Oxaza compounds comprising 6-aza moieties and uses thereof

Abstract

Provided herein are oxaza # imgabs0 #-based compounds comprising a 6-aza moiety that are useful in the treatment of cancer.

Description

Technical Field

[0001] The present disclosure provides acyclic compounds containing a 6-aza moiety, compositions of such compounds, and methods of treating cancers containing KRas mutations, which can be used for treating cancers containing KRas mutations. Background Art

[0002] Ras is a small molecule GTP-binding protein that functions as a nucleotide-dependent switch in central growth signal transduction pathways. In response to extracellular signals, Ras is converted from the GDP-bound state (Ras GDP ) to the GTP-bound (Ras GTP ) state by guanine nucleotide exchange factors (GEFs), especially the SOS1 protein. Active Ras GTP mediates its multiple growth-stimulatory effects through direct interactions with effectors, including Raf, PI3K, and Ral guanine nucleotide dissociation stimulator. Subsequently, the intrinsic GTPase activity of Ras hydrolyzes GTP to GDP, thereby terminating Ras signal transduction. The Ras GTPase activity can be further enhanced by interaction with GTPase-activating proteins (GAPs), which include the neurofibromin 1 tumor suppressor.

[0003] Mutant Ras has reduced GTPase activity, which prolongs its activated state, thereby promoting Ras-dependent signal transduction and the survival or growth of cancer cells. Mutations in Ras affect its ability to interact with GAPs or convert GTP back to GDP, leading to an extended activation time of the protein and, in turn, an extended signal telling the cell to continue growing and dividing. Since these signals cause cell growth and division, overactive RAS signal transduction may ultimately lead to cancer. Mutations in any of the three major gene subtypes of RAS (HRas, NRas, or KRas) are common events in human tumorigenesis. Among the three Ras subtypes (K, N, and H), KRas is the most frequently mutated.

[0004] The most common KRas mutations occur at residues G12 and G13 in the P-loop and residue Q61. Ras mutations in cancers are associated with poor prognosis. Inactivation of oncogenic Ras in mice results in tumor shrinkage. Thus, Ras is generally regarded as an extremely important tumor target.

[0005] Therefore, there is an urgent need for therapies for cancers mediated by mutant KRas. Summary of the Invention

[0006] The present disclosure provides solutions to the above problems and other problems in the art.

[0007] In one aspect, provided herein are compounds of formula (I) as described herein or their atropisomers, stereoisomers, tautomers or pharmaceutically acceptable salts.

[0008] In another aspect, provided herein are compounds of formula (Ia) as described herein or their atropisomers, stereoisomers, tautomers or pharmaceutically acceptable salts.

[0009] In another aspect, provided herein are compounds of formula (II), (IIa), (IIb) or (IIc) as described herein or their atropisomers, stereoisomers, tautomers or pharmaceutically acceptable salts.

[0010] In another aspect, provided herein are compounds of formula (III), (IIIa), (IIIb) or (IIIc) as described herein or their atropisomers, stereoisomers, tautomers or pharmaceutically acceptable salts.

[0011] In another aspect, provided herein are compounds of formula (IV), (IVa), (IVb) or (IVc) as described herein or their atropisomers, stereoisomers, tautomers or pharmaceutically acceptable salts.

[0012] In another aspect, provided herein are compounds of formula (V), (Va), (Vb) or (Vc) as described herein or their atropisomers, stereoisomers, tautomers or pharmaceutically acceptable salts.

[0013] In another aspect, provided herein are pharmaceutical compositions that comprise a compound as described herein or its atropisomers, stereoisomers, tautomers or pharmaceutically acceptable salts and one or more pharmaceutical excipients.

[0014] In another aspect, provided herein is a method of treating cancer as described herein by administering an effective amount of a compound as described herein or its atropisomers, stereoisomers, tautomers or pharmaceutically acceptable salts. Detailed Description

[0015] Disclosed herein are acyclic oxaazepines as described herein compounds, or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts and their pharmaceutical compositions, which in certain embodiments are inhibitors or modulators of mutant KRas. In certain instances, such compounds and compositions are inhibitors or modulators of mutant KRas as provided herein (i.e., pan-KRas inhibitors). The compounds and compositions described herein can be used to treat diseases and disorders mediated by mutant KRas.

[0016] Although the disclosure herein provides enumerated embodiments, it is to be understood that they are not intended to limit the compounds and methods described herein to those embodiments. Rather, the disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the disclosure as defined by the claims.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Unless otherwise noted, the nomenclature used in this application is based on the IUPAC system of nomenclature.

[0018] The following definitions are provided to facilitate understanding of some terms frequently used herein and are not intended to limit the scope of the disclosure. All references cited herein are incorporated by reference in their entirety.

[0019] The terms "halogen" and "halo" are used interchangeably and refer to F, Cl, Br, or I. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl, polyhaloalkyl, and perhaloalkyl.

[0020] The term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group. In one instance, the alkyl is from one to eighteen carbon atoms (C 1-18 ). In other instances, the alkyl is C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 or C 1-3 . Examples of alkyl groups include methyl (Me, –CH 3 ), ethyl (Et, –CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, –CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, isopropyl, –CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, –CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, isobutyl, –CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, sec-butyl, –CH(CH 3 )CH2 CH 3 )、2-Methyl-2-propyl (t-Bu, tert-butyl, –C(CH 3 ) 3 )、1-Pentyl (n-pentyl, –CH 2 CH 2 CH 2 CH 2 CH 3 )、2-Pentyl (–CH(CH 3 )CH 2 CH 2 CH 3 )、3-Pentyl (–CH(CH 2 CH 3 ) 2 )、2-Methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 )、3-Methyl-2-butyl (–CH(CH 3 )CH(CH 3 ) 2 )、3-Methyl-1-butyl (–CH 2 CH 2 CH(CH 3 ) 2 )、2-Methyl-1-butyl (–CH 2 CH(CH 3 )CH 2 CH 3 )、1-Hexyl (–CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 )、2-Hexyl (–CH(CH 3 )CH 2 CH 2 CH 2 CH 3 )、3-Hexyl (–CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 ))、2-Methyl-2-pentyl (–C(CH 3 ) 2 CH 2 CH 2 CH 3 )、3-Methyl-2-pentyl (–CH(CH 3 )CH(CH 3 )CH2 CH 3 )、4-methyl-2-pentyl (–CH(CH 3 )CH 2 CH(CH 3 ) 2 )、3-methyl-3-pentyl (–C(CH 3 )(CH 2 CH 3 ) 2 )、2-methyl-3-pentyl (–CH(CH 2 CH 3 )CH(CH 3 ) 2 )、2,3-dimethyl-2-butyl (–C(CH 3 ) 2 CH(CH 3 ) 2 )、3,3-dimethyl-2-butyl (–CH(CH 3 )C(CH 3 ) 3 、1-heptyl and 1-octyl.

[0021] The term "oxo" means =O.

[0022] The term "alkoxy" means –O–alkyl.

[0023] The term "cyano" or "nitrile" means –C≡N or –CN.

[0024] The term "haloalkoxy" means –O–haloalkyl.

[0025] The terms "hydroxy" and "hydroxyl" mean –OH.

[0026] The term "alkylidene" means a straight-chain or branched-chain monovalent hydrocarbon group having the formula =CR'R", where R' and R" may be the same or different. In one instance, the alkylidene is from 1 to 6 carbon atoms (C 1-6 ). In another instance, the alkylidene is C 1-3 、C 1-2 or C 1 . Exemplary alkylidenes include, but are not limited to, methylidene (=CH 2 ), ethylidene (=CHCH 3 ), and propylidene (=CH-CH 2 -CH 3 ).

[0027] The term "alkenyl" means a straight-chain or branched-chain monovalent hydrocarbon group having at least one carbon-carbon double bond, and includes groups having "cis" and "trans" orientations, or alternatively "E" and "Z" orientations. In one instance, the alkenyl is from two to eighteen carbon atoms (C2-18 ). In other instances, the alkenyl is C 2-12 , C 2-10 , C 2-8 , C 2-6 or C 2-3 . Examples include but are not limited to ethenyl (ethenyl or vinyl) (-CH=CH 2 ), prop-1-enyl (-CH=CHCH 3 ), prop-2-enyl (-CH 2 CH=CH 2 ), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl.

[0028] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group having at least one carbon-carbon triple bond. In one instance, the alkynyl is two to eighteen carbon atoms (C 2-18 ). In other instances, the alkynyl is C 2-12 , C 2-10 , C 2-8 , C 2-6 or C 2-3 . Examples include but are not limited to ethynyl (–C≡CH), prop-1-ynyl (–C≡CCH 3 ), prop-2-ynyl (propargyl, –CH 2 C≡CH), but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0029] The term "alkylene" refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent group centers, obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. In one instance, the divalent alkylene group is one to eighteen carbon atoms (C 1-18 ). In other instances, the divalent alkylene group is C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 or C 1-3 . Exemplary alkylene groups include methylene (–CH 2 –), 1,1-ethylene (–CH(CH 3 ), 1,2-ethylene (–CH 2 CH 2 –), 1,1-propylene (–CH(CH 2 CH 3)–), 2,2-propyl (–C(CH 3 ) 2 –), 1,2-propyl (–CH(CH 3 )CH 2 –), 1,3-propyl (–CH 2 CH 2 CH 2 –), 1,1-dimethylethyl-1,2-yl (–C(CH 3 ) 2 CH 2 –), 1,4-butyl (–CH 2 CH 2 CH 2 CH 2 –), etc.

[0030] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyl encompasses monocyclic, bicyclic, tricyclic, spirocyclic, and bridged-ring, saturated ring systems. In one instance, the cycloalkyl group has 3 to 12 carbon atoms (C 3-12 ). In other instances, the cycloalkyl is C 3-4 , C 3-5 , C 3-7 , C 3-8 , C 3-10 , or C 5-10 . In other instances, the cycloalkyl group as a monocyclic ring is C 3-4 , C 3-8 , C 3-6 , or C 5-6 . In another instance, the cycloalkyl group as a bicyclic ring is C 7 -C 12 . In another instance, the cycloalkyl group as a spiro ring system is C 5-12 . Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Examples of spiroalkyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane.

[0031] The terms "heterocyclic group", "heterocyclic", "heterocycle", "heterocyclic radical" or "heterocyclic moiety" are used interchangeably and refer to any monocyclic, bicyclic, tricyclic, spiro or bridged, saturated, partially saturated or unsaturated, non-aromatic ring system having 3 to 20 ring atoms, wherein the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. If any ring atom of the cyclic system is a heteroatom, the system is heterocyclic regardless of the point of attachment of the cyclic system to the remainder of the molecule. In one instance, the heterocyclic group contains 3 - 10 ring atoms ("members") and includes monocyclic, bicyclic, tricyclic, spiro and bridged ring systems, wherein the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In other instances, the heterocyclic group includes 3 to 6, 5 to 9, 4 to 10, or 5 to 10 ring atoms. In one instance, the heterocyclic group includes 1 to 4 heteroatoms. In one instance, the heterocyclic group includes 1 to 3 heteroatoms. In another instance, the heterocyclic group includes a 3 - to 7 - membered monocyclic ring having 1 to 2, 1 to 3 or 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen. In another instance, the heterocyclic group includes a 4 - to 6 - membered monocyclic ring having 1 - 2, 1 - 3 or 1 - 4 heteroatoms selected from nitrogen, sulfur or oxygen. In another instance, the heterocyclic group includes a 3 - membered monocyclic ring. In another instance, the heterocyclic group includes a 4 - membered monocyclic ring. In another instance, the heterocyclic group contains a 5 - to 6 - membered monocyclic ring. In another instance, the heterocyclic group includes an 8 - membered, 9 - membered or 10 - membered bicyclic ring. In such instances, the heterocyclic group moiety can be a 4,5 - fused ring system, 5,5 - fused ring system, 4,6 - fused ring system, 5,6 - fused ring system or 6,6 - fused ring system. In some embodiments, the heterocyclic alkyl includes at least one nitrogen. In one instance, the heterocyclic group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom can be optionally oxidized (e.g., NO, SO, SO 2 ), and any nitrogen heteroatom can be optionally quaternized (e.g., [NR 4 + Cl - , [NR 4 + OH - ). Exemplary heterocycles are oxiranyl, aziridinyl, thiopyranyl, azetidinyl, oxetanyl, thietanyl, 1,2 - dithietanyl, 1,3 - dithietanyl, pyrrolidinyl, dihydro - 1H - pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1 - dioxothiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl​​ groups, oxazepanyl, diazepanyl, 1,4-diazepanyl, diaza groups, thiaza groups, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolinyl, isothiazolidinyl, 1,1-isothiazolidinonyl, 1,1-dioxoisothiazolyl, oxazolidinonyl, imidazolinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithienyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dicarbonyl, piperazinonyl, piperazinedicarbonyl, pyrazolinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decane-2-yl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindolyl, 1,1-dioxohexahydrothiopyranyl.

[0032] As used herein, "aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused or spiro rings (e.g., naphthyl or anthracenyl), where the fused or spiro rings may or may not be aromatic. Specific aryl groups are those having 6 to 14 ring (i.e., cyclic) carbon atoms ("C 6-14 aryl"). Preferred aryl groups include those having 5 to 6 ring carbons. An aryl group having more than one ring, where at least one ring is non-aromatic, may be attached to the parent structure at an aromatic ring position or at a non-aromatic ring position. In one variant, an aryl group having more than one ring, where at least one ring is non-aromatic, is attached to the parent structure at an aromatic ring position.

[0033] The term "heteroaryl" refers to any monocyclic or bicyclic aromatic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in one exemplary embodiment, at least one heteroatom is nitrogen. It includes any bicyclic group in which any of the above heteroaryl rings is fused to an aryl ring, where the aryl ring or the heteroaryl ring is attached to the rest of the molecule. Heteroaryl groups can have a single ring (e.g., pyridyl, furyl) or multiple fused or spiro rings (e.g., indolizinyl, benzothienyl), and these fused or spiro rings can be, or not be, aromatic. In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups in which one or more ring atoms are nitrogen, sulfur, or oxygen. Exemplary heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiotriazolyl, oxatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, and purinyl, as well as benzo-fused derivatives (e.g., benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indazolyl, and indolyl).

[0034] In certain embodiments, the heterocyclic group or heteroaryl group is attached to a carbon atom of the heterocyclic group or heteroaryl group. By way of example, carbon-bonded carbonyl groups include bond arrangements at the 2, 3, 4, 5, or 6 positions of a pyridine ring, the 3, 4, 5, or 6 positions of a pyridazine ring, the 2, 4, 5, or 6 positions of a pyrimidine ring, the 2, 3, 5, or 6 positions of a pyrazine ring, the 2, 3, 4, or 5 positions of a furan, tetrahydrofuran, thiophene, thiazole, pyrrole, or tetrahydropyrrole ring, the 2, 4, or 5 positions of an oxazole, imidazole, or thiazole ring, the 3, 4, or 5 positions of an isoxazole, pyrazole, or isothiazole ring, the 2 or 3 positions of an aziridine ring, the 2, 3, or 4 positions of an azetidine ring, the 2, 3, 4, 5, 6, 7, or 8 positions of a quinoline ring, or the 1, 3, 4, 5, 6, 7, or 8 positions of an isoquinoline ring.

[0035] In some embodiments, the heterocyclic group or heteroaryl group is N-linked. By way of example, nitrogen-bonded heterocyclic or heteroaryl groups include the following bonding arrangements: the 1 position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, dihydroindole, 1H-indazole; the 2 position of isoindole or isoindolinone; the 4 position of morpholine; and the 9 position of carbazole or β-carboline.

[0036] "Fused" means any ring structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with an existing ring structure in the compounds described herein.

[0037] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens are replaced by halogens. Examples of haloalkyls are trifluoromethyl, difluoromethyl, and fluoromethyl. A substituted haloalkyl is a haloalkyl that has moieties other than halogens.

[0038] As used herein, a wavy line intersecting a bond in a chemical structure represents the point of attachment of the atom connected to the wavy bond in the chemical structure to the remainder of the molecule or the remainder of the molecular fragment.

[0039] In certain embodiments, the divalent group in the general description does not have a specific bonding configuration. It should be understood that, unless otherwise specified, the general description is intended to include both bonding structures. For example, unless otherwise indicated, in the group R 1 -R 2 -R 3 if the group R 2 is described as -CH 2 C(O)-, it should be understood that the group can bond as R 1 -CH 2 C(O)-R 3 and R 1 -C(O)CH 2 -R 3 bonded.

[0040] The term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal (e.g., a human) in an appropriate manner.

[0041] The compounds described herein may be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base and are biologically or otherwise desirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0042] The term "pharmaceutically acceptable base addition salts" includes those salts derived from inorganic bases such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Specific base addition salts are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0043] In some embodiments, the salt is selected from hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, mesylate, tosylate, bisulfate, benzenesulfonate, esylate, malonate, cinchomeronate, ascorbate, oleate, nicotinate, saccharin, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), naphthalenedisulfonate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), esylate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isothiocyanate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, oxalate, malonate, methylbenzenesulfonate (2-mesylate), naphthalenesulfonate (2-naphthalenesulfonate), camphorsulfonate (camphor-10-sulfonate, e.g., 6(1S)-(+)-10-camphorsulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylenesulfonate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

[0044] The term "stereoisomers" refers to compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space. Stereoisomers include diastereomers, enantiomers, atropisomers, conformational isomers, etc.

[0045] The term "chiral" refers to the property of non - superposability with its mirror image, while the term "achiral" refers to a molecule that is superposable on its mirror image.

[0046] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, e.g., melting point, boiling point, spectroscopic properties, or biological activity. A mixture of diastereomers can be separated under high - resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0047] The term "enantiomer" refers to two stereoisomers of a compound that are non - superposable mirror images of each other.

[0048] The term "atropisomer" refers to two conformational isomers generated by hindered rotation about a single bond, where the rotational steric strain barrier can be high enough to allow the separation of the conformational isomers.

[0049] The stereochemical definitions and conventions used herein generally follow S.P. Parker, editor, McGraw - Hill Dictionary of Chemical Terms (1984), McGraw - Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane - polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to denote the sign of the rotation of the compound for plane - polarized light, where (-) or l indicates that the compound is levorotatory. A compound with the prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except for being mirror images of each other. A specific stereoisomer can also be called an enantiomer, and a mixture of such isomers is usually called a racemic mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in chemical reactions or processes without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomeric species.

[0050] The terms "tautomer" or "tautomeric form" refer to structural isomers of different energies that interconvert via a low energy barrier. For example, prototropic tautomers (also known as prototropic tautomerides) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0051] Certain compounds described herein may exist in unsolvated as well as solvated forms, including hydrated forms. "Solvate" refers to an association or complex of one or more solvent molecules with a compound described herein. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. Certain compounds described herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are contemplated herein. The term "hydrate" refers to a complex wherein the solvent molecule is water.

[0052] The compounds and their pharmaceutically acceptable salts described herein also encompass isotopically labeled compounds, which are identical to the compounds listed herein, but in fact, one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. All isotopes of any particular atom or element designated herein and their uses are contemplated. Exemplary isotopes that can be incorporated into the compounds or their pharmaceutically acceptable salts described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. Certain isotopically labeled compounds or their pharmaceutically acceptable salts described herein (e.g., 3 H and 14 C labeled compounds) can be used in compound and / or substrate tissue distribution assays. Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes can be used because they are readily prepared and detected. In addition, heavier isotopes such as deuterium (i.e., 2H) Substitutions may provide certain therapeutic advantages due to their higher metabolic stability (e.g., extended in vivo half-life or reduced dose requirements) and may thus be preferably used in certain situations. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds or their pharmaceutically acceptable salts described herein can generally be prepared by procedures similar to those disclosed in the examples herein below by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0053] The compounds and their pharmaceutically acceptable salts described herein may contain one or more asymmetric carbon atoms. Accordingly, the compounds can exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds can utilize racemates, diastereomers, or enantiomers as starting materials or intermediates. Mixtures of specific diastereomeric compounds can be separated or enriched in one or more specific diastereomers by chromatography or crystallization. Similarly, enantiomeric mixtures can be separated or enriched in enantiomers using the same techniques or other techniques known in the art. Each of the asymmetric carbon or nitrogen atoms can be of the R or S configuration, and both of these configurations are contemplated herein.

[0054] In the structures shown herein, where no specific stereochemistry is assigned to any particular chiral atom, all stereoisomers are contemplated and included. When the stereochemistry is specified by a solid wedge or a dashed line representing a specific configuration, then that stereoisomer is assigned and defined. Unless otherwise stated, if a solid wedge or a dashed line is used, then the relative stereochemistry is meant.

