Novel quinazolinone derivatives

Abstract

The present invention relates to a compound of formula (I) TIFF2023554442000139.tif34170 (in the formula, A, L, R 1 , R 2 , R 3 and R 4 as defined in the description and claims. The compounds of formula (I) can be used as medicines.

Description

[Technical Field]

[0001] The present invention relates to organic compounds useful for the treatment and / or prevention in mammals, particularly compounds that modulate BRAF activity.

[0002] The present invention relates in particular to novel compounds of formula (I) TIFF0007877320000001.tif35170[In the formula, A is either -O- or -NH-; L is -(CH2)n-, where n = 1, 2, 3, or 4; R 1 These are alkoxycarbonyl, alkoxycarbonyl heterocycloalkyl, alkoxycarbonylamino, phenyl, alkoxycarbonyl(alkylamino), alkylcarbonyl(alkylamino), alkoxycarbonyl(alkylamino)alkylphenyl, alkoxyalkylaminocarbonyl, alkylcarbonyl heterocycloalkyl, alkoxycarbonylaminoalkoxyalkoxy, phenylalkoxy, aminoalkoxyalkoxy, hydroxycarbonyl, alkoxycarbonyl heterocycloalkylcarbonyl, alkoxycarbonyl heterocycloalkylaminocarbonyl, or alkoxycarbonyl(alkylamino)alkylaminocarbonyl; R 2 and R 3 These are independently selected from hydrogen, halogens, and cyano compounds; R 4 [These are dialkylamino, haloheterocycloalkyl, heterocycloalkyl, cycloalkyl, or alkyl]; or relating to the pharmaceutically acceptable salt thereof. [Background technology]

[0003] The serine / threonine kinases of the rapidly progressive fibrosarcoma (RAF) class include three members (ARAF, BRAF, and RAF1) that constitute the first node of the MAP kinase signaling pathway. Despite the apparent overlap of the three RAF isoforms in signal propagation via the phosphorylation of MEK1 and MEK2, frequent oncogenic activating mutations are generally found only in BRAF. In particular, substitution of V600 with glutamate or lysine highly activates the kinase, resulting in hyperstimulation of the MAPK pathway independently of external stimuli (Cell. 2015 Jun 18;161(7):1681-1696).

[0004] Mutant BRAF is a targetable oncogenic driver, and three BRAF inhibitors (vemurafenib, dabrafenib, and encorafenib) have been introduced to the market and have demonstrated efficacy in BRAFV600E-positive melanoma. However, rapid acquisition of drug resistance is observed almost universally, and the duration of therapeutic benefit from targeted therapy remains limited.

[0005] Furthermore, the developed BRAF inhibitors revealed an unexpected "paradoxical" ability to suppress MAPK signaling in BRAFV600E-driven tumors, while the same inhibitors showed MAPK-stimulating activity in BRAF wild-type (WT) models (N Engl J Med 2012;366:271-273; and British Journal of Cancer volume 111, pages 640-645 (2014)).

[0006] Subsequently, mechanistic studies of the RAF paradox revealed that oncogenic BRAFV600E phosphorylates MEK1 / 2 in its monomeric cytosolic form, while activation of WT BRAF and RAF1 requires a complex sequence of events including translocation to the cell membrane and homodimerization and / or heterodimerization facilitated by activated RAS (KRAS, NRAS, HRAS) (Nature Reviews Cancer volume 14, pages 455-467 (2014)).

[0007] Binding of inhibitors such as vemurafenib, dabrafenib, or encorafenib to WT BRAF or RAF1 protomers rapidly induces RAF homodimerization and / or heterodimerization, as well as membrane association of the newly formed RAF dimers. In the dimeric conformation, one RAF protomer allosterically induces a conformational change in the second RAF protomer, resulting in a kinase-active state, and importantly, a conformation unfavorable for inhibitor binding. The drug-induced dimers then promote MEK phosphorylation through catalysis operated by the unbound protomer due to hyperactivation of the pathway.

[0008] The RAF paradox leads to two clinically relevant consequences: 1) accelerated growth of secondary tumors (primarily keratosinous cell carcinoma and squamous cell carcinoma) with BRAFi monotherapy (N Engl J Med 2012;366:271-273), and 2) the development of drug resistance in BRAFi monotherapy and in the BRAFi+MEKi combination indicates activation of dimer-mediated RAF signaling by genetically driven events, including RAS mutations, BRAF amplification, and expression of dimeric BRAF splice variants (Nature Reviews Cancer volume 14, pages 455-467 (2014)). [Modes for carrying out the invention]

[0009] This invention relates to the surprising finding that the BRAF inhibitor of formula (I) exhibits significantly less paradoxical activation of the MAPK signaling pathway while maintaining high efficacy. Furthermore, this compound can be called a paradox blocker or RAF paradox blocker, in contrast to compounds that induce the RAF paradox (which can be called paradox inducers or RAF paradox inducers).

[0010] In this specification, the term “alkyl” means, alone or in combination, a linear or branched alkyl group having 1 to 8 carbon atoms, particularly a linear or branched alkyl group having 1 to 6 carbon atoms, and more specifically a linear or branched alkyl group having 1 to 4 carbon atoms. Examples of linear and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomer pentyl, isomer hexyl, isomer heptyl, and isomer octyl. Specific examples of alkyl are methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, and pentyl. Methyl, ethyl, and propyl are more specific examples of “alkyl” in the compounds of formula (I).

[0011] The term "cycloalkyl" alone or in combination refers to a cycloalkyl ring having 3 to 8 carbon atoms, and especially a cycloalkyl ring having 3 to 6 carbon atoms. Examples of "cycloalkyl" are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A specific example of "cycloalkyl" is cyclopentyl.

[0012] The term "heterocycloalkyl" refers to a monovalent, saturated, or partially unsaturated monocyclic or bicyclic ring system consisting of 4 to 9 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. A bicyclic ring system consists of two rings that share one or two ring atoms in common. Examples of "heterocycloalkyl" include morpholinyl, pyridinyl, pyrrolidinyl, piperidinyl, piperidyl, azetidinyl, and piperazinyl. Specific examples of "heterocycloalkyl" are pyrrolidinyl, piperidinyl, piperidyl, and piperazinyl.

[0013] The terms "alkoxy" or "alkyloxy," alone or in combination, refer to the alkyl-O- group of the formula, while the term "alkyl" refers to the previously given meanings, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Specific examples of "alkoxy" are methoxy, ethoxy, and tert-butyloxy.

[0014] The term "oxy," either alone or in combination, refers to an -O- group.

[0015] The term "oxo," either alone or in combination, means an O group.

[0016] The term "sulfonyl," either alone or in combination, refers to the -SO2- group.

[0017] The term "cyano," either alone or in combination, refers to the -CN group.

[0018] The terms "halogen" or "halo," alone or in combination, mean fluorine, chlorine, bromine, or iodine, and more specifically fluorine, chlorine, or bromine. The term "halo," in combination with another group, means the substitution of the group by at least one halogen, more particularly 1 to 5 halogens, more particularly 1 to 4 halogens, i.e., the substitution of the group by 1, 2, 3 or 4 halogens.

[0019] The terms "hydroxyl" and "hydroxy" mean the -OH group, either alone or in combination.

[0020] The term "carbonyl," either alone or in combination, refers to a -C(O)- group.

[0021] The term "amino," either alone or in combination, refers to a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0022] The term "alkylamino" refers to an alkyl group bonded to an -NH- group, either alone or in combination. The term "dialkylamino" refers to two alkyl groups bonded to an -N- atom, either alone or in combination.

[0023] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid and is not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, particularly hydrochloric acid, as well as organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. Furthermore, these salts can be prepared by adding an inorganic base or an organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, and magnesium. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. Compounds of formula (I) can also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are salts of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

[0024] If one of the starting materials or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (e.g., those described in "Protective Groups in Organic Chemistry," 3rd edition, 1999, Wiley, New York, by TW Greene and PGMWuts) can be introduced before a critical step to which methods well known in the art are applied. Such protecting groups can be removed in later steps of the synthesis using standard methods described in the literature. Examples of protecting groups include tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0025] The compound of formula (I) may contain several chiral centers and may exist in the form of an optically pure enantiomer, a mixture of enantiomers such as a racemate, a mixture of diastereoisomers, a racemate of diastereoisomers, or a mixture of diastereoisomers and racemates.

[0026] The term "chiral carbon atom" refers to a carbon atom having four different substituents. According to the Kahn-Ingold-Prelogue priority rule, a chiral carbon atom can have an "R" or "S" stereoconfiguration.

[0027] Therefore, the present invention relates in particular to the following: The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-L is an alkoxycarbonylalkyl, alkoxycarbonyl heterocycloalkylalkyl, alkoxycarbonylaminoalkyl, phenylalkyl, alkoxycarbonyl(alkylamino)alkyl, alkylcarbonyl(alkylamino)alkyl, alkoxycarbonyl(alkylamino)alkylphenylalkyl, alkoxyalkylaminocarbonylalkyl, alkylcarbonyl heterocycloalkylalkyl, alkoxycarbonylaminoalkoxyalkoxyalkyl, phenylalkoxyalkyl, aminoalkoxyalkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonyl heterocycloalkylcarbonylalkyl, alkoxycarbonyl heterocycloalkylaminocarbonylalkyl, or alkoxycarbonyl(alkylamino)alkylaminocarbonylalkyl; The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-L is an alkoxycarbonylalkyl, alkoxycarbonylpiperidinylalkyl, alkoxycarbonylpiperazinylalkyl, alkoxycarbonylaminoalkyl, phenylalkyl, alkoxycarbonyl(alkylamino)alkyl, alkylcarbonyl(alkylamino)alkyl, alkoxycarbonyl(alkylamino)alkylphenylalkyl, alkoxyalkylaminocarbonylalkyl, alkylcarbonylpiperidinylalkyl, alkoxycarbonylaminoalkoxyalkoxyalkyl, phenylalkoxyalkyl, aminoalkoxyalkoxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylpiperazinylcarbonylalkyl, alkoxycarbonylpiperidinylaminocarbonylalkyl, or alkoxycarbonyl(alkylamino)alkylaminocarbonylalkyl; The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-L is tert-butyloxycarbonylpropyl, tert-butyloxycarbonylpiperidinylethyl, tert-butyloxycarbonylpiperidinylmethyl, tert-butyloxycarbonylpiperazinylethyl, tert-butyloxycarbonylaminopropyl, phenylpropyl, tert-butyloxycarbonyl(methylamino)propyl, methylcarbonyl(methylamino)propyl, tert-butyloxycarbonyl(methylamino)methylphenylpropyl, methoxyethylaminocarbonylmethyl, methylcarbonylpiperidinylmethyl, tert-butyloxycarbonylaminoethoxyethoxyethyl, phenylmethyloxyethyl, aminoethoxyethoxyethyl, hydroxycarbonylpropyl, tert-butyloxycarbonylpiperazinylcarbonylpropyl, tert-butyloxycarbonylpiperidinylaminocarbonylpropyl, or tert-butyloxycarbonyl(methylamino)ethylaminocarbonylpropyl; The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-L is an alkoxycarbonyl heterocycloalkylalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonyl(alkylamino)alkyl, alkylcarbonyl(alkylamino)alkyl, alkoxycarbonylaminoalkoxyalkoxyalkyl, alkoxycarbonyl heterocycloalkylcarbonylalkyl, alkoxycarbonyl heterocycloalkylaminocarbonylalkyl, or alkoxycarbonyl(alkylamino)alkylaminocarbonylalkyl; The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-L is an alkoxycarbonylpiperazinyl alkyl, an alkoxycarbonylaminoalkyl, an alkoxycarbonyl(alkylamino)alkyl, an alkylcarbonyl(alkylamino)alkyl, an alkoxycarbonylaminoalkoxyalkoxyalkyl, an alkoxycarbonylpiperazinylcarbonylalkyl, an alkoxycarbonylpiperidinylaminocarbonylalkyl, or an alkoxycarbonyl(alkylamino)alkylaminocarbonylalkyl; The compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1-L is tert-butyloxycarbonylpiperazinylethyl, tert-butyloxycarbonylaminopropyl, tert-butyloxycarbonyl(methylamino)propyl, methylcarbonyl(methylamino)propyl, tert-butyloxycarbonylaminoethoxyethoxyethyl, tert-butyloxycarbonylpiperazinylcarbonylpropyl, tert-butyloxycarbonylpiperidinylaminocarbonylpropyl, or tert-butyloxycarbonyl(methylamino)ethylaminocarbonylethyl; The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is an alkoxycarbonyl, alkoxycarbonyl heterocycloalkyl, alkoxycarbonylamino, phenyl, alkoxycarbonyl(alkylamino), alkylcarbonyl(alkylamino), alkoxycarbonyl(alkylamino)alkylphenyl, alkoxyalkylaminocarbonyl, alkylcarbonyl heterocycloalkyl, alkoxycarbonylaminoalkoxyalkoxy, phenylalkoxy, aminoalkoxyalkoxy, hydroxycarbonyl, alkoxycarbonyl heterocycloalkylcarbonyl, alkoxycarbonyl heterocycloalkylaminocarbonyl, or alkoxycarbonyl(alkylamino)alkylaminocarbonyl; The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is alkoxycarbonyl, alkoxycarbonylpiperidinyl, alkoxycarbonylpiperazinyl, alkoxycarbonylamino, phenyl, alkoxycarbonyl(alkylamino), alkylcarbonyl(alkylamino), alkoxycarbonyl(alkylamino)alkylphenyl, alkoxyalkylaminocarbonyl, alkylcarbonylpiperidinyl, alkoxycarbonylaminoalkoxyalkoxy, phenylalkoxy, aminoalkoxyalkoxy, hydroxycarbonyl, alkoxycarbonylpiperazinylcarbonyl, alkoxycarbonylpiperidinylaminocarbonyl, or alkoxycarbonyl(alkylamino)alkylaminocarbonyl; A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is an alkoxycarbonyl heterocycloalkyl, alkoxycarbonylamino, alkoxycarbonyl(alkylamino), alkylcarbonyl(alkylamino), alkoxycarbonylaminoalkoxyalkoxy, alkoxycarbonyl heterocycloalkylcarbonyl, alkoxycarbonyl heterocycloalkylaminocarbonyl, or alkoxycarbonyl(alkylamino)alkylaminocarbonyl; Compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R1 is tert-butyloxycarbonyl, tert-butyloxycarbonylpiperidinyl, tert-butyloxycarbonylpiperidinyl, tert-butyloxycarbonylpiperazinyl, tert-butyloxycarbonylamino, phenyl, tert-butyloxycarbonyl(methylamino), methylcarbonyl(methylamino), tert-butyloxycarbonyl(methylamino)methylphenyl, methoxyethylaminocarbonyl, methylcarbonylpiperidinyl, tert-butyloxycarbonylaminoethoxyethoxy, phenylmethyloxy, aminoethoxyethoxy, hydroxycarbonyl, tert-butyloxycarbonylpiperazinylcarbonyl, tert-butyloxycarbonylpiperidinylaminocarbonyl, or tert-butyloxycarbonyl(methylamino)ethylaminocarbonyl; The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is tert-butyloxycarbonylpiperazinyl, tert-butyloxycarbonylamino, tert-butyloxycarbonyl(methylamino), methylcarbonyl(methylamino), tert-butyloxycarbonylaminoethoxyethoxy, tert-butyloxycarbonylpiperazinylcarbonyl, tert-butyloxycarbonylpiperidinylaminocarbonyl, or tert-butyloxycarbonyl(methylamino)ethylaminocarbonyl; A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl; The compound according to formula (I) or a pharmaceutically acceptable salt thereof, wherein L is -(CH2)n-, where n = 1, 2 or 3; The compound according to formula (I) or a pharmaceutically acceptable salt thereof, wherein L is -(CH2)n-, where n = 2 or 3; R 2 and R 3 are independently selected from hydrogen, fluorine and cyano, the compound according to formula (I) or a pharmaceutically acceptable salt thereof; R 2 and R 3 are independently selected from fluorine and cyano, the compound according to formula (I) or a pharmaceutically acceptable salt thereof; R 2 and R 3 are independently selected from hydrogen and cyano, the compound according to formula (I) or a pharmaceutically acceptable salt thereof; R 2 and R 3 are independently selected from halogen and cyano, the compound according to formula (I) or a pharmaceutically acceptable salt thereof; R 2 is hydrogen or halogen, and R 3 is cyano, the compound according to formula (I) or a pharmaceutically acceptable salt thereof; R 2 is hydrogen or fluoro, and R 3 is cyano, the compound according to formula (I) or a pharmaceutically acceptable salt thereof; R 4 is ethyl(methylamino), (cyclopropyl)(methyl)amino, fluoropyrrolidinyl, pyrrolidinyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, butyl or piperidinyl, the compound according to formula (I) or a pharmaceutically acceptable salt thereof; R 4 is dialkylamino, (cycloalkyl)(alkyl)amino, halopyrrolidinyl, pyrrolidinyl, cycloalkyl, azetidinyl, alkyl, piperidinyl, the compound according to formula (I) or a pharmaceutically acceptable salt thereof; R 4The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is a dialkylamino, haloheterocycloalkyl, heterocycloalkyl, or cycloalkyl; The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein R4 is a dialkylamino, halopyrrolidinyl, pyrrolidinyl, azetidinyl, or cycloalkyl compound; R 4 The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is ethyl (methylamino), fluoropyrrolidinyl, pyrrolidinyl, azetidinyl, or cyclopentyl; The compound described in formula (I) or a pharmaceutically acceptable salt thereof, wherein R4 is fluoropyrrolidinyl; A is -O-, the compound described in formula (I) or a pharmaceutically acceptable salt thereof; A is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is -NH-.

