethane (2.09 g, 14.7 mmol) was added dropwise to the reaction system and stirred at -78° C. for 5 hours. Upon completion, the solution was diluted with water and extracted with ethyl acetate. The organic layers were collected, dried over anhydrous sodium sulfate and concentrated in vacuo. The desired crude product 1-(tert-butyl) 2-methyl 4,4-difluoro-2-methylpyrrolidine-1,2-dicarboxylate (2.6 g, 9.3097 mmol, 82.3% yield) was obtained. LC-MS: (ESI, m/z): 280.1 [M+H] ⁺

Step 2: (4,4-dpfluoro-1,2-dimethylpyrrolidin-2-yl)methanol

[0762] A solution of 1-(t-butyl) 2-methyl 4,4-difluoro-2-methylpyrrolidine-1,2-dicarboxylate (2.5 g, 8.95 mmol) in tetrahydrofuran (25 ml) was stirred at 25° C for 0.5 hours. Then lithium aluminum hydride (1.36 g, 35.81 mmol) was added to the reaction system and stirred at 25° C. for 5 hours. Upon completion, the solution was diluted with water and extracted with ethyl acetate. The organic layers were collected, dried over anhydrous sodium sulfate and concentrated to give the crude product (4,4-difluoro-1,2-dimethyl-pyrrolidin-2-yl)methanol (1.3 g, 7.87 mmol, 87.9% exit). LC-MS: (ESI, m/z): 166.1 [M+H] ⁺

Step 3: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((4,4-difluoro- 1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0763] A solution of (4,4-difluoro-1,2-dimethyl-pyrrolidin-2-yl)methanol (130.0 mg, 0.79 mmol) in tetrahydrofuran (20 ml) was stirred at 25°C for 0, 5 o'clock. Sodium hydride (19.0 mg, 0.79 mmol) was added and stirred at 25°C for 0.5 hour, then tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)- 3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin-1-carboxylate (Intermediate 3) (400.0 mg, 0.52 mmol) and stirred at 25° C for 5 hours. Upon completion, the solution was quenched with water and extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (9:1) to give t-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridine- 2-yl)-6-chloro-2-((4,4-difluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (286 mg, 0.31 mmol , 60.1% yield) as a yellow solid. LC-MS: (ESI, m/z): 912.4 [M+H] ⁺

Step 4: 6-(6-chloro-2-((4,4-difluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5 -(trifluoromethyl)pyridine-2-amine

[0764] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((4,4-difluoro -1,2-dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (276.0 mg, 0.30 mmol) in 2,2,2-trifluoroacetic acid (25 mL) was stirred at 50°C for 8 hours. Upon completion, the solution was quenched with water and extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (97:3) to give 6-(6-chloro-2-((4,4-difluoro-1,2-dimethylpyrrolidin-2-yl)methoxy) -4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine (120 mg, 0.21 mmol, 69.4% yield) as a yellow solid. LCMS: (ESI, m/z): 572.2 [M+H] ⁺

Step 5: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((4,4-difluoro-1,2-dimethylpyrrolidin-2- yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0765] A solution of 6-(6-chloro-2-((4,4-difluoro-1,2-dimethylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)- 5-(trifluoromethyl)pyridine-2-amine (110.0 mg, 0.19 mmol) and N,N-diisopropylethylamine (75.0 mg, 0.58 mmol) in dichloromethane (10 ml) were stirred at -78°C within 5 minutes. Then, acryloyl chloride (18.0 mg, 0.20 mmol) was added dropwise to the reaction system and stirred at -78° C. for 30 minutes. Upon completion, the solution was quenched with water and extracted with dichloromethane. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((4,4-difluoro-1,2 -dimethylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (54.5mg, 0.09mmol, 45.3% yield) as white solid.

[0766] Example 73: LC-MS: (ESI, m/z): 626.2 [M+H] ⁺ , ¹ H NMR (300 MHz, methanol-d ₄ ) δ 8.09 (s, 1H), 7.80 ( d, J=9 Hz, 1H), 7.55 (s, 1H), 6.91-6.75 (m, 1H), 6.70 (d, J=9 Hz, 1H), 6.34-6.18 (m, 1H), 5.86-5.74 (m, 1H), 4.49-4.31 (m, 2H), 4.06-3.84 (m, 8H), 3.43-3.32 (m, 1H), 3.22-3.01 (m, 1H), 2.69-2.45 (m, 1H) , 2.39 (s, 3H), 2.30–2.12 (m, 1H), 1.26 (s, 3H).

Example 74: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[1-methyl-1-[(2S)-1-methylpyrrolidin-2 -yl]ethoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Synthetic way

Step 1: 2-[(2S)-1-methylpyrrolidin-2-yl]propan-2-ol

[0767] 2-[(2S)-pyrrolidin-2-yl]propan-2-ol (1.0 g, 7.74 mmol) was added to 0.2 ml of formic acid at 0°C followed by 0.15 ml 40% aqueous formaldehyde. The mixture was refluxed at 120° C. for 24 hours. Upon completion, the mixture was acidified with 5N hydrochloric acid and evaporated. The residue was dissolved in a minimum amount of water, saturated with sodium hydroxide and extracted with chloroform.

The combined extracts were dried over potassium carbonate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (96/4) to give 510 mg (46%) of 2-[(2S)-1-methylpyrrolidin-2-yl]propan-2-ol as yellowish -brown solid. LC-MS: (ESI, /i/g): 144.3 [M+H] ⁺

Step 2: tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((2- (1-methylpyrrolidin-2-yl)propan-2-yl)oxy)quinazolin-4-yl)piperazine-1-carboxylate

[0768] Sodium hydride ( 125.13 mg, 3.13 mmol, 60% dispersion in mineral oil) at 0° C. and stirred at 25° C. for 1 hour. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (300.0 mg, 0.39 mmol) and stirred at 25°C for 1 hour. Upon completion, the resulting solution was quenched with water and extracted with dichloromethane. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (4%) to give 105 mg (30.2%) t-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl) amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((2-(1-methylpyrrolidin-2-yl)propan-2-yl)oxy)quinazolin-4-yl)piperazin- 1-carboxylate as a white solid. LC-MS: (ESI, m/z): 890.4 [M+H] ⁺

Step 3: (S)-6-(6-chloro-2-((2-(1-methylpyrrolidin-2-yl)propan-2-yl)oxy)-4-(piperazin-1-yl)quinazolin-7 -yl)-5-(trifluoromethyl)pyridine-2-amine

[0769] A solution of tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((2 -(1-methylpyrrolidin-2-yl)propan-2-yl)oxy)quinazolin-4-yl)piperazin-1-carboxylate (96.0 mg, 0.11 mmol) in trifluoroacetic acid (21 ml, 0.11 mmol) was stirred at 50°C for 5 hours. After completion, the reaction was concentrated. The crude product was used in the next reaction. LC-MS: (ESI, m/z): 550.4 [M+H] ⁺

Step 4: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[1-methyl-1-[(2S)-1-methylpyrrolidin-2 -yl]ethoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0770] To a solution of (S)-6-(6-chloro-2-((2-(1-methylpyrrolidin-2-yl)propan-2-yl)oxy)-4-(piperazin-1-yl)quinazoline -7-yl)-5-(trifluoromethyl)pyridin-2-amine (59.0 mg, 0.11 mmol) and N,N-diisopropylethylamine (55.35 mg, 0.43 mmol) in dichloromethane (19 ml) acryloyl chloride (6.8 mg, 0.08 mmol) was added at -78°C and stirred at -78°C for 1 hour. Upon completion, the resulting solution was quenched with water and extracted with dichloromethane. Then the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: acetonitrile, V% (5% ~ 70% in 30 min); detector, UV 254 nm to obtain a crude product. The crude product was purified directly by preparative HPLC - Column, XBridge Prep C18 OBD Column 19*15 mm, 5 µm, C-0013; mobile phase, A: 10 mmol ammonium bicarbonate in water, B: ACN and B% (51%~73% in 7 min); detector, UV 254 nm to give 8 mg (12.3%) 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[1-methyl- 1-[(2S)-1-methylpyrrolidin-2-yl]ethoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 604.4 [M+H] ⁺ .

[0771] Example 74: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 8.00 (s, 1H), 7.77 (d,J=9.2 Hz, 1H), 7.43 (s, 1H), 6.88 -6.78 (m, 3H), 6.59 (d, J=8.8Hz, 1H), 6.16 (dd, J=16.4, 2.0Hz, 1H), 5.73 (dd,J=10.8, 2.4Hz, 1H), 3.83- 3.79 (m, 8H), 3.12-3.09 (m, 1H), 2.98-2.96 (m, 1H), 2.37 (d, J=9.6 Hz, 3H), 2.29-2.24 (m, 1H), 1.90-1.84 ( m, 1H), 1.71-1.58 (m, 3H), 1.57-1.52 (m, 6H). LC-MS: (ESI, m/z): 604.4 [M+H] ⁺ .

Examples 75a and 75b: (R)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylazetidin-2-yl) methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (Example 75a) and (S)-1-(4-(7-(6-amino-3-(trifluoromethyl) pyridin-2-yl)-6-chloro-2-((1-methylazetidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (Example 75b)

Synthetic way

Step 1: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridinyl]-6-chloro-2-[(1-methylazetidine- 2-yl)methoxy]quinazolin-4-yl]pinerazin-1-carboxylate

[0772] A solution of (1-methylazetidin-2-yl)methanol (39;5 mg, 0.3 mmol) and sodium hydride (60% pure) (23.4 mg, 0.5 mmol) in N,N-dimethylformamide (2 ml) was stirred at 0°C for 30 minutes. Then, tert-butyl 4-(7-(6-(bis-(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine was added -1-carboxylate (Intermediate 3) (150.0 mg, 0.2 mmol) and stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with saturated ammonium chloride. The resulting solution was extracted with ethyl acetate and the organic layers combined. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (10/1) to give tert-butyl 4-[7-[6-[bis(4-methoxyphenyl)methyl]amino|-3-(trifluoromethyl)- 2-pyridyl]-6-chloro-2-[(1-methylazetidin-2-yl)methoxy]quinazolin-4-yl]piperazin-1-carboxylate (120.0 mg, 0.1 mmol, 72% yield) in the form of a yellow liquid. LC-MS: (ESI, m/z): 848.3 [M+H] ⁺

Step 2: (R)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylazetidin-2-yl)methoxy) quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (Example 75a) and (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridine- 2-yl)-6-chloro-2-((1-methylazetidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1 yl)prop-2-en-1-one (Example 75b)

[0773] A solution of tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[(1-methylazetidine -2-yl)methoxy]quinazolin-4-yl]piperazin-1-carboxylate (100.0 mg, 0.1 mmol) in trifluoroacetic acid (2.6 ml, 35.3 mmol) was stirred at 50°C for 12 hours. After completion, the reaction was concentrated. The resulting mixture was re-diluted in dichloromethane (1 ml) and N,N-diisopropylethylamine (76.1 mg, 0.5 mmol) and acryloyl chloride (17.8 mg, 0.2 mmol) were added sequentially. The reaction was stirred at -78°C for 0.5 hour. The resulting solution was quenched with water and extracted with dichloromethane. The organic layer was collected, concentrated and purified by silica gel flash chromatography eluting with dichloromethane/methanol (10/1) to give the crude product. The crude product was purified by preparative HPLC - Column: XBridge Prep OBD C18 30×150 mm, 5 µm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; Flow rate: 60 ml/min; to give the diastereoisomers as a colorless oil. Diastereoisomers were isolated by preparative chiral HPLC (Column: CHIRALPAKIE-3, 4.6*50 mm 3 µm; mobile phase A: (hexane:DCM=3:1)(0.1% DEA): 1PA=80:20) to give (R)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylazetidin-2-yl)methoxy)quinazoline -4-yl)piperazin-1-yl)prop-2-en-1-one (Example 75a) (6.1 mg, 0.01 mmol, 5.5% yield) as a white solid and (S) -1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylazetidin-2-yl)methoxy)quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one (Example 75b) (6.6 mg, 0.01 mmol, 6% yield) as a white solid.

[0774] Example 75a: LC-MS: (ESI, m/z): 562.2 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.05 (s, 1H), 7.78 (d, J=8.7Hz, 1H), 7.47 (s, 1H), 6.91 (s, 2H), 6.82 (dd, J=16.5, 10.2Hz, 1H), 6.60 (d, J=8.7Hz, 1H ), 6.17 (dd, J=16.8, 2.4 Hz, 1H), 5.74 (dd, J=10.5, 2.4 Hz, 1H), 4.33 (d, J=5.4 Hz, 2H), 3.85-3.77 (m, 8H) , 2.82 - 2.72 (m, 1H), 2.29 (s, 3H), 2.02 - 1.93 (m, 2H), 1.26 - 1.23 (m, 2H). Chiral HPLC: column: CHIRALPAK IE-3 (4.6*50 mm, 3 µm); detection at 254 nm; (hexane/DCM=3:1) (0.1% DEA): 1PA=80:20; flow rate=1 ml/min; hold time: 3.723 min (faster peak).

[0775] Example 75b: LC-MS: (ESI, m/z): 562.2 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.04 (s, 1H), 7.78 (d, J=8.7Hz, 1H), 7.46 (s, 1H), 6.91 - 6.78 (m, 3H), 6.60 (d, J=8.7Hz, 1H), 6.17 (dd, J=16.8, 2.4Hz , 1H), 5.74 (dd, J=10.5, 2.4 Hz, 1H), 4.30 (d, J=5.4 Hz, 2H), 3.85 - 3.77 (m, 8H), 2.78 - 2.70 (m, 1H), 2.25 ( s, 3H), 2.01 - 1.87 (m, 2H), 1.26 - 1.23 (m, 2H). Chiral HPLC: column: CHIRALPAK IE-3 (4.6*50 mm, 3 µm); detection at 254 nm; (hexane/DCM=3:1) (0.1% DEA): IPA=80:20; flow rate=1 ml/min; hold time: 4,650 min (slower peak).

Example 76: 1-(4-(7-(6-Amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy) )quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: tert-butyl 4-(7-(6-(5is(4-methoxybenzyl)amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(2-(3-(fluoromethyl) azetidin-1-yl)ethoxy)quinazolin-4-yl)piperazin-1-carboxylate

[0776] Added a solution of 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (70.0 mg, 0.5300 mmol) and sodium hydride (20.0 mg, 0.5 mmol, 60% pure) in tetrahydrofuran (5 ml) and stirred at 25°C for 5 minutes. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (200.0 mg, 0.26 mmol) and stirred at 25° C. for 30 minutes. Upon completion, the solvent was concentrated in vacuo to give the crude product. The crude product was used directly in the next step. LC-MS: (ESI. m/z): 880.3 [M+H] ⁺

Step 2: 6-(6-chloro-2-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl )pyridine-2-amine

[0777] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(2-(3-( fluoromethyl)azetidin-1-yl)ethoxy)quinazolin-4-yl)piperazin-1-carboxylate (241.0 mg, 0.27 mmol) in 2,2,2-trifluoroacetic acid (10 ml) was stirred at 50°C within 2 hours. After completion, the reaction was concentrated. The residue was purified by C18 gel flash chromatography eluting with methanol/water (25:75) to give 6-(6-chloro-2-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)- 4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine (140 mg, 0.25 mmol, 94.7% yield) as a yellow solid. LC-MS: (PER, m/z): 540.2 [M+H] ⁺

Step 3: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy) )quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0778] 6-(6-Chloro-2-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5-( trifluoromethyl)pyridine-2-amine (140.0 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.09 ml, 0.52 mmol) in dichloromethane (10 ml) were stirred at -78°C for 5 minutes. Then acryloyl chloride (24.0 mg, 0.27 mmol) was added and stirred at -78°C for 1 hour. After completion, the reaction was concentrated. The residue was purified by C18 gel flash chromatography eluting with acetonitrile/water (25:75) to give the crude product. The crude product was purified by preparative HPLC - Column: Xselect CSH OBD Column 30*150 µm 5 µm, n; mobile phase A: Water (0.1% HA), mobile phase B: ANN; flow rate: 60 ml/min to give formic acid salt 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(2-(3-( fluoromethyl)azetidin-1-yl)ethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (16.8 mg, 0.026 mmol, 10.1% yield) as a white solid substances.

[0779] Example 76: LC-MS: (ESI, m/z): 594.2 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO, ppm) δ 8.04 (s, 1H), 7.78 (d , J=9.0 Hz, 1H), 7.46 (s, 1H), 7.00-6.67 (m, 3H), 6.60 (d, J=8.7 Hz, 1H), 6.17 (dd, J=2.1, 16.5 Hz, 1H) , 5.74 (dd, J=2.1, 10.5 Hz, 1H), 4.58 (d, J=6.3 Hz, 1H), 4.42 (d, J=6.3 Hz, 1H), 4.31-4.15 (m, 2H), 3.93- 3.70 (m, 8H), 3.32-3.29 (m, 2H), 3.02-2.93 (m, 2H), 2.83-2.66 (m, 3H).