[0055] "Subject", "individual", or "patient" is a vertebrate and is used interchangeably herein. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, livestock (such as cattle), sport animals, pets (such as guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human. In embodiments that include administering a compound to a patient, the patient generally requires the compound.

[0056] The terms "inhibit" and "reduce", or any variant of these terms, include any measurable decrease or complete inhibition to achieve the desired result. For example, compared to normal levels, the activity can be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therefrom.

[0057] The term "treatment" refers to a clinical intervention that is intended to alter the natural course of a patient or cell being treated during a clinicopathological process. Desirable treatment outcomes include reducing the rate of disease progression, slowing or alleviating the disease state, and relieving or improving the prognosis. For example, a patient is successfully "treated" if one or more symptoms associated with the cancer described herein are reduced or eliminated, including but not limited to reducing cancer cell proliferation (or destroying cancer cells), alleviating symptoms caused by the disease, improving the quality of life of a patient suffering from the disease, reducing the dosage of other medications required to treat the disease, and / or extending the survival period of the patient.

[0058] The term "delayed progression" of a disease refers to delaying, hindering, slowing, retarding, stabilizing, and / or postponing the progression of the cancer described herein. Such delay can have different time lengths, depending on the cancer history and / or the patient to be treated. It will be apparent to those skilled in the art that sufficient or significant delay can actually encompass prevention, as the patient does not develop cancer or relapse.

[0059] "Mutation KRas-mediated disease" and the like refer to the diseases (such as the cancers described herein) that have symptoms as described herein or require treatment, and these symptoms are completely or partially associated with, as a result of, a function of, or otherwise related to the mutation KRas activity described herein. In one embodiment, the mutant KRas is any G12 mutant of KRas.

[0060] The term "pan-KRas" as used herein refers to an inhibitor as described herein that inhibits the activity of mutant KRas protein. In some embodiments, the mutant KRas protein contains a mutation corresponding to position 12 (G12).

[0061] "KRasG12X mutation" refers to a mutant KRas protein having a mutation at the position corresponding to Gly12. In some embodiments, the mutation corresponds to G12A, G12C, G12D, G12R, G12S, G12V. In another embodiment, the mutation corresponds to G12C, G12D, G12R, or G12V.

[0062] "Effective amount" or "therapeutically effective amount" is the minimum amount required to at least achieve a measurable improvement or prevention of the cancer described herein. The effective amount herein can vary depending on factors such as the patient's disease state, age, gender, and weight, as well as the ability of the agent to elicit the desired response in the patient. The effective amount is also the amount where the therapeutic beneficial effects exceed any toxic or detrimental effects of the treatment. Beneficial or desired clinical outcomes include outcomes such as: elimination or reduction of risk, alleviation of severity, delaying the onset of the disease (including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that occur during the progression of the disease), reduction of one or more symptoms caused by the disease, improvement of the quality of life of patients suffering from the disease, reduction of the dosage of other medications required to treat the disease, enhancement of the effect of another medication (such as by targeting), delaying disease progression, and / or prolonging survival. In some embodiments, the effective amount of the drug may have the following effects: reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slowing or stopping) the invasion of cancer cells into surrounding organs; inhibiting (i.e., slowing or stopping) tumor metastasis; inhibiting (i.e., slowing or stopping) tumor growth; and / or alleviating one or more of the symptoms associated with the disorder. The effective amount can be administered once or multiple times.

[0063] "Administration period" or "cycle" refers to the time period that includes the administration of one or more of the compounds or their pharmaceutically acceptable salts or additional therapeutic agents (i.e., chemotherapeutic agents) described herein and an optional time period that does not include the administration of one or more of the agents or compounds described herein. "Rest period" refers to the time period during which at least one of the agents or compounds described herein is not administered. In one embodiment, the rest period refers to the time period during which the agents or compounds described herein are not administered. In some cases, as provided herein, the rest period may include the administration of additional agents in the absence of the compounds or their pharmaceutically acceptable salts described herein, and vice versa. In such cases, the administration of any agent during the rest period should not interfere with or impair the administration of the compounds or their pharmaceutically acceptable salts described herein.

[0064] "Dosing regimen" refers to the administration period of the compounds or their pharmaceutically acceptable salts described herein, which includes one or more cycles, where each cycle may include the administration of the compounds or their pharmaceutically acceptable salts described herein in different amounts at different times.

[0065] "QD" refers to the administration of the compound or its pharmaceutically acceptable salt once daily.

[0066] "BID" refers to the administration of the compound or its pharmaceutically acceptable salt twice daily.

[0067] As used herein, the terms "co-administer," "administered in combination with," and their grammatical equivalents include the administration of two or more agents to an animal (including a human) such that the agents and / or their metabolites are present in the animal's body at the same time. Co-administration includes simultaneous administration in separate compositions, administration in separate compositions at different times (i.e., sequentially), or administration in a composition in which both agents are present.

[0068] "1L therapy" refers to first-line therapy administered to cancer patients who have not received prior treatment. Similarly, 2L, 3L, etc. refer to subsequent therapies administered to the patient.

[0069] The term "package insert" is used to refer to the instructions typically included in the commercial packaging of a therapeutic product, which contain information regarding indications, usage, dosage, administration, contraindications, and / or warnings related to the use of such therapeutic product.

[0070] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds that inhibit the biological function of a target protein by inhibiting the activity or expression of a protein (such as a mutant form of KRas). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological action of the target protein. Although the preferred antagonists herein interact specifically (e.g., bind) with the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included in this definition. The preferred biological activities inhibited by antagonists are associated with the development, growth, or spread of tumors.

[0071] As used herein, the term "agonist" refers to a compound that is capable of initiating or enhancing the biological function of a target protein by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological action of the target polypeptide. Although the preferred agonists herein interact specifically (e.g., bind) with the target, compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included in this definition.

[0072] The terms “cancer” and “cancerous,” “neoplasm” and “tumor,” and related terms are used interchangeably herein and refer to or describe a physiological condition in a mammal that is generally characterized by uncontrolled cell growth. A “tumor” comprises one or more cancer cells. Examples of cancers include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma) and lung cancer, including small cell lung cancer, non-small cell lung cancer (“NSCLC”), lung adenocarcinoma, and lung squamous carcinoma. Other cancers include skin cancer, actinic keratosis, follicular carcinoma, hairy cell leukemia, oral cancer, pharyngeal (throat) cancer, lip cancer, tongue cancer, mouth cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, stomach cancer, gastric tumor, gastrointestinal cancer, small intestine cancer, colorectal cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, urinary tract tumor, biliary tract cancer, thyroid cancer, papillary carcinoma, liver tumor, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penile cancer, bone cancer, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system tumor, brain cancer, head and neck cancer, Hodgkin's disease, and related metastases. Other examples of neoplastic disorders include myeloproliferative disorders, such as polycythemia vera, essential thrombocythemia, myelofibrosis (such as primary myelofibrosis), and chronic myelogenous leukemia (CML).

[0073] A “chemotherapeutic agent” is an agent that can be used to treat a given condition (e.g., cancer or an inflammatory condition). Examples of chemotherapeutic agents are well known in the art. Additionally, chemotherapeutic agents include any pharmaceutically acceptable salt, acid, or derivative of any chemotherapeutic agent, as well as combinations of two or more of them.

[0074] Specifically contemplated is that any limitation discussed with respect to one embodiment provided herein can be applied to any other embodiment provided herein. Additionally, any compound described herein and its pharmaceutically acceptable salts or the compositions described herein can be used in any method provided herein, and any method provided herein can be used to produce or utilize any compound described herein and its pharmaceutically acceptable salts or the compositions described herein.

[0075] Throughout this application, the term “about” is used to indicate that a value includes the standard deviation of the error of the device or method used to determine the value.

[0076] Compound

[0077] Provided herein are compounds of formula (I) or their atropisomers, stereoisomers, tautomers, or pharmaceutically acceptable salts:

[0078]

[0079] Wherein,

[0080] Ring A is R 8 a substituted or unsubstituted 3- to 10-membered heterocyclic ring, or R 8 a substituted or unsubstituted 5- to 10-membered heteroaryl;

[0081] R 8 is independently halogen, CN, NH 2 、NHC 1-3 alkyl, R 8A a substituted or unsubstituted C 1-6 alkyl, or R 8A a substituted or unsubstituted C 1-6 haloalkyl;

[0082] R 8A is halogen, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl;

[0083] n is 1 or 2;

[0084] R 1 is R 7 a substituted or unsubstituted indolyl, R 7 a substituted or unsubstituted benzofuranyl, R 7 a substituted or unsubstituted naphthyl, R 7 a substituted or unsubstituted indazolyl, R 7 a substituted or unsubstituted indenyl, R 7 a substituted or unsubstituted benzothiazolyl, R 7 a substituted or unsubstituted isoquinolyl, R 7A a substituted or unsubstituted phenyl or R 7A a substituted or unsubstituted pyridyl;

[0085] Each R 7 is independently hydrogen, halogen, CN, CH 2 OH, -OH, NH 2 、N(Me) 2 、unsubstituted C 1-3 alkyl, unsubstituted C 2-5 alkynyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl;

[0086] Each R 7a is independently hydrogen, halogen, NH 2 、N(Me) 2 、unsubstituted C 1-3 alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl;

[0087] R 2 is OH, unsubstituted C 1-3 alkoxy, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl;

[0088] R 3 is R 9 a substituted or unsubstituted 4- to 10-membered heterocycle containing N, S or O;

[0089] R 9 is independently halogen, oxo, unsubstituted C 1-3 alkyl, unsubstituted C 1-3 haloalkyl, unsubstituted C 1-3 alkoxy, R 10 substituted or unsubstituted C 1-3 alkylidene, or R 10 substituted or unsubstituted C 3-4 cycloalkyl, or R 10 substituted or unsubstituted 3- or 4-membered heterocycle;

[0090] Or two of the Rs 9 together form a C 3-5 cycloalkyl or 3- to 5-membered heterocycle;

[0091] R 10 is hydrogen or halogen;

[0092] R 4 is hydrogen, halogen, unsubstituted C 1-3 alkyl, unsubstituted C 1-3 alkoxy, or unsubstituted C 1-3 haloalkyl; and

[0093] R 5 and R 6 are each independently hydrogen or unsubstituted C 1-3 alkyl.

[0094] In one embodiment of the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, R 5 and R 6 are each hydrogen. In another embodiment, R 5 is CH 3 and R 6 is hydrogen. In another embodiment, R 6 is hydrogen or unsubstituted C 1-3 alkyl. In another embodiment, R 6 is CH 3 and R 5 is hydrogen.

[0095] In one embodiment, a compound of formula (I) or a atropisomer, stereoisomer, tautomer or pharmaceutically acceptable salt thereof comprises formula (Ia):

[0096]

[0097] wherein R 1 、R 2 、R 3 、R 4 、R 8 、ring A and n are as described herein.

[0098] In one embodiment of the compounds or stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts thereof described herein, R 1 is an R 7 substituted or unsubstituted indolyl, R 7 substituted or unsubstituted benzofuranyl, R 7 substituted or unsubstituted naphthyl, R 7 substituted or unsubstituted indazolyl, R 7 substituted or unsubstituted indenyl, R 7 substituted or unsubstituted benzothiazolyl, R 7 substituted or unsubstituted isoquinolinyl, R 7A substituted or unsubstituted phenyl, or R 7A substituted or unsubstituted pyridyl.

[0099] In another embodiment, R 1 is an R 7 substituted or unsubstituted indolyl, R 7 substituted or unsubstituted benzofuranyl, R 7 substituted or unsubstituted naphthyl, R 7 substituted or unsubstituted indazolyl, R 7 substituted or unsubstituted indenyl, R 7 substituted or unsubstituted benzothiazolyl, or R 7 substituted or unsubstituted isoquinolinyl. In another embodiment, R 1 is an R 7 substituted or unsubstituted naphthyl, or R 7 substituted or unsubstituted isoquinolinyl.

[0100] In one embodiment, R 1 is an R 7 substituted or unsubstituted naphthyl, or R 7 substituted or unsubstituted isoquinolinyl. In another embodiment, R 1 is an R 7A substituted or unsubstituted phenyl, or R 7ASubstituted or unsubstituted pyridyl. In another embodiment, R 1 is

[0101] wherein R 7 is as defined herein.

[0102] In another embodiment, R 1 is

[0103]

[0104] In another embodiment, R 1 is

[0105]

[0106] In some embodiments, each R 7 is independently hydrogen, halogen, CN, CH 2 OH, -OH, NH 2 , N(Me) 2 , unsubstituted C 1-3 alkyl, or unsubstituted C 2-5 alkynyl. In one embodiment, each R 7 is independently hydrogen, halogen, -OH, NH 2 , N(Me) 2 , unsubstituted C 1-3 alkyl, or unsubstituted C 2-5 alkynyl. In another embodiment, each R 7 is independently hydrogen, halogen, -OH, NH 2 , methyl, ethyl or unsubstituted C 2-3 alkynyl. In another embodiment, each R 7 is independently halogen or -OH. In another embodiment, each R 7 is independently halogen, -OH, NH 2 or unsubstituted C 2-3 alkynyl.

[0107] In one embodiment, R 1 is R 7A substituted or unsubstituted phenyl or R 7A substituted or unsubstituted pyridyl. In one such embodiment, R 1 is R 7A substituted or unsubstituted phenyl. In another such embodiment, R 1 is R 7A substituted or unsubstituted pyridyl.

[0108] In one embodiment, R1 wherein X

[0109] is N, CH, CF or CCl; and R 1 is hydrogen, halogen, unsubstituted C 7A alkyl, or unsubstituted C 1-3 alkyl 1-3 haloalkyl.

[0110] In one embodiment, R 1 is a moiety having formula (A), X 1 is N, and R 7A is as described herein. In another embodiment, R 1 is a moiety having formula (B), X 1 is N, and R 7A is as described herein. In yet another embodiment, R 1 is a moiety having formula (A), X 1 is CH, CF or CCl, wherein R 7A is as described herein.

[0111] In some embodiments, R 1 is

[0112]

[0113] wherein

[0114] X 1 is N, CH, CF or CCl; and

[0115] R 7A is hydrogen, halogen, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl.

[0116] In one such embodiment, the moiety having formula (A) comprises a moiety wherein R 1 is as follows,

[0117]

[0118] wherein R 7A is hydrogen, halogen, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl.

[0119] In one embodiment, R 1 is

[0120]

[0121] In some embodiments, R1 is

[0122]

[0123] wherein R 7A is hydrogen, a halogen, an unsubstituted C 1-3 alkyl, or an unsubstituted C 1-3 haloalkyl.

[0124] In some embodiments, R 1 is

[0125]

[0126] wherein R 7A is hydrogen, F or Cl. In one such embodiment, R 7A is F. In another such embodiment, R 7A is Cl. In one embodiment, R 7A is methyl. In one embodiment, R 7A is hydrogen.

[0127] In some embodiments, further provided herein is a moiety of R 1 as follows,

[0128]

[0129] wherein R 7A is hydrogen, F or Cl. In one such embodiment, R 7A is F. In another such embodiment, R 7A is Cl. In one embodiment, R 7A is methyl. In one embodiment, R 7A is hydrogen.

[0130] In one embodiment of the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, R 1 is

[0131] In another embodiment of the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, R 1 is

[0132] In yet another embodiment of the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, R 1 is

[0133] In one embodiment, each R 7a is independently hydrogen, halogen, NH 2 , unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl. In another embodiment, each R 7a is independently hydrogen, F, Cl, NH 2 , methyl or CF 3 .

[0134] In one embodiment of the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, R 4 is unsubstituted C 1-3 alkyl, unsubstituted C 1-3 alkoxy, or unsubstituted C 1-3 haloalkyl. In one such embodiment, R 4 is OCH 3 . In another embodiment, R 4 is Cl or F. In one such embodiment, R 4 is F. In another such embodiment, R 4 is Cl. In one embodiment, R 1 is a moiety having formula (A) as described herein, and R 4 is Cl or F. In one such embodiment, R 1 is a moiety having formula (A) as described herein, where X 1 is N, or X 1 is CH, CF or CCl, and R 4 is F. In another such embodiment, R 1 is a moiety having formula (A) as described herein, where X 1 is N, or X 1 is CH, CF or CCl, and R 4 is Cl. In such embodiments, R 7A is hydrogen, halogen, methyl and / or CF 3 , as described herein.

[0135] In another embodiment, R 1 is a moiety having formula (C), (C1), (C2) or (C3) as described herein, where R 4 is Cl or F. In one such embodiment, R 4 is F. In another such embodiment, R 4 is Cl.

[0136] In one embodiment of the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, R3 is R 9 a 4- to 10-membered heterocycle, substituted or unsubstituted, containing one or more N or O ring heteroatoms. In one such embodiment, R 3 is R 9 a 4- to 10-membered heterocycle, substituted or unsubstituted, containing one or more N heteroatoms. In one such embodiment, the heterocycle contains 1 or 2 ring N heteroatoms.

[0137] In one embodiment, R 3 is

[0138]

[0139] wherein

[0140] Z is C(R 9 ) 2 or O;

[0141] R 9 is hydrogen, halogen, or R 10 substituted or unsubstituted C 1-3 alkylidene;

[0142] or two Rs 9 together form C 3-5 cycloalkyl or a 3- to 5-membered heterocycle

[0143] r is an integer from 0 to 12;

[0144] j is 1, 2, or 3; and

[0145] k is 1 or 2.

[0146] In one embodiment, Z is O and k is 2. In another embodiment, Z is O, k is 2, and j is 2. In another embodiment, Z is C(R 9 ) 2 , where R 9 is as described herein, k is 1, and j is 2. In one embodiment, R 3 is

[0147]

[0148] wherein

[0149] R 9 is halogen, -OCF 3 , -OCHF 2 , -OCH 2 F, R 10 substituted or unsubstituted C 1-3 alkylidene, or two Rs 9 together form R 10Substituted or unsubstituted C 3-5 cycloalkyl;

[0150] r is an integer from 0 to 12;

[0151] j is 1, 2 or 3; and

[0152] k is 1 or 2.

[0153] In one embodiment, wherein R 3 is a moiety having formula (D), R 9 is halogen, R 10 substituted or unsubstituted C 1-3 alkylidene, or two R's 9 together form R 10 substituted or unsubstituted C 3-5 cycloalkyl. In one such embodiment, two R's 9 form R 10 substituted or unsubstituted cyclopropyl. In one such embodiment, R 10 is halogen (e.g., F). In another embodiment, wherein R 3 is a moiety having formula (D), k is 1, j is 2, and R 9 is as described herein, and r is 0, 1, 2, 3 or 4. In one embodiment, R 9 is halogen, or R 10 substituted or unsubstituted C 1-3 alkylidene, and r is 2 or 3. In one embodiment, R 3 is

[0154]

[0155] Each R 9 is independently halogen, or R 10 substituted or unsubstituted C 1-3 alkylidene;

[0156] Each R 10 is independently hydrogen or halogen;

[0157] r is 0, 1 or 2; and

[0158] s is 0, 1 or 2

[0159] In one embodiment, R 3 is a moiety having (D1), (D2) or (D3), wherein

[0160] Each R 9 is independently halogen, or R 10 substituted or unsubstituted C 1-3 alkylidene;

[0161] Each R 10 is independently hydrogen or halogen;

[0162] r is 1 or 2; and

[0163] s is 0, 1 or 2.

[0164] In another embodiment, R 3 is (D1), where r is 1. In another embodiment, R 3 is (D2), where r is 0 and each R 10 is independently hydrogen or F. In another embodiment, R 3 is (D3), where r is 0 and each R 9 is independently hydrogen or halogen. In another embodiment, R 3 is (D4), where R 10 is halogen, and s is 0, 1 or 2.

[0165] In one embodiment, R 3 is

[0166]

[0167] In one embodiment, R 3 is

[0168] where R 10 is halogen, and s is 0, 1 or 2. In one such embodiment, R 10 is F, and s is 1 or 2.

[0169] In one embodiment, R 3 is

[0170] wherein each R 9 is independently halogen, oxo, or unsubstituted C 1-3 alkyl; and

[0171] r is 0, 1 or 2. In one such embodiment, R 9 is F, and r is 1 or 2.

[0172] In one embodiment, R 3 is

[0173] wherein each R 9 is independently halogen, oxo, or unsubstituted C 1-3 alkyl; and

[0174] r is 0, 1 or 2. In one embodiment, R 9is a halogen and r is 1. In another embodiment, r is 0. In one embodiment, the moiety having formula (F) comprises a compound having formula .

[0175] In another embodiment, R 3 is

[0176] wherein

[0177] each R 9 is independently a halogen, oxo, or unsubstituted C 1-3 alkyl;

[0178] or two of the Rs 9 together form a C 3-5 cycloalkyl or a 3- to 5-membered heterocycle; and r is 1 or 2.