[0028] The present invention further, tert-butyl 4-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]butanoate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[3-(azetidine-1-ylsulfonylamino)-2-cyano-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; N-[2-cyano-4-fluoro-3-[4-oxo-3-(3-phenylpropyl)quinazolin-6-yl]oxy-phenyl]cyclopentanesulfonamide; tert-butyl N-[3-[6-[2-cyano-3-(cyclohexylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-3-(cyclohexylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(1-piperidylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-carbamate; tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]-N-methylcarbamate; tert-butyl 4-[2-[6-[2-cyano-3-(cyclobutylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 3-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 3-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]-N-methylacetamide; tert-butyl 4-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-acetamide; tert-butyl 4-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl N-[[4-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]phenyl]methyl]-N-methylcarbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl N-[[4-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]phenyl]methyl]N-methyl-carbamate; 2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]-N-(2-methoxyethyl)acetamide; tert-butyl 4-[[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]methyl]piperidine-1-carboxylate; 3-[(1-acetyl-4-piperidyl)methyl]-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazoline; tert-butyl N-[2-[2-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]ethoxy]ethoxy]ethyl]carbamate; tert-butyl 4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]butanoate; (3R)-N-[3-[[3-(2-benzyloxyethyl)-4-oxoquinazolin-6-yl]amino]-2-cyanophenyl]-3-fluoropyrrolidine-1-sulfonamide; tert-butyl 4-[2-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]ethyl]piperidine-1-carboxylate; 3-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazoline; 4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]butanoic acid; tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoyl]piperazine-1-carboxylate; tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoylamino]piperidine-1-carboxylate; tert-butyl 4-[6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]butanoate; tert-butyl N-[3-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]propyl]carbamate; (3R)-N-[2-cyano-3-[[4-oxo-3-(3-phenylpropyl)quinazolin-6-yl]amino]phenyl]-3-fluoropyrrolidine-1-sulfonamide; tert-butyl N-[2-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazolin-3-yl]butanoylamino]ethyl]-N-methyl-carbamate; and tert-butyl 4-[2-[6-[2-cyano-3-(pyrrolidine-1-ylsulfonylamino)anilino]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate The invention relates to compounds of formula (I) selected from; or pharmaceutically acceptable salts thereof.

[0029] The present invention further, tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[3-(azetidine-1-ylsulfonylamino)-2-cyano-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-carbamate; tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]-N-methylcarbamate; N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]-N-methylacetamide; tert-butyl 4-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-acetamide; tert-butyl 4-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl N-[2-[2-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]ethoxy]ethoxy]ethyl]carbamate; tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoyl]piperazine-1-carboxylate; tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoylamino]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]propyl]carbamate; and tert-butyl N-[2-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoylamino]ethyl]-N-methyl-carbamate The invention relates to compounds of formula (I) selected from; or pharmaceutically acceptable salts thereof.

[0030] The present invention further relates to a compound of formula (I) which is (3R)-N-[2-cyano-3-[[4-oxo-3-(3-phenylpropyl)quinazolin-6-yl]amino]phenyl]-3-fluoropyrrolidine-1-sulfonamide or a pharmaceutically acceptable salt thereof.

[0031] The present invention further, tert-butyl 4-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]butanoate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[3-(azetidine-1-ylsulfonylamino)-2-cyano-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; N-[2-cyano-4-fluoro-3-[4-oxo-3-(3-phenylpropyl)quinazolin-6-yl]oxy-phenyl]cyclopentanesulfonamide; tert-butyl N-[3-[6-[2-cyano-3-(cyclohexylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-3-(cyclohexylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(1-piperidylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-carbamate; tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]-N-methylcarbamate; tert-butyl 4-[2-[6-[2-cyano-3-(cyclobutylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 3-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 3-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]-N-methylacetamide; tert-butyl 4-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-acetamide; tert-butyl 4-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl N-[[4-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]phenyl]methyl]-N-methylcarbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl N-[[4-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]phenyl]methyl]N-methyl-carbamate; tert-butyl 4-[[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]methyl]piperidine-1-carboxylate; 3-[(1-acetyl-4-piperidyl)methyl]-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazoline; tert-butyl N-[2-[2-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]ethoxy]ethoxy]ethyl]carbamate; tert-butyl 4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]butanoate; (3R)-N-[3-[[3-(2-benzyloxyethyl)-4-oxoquinazolin-6-yl]amino]-2-cyanophenyl]-3-fluoropyrrolidine-1-sulfonamide; tert-butyl 4-[2-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoyl]piperazine-1-carboxylate; tert-butyl 4-[6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]butanoate; tert-butyl N-[3-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]propyl]carbamate; (3R)-N-[2-cyano-3-[[4-oxo-3-(3-phenylpropyl)quinazolin-6-yl]amino]phenyl]-3-fluoropyrrolidine-1-sulfonamide; tert-butyl N-[2-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazolin-3-yl]butanoylamino]ethyl]-N-methyl-carbamate; and tert-butyl 4-[2-[6-[2-cyano-3-(pyrrolidine-1-ylsulfonylamino)anilino]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate The invention relates to compounds of formula (I) selected from; or pharmaceutically acceptable salts thereof.

[0032] The compounds of formula (I) of the present invention can be prepared by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The techniques necessary for the reaction and purification of the resulting products are known to those skilled in the art. If a mixture of enantiomers or diastereoisomers is formed during the reaction, these enantiomers or diastereoisomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization. The substituents and indices used in the following descriptions of the methods have the meanings set forth herein.

[0033] Compounds of formula (I) where A is -O- can be prepared by the reaction of aryl fluoride A with sulfonamide or sulfamide B in a solvent such as DMF or NMP in the presence of a base such as Cs2CO3 or NaH (Scheme 1).

[0034] In scheme 1 of TIFF0007877320000002.tif45170, L, R 1 , R 2 , R 3 and R 4 This is as defined above.

[0035] Compounds of formula (I) where A is -NH- can be prepared by the reaction of a bromide of formula C with aniline D in the presence of a base such as Cs2CO3, a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0), and a ligand such as BippyPhos in a solvent such as dioxane (Scheme 2).

[0036] In scheme 2 of TIFF0007877320000003.tif39170, L, R 1 , R 2 , R 3 and R 4 This is as defined above.

[0037] Compounds of formula (I) where A is -NH- can also be prepared by the reaction of an amine of formula E with a sulfonyl or sulfamoyl chloride F in a solvent such as DCM and in the presence of a base such as pyridine (Scheme 3).

[0038] In scheme 3 of TIFF0007877320000004.tif45170, L, R 1 , R 2 , R 3 and R 4 This is as defined above.

[0039] In some cases, the compound of formula (I) can be prepared by further modifying the compound prepared as described in schemes 1-3. In particular, R 1 Compound G, which contains a protecting group (PG) bonded to a carboxylic acid ester and further bonded to a quinazolinone by an alkyl linker L, can be hydrolyzed to obtain the corresponding acid H, which can be coupled with an amine to obtain a compound of formula (Ia) containing an amide (Scheme 4). Reagents and conditions for the hydrolysis of carboxylic acid esters are described in detail, for example, in "Protective Groups in Organic Chemistry," by T.W. Greene and P.G.W. Mutts, 5th edition, 2014, John Wiley & Sons, New York. Reagents and conditions for amide coupling are described in detail, for example, in A. El-Faham and F. Albericio, Chem. Rev. 2011, 111(11), 6557-6602.

[0040] In scheme 4 of TIFF0007877320000005.tif65170, L, A, R 2 , R 3 and R 4 The above definitions apply; Ra is an alkoxyalkyl, alkoxycarbonyl heterocycloalkyl, or alkoxycarbonyl(alkylamino)alkyl; and Rb is hydrogen.

[0041] Alternatively, R 1 In compound I, which contains a protected amine bonded to quinazolinone by linker L, deprotection yields a free amine or its salt J, which can be converted to an amide compound of formula (Ib) by standard procedures (e.g., reaction with an acid anhydride, or reaction with a carboxylic acid and an activator) (Scheme 5).

[0042] In scheme 5 of TIFF0007877320000006.tif70170, L, A, R 2 , R 3 and R 4Rc is as defined above; Rc is hydrogen or alkyl; Rd is alkoxy or alkyl.

[0043] General synthesis of intermediates Intermediate A can be prepared by the reaction of 6-hydroxyquinazolin-4-one K with fluorobenzonitrile L in a solvent such as DMF or NMP in the presence of a base such as NaH or Cs2CO3 (Scheme 6).

[0044] In scheme 6 of TIFF0007877320000007.tif39170, L, R 1 , R 2 and R 3 This is as defined above.

[0045] The 6-hydroxyquinazolin-4-one intermediate K (if not commercially available) can be prepared by various routes. In some examples (Scheme 7), 6-hydroxyquinazolin-4-one K can be prepared from 2-amino-5-hydroxybenzoic acid and formamide, for example, by heating in the absence of a solvent. This intermediate M can be further derivatized as an acetate ester N by protecting the hydroxyl group under standard conditions such as the use of acetic anhydride, DMAP, and triethylamine in DCM. Subsequently, alkylation over nitrogen with a suitable alkyl halide using a base such as Cs2CO3 in a solvent such as DMF yields O, followed by deprotection with an aqueous solution of the base to obtain the desired intermediate K.

[0046] In scheme 7 of TIFF0007877320000008.tif72170, L and R 1 This is as defined above.

[0047] Intermediate C can be prepared by alkylating commercially available 6-bromo-3H-quinazolin-4-one in a solvent such as DMF in the presence of a base such as Cs2CO3. Subsequently, bromide C can be converted to alcohol K by treatment with a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0), a ligand such as tBuXPhos, an aqueous solution of a base such as aqueous KOH, and a solvent such as dioxane (Scheme 8).

[0048] In scheme 8 of TIFF0007877320000009.tif41170, L and R 1 This is as defined above.

[0049] If the desired alkyl halide, as shown in Scheme 8, is not commercially available, it can be prepared by various methods known to those skilled in the art. In one example (Scheme 9), a commercially available tert-butyl 3-(4-cyanophenyl)propanoate is reduced to the corresponding amine using hydrogen and palladium catalysts, and then protected with a protecting group such as Boc under standard conditions such as di-tert-butyl dicarbonate in a solvent such as DCM. Nitrogen can be alkylated by treatment with an alkyl halide such as methyl iodide in a solvent such as DMF in the presence of a base such as NaH. The ester is reduced to an alcohol using a reducing agent such as LiBH4 in a solvent such as THF, and then the alcohol is brominated using triphenylphosphine and carbon tetrabromide in a solvent such as DCM to obtain intermediate P.

[0050] Intermediate D can be prepared by reacting 2,6-dinitrobenzonitrile Q with sulfamide B in a solvent such as DMF in the presence of a base such as Cs2CO3 to obtain R, and then reducing it to D by catalytic hydrogenation using a catalyst such as Perlman's catalyst (Scheme 10).

[0051] In scheme 10 of TIFF0007877320000011.tif46170, R2 and R 4 This is as defined above.

[0052] Intermediate E, in which A is -NH-, can also be prepared by the reaction of bromide C with 2,6-diaminobenzonitrile S in a solvent such as dioxane, in the presence of a base such as Cs2CO3, a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0), and a ligand such as BippyPhos (Scheme 11).

[0053] In scheme 11 of TIFF0007877320000012.tif46170, L, R 1 and R 2 This is as defined above.

[0054] R 4 If intermediate B, which is of the NReRf type (i.e., sulfamide), is not commercially available, it can be prepared by the reaction of a sulfodiamide with amine T in dioxane, in or without the presence of a base such as triethylamine (Scheme 12).

[0055] In scheme 12 of TIFF0007877320000013.tif37170, Re is alkyl or cycloalkyl, and Rf is alkyl; or Re and Rf together with the N atom to which they are bonded form a heterocycloalkyl, where the heterocycloalkyl is optionally substituted with a halogen.