Example 77: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2R, 3S)-3-fluoro-1-methyl-pyrrolidine -2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Synthetic way

Этап 1: [(2R, 3S)-3-фтор-1 -метил-пирролидин-2-ил]|метанол

Step 1: [(2R, 3S)-3-fluoro-1-methyl-pyrrolidin-2-yl]|methanol

[0780] Lithium aluminum hydride (146.63 mg, 3.86 mmol) was added to a solution of (2R,3S)-1-tert-butoxycarbonyl-3-fluoro-pyrrolidine-2-carboxylic acid (450.0 mg, 1.93 mmol) in tetrahydrofuran (18 ml) at 0°C. The reaction was then heated to 60°C for 1.5 hours. The reaction was cooled and quenched with water, filtered and concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (96/4) to give 80 mg (31%) of [(2R, 3S)-3-fluoro-1-methyl-pyrrolidin-2-yl]methanol in yellow oil. LC-MS: (ESI, m/z): 134.3 [M+H] ⁺ .

Step 2: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2R,3S )-3-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate

[0781] Sodium hydride (166, 84 mg, 4.17 mmol) at 0°C. The reaction was heated to 25°C and stirred for 1 hour. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (400.0 mg, 0.52 mmol) and stirred at 25° C. for 1 hour. Upon completion, the reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (1/1) to give 69 mg (15%) tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino ]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2R,3S)-3-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine -1-carboxylate as a yellow solid. LCMS: (ESI, m/z): 880.5 [M+H] ⁺ .

Step 3: 6-[6-chloro-2-[[(2R,3S)-3-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7-yl ]-5-(trifluoromethyl)pyridine-2-amine

[0782] A solution of tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2R, 3S)-3-Fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate (61.0 mg, 0.07 mmol) in trifluoroacetic acid (16 mL) was stirred at 50°C for 3 hours. After completion, the reaction was concentrated. The pH was adjusted to 10 with N,N-diisopropylethylamine. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: MeCN, V% (5%~70% in 30 min); detector, UV 254 nm to give 37 mg of 6-[6-chloro-2-[[(2R,3S)-3-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl -quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine as a light yellow solid. LCMS: (ESI, m/z): 540.3 [M+H] ⁺

Step 4: 1-[4-[7-[6-Amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2R,3S)-3-fluoro-1-methyl-pyrrolidine -2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0783] To a solution of 6-[6-chloro-2-[[(2R,3S)-3-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7 -yl]-5-(trifluoromethyl)pyridine-2-amine (37.0 mg, 0.07 mmol) and N,N-diisopropylethylamine (35.36 mg, 0.27 mmol) in dichloromethane (4.6 ml) acryloyl chloride (3.72 mg, 0.04 mmol) was added at -78°C and stirred at -78°C for 1 hour. Upon completion, the reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified directly by preparative HPLC - Column, XBridgePrep C18 OBD Column 19*15 mm, 5 µm, C-0013; mobile phase, A: TFA in water, B: ACN and B% (51%~73% in 7 min); detector, UV 254 nm to give 7.5 mg (18.4%) 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[( 2R,3S)-3-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 594.2 [M+H] ⁺

[0784] Example 77: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 8.05 (s, 1H), 7.78 (d, J-8.0 Hz, IH); 7.46 (s, 1H), 6.91 (s, 2H), 6.98-6.78 (m, 1H), 6.59 (d, J=8.8, 1H), 6.17 (dd, J- 16.8.2.0 Hz, 1H); 5.74 (dd; J-8.8. 2.0 Hz, 1H). 5.09 (d. J=52.0, 1H), 4.39-4.35 (m, 1H), 4.15-4.13 (m, 1H), 3.90-3.86 (rn, 6H), 3.76 (s, 2H), 2.94 (d, J - 6.8.1H), 2.84-2.75 (m, 1H), 2.49-2.43 (m; 4H), 1.96-1.90 (m, 2H). LC-MS: (ESI, mfz): 594.2 [M+H] ⁺ .

Example 78a: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1S,2S,5R)-3-methyl-3- azabicyclo[3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: ((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol

[0785] A solution of (1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200.0 mg, 0.88 mmol) in tetrahydrofuran (10 ml ) was stirred at 25°C for 0.5 hour. Then lithium aluminum hydride (67.0 mg, 1.77 mmol) was added and stirred at 25° C. for 6 hours. Upon completion, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate, and concentrated in vacuo to give ((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol (90 mg, 0. 71 mmol, 80.4% yield), which was taken directly to the next step. LC-MS: (ESI, m/z): 128.1 [M+H] ⁺

Step 2: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1S,2S, 5R )-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate

[0786] A solution of ((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol (100.0 mg, 0.7900 mmol) and sodium hydride (32.0 mg, 1.33 mmol) in tetrahydrofuran (10 ml) was stirred at 0°C for 0.5 hour. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (200.0 mg, 0.26 mmol) and the reaction was stirred at 25°C for 3 hours. Upon completion, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (97:3) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridine-2 -yl)-6-chloro-2-(((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1- carboxylate (56 mg, 0.06 mmol, 24.6% yield) as a yellow solid. LC-MS: (ESI, m/z): 874.4 [M+H] ⁺ .

Step 3: 6-(6-chloro-2-(((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-4-(piperazin-1- yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine

[0787] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1S,2S, 5R)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (83.0 mg, 0.09 mmol) in 2.2, 2-trifluoroacetic acid (10 ml) was stirred at 50°C for 5 hours. The reaction was concentrated to give 6-(6-chloro-2-(((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-4-(piperazin-1 -yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridin-2-amine (25 mg, 0.05 mmol, 89% yield). LC-MS: (ESI, m/z): 534.2 [M+H] ⁺

Step 4: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1S,2S,5R)-3-methyl-3- azabicyclo[3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0788] 6-(6-Chloro-2-(((1S,2S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-4-(piperazin-1) solution -yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridin-2-amine (50.0 mg, 0.09 mmol) and N,N-diisopropylethylamine (37.0 mg, 0.29 mmol) in dichloromethane (10 ml) was stirred at -78°C for 5 minutes. Then acryloyl chloride (9.0 mg, 0.10 mmol) was added and the mixture was stirred at -78° C. for 0.5 hour. Upon completion, the solution was quenched with water (2 ml) and extracted with dichloromethane (3×5 ml). The organic layer was collected and dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was further isolated by preparative HPLC - Column: Xselect CSH OBD Column 30*150 mm 5 µm, n; mobile phase A: Water (0.1% PA), mobile phase B: ACN; flow rate: 60 ml/min; to give 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1S,2S,5R)-3-methyl-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (15.2 mg, 0.03 mmol, 46% yield) in form of a white solid.

[0789] Example 78a: LC-MS: (ESI, m/z): 588.3 [M+H] ⁺ , ¹ H NMR (300 MHz, methanol-d ₄ , ppm) δ 8.09 (s, 1H ), 7.80 (d, J=9 Hz, 1H), 7.54 (s, 1H), 6.83 (dd, J=16.8, 10.8 Hz, 1H), 6.71 (d, J=8.7, 1H), 6.29 (dd, 7=16.8, 2.1 Hz, 1H), 5.82 (dd, J=10.5, 1.8 Hz, 1H), 4.62-4.51 (m, 1H), 4.48-4.33 (m, 1H), 4.05-3.86 (m, 8H) , 3.13 (d, J=9 Hz, 1H), 3.01-2.92 (m, 1H), 2.58 (dd, J=9, 3.9 Hz, 1H), 2.43 (s, 3H), 1.76-1.61 (m, 1H ), 1.58–1.39 (m, 1H), 0.82–0.63 (m, 1H), 0.45–0.26 (m, 1H).

Example 78b: 1-(4-(7-(6-Amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1S,2S,5S)-3-methyl-3- azabicyclo[3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: ((1R,2S,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol

[0790] A solution of (1R,2S,5S)-3-(tert-butoxycarbonyl)-3-azabicnclo[3.1.0]rceane-2-carboxylic acid (200.0 mg, 0.88 mmol) in tetrahydrofuran (10 ml ) was stirred at 25°C for 5 minutes. Then lithium aluminum hydride (67.0 mg, 1.77 mmol) was added and stirred at 25° C. for 6 hours. Upon completion, the solution was quenched with water and extracted with ethyl acetate. The organic layer was collected and dried over anhydrous sodium sulfate, and concentrated in vacuo to give ((1R, 2S, 5S)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol (86 mg, 0. 68 mmol, 76.8% yield), which was carried on to the next step without purification. LCMS: (ESI m/z): 128.1 [M+H] ⁺

Step 2: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,2S,5S )-3-mstyl-3-azabnclo[3.1.0]|hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate

[0791] A solution of ((1R, 2S, 5S)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol (100.0 mg, 0.79 mmol) and sodium hydride (32.0 mg, 1.33 mmol) in tetrahydrofuran (10 ml) was stirred at 0°C for 0.5 hour. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (200.0 mg, 0.26 mmol) was added and the reaction was stirred at 25° C. for 3 hours. The reaction was concentrated and the residue was purified by silica gel chromatography eluting with dichloromethane/methanol (97:3) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridine- 2-yl)-6-chloro-2-(((1R,2S,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1 -carboxylate (93 mg, 0.11 mmol, 40.8% yield) as a yellow solid. LC-MS: (ESI, m/z): 874.4 [M+H] ⁺

Step 3: 6-(6-chloro-2-(((1R,2S,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-4-(piperazin-1- yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine

[0792] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,2S, 5S)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (83.0 mg, 0.09 mmol) in 2.2, 2-trifluoroacetic acid (10 ml) was stirred at 50°C for 5 hours. The reaction was concentrated to give 6-(6-chloro-2-(((1R,2S,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-4-(piperazin-1 -yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine (40 mg, 0.09 mmol, 70.2% yield). LC-MS: (ESI, m/z): 534.2 [M+H] ⁺

Step 4: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,2S,5S)-3-methyl-3- azabicyclo[3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0793] 6-(6-Chloro-2-(((1R,2S,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-2-yl)methoxy)-4-(piperazin-1) solution -yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine (50.0 mg, 0.09 mmol) and N,N-diisopropylethylamine (37.0 mg, 0.29 mmol) in dichloromethane (10 ml) was stirred at -78°C for 0.5 hours. Then acryloyl chloride (10 mg, 0.10 mmol) was added and stirred at -78°C for 0.5 hour. Upon completion, the solution was quenched with water and extracted with dichloromethane. The organic layer was collected and dried over anhydrous sodium sulfate and concentrated. The crude product was further isolated by preparative HPLC - Column: Xselect CSH OBD Column 30*150 mm 5 µm, n; mobile phase A: Water (0.1%FA), mobile phase B: ACN; flow rate: 60 ml/min; to give 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((1R,2S,5S)-3-methyl-3-azabicyclo [3.1.0]hexan-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (15.4 mg, 0.026 mmol, 37.8% yield) in form of a white solid.

[0794] Example 78b: LC-MS: (ESI, m/z): 588.2 [M+H] ⁺ , ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 8.11 (s, 1H ), 7.82 (d, J=8.9 Hz, 1H), 7.57 (s, 1H), 6.83 (dd, J=10.8, 10.4 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.29 (dd , J=16.8, 1.6 Hz, 1H), 5.82 (dd, J=10.6, 2 Hz, 1H), 4.72-4.56 (m, 1H), 4.55-4.37 (m, 1H), 4.14-3.68 (m, 8H ), 3.29-3.13 (m, 2H), 2.79 (d, J=9.6 Hz, 1H), 2.54 (s, 3H), 1.68-1.52 (m, 2H), 0.83-0.69 (m, 1H), 0.63- 0.47(m, 1H).

Examples 79a and 79b: (R)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(dimethylamino)propan-2 -yl)oxy)quinazolin-4-yl)piperazin-1-yl)prop-2-si-1-one and (S)-1-(4-(7-(6-amino-3-(trifluoromethyl))pyridine -2-yl)-6-chloro-2-((1-(dimethylamino)propan-2-yl)oxy)quinazolin-4-yl)piperazin-1-yl)prop-2-si-1-one

Synthetic way

Step 1: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(dimethylamino)propane -2-yl)oxy)quinazolin-4-yl)piperazine-1-carboxytate

[0795] A solution of 1-dimethylamino-2-propanol (40.0 mg, 0.39 mmol) and sodium hydride (10.0 mg, 0.4200 mmol, 60% pure) in tetrahydrofuran (10 ml) was stirred at 25° C for 15 minutes. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (200.0 mg, 0.26 mmol) and stirred at 25° C. for 2 hours. After completion, the reaction was concentrated. The crude product was directly used in the next step without purification. LC-MS: (ESI, m/z): 850.2 [M+H] ⁺

Step 2: 6-(6-chloro-2-((1-(dimethylamino)propan-2-yl)oxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine -2-amine

[0796] tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(dimethylamino) propan-2-yl)oxy)quinazolin-4-yl)piperazin-1-carboxylate (243.0 mg, 0.29 mmol) in 2,2,2-trifluoroacetic acid (10 mL) was stirred at 50°C for 2 hours. Upon completion, the reaction was concentrated in vacuo and the resulting product was used directly in the next step. LC-MS: (ESI, m/z): 510.2 [M+H] ⁺

Step 3: (R)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(dimethylamino)propan-2-yl )oxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one and (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridine-2 -yl)-6-chloro-2-((1-(dimethylamino)propan-2-yl)oxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0797] 6-(6-Chloro-2-((1-(dimethylamino)propan-2-yl)oxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl) solution pyridine-2-amine (60.0 mg, 0.12 mmol) and N,N-diisopropylethylamine (0.06 ml, 0.35 mmol) in dichloromethane (5 ml) were stirred at -78°C for 5 minutes. Acrylonyl chloride (11.0 mg, 0.12 mmol) was then added and stirred at -78° C. for 30 minutes. After completion, the reaction was concentrated to obtain the crude product. The crude product was purified by preparative HPLC - Column: Xsclect CSH OBD Column 30*150 µm 5 µm, n; mobile phase A: Water (0.1%FA), mobile phase B: ACN; flow rate: 60 ml/min. The resulting product was purified by chiral preparative HPLC - Column: CHIRALPAK [C, 2*25 cm, 5 µm; mobile phase A: hekeane:DCM-3:1 (10 mM NH ₃ -MeOH)-HPLC; mobile phase B: MeOH-HPLC; flow rate: 18 ml/min to give 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[1S)-2-(dimethylamino)-1 -methyl-ethoxy[quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (8.1 mg, 0.014 mmol, 12.2% yield) as a white solid and 1-[ 4-[7-[6-Amino-3(trifluoromethyl)-2-pyridyl]-6-chloro-2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]quinazolin-4-yl]piperazine -1-yl]prop-2-en-1-one (9.5 mg, 0.016 mmol, 14.3% yield) as a white solid.

[0798] Example 79a: LC-MS: (ESI, m/z): 564.2 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO, ppm) δ 8.03 (s, 1H), 7.79 (d, J=8.0, 1H), 7.43 (s, 1H), 6.89 (s, 2H), 6.89-6.72 (m,1H), 6.58 (d, J=12.0, 1H), 6.17 (dd, J - 2.4, 16.8 Hz, 1H), 5.74 (dd, J - 2.4, 10.4 Hz, 1H), 5.41-5.23 (m, 1H), 3.95-3.62 (m, 8H), 2.60-2.51 (m, 1H), 2.40-2.31 (m, 1H), 2.19 (s, 6H), 1.35-1.20 (m, 3H). Chiral HPLC: CHIRALPAK [C-3 (0.46*5 cm; 3 µm); detection at 254 nm; (n-hexane/dichloromethane - 3/1) (0.1% diltylamine) / methanol - 7/3; flow rate - 1.0 ml/min: Retention time: 2.2 min (faster peak).

[0799] Example 79b: LC-MS: (ESI. m/z): 564.2 [M+H] ⁺ , ¹ H NMR (400 MHz. DMSO. ppm) δ 8.03 (s, 1H), 7.78 (d, J=B.B, 1H), 7.43 (s, 1H), 6.89 (s, 2H), 6.85-6.72 (m, 1H), 6.60 (d, J=8.8, 1H), 6.17 (dd, J-2.4, 16.8Hz, 1H). 5.74 (dd, J-2.4, 10.4 Hz; 1H); 5.41-5.23 (m. 1H); 3.93-3.65 (m, 8H); 2.64-2.54 (m, 1H). 2.40-2.28 (m, 1H); 2.19 (s. 6H). 1.40-1.29 (m, 3H). Chiral HPLC: CHIRALPAK IC-3 (0.46*5 cm; 3 µm); detection at 254 nm; (n-hexane / dichloromethane - 3/1) (0.1% diethylamine) / methanol - 7/3: flow rate - 1.0 ml/min; Hold time: 3.0 min (slower peak).

Example 80: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((5-(methoxymethyl)-1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one

Synthetic way

Step 1: (1-methylpyrrolidine-2,5-diyl)dimethanol

[0800] A solution of tert-butyl 2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (1500.0 mg, 6.49 mmol) and lithium aluminum hydride (369.0 mg, 9.72 mmol) in tetrahydrofuran (60 ml ) was stirred at 25°C for 8 hours. After completion, the reaction was concentrated. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (1:4) to give (1-methylpyrrolidin-2,5-diyl)dimethanol (500 mg, 3.44 mmol, 53.1% yield) as colorless oil. LC-MS: (ESI, m/z): 146.2 [M+H] ⁺

Step 2: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((5-(hydroxymethyl)- 1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0801] A solution of (1-methylpyrrolidin-2,5-diyl)dimethanol (76.0 mg, 0.52 mmol) and sodium hydride (40.0 mg, 1 mmol) in tetrahydrofuran (20 mL) was stirred at 25°C within 10 minutes. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (200.0 mg, 0.26 mmol) and stirred at 25° C. for 2 hours. Upon completion, the reaction was quenched with water and concentrated. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (5:95) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridine-2 -yl)-6-chloro-2-((5-(hydroxymethyl)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (120 mg, 0.13 mmol, 51, 4% yield) as a yellow solid. LC-MS: (ESI, m/z): 892.4 [M+H] ⁺ .