[0179] In one embodiment, R 3 is

[0180] wherein

[0181] each R 9 is independently a halogen, oxo, or unsubstituted C 1-3 alkyl;

[0182] or two of the Rs 9 together form a C 3-5 cycloalkyl or a 3- to 5-membered heterocycle; and

[0183] r is 1 or 2. In one such embodiment, R 9 is a halogen and r is 1 or 2. In one such embodiment, R 9 is a halogen and r is 1.

[0184] In one embodiment, R 3 is

[0185] In one embodiment of the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts described herein, R 2 is OH or unsubstituted C 1-3 alkoxy. In one such embodiment, R 2 is OH. In another embodiment, R 2 is unsubstituted C 1-3 alkoxy or unsubstituted C 1-3 alkyl. In another embodiment, R 2 is unsubstituted C 1-3 alkyl, or unsubstituted C 1-3Halogenoalkyl. In one such embodiment, R 2 is CHF 2 、CH 2 F or CF 3 。In another embodiment, R 2 is unsubstituted C 1-3 alkyl. In one such embodiment, R 2 is methyl.

[0186] In one embodiment of the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts described herein, ring A is an R 8 substituted or unsubstituted 3- to 10-membered heterocycle, or an R 8 substituted or unsubstituted 5- to 10-membered heteroaryl, as described herein. In one embodiment, ring A is an R 8 substituted or unsubstituted 3- to 6-membered heterocycle containing at least 1 heterocyclic ring nitrogen atom, or an R 8 substituted or unsubstituted 5- to 6-membered heteroaryl containing at least 1 heterocyclic ring nitrogen atom. In one such embodiment, the heterocycle or heteroaryl contains 1 or 2 ring nitrogen atoms. In another embodiment, ring A is an R 8 substituted or unsubstituted 5- or 6-membered heterocycle containing at least 1 heterocyclic ring nitrogen atom. In another embodiment, ring A is an R 8 substituted or unsubstituted 6-membered heteroaryl containing at least 1 heterocyclic ring nitrogen atom. In one embodiment, ring A is an R 8 substituted or unsubstituted pyridyl, an R 8 substituted or unsubstituted pyrimidinyl or an R 8 substituted or unsubstituted pyrazinyl.

[0187] In another embodiment, ring A is a moiety having the formula:

[0188]

[0189] wherein X is CH or N, and n is 1 or 2. In one such embodiment, wherein ring A is a moiety having formula (H), X is N, and n is 1.

[0190] In one embodiment, wherein ring A is a moiety having formula (H) or (H1), R 8 is independently halogen, CN, NH 2 、or an R 8A substituted or unsubstituted C 1-6 alkyl. In another embodiment, R 8 is independently halogen, CN or NH 2 。In another embodiment, R 8 is independently an R 8A substituted or unsubstituted C1-6 alkyl, or R 8A substituted or unsubstituted C 1-6 haloalkyl. In another embodiment, R 8 is NH 2 In another embodiment, R 8 is NH 2 and n is 1.

[0191] In another embodiment, ring A is a moiety having the formula:

[0192]

[0193] wherein X is CH or N. In one embodiment, X is CH. In one embodiment, X is N.

[0194] In some embodiments, ring A is a moiety having the formula:

[0195]

[0196] In one embodiment of the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, ring A is a moiety having the formula:

[0197]

[0198] In one embodiment of a compound having formula (I) or (Ia) described herein or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, the compound comprises the structural formula (II):

[0199]

[0200] including its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 , R 2 , R 4 , R 5 , R 8 , R 9 , n, r and ring A are as described herein.

[0201] In one embodiment of a compound having formula (II) described herein or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, the compound of formula (II) comprises the following structure:

[0202]

[0203]

[0204] including its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts.

[0205] In one embodiment of a compound of formula (II), (IIIa), (IIb) or (IIc) as described herein, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, R 9 is independently halogen, or R 10 substituted or unsubstituted C 1-3 alkylidene; each R 10 is independently hydrogen or halogen; and r is 1 or 2. In another such embodiment, two R 9 together form C 3-5 cycloalkyl or a 3- to 5-membered heterocycle. In one such embodiment, two R 9 together form R 10 substituted or unsubstituted cyclopropyl. In one such embodiment, R 10 is hydrogen or F. In one embodiment, the compound comprises the following moiety:

[0206]

[0207] Also provided herein are compounds of formula (III) or stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts thereof:

[0208]

[0209] including stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 4 , R 5 , R 8 , R 9 , n, r and ring A are as described herein.

[0210] In one embodiment of a compound of formula (III) as described herein, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, the compound of formula (III) comprises the following structure:

[0211]

[0212]

[0213] including stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts thereof. In one embodiment of a compound of formula (III), (IIIa), (IIIb) or (IIIc) as described herein, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, it comprises the following moiety:

[0214]

[0215] The present invention further provides a compound of formula (IV) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof:

[0216]

[0217] including its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 、R 2 、R 4 、R 5 、R 8 、R 9 、n, r and ring A are as described herein.

[0218] In one embodiment of a compound of formula (IV) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof as described herein, the compound of formula (IV) comprises the following structure:

[0219]

[0220] including its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts. In one embodiment of a compound of formula (IV), (IVa), (IVb) or (IVc) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof as described herein, it comprises the following moiety:

[0221]

[0222] The present invention further provides a compound of formula (V) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof:

[0223]

[0224] including its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 、R 2 、R 4 、R 5 、R 8 、R 9 、n, r and ring A are as described herein.

[0225] In one embodiment of a compound of formula (IV) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof as described herein, the compound of formula (IV) comprises the following structure:

[0226]

[0227] including its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts. In one embodiment of a compound having the formula (V), (Va), (Vb) or (Vc) described herein, or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, it comprises the following moiety:

[0228]

[0229] In one embodiment of a compound having the formula (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), (IVc), (V), (Va), (Vb) or (Vc) described herein, or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, ring A comprises a moiety having the following formula:

[0230]

[0231] In one embodiment of a compound having the formula (II), (IIb), (IIc), (III), (IIIb), (IIIc), (IV), (IVb), (IVc), (V), (Vb) or (Vc) described herein, or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, X 1 is N, and each R 7a is independently hydrogen, halogen, NH 2 , unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl. In another such embodiment, wherein the compound has the formula (IIb) as described herein, X 1 is CH, CF or CCl, and each R 7a is independently hydrogen, F, Cl, NH 2 , methyl or CF 3 . In one embodiment of a compound having the formula (II), (IIb) or (IIc) described herein, or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, the compound comprises the following moiety:

[0232]

[0233]

[0234] In one embodiment of a compound having the formula (I), (Ia), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), (IVc), (V), (Va), (Vb) or (Vc) described herein, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, the compound is a compound shown in Table 1 below.

[0235] Table 1: Representative Compounds

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245] In one embodiment of a compound having the formula (I), (Ia), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), (IVc), (V), (Va), (Vb) or (Vc) described herein, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, the compound is a compound shown in Table 2 below.

[0246] Table 2: Representative Compounds

[0247]

[0248]

[0249] In one embodiment of a compound having Formula (I), (Ia), (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), (IVc), (V), (Va), (Vb), or (Vc) as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, the compound is a compound shown in Table 3 below.

[0250] Table 3: Additional Representative Compounds

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] Synthesis of the Compounds

[0260] The compounds of the present disclosure, or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, as described herein, can be prepared by various methods described in the exemplary synthetic reaction schemes shown and described below. The starting materials and reagents for the preparation of these compounds are generally available from commercial suppliers such as Aldrich Chemical Co., or can be prepared by methods known to those skilled in the art according to the methods described in the following references, such as: Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, Volumes 1 - 21; R.C. LaRock, Comprehensive Organic Transformations, 2nd Edition, Wiley - VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (eds.), Volumes 1 - 9, Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A.R. Katritzky and C.W. Rees (eds.) Pergamon, Oxford 1984, Volumes 1 - 9; Comprehensive Heterocyclic Chemistry II, A.R. Katritzky and C.W. Rees (eds.), Pergamon, Oxford 1996, Volumes 1 - 11; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1 - 40. The synthetic reaction schemes provided herein are merely illustrative of some of the methods by which the compounds or their pharmaceutically acceptable salts described herein can be synthesized, and various modifications to these synthetic reaction schemes can be made and suggestions provided to those skilled in the art with reference to the disclosure contained herein.

[0261] Synthetic chemical transformations and protecting group methods (protection and deprotection) useful in synthesizing the compounds described herein, as well as the necessary reagents and intermediates, include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and its subsequent editions.

[0262] Compounds as described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be prepared individually or as a compound library comprising at least 2, e.g., 65 to 1000 compounds or 10 to 100 compounds. Libraries of compounds as described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, having a formula as described herein can be prepared by combinatorial split and pool methods or by multiple parallel syntheses using, for example, solution-phase or solid-phase chemistry. Accordingly, in another aspect, the present disclosure provides a compound library comprising at least 2 compounds as described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts.

[0263] Examples provide exemplary methods for preparing compounds as described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. Those skilled in the art will understand that other synthetic routes can be used to synthesize compounds as described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. Although specific starting materials and reagents are described and discussed in the examples, other starting materials and reagents can be substituted to provide various derivatives and / or reaction conditions. In addition, in view of the present disclosure, many of the exemplary compounds prepared by the methods can be further modified using conventional chemical methods.

[0264] In the preparation of the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein, it may be necessary to protect the distal functional groups (e.g., primary or secondary amines) of the intermediates. The need for such protection will vary depending on the nature of the distal functionality and the conditions of the preparation method. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyloxycarbonyl (Fmoc). The need for such protection can be readily determined. For general descriptions of protecting groups and their use, see: T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0265] In the methods for preparing the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein, it is advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified to the desired degree of homogeneity by techniques common in the art. Such separations typically involve multiphase extraction, crystallization from solvents or solvent mixtures, distillation, sublimation, or chromatography. Chromatography can involve any of a variety of methods, including, for example: reverse-phase and normal-phase chromatography; size-exclusion chromatography; ion-exchange chromatography; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatuses; small-scale analytical chromatography; simulated moving bed (SMB) and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer methods and flash chromatography techniques.

[0266] Another class of separation methods involves treating the mixture with a reagent selected to bind to or otherwise render separable the desired product, unreacted starting material, reaction by-products, etc. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion-exchange media, etc. Alternatively, the reagent can be an acid (in the case of basic materials); a base (in the case of acidic materials); a binding reagent such as an antibody, a binding protein, a selective chelating agent such as a crown ether; a liquid / liquid ion extraction reagent (LIX), etc. The choice of a suitable separation method depends on the nature of the materials involved, such as the boiling point and molecular weight for distillation and sublimation, the presence of polar functional groups in chromatography, the stability of the materials in acidic and basic media in multiphase extraction, etc.

[0267] A mixture of diastereomers can be separated into its individual diastereomers based on differences in the physicochemical properties of the diastereomers by methods such as chromatography and / or fractional crystallization. Enantiomers can be separated by reacting a mixture of enantiomers with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride) to convert the mixture of enantiomers into a mixture of diastereomers, separating the diastereomers, and converting the individual diastereomers (e.g., by hydrolysis) into the corresponding pure enantiomers. Additionally, some of the compounds or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein can be atropisomers (e.g., substituted biaryls). Enantiomers can also be separated using a chiral HPLC column.

[0268] A single stereoisomer, e.g., an enantiomer substantially free of its stereoisomers, can be obtained by methods such as forming diastereomers using an optically active resolving agent (Eliel, E. and Wilen, S. “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283 - 302). A racemic mixture of a chiral compound or its pharmaceutically acceptable salt described herein can be separated and resolved by any suitable method, including: (1) forming an ionic diastereomeric salt with a chiral compound and separating by fractional crystallization or other means; (2) forming a diastereomeric compound with a chiral derivatizing reagent, separating the diastereomers, and converting to the pure stereoisomers; and (3) direct separation of a substantially pure or enriched stereoisomer under chiral conditions. See: “Drug Stereochemistry, Analytical Methods and Pharmacology,” edited by Irving W. Wainer, Marcel Dekker, Inc., New York (1993).

[0269] According to method (1), diastereomeric salts can be formed by reacting enantiopure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), etc. with asymmetric compounds bearing acidic functional groups such as carboxylic acids and sulfonic acids. The separation of diastereomeric salts can be induced by fractional crystallization or ion chromatography. For the separation of the optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can cause the formation of diastereomeric salts.

[0270] Alternatively, by method (2), the substrate to be separated is reacted with one enantiomer of a chiral compound to form a pair of diastereomers (E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting an asymmetric compound with an enantiopure chiral derivatizing reagent such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to obtain pure or enriched enantiomers. Methods for determining optical purity involve the preparation of chiral esters of racemic mixtures, such as menthyl esters, for example, the preparation of (-)-menthyl chloroformate in the presence of a base, or Mosher esters, α-methoxy-α-(trifluoromethyl)phenylacetic acid esters (Jacob III. J. Org. Chem. (1982) 47:4165), and analysis 1 of the 1H NMR spectrum to determine the presence of two atropisomeric enantiomers or diastereomers. The stable diastereomers of atropisomeric compounds can be separated and isolated by normal and reverse phase chromatography, following the method for separating atropisomeric naphthyl-isoquinolines (WO 96 / 15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (“Chiral Liquid Chromatography” (1989) edited by W. J. Lough, Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375 - 378). Enriched or purified enantiomers can be distinguished by methods for discriminating other chiral molecules bearing asymmetric carbon atoms, such as optical rotation or circular dichroism.

[0271] The chemical reactions described herein can be readily adapted to prepare other compounds described herein and their pharmaceutically acceptable salts. For example, by modifications that will be apparent to those skilled in the art, such as by appropriately protecting interfering groups, using other suitable reagents known in the art, or by routine modifications of the reaction conditions, the synthesis of the non-exemplary compounds and their pharmaceutically acceptable salts described herein can be successfully achieved. Alternatively, other reactions disclosed herein or known in the art will be considered applicable to the preparation of other compounds described herein and their pharmaceutically acceptable salts.

[0272] Pharmaceutical formulations

[0273] The present invention also provides pharmaceutical compositions, which comprise a compound or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein and one or more pharmaceutical excipients.

[0274] A compound or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein can be formulated into pharmaceutical compositions according to standard pharmaceutical practice. Accordingly, the present invention further provides a pharmaceutical composition, which comprises a compound or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein, and one or more pharmaceutical excipients.

[0275] Typical formulations are prepared by mixing a compound or its pharmaceutically acceptable salt as described herein with an excipient. Suitable carriers, diluents and excipients include, but are not limited to, materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The particular excipient used will depend on the mode and purpose of administering the compound or its pharmaceutically acceptable salt as described herein. Generally, solvents are selected based on Generally Recognized as Safe (GRAS) solvents for mammals. Usually, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (such as PEG 400, PEG 300), etc. and mixtures thereof. The formulations may also contain one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavoring agents, flavor enhancers and other known additives to provide an aesthetically pleasing presentation of the medicament (i.e., the compound or its pharmaceutical composition as described herein) or to facilitate the preparation of the pharmaceutical product (e.g., the medicament).

[0276] Conventional dissolution and mixing procedures can be used to prepare the formulations. For example, in the presence of one or more of the excipients described above, the active pharmaceutical ingredient (i.e., the compound or its pharmaceutically acceptable salt, or its stable form (e.g., a complex with a cyclodextrin derivative or other known complexing agent) as described herein) is dissolved in a suitable solvent. The compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein are generally formulated into pharmaceutical dosage forms to provide an easily controllable drug dose and to enable the patient to comply with the prescription regimen.

[0277] Depending on the method for administering the drug, the pharmaceutical composition (or formulation) for administration can be packaged in a variety of ways. Generally, the article for distribution includes a container in which the pharmaceutical formulation is deposited in a suitable form. Suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-proof component to prevent inadvertent contact with the contents of the package. In addition, a label describing the contents of the container is provided on the container. Appropriate warnings may also be included on the label.

[0278] The pharmaceutical formulations of the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein can be prepared for various routes and types of administration. For example, the compound or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts having the desired purity can be optionally mixed with one or more pharmaceutical excipients (Remington's Pharmaceutical Sciences (1980) 16th edition, edited by Osol, A.) in the form of a lyophilized formulation, a milled powder or an aqueous solution. It can be formulated by mixing at ambient temperature at an appropriate pH value and the desired purity with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the doses and concentrations employed). The pH of the formulation depends mainly on the specific use and concentration of the compound, but can be in the range of about 3 to about 8. For example, formulation in an acetate buffer at pH 5 can be a suitable example.

[0279] The pharmaceutical composition can generally be stored as a solid composition, a lyophilized formulation or as an aqueous solution.

[0280] The pharmaceutical compositions described herein can be formulated, administered, and dispensed in a manner consistent with good medical practice, i.e., dosage, concentration, schedule, course, vehicle, and route of administration. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site to which the agent is to be delivered, the method of administration, the timing of administration, and other factors known to the practicing physician. The effective amount of the compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts to be administered will be influenced by these considerations and will be the minimum amount necessary to ameliorate or treat the hyperproliferative disorder.

[0281] Generally, the initial therapeutically effective amount of the compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts administered parenterally will be in the range of about 0.01 mg / kg to 100 mg / kg per day (i.e., about 0.1 mg / kg of patient body weight to 20 mg / kg of patient body weight), and a typical initial range of the compound used is 0.3 mg / kg / day to 15 mg / kg / day. In another embodiment, the pharmaceutical compositions described herein comprise an effective amount of the compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein, the amount being about: 1 mg - 10 mg; 10 mg - 25 mg; 20 mg - 50 mg; 50 mg - 75 mg; 70 mg - 100 mg; 100 mg - 150 mg; 100 mg - 200 mg; 100 mg - 500 mg; 200 mg - 500 mg; 250 mg - 500 mg; 500 mg - 1000 mg; or 750 mg - 1000 mg.

[0282] Acceptable pharmaceutical excipients are non-toxic to the recipient at the dosages and concentrations employed and include buffers, such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butanol, or benzyl alcohol; alkyl parabens, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc-protein complexes); and / or nonionic surfactants, such as TWEEN TM , PLURONICS TMor polyethylene glycol (PEG). The active pharmaceutical ingredient can be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), encapsulated in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in a coarse emulsion. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th Edition (Osol, A., Ed. (1980)).

[0283] Sustained-release formulations of the compounds or their pharmaceutically acceptable salts as described herein can be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds or their pharmaceutically acceptable salts as described herein, which matrices are in the form of shaped articles such as membranes or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid (US 3773919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.

[0284] The formulations include those suitable for the routes of administration detailed herein. The formulations can conveniently be in unit dosage form and can be prepared by any method. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of associating the active ingredient with a carrier which constitutes one or more accessory ingredients. In general, the method of preparing a formulation is to uniformly and intimately bring the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0285] Preparations of compounds suitable for oral administration as described herein, or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, can be formulated into discrete units such as pills, capsules, cachets or tablets, each unit containing a predetermined amount of such compound or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets can optionally be coated or scored and can optionally be formulated to provide slow or controlled release of the active ingredient therefrom. Tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules such as gelatin capsules, syrups or elixirs can be prepared for oral use. Preparations of compounds for oral administration as described herein, or their pharmaceutically acceptable salts, can be prepared according to any method used for the preparation of pharmaceutical compositions, and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preservatives to provide palatable preparations. Tablets containing the active ingredient mixed with non-toxic pharmaceutical excipients suitable for the preparation of tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; lubricants such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, delayed release materials such as glyceryl monostearate or glyceryl distearate used alone or in combination with waxes can be used.

[0286] For treating the eye or other external tissues (such as the oral cavity and skin), the preparation is preferably administered in the form of a topical ointment or cream, which contains, for example, an active ingredient in a content of 0.075% w / w to 20% w / w. When formulated as an ointment, the active ingredient can be used with paraffin or a water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can include polyols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, 1,3-butanediol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400) and mixtures thereof. The topical preparation can desirably include a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues. The oil phase of the emulsion of the composition provided herein can be constituted in a known manner from known ingredients. Although this phase can contain only an emulsifier, it desirably contains at least one emulsifier in combination with a fat or an oil or with a mixture of a fat and an oil. Preferably, a hydrophilic emulsifier is used together with a lipophilic emulsifier as a stabilizer. It is also preferred to include both an oil and a fat. The emulsifier with or without a stabilizer together constitutes a so-called emulsifying wax, and the wax together with the oil and the fat constitutes a so-called emulsifying ointment base, forming the oily disperse phase of the cream preparation. Emulsifiers and emulsion stabilizers suitable for the preparations described herein include 60, 80, cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0287] An aqueous suspension containing a compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts as described herein can contain the active substance mixed with excipients suitable for the manufacture of an aqueous suspension. Such excipients include suspending agents such as sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth, and gum arabic, and dispersing or wetting agents such as naturally occurring phospholipids (such as lecithin), condensation products of alkylene oxides with fatty acids (such as, polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (such as, heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fats and hexitol anhydrides (such as, polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

[0288] The pharmaceutical composition of the compound or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. The suspension can be formulated with the appropriate dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or made into a lyophilized powder. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils can conventionally be used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic mono- or di-glycerides of fatty acids. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables.