[0056] R 4 If intermediate B, which is of the CHRgRh type (i.e., sulfonamide), is not commercially available, it can be prepared from the corresponding sulfonyl chloride U by reaction with aqueous ammonia (Scheme 13).

[0057] In scheme 13 of TIFF0007877320000014.tif34170, Rg is alkyl or cycloalkyl, and Rh is alkyl; or Rg and Rh together with the carbon atom to which they are bonded form a cycloalkyl.

[0058] Therefore, the present invention relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) Compound of formula (A1) in the presence of a base TIFF0007877320000015.tif28170 and the compound of formula (A2) Reaction to TIFF0007877320000016.tif23170; (b) Compound of formula (B1) in the presence of a base, a palladium catalyst, and a suitable ligand. TIFF0007877320000017.tif28170 and the compound of formula (B2) Reaction to TIFF0007877320000018.tif28170; (c) Compound of formula (C1) in the presence of a base TIFF0007877320000019.tif28170 and the compound of formula (C2) Reaction with TIFF0007877320000020.tif23170 (In the above formula, L, R 1 , R 2 , R 3 and R 4 (As stipulated above) This concerns a method that includes one of the following.

[0059] The reaction in step (a) can be conveniently carried out in a solvent. The solvent may be, for example, DMF, DMF, or a mixture thereof.

[0060] In the reaction of step (a), the base may be, for example, triethylamine, DIPEA, Cs2CO3, or NaH. Conveniently, the base is Cs2CO3 or NaH.

[0061] The conditions favorable for the reaction in step (a) may be between approximately 0°C and 100°C, particularly between approximately 20°C and 80°C, and more specifically between approximately 40°C and 60°C.

[0062] The preferred conditions for the reaction in step (a) are to use DMF and Cs2CO3 or NMP and NaH at approximately 50°C for approximately 10 minutes to approximately 5 hours, and especially for approximately 15 minutes to approximately 1 hour.

[0063] The reaction in step (b) can be conveniently carried out in a solvent. The solvent may be, for example, dioxane.

[0064] In the reaction of step (b), the base may be, for example, Cs2CO3.

[0065] The conditions favorable for the reaction in step (b) may be between approximately 60°C and 160°C, particularly between approximately 80°C and 140°C, and more specifically between approximately 100°C and 120°C.

[0066] The preferred conditions for the reaction in step (b) are to use dioxane NMP and Cs2CO3 at approximately 110°C for approximately 30 minutes to approximately 10 hours, and especially for approximately 1 hour to approximately 4 hours.

[0067] The reaction in step (c) can be conveniently carried out in a solvent. The solvent may be, for example, DCM.

[0068] In the reaction of step (c), the base may be, for example, triethylamine, DIPEA, or pyridine. Conveniently, the base is pyridine.

[0069] The conditions favorable for the reaction in step (c) may be between approximately 10°C and 130°C, particularly between approximately 30°C and 110°C, and more specifically between approximately 50°C and 90°C.

[0070] The preferred conditions for the reaction in step (c) are to use DCM and pyridine at approximately 70°C for approximately 1 to 30 hours, and especially for approximately 12 to 22 hours.

[0071] The present invention also relates to compounds according to the present invention when produced according to the method of the present invention.

[0072] Another embodiment of the present invention provides a pharmaceutical composition or medicine containing the compound of the present invention and a therapeutically inert carrier, diluent, or additive, as well as a method of using the compound of the present invention to prepare such compositions and medicines. In one example, the compound of formula (I) can be formulated by mixing it with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at doses and concentrations adopted in the dosage form of herbal medicine, at ambient temperature, appropriate pH, and desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0073] The composition shall be formulated, administered, and given in a manner consistent with appropriate medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disorder, the site of drug delivery, the method of administration, the schedule of administration, and other factors known to the healthcare professional.

[0074] The compounds of the present invention may be administered by any suitable means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, subarachnoidally, epidurally, and intranasally, and, if topical treatment is desired, intra-focal administration. Parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneally, or subcutaneously.

[0075] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, and patches. Such compositions may contain elements common in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further active agents.

[0076] Typical formulations are prepared by mixing the compound of the present invention with a carrier or additive. Suitable carriers and additives are well known to those skilled in the art and are described in detail, for example, Ansel, Howard 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, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, flow enhancers, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide accurate presentation of a drug (i.e., the compound or its pharmaceutical composition) or to assist in the manufacture of a pharmaceutical product (i.e., a medicine).

[0077] The present invention also relates in particular to the following: Compounds of formula (I) or pharmaceutically acceptable salts thereof for use as therapeutic agents; A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier; Use of compounds of formula (I) or pharmaceutically acceptable salts thereof for the treatment or prevention of cancer, particularly melanoma or non-small cell lung cancer (NSCLC); Use of compounds of formula (I) or pharmaceutically acceptable salts thereof for the preparation of medicines for the treatment or prevention of cancer, particularly melanoma or non-small cell lung cancer (NSCLC); Compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment or prevention of cancer, particularly melanoma or non-small cell lung cancer (NSCLC); and A method for the treatment of cancer, particularly melanoma or non-small cell lung cancer (NSCLC), comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0078] Specific embodiments of the present invention relate to compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of cancers characterized by BRAF mutations selected from V600E and V600K, particularly melanoma or NSCLC.

[0079] A particular embodiment of the present invention relates to a method for the treatment or prevention of cancer, particularly melanoma or NSCLC, in which a BRAF mutation selected from V600E and V600K is present in the cancer, wherein the method comprises administering an effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof to a patient in need.

[0080] Furthermore, the present invention includes, where applicable, all substituents of the corresponding deuterated form of the compound of formula (I).

[0081] Furthermore, the present invention includes, where applicable, the corresponding carboxylic acid in the ester form of the compound of formula (I).

[0082] Furthermore, the present invention includes, where applicable, all optical isomers of the compounds of formula (I), namely diastereoisomers, diastereoisomer mixtures, racemic mixtures, all their corresponding enantiomers, and / or tautomers, as well as solvated compounds thereof.

[0083] Next, the present invention will be described by the following embodiments, but these embodiments are not limiting. [Examples]

[0084] Examples Abbreviation BOC = tert-butyloxycarbonyl; CAS = Chemical Abstract Service; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMF = dimethylformamide; DMAP = dimethylaminopyridine; DMSO = dimethyl sulfoxide; ESI = electrospray ionization; Ã = ethyl acetate; HATU = azabenzotriazoletetramethyluronium hexafluorophosphate; HPLC = high-performance liquid chromatography; MeOH = methanol; MS = mass spectrometry; NMP = N-methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; rt = room temperature; SFC = supercritical fluid chromatography; THF = tetrahydrofuran.

[0085] Intermediate A (IA) IA1: tert-butyl 4-(6-hydroxy-4-oxoquinazolin-3-yl)butanoate TIFF0007877320000021.tif23170

[0086] Step 1: 6-Hydroxy-3H-Quinazolin-4-one TIFF0007877320000022.tif221702-amino-5-hydroxybenzoic acid (5.0 g, 32.7 mmol, equivalent: 1.0) and formamide (11.3 g, 10 mL, 251 mmol, equivalent: 7.7) were heated in a sealed tube at 165°C for 1 hour, and then cooled to room temperature. The reaction mixture was diluted with 35 mL of water and stirred at room temperature for approximately 30 minutes. The resulting precipitate was collected by filtration, and the gray solid was washed three times with 10 mL of water and twice with 6 mL of diethyl ether. The solid was dissolved in toluene and evaporated (three times), and then vacuum-dried overnight at 40°C under high vacuum to obtain the title compound as a gray solid (4.92 g, yield 93%). MS(ESI):163.1[M+H] + .

[0087] Step 2: (4-oxo-3H-quinazoline-6-yl)acetate In 40 mL of DCM, a suspension of 6-hydroxyquinazoline-4(3H)-one (1.0 g, 6.17 mmol, equivalent: 1.0) and triethylamine (125 mg, 172 μL, 1.23 mmol, equivalent: 0.2) was prepared by adding acetic anhydride (1.84 g, 1.7 mL, 18 mmol, equivalent: 2.92) and DMAP (23.1 mg, 185 μmol, equivalent: 0.03) at 0°C. The reaction mixture was warmed to room temperature, stirred for 20 hours and 45 minutes, and then concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a white solid by purification by flash chromatography (40 g silica, heptane with 0-60% siRNA, followed by 0-11% MeOH in DCM) (711 mg, yield 57%). MS(ESI): 205.1[M+H] + .

[0088] Step 3: tert-butyl 4-(6-acetoxy-4-oxoquinazolin-3-yl)butanoate In a three-necked flask, (4-oxo-3H-quinazolin-6-yl)acetate (200 mg, 980 μmol, equivalent: 1.0) and Cs2CO3 (479 mg, 1.47 mmol, equivalent: 1.5) were combined with DMF (5 mL) to obtain a brown suspension. Then, tert-butyl 4-bromobutanoate (334 mg, 1.47 mmol, equivalent: 1.5) was added at room temperature. The reaction mixture was stirred at room temperature for 14.5 hours and then concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a colorless viscous oil (250 mg, yield 74%) by purification by flash chromatography (40 g silica, heptane with 0-90% siRNA). MS(ESI):347.2[M+H] + .

[0089] Step 4: tert-butyl 4-(6-hydroxy-4-oxo-quinazolin-3-yl)butanoate LiOH (1M aqueous solution, 617 μL, 617 μmol, equivalent: 1.8) was added dropwise to a solution of tert-butyl 4-(6-acetoxy-4-oxoquinazoline-3(4H)-yl)butanoate (118.8 mg, 343 μmol, equivalent: 1.0) in THF (2 mL) at room temperature under an argon atmosphere. The mixture was stirred at room temperature for 1.5 hours, and then LiOH (1M aqueous solution, 137 μL, 137 μmol, equivalent: 0.4) was added. The mixture was stirred at room temperature for 1 hour and 50 minutes, and then LiOH (1M aqueous solution, 137 μL, 137 μmol, equivalent: 0.4) was added. The mixture was stirred at room temperature for 1 hour, and then diluted with 5 mL of water and 15 mL of SiO2. HCl (0.5 M aqueous solution, 1.78 mL, 892 μmol, equivalent: 2.6) was added, and the organic layer was extracted again with 15 mL of siRNA. The combined organic layers were washed once with brine, dried over Na2SO4, filtered, and the solvent was evaporated. The residue was dried under high vacuum to obtain the title compound as a white solid (104 mg, yield 97%). MS(ESI): 305.2[M+H] + .

[0090] IA2: tert-butyl 4-[2-(6-hydroxy-4-oxoquinazoline-3-yl)ethyl]piperidine-1-carboxylate TIFF0007877320000026.tif28170

[0091] Step 1: tert-butyl 4-[2-(6-bromo-4-oxoquinazolin-3-yl)ethyl]piperidine-1-carboxylate TIFF0007877320000027.tif291706-bromoquinazoline-4(3H)-one (1.0 g, 4.44 mmol, equivalent: 1.0) and Cs2CO3 (1.74 g, 5.33 mmol, equivalent: 1.2) were combined with DMF (20 mL), and then tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (1.61 g, 5.33 mmol, equivalent: 1.2) was added at room temperature. The reaction mixture was stirred at room temperature for 15 hours and 40 minutes, and then concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a colorless viscous oil by purification by flash chromatography (80 g silica, heptane with 0-100% siRNA) (1.83 g, yield 94%). MS(ESI)m / z:336.1[M+H-Boc] + .

[0092] Step 2: tert-butyl 4-[2-(6-hydroxy-4-oxoquinazoline-3-yl)ethyl]piperidine-1-carboxylate In a microwave vial under argon, KOH (637 mg, 9.76 mmol, equivalent: 4.0) was dissolved in water (15 mL), and then dioxane (20 mL) was added. The mixture was flushed with argon, and then tBuXPhos (64.1 mg, 146 μmol, equivalent: 0.06), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (75.8 mg, 73.2 μmol, equivalent: 0.03), and tert-butyl 4-[2]-(6-bromo-4-oxoquinazolin-3-yl)ethyl]piperidine-1-carboxylate (1065 mg, 2.44 mmol, equivalent: 1.0) were added. Argon was blown into the reaction mixture, and the vial was closed. The reaction mixture was heated to 105°C for 1 hour and 30 minutes, then cooled to room temperature. The reaction mixture was diluted with 25 mL of water and extracted three times with diethyl ether. The combined organic layers were washed with 25 mL of water. The combined aqueous layer was acidified with HCl (0.5 M aqueous solution, 19.5 mL, 9.76 mmol, equivalent: 4.0) and extracted twice with ethyl acetate. The combined ethyl acetate layer was washed once with brine, dried over Na₂SO₄, filtered, and the solvent was evaporated. The residue was dried under high vacuum to obtain the title compound as a light brown solid (880 mg, yield 97%). MS(ESI)m / z: 372.3[MH] - .

[0093] The following intermediate A(IA) was prepared in step 1 using a suitable bromide reagent in a manner similar to that of intermediate IA3. TIFF0007877320000029.tif140170

[0094] IA8: tert-butyl N-[[4-[3-(6-hydroxy-4-oxoquinazoline-3-yl)propyl]phenyl]methyl]-N-methyl-carbamate TIFF0007877320000030.tif27170

[0095] Step 1: tert-butyl 3-[4-[(tert-butoxycarbonylamino)methyl]phenyl]propanoate TIFF0007877320000031.tif28170tert-butyl 3-(4-cyanophenyl)propanoate (2.43 g, 10.5 mmol, equivalent: 1.0) was dissolved in methanol (104 mL), THF (43.4 mL), and acetic acid (8.7 mL) in an autoclave. Palladium-carbon (10% supported, Degussa type E101, 782 mg, 735 μmol, equivalent: 0.07) was added, and the reaction mixture was stirred under a hydrogen atmosphere (3 bar) at room temperature for 1 hour. The reaction mixture was filtered (dicholite), the solvent was evaporated, and the crude product was dried. The residue was dissolved in siRNA, washed with a saturated aqueous NaHCO3 solution, the aqueous layer (pH 7) was extracted twice with siRNA, the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to obtain a pale yellow viscous oil (2.24 g), which was used in the next step without purification. 1 H NMR(300MHz,CHLOROFORM-d) δ ppm 1.42(s,9H) 2.46-2.60(m,2H) 2.83-2.97(m,2H) 3.84(s,2H) 7.06-7.26(m,4H).