Step 3: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((5-(methoxymethyl)- 1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0802] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((5-(hydroxymethyl) -1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (100.0 mg, 0.11 mmol) and sodium hydride (9.0 mg, 0.23 mmol) in tetrahydrofuran ( 10 ml) was stirred at 40°C for 5 minutes. Then iodomethane (32.0 g, 0.23 mmol) was added and stirred at 40° C. for 2 hours. Upon completion, the reaction was concentrated and the residue was purified by C18 gel flash chromatography eluting with acetonitrile/water (97:3) to give t-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)- 3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((5-(methoxymethyl)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (50 mg , 0.055 mmol, 49.2% yield) as a yellow solid. LC-MS: (ESI, m/z): 906.4 [M+H] ⁺ .

Step 4: 6-(6-chloro-2-((5-(methoxymethyl)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5-( trifluoromethyl)pyridine-2-amine

[0803] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((5-(methoxymethyl) -1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (10.0 mg, 0.01 mmol) in 2,2,2-trifluoroacetic acid (0.8 ml) was stirred at 50°C for 2 hours. Upon completion, the reaction was concentrated in vacuo and the crude product was used directly in the next step. LC-MS: (ESI, m/z): 566.3 [M+H] ⁺

Step 5: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((5-(methoxymethyl)-1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) piperazin-1-yl) prop-2-en-1-one

[0804] A solution of 6-(6-chloro-2-((5-(methoxymethyl)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5- (trifluoromethyl)pyridine-2-amine (100.0 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.06 ml, 0.33 mmol) in dichloromethane (10 ml) were stirred at -78°C for 5 minutes. Then acryloyl chloride (15.0 mg, 0.17 mmol) was added and stirred at -78° C. for 30 minutes. Upon completion, the reaction was quenched with water and concentrated. The resulting residue was purified by C18 gel flash chromatography eluting with acetonitrile/water (95:5) to give the crude product. The crude product was purified by preparative HPLC - Column: XBridge Prep OBD C18 Column, 30×150 µm 5 µm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 ml/min to give the format 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((5-(methoxymethyl)-1 -methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (34.4 mg, 0.051 mmol, 30.2% yield) as a white solid .

[0805] Example 80: LC-MS: (ESI, m/z): 620.4 [M+H] ⁺ , ¹ H NMR (300 MHz, MeOD, ppm) δ 8.09 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.54 (s, 1H), 6.82 (dd, J=10.5, 16.8 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.27 (dd, J= 1.8, 16.8 Hz, 1H), 5.80 (dd, J=1.8, 10.5 Hz, 1H), 4.59-4.45 (m, 2H), 4.10-3.89 (m, 10H), 3.54-3.41 (m, 2H), 3.39 (s, 3H), 2.78-2.53 (m, 3H), 2.20-1.87 (m, 2H), 1.83-1.59 (m, 2H).S

Examples 81a and 81b: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro-2- (((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 81a) and 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro-2-(((2S ,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 81b) (2 atropisomers)

Synthetic way

Stage 1: 3-bromo-2,4-difluoro-6-iodaniline

[0806] A solution of 3-bromo-2,4-difluoroaniline (10.0 g, 48.08 mmol) and silver sulfate (14.98 g, 48.32 mmol) and iodine (13.5 g, 53.15 mmol) in ethanol (200 ml) was stirred at 20°C for 4 hours. The reaction was filtered and the filtrate was concentrated on silica gel. The resulting mixture was purified by flash chromatography eluting with petroleum ether to give 3-bromo-2,4-difluoro-6-iodaniline (15 g, 44.92 mmol, 93.4% yield) as a brown solid. LC-MS: (ESI. m/z): 333.9 [M+H] ⁺

Step 2: Methyl 2-amino-4-bromo-3,5-difluorobenzoate

[0807] In carbon monoxide, 3-bromo-2,4-difluoro-6-iodaniline solution (15.0 g, 44.92 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex dichloride (3.3 g, 4.51 mmol) in methanol (500 ml) was stirred at 25° C. for 5 minutes. Triethylamine (21 ml, 314.47 mmol) was then added and stirred at 25° C. for 8 hours. The solvent was concentrated and the residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (3/97) to give methyl 2-amino-4-bromo-3,5-difluoro-benzoate (8.6 g, 32.3 mmol) as a light yellow solid. LC-MS: (ESI, m/z): 266.0 [M+H] ⁺

Stage 3: 7-bromo-6,8-difluoroquinazolin-2,4-diol

[0808] A solution of methyl 2-amino-4-bromo-3,5-difluoro-benzoate (15.0 g, 56.4 mmol) and NaOH (4.5 g, 112.8 mmol) in water (300 ml) and methanol (300 ml) was stirred at 25°C for 3 hours. After the disappearance of methyl 2-amino-4-bromo-3,5-difluoro-benzoate, the reaction system was washed with diethyl ether. Then, the pH of the solution was adjusted to 4 with HOAc (30 ml, 56.4 mmol). To the resulting solution was added KOCN (11.4 g, 140.53 mmol) and stirred at 40° C. for 3 hours. This operation was repeated three times until most of the intermediate was formed on LCMS. Then NaOH (90 g, 2256 mmol) was added and stirred at room temperature for 2 hours. Upon completion, the pH of the reaction system was adjusted to 4 with concentrated hydrochloric acid. The solids were collected after filtration and washed with water to give 7-bromo-6,8-difluoroquinazolin-2,4-diol (5 g, 18.049 mmol, 32% yield) as a red solid. LC-MS: (ESI, m/z): 276.9 [M+H] ⁺

Step 4: 7-bromo-2,4-dichloro-6,8-difluoroquinazoline

[0809] A solution of 7-bromo-6,8-difluoro-quinazolin-2,4-diol (5.0 g, 18.05 mmol) in POCl ₃ (150 ml) was stirred at 120° C. for 5 minutes. Then N,N-diisopropylethylamine (46.7 mg, 361.0 mmol) was added and stirred at 120° C. for 3 hours. Upon completion, the solvent was concentrated in vacuo to give 7-bromo-2,4-dichloro-6,8-difluoro-quinazoline (4 g, yellow oil, crude) which was used for the next step without purification. LC-MS: (ESI, m/z): 312.9 [M+H] ⁺

Step 5: tert-butyl (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0810] To a solution of 7-bromo-2,4-dichloro-6,8-difluoro-quinazoline (4 g, crude) in dichloromethane (120 ml) was added N,N-diisopropylethylamine (10 ml), the resulting solution was stirred at 20°C for 5 minutes, then tert-butyl (S)-3-methylpiperazine-1-carboxylate (5.96 g, 29.8 mmol) was added and the reaction was stirred at 20°C for 5 hours. Upon completion, the resulting solution was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (1/4) to give t-butyl (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl) -3-methylpiperazine-1-carboxylate (4.6 g, 9.6 mmol, 65% yield) as a yellow solid. LC-MS: (ESI, m/z): 477.0 [M+H] ⁺

Step 6: tert-butyl (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0811] Tert-butyl (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate mixture (1.0 g, 2.1 mmol ) and potassium fluoride (2.5 g, 43.0 mmol) in DMSO (25 ml) was stirred at 120° C. for 2 hours under nitrogen. The reaction was filtered, the filtrate was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (10/1) to give t-butyp (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3 -methylpiperazine-1-carboxylate (600 mg, 1.3 mmol, 62.1% yield) as a white solid. LC-MS: (ESI, m/z): 461.1 [M+H] ⁺

Step 7: tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-2,6,8-trifluoroquinazolin-4-yl)- 3-methylpiperazine-1-carboxylate

[0812] To a solution of tert-butyl (S)-4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (500.0 mg, 1.08 mmol) , (6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid (850.0 mg, 2.17 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloromethane complex (II) dichloride (90.0 mg, 0.11 mmol) in tetrahydrofuran (30 ml) and water (6 ml) was added potassium phosphate (460.0 mg, 2.17 mmol) at 65° C. under nitrogen. The resulting solution was stirred at 65° C. for 3 hours. The reaction was concentrated and the residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (9/1) to give t-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)- 4-methylpyridin-2-yl)-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (650 mg, 0.89 mmol, 82.3% yield) as a yellow solid. LC-MS: (ESI, m/z): 729.3 [M+H] ⁺ .

Step 8: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-2,6,8-trifluoroquinazolin-4 -yl)-3-methylpiperazine-1-carboxylate

[0813] tert-Butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-2,6,8-trifluoroquinazolin-4-yl) solution -3-methylpiperazine-1-carboxylate (500.0 mg, 0.69 mmol) and p-toluenesulfonic acid (12.0 mg, 0.07 mmol) in N,N-dimethylformamide (10 ml) were stirred at 25°C within 5 minutes. Then NIS (309.0 mg, 1.37 mmol) was added and stirred at 25° C. for 3 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (30/1) to give tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodine -4-methylpyridin-2-yl)-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (200.0 mg, 0.23 mmol, 34.1% yield) as yellow solid. LC-MS: (ESI, m/z): 855.2 [M+H] ⁺ .

Step 9: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6,8- trifluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0814] A solution of tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-2,6,8-trifluoroquinazolin- 4-yl)-3-methylpiperazin-1-carboxylate (500.0 mg, 0.59 mmol) and CuI (450.0 mg, 2.36 mmol) in N,N-dimethylacetamide (20 ml) was stirred at 25° C for 5 minutes. Then, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1130.0 mg, 5.88 mmol) was added and stirred at 90° C. for 3 hours under nitrogen. The reaction was concentrated and the residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (20/1) to give t-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)- 4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (430 mg, 0.54 mmol, 92.2% yield ) as a yellow solid. LC-MS: (ESI, m/z): 797.3 [M+H] ⁺ .

Step 10: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro- 2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0815] A solution of ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (168.0 mg, 1.26 mmol) and NaH (101.6 mg, 2.54 mmol, 60% dispersion in mineral oil) in tetrahydrofuran (20 ml) was stirred at 25° C. for 0.5 hour. Then, tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6,8- trifluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (500.0 mg, 0.63 mmol) and stirred at 25° C. for 2 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (4/1) to give t-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl -3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)- 3-methylpiperazine-1-carboxylate (350 mg, 0.38 mmol, 61.3% yield) as a yellow solid. LC-MS: (ESI, m/z): 910.4 [M+H] ⁺

Step 11: 6-(6,8-difluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-((S)-2-methylpiperazin-1- yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0816] tert-Butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro solution -2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (350.0 mg, 0.38 mmol) in triperoxonane acid (10 ml) was stirred at 50°C for 6 hours. Upon completion, the solvent was concentrated in vacuo to give 6-(6,8-difluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-((S)- 2-methylpiperazin-1-yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (200 mg, crude), which was used for the next step without purification. LC-MS: (ESI, m/z): 570.2 [M+H]+

Step 12: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro-2-(( (2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 81a) and 1 -((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro-2-(((2S,4R )-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 81b) (2 atropisomers)

[0817] 6-(6,8-Difluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-((S)-2-methylpiperazin-1 solution -yl)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (400.0 mg, 0.70 mmol) and DIEA (274.0 mg, 2.12 mmol) in dichloromethane (40 ml) was stirred at -78°C for 5 min. Then acryloyl chloride (64.0 mg, 0.71 mmol) was added and stirred at -78°C for 0.5 hour. Upon completion, the solution was quenched with water and concentrated in vacuo. The residue was purified by sequential preparative HPLC and chiral HPLC to give the title compounds. The stereochemistry of the title compounds was assigned based on activity.

[0818] Example 81a: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro-2 -(((2S,4R-)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (67 .7 mg, 0.11 mmol, 15.5% yield, white solid). ¹ H NMR (300 MHz, methanol-d ₄ , ppm) δ 7.53 (dd, J=9.9, 8.1 Hz, 1H), 6.89 - 6.72 (m, 1H), 6.60 (s, 1H), 6.31 - 6.25 (m, 1Н), 5.81 (dd, J=18, 10.5 Hz, 1Н), 5.35 - 5.03 (m, 1Н), 4.81 (s, 1Н), 4.64 - 4.31 (m, 3H), 4.31 - 3.94 (m , 2H), 3.82 - 3.45 (m, 3H), 3.28 - 3.06 (m, 2H), 2.73 - 2.62 (m, 1H), 2.55 (s, 3H), 2.45 (d, J=1.5, 3H), 2.32 - 2.20 (m, 1H), 2.17 - 1.98(m, 1H), 1.40 (d, J=6.6 Hz, 3H). LC-MS: (ESI, m/z): 624.3 [M+H]+. Chiral HPLC: column: CHIRALPAK IE-3, 4.6*50 mm 3 µm; mobile phase: (hexane:DCM=3:1)(0.1% DEA):EtOH=80:20, flow rate: 1.0 ml/min; hold time: 1.836 min (faster peak).

[0819] Example 81b: 1-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro-2 -(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one ¹ H NMR (300 MHz, methanol-d ₄ , ppm) δ 7.53 (dd, J=9.9, 8.1 Hz, 1H), 6.94 - 6.71 (m, 1H), 6.60 (s, 1H), 6.38 - 6.20 (m, 1Н), 5.81 (dd, J=18, 10.5 Hz, 1Н), 5.45 - 5.03 (m, 1Н), 4.81 (s, 1Н), 4.64 - 4.31 (m, 3H), 4.31 - 3.94 (m, 2H) , 3.82 - 3.45 (m, 3H), 3.28 - 3.06 (m, 2H), 2.79 - 2.60 (m, 1H), 2.55 (s, 3H), 2.45 (d, J - 1.5, 3H), 2.39 - 2.20 ( m, 1Н), 2.17 - 1.78 (m, 1Н), 1.40 (d, J=6.6 Hz, 3Н). LC-MS: (ESI, m/z): 624.3 [M+H]+. Chiral HPLC: column: CHIRALPAK IE-3, 4.6*50 mm 3 µm; mobile phase: (hexane:DCM=3:1)(0.1% DEA):EtOH=80:20, flow rate: 1.0 ml/min; hold time: 2.322 min (faster peak). Examples 82a and 82b: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro- 2-(((2S,4R)4-fluoro-1-methylpyrrolidin-2-yl)methoxy)hipazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoroiron-2-on-1-one (Example 82a) and 1-((S)-4-((S)-7-(6-amio-4-methyl-3-(trifluoromethyl)pridin-2-yl)-6-chloro-8-fluoro- 2-(((2S;4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoroprop-2-on-1- he (Ex 82b)

Synthetic way

[0820] 6-|6-Chloro-8-fluoro-2-||(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl|methoxy|-4-|(2S)-2 solution -methylpiperazin-1-yl|hipazolin-7-yl|-4-methyl-5-(trifluoromethyl)pyridin-2-amine (prepared as an intermediate in Step 2 of Example 69) (0.6 g, 1.02 mmol ), 2-fluoroacrylic acid (0.09 g, 1.02 mmol), HATU (0.58 g, 1.54 mmol) and N,N-diisopropylethylamine (397 mg, 3.07 mmol) in dichloromethane (5 ml ) and stirred at RT for 2 hours. Upon completion, the reaction system was diluted with water and extracted with dichloromethane. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC and chiral HPLC to give 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6 -chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-2-fluoroprop -2-en-1-one (55.2 mg, 0.084 mmol, 8.2% yield) and 1-((S)-4-((S)-7-(6-amino-4-methyl-3 -(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)- 3-methylpiperazin-1-yl)-2-fluoroprop-2-en-1-one (42.8 mg, 0.065 mmol, 6.4% yield) as a yellow solid. LCMS (ESI, m/z): 658.3 [M+H] ⁺ . Preparative HPLC conditions: column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 µm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 ml/min;, chiral HPLC CHIRALPAK IC, 3*25 cm, 5 µm; mobile phase A:hexane:DCM=3:1(10 mM NH ₃ -MeOH)-HPLC, mobile phase B:EtOH-HPLC; flow rate: 2 ml/min.

[0821] Example 82a ¹ H NMR (300 MHz, methanol-d ₄ , ppm) δ 7.82 (s, 1H), 6.60 (s, 1H), 5.42-5.02 (m, 3H), 4.82 (s, 1H ), 4.50 (d, J=5.0 Hz, 2H), 4.42 - 3.93 (m, 3H), 3.86 - 3.39 (m, 4H), 3.21-3.00 (m, 1H), 2.77 - 2.51 (s, 4H), 2.51 - 2.39 (m, 3H), 2.38 - 1.92 (m, 2H), 1.43 (d, J=6.7 Hz, 3H).