[0289] The amount of the active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. For example, a sustained-release preparation for oral administration to humans may contain about 1 to 1000 mg of the active substance compounded with a suitable and convenient amount of a carrier substance, which may account for about 5% to about 95% (weight: weight) of the total composition. The pharmaceutical composition can be prepared to provide an easily measurable dosage. For example, an aqueous solution for intravenous infusion can contain about 3 to 500 μg of the active ingredient per milliliter of solution so that a suitable volume can be infused at a rate of about 30 mL / hr.

[0290] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic agents and solutes to render the preparation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.

[0291] Preparations suitable for topical administration to the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent of the active ingredient. The active ingredient is preferably present in such preparations at a concentration of about 0.5% w / w to 20% w / w, for example about 0.5% w / w to 10% w / w, for example about 1.5% w / w.

[0292] Preparations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base (usually sucrose and gum arabic or tragacanth); troches containing the active ingredient in an inert base (such as gelatin and glycerin, or sucrose and gum arabic); and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0293] Preparations for rectal administration can be presented as suppositories with a suitable base containing, for example, cocoa butter or a salicylate.

[0294] Preparations suitable for pulmonary or nasal administration have a particle size, for example, in the range of 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns in increments such as 0.5 microns, 1 micron, 30 microns, 35 microns, etc.), and can reach the alveolar sacs by rapid inhalation through the nasal cavity or by inhalation through the mouth. Suitable preparations include aqueous or oily solutions of the active ingredient. Preparations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents, such as compounds used for treating or preventing disorders as described hitherto below.

[0295] Preparations suitable for vaginal administration can be presented as vaginal suppositories, tampons, creams, gels, pastes, foams or spray preparations, containing a carrier considered appropriate in addition to the active ingredient.

[0296] The preparations can be packaged in unit-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier for injection, such as water, before use. The temporary injection solutions and suspensions are prepared from sterile powders, granules and tablets of the aforementioned types. Preferred unit-dose preparations are those containing the active ingredient in the daily dose or unit daily sub-dose as described above herein, or an appropriate fraction thereof.

[0297] In one embodiment, the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt is formulated as a prodrug. As used herein, the term prodrug refers to a derivative of a compound that can be hydrolyzed, oxidized or cleaved under biological conditions to provide the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt. Prodrugs as defined herein include derivatives containing one or more moieties that modulate or improve one or more physical, physiological or pharmaceutical properties (such as but not limited to solubility, permeability, uptake, biodistribution, metabolic stability, onset or some other druglike properties) and are converted to the bioactive substance or a more bioactive substance as provided herein. In one embodiment, the prodrugs herein are not biologically active until the compound or its pharmaceutically acceptable salt is released.

[0298] Route of Administration

[0299] The compounds or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein can be administered by any route suitable for the disorder to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal. For local immunosuppressive therapy, the compounds can be administered by intralesional administration, including perfusing the graft before transplantation or otherwise contacting the graft with the inhibitor. It should be understood that the preferred route may vary depending on, for example, the disorder of the recipient. In the case of oral administration of the compounds or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, the compounds or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts can be formulated with a pharmaceutical carrier or excipient into pills, capsules, tablets, etc. In the case of parenteral administration of the compounds or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, the compounds or their pharmaceutically acceptable salts can be formulated with a pharmaceutical parenteral vehicle in unit dose injection form, as detailed below.

[0300] Accordingly, in one aspect, the present disclosure provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described herein, and one or more pharmaceutical excipients. In one embodiment, the compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein are administered as a pharmaceutical composition capable of being administered orally or parenterally to a subject. The compounds or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein can be formulated for topical or parenteral use, wherein the compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts are dissolved or otherwise suspended in a solution suitable for injections, suspensions, syrups, creams, ointments, gels, sprays, solutions, and emulsions.

[0301] Oral administration can promote patient compliance in taking the compounds (e.g., formulated as a pharmaceutical composition), thereby increasing compliance and efficacy. Oral pharmaceutical compositions comprising the compounds described herein include, but are not limited to, (e.g., coated, uncoated, and chewable) tablets and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric-coated capsules, and sustained-release capsules). Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Oral pharmaceutical compositions comprising the compounds described herein can be formulated for delayed or extended release.

[0302] The dosage range for treating a human patient can be from about 10 mg to about 1000 mg of the compounds described herein. A typical dose of the compound can be from about 100 mg to about 300 mg. A certain dose can be administered once a day (QID), twice a day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including the absorption, distribution, metabolism, and excretion of the specific compound. As used herein, administration refers to the dosing frequency, rather than, for example, the number of individual units that a patient must take in one dose as described herein. Thus, in some embodiments, a patient can take two or more dose units (e.g., two or more pills / tablets / capsules) QD. Additionally, toxicity factors may affect the dose and administration regimen. When administered orally, the pills, capsules, or tablets can be ingested daily or at a lower frequency over a specified period of time. This regimen can be repeated for multiple treatment cycles.

[0303] Methods of treatment and uses

[0304] The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts can be used as Ras inhibitors. In one aspect, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts can be used as KRas inhibitors. In another embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts can be used as pan-KRas inhibitors (i.e., compounds that inhibit the activity of mutant KRas proteins). In one such embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts can be pan-KRas inhibitors that contain a mutation at position 12 (e.g., a G12X mutation, where X is a mutation of the naturally occurring Gly residue to a different amino acid). In one embodiment, the compounds of Tables 1 and 2, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts can be used as pan-KRas inhibitors.

[0305] Methods are provided herein for contacting a cell, such as an isolated cell, with a compound described herein, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts to inhibit KRas activity in the cell. In another embodiment, the activity is mutant KRas activity (e.g., mutant pan-KRas activity).

[0306] As used herein, the inhibition of the activity of more than one KRas mutant is referred to as pan-KRas inhibition. In such cases, a compound or a pharmaceutically acceptable salt thereof as described herein inhibits the activity of more than one mutant KRas protein. In certain cases, such a compound or a pharmaceutically acceptable salt thereof selectively inhibits the activity of more than one mutant KRas protein relative to the wild-type (WT) KRas protein activity. In one such embodiment, the pan-KRas inhibitor as described herein and used in the methods provided herein inhibits at least one mutant KRas protein at least 5-fold, 8-fold, 10-fold, 12-fold, 15-fold, 20-fold, 24-fold, 27-fold, 50-fold, 100-fold, 500-fold, 700-fold, 1000-fold, 1300-fold, 1700-fold, 2000-fold, 5000-fold or more than the inhibition of the WT KRas protein. In one embodiment, such KRas mutations are in the SWII domain. In one embodiment, such KRas mutations correspond to a change in the native amino acid at a position corresponding to G12, G13, Q61 or A146. In such embodiments, such compounds can be used in the methods described herein, wherein such cancer or disease is mediated by a KRasG12X mutation (where X is C, D, R or V). In some embodiments, the mutation corresponds to G12A, G12C, G12D, G12R, G12S, G12V, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V or A146T.

[0307] The present invention further provides a method for treating a cancer comprising a KRas mutation, the method comprising administering to a patient suffering from such cancer an effective amount of a compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In one embodiment, the mutation is a known KRas mutation as described herein (e.g., a KRasG12X mutation) and exhibits pan-KRas inhibition.

[0308] In one embodiment, the method further comprises testing a sample from a patient (e.g., as described herein) for the absence or presence of a KRas mutation (e.g., a KRas G12X mutation) before administering a compound or a pharmaceutically acceptable salt thereof described herein. In one such embodiment, after determining that the patient sample is positive for a KRas mutation (e.g., is present), the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is administered to the patient. In one embodiment, the method further comprises testing a sample from a patient (e.g., as described herein) for the absence or presence of a KRas mutation before administering a compound or a pharmaceutically acceptable salt thereof described herein, wherein after determining that the patient sample is positive for a KRas mutation (e.g., is present), the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is administered to the patient.

[0309] The methods for treating cancer described herein relate to the treatment of cancers such as acute myeloid leukemia, adolescent cancers, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS) of the extrahepatic bile duct, embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, sensory neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, primary occult metastatic squamous neck cancer, midline cancer, oral cancer, multiple endocrine neoplasia, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid carcinoma, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.

[0310] In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendiceal cancer, or pancreatic cancer. In one embodiment, the cancer is pancreatic cancer, lung cancer, or colon cancer. The lung cancer can be adenocarcinoma, non-small cell lung cancer (NSCLC), or small cell lung cancer (SCLC). In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is lung adenocarcinoma.

[0311] The methods provided herein can further include testing a sample from a patient for the absence or presence of a KRas mutation at position 12 corresponding to KRas (e.g., Gly12) prior to administering a compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein. In one embodiment, after the patient sample shows the presence of a KRas mutation at position 12 corresponding to KRas (e.g., Gly12), a compound, its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, or a pharmaceutical composition is administered to the patient. In one embodiment, a compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein are not administered unless the patient sample contains a KRas mutation at position 12 corresponding to KRas (e.g., Gly12).

[0312] The methods provided herein can further include testing a sample from a patient for the absence or presence of a KRas mutation prior to administering a compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein, wherein the compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein have pan-KRas inhibitory activity. In one embodiment, after the patient sample shows the presence of a KRas mutation, a compound, its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, or a pharmaceutical composition is administered to the patient, wherein the compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein have pan-KRas inhibitory activity. In one embodiment, a compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein are not administered unless the patient sample contains a KRas mutation, wherein the compound or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts described herein have pan-KRas inhibitory activity.

[0313] In one embodiment, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In another embodiment, the pancreatic cancer, lung cancer, or colorectal cancer contains a KRasG12X mutation. In yet another embodiment, the cancer is of unknown histology but contains a KRasG12X mutation.

[0314] In another embodiment, pancreatic, lung, or colorectal cancer comprises a KRas mutation. In one such embodiment, the cancer is of undetermined histology but comprises a KRas mutation. In such embodiments, the cancer can be treated with a compound as described herein having pan-KRas inhibitory activity or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein. In some embodiments, the KRas mutation is a mutation of a residue other than Gly12.

[0315] The present disclosure further provides a method of treating such lung cancer in a patient having lung cancer comprising a KRasG12X mutation, the method comprising administering to the patient a therapeutically effective amount of a compound as described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof). In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC). The NSCLC can be, for example, adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is adenoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer. The methods provided herein comprise administering the compound as a 1L therapy. In one embodiment, the compound as described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof has pan-KRas inhibitory activity.

[0316] The present disclosure also further provides a method of treating such lung cancer in a patient having lung cancer comprising a KRas mutation (e.g., corresponding to a position other than Gly12), the method comprising administering to the patient an effective amount of a compound as described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof), wherein the compound as described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof has pan-KRas inhibitory activity. In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC). The NSCLC can be, for example, adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is adenoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer. The methods provided herein comprise administering the compound as a 1L therapy.

[0317] The present invention further provides a method for treating pancreatic cancer in a patient having pancreatic cancer comprising a KRasG12X mutation, the method comprising administering to the patient a therapeutically effective amount of a compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein. In one embodiment, the patient has previously been treated with radiotherapy and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is in stage 0, I or II. In another embodiment, the pancreatic cancer is in stage III or IV. In one embodiment, the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity.

[0318] The present invention further provides a method for treating pancreatic cancer in a patient having pancreatic cancer comprising a KRas mutation (e.g., at a position other than corresponding to Gly12), the method comprising administering to the patient an effective amount of a compound, a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein, wherein the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity. In one embodiment, the patient has previously been treated with radiotherapy and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is in stage 0, I or II. In another embodiment, the pancreatic cancer is in stage III or IV.

[0319] The present invention also further provides a method for treating colon cancer in a patient having colon cancer comprising a KRasG12X mutation, the method comprising administering to the patient a therapeutically effective amount of a compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein. In one embodiment, the colon cancer is in stage I or II. In another embodiment, the colon cancer is in stage III or IV. In one embodiment, the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity.

[0320] The present invention also further provides a method for treating colon cancer in a patient having colon cancer comprising a KRas mutation (e.g., at a position other than corresponding to Gly12), the method comprising administering to the patient an effective amount of a compound, a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein, wherein the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity. In one embodiment, the colon cancer is in stage I or II. In another embodiment, the colon cancer is in stage III or IV.

[0321] The present invention further provides a method for treating cancer of unknown primary origin comprising a KRasG12X mutation. In one embodiment of such methods, method (Ag2) comprises:

[0322] Determine whether a KRasG12X mutation is absent or present in a patient sample suspected of being diagnosed with cancer; and

[0323] Administer to the patient an effective amount of a compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein. In one embodiment, the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity.

[0324] The present disclosure further provides methods for treating carcinomas of undetermined histology that contain a KRas mutation (e.g., at a position other than Gly12). In one embodiment of such methods, method (Ag3) comprises:

[0325] Determine whether a KRas mutation is absent or present in a patient sample suspected of being diagnosed with cancer; and

[0326] Administer to the patient an effective amount of a compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein, wherein the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity.

[0327] In one embodiment of the methods of Ag1, Ag2 and Ag3, the patient is diagnosed with a cancer described herein. In another embodiment of the methods of Ag1, Ag2 and Ag3, the sample is a tumor sample taken from a subject. In one such embodiment, the sample is collected prior to administration of any therapy. In another such embodiment, the sample is collected before administration of a compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein and after administration of another chemotherapeutic agent. In another embodiment of the methods of Ag1, Ag2 and Ag3, the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein is administered in a manner provided herein (e.g., orally).

[0328] The present disclosure also provides a compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof for use as a therapeutic agent. In another such embodiment, the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof can be used for the therapeutic treatment of cancers that contain a KRasG12X mutation. In one embodiment, the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity.

[0329] In yet another such embodiment, a compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof can be used to treat cancers that contain a KRas mutation (e.g., corresponding to a position other than Gly12), wherein the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt described herein has pan-KRas inhibitory activity.

[0330] The present invention further provides a compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of cancers that contain a KRas G12X mutation. In one embodiment, the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt described herein has pan-KRas inhibitory activity.

[0331] The present invention also further provides a compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of cancers that contain a KRas mutation (e.g., corresponding to position Gly12), wherein the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt described herein has pan-KRas inhibitory activity.

[0332] In one embodiment, the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt described herein is used in the preparation of a medicament for the therapeutic treatment of cancers that contain a KRas G12X mutation. In one embodiment, the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt described herein has pan-KRas inhibitory activity.

[0333] Used therein. In one embodiment, the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt described herein is used in the preparation of a medicament for the therapeutic treatment of cancers that contain a KRas mutation (e.g., corresponding to a position other than Gly12), wherein the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt described herein has pan-KRas inhibitory activity.

[0334] The present invention also further provides the use of a compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for inhibiting tumor metastasis.

[0335] The present invention further provides a method for inhibiting tumor metastasis, which comprises administering to a patient suffering from a tumor a therapeutically effective amount of a compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof as described herein. In one embodiment, the inhibition is directed against tumors that contain a KRas G12X mutation. In one embodiment, the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt described herein has pan-KRas inhibitory activity.

[0336] In one embodiment, the inhibition is directed against tumors comprising a KRas mutation (e.g., at a position other than corresponding to Gly12), wherein the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts described herein have pan-KRas inhibitory activity.

[0337] In some embodiments of the methods described herein, inhibiting tumor metastasis in a patient as described herein results in a decrease in tumor size. In another embodiment, inhibiting tumor metastasis in a patient as described herein results in stabilization of tumor size (e.g., no further growth). In another embodiment, inhibiting tumor metastasis in a patient as described herein results in remission of cancer and / or its symptoms.

[0338] The present invention further provides methods for inhibiting the proliferation of a cell population, the method comprising contacting the cell population with a compound or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts described herein. In one embodiment, the cell population is in a human patient. In another embodiment, the cell population comprises a KRasG12X mutation. In one embodiment, the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts described herein have pan-KRas inhibitory activity.

[0339] In another embodiment, the cell population comprises a KRas mutation (e.g., at a position other than corresponding to Gly12), wherein the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts described herein have pan-KRas inhibitory activity.

[0340] The present invention further provides methods for inhibiting KRas in a patient in need of treatment, the methods comprising administering to the patient a therapeutically effective amount of a compound or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts described herein. In one embodiment, the KRas being inhibited is KRasG12X. In one embodiment, the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts described herein have pan-KRas inhibitory activity.

[0341] In one embodiment, the KRas being inhibited is a tumor with a mutant KRas protein (e.g., at a position other than corresponding to Gly12), wherein the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts described herein have pan-KRas inhibitory activity. In another embodiment, inhibiting KRas results in a decrease in tumor size. In another embodiment, inhibiting KRas results in remission of cancer and / or its symptoms.

[0342] The present invention further provides a method for modulating the activity of a KRas mutant protein, which method comprises reacting the mutant protein with a compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein. In one embodiment, the mutant protein comprises a KRasG12X mutation. In one embodiment, the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity.

[0343] In another embodiment, the mutant protein comprises a KRas mutation, wherein the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity. In one embodiment, the activity of KRas is reduced after contact with the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein. In another embodiment, downregulation of the activity of the KRas mutant protein treats the cancer described herein in a patient described herein. In another embodiment, downregulation of the activity of the KRas mutant protein results in a reduced tumor size. In another embodiment, downregulation of the activity of the KRas mutant protein results in remission of the cancer and / or its symptoms described herein.

[0344] In some embodiments, the method provided herein comprises inhibiting the activity of KRasG12X in a cell by contacting the cell with an amount of the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRasG12X in the cell. In one embodiment, the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity.

[0345] In some embodiments, the method provided herein comprises inhibiting the activity of KRasG12X in a tissue by contacting the tissue with an amount of the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRasG12X in the tissue. In some embodiments, the method provided herein comprises inhibiting the activity of KRasG12X in a patient described herein by contacting the patient described herein with an amount of the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRasG12X in the patient. In one embodiment, the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory activity.

[0346] In some embodiments, the methods provided herein include inhibiting mutant KRasG12X activity in a cell by contacting the cell with an amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein sufficient to inhibit mutant KRasG12X activity in the cell. In some embodiments, the methods provided herein include inhibiting mutant KRasG12X activity in a tissue by contacting the tissue with an amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein sufficient to inhibit mutant KRasG12X activity in the tissue. In some embodiments, the methods provided herein include inhibiting mutant KRasG12X activity in a patient described herein by contacting the patient with an amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein sufficient to inhibit mutant KRasG12X activity in the patient. In such embodiments, it should be understood that the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory effects.

[0347] The present disclosure further provides a method for preparing a labeled KRasG12X mutant protein, the method comprising reacting a KRasG12X mutant protein with a labeled compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein to produce a labeled KRasG12X mutant protein. In one embodiment, the label is an imaging agent. In one embodiment, the labeled KRasG12X can be used to detect the absence or presence of a KRasG12X mutant protein in a patient sample, thereby detecting the presence or absence of cancer mediated by mutant KRas.

[0348] The present disclosure further provides a method for preparing a labeled mutant KRasG12X protein, the method comprising reacting a mutant KRasG12X protein with a labeled compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein, wherein the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein has pan-KRas inhibitory effects, to produce a labeled mutant KRasG12X protein. In one embodiment, the label is an imaging agent. In one embodiment, the labeled mutant KRasG12X protein can be used to detect the absence or presence of a mutant KRasG12X protein in a patient sample, thereby detecting the presence or absence of cancer mediated by mutant KRas.

[0349] The present invention further provides methods for inhibiting Ras-mediated cell signaling. In one embodiment, the method comprises contacting a cell with an effective amount of one or more of the compounds disclosed herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. Inhibition of Ras-mediated signal transduction can be evaluated and demonstrated by a variety of methods known in the art. Non-limiting examples include showing (a) a decrease in the GTPase activity of Ras; (b) a decrease in GTP-binding affinity or an increase in GDP-binding affinity; (c) an increase in the Koff of GTP or a decrease in the Koff of GDP; (d) a decrease in the level of signal transduction molecules downstream of the Ras pathway, such as a decrease in the level of pMEK; and / or (e) a decrease in the binding of the Ras complex to downstream signal transduction molecules (including but not limited to Raf). Kits and commercially available assays can be used to determine one or more of the above manifestations.