[0096] To a solution of 2.24 g of presumed tert-butyl 3-[4-(aminomethyl)phenyl]propanoate in 45 mL of DCM, di-tert-butyl dicarbonate (2.24 g, 10.3 mmol, equivalent: 1.35) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours and 45 minutes, and then washed with saturated aqueous NaHCO3 solution. The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was diluted with ethyl acetate and purified by flash chromatography (Isco CombiFlash Companion, SILICYCLE FLH-R10017B-ISO80, SiliaSep TM, HP 80 g, containing 0%-15% ethyl acetate in heptane) to obtain the title compound as a colorless viscous oil (2.21 g, yield 63%). 1H NMR(300MHz,CHLOROFORM-d) δ ppm 1.42(s,9H) 1.46(s,9H) 2.42-2.64(m,2H) 2.78-3.01(m,2H) 4.28(br d,J=5.6Hz,2H) 4.59-5.02(m,1H) 7.12-7.24(m,4H).

[0097] Step 2: tert-butyl 3-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]propanoate TIFF0007877320000032.tif26170 A clear solution of tert-butyl 3-[4-[(tert-butoxycarbonylamino)methyl]phenyl]propanoate (800 mg, 2.38 mmol, equivalent: 1.0) in 16 mL of DMF was mixed with NaH (60% in mineral oil, 238 mg, 5.96 mmol, equivalent: 2.5) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes, then cooled again to 0°C, and methyl iodide (1.35 g, 596 μL, 9.54 mmol, equivalent: 4.0) was added. The reaction mixture was stirred at 0°C for 15 minutes, then warmed to room temperature. After 30 minutes, the reaction mixture was cooled to 0°C, and saturated aqueous NH4Cl was carefully added to the reaction mixture (dropwise), followed by extraction with RINKAN. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound as a pale yellow oil (889 mg, purity 94%, yield 100%). MS(ESI)m / z:292.2[MH-C4H8] - .

[0098] Step 3: tert-butyl N-[[4-(3-hydroxypropyl)phenyl]methyl]-N-methyl-carbamate TIFF0007877320000033.tif21170 Tert-butyl 3-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]propanoate (597 mg, 1.71 mmol, equivalent: 1.0) was dissolved in THF (11 mL). LiBH4 (2 M in THF, 2.56 mL, 5.12 mmol, equivalent: 3.0) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 20 minutes, the reaction mixture was cooled to 0°C, and then ethanol (472 mg, 598 μL, 10.2 mmol, equivalent: 6.0) was added dropwise. The reaction mixture was stirred at 0°C for 30 minutes, and then stirred at room temperature for 4.5 hours. The reaction mixture was cooled to 0°C, and LiBH4 (2 M in THF, 427 μL, 854 μmol, equivalent: 0.5) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours and 15 minutes, then cooled to 0°C and carefully quenched with saturated NH4Cl aqueous solution. The mixture was extracted twice with siRNA. The combined organic layer was washed once with brine, then dried over Na2SO4, filtered, and concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. Purification by flash chromatography (40 g silica, heptane with 0-75% siRNA) yielded the title compound as a colorless, viscous oil (437 mg, 92% yield). MS(ESI) m / z: 224.2 [M+H-C4H8] + .

[0099] Step 4: tert-butyl N-[[4-(3-bromopropyl)phenyl]methyl]-N-methyl-carbamate In a three-necked flask, triphenylphosphine (883 mg, 3.27 mmol, equivalent: 2.1) was dissolved in DCM (3 mL). At 0°C, a solution of carbon tetrabromide (1.11 g, 3.27 mmol, equivalent: 2.1) in DCM (3 mL) was added dropwise, followed by a solution of tert-butyl N-[[4-(3-hydroxypropyl)phenyl]methyl]-N-methyl-carbamate (435 mg, 1.56 mmol, equivalent: 1.0) in DCM (6 mL). The reaction mixture was warmed to room temperature over 17 hours, then diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a colorless, viscous oil (256 mg, 48% yield) by purification using flash chromatography (containing 0-20% toluene in 40 g of silica and heptane). MS(ESI)m / z:286.1,288.1[M+H-C4H8] + .

[0100] Step 5: tert-butyl N-[[4-[3-(6-bromo-4-oxoquinazoline-3-yl)propyl]phenyl]methyl]-N-methyl-carbamate TIFF0007877320000035.tif26170tert-butyl N-[[4-(3-bromopropyl)phenyl]methyl]-N-methyl-carbamate (253 mg, 740 μmol, equivalent: 1.2), 6-bromoquinazoline-4(3H)-one (146 mg, 616 μmol, equivalent: 1.0), and Cs2CO3 (241 mg, 740 μmol, equivalent: 1.2) were combined with DMF (7 mL) to obtain a white suspension. The reaction mixture was stirred at room temperature for 15 hours and 45 minutes, and then concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a white foam (289 mg, yield 97%) by purification by flash chromatography (40 g silica, heptane with 0-67% ethyl phosphate). MS(ESI)m / z:486.3,488.3[M+H] + .

[0101] Step 6: tert-butyl N-[[4-[3-(6-hydroxy-4-oxoquinazoline-3-yl)propyl]phenyl]methyl]-N-methyl-carbamate In a microwave vial under argon, KOH (152 mg, 2.33 mmol, equivalent: 4.0) was dissolved in water (3.5 mL), and then dioxane (5 mL) was added. The mixture was flushed with argon, and then tBuXPhos (15.3 mg, 35 μmol, equivalent: 0.06), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (18.1 mg, 17.5 μmol, equivalent: 0.03), and tert-butyl N-[[4-[3-(6)]-bromo-4-oxoquinazolin-3-yl)propyl]phenyl]methyl]-N-methyl-carbamate (283.7 mg, 583 μmol, equivalent: 1.0) were added. The reaction mixture was flushed again with argon, and the vial was closed. The reaction mixture was heated to 105°C, stirred for 1 hour, and then cooled to room temperature. The reaction mixture was diluted with 5 mL of water and extracted three times with diethyl ether. The organic layer was washed with 5 mL of water, and the combined aqueous layer was acidified with HCl (0.5 M aqueous solution, 4.67 mL, 2.33 mmol, equivalent: 4.0) and extracted twice with ethyl phosphate. The combined organic layer was washed once with brine, dried over Na2SO4, filtered, and the solvent was evaporated. The residue was dried under high vacuum to obtain the title compound as a light brown solid (226 mg, 91%). MS(ESI)m / z 424.4[M+H] + .

[0102] IA9:tert-butyl 4-[6-(2-cyano-3,6-difluorophenoxy)-4-oxoquinazolin-3-yl]butanoate TIFF0007877320000037.tif25170NaH (60% in mineral oil, 16.5 mg, 378 μmol, equivalent: 1.15) was added at 0°C to a solution of IA1 [tert-butyl 4-(6-hydroxy-4-oxinazolin-3(4H)-yl)butanoate] (100 mg, 329 μmol, equivalent: 1.0) in DMF (2 mL). The condenser was removed and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled again to 0°C and a solution of 2,3,6-trifluorobenzonitrile (52.7 mg, 329 μmol, equivalent: 1.0) in DMF (500 μL) was added. The mixture was stirred at room temperature for 45 minutes and then concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a white foam by purification using flash chromatography (0-100% SiO in 40 g silica and heptane) (114 mg, yield 79%). MS(ESI)m / z:442.3[M+H] + .

[0103] IA10: tert-butyl 4-[2-[6-(2-cyano-3,6-difluorophenoxy)-4-oxoquinazoline-3-yl]ethyl]piperidine-1-carboxylate TIFF0007877320000038.tif27170Cs2CO3 (892 mg, 2.71 mmol, equivalent: 1.15) was added at room temperature to a solution of IA2 [tert-butyl 4-(2-(6-hydroxy-4-oxoquinazoline-3(4H)-yl)ethyl)piperidine-1-carboxylate] (880 mg, 2.36 mmol, equivalent: 1.0) in DMF (20 mL). The mixture was stirred at room temperature for 30 minutes, and then a solution of 2,3,6-trifluorobenzonitrile (416 mg, 2.59 mmol, equivalent: 1.1) in DMF (6 mL) was added. The reaction mixture was stirred at room temperature for 2.5 hours, and then concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a viscous, colorless oil (1.13 g, 94% yield) by purification using flash chromatography (0-100% HCl in 40 g silica and heptane). MS(ESI)m / z:411.3[M+H-Boc] +.

[0104] The following intermediates were prepared using appropriate phenol reagents in a manner similar to that of intermediate IA10 (yield 76%–85%). TIFF0007877320000039.tif233170

[0105] Intermediate B (IB) IB1: 1-amino-2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]benzene TIFF0007877320000040.tif27170

[0106] Step 1: 2-Cyano-1-[[ethyl(methyl)sulfamoyl]amino]-3-nitrobenzene TIFF0007877320000041.tif281702,6-dinitrobenzonitrile (1.46 g, 7.56 mmol, equivalent: 1.1) was dissolved in DMF (15 mL). Cs2CO3 (2.46 g, 7.56 mmol, equivalent: 1.1) and [methyl(sulfamoyl)amino]ethane (1 g, 6.87 mmol, equivalent: 1.0) were added. The reaction mixture was stirred at 65°C for 2 hours and then concentrated under vacuum. The residue was dissolved in 2-methyl-THF, washed with water-brine solution, and the aqueous layer was extracted twice with 2-methyl-THF. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a pale red, viscous oil (720 mg, purity 77%) by purification using flash chromatography (40 g silica, 0-100% siRNA in DCM), and was used without further purification. MS(ESI)m / z:285.1[M+H] + .

[0107] Step 2: 1-amino-2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]benzene TIFF0007877320000042.tif271702-Cyano-1-[[ethyl(methyl)sulfamoyl]amino]-3-nitrobenzene (703 mg, 1.9 mmol, equivalent: 1.0) was dissolved in MeOH (17 mL) and THF (7 mL), then Pd(OH)2 (Perlman catalyst, 26.7 mg, 190 μmol, equivalent: 0.1) was added, and the reaction mixture was stirred at room temperature under a hydrogen balloon. After 1 hour, the reaction mixture was filtered through a Whatman Spartan 30 / 0.45 RC filter, and the filtrate was evaporated. The residue was diluted with siRNA and transferred to a column. The title compound was obtained as a viscous orange oil by purification by flash chromatography (0-68% siRNA in 80 g silica and heptane) (457 mg, 100% purity, 27% yield over two steps). MS(ESI)m / z:255.1[M+H] + .

[0108] IB2:(3R)-N-(3-amino-2-cyanophenyl)-3-fluoropyrrolidine-1-sulfonamide TIFF0007877320000043.tif35170

[0109] Step 1: (3R)-N-(2-cyano-3-nitrophenyl)-3-fluoropyrrolidine-1-sulfonamide TIFF0007877320000044.tif341702,6-dinitrobenzonitrile (900 mg, 4.66 mmol, equivalent: 1.0) was dissolved in DMF (10 mL). Cs2CO3 (2.28 g, 6.99 mmol, equivalent: 1.5) and intermediate IC1 (1.18 g, 6.99 mmol, equivalent: 1.5) were added. The reaction mixture was stirred at 60°C for 1 hour and then concentrated under vacuum. The residue was dissolved in 2-methyl-THF, washed with NH4Cl aqueous solution, and the aqueous layer was extracted once with 2-methyl-THF. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a pale red, viscous oil (795 mg) by purification using flash chromatography (40 g silica, 0-100% toluene in DCM). MS(ESI)m / z:315.1[M+H] + .

[0110] Step 2: (3R)-N-(3-amino-2-cyanophenyl)-3-fluoropyrrolidine-1-sulfonamide TIFF0007877320000045.tif34170 (3R)-N-(2-cyano-3-nitro-phenyl)-3-fluoropyrrolidine-1-sulfonamide (751 mg, 2.39 mmol, equivalent: 1.0) was dissolved in MeOH (13 mL) and THF (6 mL), and then Pd(OH)2 (Perlman catalyst, 33.6 mg, 239 μmol, equivalent: 0.1) was added. The reaction mixture was stirred at room temperature under a hydrogen balloon. After 1 hour, the reaction mixture was filtered through a Whatman Spartan 30 / 0.45 RC filter, and the filtrate was evaporated. The residue was diluted with  and transferred to a column. The title compound was obtained as a viscous orange oil by purification by flash chromatography (80 g silica, 0-79%  in heptane) (560 mg, 100% purity, 42% yield over two steps). MS(ESI)m / z:285.1[M+H] + .

[0111] IB3: 1-Amino-2-Cyano-3-[[Cyclopropyl(methyl)sulfamoyl]amino]benzene TIFF0007877320000046.tif28170

[0112] Step 1: 2-Cyano-1-[[Cyclopropyl(methyl)sulfamoyl]amino]-3-nitrobenzene TIFF0007877320000047.tif271702,6-dinitrobenzonitrile (167 mg, 865 μmol, equivalent: 1.0) was dissolved in DMF (2 mL). Cs2CO3 (423 g, 1.3 mmol, equivalent: 1.5) and intermediate IC5 (195 mg, 1.3 mmol, equivalent: 1.5) were added. The reaction mixture was stirred at 60°C for 1 hour and then concentrated under vacuum. The residue was dissolved in 2-methyl-THF, washed with water-brine solution, and the aqueous layer was extracted twice with 2-methyl-THF. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a pale red solid (255 mg, purity approximately 65%) by purification by flash chromatography (40 g silica, 0-100% siRNA in DCM). MS(ESI)m / z:297.0[M+H] + .

[0113] Step 2: 1-amino-2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]benzene TIFF0007877320000048.tif251702-Cyano-1-[[Cyclopropyl(methyl)sulfamoyl]amino]-3-nitrobenzene (253 mg, 555 μmol, equivalent: 1.0) was dissolved in MeOH (4 mL) and THF (2 mL), then Pd(OH)2 (Perlman catalyst, 7.8 mg, 56 μmol, equivalent: 0.1) was added, and the reaction mixture was stirred at room temperature under a hydrogen balloon. After 2 hours and 10 minutes, the reaction mixture was filtered through a Whatman Spartan 30 / 0.45 RC filter, and the filtrate was evaporated. The residue was diluted with siRNA and transferred to a column. The title compound was obtained as an off-white solid by purification by flash chromatography (40 g silica, heptane with 0-69% siRNA) (101 mg, 100% purity, 44% yield over two steps). MS(ESI)m / z:267.1[M+H] + .

[0114] IB4:N-(3-amino-2-cyanophenyl)pyrrolidine-1-sulfonamide TIFF0007877320000049.tif27170

[0115] Step 1: N-(2-cyano-3-nitro-phenyl)pyrrolidine-1-sulfonamide TIFF0007877320000050.tif261702,6-dinitrobenzonitrile (1.00 g mg, 5.18 mmol, equivalent: 1.0) was dissolved in DMF (10 mL). Cs2CO3 (2.53 g, 7.77 mmol, equivalent: 1.5) and intermediate IC2 (1.17 mg, 7.77 mmol, equivalent: 1.5) were added. The reaction mixture was stirred at 60°C for 1 hour and then concentrated under vacuum. The residue was dissolved in 2-methyl-THF, washed with aqueous NH4Cl solution, and the aqueous layer was extracted once with 2-methyl-THF. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was suspended in 25 mL of siRNA, stirred at room temperature for 15 minutes, and then filtered. The filter cake was washed with 3 × 8 mL of Et2O and dried under vacuum to obtain the title compound as a red solid (380 mg). The filtrate was concentrated under vacuum, diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. Purification by flash chromatography (40 g silica, 0-100% siRNA in DCM) yielded the title compound as a red solid (642 mg, total yield 67%). MS(ESI) m / z: 297.1[M+H] + .