[0822] Example 82b ¹ H NMR (300 MHz, methanol-d ₄ , ppm) 5 7.82 (s, 1H), 6.60 (s, 1H), 5.51-5.00 (m, 3H), 4.82 (s, 1H ), 4.50 (d, J=5.0 Hz, 2H), 4.46 - 3.93 (m, 3H), 3.88 - 3.39 (m, 4H), 3.26 - 3.00 (m, 1H), 2.78 - 2.51 (m, 4H), 2.51 - 2.40 (m, 3H), 2.40 - 1.90 (m, 2H), 1.43 (d, J=6.7 Hz, 3H). Examples 83a, 83b, 83c and 83d: 2-((R)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro -8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (Example 83a); 2-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((( 2S;4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)hipazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetopitrile (Example 83b),

2-((R)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((( 2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (Example 83c); and

2-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((( 2S;4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacrylopyl)piperazin-2-yl)acetonitrile (Example 83d)

Synthetic way

Step 1: tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0823] A solution of 7-bromo-2,6-dichloro-8-fluoroquinazolin-4(3H)-one (3.9 g, 12.5 mmol) and N,N-diisopropylethylamine (6.5 g, 50.3 mmol) in dichloromethane (80 ml) was stirred at 20° C. for 5 minutes. Methanesulfonic anhydride (8.8 g, 50.3 mmol) was added and the resulting mixture was stirred at 20° C. for 20 minutes. Then, 2-piperazin-2-ylapetonitrile (5.0 g, 40.0 mmol) and N,N-diisopropylethylamine (9.7 g, 75.5 mmol) were added and the mixture was stirred at 20°C for an additional 1 hour . After complete conversion to the desired product, di-tert-butyl dicarbonate (32.7 g, 150 mmol) was added and the mixture was stirred at 20° C. for 2 hours. The reaction was poured into a sorting funnel and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate (1/4) to give tert-butyl 4-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-2-( cyanomethyl)piperazine-1-carboxylate (4.9 g, 9.4 mmol, 75.5% yield) as a yellow solid. LC-MS: (ESI, m/z): 518.0, 520.0 [M+H] ⁺ .

Step 2: tert-butl 4-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate

[0824] tert-Butyl 4-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate solution (9.7 g, 18.7 mmol) and potassium fluoride (43.7 g, 752.6 mmol) in DMA (200 ml) were stirred at 120°C for 3 hours. The reaction was filtered, diluted with ethyl acetate (1 L) and washed with brine (200 ml*5). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (1/5) to give tert-butyl 4-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)-2 -(cyanomethyl)piperazine-1-carboxylate (6.6 g, 13.1 mmol, 70.3% yield) as a yellow solid. LC-MS: (ESI, m/z): 502.0, 504.0 [M+H] ⁺

Step 3: mpem-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-2,8-difluoro-quinazoline-4- yl]-2-(cyanomethyl)piperazine-1-carboxylate

[0825] MPem-butyl 4-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate solution (5.5 g, 10.9 mmol), [6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]boronic acid (12.0 g, 30.6 mmol), dichloromethane complex 1,H-bis(diphenylphosphino )ferronene-palladium(11) dichloride (1.32 g, 1.8 mmol) and potassium phosphate (5.12 g, 24.1 mmol) in tetrahydrofuran (400 ml) and water (80 ml) were stirred at 65°C for 2 hours in nitrogen. The reaction system was filtered and the filtrate was diluted with dichloromethane (500 ml) and washed with brine (50 ml x 5). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (1/3) to give tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl- 2-pyridyl]-6-chloro-2,8-difluoro-quinazolin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate (5 g, 6.5 mmol, 59.3% yield) as yellow solid. LC-MS: (ESI, m/z): 770.3 [M+H] ⁺ .

Step 4: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-iodo-4-methyl-2-pyridyl]-6-chloro-2,8-difluoro- quinazolin-4-yl]-2-(pianomethyl)piperazine-1-carboxylate

[0826] 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-2-pyridyl]-6-chloro-2,8-difluoroquinazoline-4 tert-butyl solution -yl]-2-(cyanomethyl)piperazine-1-carboxylate (5.0 g, 6.5 mmol) and silver acetate (2.7 g, 16.3 mmol) and iodine (4.97 g, 19.57 mmol) in N,N-dimethylformamide (50 ml) was stirred at 20°C for 4 hours. The reaction was filtered. The filtrate was diluted with ethyl acetate (250 ml) and washed with a solution of saturated sodium thiosulfate (100 ml × 5). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (1/3) to give t-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-iodo- 4-methyl-2-pyridyl]-6-chloro-2,8-difluoro-quinazolin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate (4.8 g, 5.4 mmol, 82.5 % yield) as a yellow solid. LC-MS: (ESI, m/z): 896.2 [M+H] ⁺ .

Step 5: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2,8- difluoroquinazolin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate

[0827] Tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-iodo-4-methyl-2-pyridyl]-6-chloro-2,8-difluoro solution -quinazolin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate (2.5 g, 2.8 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (13.4 g, 69 .8 mmol) and copper iodide (5.3 g, 27.9 mmol) in N,N-dimethylacetamide (80 ml) was stirred at 90° C. for 6 hours. The reaction was filtered. The filtrate was diluted with ethyl acetate (400 ml) and washed with brine (100 ml x 5). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (1/3) to give tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl- 3-(trifluoromethyl)-2-pyridyl]-6-chloro-2,8-difluoro-quinazolin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate (2.2 g, 2.6 mmol, 94 , 1% yield) as a yellow solid. LC-MS: (ESI, m/z): 838.4 [M+H] ⁺ .

Step 6: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro- 2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-2-prop-2-ynyl-piperazin-1-carboxylate

[0828] A solution of [(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (420.37 mg, 3.16 mmol) in tetrahydrofuran (43 ml) was added sodium hydride (180.39 mg, 4.51 mmol, 60% dispersion in mineral oil) at 0° C. and stirred at 25° C. for 1 hour. Then, tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2,8- difluoro-quinazolin-4-yl]-2-(cyanomethyl)piperazine-1-carboxylate (944.0 mg, 1.13 mmol) and stirred at 25° C. for 1 hour. Upon completion, the reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (4%) to give t-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3 -(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl] -2-prop-2-ynyl-piperazine-1-carboxylate (929 mg, 0.98 mmol, 86.3% yield) as a yellow solid. LC-MS: (ESI, miz): 951.3 [M+H] ⁺ .

Step 7: 2-[4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S,4R)-4 -fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-2-yl]acetonitrile

[0829] A solution of tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro -2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-2-prop-2-ynyl-piperazin-1-carboxylate (909, 0 mg, 0.96 mmol) in trifluoroacetic acid (91 ml, 0.96 mmol) was stirred at 50° C. for 3 hours. Upon completion, the reaction was concentrated and the residue was diluted with dichloromethane and the pH was adjusted to 10 with N,N-diisopropylethylamine. The mixture was concentrated and the Residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: MeCN, B% (5% ~ 70% in 30 min); detector, UV 254 nm to give 2-[4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S, 4R)-4-Fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-2-yl]acetonitrile (373 mg, 0.61 mmol, 63.9%) as a white solid substances. LC-MS: (ESI, m/z): 611.2 [M+H] ⁺ .

Step 8: 2-((R)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2- (((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (Example 83a); 2-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((( 2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (Example 83b); 2-((R)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((( 2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (Example 83c); and 2-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(( (2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (Example 83d)

[0830] A solution of 2-[4-[7-[6-amino-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S,4R)- 4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-2-yl]acetonitrile (373.0 mg, 0.61 mmol), N,N-diisopropylethylamine (393.75 mg, 3.05 mmol), HATU (232.12 mg, 0.61 mmol) and 2-fluoroacrylic acid (71.46 mg, 0.79 mmol) in dichloromethane (10 ml) and N,N-dimethylformamide (0 .5 ml) was stirred at 25°C for 1 hour. After completion, the resulting reaction was concentrated. The crude product was purified directly by preparative HPLC - Column, XBridge Prep C18 OBD Column 19*15 mm, 5 µm, C-0013; mobile phase, A: 1 mmol FA in water, B: ACN and B% (51%~73% in 7 min); detector, UV 254 nm to give 480 mg of 2-(4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(( (2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile as a white solid. The product was further purified by chiral preparative HPLC under the following conditions (Column, CHIRALPAK IE-3 4.6*50 mm 3 µm; mobile phase, hexane (0.1% DEA): EtOH=50:50; detector, 254 nm; Flow, 1.0 ml/min; Temperature: 25°C) and (Column, CHIRAL Cellulose-SB4.6*100 mm 3 µm; mobile phase, MtBE (0.1% DEA): EtOH=70:30; detector , 254 nm; Flow, 1.0 ml/min; Temperature: 25° C.) to give the title compounds. The stereochemistry of the title compounds was assigned based on activity data.

[0831] Example 83a: 2-((R)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro -2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)apetonitrile; (62.4 mg, 0.09 mmol, 15% yield, white solid). ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 7.96 (d, J=1.6 Hz, 1H), 6.62 (s, 1H), 5.42 - 5.12 (m, 3H), 5.11 - 4.90 (m , 1Н), 4.58 - 4.40 (m, 4H), 4.35 - 4.01 (m, 1Н), 3.91 - 3.59 (m, 3H), 3.57 - 3.46 (m, 1Н), 3.18 - 3.07 (m, 3H), 2.73 - 2.62 (m, 1H), 2.57 (s, 3H), 2.46 (d, J=1.2 Hz, 3H), 2.36 -2.25 (m, 1H), 2.12 - 1.96 (m, 1H). LC-MS: (ESI, m/z): 683.3 [M+H] ⁺ . Chiral HPLC: CHIRAL Cellulose-SB, 4.6*100 mm, 3 µm; detection at 214 nm; MtBE (0.1% DEA): EtOH=70:30; flow rate=1 ml/min; retention time: 2.041 min (first peak).

[0832] Example 83b: 2-((S)-4-((S)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro -2-(((2s,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)apetonitrile (64mg, 0.09 mmol, 15.3% yield, white solid). ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 7.96 (d, J=1.6 Hz, 1H), 6.62 (s, 1H), 5.42 - 5.12 (m, 3H), 5.11 - 4.92 (m , 1Н), 4.53 - 4.40 (m, 4H), 4.38 - 4.00 (m, 1Н), 3.89 - 3.59 (m, 3H), 3.62 - 3.46 (m, 1Н), 3.19 - 3.13 (m, 2H), 3.09 - 3.03 (m, 1H), 2.73 - 2.62 (m, 1H), 2.57 (s, 3H), 2.46 (d, J=1.6 Hz, 3H), 2.33 - 2.18 (m, 1H), 2.15 1.91 (m, 1H). LCMS: (ESI, m/z): 683.3 [M+H] ⁺ . Chiral HPLC: CHIRAL Cellulose-SB, 4.6*100 mm, 3 µm; detection at 214 nm; MtBE (0.1% DEA): EtOH=70:30; flow rate=1 ml/min; hold time: 2.704 min (second peak)

[0833] Example 83c: 2-((R)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8- fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (40, 2 mg, 0.0589 mmol, 9.6% yield, white solid). ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 7.96 (d, J=1.6 Hz, 1H), 6.62 (s, 1H), 5.42 - 5.11 (m, 3H), 5.08 - 4.93 (m , 1H), 4.66 - 4.39 (m, 4H), 4.38 - 4.10 (m, 1H), 3.89 - 3.49 (m, 4H), 3.19 - 3.04 (m, 3H), 2.76 - 2.63 (m, 1H), 2.59 (s, 3H), 2.46 (d, J=1.2 Hz, 3H), 2.33 - 2.26 (m, 1H), 2.16 - 1.98 (m, 1H). LC-MS: (ESI, m/z): 683.3 [M+H] ⁺ . Chiral HPLC: CHIRALPAK IE-3, 4.6*50 mm, 3 µm; detection at 254 nm; hexane (0.1% DEA): EtOH=50:50; flow rate = 1 ml/min; retention time: 2.395 min (third peak).

[0834] Example 83d: 2-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro -2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile. (92.1 mg, 0.13 mmol, 22.1% yield, white solid). ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 7.96 (d, J=1.6 Hz, 1H), 6.62 (s, 1H), 5.43 - 5.14 (m, 3H), 5.11 - 4.91 (m , 1H), 4.62 - 4.40 (m, 4H), 4.37 - 3.98 (m, 1H), 3.90 - 3.47 (m, 4H), 3.22 - 3.05 (m, 3H), 2.89 - 2.69 (m, 1H), 2.61 (s, 3H), 2.46 (d, J=4.0 Hz, 3H), 2.39 - 2.28 (m, 1H), 2.15 - 1.99 (m, 1H). LC-MS: (ESI, m/z): 683.3 [M+H] ⁺ . Chiral HPLC: CHIRALPAK IE-3, 4.6*50 mm, 3 µm; detection at 254 nm; hexane (0.1% DEA): EtOH=50:50; flow rate=1 ml/min; hold time: 3.052 min (fourth peak)

Examples 84a and 84b: 1-((S)-4-((R)-7-(6-amino-3,4-dimethylpyridin-2-yl)-6-chloro-8-fluoro-2-((( 2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 84a) and 1- ((S)-4-((S)-7-(6-amino-3,4-dimethylpyridin-2-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4- fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 84b) (2 atropisomers)

Synthetic way

Step 1: tert-butyl (3S)-4-[7-[6-[bis](4-methoxyphenyl)methyl[amino]-3,4-dimethyl-2-pyridyl|-6-chloro-2,8- difluoro-quinazolin-4-yl-|-3-methyl-piperazine-1-carboxylate

[0835] tert-Butyl (3S)-4-|7-|6-|bis|(4-methoxyphenyl)methyl|amino|-3-iodo-4-methyl-2-pyridyl|-6-chloro-2 solution ,8-difluoro-quinazolin-4-yl |-3-methyl-piperazin-1-carboxylate (4.00; 4; 5 mmol) and bis (triphenylphosphyl) palladium ([[) chloride (321.8 m; 0, 4 mmol) in 1,4-dioxane (40 ml) was stirred at 25° C. for 5 minutes under nitrogen. Then dimethylzinc in toluene (1.2 M) (7.6 ml, 9.1 mmol) was added and stirred at 50° C. for 20 hours. Upon completion, the reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography and silica gel eluting with petroleum ether/ethyl acetate (10/1) to give tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino] -3,4-dimethyl-2-pyridyl]-6-chloro-2,8-difluoro-quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate (3.00 g, 3.9 mmol, 86 , 1% yield) as a yellow oil. LCMS (PER, m/z): 759.3 [M+H] ⁺ .

Step 2: tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3,4-dimethyl-2-pyridyl]-6-chloro-8-fluoro- 2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate

[0836] A solution of [(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methanol (1052.2 mg, 7.9 mmol) in tetrahydrofuran (30 ml) was stirred at 0°C for 2 minutes. Then, sodium hydride (60% pure) (632.1 mg, 15.8 mmol) was added and stirred at 0° C. for 10 minutes. Then, tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3,4-dimethyl-2-pyridyl]-6-chloro-2,8- difluoro-quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate (3.0 g, 3.9 mmol) and stirred at 25° C. for 1 hour. Upon completion, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (10/1) to give tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3 ,4-dimethyl-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl] -3-methyl-piperazine-1-carboxylate (2.4 g, 2.7 mmol, 69.6% yield) as a yellow solid. LCMS (ESI, m/z): 872.4 [M+H] ⁺ .

Step 3: 6-[6-chloro-8-fluoro-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-[(2S)-2- methylpiperazin-1-yl]quinazolin-7-yl]-4,5-dimethyl-pyridin-2-amine

[0837] tert-Butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3,4-dimethyl-2-pyridyl]-6-chloro-8-fluoro solution -2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazin-1-carboxylate (2.4 g, 2 .7 mmol) in trifluoroacetic acid (9 g, 82.5 mmol) was stirred at 50° C. for 1 hour. After completion, the reaction was concentrated. The residue was purified by silica gel flash chromatography eluting with acetonitrile/water (40:60) to give 6-[6-chloro-8-fluoro-2-[[(2S,4R)-4-fluoro-1-methyl- pyrrolidin-2-yl]methoxy]-4-[(2S)-2-methylpiperazin-1-yl]quinazolin-7-yl]-4,5-dimethyl-pyridin-2-amine (1.2 g, 2, 2 mmol, 82% yield) as a yellow solid. LCMS (ESI, m/z): 532.2 [M+H] ⁺ .