[0350] KRas mutations have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to administering to a patient in need of treatment for a hematological malignancy a compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof as disclosed herein (e.g., in the form of a pharmaceutical composition). Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the compounds disclosed by the present invention can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL) and / or other leukemias. In other embodiments, the compounds or pharmaceutically acceptable salts thereof described herein can be used to treat lymphomas, such as all subtypes of Hodgkin lymphoma or non-Hodgkin lymphoma.

[0351] Whether a tumor or cancer contains a KRas mutation as described herein can be determined by assessing the nucleotide sequence encoding the KRas protein, by assessing the amino acid sequence of the KRas protein, or by assessing the characteristics of a putative KRas mutant protein. The sequence of wild-type human KRas (e.g., accession number NP203524) is known in the art.

[0352] Methods for detecting mutations in the KRas nucleotide sequence are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis, real-time PCR analysis, PCR sequencing, mutant allele-specific PCR amplification (MASA) analysis, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation analysis, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting curve analysis, and microarray analysis. In some embodiments, the KRas mutations as described herein in a sample are evaluated by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRas mutation is used. When a mutation is present, the probe binds to it and fluorescence is detected. In some embodiments, direct sequencing methods of specific regions (e.g., exon 2 and / or exon 3) in the KRas gene are used to identify KRas mutations. This technique will identify all possible mutations in the sequenced region.

[0353] Methods for determining whether a tumor or cancer contains a KRas mutation as described herein can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0354] The present invention further provides the use of the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein in the manufacture of a medicament for treating cancer. In some embodiments, the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for injection. In some embodiments, the cancer contains a KRasG12X mutation. In some embodiments, the cancer contains a KRas mutation (e.g., a mutation other than Gly12), wherein the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein have a pan-KRas inhibitory effect. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the use of the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts as described herein in the manufacture of a medicament for inhibiting tumor metastasis is provided.

[0355] The present invention further provides a compound or a pharmaceutically acceptable salt thereof as described herein for use in a method of treating cancer. In one embodiment, the cancer comprises a KRasG12X mutation. In one embodiment, the cancer comprises a KRas mutation (e.g., a mutation other than Gly12), wherein the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof as described herein has pan-KRas inhibitory activity. In one such embodiment, the cancer is a blood cancer, pancreatic cancer, MYH-related polyposis, colorectal cancer or lung cancer. In one such embodiment, the cancer is lung cancer, colorectal cancer or pancreatic cancer. In one such embodiment, the cancer is colorectal cancer. In one such embodiment, the cancer is pancreatic cancer. In one such embodiment, the cancer is lung adenocarcinoma.

[0356] Combination therapy

[0357] The compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof as described herein can be used alone or in combination with other therapeutic agents for treating the diseases or disorders as described herein. The second compound of the pharmaceutical combination preparation or dosing regimen preferably has an activity complementary to that of the compound or a pharmaceutically acceptable salt thereof as described herein, such that they do not have an adverse effect on each other. The combination therapy may provide "synergy" and prove "synergistic", i.e., the effect achieved when the active ingredients are used together is better than the sum of the effects produced when the compounds are used alone.

[0358] The combination therapy can be administered simultaneously or sequentially. When administered sequentially, the combination can be administered two or more times. The combination administration includes simultaneous administration, which uses separate formulations or a single pharmaceutical formulation and is administered continuously in any order, wherein preferably, the two (or all) active agents exert their biological activities simultaneously for a certain period of time.

[0359] The combination therapy of the present invention includes administering the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof as described herein, and using at least one other treatment method. The amounts of the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof as described herein and one or more other pharmaceutically active agents and the relative timing of administration will be selected to obtain the desired combined therapeutic effect.

[0360] In various embodiments of the method, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor (such as irinotecan, or such as etoposide, or such as doxorubicin), a taxane drug (such as an anti-microtubule agent, including paclitaxel and docetaxel), an antimetabolite (such as 5-FU, or such as gemcitabine, etc.) or an alkylating agent (such as cisplatin, or such as cyclophosphamide) or a taxane.

[0361] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, such as erlotinib or afatinib. In some embodiments, the additional therapeutic agent is gefitinib, osimertinib or dacomitinib. In some embodiments, the additional therapeutic agent is a monoclonal antibody, such as cetuximab (Erbitux) or panitumumab (Vectibix). In some embodiments, the EGFR inhibitor is a dual or pan-HER inhibitor. In other embodiments, the additional therapeutic agent is a phosphatidylinositol-3-kinase (PI3K) inhibitor, such as GDC-0077, GDC-0941, MLN1117, BYL719 (alpelisib) or BKM120 (buparlisib). GDC-0941 refers to 2-(1H-indazol-4-yl)-6-(4-methylsulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine or a salt thereof (for example, dimethanesulfonate).

[0362] In other embodiments, the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor. For example, in some embodiments, the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541. In other embodiments, the additional therapeutic agent is IGOSI-906 (linsitinib), BMS-754807; or in other embodiments, the additional therapeutic agent is an IGF1R-specific neutralizing monoclonal antibody, such as AMG-479 (ganitumab), CP-751,871 (figitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab) or R-1507 (robatumumab).

[0363] In some embodiments, the additional therapeutic agent is a SH2-containing protein tyrosine phosphatase-2 (SHP2) inhibitor. In one embodiment, the SHP2 inhibitor is RMC4550, GDC-1971, JAB-3068, JAB-3312, or TNO155, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0364] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor. In some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, lestaurtinib, momelotinib, paritaprevir, ruxolitinib, or TG101348.

[0365] In some other embodiments, the additional therapeutic agent is an anti-Glypican-3 antibody. In some embodiments, the anti-Glypican-3 antibody is codrituzumab.

[0366] In some other embodiments, the additional therapeutic agent is an antibody-drug conjugate (ADC). In some embodiments, the ADC is polatuzumab vedotin, RG7986, RG7882, RG6109, or RO7172369.

[0367] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist. In some embodiments, the MDM2 antagonist is idasanutlin.

[0368] In some other embodiments, the additional therapeutic agent is an agonistic antibody against CD40. In some embodiments, the agonistic antibody against CD40 is selicrelumab (RG7876).

[0369] In some other embodiments, the additional therapeutic agent is a bispecific antibody. In some embodiments, the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP-DR5), RG6160, RG6026, ERY974, or anti-HER2 / CD3.

[0370] In some other embodiments, the additional therapeutic agent is a targeted immunocytokine. In some embodiments, the targeted immunocytokine is RG7813 or RG7461.

[0371] In some other embodiments, the additional therapeutic agent is an antibody targeting colony-stimulating factor-1 receptor (CSF-1R). In some embodiments, the CSF-1R antibody is emactuzumab.

[0372] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine. In some embodiments, the personalized cancer vaccine is RG6180.

[0373] In some other embodiments, the additional therapeutic agent is an inhibitor of BET (bromodomain and extra terminal domain family) proteins (BRD2 / 3 / 4 / T). In some embodiments, the BET inhibitor is RG6146.

[0374] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT. In some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0375] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor downregulator (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545).

[0376] In some other embodiments, the additional therapeutic agent is a MET kinase inhibitor, such as crizotinib, tivantinib, AMG337, cabozantinib or foretinib. In other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody against MET, such as onartuzumab.

[0377] In more embodiments, the additional therapeutic agent is an SRC family non-receptor tyrosine kinase inhibitor. For example, in some embodiments, the additional therapeutic agent is an inhibitor of an SRC family non-receptor tyrosine kinase subfamily. In this regard, exemplary inhibitors include dasatinib. Other examples in this regard include ponatinib, seretinib and bosutinib.

[0378] In yet some other embodiments, the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is trametinib, selumetinib, (cobimetinib), PD0325901 or RO5126766. In other embodiments, the MEK inhibitor is GSK-1120212, also known as trametinib.

[0379] In yet some other embodiments, the additional therapeutic agent is an extracellular signal-regulated kinase (ERK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is SCH722984 or GDC-0994.

[0380] In other embodiments, the protein kinase inhibitor is taselisib, ipatasertib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, afatinib, axitinib, atezolizumab, bevacizumab, bosutinib, cetuximab, crizotinib, dasatinib, erlotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pegaptanib sodium, ranibizumab, ruxolitinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, or vemurafenib. In further embodiments, the additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is irinotecan. In some further embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include paclitaxel and docetaxel.

[0381] In addition to the additional therapeutic agents described above, other chemotherapeutic agents are currently known in the art and can be used in combination with the compounds or their pharmaceutically acceptable salts described herein. In some embodiments, the chemotherapeutic agent is selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologic response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0382] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as (imatinib mesylate), (bortezomib), Casodex (bicalutamide), (gefitinib) and doxorubicin, and numerous chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include: alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN TM);alkyl sulfonates, such as busulfan, improsulfan and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; nitrogen mustards, such as chlorambucil, chlorphenazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mephalan, novembichin, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, such as aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex TM, chromomycin, actinomycin D, daunomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, triferrioxamine doxorubicin, rhodomycin, streptozocin, streptozotocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thioguanine, thiopurine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, drostanolone propionate, thiotriol, methyltrienolone, testolactone; antiadrenal such as aminoglutethimide, mitotane, dicofol; folic acid supplements such as folinic acid; acetylacetone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; mitolactol; elfornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllic acid; 2-acetylhydrazine; procarbazine; polysaccharide K; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2”-trichloroethylamine; urethane; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; cytarabine (“Ara-C”); cyclophosphamide; thiotepa; taxanes such as paclitaxel (TAXOL TM , Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERE TM , Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of the above compounds. Also included are antihormonal agents as suitable chemotherapeutic cell regulators for modulating or inhibiting the action of hormones on tumors, such as antiestrogens including, for example, tamoxifen (Nolvadex TM)、raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, raloxifene, LY117018, onapristone, and toremifene (Fareston); antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; mitoxantrone; teniposide; daunomycin; aminopterin; ibandronate; irinotecan 11 (CPT-11); topoisomerase inhibitor RFS2000; and difluoromethylornithine (DMFO). Where needed, the compounds or their pharmaceutically acceptable salts or pharmaceutical compositions as described herein can be used in combination with commonly prescribed anticancer drugs, such as Venclexta TM 、 ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, anti-CD22 immunotoxin, antineoplastic agent, antineoplastic herb, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy), Calyculin, cell cycle non-specific antineoplastic agent, Dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, proteasome inhibitor, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel, Tris(platinum(IV) nitrate), Tris(2-chloroethyl)amine, Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

[0383] The exact method of administering the compounds and additional therapeutic agents will be apparent to those of ordinary skill in the art. In some exemplary embodiments, the compounds and additional therapeutic agents are administered simultaneously. In other embodiments, the compounds and additional therapeutic agents are administered separately.

[0384] In some embodiments, the compounds and additional therapeutic agents are administered simultaneously or separately with a second medicament. Such combination administration can include administering two medicaments of the same dosage form simultaneously, administering separate dosage forms simultaneously, and administering separately. That is, the compounds and any additional therapeutic agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds and any additional therapeutic agents described herein can be administered simultaneously, where the two medicaments are present in separate formulations. In another alternative, the compounds can be administered after any of the additional therapeutic agents described herein, and vice versa. In some embodiments of a separate administration regimen, the compounds and any additional therapeutic agents described herein are administered at intervals of minutes, or hours or days.

[0385] Article

[0386] The present invention also provides articles or "kits" containing materials useful for treating the cancers provided herein. In one embodiment, the kit comprises a container containing a compound described herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof. The kit may further comprise a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. The container may be formed from a variety of materials such as glass or plastic. The container may contain a compound described herein or a pharmaceutically acceptable salt thereof, or a formulation thereof, effective for treating the condition, and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). At least one active agent in the composition is a compound described herein or a pharmaceutically acceptable salt thereof. Alternatively or additionally, the article may further comprise a second container comprising a pharmaceutically acceptable diluent such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution or dextrose solution. The kit may also include other substances required from a commercial and user perspective, including other buffers, diluents, filters, needles and syringes.

[0387] In another embodiment, the kit is suitable for delivering a solid oral form of a compound described herein or a pharmaceutically acceptable salt thereof, such as a tablet or a capsule. Such kits may include a number of unit doses. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.

[0388] Examples

[0389] Exemplary embodiments of the invention described herein are provided below.

[0390] Example 1: A compound having the formula (I) as described herein or an atropisomer, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0391] Ring A is R 8 a substituted or unsubstituted 3- to 10-membered heterocycle, or R 8 a substituted or unsubstituted 5- to 10-membered heteroaryl;

[0392] R 8 is independently halogen, CN, NH 2 , NHC 1-3 alkyl, R 8A substituted or unsubstituted C 1-6 alkyl, or R 8A substituted or unsubstituted C 1-6 haloalkyl;

[0393] R 8A is halogen, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3Halogenated alkyl;

[0394] n is 1 or 2

[0395] R 1 is R 7 substituted or unsubstituted indolyl, R 7 substituted or unsubstituted benzofuranyl, R 7 substituted or unsubstituted naphthyl, R 7 substituted or unsubstituted indazolyl, R 7 substituted or unsubstituted indenyl, R 7 substituted or unsubstituted benzothiazolyl, R 7 substituted or unsubstituted isoquinolyl, R 7A substituted or unsubstituted phenyl or R 7A substituted or unsubstituted pyridyl;

[0396] Each R 7 independently is hydrogen, halogen, CN, CH 2 OH, -OH, NH 2 , N(Me) 2 , unsubstituted C 1-3 alkyl, unsubstituted C 2-5 alkynyl, unsubstituted C 1-3 halogenated alkyl, or unsubstituted cyclopropyl;

[0397] Each R 7a independently is hydrogen, halogen, NH 2 , N(Me) 2 , unsubstituted C 1-3 alkyl, unsubstituted C 1-3 halogenated alkyl, or unsubstituted cyclopropyl;

[0398] R 2 is OH, unsubstituted C 1-3 alkoxy, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 halogenated alkyl;

[0399] R 3 is R 9 substituted or unsubstituted 4- to 10-membered heterocycle containing N, S or O;

[0400] R 9 independently is halogen, oxo, unsubstituted C 1-3 alkyl, unsubstituted C 1-3 halogenated alkyl, unsubstituted C 1-3 alkoxy, R 10 substituted or unsubstituted C 1-3 alkylidene, or R 10 substituted or unsubstituted C3-4 cycloalkyl, or R 10 a substituted or unsubstituted 3- or 4-membered heterocycle; or two of the Rs 9 together form a C 3-5 cycloalkyl or a 3- to 5-membered heterocycle;

[0401] R 10 is hydrogen or a halogen;

[0402] R 4 is hydrogen, a halogen, an unsubstituted C 1-3 alkyl, an unsubstituted C 1-3 alkoxy, or an unsubstituted C 1-3 haloalkyl; and

[0403] R 5 and R 6 are each independently hydrogen or an unsubstituted C 1-3 alkyl.

[0404] Example 2: The compound according to claim 1, wherein R 1 is R 7 a substituted or unsubstituted indolyl, R 7 a substituted or unsubstituted benzofuranyl, R 7 a substituted or unsubstituted naphthyl, R 7 a substituted or unsubstituted indazolyl, R 7 a substituted or unsubstituted indenyl, R 7 a substituted or unsubstituted benzothiazolyl, or R 7 a substituted or unsubstituted isoquinolinyl.

[0405] Example 3: The compound according to claim 1 or 2, wherein R 1 is R 7 a substituted or unsubstituted naphthyl, or R 7 a substituted or unsubstituted isoquinolinyl.

[0406] Example 4: The compound according to any one of Examples 1 to 3, wherein R 1 is a moiety having formula (C), (C1), (C2) or (C3) as described herein.

[0407] Example 5: The compound according to any one of Examples 1 to 4, wherein R 1 is

[0408] Example 6: The compound according to any one of Examples 1 to 5, wherein R 1 is

[0409]

[0410] Example 7: The compound according to Example 1, wherein R 1 is R 7A a substituted or unsubstituted phenyl or R 7A a substituted or unsubstituted pyridyl.

[0411] Example 8: The compound according to Example 1 or 7, wherein R 1 is a moiety having formula (A) or (B) as described herein, wherein X 1 is N, CH, CF or CCl; and R 7A is hydrogen, a halogen, an unsubstituted C 1-3 alkyl, or an unsubstituted C 1-3 haloalkyl.

[0412] Example 9: The compound according to Example 1 or any one of 7 to 8, wherein R 1 is a moiety having formula (A) as described herein, wherein, X 1 is N, CH, CF or CCl; and R 7A is hydrogen, a halogen, an unsubstituted C 1-3 alkyl, or an unsubstituted C 1-3 haloalkyl.

[0413] Example 10: The compound according to Example 9, wherein X 1 is N.

[0414] Example 11: The compound according to Example 1 or any one of 9 to 10, wherein R 1 is wherein R 7A is hydrogen, a halogen, an unsubstituted C 1-3 alkyl, or an unsubstituted C 1-3 haloalkyl.

[0415] Example 12: The compound according to Example 1 or any one of 9 to 11, R 1 is

[0416] Example 13: The compound according to Example 9, wherein X 1 is CH, CF or CCl.

[0417] Example 14: The compound according to Example 9 or 13, wherein R 1 is wherein R 7A is hydrogen, F or Cl.

[0418] Example 15: The compound according to Example 9 or 13, wherein R1 is wherein R 7A is hydrogen, F or Cl.

[0419] Example 16: A compound according to any one of Examples 1 or 7 to 8, wherein R 1 is wherein R 7A is hydrogen, a halogen, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl.

[0420] Example 17: A compound according to any one of Examples 1 or 7 to 16, wherein R 1 is

[0421] Example 18: A compound according to any one of Examples 1 or 7 to 17, wherein R 1 is

[0422] Example 19: A compound according to any one of Examples 1 or 7 to 18, R 1 is

[0423] Example 20: A compound according to any one of Examples 1 to 19, wherein R 4 is Cl or F.

[0424] Example 21: A compound according to any one of Examples 1 to 20, wherein R 4 is F.

[0425] Example 22: A compound according to any one of Examples 1 to 21, wherein R 4 is Cl.

[0426] Example 23: A compound according to any one of Examples 1 to 22, wherein R 4 is OCH 3 .

[0427] Example 24: A compound according to any one of Examples 1 to 23, wherein R 3 is a moiety having formula (D0) as described herein, wherein Z is C(R 9 ) 2 or O; R 9 is hydrogen, a halogen, or R 10 substituted or unsubstituted C 1-3 alkylidene; or wherein two R 9 together form C 3-5A cycloalkyl group or a 3- to 5-membered heterocyclic ring, r is an integer from 0 to 12; j is 1, 2, or 3; and k is 1 or 2.

[0428] Example 25: The compound according to any one of Examples 1 to 24, R 3 is a moiety having formula (D) as described herein, wherein R 9 is a halogen, -OCF 3 -, -OCHF 2 -, -OCH 2 F, R 10 substituted or unsubstituted C 1-3 alkylidene, or two R 9 together form R 10 substituted or unsubstituted C 3-5 cycloalkyl; r is an integer from 0 to 12; j is 1, 2, or 3; and k is 1 or 2.

[0429] Example 26: The compound according to any one of Examples 1 to 25, R 3 is a moiety having formula (D1), (D2), (D3), or (D4) as described herein, each R 9 is independently a halogen, or R 10 substituted or unsubstituted C 1-3 alkylidene; each R 10 is independently hydrogen or a halogen; r is 0, 1, or 2; and s is 0, 1, or 2.

[0430] Example 27: The compound according to any one of Examples 1 to 26, R 3 is a moiety having formula (D1), (D2), or (D3) as described herein, wherein each R 9 is independently a halogen, or R 10 substituted or unsubstituted C 1-3 alkylidene; each R 10 is independently hydrogen or a halogen; r is 0, 1, or 2; and s is 0, 1, or 2.

[0431] Example 28: The compound according to any one of Examples 1 to 27, wherein R 3 is

[0432] Example 29: The compound according to any one of Examples 1 to 27, R 3 is a moiety having formula (D1), wherein r is 1.

[0433] Example 30: The compound according to any one of Examples 1 to 27, R 3 is a moiety having formula (D2), wherein r is 0 and each R 10Independently hydrogen or F.

[0434] Example 31: For the compound according to any one of Examples 1 to 27, R 3 is a moiety having formula (D3), where r is 0 and each R 9 is independently hydrogen or halogen.

[0435] Example 32: For the compound according to any one of Examples 1 to 26, R 3 is a moiety having formula (D4), where R 10 is halogen and s is 0, 1 or 2.