[0116] Step 2: N-(3-amino-2-cyanophenyl)pyrrolidine-1-sulfonamide N-(2-cyano-3-nitrophenyl)pyrrolidine-1-sulfonamide (614 mg, 2.07 mmol, equivalent: 1.0) was dissolved in MeOH (10 mL) and THF (5 mL), and then Pd(OH)2 (Perlman catalyst, 29.1 mg, 207 μmol, equivalent: 0.1) was added. The reaction mixture was stirred at room temperature under hydrogen balloon pressure. After 1 hour and 7 minutes, the reaction mixture was filtered through a Whatman Spartan 30 / 0.45 RC filter, and the filtrate was evaporated. The residue was diluted with siRNA and transferred to a column. Purification by flash chromatography (40 g silica, heptane with 0-67% siRNA) yielded the title compound as a pale yellow solid (374 mg, purity 100%, yield 68%). MS(ESI) m / z: 267.1[M+H] + .

[0117] IB5:2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]acetic acid TIFF0007877320000052.tif28170

[0118] Step 1: tert-butyl 2-(6-bromo-4-oxoquinazolin-3-yl)acetate TIFF0007877320000053.tif221706-bromoquinazoline-4(3H)-one (1.0 g, 4.44 mmol, equivalent: 1.0) and Cs2CO3 (2.17 g, 6.67 mmol, equivalent: 1.5) were combined with DMF (12 mL). Then, tert-butyl 2-bromoacetate (1.33 g, 997 μL, 6.67 mmol, equivalent: 1.5) was added at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and then concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a white solid by purification by flash chromatography (40 g silica, heptane with 0-60% siRNA) (1.26 g, purity 100%, yield 83%). MS(ESI)m / z:339.1,341.1[M+H] + .

[0119] Step 2: tert-butyl 2-[6-(3-amino-2-cyano-anilino)-4-oxo-quinazolin-3-yl]acetate In a vial (TIFF0007877320000054.tif26170), tert-butyl 2-(6-bromo-4-oxoquinazolin-3-yl) acetate (100 mg, 295 μmol, equivalent: 1.0) and 2,6-diaminobenzonitrile (39.3 mg, 295 μmol, equivalent: 1.0) were dissolved in dioxane (10 mL), and then Cs2CO3 (291 mg, 884 μmol, equivalent: 3.0) was added. The reaction mixture was flushed with argon, and then BippyPhos (9.23 mg, 17.7 μmol, equivalent: 0.06) and Tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (9.34 mg, 8.84 μmol, equivalent: 0.03) were added. The reaction mixture was flushed again with argon, and the vial was closed. The reaction mixture was stirred at 110°C for 2.5 hours. The reaction mixture was dissolved in 2-methyl-THF and ice, and washed with 1% aqueous citrate. The aqueous layer was back-extracted with 2-methyl-THF. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was diluted with ethyl acetate and transferred to a column. Purification by flash chromatography (a gradient of ethyl acetate in 40 g silica and heptane) yielded the title compound as a pale yellow solid (42 mg, purity 92%, yield 34%). MS(ESI) m / z: 392.3[M+H] + .

[0120] Step 3: tert-butyl 2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]acetate TIFF0007877320000055.tif23170tert-butyl 2-[6-(3-amino-2-cyanoanilino)-4-oxoquinazolin-3-yl]acetate (40.3 mg, 94.7 μmol, equivalent: 1.0) was suspended in DCM (600 μL). At room temperature, pyridine (345 mg, 351 μL, 4.36 mmol, equivalent: 46), DMAP (590 μg, 4.74 μmol, equivalent: 0.05), and N-ethyl-N-methylsulfamoyl chloride (29.9 mg, 23.4 μL, 189 μmol, equivalent: 2.0) were added. The reaction mixture was stirred at 70°C for 17 hours. The reaction mixture was dissolved in 2-methyl-THF, ice, and saturated NaHCO3 aqueous solution. The phases were separated, and the aqueous layer was back-extracted twice with 2-methyl-THF. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was diluted with DCM and transferred to a column. Purification by flash chromatography (0-100% ethyl phosphate in 80 g silica and heptane) yielded the title compound as a pale yellow foam containing approximately 10% of the starting material (tert-butyl 2-[6-(3-amino-2-cyano-anilino)-4-oxo-quinazolin-3-yl]acetate) (15 mg, yield 28%). MS(ESI) m / z: 513.3[M+H] + .

[0121] Step 4: 2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]acetic acid TIFF0007877320000056.tif26170tert-butyl 2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]acetate was suspended in DCM (850 μL), and then trifluoroacetic acid (90.1 mg, 60.5 μL, 790 μmol, equivalent: 30) was added at room temperature. The reaction mixture was stirred for 46 hours and then concentrated under vacuum to obtain the title compound as a light brown semi-solid (16.5 mg, purity 63%, yield 87%). MS(ESI)m / z:457.2[M+H] + .

[0122] IB6: tert-butyl 4-[(6-bromo-4-oxoquinazolin-3-yl)methyl]piperidine-1-carboxylate TIFF0007877320000057.tif261706-bromoquinazoline-4(3H)-one (1.08 g, 4.8 mmol, equivalent: 1.0) and Cs2CO3 (2.35 mg, 7.2 mmol, equivalent: 1.5) were combined with DMF (15 mL) to obtain a brown suspension. tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (2.0 g, 7.2 mmol, equivalent: 1.5) was added at room temperature, and the reaction mixture was stirred at room temperature for 68 hours. The concentrated residue was then diluted with DCM under vacuum, evaporated to dryness over silica gel, and transferred to a column. Purification by flash chromatography (40 g silica, heptane with 0-100% siRNA) yielded the title compound as a white solid (1.82 mg, yield 90%). MS(ESI)m / z:366.1,368.1[M+H-C4H8] + .

[0123] IB7: tert-butyl N-[2-[2-[2-(6-bromo-4-oxoquinazolin-3-yl)ethoxy]ethoxy]ethyl]carbamate Following the procedure described for intermediate IB6 in TIFF0007877320000058.tif21170, the title compound was obtained as a pale yellow viscous oil (136 mg, purity 100%, yield 89%) from 6-bromo-3H-quinazolin-4-one (75 mg, 333 μmol, equivalent: 1.0) and tert-butyl N-[2-[2-(2-bromoethoxy)ethoxy]ethyl]carbamate (114 mg, 367 μmol, equivalent: 1.1) after flash chromatography (eluent: SiO). MS(ESI)m / z:456.2,458.2[M+H] + .

[0124] IB8: tert-butyl 4-(6-bromo-4-oxoquinazoline-3-yl)butanoate Following the procedure described for intermediate IB6 in TIFF0007877320000059.tif21170, the title compound was obtained as a white solid (1.49 mg, purity 100%, yield 91%) from 6-bromo-3H-quinazolin-4-one (1.0 g mg, 4.44 mmol, equivalent: 1.0) and tert-butyl 4-bromobutanoate (1.52 g, 6.67 mmol, equivalent: 1.5) after flash chromatography (eluent: 0-69% SiO in heptane). MS(ESI)m / z:367.1,369.1[M+H] + .

[0125] IB9:3-(2-benzyloxyethyl)-6-bromoquinazoline-4-one Following the procedure described for intermediate IB6 in TIFF0007877320000060.tif24170, the title compound was obtained as a white solid (738 mg, purity 100%, yield 93%) from 6-bromo-3H-quinazolin-4-one (500 mg, 2.22 mmol, equivalent: 1.0) and 2-bromoethoxymethylbenzene (739 mg, 543 μL, 3.33 mmol, equivalent: 1.5) after flash chromatography (eluent: 0-77% siRNA in heptane). MS(ESI)m / z:359.1,361.1[M+H] + .

[0126] IB10: tert-butyl 4-[2-(6-bromo-4-oxoquinazoline-3-yl)ethyl]piperidine-1-carboxylate Following the procedure described for intermediate IB6 in TIFF0007877320000061.tif29170, the title compound was obtained as a white foam (171 mg, purity 100%, yield 88%) from 6-bromo-3H-quinazolin-4-one (100 mg, 444 μmol, equivalent: 1.0) and tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (201 mg, 667 μmol) by flash chromatography (eluent: 0-100% SiO2 in heptane). MS(ESI)m / z:380.1,382.1[M+H-C4H8] + .

[0127] IB11: tert-butyl N-[3-(6-bromo-4-oxoquinazolin-3-yl)propyl]carbamate Following the procedure described for intermediate IB6 in TIFF0007877320000062.tif22170, the title compound was obtained as a white foam (148 mg, purity 100%, yield 87%) from 6-bromo-3H-quinazolin-4-one (100 mg, 444 μmol, equivalent: 1.0) and tert-butyl(3-bromopropyl)carbamate (165 mg, 667 μmol, equivalent: 1.5) via flash chromatography (eluent: 0-100% SiO2 in heptane). MS(ESI)m / z:382.4,384.1[M+H] + .

[0128] IB12:6-Bromo-3-(3-phenylpropyl)quinazolin-4-one Following the procedure described for intermediate IB6 in TIFF0007877320000063.tif23170, the title compound was obtained as a white solid (689 mg, purity 100%, yield 90%) from 6-bromo-3H-quinazolin-4-one (500 mg, 2.22 mmol, equivalent: 1.0) and 3-bromopropylbenzene (677 mg, 517 μL, 3.33 mmol, equivalent: 1.5) after flash chromatography (eluent: 0-74.5% siRNA in heptane). MS(ESI)m / z:343.1,345.1[M+H] + .

[0129] Intermediate C (IC) IC1:(3R)-3-fluoropyrrolidine-1-sulfonamide TIFF0007877320000064.tif20170 (R)-3-Fluoropyrrolidine hydrochloride (1.8 g, 14.3 mmol, equivalent: 1.2) was added to a solution of diammonium sulfate (1.148 g, 11.9 mmol, equivalent: 1.0) and triethylamine (2.42 g, 3.33 mL, 23.9 mmol, equivalent: 2.0) in dioxane (10 mL). The reaction mixture was stirred in a sealed tube at 115 °C for 15.5 h, then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, evaporated to dryness on silica gel and transferred to a column. Purification by flash chromatography (40 g of silica, 80% EtOAc) afforded the title compound as a white crystalline solid (1.82 g, yield 91%). MS(ESI) m / z: 169.1 [M+H] + .

[0130] IC2: Pyrrolidine-1-sulfonamide TIFF0007877320000065.tif20170 Pyrrolidine (1.78 g, 2.07 mL, 25 mmol, equivalent: 1.2) was added to a solution of diammonium sulfate (2.0 g, 20.8 mmol, equivalent: 1.0) in dioxane (20 mL). The reaction mixture was stirred in a sealed tube at 115 °C for 15.5 h, then cooled to room temperature and concentrated in vacuo. The residue was diluted with MeOH, evaporated to dryness on silica gel and transferred to a column. Purification by flash chromatography (40 g of silica, 0 - 100% EtOAc in heptane) afforded the title compound as a white solid (2.5 g, yield 80%). MS(ESI) m / z: 151.1 [M+H] + .

[0131] IC3: Azetidine-1-sulfonamide Azetidine hydrochloride (2.34 g, 25 mmol, equivalent: 1.2) was added to a solution of dioxane (17 mL) containing diamide sulfate (2 g, 20.8 mmol, equivalent: 1.0) and triethylamine (4.21 g, 5.79 mL, 41.6 mmol, equivalent: 2.0). The reaction mixture was stirred in a sealed tube at 115°C for 20.25 hours, then cooled to room temperature and filtered. The filtrate was concentrated under vacuum, diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a white solid by purification by flash chromatography (40 g silica, 100% siRNA) (85 mg, yield 3%). MS(ESI) m / z: 137.0 [M+H] + .

[0132] IC4: Piperidine-1-sulfonamide TIFF0007877320000067.tif20170 Piperidine (886 mg, 1.03 mL, 10.3 mmol, equivalent: 1.0) was added to a solution of diamide sulfate (1 g, 10.3 mmol, equivalent: 1.0) in dioxane (10 mL). The reaction mixture was stirred in a sealed tube at 115°C for 16 hours and then concentrated under vacuum. The residue was diluted with MeOH, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a white solid by purification by flash chromatography (40 g silica, 0-100% siRNA in heptane) (965 mg, yield 57%). 1 H NMR(300MHz,DMSO-d6) δ ppm 1.37-1.49(m,2H) 1.50-1.65(m,4H) 2.81-3.01(m,4H) 6.65(s,2H).

[0133] IC5: [Methyl(sulfamoyl)amino]cyclopropane N-methylcyclopropanamine oxalate (1.21 g, 7.49 mmol, equivalent: 1.2) was added to a solution of dioxane (5 mL) containing diamide sulfate (600 mg, 6.24 mmol, equivalent: 1.0) and triethylamine (2.53 g, 3.48 mL, 25 mmol, equivalent: 4.0). The reaction mixture was stirred in a sealed tube at 115°C for 16 hours and then concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a white crystalline solid by purification by flash chromatography (40 g silica, 75% siRNA in heptane) (204 mg, yield 22%). 1 H NMR(300MHz,DMSO-d6) δ ppm 0.58-0.67(m,4H) 2.12-2.22(m,1H) 2.65(s,3H) 6.82(s,2H).

[0134] IC6: Cyclopentanesulfonamide TIFF0007877320000069.tif21170 Cyclopentanesulfonyl chloride (675 mg, 619 μL, 4.0 mmol, equivalent: 1.0) was added dropwise to an ammonium hydroxide solution (30-33% in water, 10.8 g, 12 mL, 92.5 mmol, equivalent: 23.1) at room temperature. The reaction mixture was stirred overnight at room temperature. After 20.5 hours, HCl (25% aqueous solution) was added dropwise until the pH of the solution reached 7. The reaction mixture was extracted three times with siRNA, the combined organic layers were washed once with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dried under high vacuum to obtain the title compound as a light brown solid (658 mg, purity 91%, yield 100%). 1 H NMR(300MHz,DMSO-d6) δ ppm 1.42-1.74(m,4H) 1.76-1.95(m,4H) 3.33-3.45(m,1H) 6.69(s,2H).