Step 4: 1-((S)-4-((R)-7-(6-amino-3,4-dimethylpyridin-2-yl)-6-chloro-8-fluoro-2-(((2S, 4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 84a) and 1-(( S)-4-((S)-7-(6-amino-3,4-dimethylpyridin-2-yl)-6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro- 1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (Example 84b) (2 atropisomers)

[0838] Solution 6-|6-chloro-8-fluoro-2-||(2S;4R)-4-fluoro-1-methyl-pyrrolidin-2-yl |methoxy|-4-|(2S)-2 -methylpiperazin-1-yl|quinazolin-7-yl|-4,5-dimethyl-pyridine-2-amine (900.0 mg; 1.6 mmol), acrylic acid (97.5 mg; 1.3 mmol) and N,N-diisopropylethylamine (654.6 mg; 5.0 mmol) in dichloromethane (9 ml) was stirred at -78°C for 2 minutes. Then, HATU (643.2 mg; 1.6 mmol) was added at -78°C for 1 hour. Upon completion, the reaction was quenched with water, extracted with ethyl acetone, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (10/1) to give 197 mg of a crude solid. The crude product was purified by preparative HPLC - Column: XBridge Prep OBD C18 Column; 30×150 mm 5 µm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: LCN; flow rate: 60 t ml/min; to obtain 117 ml of the desired product. The resulting solid was purified by chiral preparative HPLC - Column, CHIRALPAK [C-3, 0.46*5 cm; 3 µm; mobile phase; MIBE (0.3% IPAmic): MeOH-50:50; detector; UV 254 nm. A faster nick was obtained at 1.142 min. A slower peak was obtained at 1.629 min to give 1-((S)-4-((R)-7-(6-amino-3,4-dimethylpyridin-2-yl)-6-chloro-8-fluoro-2 -(((2S;4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (38 mg ; 0.06 mmol; 3.8% yield) as a white solid and 1-((S)-4-((S)-7-(6-amino-3,4-dimethylpyridin-2-yl)- 6-chloro-8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2 -en-1-one (35.1 mg; 0.06 mmol; 3.5% yield) as a white solid.

[0839] Example 84a: ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 7.82 (s, 1H), 6.92 - 6.74 (m, 1H), 6.39 (s, 1H), 6.26 - 6.11 ( m, 1H), 5.81 - 5.66 (m, 3H), 5.18 (d,J=56.2 Hz, 1H), 4.75 (s, 1H), 4.50 - 4.23 (m, 3H), 4.19 - 3.91 (m, 2H) , 3.74 - 3.38 (m, 3H), 3.26 - 2.85 (m, 2H), 2.44 - 2.29 (m, 4H), 2.24 - 2.05 (m, 4H), 2.03 - 1.87(m, 1H), 1.81 (s, 3H), 1.28 (d,.7=6.5 Hz, 3H). LCMS (ESI, m/z): 586.3 [M+H] ⁺ . Chiral HPLC: column: CHIRALPAK IC-3, 4.6*50 mm 3 µm; detection at 254 im; MTBE (0.3% IPAmine): MeOH=50:50; flow rate=1 ml/min; hold time: 1.136 min; (faster peak).

[0840] Example 84b: ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 7.82 (s, 1H), 6.95 - 6.74 (m, 1H), 6.39 (s, 1H), 6.25 - 6.11 ( m, 1H), 5.84 - 5.65 (m, 3H), 5.19 (d, J=56.1 Hz, 1H), 4.74 (s, 1H), 4.49 - 4.22 (m, 3H), 4.21 - 3.88 (m, 2H) , 3.74 - 3.53 (m, 2H), 3.50 - 3.38 (m, 2H), 3.25 - 3.01 (m, 1H), 3.03 - 2.86 (m, 1H), 2.41 (s, 3H), 2.20 (s, 3H) , 2.13 - 1.87 (m, 2H), 1.83 (s, 3H), 1.30 (d, J=6.5 Hz, 3H). LCMS (ESI, m/z): 586.3 [M+H] ⁺ . Chiral HPLC: column: CHIRALPAK IC-3, 4.6*50 mm 3 µm; detection at 254 nm; MTBE (0.3% IPAmine): MeOH=50:50; flow rate=1 ml/min; hold time: 1.629 min (slower peak).

Example 85: (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8- fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-hydroxybut-2-en-1-one

Synthetic way

[0841] 6-((R)-6-chloro-8-fluoro-4-((S)-2-methylpiperazil-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl) solution )methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (see Step 11 of Example 17a/17b) (156.0 mg; 0.27 mmol); 4-hydroxy-but-2-hydroxy acid (42.06 mg; 0.41 mmol); N,N-diisopropylethylamine (141.72 mg; 1.1 mmol) and HATU (156.64 mg; 0.4100 mmol) in dichloromethane (6.5 ml) were stirred at 25°C for 1 hour. Upon completion, the reaction was diluted with dichloromethane and washed with brine. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B:McCN, B% (5%~70% in 30 min); detector, UV 254 im to give 117 mg (65.3%) of the desired atropisomer (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl )pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)- 4-hydroxybut-2-eu-1-one as a white solid.

[0842] Example S5: LC-MS: (ESI, m/z): 652.3 [M+H] ⁺ , ¹ H NMR: (400 MHz, DMSO-d ₆ , ppm) δ 7.83 (s, 1Н), 6.83 - 6.79 (m, 3Н), 6.64 - 6.55 (m, 1H), 6.50 (s, 1H), 5.03 - 5.01 (m, 1H), 4.76 (s, 1H), 4.47 - 4.23 (m, 3H), 4.15 - 3.88 (m, 4H), 3.65 - 3.30 (m, 3H), 3.24 - 2.98 (m, 2H), 2.90 - 2.68 (m, 1H), 2.49 - 2.44 (m, 3H), 2.37 - 2.32 (m, 3H), 1.99 - 1.91 (m, 1H), 1.72 - 1.65 (m, 3H), 1.27 (s, 3H).

Example 86: (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8- fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4-chlorobut-2-on-1-one

Synthetic way

[0843] A solution of the desired atropisomer 6-((R)-6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2 -yl)methoxy)quinazolin-7-yl)-4-metpl-5-(trifluoromethyl)pyridin-2-ampia (see Step II of Example 17a/17b) (108.0 mg; 0.190 mmol); (E)-4-chlorobut-2-opic acid (20.63 mg; 0.1700 mmol), N,N-diisopropylethylamine (98.11 mg; 0.7600 mmol) and HATU (108.44 mg; 0. 2900 mmol) in dichloromethane (2 ml) was stirred at 25°C for 1 hour. After completion, the reaction was washed with water and extracted with dichloromethone. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography. Column, C18 silica gel; mobile phase, A: water, B:MeCN, B% (5%E 70% in 30 min); detector, UV 254 nm to give a white solid. The crude product was purified directly by preparative HPLC - Column, XBridge Prep C18OBD Column 19*15 mm; 5 µm; C-0013; mobile phase, A: 0.1% mm FA in water, B: ACN and B% (51%~73% in 7 min); detector, UV 254 nm yielding 44 mg (34.5%) (E)-1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine -2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)-4- chlorobut-2-one-1-one as a white solid.

[0844] Example 86: LC-MS: (ESI, m/z): 670.3 [M+H] ⁺ , ¹ H NMR: (400 MHz, DMSO-d ₆ , ppm) δ 8.18 (s, 1H), 7.82 (s, 1H), 6.83 - 6.71 (m, 3H), 6.49 (s, 1H), 4.90 - 4.75 (m, 1H), 4.40 - 4.30 (m, 3H), 4.30 - 4.06 (m, 3H), 4.01 - 3.88 (m, 1H), 3.67 - 3.55 (m, 2H), 3.13 - 3.15 (m, 1H), 3.05 - 2.93 (m, 1H), 2.61 - 2.56 (m, 1H), 2.43 - 2.26 (m, 6H), 2.19 - 2.15 (m, 1H), 1.97 - 1.93 (m, 1H), 1.70 - 1.62 (m, 3H), 1.28 - 1.25 (m, 3H).

Example 87: 1-[4-[7-[6-Amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)-1-(oxetan-3-yl)pyrrolidin- 2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Synthetic way

Step 1: tert-butyl-dimethyl-||(2S)-1-(oxetan-3-yl)pyrrolidin-2-yl[methoxy]silane

[0845] A mixture of tert-butyl-dimethyl-||(2S)-pyrrolidin-2-yl[methoxy]silane (1600.0 mg; 7.43 mmol); 3-oxetanol (2700.0 mg; 37.47 mmol) and sodium cyanoborohydride (500.0 mg; 7.94 mmol) in methyl alcohol (10 ml) were stirred at 50° C. for 4 hours. The resulting solution was diluted with water, extracted with dichloromethane and combined organic layers. The resulting mixture was purified by preparative HPLC to give t-butyl-dimethyl-|| (2S)-1-(oxetan-3-yl)pyrrolidin-2-yl[methoxy]silane (1200 mg; 4.41 mmol 59.5% yield) as a yellow oil. LC-MS: (ESI; m/z): 272.2 [M+H] ⁺ .

Step 2: [(2S)-1-(oxetan-3-yl)pyrrolidin-2-yl]methanol

[0846] In a mixture of tert-butyl-dimethyl-[[(2S)-1-(oxetan-3-yl)pyrrolidin-2-yl]methoxy]silane (1800.0 mg, 6.63 mmol) in trifluoroacetic acid ( 3 ml, 40.39 mmol), the mixture was stirred for 3 hours at 50°C. Upon completion, the pH was adjusted to -8.0 with N,N-diisopropylethylamine. The crude product was purified by preparative HPLC to give [(2S)-1-(oxetan-3-yl)pyrrolidin-2-yl]methanol (880 mg, 5.57 mmol, 84.4% yield) as a yellow oil. LC-MS: (ESI, m/z): 158.1 [M+H] ⁺ .

Step 3: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)- 1-(oxetan-3-yl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate

[0847] To a mixture of sodium hydride (36.0 mg, 1.5 mmol) in tetrahydrofuran (3 mL) was added [(2S)-1-(oxetan-3-yl)pyrrolidin-2-yl]methanol (90.0 mg, 0.57 mmol), the mixture was stirred for 15 minutes at 0°C. yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate (Intermediate 3) (300.0 mg, 0.39 mmol) and stirred for 2 hours at room temperature. Upon completion, the reaction was quenched with saturated ammonium chloride and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude product which was used directly in the next step. LC-MS: (ESI, m/z): 904D [M+N] ⁺

Step 4: 6-[6-chloro-2-[[(2S)-1-(oxetan-3-yl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7-yl] -5-(trifluoromethyl)pyridine-2-amine

[0848] In a mixture of tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S )-1-(oxetan-3-yl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate (250.0 mg, 0.28 mmol) in trifluoroacetic acid (3 mL, 40, 39 mmol), the mixture was stirred for 3 hours at 50°C. The reaction system was adjusted to pH8 with N,N-diisopropylethylamine. The resulting solution was diluted with water, extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give 6-[6-chloro-2-[[(2S)-1-(oxetan-3-yl)pyrrolidin-2-yl]methoxy]-4-piperazin- 1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.27 mmol, 96.2% yield) as crude product. The crude product was directly used in the next step without purification. LC-MS: (ESI, m/z): 564.2 [M+H] ⁺

Step 5: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)-1-(oxetan-3-yl)pyrrolidin- 2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0849] N,N-diisopropylethylamine ( 25.0 mg, 0.19 mmol), 6-[6-chloro-2-[[(2S)-1-(oxetan-3-yl)pyrrolidin-2-yl]methoxy]-4-piperazin-1- yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine (60.0 mg, 0.11 mmol) and the mixture was stirred for 0.5 hour at -78°C. Upon completion, the organic layer was concentrated and the crude product was purified by preparative HPLC - Column: Xselect CSH F-phenyl OBD column, 19*250, 5 µm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: EtOH; flow rate: 25 ml/min; to give 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)-1-(oxetan-3-yl)pyrrolidin-2 -yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (14.2 mg, 0.023 mmol, 21.6% yield) as a white solid.

[0850] Example 87: LC-MS: (ESI, m/z): 618.3 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.05 (s, 1H ), 7.78 (d, J=8.9 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 6.98 - 6.75 (m, 3H), 6.60 (d, J=8.8 Hz, 1H), 6.17 (dd , J=16.7, 2.4 Hz, 1H), 5.74 (dd, J=10.4, 2.4 Hz, 1H), 4.65 - 4.15 (m, 2H), 3.95 - 3.60(m, 10H), 3.29-3.07 (m, 3H ), 2.97 - 2.69 (m, 1H), 2.65 - 2.55 (m, 1H), 2.18 - 2.01 (m, 1H), 1.77 - 1.46 (m, 3H), 1.38 - 1.13 (m, 1H).

Example 88: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(dimethylamino)cyclopropyl)methoxy)quinazolin-4-yl )piperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: (1-aminocyclopropyl)methanol

[0851] A solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (10.0 g; 53.41 mmol) in tetrahydrofuran (100 ml) was added hydrochloric acid (200 ml, 2M in tetrahydrofurans). The mixture was stirred at 25°C for 16 hours. Upon completion, the reaction was concentrated and purified by flash chromatography using silica gel eluting with dichloromethane/methanol (4:1) to give (1-aminocyclopropyl)methanol (4 g; 45.9 mmol, 86% yield) as white solid. LC-MS: (ESI, m/z): 88.3 [M+H] ⁺

Step 2: (1-(dimethylamino)cyclopropyl)methanol

[0852] A solution of (1-aminocyclopropyl)methanol (500.0 mg, 5.74 mmol), formaldehyde (16.7 ml, 66.6 mmol) and formic acid (500.0 mg, 10.86 mmol) was stirred at 100°C for 8 hours. After completion, the reaction was concentrated and sodium hydroxide was added to adjust the pH to 13. The residue was purified by silica gel flash chromatography eluting with methanol/dichloromethane (3:7) to give (1-(dimethylamino)niclopropyl)methanol (150 mg, 1 .3 mmol, 22.7% yield) as a colorless oil. LC-MS: (ESI, m/z): 116.2 [M+H] ⁺

Stage 3: tert-butyl. 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(dimethylamino)niclopropyl)methoxy)quinazolin-4 -yl)piperazine-1-carboxylate

[0853] A solution of (1-(dimethylamino)cyclopropyl)methanol (60 mg, 0.50 mmol) and sodium hydride (25.0 mg, 1.1 mmol) in tetrahydrofuran (10 ml) was stirred at 40°C for 5 minutes. Then, tert-butyp 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl) was added piperazine-1-carboxylate (Intermediate 3) (200.0 mg, 0.3 mmol) and stirred at 40°C for 1 hour. After completion, the reaction was concentrated to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1- (dimethylamino)cyclopropyl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (250 mg, 0.17 mmol, 56.7% yield, 60% purity) as a yellow oil, which was used directly in the next step. LC-MS: (ESI, w/z): 862.4 [M+H] ⁺

Step 4: 6-(6-chloro-2-((1-(dimethylamino)cyclopropyl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine

[0854] 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(dimethylamino) tert-butyp solution) cyclopropyl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate (250mg, 0.17mmol, 60% pure) in 2,2,2-trifluoroacetic acid (5mL) and dichloromethane (15mL) were stirred at 50 °C for 2 hours. The reaction was concentrated and the resulting mixture was purified by C18 gel flash chromatography eluting with methanol/water (3:7) to give 6-(6-chloro-2-((1-(dimethylamino)cyclopropyl)methoxy)- 4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridin-2-amine (80 mg, 0.15 mmol, 90.3% yield) as a yellow solid. LC-MS: (ESI, w/z): 522.3 [M+H] ⁺

Step 5: 1-(4-(7-(6-Amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(dimethylamino)piclopropyl)methoxy)quinazolin-4-yl )piperazin-1-yl)prop-2-en-1-one

[0855] A solution of 6-(6-chloro-2-((1-(dimethylamino)cyclopropyl)methoxy)-4-(piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2- amine (30.0 mg, 0.057 mmol), N,N-diisopropylethylamine (10.0 mg, 0.077 mmol) and dichloromethane (5 ml) were stirred at -78°C for 5 minutes. Then acryloyl chloride (5.2 mg, 0.06 mmol) was added and stirred at -78° C. for 30 minutes. The reaction was concentrated and purified by C18 gel flash chromatography eluting with acetonitrile/water (7:3) to give the crude product. The crude product was purified by preparative HPLC - Column: XBridge Prep OBD C 18 Column, 30×150 mm 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 ml/min; to give 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(dimethylamino)cyclopropyl)methoxy)quinazolin-4-yl) piperazin-1-yl)prop-2-en-1-one (17.3 mg, 0.03 mmol, 52.3% yield) as a white solid.

[0856] Example 88: LC-MS: (ESI, m/z): 576.2 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO, ppm) δ 8.04 (s, 1H), 7.77 (d ,.7=9.0 Hz, 1H), 7.43 (s, 1H), 6.87 (s, 2H), 6.79 (dd, J=12.0, 18.0 Hz, 1H), 6.58 (d, J=9.0 Hz, 1H), 6.15 (dd, J=3.0, 18.0 Hz, 1H), 5.72 (dd, J=3.0, 9.0 Hz, 1H), 4.40 (dd, J=12.0, 27.0 Hz, 2H), 3.93-3.80 (m, 6H) , 3.81-3.72 (m, 2H), 2.34 (s, 6H), 0.75-0.53 (m, 4H).