[0436] Example 33: For the compound according to any one of Examples 1 to 25, R 3 is a moiety having formula (D5), where R 10 is halogen and s is 0, 1 or 2.

[0437] Example 34: For the compound according to any one of Examples 1 to 25, wherein R 3 is a moiety having formula (E), where each R 9 is independently halogen, oxo or unsubstituted C 1-3 alkyl; and r is 0, 1 or 2.

[0438] Example 35: For the compound according to any one of Examples 1 to 25, wherein R 3 is a moiety having formula (F), where each R 9 is independently halogen, oxo or unsubstituted C 1-3 alkyl; and r is 0, 1 or 2.

[0439] Example 36: For the compound according to any one of Examples 1 to 23, wherein R 3 is a moiety having formula (G) as described herein, where each R 9 is independently halogen, oxo or unsubstituted C 1-3 alkyl; or where two R 9 together form C 3-5 cycloalkyl or a 3- to 5-membered heterocycle; and r is 1 or 2.

[0440] Example 37: For the compound according to any one of Examples 1 to 23, wherein R 3 is

[0441] Example 38: For the compound according to any one of Examples 1 to 23, wherein R 3 is

[0442] Example 39: A compound according to any one of Examples 1 to 38, wherein R 2 is methyl.

[0443] Example 40: A compound according to any one of Examples 1 to 38, wherein R 2 is CHF 2 , CH 2 F or CF 3 .

[0444] Example 41: A compound according to any one of Examples 1 to 40, wherein ring A is an optionally substituted 3- to 10-membered heterocycle, or an optionally substituted 5- to 10-membered heteroaryl. 8 substituted or unsubstituted; or 8 substituted or unsubstituted 5- to 10-membered heteroaryl.

[0445] Example 42: A compound according to any one of Examples 1 to 41, wherein ring A is an optionally substituted 3- to 6-membered heterocycle, or an optionally substituted 5- to 6-membered heteroaryl. 8 substituted or unsubstituted; or 8 substituted or unsubstituted 5- to 6-membered heteroaryl.

[0446] Example 43: A compound according to any one of Examples 1 to 42, wherein ring A is an optionally substituted 3- to 6-membered heterocycle containing at least 1 heterocyclic ring nitrogen atom, or an optionally substituted 5- to 6-membered heteroaryl containing at least 1 heterocyclic ring nitrogen atom. 8 substituted or unsubstituted; or 8 substituted or unsubstituted 5- to 6-membered heteroaryl containing at least 1 heterocyclic ring nitrogen atom.

[0447] Example 44: A compound according to any one of Examples 1 to 43, wherein ring A is an optionally substituted 5- or 6-membered heterocycle containing at least 1 heterocyclic ring nitrogen atom. 8 substituted or unsubstituted.

[0448] Example 45: A compound according to any one of Examples 1 to 44, wherein ring A is an optionally substituted 6-membered heteroaryl containing at least 1 heterocyclic ring nitrogen atom. 8 substituted or unsubstituted.

[0449] Example 46: A compound according to any one of Examples 1 to 45, wherein ring A is an optionally substituted pyridyl, an optionally substituted pyrimidinyl or an optionally substituted pyrazinyl. 8 substituted or unsubstituted; 8 substituted or unsubstituted pyrimidinyl; or 8 substituted or unsubstituted pyrazinyl.

[0450] Example 47: A compound according to any one of claims 1 to 46, wherein ring A has a moiety of formula (H) or (H1) as described herein, wherein X is CH or N and n is 1 or 2.

[0451] Example 48: A compound according to any one of claims 1 to 47, wherein Ring A is a moiety having the formula wherein X is CH or N.

[0452] Example 49: A compound according to any one of Examples 1 to 48, wherein R 5 and R 6 are each hydrogen.

[0453] Example 50: A compound according to any one of Examples 1 to 49, wherein R 5 is CH 3 and R 6 is hydrogen.

[0454] Example 51. A compound of Table 1 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0455] Example 52. A compound of Table 2 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0456] Example 53. A compound of Table 3 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0457] Example 54. A pharmaceutical composition comprising a compound according to any one of Examples 1 to 53 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients.

[0458] Example 55. A method for treating cancer, the method comprising administering an effective amount of a compound according to any one of Examples 1 to 53 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 54.

[0459] Example 56. A method for treating cancer, the method comprising administering an effective amount of a compound according to any one of Examples 1 to 53 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0460] Example 57. The method according to Example 56, wherein the cancer is characterized by the presence of a KRas mutation.

[0461] Example 58. The method according to Example 57, wherein the KRas mutation corresponds to a KRas G12D mutation or a KRas G12V mutation.

[0462] Example 59. The method according to Example 57, further comprising testing a sample from a patient for the absence or presence of a KRas mutation prior to administration.

[0463] Example 60. The method according to Example 59, wherein after the patient sample shows the presence of a KRas mutation, the compound, its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, or pharmaceutical composition is administered to the patient.

[0464] Example 61. The method according to any one of Examples 56 to 60, wherein the cancer is of undetermined histology.

[0465] Example 62. The method according to any one of Examples 56 to 60, wherein the cancer is pancreatic cancer, lung cancer or colorectal cancer.

[0466] Example 63. The method according to Example 62, wherein the lung cancer is lung adenocarcinoma, NSCLC or SCLC.

[0467] Example 64. The method according to Example 62, wherein the cancer is pancreatic cancer.

[0468] Example 65. The method according to Example 62, wherein the cancer is colorectal cancer.

[0469] Example 66. The method according to any one of Examples 56 to 65, which further comprises administering at least one additional therapeutic agent.

[0470] Example 67. The method according to Example 66, wherein the additional therapeutic agent comprises an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an antimetabolite, or an alkylating agent.

[0471] Example 68. The compound according to any one of Examples 1 to 68, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, for use as a therapeutic agent.

[0472] Example 69. Use of the compound according to any one of Examples 1 to 53, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt for the therapeutic treatment of cancer comprising a KRas mutation.

[0473] Example 70. Use of the compound according to any one of Examples 1 to 53, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt for the preparation of a medicament for the therapeutic treatment of cancer comprising a KRas mutation.

[0474] Use of the compound according to any one of Examples 1 to 53, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0475] Example 72. The compound according to any one of Examples 1 to 53, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of cancers comprising a KRas mutation.

[0476] Example 73. A method for modulating the activity of a KRas mutant protein, the method comprising reacting the mutant protein with the compound according to any one of Examples 1 to 53, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0477] Example 74. A method for inhibiting the proliferation of a cell population, the method comprising contacting the cell population with the compound according to any one of Examples 1 to 53, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0478] Example 75. The method according to Example 74, wherein the inhibition of proliferation is measured by a decrease in the cell viability of the cell population.

[0479] Example 76. A method for preparing a labeled KRas mutant protein, the method comprising reacting a KRas mutant protein with a labeled compound according to any one of Examples 1 to 53, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, to produce the labeled KRas mutant protein.

[0480] Example 77. A method for inhibiting tumor metastasis, the method comprising administering a therapeutically effective amount of the compound according to any one of Examples 1 to 53, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 55, to a subject in need thereof.

[0481] Example 78. A method for synthesizing a compound of formula (I) as described herein.

[0482] Examples

[0483] The following examples illustrate the preparation and biological evaluation of compounds within the scope of the present invention. These examples and formulations are provided to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the present invention, but merely for illustration and representation of the scope of the present invention.

[0484] Example 1: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-((3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol

[0485]

[0486] Synthesis route

[0487]

[0488] Step 1: tert-Butyl N-[3-[(1R)-1-[7-chloro-3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate

[0489]

[0490] At 0 °C, sodium tert-butoxide (428.6 mg, 4.46 mmol) was added to a solution of (3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol (315.3 mg, 1.93 mmol) in toluene (10 mL), and the mixture was stirred at 0 °C for 30 min. Then, tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-(7-chloro-6-fluoro-3-(methylsulfonyl)-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-2-pyridyl]carbamate (950.0 mg, 1.49 mmol) was added at 25 °C, and the mixture was stirred at 25 °C for 1.5 h. After completion, the reaction was quenched with a saturated ammonium chloride solution, concentrated under vacuum, diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (93:7) to give tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-chloro-3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (680.3 mg, 0.73 mmol, yield 49.4%), which was a white solid. LC-MS: (ESI, m / z): 722.3 [M+H] +

[0491] Step 2: tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-7-[3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate

[0492]

[0493] Under nitrogen, a solution of N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-chloro-3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamic acid tert-butyl ester (630.0 mg, 0.68 mmol), tetrakis(triphenylphosphine)palladium(0) (157.3 mg, 0.14 mmol), cesium carbonate (669.3 mg, 2.04 mmol) and triisopropyl-[2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl]silane (403.8 mg, 0.82 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was stirred at 100 °C for 1 h. After completion, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10:1) to afford N-tert-butoxycarbonyl-N-[3-[(1R)-1-[3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-6-fluoro-7-[3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamic acid tert-butyl ester (500.6 mg, 0.35 mmol, 50.9% yield), which was a yellow solid. LC-MS: (ESI, m / z): 1054.5 [M+H] +

[0494] Step 3: N-tert-butoxycarbonyl-N-[3-[(1R)-1-[3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-7-[8-ethynyl-3-(methoxymethoxy)-1-naphthyl]-6-fluoro-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamic acid tert-butyl ester

[0495]

[0496] tert-Butyl N-(3-((1R)-1-(3-((3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-6-fluoro-7-(3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthalenyl)-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl)-2-pyridinyl)carbamate (480.0 mg, 0.33 mmol) and cesium fluoride (350.0 mg, 2.33 mmol) in N,N-dimethylformamide (3 mL) were stirred at 25 °C for 1 h. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (93:7) to afford tert-butyl N-(3-((1R)-1-(3-((3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-7-(8-ethynyl-3-(methoxymethoxy)-1-naphthalenyl)-6-fluoro-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl)-2-pyridinyl)carbamate (310.5 mg, 0.25 mmol, 75.8% yield), which was a yellow solid. LC-MS: (ESI, m / z): 898.4 [M+H] +

[0497] Step 4: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-((3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol

[0498]

[0499] tert-Butyl N-[3-[(1R)-1-[3-[(3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy]-7-[8-ethynyl-3-(methoxymethoxy)-1-naphthalenyl]-6-fluoro-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate (300.0 mg, 0.33 mmol) was stirred in a solution of hydrogen chloride in 1,4-dioxane (3 mL, 12.00 mmol, 4.0 M in 1,4-dioxane) and acetonitrile (3 mL) at 25 °C for 5 h. After completion, the reaction mixture was concentrated in vacuo, adjusted to pH > 7 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (8:1) to afford the product. The product was further purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: B increased from 43% to 58% in 10 min, hold 58% B; wavelength: 254 / 220 nm; RT1 (min): 7 to afford 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-2-((3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol (14.6 mg, 0.02 mmol, 6.6% yield) LC-MS: (ESI, m / z): 654.3 [M+H] +

[0500] Example 1: 1 H NMR (300 MHz, DMSO-d 6, ppm) δ 10.14 (s, 1H), 7.98 (d, J = 4.5 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.53–7.34 (m, 2H), 7.32 (s, 1H), 7.10 (s, 1H), 6.79–6.60 (m, 1H), 6.49–6.23 (m, 1H), 5.93–5.65 (m, 2H), 4.55–4.17 (m, 4H), 3.88–3.71 (m, 1H), 3.70–3.61 (m, 1H), 3.62–3.43 (m, 1H), 3.28–3.06 (m, 3H), 2.79–2.54 (m, 2H), 2.47–2.23 (m, 3H), 1.61 (d, J = 6.0 Hz, 3H). LC-MS: (ESI, m / z): 654.3 [M + H] + 。

[0501] Example 2: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0502] Synthetic route

[0503]

[0504] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol

[0505]

[0506] A solution of 7-fluoronaphthalene-1,3-diol (5.00 g, 28.1 mmol), (bromoethynyl)triisopropylsilane (11.00 g, 42.10 mmol), potassium acetate (5.51 g, 56.13 mmol) and dichloro(p-cymene)ruthenium(II) dimer (1.73 g, 2.81 mmol) in 1,4-dioxane (80 mL) was stirred at 110 °C for 2 h. After completion, the solution was concentrated in vacuo, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (8.7 g, crude product) as a yellow solid. The crude product was used directly in the next step without purification. LC-MS: (ESI, m / z): 359.2 [M + H] +

[0507] Step 2: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol

[0508]

[0509] Under nitrogen, a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (7.70 g, crude product), bromo(methoxy)methane (4.03 g, 32.22 mmol), and N,N-diisopropylethylamine (8.33 g, 64.43 mmol) in dichloromethane (100 mL) was stirred at 0 °C for 1.5 h. After completion, the reaction solution was quenched with saturated ammonium chloride solution, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (3:97) to afford 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (6.60 g, 15.66 mmol, 72.9% yield), which was a yellow solid. LC-MS: (ESI, m / z): 403.2 [M+H] +

[0510] Step 3: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate

[0511]

[0512] To a solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (5.00 g, 12.42 mmol) in tetrahydrofuran (50 mL) at 0 °C was added sodium hydride (546.6 mg, 13.66 mmol, 60%, dispersed in mineral oil), and the mixture was stirred at 25 °C for 15 min. Then N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (5.85 g, 14.91 mmol) was added, and the mixture was stirred at 25 °C for 1 h. After completion, the reaction solution was quenched with saturated ammonium chloride solution, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (10:1) to afford 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (5.10 g, 9.54 mmol, 76.8% yield), which was a yellow oil. LC-MS: (ESI, m / z): 535.1 [M+H] +

[0513] Step 4: ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0514]

[0515] A solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (700.0 mg, 1.31 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (499.0 mg, 1.96 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (97.0 mg, 0.13 mmol), and potassium acetate (385.0 mg, 3.93 mmol) in toluene (15 mL) was stirred at 110 °C for 12 h. After completion, the reaction solution was concentrated in vacuo, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (1:1) to afford ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (320.0 mg, 0.62 mmol, 47.6% yield) as a yellow solid. LC-MS: (ESI, m / z): 513.3 [M+H] +

[0516] Step 5: tert-Butyl (3-((R)-1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

[0517]

[0518] A solution of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (256.9 mg, 0.50 mmol), tert-butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (300.0 mg, 0.49 mmol), methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (30.4 mg, 0.04 mmol) and tripotassium phosphate (266.0 mg, 1.25 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 80 °C for 1.5 h. After completion, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (1:9) to afford tert-butyl (3-((R)-1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (190.0 mg, 0.20 mmol, 42.6% yield), which was a yellow oil. LC-MS: (ESI, m / z): 1068.5 [M+H] +

[0519] Step 6: tert-butyl (3-((R)-1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

[0520]

[0521] To a solution of tert-butyl (3-((R)-1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (190.0 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL) was added cesium fluoride (189.1 mg, 1.24 mmol), and the mixture was stirred at 25 °C for 2 h. After completion, the reaction was diluted with water, extracted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (3:2) to afford the title compound (144.9 mg, 0.26 mmol, 89.3% yield) as a yellow solid. LC-MS: (ESI, m / z): 912.4 [M+H] +

[0522] Step 7: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0523] tert-Butyl (3-((R)-1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (190.0 mg, 0.21 mmol) in a solution of hydrochloric acid / 1,4-dioxane (3 mL, 12.00 mmol, 4.0 M in 1,4-dioxane) was stirred at 25 °C for 0.5 h. After completion, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate and adjusted to pH > 7 with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The product was further purified by preparative HPLC using the following conditions: column: Xselect CSH C18 OBD column, 30 × 150 mm, 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: within 8 min, B increased from 9% to 22%, maintaining 22% B; wavelength: 254 / 220 nm; RT1 (min): 8, to give the title compound (26.4 mg, 0.04 mmol, yield 17.8%). LC-MS: (ESI, m / z): 668.6 [M+H] +

[0524] Example 2: 1 1H NMR (300 MHz, methanol-d 4, ppm) δ 8.05–7.96 (m, 1H), 7.91–7.78 (m, 2H), 7.40–7.29 (m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 6.85 (ddd, J = 7.4, 5.2, 2.1 Hz, 1H), 6.66–6.53 (m, 1H), 5.57 (d, J = 51.9 Hz, 1H), 4.72 (s, 2H), 4.61–4.30 (m, 2H), 4.11–3.83 (m, 4H), 3.82–3.63 (m, 1H), 3.62–3.51 (m, 1H), 3.52–3.38 (m, 1H), 2.82–2.54 (m, 2H), 2.53–2.26 (m, 3H), 2.27–2.07 (m, 1H), 1.72 (dd, J = 7.0, 2.3 Hz, 3H). LC-MS: (ESI, m / z): 668.6 [M+H] +

[0525] Example 3: 3-((R)-1-(5-(5-Amino-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0526] Synthetic route

[0527]

[0528] Step 1: 3-((R)-1-(5-(5-(Bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0529]

[0530] Under nitrogen, a solution of tert-butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (150.0 mg, 0.24 mmol), [5-[bis[(4-methoxyphenyl)methyl]amino]-3-methyl-2-(trifluoromethyl)phenyl]boronic acid (191.8 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (24.1 mg, 0.02 mmol) and cesium carbonate (136.1 mg, 0.4 mmol) in dioxane / water (5 / 1) (2 mL) was stirred at 100 °C for 2 h. After completion, the filtrate was concentrated under reduced pressure. The reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10:1) to give the title compound (60.0 mg, 0.1 mmol, 32% yield), which was a yellow solid. LC-MS: (ESI, m / z): 897.4 [M+H] +

[0531] Step 2: 3-((R)-1-(5-(5-Amino-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0532] A solution of 3-((R)-1-(5-(5-(Bis(4-methoxybenzyl)amino)-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (60.0 mg, 0.07 mmol) in trifluoroacetic acid / trifluoromethanesulfonic acid (10 / 1) (0.5 mL) was stirred at 25 °C for 1 h. After completion, the reaction mixture was adjusted to pH = 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with methanol / dichloromethane (1:30), to afford a crude solid. The crude product was purified by preparative HPLC using the following conditions: (Column: XBridge Prep OBD C18 column, 30 * 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: within 9 min, B increased from 29% to 54% and held at 54% B; Wavelength: 254 / 220), to afford the title compound (8.6 mg, 0.01 mmol, 19.6% yield). LC-MS: (ESI, m / z): 657.3 [M + H] +

[0533] Example 3: 1 H NMR (300 MHz, DMSO-d 6,ppm) δ 7.96 (dd, J = 4.9, 1.7 Hz, 1H), 7.62 (dd, J = 7.6, 1.8 Hz, 1H), 6.66 (dd, J = 7.5, 4.9 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.41–6.24 (m, 2H), 5.86 (s, 2H), 5.70 (s, 2H), 5.28 (d, J = 54.3 Hz, 1H), 4.41 (dd, J = 12.7, 6.3 Hz, 1H), 4.28 (dd, J = 12.7, 6.4 Hz, 1H), 4.12 (s, 2H), 3.71 (dd, J = 15.9, 6.4 Hz, 1H), 3.52–3.36 (m, 1H), 3.20–3.02 (m, 2H), 3.00 (s, 1H), 2.91–2.76 (m, 1H), 2.35 (d, J = 2.3 Hz, 3H), 2.25–2.11 (m, 1H), 2.10–1.93 (m, 2H), 1.92–1.70 (m, 3H), 1.55 (d, J = 6.8 Hz, 3H).