[0135] IC7:(RS)-butane-2-sulfonamide According to the procedure described for TIFF0007877320000070.tif20170IC6, the title compound was obtained as a pale yellow oil from butane-2-sulfonyl chloride (626 mg, 4 mmol) (397 mg, yield 73%). 1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06 (t, J=7.5 Hz, 3H) 1.41 (d, J=6.9 Hz, 3H) 1.49 - 1.68 (m, 1H) 1.98 - 2.27 (m, 1H) 2.85 - 3.12 (m, 1H) 4.44 (br s, 2H).

[0136] IC8: Cyclohexanesulfonamide According to the procedure described for TIFF0007877320000071.tif20170IC6, the title compound was obtained as a white solid from cyclohexanesulfonyl chloride (568 mg, 2.8 mmol) (371 mg, yield 81%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.14 - 1.41 (m, 5H) 1.55 - 1.69 (m, 1H) 1.72 - 1.86 (m, 2H) 2.06 (br d, J=10.7 Hz, 2H) 2.63 - 2.89 (m, 1H) 6.61 (s, 2H).

[0137] IC9: Cyclobutanesulfonamide According to the procedure described for TIFF0007877320000072.tif20170IC6, the title compound was obtained as a white solid from cyclobutanesulfonyl chloride (462 mg, 2.98 mmol) (309 mg, yield 77%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.79 - 1.97 (m, 2H) 2.14 - 2.35 (m, 4H) 3.56 - 3.83 (m, 1H) 6.71 (s, 2H).

[0138] Example A Example 1 tert-butyl 4-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]butanoate Ethyl-(methyl)sulfamoylamine (71 mg, 514 μmol, equivalent: 2.1) was dissolved in NMP (2 mL). NaH (55% in mineral oil, 23.5 mg, 538 μmol, equivalent: 2.2) was added at 0°C, the condenser was removed, and the reaction mixture was stirred at 50°C for 30 minutes. The reaction mixture was cooled to 0°C, and then a solution of intermediate IA9 [3,6-difluoro-2-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)benzonitrile] (108 mg, 245 μmol, equivalent: 1.0) in NMP (1 mL) was added. The reaction mixture was stirred at 125°C for 1 hour. The reaction mixture was cooled to room temperature, and the reaction mixture was dissolved in 3.8 mL of 0.1 M NaOH aqueous solution, ice, and RINKAN. The aqueous layer was separated and extracted again with ethyl acetate. The organic layer was washed with saturated NH4Cl aqueous solution. The aqueous layer was acidified to pH 4 with 2M HCl aqueous solution and extracted twice with ethyl acetate. The combined organic layers were washed three times with water and once with brine, then dried over Na2SO4, filtered, and evaporated. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a white foam by purification by flash chromatography (0-100% ethyl acetate in heptane) (39 mg, purity 100%, yield 28%). MS(ESI) m / z: 560.2[M+H] + .

[0139] Example 2 tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate Intermediate IC1 (31.8 mg, 189 μmol, equivalent: 2.1) was dissolved in DMF (500 μL). At room temperature, Cs2CO3 (64.6 mg, 198 μmol, equivalent: 2.2) was added, and the reaction mixture was stirred at 50°C for 30 minutes. The reaction mixture was cooled to room temperature, and a solution of intermediate IA10 (46 mg, 90.1 μmol, equivalent: 1.0) in DMF (1.1 mL) was added. The reaction mixture was stirred at 105°C for 3 hours, and then concentrated under vacuum. The residue was dissolved in DCM and washed with saturated NH4Cl aqueous solution. The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was diluted with DCM and transferred to a column. The title compound was purified by flash chromatography (40 g silica, containing 0-100% ethyl phosphate in DCM) along with the mixed fraction to obtain a white foamy substance (18 mg, 99% purity). This was further purified by SFC to obtain an additional white foamy substance of the title compound (17 mg, 98% purity, 59% total yield). MS(ESI) m / z: 657.5 [MH] - .

[0140] Example 3 tert-butyl 4-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate Following the procedure described in Example 1 (TIFF0007877320000075.tif30170), intermediate IA10 (85 mg, 166 μmol, equivalent: 1.0) and [methyl(sulfamoyl)amino]ethane (48 mg, 350 μmol, equivalent: 2.1) were further purified by reverse-phase HPLC to obtain the title compound as a white foam (61 mg, purity 97%, yield 57%). MS(ESI)m / z:627.2[MH] - .

[0141] Example 4 tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate Following the procedure described in Example 2 of TIFF0007877320000076.tif30170, the title compound was obtained as a white foamy substance (36 mg, purity 100%, yield 54%) from intermediate IA11 (50 mg, 110 μmol, equivalent: 1.0) and intermediate IC1 (39 mg, 230 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:603.4[MH] - .

[0142] Example 5 tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate Following the procedure described in Example 2 of TIFF0007877320000077.tif25170, the title compound was obtained as a white foamy substance (24 mg, purity 100%, yield 48%) from intermediate IA11 (55.7 mg, 122 μmol, equivalent: 1.0) and intermediate IC2 (38.5 mg, 256 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:585.4[MH] - .

[0143] Example 6 tert-butyl N-[3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate Following the procedure described in Example 2 of TIFF0007877320000078.tif27170, the title compound was obtained as a white foamy substance (27.7 mg, purity 100%, yield 41%) from intermediate IA11 (53.81 mg, 118 μmol, equivalent: 1.0) and [methyl(sulfamoyl)amino]ethane (36 mg, 248 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:573.5[MH] - .

[0144] Example 7 tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate Following the procedure described in Example 2 (TIFF0007877320000079.tif28170), the title compound was obtained as a white foamy substance (55 mg, purity 100%, yield 55%) from intermediate IA10 (79.5 mg, 156 μmol, equivalent: 1.0) and intermediate IC2 (49.1 mg, 327 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:639.5[MH] - .

[0145] Example 8 tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]carbamate Following the procedure described in Example 2 (TIFF0007877320000080.tif26170), the title compound was obtained as a white foamy substance (34 mg, purity 97%, yield 64%) from intermediate IA11 (40 mg, 87.6 μmol, equivalent: 1.0) and intermediate IC6 (28.9 mg, 184 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:584.4[MH] - .

[0146] Example 9 tert-butyl N-[3-[6-[3-(azetidine-1-ylsulfonylamino)-2-cyano-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate Following the procedure described in Example 2 (TIFF0007877320000081.tif27170), the title compound was obtained as a white foamy substance (25 mg, 100% purity, 55% yield) from intermediate IA11 (36 mg, 78.9 μmol, equivalent: 1.0) and intermediate IC3 (22.6 mg, 166 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z: 571.5[MH] - .

[0147] Example 10 tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate Following the procedure described in Example 2 (TIFF0007877320000082.tif32170), the title compound was obtained as a white foamy substance (39 mg, purity 100%, yield 61%) from intermediate IA12 (50 mg, 97.7 μmol, equivalent: 1.0) and intermediate IC1 (34.5 mg, 205 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:660.4[M+H] + .

[0148] Example 11 N-[2-Cyano-4-Fluoro-3-[4-Oxo-3-(3-phenylpropyl)quinazoline-6-yl]oxy-phenyl]cyclopentanesulfonamide Following the procedure described in Example 2 (TIFF0007877320000083.tif27170), the title compound was obtained as a white foamy substance (18 mg, purity 100%, yield 34%) from intermediate IA13 (40 mg, 95.8 μmol, equivalent: 1.0) and intermediate IC6 (31.6 mg, 201 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:547.4[M+H] + .

[0149] Example 12 tert-butyl N-[3-[6-[2-cyano-3-(cyclohexylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate Following the procedure described in Example 2 of TIFF0007877320000084.tif27170, the title compound was obtained as a white foam (46 mg, purity 100%, yield 70%) from intermediate IA11 (50 mg, 110 μmol, equivalent: 1.0) and intermediate IC8 (37.5 mg, 230 μmol, equivalent: 2.1). MS(ESI)m / z:598.5[MH] - .

[0150] Example 13 tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]carbamate Following the procedure described in Example 2 (TIFF0007877320000085.tif27170), the title compound was obtained as a white foam (43 mg, purity 98%, yield 67%) from intermediate IA11 (50 mg, 110 μmol, equivalent: 1.0) and intermediate IC7 (31.6 mg, 230 μmol, equivalent: 2.1). MS(ESI)m / z: 572.5[MH] - .

[0151] Example 14 tert-butyl 4-[2-[6-[2-cyano-3-(cyclohexylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate Following the procedure described in Example 2 of TIFF0007877320000086.tif27170, the title compound was obtained as a white foam (45 mg, purity 100%, yield 70%) from intermediate IA10 (50 mg, 97.9 μmol, equivalent: 1.0) and intermediate IC8 (33.6 mg, 206 μmol, equivalent: 2.1). MS(ESI)m / z:652.5[MH] - .

[0152] Example 15 tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate Following the procedure described in Example 2 of TIFF0007877320000087.tif27170, the title compound was obtained as a white foam (45 mg, purity 100%, yield 73%) from intermediate IA10 (50 mg, 97.9 μmol, equivalent: 1.0) and intermediate IC7 (28.2 mg, 206 μmol, equivalent: 2.1). MS(ESI)m / z:626.5[MH] - .

[0153] Example 16 tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate Following the procedure described in Example 2 (TIFF0007877320000088.tif28170), the title compound was obtained as a white solid (33 mg, 100% purity, 53% yield) from intermediate IA12 (50 mg, 97.7 μmol, equivalent: 1.0) and intermediate IC2 (30.8 mg, 205 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:642.5[M+H] + .

[0154] Example 17 tert-butyl 4-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate Following the procedure described in Example 2 of TIFF0007877320000089.tif28170, the title compound was obtained as a white foamy substance (38 mg, purity 100%, yield 61%) from intermediate IA10 (50 mg, 97.9 μmol, equivalent: 1.0) and intermediate IC6 (30.7 mg, 206 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:638.6[MH] - .

[0155] Example 18 tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(1-piperidylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate Following the procedure described in Example 2 of TIFF0007877320000090.tif28170, the title compound was obtained as a white foamy substance (38 mg, purity 100%, yield 60%) from intermediate IA10 (50 mg, 97.9 μmol, equivalent: 1.0) and intermediate IC4 (33.8 mg, 206 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:555.4[M+H-Boc] + .

[0156] Example 19 tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-carbamate Following the procedure described in Example 2 of TIFF0007877320000091.tif27170, the title compound was obtained as a white foamy substance (37 mg, purity 100%, yield 53%) from intermediate IA14 (54.5 mg, 116 μmol, equivalent: 1.0) and intermediate IC2 (36.5 mg, 243 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:599.5[MH] - .

[0157] Example 20 tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-carbamate TIFF0007877320000092.tif25170 According to the procedure described in Example 2, from intermediate IA14 (51 mg, 108 μmol, equivalent: 1.0) and intermediate IC6 (34 mg, 228 μmol, equivalent: 2.1), after SFC purification, the title compound was obtained as a white foam (45 mg, purity 100%, yield 69%). MS(ESI) m / z: 598.5 [M-H] - .

[0158] Example 21 tert-butyl 4-[2-[6-[2-cyano-3-(cyclobutylsulfonylamino)-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]ethyl]piperidine-1-carboxylate TIFF0007877320000093.tif30170 According to the procedure described in Example 2, from intermediate IA10 (50 mg, 97.9 μmol, equivalent: 1.0) and intermediate IC9 (27.8 mg, 206 μmol, equivalent: 2.1), after SFC purification, the title compound was obtained as a white foam (38 mg, purity 100%, yield 62%). MS(ESI) m / z: 624.5 [M-H] - .

[0159] Example 22 tert-butyl 3-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]ethyl]piperidine-1-carboxylate TIFF0007877320000094.tif37170 According to the procedure described in Example 2, from intermediate IA15 (50 mg, 97.9 μmol, equivalent: 1.0) and intermediate IC6 (30.7 mg, 206 μmol, equivalent: 2.1), after flash chromatography (eluent; 0 - 100% EtOAc in DCM), the title compound was obtained as a white foam (45 mg, purity 100%, yield 72%). MS(ESI) m / z: 638.6 [M-H] - .

[0160] Example 23 tert-Butyl 3-[2-[6-[2-Cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazolin-3-yl]ethyl]piperidine-1-carboxylate TIFF0007877320000095.tif39170 According to the procedure described in Example 2, from Intermediate IA15 (55 mg, 108 μmol, equivalent: 1.0) and Intermediate IC2 (34 mg, 226 μmol, equivalent: 2.1), after SFC, the title compound was obtained as a white foam (40.5 mg, purity 98%, yield 58%). MS (ESI) m / z: 639.5 [M-H] - .

[0161] Example 24 N-[3-[6-[2-Cyano-3-(cyclopentylsulfonylamino)-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]propyl]-N-methyl-acetamide TIFF0007877320000096.tif27170

[0162] Step 1: N-[2-Cyano-4-fluoro-3-[3-[3-(methylamino)propyl]-4-oxo-quinazolin-6-yl]oxy-phenyl]cyclopentanesulfonamide hydrochloride TIFF0007877320000097.tif29170 Example 20 (30.8 mg, 51.4 μmol, equivalent: 1.0) was dissolved in dioxane (210 μL). At room temperature, HCl (4 M in dioxane, 257 μL, 1.03 mmol, equivalent: 20) was added. The reaction mixture was stirred at room temperature for 2 hours and 50 minutes, then concentrated in vacuo to obtain the title compound as a white solid (30.2 mg, purity 90%, yield 99%). MS (ESI) m / z: 498.5 [M-H] - .

[0163] Step 2: N-[3-[6-[2-Cyano-3-(cyclopentylsulfonylamino)-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]propyl]-N-methyl-acetamide DIPEA (34.4 mg, 45.5 μL, 261 μmol, equivalent: 5.55) was added to a stirred suspension of N-[2-cyano-4-fluoro-3-[3-[3-(methylamino)propyl]-4-oxo-quinazolin-6-yl]oxyphenyl]cyclopentanesulfonamide hydrochloride (28 mg, 47 μmol, equivalent: 1.0) in DMF (1.4 mL). The reaction mixture was cooled to 0°C, and acetic anhydride (7.73 mg, 7.16 μL, 75.7 μmol, equivalent: 1.61) was added. The reaction mixture was stirred at 0°C for 40 minutes, then warmed to room temperature. After 1 hour and 25 minutes, the reaction mixture was concentrated under vacuum. The residue was diluted with DCM, evaporated to dryness over silica gel, and transferred to a column. The title compound was obtained as a white foam by purification using flash chromatography (25 g silica, 0-9.2% MeOH in DCM) (22 mg, 100% purity, 88% yield). MS(ESI) m / z: 542.4[M+H] + .