Example 89: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S, 4R)-4-fluoro-1-(2- methoxyethyl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Synthetic way

Step 1: methyl (2S,4R)-4-fluoroiprrolidine-2-carboxylate

[0857] A solution of 1-(t-butyl) 2-methyl (2S, 4R)-4-fluoropyrrolidine-1,2-dicarboxylate (5.0 g; 20.22 mmol) in trifluoroacetic acid (192 ml) was stirred at 25 °C for 1 hour. Upon completion, the solvent was concentrated pH was adjusted to 10 with N,N-diisopropylethylamine and the mixture was concentrated and used directly in the following LC-MS reaction: (ESI, m/z): 148.0 [M+H] ⁺

Step 2: methyl (2S,4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidine-2-carboxylate

[0858] Methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate solution (2.8 g; 19.03 mmol); 2-bromoethyl methyl ester (5.8 g; 41.86 mmol) and potassium carbonate (5.78 g; 41.86 mmol) in N,N-dimethylformamide (40.8 ml) was stirred at 50°C for 4 hours. Upon completion, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was used in the next reaction. LC-MS: (ESI, m/z): 206.1 [M+H] ⁺

Step 3: [(2S, 4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidin-2-yl]methanol

[0859] A solution of methyl (2S, 4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidine-2-carboxylate (1.45 g, 7.07 mmol) in tetrahydrofuran (14 ml) was stirred at 0°C. Lithium aluminum hydride (0.54 g, 14.13 mmol) was added and the reaction was stirred at 25° C. for 1 hour. The reaction was quenched with water (0.5 ml), sodium hydroxide solution (15%) (0.5 ml), water (1.5 ml) was stirred at 0°C for 1 hour. The mixture was diluted with methanol (50 ml) and stirred at 25°C for 30 minutes. Then, the mixture was filtered and concentrated. The resulting oil was re-diluted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product which was taken to the next step. LC-MS: (ESI, m/z): 178.3 [M+H] ⁺

Stage 4: tert-butyl. 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R)-4-fluoro- 1-(2-Methoxyethyl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate

[0860] To a solution of [(2S,4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidin-2-yl]methanol (250.86 mg, 1.42 mmol) in tetrahydrofuran (27.84 mL) was added sodium hydride (188.74 mg, 4.72 mmol, 60% dispersion in mineral oil) at 0°C and stirred at 25°C for 1 hour. tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin-1- carboxylate (Intermediate 3) (362.0 mg, 0.4700 mmol) and the reaction was stirred at 25° C. for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: MeCN, B% (5%~70% in 30 min); detector, UV 254 nm to give 180 mg (41.3%) tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]- 6-chloro-2-[[(2S,4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate as a yellow solid. LCMS: (ESI, w/z): 924.5 [M+H] ⁺

Step 5: 6-[6-chloro-2-[[(2S, 4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin- 7-yl]-5-(trifluoromethyl)pyridine-2-amine

[0861] A solution of tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S, 4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate (164.0 mg, 0.18 mmol) in trifluoroacetic acid (23 ml ) was stirred at 50°C for 5 hours. After completion, the reaction was concentrated. The pH was adjusted to 10 with N,N-diisopropylethylamine. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: MeCN, B% (5%~70% in 30 min); detector, UV 254 nm yielding 60 mg (57.9%) 6-[6-chloro-2-[[(2S,4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy ]-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine as a yellow solid. LC-MS: (ESI, m/z): 584.2 [M+H] ⁺

Step 6: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R)-4-fluoro-1-(2- methoxyethyl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0862] To a solution of 6-[6-chloro-2-[[(2S,4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl- quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine (48.0 mg, 0.0800 mmol) and N,N-diisopropylethylamine (42.41 mg, 0.3300 mmol) in dichloromethane (4 ml ) was added acryloyl chloride (4.46 mg, 0.0500 mmol) at -78°C and stirred at -78°C for 1 hour. The reaction was quenched with water and extracted with dichloromethane. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified directly by preparative HPLC - Column, XBridge Prep C18 OBD Column 19*15 µm 5 µm C-0013; mobile phase, A: ammonium bicarbonate and NH ₃ H ₂ O in water, B: ACN and B% (51%~73% in 7 min); detector, UV 254 nm to give 17 mg (32.4%) 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S, 4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 638.2 [M+H] ⁺

[0863] Example 89 ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 8.04 (s, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.46 (s, 1H), 6.89 ( s, 2H), 6.86-6.72 (m, 1H), 6.59 (d, J=8.8 Hz, 1H), 6.19 (d, J=2.4 Hz, 1H), 5.73 (dd, J=12.4, 2.0 Hz, 1H ), 5.18 (d, J=48 Hz, 1H), 4.43 - 4.31 (m, 1H), 4.30 - 4.18 (m, 1H), 3.98 - 3.58 (m, 8H), 3.52 - 3.42 (m, 1H), 3.41 - 3.37 (m, 2H), 3.22 - 3.13 (m, 4H), 3.13 - 3.05 (m, 1H), 2.72 - 2.57 (m, 2H), 2.21 - 2.09 (m, 1H), 1.98 - 1.78 (m , 1H). LC-MS: (ESI, m/z): 638.2 [M+H] ⁺ .

Example 90: |-|4-|7-|6-amino-3-(trifluoromethyl)-2-pyridyl|-6-chloro-2-[[(2S,4R,5S)-4-fluoro-1,5 -dimtyl-pyrrolidin-2-yl |methoxy|quinazolin-4-yl [cinerazin-1-pl]prop-2-cn-1-ol

Synthetic way

Step 1: 1(2S,4R,5S)-4-fluoro-1,5-dimethyl-pyrrolidin-2-yl[methanol]

[0864] Lithium aluminum hydride (310 mg; 8.1 mmol) was added to a solution of (2S,4R,5S)-1-tert-butoxycarbonyl-4-fluoro-5-methyl-pyrrolidine-2-carboxylic acid (1.0 g , 4.0 mmol) in tetrahydrofural (25 ml) 0°C. Then, the reaction was heated to 60°C for 1.5 hours. After completion, the reaction was quenched with water. After completion, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (96/4) to give 139 mg (15%) of [(2S,4R,5S)-4-fluoro-1,5-dimethyl-pyrrolidine-2- yl]methanol as a yellow solid. LC-MS: (ESI, m/z): 148.3 [M+H] ⁺

Step 2: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R ,5S)-4-fluoro-1,5-dimethyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate

[0865] To a solution of [(2S,4R,5S)-4-fluoro-1,5-dimethyl-pyrrolidin-2-yl]methanol (95.9 mg, 0.66 mmol) in tetrahydrofuran (8 ml) was added sodium hydride (62.56 mg, 1.56 mmol) at 0° C. and the mixture was stirred for 30 minutes. tert-Butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin-1- carboxylate (Intermediate 3) (200.0 mg, 0.26 mmol) and stirred at 25°C for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (97/3) to give 170 mg (72.9%) tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl] amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R,5S)-4-fluoro-1,5-dimethyl-pyrrolidin-2-yl]methoxy]quinazolin- 4-yl]piperazine-1-carboxylate as a yellow solid. LC-MS: (ESI, m/z): 894.5 [M+H] ⁺

Step 3: 6-[6-chloro-2-[[(2S,4R,5S)-4-fluoro-1,5-dimethyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazoline -7-yl]-5-(trifluoromethyl)pyridin-2-amine

[0866] A solution of tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S, 4R,5S)-4-fluoro-1,5-dimethyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate (170.0 mg, 0.19 mmol) in trifluoroacetic acid (26 ml) was stirred at 50°C for 3 hours. After completion, the reaction was concentrated. The pH was adjusted to 10 with N,N-diisopropylethylamine. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: MeCN, B% (5% ~ 70% in 30 min); detector, UV 254 nm yielding 105 mg 6-[6-chloro-2-[[(2S,4R,5S)-4-fluoro-1,5-dimethyl-pyrrolidin-2-yl]methoxy]-4-piperazine -1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridin-2-amine as a light yellow solid. LC-MS: (ESI, m/z): 554.2 [M+H] ⁺

Step 4: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R,5S)-4-fluoro-1,5 -dimethyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0867] To a solution of 6-[6-chloro-2-[[(2S,4R,5S)-4-fluoro-1,5-dimethyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl -quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine (105.0 mg, 0.19 mmol) and N,N-diisopropylethylamine (122.25 mg, 0.95 mmol) in dichloromethane (12 ml) was added acryloyl chloride (10.29 mg, 0.11 mmol) at -78°C and the mixture was stirred for 1 hour (-78°C). The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: MeCN, B% (40%); detector, UV 254 nm to give a crude product which was purified by preparative HPLC - Column, XBridge Prep C18 OBD Column 19*15 µm 5 µm C-0013; mobile phase, A: FA in water, B: ACN and B% (51% ~ 73% in 7 min); detector, UV 254 nm to give 25 mg (21.7%) 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S, 4R,5S)-4-fluoro-1,5-dimethyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 608.2 [M+H] ⁺

[0868] Example 90: ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 8.10 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 6.86 -6.79 (m, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.29 (dd, J = 8.4, 2.0 Hz, 1H), 5.82 (dd, J = 10.4, 1.6 Hz, 1H), 4.88- 4.62 (m, 1H), 4.54-4.44 (m, 2H), 4.00-3.93 (m, 8H), 3.15-3.11 (m, 1H), 2.75-2.62 (m, 1H), 2.51 (s, 3H), 2.26-1.98 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H. LC-MS: (ESI, m/z): 608.2 [M+H] ⁺ .

Example 91: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)-1-(2-methoxyethyl)pyrrolidine-2- yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Synthetic way

Stage 1: tert-butyl-dimethyl-[[(2S)-pyrrolidin-2-yl]methoxy]silane

[0869] To a mixture of L-prolinol (20 g, 193.73 mmol), imidazole (4 g, 587.54 mmol) in tetrahydrofuran (200 ml) was added tert-butyl dimethylchlorosilane (45 g, 298.57 mmol), a mixture stirred for 2 hours at room temperature. Upon completion, the resulting solution was diluted with water, extracted with dichloromethane, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude product which was used directly in the next step without purification. LC-MS: (ESI, m/z): 216.2 [M+H] ⁺

Stage 2: tert-butyl-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-dimethyl-silane

[0870] A mixture of tert-butyl-dimethyl-[[(2S)-pyrrolidin-2-yl]methoxy]silane (3.8 g, 13.93 mmol), 2-bromoethyl methyl ester (3.85 g, 27. 7 mmol) and potassium carbonate (5.77 g, 41.81 mmol) in N,N-dimethylformamide (30 ml) were stirred at room temperature for 2 hours. After completion, the reaction was diluted with water, extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was directly used in the next step without purification. LC-MS: (ESI, m/z): 274.2 [M+H] ⁺

Step 3: [(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methanol

[0871] A mixture of tert-butyl-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-dimethylsilane (2.0 g, 7.31 mmol) in trifluoroacetic acid (2 ml , 26.93 mmol) was stirred for 4 hours at 50°C. The reaction system was adjusted to pH 8 with N,N-diisopropylethylamine. The crude product was purified by preparative HPLC to give [(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methanol (800 mg, 5.0 mmol, 68.7% yield) as a yellow oil. LC-MS: (ESI, m/z): 160.1 [M+H] ⁺

Step 4: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)- 1-(2-Methoxyethyl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazine-1-carboxylate

[0872] Sodium hydride (20.0 mg, 0.83 mmol) and stirred at 0°C for 15 minutes. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (200.0 mg, 0.26 mmol) and stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was concentrated and purified by silica gel flash chromatography eluting with dichloromethane/methanol (19:1) to give t-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3- (trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate (120 mg , 0.125 mmol, 50.8% yield) as a yellow solid. LCMS: (ESI, m/z): 906.4 [M+H] ⁺

Step 5a: 6-[6-chloro-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7-yl]-5 -(trifluoromethyl)pyridine-2-amine

[0873] K tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S) -1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate (150.0 mg, 0.17 mmol) was added trifluoroacetic acid (1 ml, 13.23 mmol) . The mixture was stirred for 2 hours at 50°C. The reaction system was adjusted to pH 8 with N,N-diisopropylethylamine. The crude product was purified by silica gel flash chromatography eluting with methanol/water (3/1) to give 6-[6-chloro-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl] methoxy]-4-piperazin-1-yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine (80 mg, 0.14 mmol, 85.4% yield) as a yellow oil. LC-MS: (ESI, m/z): 566.2 [M+H] ⁺

Step 5b: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)-1-(2-methoxyethyl)pyrrolidine-2- yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0874] To a mixture of 6-[6-chloro-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7-yl] -5-(trifluoromethyl)pyridine-2-amine (80.0 mg, 0.14 mmol) and N,N-diisopropylethylamine (54 mg, 0.42 mmol) in dichloromethane (1 ml) were added acryloyl chloride (14.0 mg, 0.15 mmol) and the mixture was stirred for 0.5 hour at -78°C. The crude product was purified by preparative HPLC - Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 µm; mobile phase A: Water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: MeOH--HPLC; flow rate: 25 ml/min; to give 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S)-1-(2-methoxyethyl)pyrrolidin-2-yl ]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one (15.1 mg, 0.024 mmol, 17.2% yield) as a white solid.

[0875] Example 91: LC-MS: (ESI, m/z): 620.3 [M+H] ⁺ , ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.04 (s, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.46 (s, 1H), 6.96-6.74 (m, 3H), 6.60 (d, J = 8.8 Hz, 1H), 6.17 (dd, J = 16.6, 2.4 Hz , 1Н), 5.74 (dd, J = 10.4, 2.4 Hz, 1H), 4.38–4.27 (m, 1Н), 4.15–3.99 (m, 1H), 3.94–3.70 (m, 8Н), 3.42 (t, J = 6.2 Hz, 3H), 3.21 (s, 3H), 3.09-2.95 (m, 2H), 2.84 (s, 1H), 2.31-2.18 (m, 1H), 1.95-1.80 (m, 1H), 1.75- 1.54 (m, 3H).

Example 92: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R)-4-(difluoromethoxy)-1-methyl -pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Synthetic way

Step 1: 1-(tert-butyl)2-methyl(2S,4R)-4-(difluoromethoxy)pyrrolidine-1,2-dicarboxylate

[0876] In nitrogen, to a solution of 1-(tert-butyl)2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (4.8 g, 19.57 mmol) in acetonitrile (66 ml) was added iodide copper (0.74 g, 3.91 mmol) at 25°C and stirred at 50°C. Then, a solution of difluoro(fluorosulfonyl)acetic acid (4.18 g, 23.48 mmol) in acetonitrile (19.8 ml) was added and stirred at 50° C. for 1 hour. The reaction was concentrated and the residue was stirred in ethyl acetate. After completion, the filtrate was concentrated under reduced pressure. The crude product was used in the next reaction. LC-MS: (ESI m/z): 296.3 [M+H] ⁺

Step 2: ((2S,4R)-4-(difluoromethoxy)-1-methylpyrrolidin-2-yl)methanol

[0877] To a solution of 1-(tert-butyl)2-methyl(2S,4R)-4-(difluoromethoxy)pyrrolidine-1,2-dicarboxylate (5.0 g, 16.93 mmol) in tetrahydrofuran (66 ml) lithium aluminum hydride (1.29 g, 33.87 mmol) was added at 0°C and stirred at 60°C for 30 minutes. The reaction was quenched with water and filtered. The filtrate was concentrated, purified by silica gel flash chromatography using dichloromethane/methanol (96/4) to give 320 mg (10.4%) of ((2S,4R)-4-(difluoromethoxy)-1-methylpyrrolidine-2 -yl)methanol as a yellow oil. LCMS: (ESI, m/z): 182.3 [M+H] ⁺

Step 3: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R )-4-(difluoromethoxy)-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate

[0878] To a solution of [(2S,4R)-4-(difluoromethoxy)-1-methyl-pyrrolidin-2-yl]methanol (183.02 mg, 1.01 mmol) in tetrahydrofuran (16.5 ml) was added sodium hydride (80.81 mg, 2.02 mmol, 60% dispersion in mineral oil) at 0° C. and stirred at 25° C. for 1 hour. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (310.0 mg, 0.40 mmol) and stirred at 25°C for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (96/4) to give 245 mg (65.3%) tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl] amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R)-4-(difluoromethoxy)-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4- yl]piperazine-1-carboxylate

as a yellow solid. LC-MS: (ESI, m/z): 928.5 [M+H] ⁺ .

Step 4: 6-[6-chloro-2-[[(2S,4R)-4-(difluoromethoxy)-1-methyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7 -yl]-5-(trifluoromethyl)pyridine-2-amine

[0879] A solution of tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S, 4R)-4-(difluoromethoxy)-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate (229.0 mg, 0.25 mmol) in trifluoroacetic acid (29 ml) stirred at 50°C for 3 hours. The reaction was concentrated, the pH was adjusted to ~10 with N,N-diisopropylethylamine and the mixture was concentrated. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B:MeOH, V% (5% ~ 70% in 30 min); detector, UV 254 nm to give 93 mg of 6-[6-chloro-2-[[(2S,4R)-4-(difluoromethoxy)-1-methyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1 -yl-quinazolin-7-yl]-5-(trifluoromethyl)pyridine-2-amine as a yellow solid. LC-MS: (ESI, m/z): 588.4 [M+H] ⁺

Step 5: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S,4R)-4-(difluoromethoxy)-1-methyl -pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0880] To a solution of 6-[6-chloro-2-[[(2S,4R)-4-(difluoromethoxy)-1-methyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazoline -7-yl]-5-(trifluoromethyl)pyridin-2-amine (87.0 mg, 0.15 mmol) and N,N-diisopropylethylamine (95.44 mg, 0.74 mmol) in dichloromethane (14.5 ml) was added acryloyl chloride (10.71 mg, 0.12 mmol) at -78°C and stirred at -78°C for 1 hour. Upon completion, the resulting solution was quenched with water and extracted with dichloromethane. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: MeCN, B% (40%); detector, UV 254 nm. The mixture was repurified by preparative HPLC - Column, XBridge Prep C18 OBD Column 19*15 mm 5 µm C-0013; mobile phase, A: TFA in water, B: ACN and B% (51% ~ 73% in 7 min); detector, UV 254 nm to give 30 mg (31.6%) 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(2S, 4R)-4-(Difluoromethoxy)-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 642.1 [M+H] ⁺

[0881] Example 92: ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 8.14 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 6.86 -6.79 (m, 1H), 6.73-6.71 (m, 1H), 6.52 (s, 1H), 6.33-6.27 (m, 1H), 5.82 (dd, J = 10.4, 1.6 Hz, 1H), 4.99-4.98 (m, 1Н), 4.77-4.73 (m, 1H), 4.63-4.58 (m, 1Н), 3.98 (d, J = 3.6 Hz, 8Н), 3.83-3.79 (m, 2Н), 3.17-3.14 (m , 1H), 2.93 (s, 3Н), 2.43–2.33 (m, 2Н). LC-MS: (ESI, m/z): 642.1 [M+H] ⁺ .