[0534] Example 4: 3-((R)-1-(5-(3-Amino-8-ethynylnaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0535] Synthetic route

[0536]

[0537] Step 1: (3-Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid

[0538]

[0539] A solution of triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (700.0 mg, 1.42 mmol) in hydrochloric acid / 1,4-dioxane (4.86 mL, 19.44 mmol, 4.0 M in 1,4-dioxane) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (9:1) to afford the title compound (575.3 mg, 1.40 mmol, 99.3% yield), which was a white solid. LC-MS: (ESI, m / z): 369.2 [M+H] +

[0540] Step 2: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0541]

[0542] Under nitrogen, a solution of (3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid (420.1 mg, 1.14 mmol), tert-butyl N-[3-[(1R)-1-[7-chloro-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate (630.0 mg, 0.88 mmol), palladium(II) mesylate [(di(1-adamantyl)-butylphosphine)-2-(2′-amino-1,1′-biphenyl)] (63.9 mg, 0.09 mmol), and tripotassium phosphate (558.6 mg, 2.63 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was stirred at 80 °C for 1 h. After completion, the reaction was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (7:3) to afford the title compound (300.0 mg, 0.24 mmol, 27.9% yield) as a white solid. LC-MS: (ESI, m / z): 806.4 [M+H] +

[0543] Step 3: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl trifluoromethanesulfonate

[0544]

[0545] A solution of 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (255.0 mg, 0.33 mmol), N-phenylbis(trifluoromethanesulfonimide) (147.3 mg, 0.42 mmol), and N,N-diisopropylethylamine (122.7 mg, 0.96 mmol) in dichloromethane (5 mL) was stirred at 25 °C for 2.5 h. After completion, the reaction was concentrated in vacuo. The residue was purified by flash chromatography on a reverse-phase column, eluting with water / acetonitrile (1:49) to afford the title compound (165.0 mg, 0.18 mmol, 52.8% yield), which was an orange oil. LC-MS: (ESI, m / z): 938.3 [M+H] +

[0546] Step 4: [4-[13-[(1R)-1-[2-[bis(tert-butoxycarbonyl)amino]-3-pyridinyl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-5-(2-triisopropylsilylethynyl)-2-naphthalenyl] trifluoromethanesulfonate

[0547]

[0548] A solution of triethylamine (42.1 mg, 0.42 mmol), 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl trifluoromethanesulfonate (130.0 mg, 0.14 mmol), 4-dimethylaminopyridine (16.9 mg, 0.14 mmol), and di-tert-butyl dicarbonate (151.2 mg, 0.69 mmol) in tetrahydrofuran (3 mL) was stirred at 70 °C for 1 h. After completion, the reaction was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / ethyl acetate (8:1) to afford the title compound (140.0 mg, 0.10 mmol, 72.8% yield), which was a white solid. LC-MS: (ESI, m / z): 1138.4 [M+H] +

[0549] Step 5: tert-Butyl ((3-((R)-1-(5-(3-((tert-butoxycarbonyl)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

[0550]

[0551] Under nitrogen, a solution of tris(dibenzylideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol), cesium carbonate (98.6 mg, 0.30 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11.7 mg, 0.02 mmol), [4-[13-[(1R)-1-[2-[bis(tert-butoxycarbonyl)amino]-3-pyridinyl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-5-(2-triisopropylsilylethynyl)-2-naphthalenyl] trifluoromethanesulfonate (140.0 mg, 0.10 mmol), and tert-butyl carbamate (11.8 mg, 0.10 mmol) in 1,4-dioxane (2 mL) was stirred at 100 °C for 2 h. After completion, the reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (70.2 mg, 0.06 mmol, 55.9% yield) as a yellow oil. LC-MS: (ESI, m / z): 1105.6 [M+H] +

[0552] Step 6: tert-Butyl (3-((R)-1-(5-(3-((tert-butoxycarbonyl)amino)-8-ethynylnaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

[0553]

[0554] A solution of tert-butyl ((tert-butoxycarbonyl)(3-((R)-1-(5-(3-((tert-butoxycarbonyl)amino)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (70.0 mg, 0.06 mmol) and cesium fluoride (0.06 g, 0.39 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (49:1) to afford the title compound (55.2 mg, 0.05 mmol, 94.6% yield). LC-MS: (ESI, m / z): 949.4 [M+H] +

[0555] Step 7: 3-((R)-1-(5-(3-Amino-8-ethynylnaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0556]

[0557] A solution of tert-butyl ((tert-butoxycarbonyl)(3-((R)-1-(5-(3-ethynylnaphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (50.0 mg, 0.05 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (0.4 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was concentrated in vacuo, diluted with dichloromethane, adjusted to pH > 7 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (8:1) to afford the product. The product was further purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4 HCO 3 ) Mobile phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: within 8 min, from 34% B to 48% B, then 48% B; Wavelength: 254 / 220 nm; RT1 (min): 8 to obtain the title compound (5.3 mg, 0.01 mmol, yield 14.9%). LC-MS: (ESI, m / z): 649.3 [M+H] +

[0558] Example 4: 1 1H NMR (300 MHz, methanol-d 4, ppm) δ 7.96 (d, J = 5.1 Hz, 1H), 7.76 (d, J = 7.4, 1.5 Hz, 1H), 7.71–7.62 (m, 1H), 7.38 (dd, J = 7.1, 3.6, 1.4 Hz, 1H), 7.34–7.24 (m, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.07 (t, J = 2.6 Hz, 1H), 6.84–6.74 (m, 1H), 6.67–6.52 (m, 1H), 5.31 (d, J = 53.5 Hz, 1H), 4.53–4.37 (m, 2H), 4.38–4.20 (m, 2H), 3.85–3.66 (m, 1H), 3.64–3.39 (m, 1H), 3.29–3.12 (m, 3H), 3.10–2.94 (m, 2H), 2.51–2.08 (m, 3H), 2.07–1.80 (m, 3H), 1.67 (d, J = 6.9 Hz, 3H). LC-MS: (ESI, m / z): 649.3 [M+H] +

[0559] Example 5: 3-((R)-1-(5-(5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0560] Synthetic route

[0561]

[0562] Step 1: tert-Butyl (3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

[0563]

[0564] Under nitrogen, cesium carbonate (118.0 mg, 0.36 mmol) and tetrakis(triphenylphosphine)palladium (21.0 mg, 0.02 mmol) were added to a solution of tert-butyl N-(3-(racemic-(1R)-1-(7-chloro-6-fluoro-3-((racemic-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl)-2-pyridinyl)carbamate (130.0 mg, 0.18 mmol) and 2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (121.0 mg, 0.22 mmol) in 1,4-dioxane (2.0 mL) and water (0.2 mL), and the mixture was stirred at 100 °C for 3 h. After completion, the resulting solution was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (9:1) to afford the title compound (158.0 mg, 0.15 mmol, 78.3% yield), which was a brown solid. LC-MS: (ESI, m / z): 1115.5 [M+H] +

[0565] Step 2: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0566]

[0567] A solution of tert-butyl (3-((R)-1-(5-(5-bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (158.0 mg, 0.15 mmol) in trifluoroacetic acid (1.5 mL) and trifluoromethanesulfonic acid (0.15 mL) was stirred at 25 °C for 15 minutes. After completion, the mixture was concentrated under vacuum. The residue was diluted with dichloromethane and adjusted to pH = 7 with saturated sodium bicarbonate solution. The mixture was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: within 9 min, B increased from 34% to 59% and maintained 59% B; wavelength: 254 / 220 nm; RT1 (min): 8.6 to obtain the title compound (26.0 mg, 0.04 mmol, 27.2% yield), which was a white solid. LC-MS: (ESI, m / z): 675.2 [M+H] +

[0568] Example 5: 1 H NMR (300 MHz, DMSO-d 6,ppm) δ 7.96 (dd, J = 4.9, 1.7 Hz, 1H), 7.62 (dd, J = 7.5, 1.8 Hz, 1H), 6.67 (dd, J = 7.5, 4.9 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.34 (q, J = 6.7 Hz, 1H), 6.01 (s, 2H), 5.71 (s, 2H), 5.29 (d, J = 54.5 Hz, 1H), 4.42 (dd, J = 12.9, 6.3 Hz, 1H), 4.28 (dd, J = 12.6, 6.3 Hz, 1H), 4.13 (s, 2H), 3.72 (dd, J = 16.0, 6.4 Hz, 1H), 3.46–3.35 (m, 1H), 3.23–2.93 (m, 3H), 2.93–2.78 (m, 1H), 2.31 (s, 3H), 2.22–1.96 (m, 3H), 1.96–1.72 (m, 3H), 1.55 (d, J = 6.8 Hz, 3H). LC-MS: (ESI, m / z): 675.2 [M+H] +

[0569] Example 6: 6-(10-((R)-1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0570] Synthetic route

[0571]

[0572] Step 1: 6-(Allylthio)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0573]

[0574] Under nitrogen, a mixture of 6-bromo-N,N-bis(4-methoxyphenyl)methyl-4-methyl-5-(trifluoromethyl)pyridin-2-amine (5.0 g, 10.09 mmol) and potassium carbonate (2.8 g, 20.21 mmol) in N,N-dimethylformamide (48 mL) was stirred at 25 °C for 5 minutes. Then allyl mercaptan (4.03 mL, 50.58 mmol) was added, and the mixture was stirred at 25 °C for 2 days. After completion, the resulting solution was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (10:1) to afford the title compound (4.89 g, 10.01 mmol, 99.2% yield), which was a yellow solid. LC-MS: (ESI, m / z): 489.2 [M+H] +

[0575] Step 2: 6-(Allylsulfonyl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0576]

[0577] A solution of 6-(allylthio)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (4.92 g, 10.07 mmol) and 3-chloroperoxybenzoic acid (5.16 g, 29.90 mmol) in dichloromethane (40 mL) was stirred at 25 °C for 4 hours. Then 3-chloroperoxybenzoic acid (1.72 g, 9.97 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. After completion, the solvent was added to a saturated sodium sulfite solution and stirred for 5 min. Then the solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (1:1) to afford the title compound (1.12 g, 2.15 mmol, 21.4% yield), which was a white solid. LC-MS: (ESI, m / z): 520.9 [M+H] +

[0578] Step 3: 6-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0579]

[0580] Under nitrogen, a mixture of tert-butyl N-(3-(racemic-(1R)-1-(7-chloro-6-fluoro-3-((racemic-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)-10-oxa-2,4,8,13-tetraazatricyclo(7.4.1.05,14)tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl)-2-pyridinyl)carbamate (300.0 mg, 0.42 mmol), 6-(allylsulfonyl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (330.0 mg, 0.64 mmol), palladium(II) acetate (10.0 mg, 0.04 mmol), cesium carbonate (270.0 mg, 0.82 mmol) and methyl(bis(2-methyl-2-propyl))phosphonium tetrafluoroborate (22.0 mg, 0.09 mmol) in 1,4-dioxane (6 mL) was stirred at 110 °C for 12 h. After completion, the resulting solution was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (93:7) to afford the title compound (163.0 mg, 0.18 mmol, 43.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 898.3 [M+H] +

[0581] Step 4: 6-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0582]

[0583] A solution of 6-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (163.0 mg, 0.18 mmol) in trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (0.5 mL) was stirred at 25 °C for 0.5 h. After completion, the mixture was concentrated under vacuum. The residue was diluted with dichloromethane and adjusted to pH = 7 with saturated sodium bicarbonate solution. The mixture was washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: within 9 min, B increased from 17% to 42% and maintained 42% B; wavelength: 254 / 220 nm; RT1 (min): 8.9; to obtain the title compound (24.1 mg, 0.037 mmol, yield 20.2%). LC-MS: (ESI, m / z): 658.2 [M+H] +

[0584] Example 6: 1 H NMR (300 MHz, DMSO-d 6,ppm) δ 7.96 (dd, J = 4.9, 1.7 Hz, 1H), 7.62 (dd, J = 7.6, 1.8 Hz, 1H), 6.77 (s, 2H), 6.66 (dd, J = 7.5, 4.9 Hz, 1H), 6.47 (s, 1H), 6.33 (q, J = 6.8 Hz, 1H), 5.70 (s, 2H), 5.29 (d, J = 54.3 Hz, 1H), 4.41 (dd, J = 12.8, 6.4 Hz, 1H), 4.28 (dd, J = 12.8, 6.3 Hz, 1H), 4.13 (s, 2H), 3.71 (dd, J = 15.9, 6.4 Hz, 1H), 3.47–3.36 (m, 1H), 3.22–2.93 (m, 3H), 2.92–2.76 (m, 1H), 2.35 (d, J = 2.2 Hz, 3H), 2.28–2.11 (m, 1H), 2.12–1.93 (m, 2H), 1.93–1.68 (m, 3H), 1.56 (d, J = 6.8 Hz, 3H). LC-MS: (ESI, m / z): 658.2 [M+H] +

[0585] Example 7: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol

[0586] Synthetic route

[0587]

[0588] Step 1: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol

[0589] A solution of 3-((R)-1-(5-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[3,4-c]pyridin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (91.0 mg, 0.13 mmol) and hydrochloric acid (0.5 mL, 2.00 mmol, a solution of 4 mol / L in 1,4-dioxane) in acetonitrile (1 mL) was stirred at 25 °C for 0.5 h. After completion, the reaction mixture was concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: column: Xselect CSH C18 OBD column, 30×150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: within 8 min, B increased from 8% to 24% and maintained 24% B; wavelength: 254 / 220 nm; RT1 (min): 7.5 to obtain the title compound (13.0 mg, 0.02 mmol, yield 19.7%). LC-MS: (ESI, m / z): 650.2 [M+H] +

[0590] Example 7: 1 1H NMR (300 MHz, methanol-d 4, ppm) δ 8.26 (s, 1H), 7.99–7.88 (m, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.56–6.81 (m, 2H), 6.75 (t, J = 6.4 Hz, 1H), 6.44 (d, J = 7.1 Hz, 1H), 5.42 (d, J = 52.9 Hz, 1H), 4.52–4.05 (m, 4H), 3.80–3.38 (m, 5H), 3.22 (s, 1H), 2.59–1.89 (m, 7H), 1.57 (d, J = 6.7 Hz, 3H).

[0591] Example 8: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0592] Synthetic route

[0593]

[0594] Step 1: (R)-7-chloro-8-fluoro-5-(2-((1-(3-((4-methoxybenzyl)amino)pyrazin-2-yl)ethyl)amino)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0595]

[0596] Under a nitrogen atmosphere, sodium hydride (2.9 g, 72.5 mmol, 60%, in mineral oil) was added to a solution of 2-[[(1R)-1-[3-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]ethyl]amino]ethanol (6.5 g, 21.4 mmol) in tetrahydrofuran (50.0 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then the mixture was added to a solution of 5,7-dichloro-8-fluoro-2-methylthio-3H-pyrido[4,3-d]pyrimidin-4-one (5.0 g, 17.8 mmol) in tetrahydrofuran (50.0 mL), and the mixture was stirred at room temperature for 1 h. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was used in the next step without purification. LC-MS: (ESI, m / z): 546.2 [M+H] +

[0597] Step 2: (R)-3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine

[0598]

[0599] A mixture of 7-chloro-8-fluoro-5-[2-[[(1R)-1-[3-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]ethyl]amino]ethoxy]-2-methylthio-3H-pyrido[4,3-d]pyrimidin-4-one (9.8 g, crude product), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (6.8 g, 26.9 mmol), and N,N-diisopropylethylamine (9.4 mL, 53.8 mmol) in chloroform (80 mL) was stirred at 70 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (4:1), to afford the title compound (7.0 g, 13.3 mmol, 74% yield), which was a light yellow solid. LC-MS: (ESI, m / z): 528.0 [M+H] +

[0600] Step 3: (R)-3-(1-(5-(5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine

[0601]

[0602] A mixture of (R)-3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (350.0 mg, 0.66 mmol), [5-[Bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]boronic acid (474.0 mg, 0.99 mmol), tetrakis(triphenylphosphine)palladium (77 mg, 0.07 mmol), and cesium carbonate (652 mg, 1.99 mmol) in 1,4-dioxane (5.0 mL) and water (0.2 mL) was stirred at 100 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (98:2), to afford the title compound (480.0 mg, 0.52 mmol, 79% yield), which was a light yellow solid. LC-MS: (ESI, m / z): 925.5 [M+H] +

[0603] Step 4: (R)-3-(1-(5-(5-(Bis((4-methoxybenzyl)amino))-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine

[0604]

[0605] 3-Chloroperoxybenzoic acid (176.0 mg, 0.86 mmol, purity 85%) was added to a solution of 3-[(1R)-1-[7-[5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-6-fluoro-3-methylthio-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (200.0 mg, 0.22 mmol) in dichloromethane (10.0 mL), and the mixture was stirred at room temperature for 1 h. After completion, the reaction was quenched with saturated aqueous sodium sulfite and extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (97:3) to afford the title compound (180.0 mg, 0.19 mmol, 87% yield), which was a pale yellow oil. LC-MS: (ESI, m / z): 957.4 [M+H] +

[0606] Step 5: 3-((R)-1-(5-(5-(Bis((4-methoxybenzyl)amino))-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine

[0607]

[0608] Under a nitrogen atmosphere, sodium tert-butoxide (72 mg, 0.75 mmol) was added to a solution of [(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methanol (85 mg, 0.56 mmol) in toluene (3.0 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then the mixture was added to a solution of 3-[(1R)-1-[7-[5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-6-fluoro-3-methanesulfonyl-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (180.0 mg, 0.19 mmol) in toluene (3.0 mL), and the mixture was stirred at room temperature for 1 h. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (97:3) to afford the title compound (130.0 mg, 0.13 mmol, 67% yield), which was a light yellow solid. LC-MS: (ESI, m / z): 1028.4 [M+H] +

[0609] Step 6: 3-((R)-1-(5-(5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0610]

[0611] A mixture of 3-[(1R)-1-[7-[5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-3-[[(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methoxy]-6-fluoro-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (125.0 mg, 0.12 mmol) in trifluoroacetic acid (5.0 mL) and trifluoromethanesulfonic acid (0.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane, basified with saturated aqueous sodium bicarbonate to adjust the pH to 8, extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 55% B in 11 min; wavelength: 254 nm; RT1 (min): 10.8 to give the title compound (23.8 mg, 0.04 mmol, 29% yield).

[0612] Example 8: 1 1H NMR (300 MHz, DMSO-d 6, ppm) δ 7.95 (d, J = 2.7 Hz, 1H), 7.78 (d, J = 2.7 Hz, 1H), 6.55 (d, J = 8.6 Hz, 1H), 6.44–6.24 (m, 3H), 6.00 (s, 2H), 4.65–4.26 (m, 4H), 3.88 (dd, J = 15.7, 6.4 Hz, 1H), 3.79–3.60 (m, 1H), 3.50–3.36 (m, 1H), 3.03–2.86 (m, 1H), 2.78–2.56 (m, 1H), 2.48–2.39 (m, 1H), 2.37 (s, 3H), 2.32 (s, 3H), 2.28–2.05 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H). LC-MS: (ESI, m / z): 668.2 [M+H] +

[0613] Example 9: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]diazepin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0614] Synthetic route

[0615]

[0616] Step 1: 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]diazepin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine

[0617]

[0618] Under a nitrogen atmosphere, sodium tert-butoxide (350.0 mg, 3.6 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]diazepin-7a(5H)-yl)methanol (435.0 mg, 2.7 mmol) in toluene (15.0 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then the mixture was added to a solution of 3-[(1R)-1-(7-chloro-6-fluoro-3-methanesulfonyl-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (510.0 mg, 0.9 mmol) in toluene (15.0 mL), and the mixture was stirred at room temperature for 1 h. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (97:3) to give the title compound (195.0 mg, 0.3 mmol, 34% yield), which was a light yellow solid. LC-MS: (ESI, m / z): 639.2 [M+H] +

[0619] Step 2: 3-((R)-1-(5-(5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine

[0620]

[0621] A mixture of 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (195.0 mg, 0.3 mmol), [5-[Bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]boronic acid (218.0 mg, 0.5 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol), and cesium carbonate (300.0 mg, 0.9 mmol) in 1,4-dioxane (6.0 mL) and water (0.6 mL) was stirred at 100 °C for 1 hour. After completion, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (49:1) to afford the title compound (300.0 mg, 0.3 mmol, 95% yield), which was a light yellow solid. LC-MS: (ESI, m / z): 1036.6 [M+H] +

[0622] Step 3: 3-((R)-1-(5-(5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0623]

[0624] The mixture of 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (300.0 mg, 0.3 mmol) in trifluoroacetic acid (6.0 mL) and trifluoromethanesulfonic acid (0.6 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and basified with saturated aqueous sodium bicarbonate to adjust the pH to 8, extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: within 9.5 min, B increased from 29% to 56%, maintaining 56% B; wavelength: 254 / 220 nm; RT1 (min): 8.33), to obtain the title compound (31.8 mg, 0.047 mmol, 16% yield).