[0164] Example 25 tert-butyl 4-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate Following the procedure described in Example 2 (TIFF0007877320000099.tif29170), the title compound was obtained as an off-white solid (53 mg, 100% purity, 56% yield) from intermediate IA12 (75 mg, 147 μmol, equivalent: 1.0) and intermediate IC6 (308 mg, 226 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:641.5[M+H] + .

[0165] Example 26 N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-acetamide Following the procedure described for Example 24 (TIFF0007877320000100.tif26170), the title compound was obtained from Example 19 as a white foamy substance after SFC purification. MS(ESI)m / z:543.4[M+H] + .

[0166] Example 27 tert-butyl 4-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate Following the procedure described in Example 2 of TIFF0007877320000101.tif27170, the title compound was obtained as a white foamy substance (22.6 mg, yield 36%) from intermediate IA12 (51.6 mg, 101 μmol, equivalent: 1.0) and [methyl(sulfamoyl)amino]ethane (29.3 mg, 212 μmol, equivalent: 2.1) after SFC purification. MS(ESI)m / z:630.5[M+H] + .

[0167] Example 28 tert-butyl N-[[4-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]phenyl]methyl]-N-methyl-carbamate Following the procedure described in Example 2 of TIFF0007877320000102.tif30170, the title compound was obtained as a white solid (1.7 mg, purity 100%, yield 7%) from intermediate IA16 (19.7 mg, 35.1 μmol, equivalent: 1.0) and intermediate IC6 (11.5 mg, 77.1 μmol, equivalent: 2.1) after flash chromatography (0-100% SiO in DCM). MS(ESI)m / z:690.6[M+H] + .

[0168] Example 29 tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate Following the procedure described in Example 2 (TIFF0007877320000103.tif27170), the title compound was obtained as an off-white foam (34 mg, purity 96%, yield 72%) from intermediate IA12 (38.5 mg, 75.2 μmol, equivalent: 1.0) and intermediate IC7 (21.7 mg, 158 μmol, equivalent: 2.1) after flash chromatography (eluent: 0-10% MeOH in DCM). MS(ESI)m / z:629.5[M+H] + .

[0169] Example 30 tert-butyl N-[[4-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]]-4-oxo-quinazoline-3-yl]propyl]phenyl]methyl]-N-methyl-carbamate Following the procedure described in Example 2 of TIFF0007877320000104.tif30170, the title compound was obtained as a white foamy substance (35.5 mg, purity 100%, yield 58%) from intermediate IA16 (50 mg, 89.2 μmol, equivalent: 1.0) and intermediate IC2 (28.1 mg, 187 μmol, equivalent: 2.1) after SFC. MS(ESI)m / z:629.5[M+H] + .

[0170] Example 31 2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]-N-(2-methoxyethyl)acetamide Intermediate IB5 (15.8 mg, 34.6 μmol, equivalent: 1.0) was dissolved in DMF (455 μL), and then DIPEA (26.8 mg, 35.6 μL, 208 μmol, equivalent: 6.0) was added. HATU (14.5 mg, 38.1 μmol, equivalent: 1.1) and 2-methoxyethane-1-amine (8.0 mg, 9.1 μL, 104 μmol, equivalent: 3.0) were added at 0°C, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. The residue was diluted with DCM and transferred to a column. The title compound was obtained as an off-white solid (5.4 mg, 100% purity, 30% yield) by flash chromatography (12 g silica, 10% MeOH in DCM) followed by preparative reverse-phase HPLC. MS(ESI)m / z:514.3[M+H] + .

[0171] Example 32 tert-butyl 4-[[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazoline-3-yl]methyl]piperidine-1-carboxylate In a microwave vial under argon, intermediates IB6 (94 mg, 223 μmol, equivalent: 1.0) and IB1 (56.6 mg, 223 μmol, equivalent: 1.0) were dissolved in dioxane (6 mL), and then Cs2CO3 (220 mg, 668 μmol, equivalent: 3.0) was added. The reaction mixture was flushed with argon, and then BippyPhos (6.97 mg, 13.4 μmol, equivalent: 0.06) and Tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (7.05 mg, 6.68 μmol, equivalent: 0.03) were added. The reaction mixture was flushed again with argon, and the vial was closed. The reaction mixture was stirred at 110°C for 2.5 hours. The reaction mixture was dissolved in ethyl acetate and ice, and washed once with water and twice with 2M aqueous NaOH solution. The aqueous layer was back-extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was diluted with ethyl acetate and transferred to a column. Purification by flash chromatography (40 g silica, heptane with 0-100% ethyl acetate) yielded the title compound as an off-white foam (76 mg, purity 90%, yield 51%). MS(ESI) m / z: 494.4[M+H] + .

[0172] Example 33 3-[(1-acetyl-4-piperidyl)methyl]-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazoline TIFF0007877320000107.tif31170

[0173] Step 1: 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-3-(4-piperidylmethyl)quinazoline hydrochloride TIFF0007877320000108.tif Example 32 (17.9 mg, 30 μmol, equivalent: 1.0) was dissolved in DCM (100 μL). At room temperature, HCl (4 M in dioxane, 37.6 μL, 150 μmol, equivalent: 5.0) was added, followed by additional DCM (200 μL). The reaction mixture was stirred at room temperature for 20 hours and 15 minutes, then additional DCM (200 μL) and HCl (4 M in dioxane, 37.6 μL, 150 μmol, equivalent: 5.0) were added. After 4.5 hours, the reaction mixture was concentrated in vacuo to afford the title compound as an off-white solid (18 mg, purity 90%, yield 100%). MS (ESI) m / z: 494.3 [M-H] - .

[0174] Step 2: 3-[(1-Acetyl-4-piperidyl)methyl]-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazoline TIFF0007877320000109.tif A stirred suspension of 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-3-(4-piperidylmethyl)quinazoline hydrochloride (16 mg, 30.1 μmol, equivalent: 1.0) in DMF (800 μL)) was treated with DIPEA (19.8 mg, 26.2 μL, 150 μmol, equivalent: 5.0). The reaction mixture was cooled to 0 °C and acetic anhydride (4.45 mg, 4.12 μL, 43.6 μmol, equivalent: 1.45) was added. The reaction mixture was stirred at 0 °C for 40 minutes and then warmed to room temperature. After 1 hour and 15 minutes, the reaction was concentrated in vacuo. The residue was diluted with DCM, evaporated to dryness on silica gel, and transferred to a column. Purification by flash chromatography (Isco CombiFlash Companion, SILICYCLE FLH-R10017B-ISO40 Silia Sep TM, HP 40 g, containing 0% - 9.2% MeOH in DCM) afforded the title compound as a white foam (8.2 mg, purity 100%, yield 51%). MS (ESI) m / z: 536.3 [M+H] + .

[0175] Example 34 tert-butyl N-[2-[2-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazoline-3-yl]ethoxy]ethoxy]ethyl]carbamate Following the procedure described in Example 32 of TIFF0007877320000110.tif25170, the title compound was obtained as a white foam (18 mg, 100% purity, 37% yield) from intermediate IB7 (35 mg, 76.7 μmol, equivalent: 1.0) and intermediate IB1 (19.5 mg, 76.7 μmol, equivalent: 1.0) after preparative reverse-phase HPLC purification. MS(ESI)m / z:630.5[M+H] + .

[0176] Example 35 tert-butyl 4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoate Following the procedure described in Example 32 (TIFF0007877320000111.tif28170), intermediate IB8 (200 mg, 545 μmol, equivalent: 1.0) and intermediate IB2 (163 mg, 572 μmol, equivalent: 1.05) were subjected to flash chromatography (0-90% SiO in heptane) to obtain the title compound as a pale yellow foam (234 mg, purity 95%, yield 72%). MS(ESI)m / z: 571.3[M+H] + .

[0177] Example 36 (3R)-N-[3-[[3-(2-benzyloxyethyl)-4-oxoquinazoline-6-yl]amino]-2-cyanophenyl]-3-fluoropyrrolidine-1-sulfonamide Following the procedure described in Example 32 of TIFF0007877320000112.tif30170, the title compound was obtained as an off-white foam (26 mg, purity 98%, yield 55%) from intermediate IB9 (30 mg, 84 μmol, equivalent: 1.0) and intermediate IB2 (25 mg, 88 μmol, equivalent: 1.05) after flash chromatography (0-90% SiO in DCM). MS(ESI)m / z:563.3[M+H] + .

[0178] Example 37 tert-butyl 4-[2-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate Following the procedure described in Example 32 (TIFF0007877320000113.tif32170), the title compound was obtained as an off-white foam from intermediate IB10 (30 mg, 69 μmol, equivalent: 1.0) and intermediate IB2 (20.5 mg, 72.2 μmol, equivalent: 1.05) after flash chromatography (0-100% SiO in DCM) (26 mg, purity 100%, yield 59%). MS(ESI) m / z: 638.4 [MH] - .

[0179] Example 38 3-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazoline hydrochloride TIFF0007877320000114.tif25170 Example 34 (13.3 mg, 21.1 μmol, equivalent: 1.0) was dissolved in dioxane (200 μL). At room temperature, HCl (4 M in dioxane, 26.4 μL, 106 μmol, equivalent: 5.0) was added. The reaction mixture was stirred at room temperature for 141.5 hours, then concentrated under vacuum to obtain the title compound as a pale yellow solid (12 mg, purity 100%, yield 100%). MS(ESI) m / z: 528.3 [MH] - .

[0180] Example 39 4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]butanoic acid TIFF0007877320000115.tif30170 Example 35 (226 mg, 376 μmol, equivalent: 1.0) was suspended in DCM (6 mL), and then trifluoroacetic acid (1.35 g, 910 μL, 11.9 mmol, equivalent: 31.6) was added at room temperature. The reaction mixture was stirred at room temperature for 17 hours, and then concentrated under vacuum to obtain the title compound as a pale yellow solid (258 mg, purity 98%, yield 98%). MS(ESI) m / z: 515.2 [M+H] + .

[0181] Example 40 tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazolin-3-yl]butanoyl]piperazine-1-carboxylate To a stirred solution of Example 39 (30 mg, 43 μmol, equivalent: 1.0) in 700 μL of butyl (TIFF0007877320000116.tif31170), 4-methylmorpholine (47.8 mg, 52 μL, 473 μmol, equivalent: 11) and tert-butylpiperazine-1-carboxylate (8 mg, 43 μmol, equivalent: 1.0) were added at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and then n-propylphosphonic anhydride (T3P, 54.7 mg, 51.1 μL, 85.9 μmol, equivalent: 2.0) was added. The reaction mixture was stirred at room temperature for 5 hours and 38 minutes, and then diluted with butyl and 5 mL of water. The phases were separated, and the aqueous phase was further extracted twice with butyl. The combined organic phase was washed with 5 mL of brine, dried, filtered, and concentrated under vacuum. The residue was diluted with DCM and transferred to a column. The title compound was obtained as an off-white solid by purification by flash chromatography (40 g silica, 0-11.5% MeOH in DCM) (19 mg, 100% purity, 65% yield). MS(ESI) m / z: 681.5 [MH]- .

[0182] Example 41 tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoylamino]piperidine-1-carboxylate) To a stirred solution of Example 39 (30 mg, 43 μmol, equivalent: 1.0) in 700 μL of butyl, 4-methylmorpholine (47.8 mg, 52 μL, 473 μmol, equivalent: 11) and tert-butyl 4-aminopiperidine-1-carboxylate (9.46 mg, 47.3 μmol, equivalent: 1.1) were added. The reaction mixture was stirred at room temperature for 10 minutes, and then n-propylphosphonic anhydride (T3P, 54.7 mg, 51.1 μL, 85.9 μmol, equivalent: 2.0) was added. The reaction mixture was stirred at room temperature for 15 hours and 40 minutes, and then DMF (700 μL) and HATU (16.3 mg, 43 μmol, equivalent: 1.0) were added. The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated under vacuum. The residue was diluted with Âi and 5 mL of water. The phases were separated, and the aqueous phase was extracted twice with Âi. The combined organic phase was washed with 5 mL of brine, dried, filtered, and concentrated under vacuum. The residue was diluted with DCM and transferred to a column. The title compound was obtained as a white solid by purification by flash chromatography (40 g silica, 0-8% MeOH in DCM) (19 mg, 100% purity, 64% yield). MS(ESI) m / z: 695.5 [MH] - .

[0183] Example 42 tert-butyl 4-[6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]butanoate Following the procedure described in Example 32 (TIFF0007877320000118.tif23170), intermediate IB8 (30 mg, 82 μmol, equivalent: 1.0) and intermediate IB3 (22.8 mg, 85.8 μmol, equivalent: 1.05) were subjected to flash chromatography (0-90% SiO in DCM) to obtain the title compound as a pale yellow foam (13.5 mg, yield 30%). MS(ESI) m / z: 553.3[M+H] + .

[0184] Example 43 tert-butyl N-[3-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]propyl]carbamate Following the procedure described in Example 32 (TIFF0007877320000119.tif28170), intermediate IB11 (30 mg, 78.5 μmol, equivalent: 1.0) and intermediate IB2 (23.4 mg, 82.4 μmol, equivalent: 1.05) were flash-chromatographed (0-65% SiO in DCM) to obtain the title compound as a pale yellow solid (30 mg, 100% purity, 65% yield). MS(ESI) m / z: 584.2 [MH] - .

[0185] Example 44 (3R)-N-[2-cyano-3-[[4-oxo-3-(3-phenylpropyl)quinazoline-6-yl]amino]phenyl]-3-fluoropyrrolidine-1-sulfonamide Following the procedure described in Example 32 (TIFF0007877320000120.tif28170), intermediate IB12 (40 mg, 117 μmol, equivalent: 1.0) and intermediate IB2 (34.8 mg, 122 μmol, equivalent: 1.05) were subjected to flash chromatography (0-100% SiO in heptane) to obtain the title compound as a pale yellow foam (35 mg, purity 100%, yield 55%). MS(ESI)m / z: 547.3[M+H] + .

[0186] Example 45 tert-butyl N-[2-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoylamino]ethyl]-N-methyl-carbamate TIFF0007877320000121.tif27170 Example 39 (40 mg, 63.6 μmol, equivalent: 1.0) was dissolved in DMF (2 mL), and then DIPEA (24.7 mg, 33.3 μL, 191 μmol, equivalent: 3.0) was added. At 0°C, HATU (26.6 mg, 70 μmol, equivalent: 1.1) was added. After 15 minutes, tert-butyl N-(2-aminoethyl)-N-methyl-carbamate (16.6 mg, 17.1 μL, 95.5 μmol, equivalent: 1.5) was added, and the reaction mixture was stirred overnight at room temperature. After 16 hours, the reaction mixture was concentrated under vacuum. The residue was diluted with DCM and transferred to a column. The title compound was obtained as a white foamy substance by purification using flash chromatography (40 g silica, 0-11.5% MeOH in DCM) (29 mg, purity 99%, yield 68%). MS(ESI) m / z: 669.5 [MH] - .