Example 93: 1-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S )-pyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-(((S )-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0882] A solution of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (149.0 mg, 0.74 mmol) and sodium hydride (30.0 mg, 0.75 mmol, 60% dispersion in mineral oil) in tetrahydrofuran (10 ml) was stirred at 25°C for 0.5 hour. Then, tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2, 8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (see Step 9 of Example 17a/17b) (300.0 mg, 0.37 mmol) and stirred at 25° C. for 3 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether/ethyl acetate (10/1) to give t-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl -3-(trifluoromethyl)pyridin-2-yl)-2-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)- 3-methylpiperazine-1-carboxylate (298 mg, 0.30 mmol, 81.2% yield) as a yellow solid. LC-MS: (ESI, m/z): 994.4 [M+H] ⁺

Step 2: 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)quinazolin-7- yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine

[0883] A solution of tert-butyl (3S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2-((( 5)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-6-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (283.0 mg, 0.28 mmol) in triperoxonane acid (10 ml) was stirred at 50°C for 6 hours. The reaction was concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (20/1) to give 6-(6-chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2- (((S)-pyrrolidin-2-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (140 mg, 0.25 mmol, 88.8% yield) as a yellow solid. LC-MS: (ESI, m/z): 554.2 [M+H] ⁺

Step 3: 1-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S )-pyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

[0884] 6-(6-Chloro-8-fluoro-4-((S)-2-methylpiperazin-1-yl)-2-(((S)-pyrrolidin-2-yl)methoxy)quinazolin-7 solution -yl)-4-methyl-5-(trifluoromethyl)pyridine-2-amine (70.0 mg, 0.13 mmol) and N,N-diisopropylethylamine (49.0 mg, 0.38 mmol) in dichloromethane (10 ml) was stirred at -78°C for 5 minutes. Then acryloyl chloride (12.0 mg, 0.13 mmol) was added and stirred at -78°C for 0.5 hour. Upon completion, the solution was concentrated in vacuo. The residue was purified by preparative HPLC to give 1-((3S)-4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2 -(((S)-pyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (4.3 mg, 0.0071 mmol, 5.6% yield) as a white solid.

[0885] Example 93: ¹ H NMR (400 MHz, methanol-d ₄ , ppm) δ 7.67 (d, J = 1.6 Hz, 1H), 6.92-6.73 (m. 1H), 6.60 (s, 1H) , 6.29 (d, J = 18.0 Hz, 1H), 5.87-5.76 (m, 1H), 4.69 (s, 1H), 4.54 (d, J = 16.2 Hz, 1H), 4.41-4.23 (m, 1H), 4.22-3.96 (m, 2Н), 3.95-3.81 (m, 1Н), 3.80-3.52 (m, 6Н), 2.46 (s, 3Н), 2.28-1.77 (m, 4Н), 1.37 (d, J = 6.6 Hz, 3H). LC-MS: (ESI, m/z): 608.2 [M+H] ⁺ .

Example 94: (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(2,2-difluoroethyl)pyrrolidine -2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthetic way

Step 1: (S)-2,2-difluoro-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one

[0886] A solution of (S)-pyrrolidin-2-ylmethanol (5.0 g, 49.4 mmol), 2,2-difluoroacetic acid (7.1 g, 74.1 mmol), HATU (28.2 g, 74.1 mmol), and N,N-diisopropylethylamine (19.1 g, 148.3 mmol) in dichloromethane (50 ml) was stirred at 20° C. for 1 hour. The reaction system was washed with saturated sodium chloride (200 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give (S)-2,2-difluoro-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethan- 1-one (8.0 g, 44.7 mmol, 90.3% yield) as a brown oil. LC-MS: (ESI, m/z): 178.1 [M+H] ⁺

Step 2: (S)-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol

[0887] A solution of (S)-2,2-difluoro-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one (5.0 g, 27.9 mmol) and lithium aluminum hydride (4, 2 g, 111.6 mmol) in tetrahydrofuran (40 ml) was stirred at 20° C. for 1 hour. The reaction was quenched with aqueous ammonium chloride (40 ml). The mixture was filtered and the filtrate was extracted with dichloromethane (5×40 ml). The organic layers were combined, dried over sodium sulfate and concentrated to give (S)-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol (380 mg, 2.3005 mmol, 8.2% yield) as yellow solid. LC-MS: (ESI, m/z): 166.1 [M+H] ⁺

Step 3: tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1- (2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0888] Sodium hydride (124.0 mg, 3.1 mmol) was added to a solution of (S)-(1-(2,2-difluoroethyl)pyrrolidin-2-yl)methanol (320.0 mg, 1.9 mmol ) in tetrahydrofuran (8 ml). Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (297 mg, 0.4 mmol) was added and the reaction was stirred at 25° C. for 1 hour. The reaction was quenched with aqueous ammonium chloride (20 ml) and then extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography using dichloromethane/methanol (10/1) to give tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-( trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (320 mg, 0 .35 mmol, 18.1% yield) as a yellow solid. LC-MS: (ESI, m/z): 912.3 [M+H] ⁺ .

Step 4: (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(2,2-difluoroethyl)pyrrolidine -2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0889] A solution of tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1 -(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (150.0 mg, 0.16 mmol) in trifluoroacetic acid (16 ml) was stirred at 50°C for 12 hours and concentrated. The resulting oil was then diluted in dichloromethane (9 ml) and N,N-diisopropylethylamine (424.0 mg, 3.3 mmol) was added. Acryloyl chloride (13.0 mg, 0.14 mmol) was added to the resulting mixture at -78° C. and the reaction was stirred for 15 minutes. The reaction was quenched with saturated ammonium chloride (30 ml). The reaction system was extracted with dichloromethane (5×25 ml) and the organic layers combined. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC to give (S)-1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-(2 ,2-difluoroethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (33.9 mg, 0.05 mmol, 32.9% yield ) as a white solid. LC-MS: (ESI, m/z): 626.3 [M+H] ⁺

[0890] Example 94: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 8.04 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 6.90 (s, 2H), 6.82 (dd, J = 10.4, 10.8 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 6.24-5.88 (m, 2H), 5.79-5.68 (m, 1H), 4.38-4.24 (m, 1H), 4.20-4.07 (m, 1H), 3.92-3.68 (m, 8H), 3.39-3.21 (m, 1H), 3.16-3.06 (m, 1H), 3.05-2.95 (m , 1H), 2.90-2.74 (m, 1H), 2.45-2.37 (m, 1H), 1.98-1.86 (m, 1H), 1.79-1.68 (m, 2H), 1.67-1.56 (m, 1H).

Example 95: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((2S,4R)-4-methoxy-1-(2 -methoxyethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Synthetic way

Stage 1; 1-(tert-butyl)2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate

[0891] A solution of 1(tert-butyl)2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (30.0 g, 122.3 mmol) and sodium hydride (5.88 g, 245 mmol ) in tetrahydrofuran (1.3 L) was stirred at 20° C. for 0.5 hour. Iodomethane (34.74 g, 244.7 mmol) was added and the reaction was stirred at 20° C. for 1 hour. The reaction was quenched with aqueous ammonium chloride (300 ml). The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to give 1-(tert-butyl)2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (22 g, 84.8 mmol, 69.4% yield) as a brown oil. LC-MS: (ESI, m/z): 260.3 [M+H] ⁺

Step 2: methyl (2S,4R)-4-methoxypyrrolidine-2-carboxylate

[0892] A solution of 1-(tert-butyl)2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (30.0 g, 115.7 mmol) and hydrogen chloride in 1,4-dioxane ( 200 ml) was stirred at 20°C for 1.5 hours. The mixture was concentrated in vacuo to give methyl (2S,4R)-4-methoxypyrrolidine-2-carboxylate (12 g, 75.4 mmol) as a brown solid. LC-MS: (ESI, m/z): 160.2 [M+H] ⁺

Step 3: methyl (2S,4R)-4-methoxy-1-(2-methoxyethyl)pyrrolidine-2-carboxylate

[0893] A solution of methyl (2S,4R)-4-methoxypyrrolidine-2-carboxylate (5.0 g, 31.4 mmol) and 1-bromo-2-methoxyethane (6.51 g, 46.8 mmol) and cesium carbonate (20.5 g, 62.9 mmol) in acetonitrile (150 ml) was stirred at 80°C for 2 hours. After filtration, the filtrate was concentrated under reduced pressure to give methyl (2S,4R)-4-methoxy-1-(2-methoxyethyl)pyrrolidine-2-carboxylate (4.4 g, 20.252 mmol, 64.5% yield) as brown oil. LC-MS: (ESI, m/z): 218.3 [M+H] ⁺

Step 4: ((2S,4R)-4-methoxy-1-(2-methoxyethyl)pyrrolidin-2-yl)methanol

[0894] A solution of methyl (2S,4R)-4-methoxy-1-(2-methoxyethyl)pyrrolidine-2-carboxylate (2.0 g, 9.2 mmol) and lithium aluminum hydride (700.0 mg, 18.42 mmol) in tetrahydrofuran (40 ml) was stirred at 20°C for 1 hour. The reaction was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give ((2S,4R)-4-methoxy-1-(2-methoxyethyl)pyrrolidin-2-yl)methanol (750 mg, 3.963 mmol, 43.1% yield) in brown oil. LC-MS: (ESI, m/z): 190.3 [M+H] ⁺

Step 5: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((2S,4R)- 4-Methoxy-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

[0895] A solution of ((2S,4R)-4-methoxy-1-(2-methoxyethyl)pyrrolidin-2-yl)methanol (650.0 mg, 3.4 mmol) in tetrahydrofuran (20 mL) and sodium hydride ( 275.0 mg, 6.9 mmol) was added at 0°C. The resulting solution was stirred at 20°C for 0.5 hour. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (300.0 mg, 0.39 mmol) and stirred at 20° C. for 1 hour. The reaction was quenched with aqueous ammonium chloride (15 ml). The resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methyl alcohol (10/1) to give tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridine- 2-yl)-6-chloro-2-(((2S,4R)-4-methoxy-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate ( 240 mg, 0.26 mmol, 7.5% yield) as a brown solid. LC-MS: (ESI, m/z): 936.6 [M+H] ⁺

Step 6: 6-(6-chloro-2-(((2S,4R)-4-methoxy-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinazoline -7-yl)-5-(trifluoromethyl)pyridine-2-amine

[0896] A solution of tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((2S,4R) -4-methoxy-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-carboxylate (230.0 mg, 0.250 mmol) in 2,2,2-trifluoroacetic acid ( 50 ml) was stirred at 50°C for 4 hours. The resulting mixture was filtered and the filtrate was concentrated to give 6-(6-chloro-2-(((2S,4R)-4-methoxy-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)-4-( piperazin-1-yl)quinazolin-7-yl)-5-(trifluoromethyl)pyridin-2-amine (120 mg, 0.20 mmol, 81.9% yield) as a brown solid. LC-MS: (ESI, m/z): 596.2 [M+H] ⁺

Step 7: 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((2S,4R)-4-methoxy-1-(2 -methoxyethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

[0897] 6-(6-Chloro-2-(((2S,4R)-4-methoxy-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl) solution quinazolin-7-yl)-5-(trifluoromethyl)pyridine-2-amine (110 mg, 0.18 mmol) and N,N-diisopropylethylamine (71.0 mg, 0.55 mmol) in dichloromethane (10 ml) were stirred at -78°C for 5 min. Then acryloyl chloride (15.0 mg, 0.17 mmol) was added and the mixture was stirred at -78° C. for 15 minutes. The reaction was quenched with aqueous ammonium chloride (5 ml). The resulting solution was extracted with dichloromethane (5×8 ml) and combined organic layers. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC to give 1-(4-(7-(6-amino-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-(((2S,4R)-4- methoxy-1-(2-methoxyethyl)pyrrolidin-2-yl)methoxy)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one (22.2 mg, 0.034 mmol, 18.5 % yield) as a white solid. LC-MS: (ESI, m/z): 650.4 [M+H] ⁺

[0898] Example 95: ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.10 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.57 (m, 1H), 6.87-6.76 (m , 1H), 6.70 (d, J = 8.8 Hz, 1H), 6.31-6.23 (m, 1H), 5.84-5.77 (m, 1H), 4.63-4.48 (m, 2H), 4.05-3.99 (m, 5H ), 3.92 (s, 4Н), 3.66-3.36 (m, 5Н), 3.33 (s, 5Н), 3.29 (d, J = 1.2 Hz, 1H), 3.05-2.78 (m, 2Н), 2.55-1.88 ( m, 2H).

Example 96: 1-[4-[7-[6-Amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(4R)-4-fluoro-1,2-dimethyl-pyrrolidine -2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

Synthetic way

Step 1: 1-(tert-butyl)2-methyl(4R)-4-fluoro-2-methylpyrrolidine-1,2-dicarboxylate

[0899] A solution of 1-(tert-butyl)2-methyl(4R)-4-fluoropyrrolidine-1,2-dicarboxylate (5.00 g, 20.22 mmol) in tetrahydrofuran (19 ml) was added and lithium diisopropylamide (12.1 ml, 24.27 mmol 2.0M in tetrahydrofuran) and stirred at -78°C for 1 hour. Iodomethane (4.31 g, 30.33 mmol) was added at -78°C and the reaction was stirred at 25°C for 1 hour. The reaction was concentrated and the crude product was used in the next reaction. LC-MS: (ESI, m/z)=206.1 [M-55] ⁺ .

Step 2: [(4R)-4-fluoro-1,2-dimethyl-pyrrolidin-2-yl]methanol

[0900] Lithium aluminum hydride ( 1.45 to 38.27 mmol) at 0°C and stirred at 25°C for 1 hour. The reaction was quenched with water, filtered and the filtrate was concentrated. The resulting mixture was purified by silica gel flash chromatography eluting with dichloromethane/methanol (96/4) to give 700 mg (31.1%) of [(4R)-4-fluoro-1,2-dimethyl-pyrrolidine-2 -yl]methanol as a yellow oil. LC-MS: (ESI, m/z): 148.1 [M+H] ⁺

Step 3: tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(4R)- 4-fluoro-1,2-dimethyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate

[0901] Sodium hydride (208, 5 mg, 5.21 mmol, 60% dispersion in mineral oil) at 0° C. and stirred at 25° C. for 1 hour. Then, tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazin- 1-carboxylate (Intermediate 3) (500.0 mg, 0.65 mmol) and stirred at 25° C. for 1 hour. The reaction was quenched with water and extracted with dichloromethane. Then, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (96/4) to give 450 mg (80%) tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino] -3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(4R)-4-fluoro-1,2-dimethyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin- 1-carboxylate as a yellow oil. LC-MS: (ESI, m/z): 894.5 [M+H] ⁺

Step 4: 6-[6-chloro-2-[[(4R)-4-fluoro-1,2-dimethyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7-yl ]-5-(trifluoromethyl)pyridine-2-amine

[0902] A solution of tert-butyl 4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(4R) -4-fluoro-1,2-dimethyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-carboxylate (420.0 mg, 0.47 mmol) in trifluoroacetic acid (42 ml) was stirred at 50°C for 3 hours. After completion, the reaction was concentrated. The pH was adjusted to 10 with N,N-diisopropylethylamine and the mixture was concentrated. The crude material was used in the next reaction without purification. LC-MS: (ESI, m/z): 554.2 [M+H] ⁺

Step 5: 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(4R)-4-fluoro-1,2-dimethyl-pyrrolidine -2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one

[0903] To a solution of 6-[6-chloro-2-[[(4R)-4-fluoro-1,2-dimethyl-pyrrolidin-2-yl]methoxy]-4-piperazin-1-yl-quinazolin-7 -yl]-5-(trifluoromethyl)pyridine-2-amine (160.0 mg, 0.29 mmol) and N,N-diisopropylethylamine (149.03 mg, 1.16 mmol) in dichloromethane (14.76 ml) acryloyl chloride (18.3 mg, 0.20 mmol) was added at -78°C and stirred at -78°C for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified using reverse phase chromatography - Column, C18 silica gel; mobile phase, A: water, B: acetonitrile, V% (5% ~ 70% in 30 min); detector, UV 254 nm. The resulting mixture was repurified directly by preparative HPLC - Column, XBridge Prep C18 OBD Column 19*15 mm 5 µm C-0013; mobile phase, A: 10 mmol/l NH ₄ HCO ₃ in water, B: ACN and B% (51% ~ 73% in 7 min); detector, UV 254 nm yielding 47 mg (26.8%) 1-[4-[7-[6-amino-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2-[[(4R) -4-fluoro-1,2-dimethyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one as a white solid. LC-MS: (ESI, m/z): 608.2 [M+H] ⁺

[0904] Example 96: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 8.04 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 6.90 (s, 2Н), 6.85-6.82 (m, 1Н), 6.59 (d, J = 8.8 Hz, 1Н), 6.19 (d, J = 2.4 Hz, 1Н), 5.73 (dd, J = 10.4, 2.4 Hz, 1Н), 5.26 (d, J = 56 Hz, 1H), 4.26-4.16 (m, 2Н), 3.88-3.85 (m, 6Н), 3.85-3.70 (m, 2Н), 3.07-2.99 (m, 1H) , 2.91-2.78 (m, 1H), 2.27 (s, 3H), 2.19-2.00 (m, 2H), 1.02 (s, 3H). LC-MS: (ESI, m/z): 608.2 [M+H] ⁺

Example 97: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2- ((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

Synthetic way

3 Thai 1: 2-methyl-3,4-dihydro-1H-isoquinolin-5-ol

[0905] A solution of 1,2,3,4-tetrahydroisoquinolin-5-ol (1.0 g, 6.7 mmol) and formaldehyde (0.4 g, 13.4 mmol) in MeOH (10 mL) was stirred at 25 °C for 10 minutes. Sodium cyanoborohydride (1.3 g, 20.1 mmol) was then added and stirred at 25° C. for 30 minutes. Upon completion, the mixture was concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (10:1) to give 2-methyl-3,4-dihydro-1H-isoquinolin-5-ol (0.8 g, 4.5 mmol, 67 .3% yield) as a white solid. LC-MS (ESI m/z): 164.2 [M+H] ⁺ .