[0187] Example 46 tert-butyl 4-[2-[6-[2-cyano-3-(pyrrolidine-1-ylsulfonylamino)anilino]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate Following the procedure described in Example 32 of TIFF0007877320000122.tif26170, the title compound was obtained as a pale yellow foam (18.5 mg, purity 100%, yield 43%) from intermediate IB10 (30 mg, 68.8 μmol, equivalent: 1.0) and intermediate IB4 (19.2 mg, 72.2 μmol, equivalent: 1.05) after flash chromatography (0-100% SiO2 in heptane). MS(ESI)m / z:620.5[M+H] + .

[0188] Example 47 material cell line A375 is a cell carcinoma model expressing V600E mutant BRAF, and HCT116 is a cell carcinoma model expressing WT BRAF. First-generation BRAF inhibitors, such as dabrafenib, induce a paradoxical effect on tumor cells by inhibiting the proliferation of V600E mutant BRAF cells (e.g., A375) while activating the proliferation of WT BRAF cells (e.g., HCT116). ERK1,2 phosphorylation (terminal members of the MAPK pathway phosphorylation cascade) has since been reported as the main readout of the activated state of the MAPK pathway. L-glutamine-supplemented DMEM phenol-free red medium was purchased from Thermo Fisher Scientific. Fetal bovine serum (FBS) was purchased from VWR. The high-performance ERK phospho-T202 / Y204 kit-10,000 was purchased from Cisbio catalog number 64AERPEH. A375 (catalog number CRL-1619) and HCT116 (catalog number CCL-247) cells were originally obtained from the American Type Culture Collection (ATCC) and banked by the Roche Repository. The 384-well microplate used was a 384-well (lidded, HiBase, low-volume catalog 784-080) purchased from Greiner Bio-One.

[0189] HTRF assay for P-ERK determination in A375 or HCT116 cells Prior to the assay, A375 and HCT116 cell lines are maintained in DMEM phenol-free red medium supplemented with 10% fetal bovine serum (FBS). After compound treatment, P-ERK levels are determined by measuring the FRET fluorescence signal induced by the selective binding of the two antibodies (Cisbio catalog number 64AERPEH) included in the aforementioned kit to the ERK protein when phosphorylated at Thr202 / Tyr204. In short, 8000 cells / well in 12 μl of medium / well are seeded into a 384-well plate and left overnight in an incubator (37°C, 5% CO2 humidified atmosphere). The next day, the plate is treated in double rows with the test compounds dabrafenib and PLX8394 (the latter two as controls) at the following final drug concentrations: 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, and 0.001 μM. All wells undergo DMSO normalization, and the drugs are incubated for 1 hour. Then, 4 μl of 4X lysis buffer provided in the kit is added to the wells, the plate is centrifuged for 30 seconds (3000 rpm), and incubated on a plate shaker at room temperature for 1 hour.

[0190] At the end of incubation, add 4 μL / well of high-performance P-ERK antibody solution (prepared according to the manufacturer's instructions), followed by 4 μL / well of cryptotate P-ERK antibody solution (prepared according to the manufacturer's instructions) (Cisbio catalog number 64AERPEH) to the test wells.

[0191] To enable proper data normalization, the non-pharmacological treatment control wells reported in the table below are always included in each plate (as per the manufacturer's instructions). TIFF0007877320000123.tif63170

[0192] Next, the plate is centrifuged at 3000 rpm for 30 seconds, sealed to prevent evaporation, and incubated overnight in a dark place at room temperature.

[0193] Next, the plate is analyzed, and fluorescence emission values ​​are collected at 665 and 620 nM using a Pherastast FSX (BMG Labtech) instrument.

[0194] The obtained fluorescence values ​​are processed according to the formula "Ratio = Signal (620nm) / Signal (625nm) * 10000", and the average ratio of the blank values ​​is subtracted from all values.

[0195] For A375 cells (BRAF inhibition), the average percentage of cells induced by DMSO-treated cells alone (after subtracting the blank) is considered 100%, and the average percentage of cells induced by 10 μM dabrafenib-treated cells (after subtracting the blank) is considered 0%, thereby normalizing the data. The average of the normalized points is fitted with a sigmoid curve to determine the IC50.

[0196] For HCT116 cells (BRAF activated), the data is normalized by considering the mean percentage (after subtracting the blank) of cells induced by DMSO-treated cells alone as 0%, and the mean percentage (after subtracting the blank) of cells induced by dabrafenib-treated cells at the concentration that provides the highest signal as 100%. Each point is fitted to either an S-shaped or bell-shaped curve. EC 50 This concentration yields activation equivalent to 50% of the maximum activation achieved by dabrafenib. The results are shown in Table 1 below.

[0197] TIFF0007877320000124.tif231170TIFF0007877320000125.tif235170TIFF0007877320000126.tif231170TIFF0007877320000127.tif212170

[0198] Example A Film-coated tablets containing the following ingredients can be manufactured in the conventional manner. TIFF0007877320000128.tif79170

[0199] The active ingredients are sieved and mixed with microcrystalline cellulose, and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules are then mixed with sodium starch glycolate and magnesium stearate, and compressed to obtain 120 or 350 mg of nuclei, respectively. The nuclei are lacquered with an aqueous solution / suspension of the above-mentioned film coat.

[0200] Example B Capsules containing the following ingredients can be manufactured in the conventional manner. TIFF0007877320000129.tif28170

[0201] The ingredients are sieved, mixed, and filled into size 2 capsules.

[0202] Example C The injection solution may have the following composition: TIFF0007877320000130.tif23170

[0203] Dissolve the active ingredient in a mixture of polyethylene glycol 400 and part of sterile water for injection. Adjust the pH to 5.0 by adding acetic acid. Add the remaining water to adjust the volume to 1.0 ml. Filter the solution, fill the vial with an appropriate excess volume, and sterilize.

Claims

1. Compound of formula (I) [In the formula, A is -O- or -NH-; L is - (CH ２ )n-, where n = 1, 2, 3, or 4; R １ These are alkoxycarbonyl, alkoxycarbonyl heterocycloalkyl, alkoxycarbonylamino, phenyl, alkoxycarbonyl (alkylamino), alkylcarbonyl (alkylamino), alkoxycarbonyl (alkylamino)alkylphenyl, alkoxyalkylaminocarbonyl, alkylcarbonyl heterocycloalkyl, alkoxycarbonylaminoalkoxyalkoxy, phenylalkoxy, aminoalkoxyalkoxy, hydroxycarbonyl, alkoxycarbonyl heterocycloalkylcarbonyl, alkoxycarbonyl heterocycloalkylaminocarbonyl, or alkoxycarbonyl (alkylamino)alkylaminocarbonyl; R ２ is hydrogen or fluorine, R ３ is cyano; R ４ [These are dialkylamino, (cycloalkyl)(alkyl)amino, haloheterocycloalkyl, heterocycloalkyl, cycloalkyl, or alkyl]; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R1 is alkoxycarbonyl, alkoxycarbonylpiperidinyl, alkoxycarbonylpiperazinyl, alkoxycarbonylamino, phenyl, alkoxycarbonyl(alkylamino), alkylcarbonyl(alkylamino), alkoxycarbonyl(alkylamino)alkylphenyl, alkoxyalkylaminocarbonyl, alkylcarbonylpiperidinyl, alkoxycarbonylaminoalkoxyalkoxy, phenylalkoxy, aminoalkoxyalkoxy, hydroxycarbonyl, alkoxycarbonylpiperazinylcarbonyl, alkoxycarbonylpiperidinylaminocarbonyl, or alkoxycarbonyl(alkylamino)alkylaminocarbonyl.

3. The compound according to claim 1 or 2, wherein R1 is an alkoxycarbonyl heterocycloalkyl, an alkoxycarbonylamino, an alkoxycarbonyl (alkylamino), an alkylcarbonyl (alkylamino), an alkoxycarbonylaminoalkoxyalkoxy, an alkoxycarbonyl heterocycloalkylcarbonyl, an alkoxycarbonyl heterocycloalkylaminocarbonyl, or an alkoxycarbonyl (alkylamino)alkylaminocarbonyl.

4. The compound according to any one of claims 1 to 3, wherein R1 is tert-butyloxycarbonyl, tert-butyloxycarbonylpiperidinyl, tert-butyloxycarbonylpiperidinyl, tert-butyloxycarbonylpiperazinyl, tert-butyloxycarbonylamino, phenyl, tert-butyloxycarbonyl(methylamino), methylcarbonyl(methylamino), tert-butyloxycarbonyl(methylamino)methylphenyl, methoxyethylaminocarbonyl, methylcarbonylpiperidinyl, tert-butyloxycarbonylaminoethoxyethoxy, phenylmethyloxy, aminoethoxyethoxy, hydroxycarbonyl, tert-butyloxycarbonylpiperazinylcarbonyl, tert-butyloxycarbonylpiperidinylaminocarbonyl, or tert-butyloxycarbonyl(methylamino)ethylaminocarbonyl.

5. The compound according to any one of claims 1 to 4, wherein R1 is tert-butyloxycarbonylpiperazinyl, tert-butyloxycarbonylamino, tert-butyloxycarbonyl(methylamino), methylcarbonyl(methylamino), tert-butyloxycarbonylaminoethoxyethoxy, tert-butyloxycarbonylpiperazinylcarbonyl, tert-butyloxycarbonylpiperidinylaminocarbonyl, or tert-butyloxycarbonyl(methylamino)ethylaminocarbonyl.

6. R ４ The compound according to any one of claims 1 to 5, wherein the compound is a dialkylamino, a haloheterocycloalkyl, a heterocycloalkyl, or a cycloalkyl.

7. R ４ The compound according to any one of claims 1 to 6, wherein the compound is ethyl (methylamino), (cyclopropyl)(methyl)amino, fluoropyrrolidinyl, pyrrolidinyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, butyl, or piperidinyl.

8. R ４ The compound according to any one of claims 1 to 7, wherein the compound is ethyl (methylamino), fluoropyrrolidinyl, pyrrolidinyl, azetidinyl, or cyclopentyl.

9. The compound according to any one of claims 1 to 8, wherein A is -O-.

10. L is -(CH ２ ), where n = 1, 2 or 3, a compound according to any one of claims 1 to 9.

11. tert-butyl 4-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]butanoate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[3-(azetidine-1-ylsulfonylamino)-2-cyano-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; N-[2-cyano-4-fluoro-3-[4-oxo-3-(3-phenylpropyl)quinazolin-6-yl]oxyphenyl]cyclopentanesulfonamide; tert-butyl N-[3-[6-[2-cyano-3-(cyclohexylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-3-(cyclohexylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(1-piperidylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-carbamate; tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]propyl]-N-methyl-carbamate; tert-butyl 4-[2-[6-[2-cyano-3-(cyclobutylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 3-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; tert-butyl 3-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate; N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]-N-methylacetamide; tert-butyl 4-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methylacetamide; tert-butyl 4-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl N-[[4-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]propyl]phenyl]methyl]-N-methylcarbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(sec-butylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl N-[[4-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]phenyl]methyl]-N-methyl-carbamate; 2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]-N-(2-methoxyethyl)acetamide; tert-butyl 4-[[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]methyl]piperidine-1-carboxylate; 3-[(1-acetyl-4-piperidyl)methyl]-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazoline; tert-butyl N-[2-[2-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]ethoxy]ethoxy]ethyl]carbamate; tert-butyl 4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazolin-3-yl]butanoate; (3R)-N-[3-[[3-(2-benzyloxyethyl)-4-oxoquinazolin-6-yl]amino]-2-cyanophenyl]-3-fluoropyrrolidine-1-sulfonamide; tert-butyl 4-[2-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]ethyl]piperidine-1-carboxylate; 3-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazoline; 4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazoline-3-yl]butanoic acid; tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazolin-3-yl]butanoyl]piperazine-1-carboxylate; tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoylamino]piperidine-1-carboxylate; tert-butyl 4-[6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]butanoate; tert-butyl N-[3-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazolin-3-yl]propyl]carbamate; (3R)-N-[2-cyano-3-[[4-oxo-3-(3-phenylpropyl)quinazolin-6-yl]amino]phenyl]-3-fluoropyrrolidine-1-sulfonamide; tert-butyl N-[2-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazolin-3-yl]butanoylamino]ethyl]-N-methyl-carbamate; and tert-butyl 4-[2-[6-[2-cyano-3-(pyrrolidine-1-ylsulfonylamino)anilino]-4-oxo-quinazoline-3-yl]ethyl]piperidine-1-carboxylate A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, selected from among.

12. tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl N-[3-[6-[3-(azetidine-1-ylsulfonylamino)-2-cyano-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]propyl]carbamate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl 4-[2-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methyl-carbamate; tert-butyl N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]propyl]-N-methyl-carbamate; N-[3-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxoquinazoline-3-yl]propyl]-N-methylacetamide; tert-butyl 4-[2-[6-[2-cyano-3-(cyclopentylsulfonylamino)-6-fluorophenoxy]-4-oxo-quinazoline-3-yl]ethyl]piperazine-1-carboxylate; N-[3-[6-[2-cyano-6-fluoro-3-(pyrrolidine-1-ylsulfonylamino)phenoxy]-4-oxo-quinazoline-3-yl]propyl]-N-methylacetamide; tert-butyl 4-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxo-quinazolin-3-yl]ethyl]piperazine-1-carboxylate; tert-butyl N-[2-[2-[2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]anilino]-4-oxo-quinazolin-3-yl]ethoxy]ethoxy]ethyl]carbamate; tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazolin-3-yl]butanoyl]piperazine-1-carboxylate; tert-butyl 4-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoylamino]piperidine-1-carboxylate; tert-butyl N-[3-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxoquinazolin-3-yl]propyl]carbamate; and tert-butyl N-[2-[4-[6-[2-cyano-3-[[(3R)-3-fluoropyrrolidine-1-yl]sulfonylamino]anilino]-4-oxo-quinazoline-3-yl]butanoylamino]ethyl]-N-methyl-carbamate A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, selected from among.

13. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: (a) Compound of formula (A1) in the presence of a base and the compound of formula (A2) The reaction: (b) Compound of formula (B1) in the presence of a base, a palladium catalyst, and a suitable ligand. and the compound of formula (B2) The reaction; or (c) Compound of formula (C1) in the presence of a base and the compound of formula (C2) The reaction (In the above formula, L, R １ , R ２ , R ３ and R ４ (This is as specified in any one of claims 1 to 10.) A method that includes one of the following.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

15. A pharmaceutical agent for the treatment or prevention of cancer, particularly melanoma or non-small cell lung cancer (NSCLC), comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

16. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of cancer, particularly melanoma or non-small cell lung cancer (NSCLC).

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