Step 2: tert-butyl (S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6- chloro-8-fluoro-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate

[0906] A solution of 2-methyl-3,4-dihydro-1H-isoquinolin-5-ol (0.8 g, 4.92 mmol) and sodium hydride (0.4 g, 9.84 mmol) in N,N -dimethylformamide (20 ml) was stirred at room temperature for 20 minutes. Then, tert-butyl (S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6- chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazin-1-carboxylate (see Step 9 of Example 17a/17b) (2.0 g, 2.46 mmol) and stirred at 60° C. for 30 minutes. The reaction was quenched with water (10 ml), diluted with dichloromethane (100 ml). The organic layer was washed with water (30 ml×3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (10:1) to give tert-butyl (S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)- 4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)quinazolin- 4-yl)-3-methylpiperazin-1-carboxylate (0.8 g, 0.77 mmol, 31.3% yield) as a white solid. LCMS (ESI, m/z): 956.3 [M+H] ⁺ .

Step 3: 6-((R)-6-chloro-8-fluoro-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-4-((S)- 2-methylpiperazin-1-yl)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0907] tert-Butyl (S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6 solution -chloro-8-fluoro-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)quinazolin-4-yl)-3-methylpiperazin-1-carboxylate (0.8 g , 0.78 mmol) in trifluoroacetic acid (10 ml) was stirred at 50° C. for 5 hours. After concentration, the pH was adjusted to ~7 with N,N-diisopropylethylamine (10 ml). The resulting residue was purified by reverse phase chromatography (acetonitrile 0-40/ in water) to give 6-((R)-6-chloro-8-fluoro-2-((2-methyl-1,2,3 ,4-tetrahydroisoquinolin-5-yl)oxy)-4-((S)-2-methylpiperazin-1-yl)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5 -(trifluoromethyl)pyridine-2-amine (0.23 g, 0.34 mmol, 43.8% yield) as a white solid. LCMS (ESI, m/z): 616.2 [M+H] ⁺ .

Step 4: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2- ((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one

[0908] 6-((R)-6-chloro-8-fluoro-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)-4-((8) solution -2-methylpiperazin-1-yl)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (0.23 g, 0.37 mmol) and N,N-diisopropylethylamine (0.1 g, 0.75 mmol) in dichloromethane (5 ml) was stirred at -78°C for 2 minutes. Then acryloyl chloride (0.03 mg, 0.37 mmol) was added and stirred at -78° C. for 20 minutes. The reaction was quenched with water (5 ml). The reaction system was diluted with dichloromethane (50 ml) and washed with water (20 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (10:1) to give the crude product. The mixture was purified using chiral preparative HPLC - Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 µm; mobile phase A: Hexane (8 mmol/l ammonium, methanol), mobile phase B: EtOH; flow rate: 18 ml/min to give 1-((S)-4-(R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8 -fluoro-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1- she (38.9 mg, 0.0575 mmol, 15.4% yield) at 6.942 min. LCMS (ESI, m/z): 670.3 [M+H] ⁺

[0909] Example 97: ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) 7.84 (s, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.99 (t, J = 8.5 Hz, 2Н), 6.87 (s, 2Н), 6.83-6.74 (m, 1H), 6.50 (s, 1Н), 6.22-6.12 (m, 1Н), 5.78-5.70 (m, 1H), 4.54 (d, J = 29.3 Hz, 1H), 4.30-3.86 (m, 3H), 3.55 (td, J = 24.5, 23.0, 13.2 Hz, 4H), 3.24-3.02 (m, 1H), 2.60 (d, J = 6.0 Hz, 2H ), 2.57-2.52 (m, 2Н), 2.37 (d, J = 2.3 Hz, 3Н), 2.32 (s, 3Н), 1.19 (t, J = 5.8 Hz, 3Н).

[0910] The data from Examples 1-97 are summarized in Table 2.

Biological examples

Time-Resolved Homogeneous Fluorescence Analysis (HRFR) K-Ras G12C, SOS1, Raf RBD for inhibition of GTP metabolism

[0911] To determine the activity of compounds in inhibiting nucleotide exchange, various concentrations were incubated with K-Ras G12C (25 nM in reaction, 12.5 nM final). After 18 hours at room temperature, the GTP exchange factor SOS1 GTP (1.67 nM during exchange, 1.25 nM final) was added to initiate the exchange of nucleotides for GTP (200 μM during exchange, 150 μM final). The level of GTP metabolism was assessed by adding the Ras-binding domain derived from C-Raf and the antibodies for detecting HFVR Tb-anti-FLAG and D2-anti-his (Cis-Bio) at a concentration of 50 nM, 1 nM and 12.5 nM, respectively. After 2 hours, the ratio of emission at 665 and 615 nm was measured with excitation at 320 nm on an Envision plate reader (Perkin Elmer).

[0912] The final reaction volume was 20 μl in a ProxiPlate-384F Plus plate (Perkin Elmer) in buffer containing 20 mM HEPES, 150 mM NaCl, 1 mM MgC12, 0.1% BSA, 0.03% Tween-20 and 1 mm DTT. K-Ras G12C (residues 2-188) and SOS1 (residues 564-1049) had an N-terminal 6-His tag, and the Raf-RBD construct (RAF1 residues 51-186) had an N-terminal Flag tag. All constructs were expressed in E. coli and had a Tev cleavage site between the label and the protein of interest, which was not used during purification. HRWR data are presented in Table 3 below.

Western blot analysis for cellular alkylation of K-Ras G12C

[0913] HCC1171 cells were maintained in RPMI1640 medium supplemented with 10% FBS. Cells were seeded in a 96-well plate at 20,000 cells/well, and compounds were added to the cells the following day. After 18 hours at 37° C., cells were lysed in RIPA buffer (Sigma R0278) with 0.5% SDS and a protease/phosphatase inhibitor cocktail. After thorough mixing to ensure complete lysis, the lysates were cleared by centrifugation before being transferred from each well at 20 μl and combined with loading buffer and reducing agent. After heating for 10 minutes at 95° C., 15 μl of each sample was loaded onto a 4-20% Tris-glycine gel and electrophoresis was performed at 110 V for 165 minutes in SDS-PAGE running buffer. The gels were transferred to a nitrocellulose membrane, blocked for 1 hour and stained overnight at 4° C. with a primary anti-K-Ras antibody (polyclonal Proteintech 12063-1-AP). The membrane was then thoroughly washed and counterstained with IRDye 800CW anti-rabbit stain (LI-COR 926-32211) for one hour at room temperature. After the final washes, the membrane was visualized on a LI-COR Odyssey CLx at medium resolution. Alkylated K-Ras was visible by electrophoretic shift relative to unmodified K-Ras. To quantify this effect, the LICOR software was used to draw a box around the alkylated and non-alkylated bands for each well and the total fluorescence intensity (FI) in each of these bands was measured. Thereafter, the following formula was used to calculate % alkylation: IP _(alkylated) /(IF _(alkylated) +IF _{(nsalkylated)} )*100 for each well.

[0914] A 7-point dose-response curve was used to determine the IC ₅₀ for each compound. Cellular alkylation data are presented in Table 3 below.

[0915] Table 3 shows the results of the above analysis of HPF and Western blot analysis.

Whole blood stability assay

[0916] Whole blood stability analysis was performed using fresh blood with a final drug concentration of 1 μM. Drug-blood mixtures were stirred at 37° C. for 180 minutes. The half-life of the exemplary compounds is shown in Table 4.

Table 4

CTG analysis of viability and selectivity of K-Ras G12C in 3D culture

[0917] Assessing proliferation may allow the effect of compounds on viability and specificity for K-Ras G12C-mediated cancer cell lines to be assessed. Proliferation was assessed using 3 G12C conditioned (H358, HCC1171 and HCC1792) and 2 non-G12C conditioned (PC-9 and A427) lines in ultra-low attachment plates to stimulate the growth of 3D spheroids. On day 1, 1000 cells per well in 50 µl of RPMI1640 medium supplemented with 10% PBS and 2 mM L-glutamine were seeded in 384-well black ultra-low round bottom attachment plates (Corning 3830). The next day, various concentrations of compounds were added using a dose-response titration starting at 20 μM and keeping the final amount of DMSO constant at 0.3%. Seven days after compound addition, viable cell count was determined by adding 40 μl of 3D CTG reagent (Promega G9683), which lyses cells and generates a luciferase signal proportional to the amount of ATP released. The plates were shaken vigorously for 25 minutes. The plates were then incubated for an additional 10 minutes. The plates were then briefly centrifuged before reading the luminescence on an Envision plate reader (Perkin Elmer). Luminescence from wells treated with DMSO alone was used to determine total proliferation and 1 μM staurosporine was used to determine 100% inhibition.

[0918] The features disclosed in the foregoing description or the following claims, expressed in specific forms or in terms of a means for carrying out the disclosed function, or a method or process for achieving the disclosed result, if necessary, can be used separately or as a combination of such features to implement inventions in their various forms.

[0919] The foregoing invention has been described in detail by way of illustration and example for the purposes of clarity and understanding. It will be apparent to a person skilled in the art that changes and modifications may be made in practice within the scope of the appended claims. Therefore, it should be understood that the foregoing description is intended to be illustrative and not limiting. Therefore, the scope of the invention should not be determined by reference to the above description, but instead should be determined by reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

The patents, published applications, and scientific literature cited herein constitute the body of knowledge of those skilled in the art and are incorporated herein by reference in their entirety to the same extent as if they were expressly and individually incorporated.

Claims (148)

1. Compound of formula (II):

or a pharmaceutically acceptable salt or isomer thereof; where R ₂ is NH ₂ ; R ₃ is H; R ₄ is H or C _1-6 alkyl; R ₅ is CF ₃ ; R ₇ is selected from the group consisting of H, cyano and halo; each of R ₈ and R ₉ is independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, cyano and halogen; where C _1-6 alkyl is optionally substituted with one substituent selected from the group consisting of: methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), an alkyl or arylsulfonate leaving group, C _1-6 alkanoylamino, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 alkylsulfonylamino, C _6-12 dialkylamino and C _1-6 haloalkoxy; X is piperazinyl optionally substituted with 1-4 substituents, where each substituent is independently selected from the group consisting of cyano, C _1-6 alkyl, C _1-6 cyanoalkyl and C _1-6 haloalkyl; Y represents

U is C(R _6a ), where R _6a is H; V is C(R _6b ), where R _6b is H or halogen; W is C(R _6c ), where R _6c is H or halogen; and n is 0. 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, where X is:

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is

4. Compound of formula (IV):

or a pharmaceutically acceptable salt or isomer thereof; where R ₁ is

X represents

Y represents

U is C(R _6a ), where R _6a is H; V is C(R _6b ), where R _6b is H or halogen; W is C(R _6c ), where R _6c is H or halogen; n is 0; and R ₁₁ is selected from the group consisting of:

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R ₁ is

6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, where R ₁ is

7. Connection according to any one of paragraphs. 4-6 or a pharmaceutically acceptable salt thereof, wherein R ₁₁ is

8. Connection according to any one of paragraphs. 4-7 or a pharmaceutically acceptable salt thereof, wherein R ₁₁ is

9. Connection according to any one of paragraphs. 4-6 or a pharmaceutically acceptable salt thereof, wherein R ₁₁ is

10. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, wherein R _6c is halogen. 11. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, wherein R _6c is hydrogen. 12. Connection according to any one of paragraphs. 1-11 or a pharmaceutically acceptable salt thereof, wherein R _6b is halogen. 13. Connection according to any one of paragraphs. 1-12 or a pharmaceutically acceptable salt thereof, where X is

14. The compound according to claim 1, having the formula:

or a pharmaceutically acceptable salt thereof. 15. The compound according to claim 1 or 4, having the formula:

(IVg), or a pharmaceutically acceptable salt thereof. 16. A compound having the formula:

or a pharmaceutically acceptable salt thereof. 17. Compound formula:

or a pharmaceutically acceptable salt thereof. 18. Compound formula:

or a pharmaceutically acceptable salt thereof. 19. Compound formula:

or a pharmaceutically acceptable salt thereof. 20. Compound formula:

or a pharmaceutically acceptable salt thereof. 21. Compound formula:

or a pharmaceutically acceptable salt thereof. 22. Compound formula:

23. A pharmaceutically acceptable salt of a compound of the formula:

24. Compound formula:

or a pharmaceutically acceptable salt thereof. 25. Compound formula:

26. A pharmaceutically acceptable salt of a compound of the formula:

27. Compound formula:

or a pharmaceutically acceptable salt thereof. 28. Compound formula:

29. A pharmaceutically acceptable salt of a compound of the formula:

30. Compound formula:

or a pharmaceutically acceptable salt thereof. 31. Compound formula:

32. A pharmaceutically acceptable salt of a compound of the formula:

33. Compound formula:

or a pharmaceutically acceptable salt thereof. 34. Compound formula:

35. A pharmaceutically acceptable salt of a compound of the formula:

36. Compound formula:

or a pharmaceutically acceptable salt thereof. 37. Compound formula:

38. A pharmaceutically acceptable salt of a compound of the formula:

39. Compound formula:

or a pharmaceutically acceptable salt thereof. 40. Compound formula:

41. A pharmaceutically acceptable salt of a compound of the formula:

42. Compound formula:

or a pharmaceutically acceptable salt thereof. 43. Compound formula:

44. A pharmaceutically acceptable salt of a compound of the formula:

45. Pharmaceutical composition for regulating the activity of the mutant protein K-Ras G12C, containing an effective amount of the compound according to any one of paragraphs. 1-44 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 46. The use of a compound according to any one of paragraphs. 1-44 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for regulating the activity of the K-Ras G12C mutant protein. 47. The use of a compound according to any one of paragraphs. 1-44 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the proliferation of a cell population having a mutant K-Ras G12C protein. 48. The use of a compound according to any one of paragraphs. 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 45 in the manufacture of a medicament for the treatment of cancer mediated by a K-Ras G12C mutation in an individual in need thereof and having a mutation, wherein the medicament is to be administered by the method , including the following steps: determining whether an individual has a mutation; as well as if the individual is found to have the mutation, then administering the drug to the individual. 49. The use of a compound according to any one of paragraphs. 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 45 in the manufacture of a medicament for the treatment of cancer mediated by a K-Ras G12C mutation in an individual in whom the mutation has been determined. 50. Use according to claim 48 or 49, wherein the cancer is lung cancer, colorectal cancer, appendix cancer, or pancreatic cancer. 51. The use of a compound according to any one of paragraphs. 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 45 in the manufacture of a medicament for the treatment of lung cancer containing a KRas G12C mutation in an individual with such cancer. 52. The use of claim 51 wherein the cancer is NSCLC. 53. The use of a compound according to any one of paragraphs. 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 45 in the manufacture of a medicament for the treatment of cancer mediated by a G12C K-Ras agnostic mutation, and determining the absence or presence of a K-Ras G12C mutation in a sample taken from a patient with suspected cancer. 54. The use of a compound according to any one of paragraphs. 1-44 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the production of a labeled mutant K-Ras G12C protein. 55. The use of a compound according to any one of paragraphs. 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 45 in the manufacture of a medicament for the treatment of cancer mediated by a K-Ras G12C mutation. 56. The use of claim 55 wherein the cancer is hemoblastosis, pancreatic cancer, MYH associated polyposis, colorectal cancer, or lung cancer. 57. Use according to claim 56 wherein the cancer is adenocarcinoma of the lung. 58. The use of a compound according to any one of paragraphs. 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 45 in the manufacture of a medicament for inhibiting K-Ras G12C mediated tumor metastases.