[0625] Example 9: 1 1H NMR (300 MHz, DMSO-d 6, ppm) δ 7.94 (d, J = 2.7 Hz, 1H), 7.78 (d, J = 2.7 Hz, 1H), 6.55 (d, J = 8.7 Hz, 1H), 6.37 (d, J = 6.8 Hz, 3H), 6.00 (s, 2H), 5.27 (d, J = 56.1, Hz, 1H), 4.64–4.45 (m, 1H), 4.39 (dd, J = 12.8, 6.4 Hz, 1H), 4.21–3.99 (m, 2H), 3.89 (dd, J = 15.9, 6.5 Hz, 1H), 3.78–3.55 (m, 1H), 3.17–3.02 (m, 2H), 3.05–2.92 (m, 1H), 2.92–2.69 (m, 1H), 2.44–2.26 (m, 3H), 2.21–2.08 (m, 1H), 2.00 (s, 2H), 1.89–1.67 (m, 3H), 1.56 (d, J = 6.8 Hz, 3H). LC-MS: (ESI, m / z): 676.2 [M+H] +

[0626] Example 10: 3-((R)-1-(5-(5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohept[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0627] Synthetic route

[0628]

[0629] Step 1: 3-((R)-1-(5-(5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohept[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine

[0630]

[0631] Under a nitrogen atmosphere, sodium tert-butoxide (72.0 mg, 0.75 mmol) was added to a solution of ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (98.0 mg, 0.63 mmol) in toluene (3.0 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then the mixture was added to a solution of 3-[(1R)-1-[7-[5-[Bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-6-fluoro-3-methanesulfonyl-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (200.0 mg, 0.21 mmol) in toluene (3.0 mL), and the mixture was stirred at room temperature for 1 h. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (97:3) to give the title compound (130.0 mg, 0.13 mmol, 60% yield), which was a pale yellow solid. LC-MS: (ESI, m / z): 1034.5 [M+H] +

[0632] Step 2: 3-((R)-1-(5-(5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0633]

[0634] A mixture of 3-((R)-1-(5-(5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (130.0 mg, 0.13 mmol), trifluoroacetic acid (4.0 mL), and trifluoromethanesulfonic acid (0.4 mL) was stirred at room temperature for 1 h. After completion, the reaction mixture was diluted with dichloromethane and basified with saturated aqueous sodium bicarbonate to adjust the pH to 10. Then it was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: (Column: XBridge Prep OBD C18 column, 30 * 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 29% B to 49% B in 10 min; Wavelength: 254 nm; RT1 (min): 10.2), to give the title compound (38.0 mg, 0.06 mmol, 45% yield, 99.1% purity).

[0635] Example 10: 1 H NMR (300 MHz, DMSO-d 6,ppm) δ 7.94 (d, J = 2.7 Hz, 1H), 7.78 (d, J = 2.7 Hz, 1H), 6.55 (d, J = 8.6 Hz, 1H), 6.46–6.24 (m, 3H), 6.00 (s, 2H), 4.69–4.13 (m, 4H), 3.88 (dd, J = 15.9, 6.4 Hz, 1H), 3.77–3.58 (m, 1H), 3.58–3.47 (m, 1H), 3.48–3.38 (m, 3H), 3.13 (t, J = 10.3 Hz, 1H), 3.03–2.74 (m, 3H), 2.32 (dd, J = 4.4, 2.1 Hz, 3H), 2.17–1.96 (m, 1H), 1.87–1.68 (m, 1H), 1.69–1.49 (m, 4H), 1.43–1.19 (m, 1H). LC-MS: (ESI, m / z): 674.2 [M+H] +

[0636] Example 11: 4-(10-((R)-1-(3-Aminopyrazin-2-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol

[0637] Synthetic route

[0638]

[0639] Step 1: 3-((R)-1-(5-Chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0640]

[0641] A solution of 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (644.7 mg, 0.4 mmol) in 2,2,2-trifluoroacetic acid (5.0 mL) and trifluoromethanesulfonic acid (0.5 mL) was stirred at 25 °C for 10 minutes. After completion, the solvent was concentrated under vacuum. The reaction mixture was diluted with dichloromethane and adjusted to pH = 8 with saturated aqueous sodium carbonate. The solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10:1) to afford the title compound (277.1 mg, 0.5 mmol, 52.6% yield), which was a yellow solid. LC-MS: (ESI, m / z): 519.2 [M+H] +

[0642] Step 2: 3-((R)-1-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0643]

[0644] Under nitrogen, 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine (277.1 mg, 0.5 mmol), (3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)boronic acid (880.8 mg, 2.1 mmol), [(di(1-adamantyl)-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (155.4 mg, 0.2 mmol), and tripotassium phosphate (452.8 mg, 2.1 mmol) were added to a solution of tetrahydrofuran (3.0 mL) and water (0.6 mL). The resulting solution was stirred at 60 °C for 1 hour. After completion, the resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10:1) to afford the title compound (365.1 mg, 0.3 mmol, 71.9% yield), which was a yellow solid. LC-MS: (ESI, m / z): 851.4 [M+H] +

[0645] Step 3: 3-((R)-1-(5-(8-Ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0646]

[0647] A solution of 3-((R)-1-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine (365.1 mg, 0.3 mmol) and cesium fluoride (184.5 mg, 1.2 mmol) in N,N-dimethylformamide (4.0 mL) was stirred at 25 °C for 1 hour. After completion, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / ethyl acetate (1:1) to afford the title compound (244.4 mg, 0.3 mmol, 82.5% yield), which was a yellow solid. LC-MS: (ESI, m / z): 695.3 [M+H] +

[0648] Step 4: 4-(10-((R)-1-(3-aminopyrazin-2-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol

[0649]

[0650] A solution of 3-((R)-1-(5-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine (50.0 mg, 0.07 mmol) and hydrochloric acid / 1,4-dioxane (1 mL, 4.0 M in 1,4-dioxane) in acetonitrile (0.5 mL) was stirred at 25 °C for 30 minutes. After completion, the solvent was concentrated under vacuum. The residue was dissolved in dichloromethane and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The resulting solution was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10:1) to afford the product as a yellow solid. The product was further purified by preparative HPLC under the following conditions: column: Xselect CSH C18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: B increased from 12% to 30% in 9 min, holding at 30% B; wavelength: 254 / 220 nm; RT1 (min): 9 to afford the title compound (4.6 mg, 0.007 mmol, 9.8% yield). LC-MS: (ESI, m / z): 651.2 [M+H] +

[0651] Example 11: 1 H NMR (300 MHz, methanol-d 4 , ppm) δ 7.93 (dd, J = 2.8, 1.4 Hz, 1H), 7.85 (d, J = 2.7 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.55–7.46 (m, 1H), 7.45–7.33 (m, 1H), 7.30 (d, J = 2.6 Hz, 1H), 7.14 (dd, J = 6.4, 2.6 Hz, 1H), 6.51 (q, J = 6.9 Hz, 1H), 5.40 (d, J = 52.7 Hz, 1H), 4.73–4.31 (m, 4H), 4.17–3.84 (m, 2H), 3.70–3.42 (m, 3H), 3.26–3.03 (m, 2H), 2.58–1.88 (m, 6H), 1.71 (dd, J = 6.9, 2.5 Hz, 3H). LC-MS: (ESI, m / z): 651.3 [M+H] +

[0652] Example 12: 3-((1R)-1-(5-(3-amino-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0653] Synthesis route

[0654]

[0655] Step 1: (R)-5-(2-((1-(2-(bis((4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0656]

[0657] Sodium hydride (1.14 g, 28.5 mmol, purity 60%) was added to a solution of 2-[[(1R)-1-[2-[bis[(4-methoxyphenyl)methyl]amino]-3-pyridinyl]ethyl]amino]ethanol (3.31 g, 7.8 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 10 min. Then the reaction mixture was added to a solution of 5,7-dichloro-8-fluoro-2-methylthio-3H-pyrido[4,3-d]pyrimidin-4-one (2.00 g, 7.1 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred for 1 h. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10:1) to give the title compound (2.4 g, 3.6 mmol, yield 50.5%) as a white solid. LC-MS: (ESI, m / z): 665.3 [M+H] +

[0658] Step 2: (R)-3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0659]

[0660] To a solution of (R)-5-(2-((1-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (3.6 g, 5.41 mmol) and N,N-diisopropylethylamine (4.7 mL, 27.0 mmol) in chloroform (40 mL) was added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.1 g, 8.1 mmol), and the mixture was stirred at 70 °C for 1 h. After completion, the reaction was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (3:2) to afford the title compound (1.37 g, 1.9 mmol, 36.2% yield), which was a white solid. LC-MS: (ESI, m / z): 647.5 [M+H] +

[0661] Step 3: 3-Bromo-2,6-difluoro-5-methylbenzoic acid

[0662]

[0663] Under nitrogen, to a solution of 1-bromo-2,4-difluoro-5-methyl-benzene (10.0 g, 48.3 mmol) in tetrahydrofuran (100 mL) at -78 °C was slowly added lithium diisopropylamide (31.5 mL, 63.0 mmol) (2 M in tetrahydrofuran), and the mixture was stirred at -78 °C for 2 h. Then dry ice was poured into the reaction solution, and the mixture was stirred at room temperature for 1 h. After completion, the reaction solution was quenched with saturated ammonium chloride solution and adjusted to pH = 7 with 1 N hydrochloric acid. Then the reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-bromo-2,6-difluoro-5-methyl-benzoic acid (9.00 g, crude product), which was a light yellow solid. The crude product was used directly in the next step. LC-MS: (ESI, m / z): 251.3 [M-H] +

[0664] Step 4: 3-Bromo-2,6-difluoro-5-methylaniline

[0665]

[0666] A solution of 3-bromo-2,6-difluoro-5-methyl-benzoic acid (5.80 g, 19.9 mmol), diphenylphosphoryl azide (12.70 g, 39.8 mmol) and triethylamine (7.0 g, 59.7 mmol) in tert-butanol (50.0 mL) was stirred at 85 °C for 1.5 h. Then 2N hydrochloric acid (10 mL) was added to the solution and stirred for 1 h. After completion, the reaction mixture was quenched with saturated aqueous sodium carbonate. The resulting solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (2.50 g, crude product) as a yellow oil. The crude product was used directly in the next step. LC-MS: (ESI, m / z): 222.4 [M+H] +

[0667] Step 5: 3-Bromo-2,6-difluoro-4-iodo-5-methylaniline

[0668]

[0669] To a solution of 3-bromo-2,6-difluoro-5-methyl-aniline (1.0 g, 4.5 mmol) in acetic acid (10 mL) was added N-iodosuccinimide (1.22 g, 5.4 mmol) and stirred at 25 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure. Then the reaction was quenched with saturated sodium bicarbonate solution. Then the reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with methanol / dichloromethane (1:8) to give the title compound (1.10 g, 3.1 mmol) as a white solid. LC-MS: (ESI, m / z): 348.2 [M+H] +

[0670] Step 6: 3-Bromo-2,6-difluoro-4-iodo-N,N-bis(4-methoxybenzyl)-5-methylaniline

[0671]

[0672] To a solution of 3-bromo-2,6-difluoro-4-iodo-5-methyl-aniline (1.0 g, 2.87 mmol) and potassium tert-butoxide (1.29 g, 11.5 mmol) in N,N-dimethylformamide (10 mL) was added p-methoxybenzyl chloride (1.3 g, 8.6 mmol), and the mixture was stirred at 0 °C for 1.5 h. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:9) to afford the title compound (1.2 g, 2.0 mmol, 71% yield), which was a white solid. LC-MS: (ESI, m / z): 588.7 [M+H] +

[0673] Step 7: 3-Bromo-2,6-difluoro-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline

[0674]

[0675] Under nitrogen, a solution of 3-bromo-2,6-difluoro-4-iodo-N,N-bis[(4-methoxyphenyl)methyl]-5-methyl-aniline (100.0 mg, 0.2 mmol) and copper(I) iodide (323.0 mg, 1.7 mmol) in N,N-dimethylformamide (1 mL) was stirred at -40 °C for 10 min. Then methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.2 mL, 1.7 mmol) was added at room temperature, and the mixture was stirred at 90 °C for 1 h. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with methanol / dichloromethane (1:8) to afford the title compound (80.0 mg, 0.15 mmol, 88.7% yield), which was a white solid. LC-MS: (ESI, m / z): 530.1 [M+H] +

[0676] Step 8: 3-((1R)-1-(5-(3-(Bis(4-methoxybenzyl)amino)-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0677]

[0678] Under a nitrogen atmosphere, isopropylmagnesium chloride - lithium chloride (1.3 M in tetrahydrofuran) (2.6 mL, 3.4 mmol) was added to a solution of 3-bromo-2,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]-5-methyl-4-(trifluoromethyl)aniline (1.20 g, 2.3 mmol) in tetrahydrofuran (13 mL) at -78 °C. After stirring for 30 min at -78 °C, zinc chloride (1.9 M in 2-methyltetrahydrofuran) (3.4 mL, 6.79 mmol) was added to the mixture and stirred for 10 min. Then the mixture was warmed to room temperature and stirred at room temperature for 30 min. Then the reaction solution was added under nitrogen to a solution of 3-[(1R)-1-(7-chloro-6-fluoro-3-methylthio-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (1.40 g, 2.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.2 mmol) in tetrahydrofuran (13 mL), and stirred at 80 °C for 5 h. After completion, the reaction was quenched with saturated ammonium chloride solution, diluted with water, extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with methanol / dichloromethane (1:8) to afford the title compound (600.0 mg, 0.5 mmol, 25% yield), which was a white solid. LC-MS: (ESI, m / z): 1062.5 [M+H] +

[0679] Step 9: 3-((1R)-1-(5-(3-(Bis(4-methoxybenzyl)amino)-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0680]

[0681] Under nitrogen, a solution of 3-[(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl]-6-fluoro-3-methylthio-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (100.0 mg, 0.1 mmol) and 3-chloroperoxybenzoic acid (48.7 mg, 0.3 mmol) in dichloromethane (1 mL) was stirred at 25 °C for 1.5 h. After completion, the reaction was quenched with saturated sodium sulfite solution. The resulting solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with methanol / dichloromethane (1:8) to afford the title compound (70.0 mg, 0.06 mmol, 68% yield), which was a white solid. LC-MS: (ESI, m / z): 1093.9 [M+H]+ +

[0682] Step 10: 3-((1R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0683]

[0684] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (43.6 mg, 0.3 mmol) in toluene (1 mL) was added sodium tert-butoxide (43.8 mg, 0.5 mmol), and the mixture was stirred at 0 °C for 10 minutes. Then 3-[(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl]-6-fluoro-3-(methylsulfonyl)-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-N,N-bis[(4-methoxyphenyl)methyl]pyridin-2-amine (100.0 mg, 0.1 mmol) was added to the reaction mixture, and the mixture was stirred at 25 °C for 1.5 hours. After completion, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:8) to give the title compound (90.0 mg, 0.07 mmol, 83.9% yield), which was a yellow solid. LC-MS: (ESI, m / z): 1173.6 [M+H] +

[0685] Step 11: 3-((1R)-1-(5-(3-amino-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0686]

[0687] A solution of 3-((1R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,3,6,10]tetraazacyclotetradec-10-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradec-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (120.0 mg, 0.1 mmol) in trifluoroacetic acid (1.0 mL) and trifluoromethanesulfonic acid (0.1 mL) was stirred at 25 °C for 20 minutes. After completion, the filtrate was concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane and adjusted to pH = 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10:1) to afford a crude solid. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: within 10 min, B increased from 38% to 60% and maintained 60% B; wavelength: 220 / 254 nm; RT1 (min): 7.72 to afford the title compound (59.0 mg, 0.08 mmol, 83.3% yield).

[0688] Example 12: 1 1H NMR (300 MHz, DMSO-d 6, ppm) δ 7.96 (d, J = 4.9 Hz, 1H), 7.68–7.58 (m, 1H), 6.67 (dd, J = 7.5, 4.9 Hz, 1H), 6.34 (d, J = 7.0 Hz, 1H), 6.15 (s, 2H), 5.68 (s, 2H), 5.28 (d, J = 54.5 Hz, 1H), 4.51–4.36 (m, 1H), 4.29 (dd, J = 12.8, 6.3 Hz, 1H), 4.12 (s, 2H), 3.80–3.55 (m, 2H), 3.17–3.00 (m, 2H), 2.99 (s, 1H), 2.89–2.68 (m, 1H), 2.30 (s, 3H), 2.23–2.08 (m, 1H), 2.07–1.91 (m, 2H), 1.91–1.70 (m, 3H), 1.62–1.47 (m, 3H). LC-MS: (ESI, m / z): 693.3 [M+H] +

[0689] Example 13: 3-((1R)-1-(5-(3-Amino-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0690] Synthetic route

[0691]

[0692] Step 1: 2,6-Difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0693]

[0694] Under nitrogen, a solution of 3-bromo-2,6-difluoro-5-methyl-aniline (3.0 g, 13.5 mmol), bis(pinacolato)diboron (5.1 g, 20.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.0 g, 1.3 mmol) and potassium acetate (3.9 g, 40.5 mmol) in N,N-dimethylformamide (30 mL) was maintained at 80 °C for 12 h. After completion, the reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:8) to afford 2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.0 g, 11.1 mmol, 99% yield), which was a yellow solid. LC-MS: (ESI, m / z): 270.2 [M+H] +

[0695] Step 2: (R)-5-(2-((1-(3-(Bis(4-methoxybenzyl)amino)pyrazin-2-yl)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0696]

[0697] Under a nitrogen atmosphere, sodium hydride (828.0 mg, 20.7 mmol, 60%, in mineral oil) was added to a solution of 2-[[(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]amino]ethanol (3.30 g, 7.8 mmol) in tetrahydrofuran (15.0 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then the mixture was added to a solution of 5,7-dichloro-8-fluoro-2-methylthio-3H-pyrido[4,3-d]pyrimidin-4-one (1.40 g, 5.0 mmol) in tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 1 h. After completion, the reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was used in the next step without purification. LC-MS: (ESI, m / z): 666.0 [M+H] +

[0698] Step 3: (R)-3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine

[0699]

[0700] A solution of 7-chloro-8-fluoro-2-methylthio-5-[2-[[(rac-(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]amino]ethoxy]-3H-pyrido[4,3-d]pyrimidin-4-one (2.88 g, crude product), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.2 g, 8.65 mmol), and N,N-diisopropylethylamine (3.7 mL, 21.6 mmol) in chloroform (28 mL) was stirred at 70 °C for 1 h. After completion, the resulting solution was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (1:1), to afford the title compound (1.58 g, 2.3 mmol, 55.1% yield) as a white solid. LC-MS: (ESI, m / z): 648.3 [M+H] +

[0701] Step 4: (R)-3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine

[0702]

[0703] 3-[(1R)-1-(7-chloro-6-fluoro-3-methylthio-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-N,N-bis[(4-methoxyphenyl)methyl]pyrazin-2-amine (300.0 mg, 0.4 mmol) and 3-chloroperoxybenzoic acid (319.5 mg, 1.8 mmol) were stirred in dichloromethane (3 mL) at 25 °C for 1 h. After completion, the reaction was quenched with saturated sodium sulfite solution. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:8) to afford the title compound (190.0 mg, 0.3 mmol, 60.4% yield), which was a yellow solid. LC-MS: (ESI, m / z): 680.3 [M+H] +

[0704] Step 5: 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine

[0705]

[0706] A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.33 g, 8.3 mmol) and sodium tert-butoxide (1.34 g, 13.8 mmol) in toluene (20 mL) was stirred at 0 °C for 20 minutes. Then the reaction mixture was added to a solution of (R)-3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (1.89 g, 2.7 mmol) in toluene (20 mL), and the mixture was stirred at 25 °C for 1.5 hours. After completion, the reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:8), to afford the title compound (910.0 mg, 1.1 mmol, 43.1% yield), which was a yellow solid. LC-MS: (ESI, m / z): 759.3 [M+H] +

[0707] Step 6: 3-((R)-1-(5-(3-amino-2,4-difluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine

[0708]

[0709] Under nitrogen, a solution of 3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (910.0 mg, 1.2 mmol), 2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (387.0 mg, 1.4 mmol), tetrakis(triphenylphosphine)palladium (138.5 mg, 0.12 mmol), and potassium carbonate (331.2 mg, 2.4 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 100 °C for 1.5 h. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10:1) to afford the title compound (330.0 mg, 0.4 mmol, 31.8% yield) as a yellow oil. LC-MS: (ESI, m / z): 866.3 [M+H] +

[0710] Step 7: 3-((1R)-1-(5-(3-amino-2,4-difluoro-6-iodo-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine

[0711]

[0712] A solution of 3-((R)-1-(5-(3-amino-2,4-difluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,3,6,10]tetraazacyclotetradecin-10-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradecin-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazin-2-amine (600.0 mg, 0.7 mmol) and N-iodosuccinimide (155.4 mg, 0.7 mmol) in acetic acid (3.0 mL) and N,N-dimethylformamide (3.0 mL) was stirred at 25 °C for 1.5 h. After completion, the reaction was quenched with saturated sodium carbonate solution. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:8) to afford the title compound (500.0 mg, 0.5 mmol, 72.8% yield), which was a yellow solid. LC-MS: (ESI, m / z): 992.4 [M+H] +

[0713] Step 8: N-[3-[13-[(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolo[2,1-c][1,3,6,10]tetraazacyclotetradecin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-2,6-difluoro-4-iodo-5-methyl-phenyl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

[0714]

[0715] Under nitrogen, a solution of 3-((1R)-1-(5-(3-amino-2,4-difluoro-6-iodo-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyrazine-2-amine (500.0 mg, 0.5 mmol), 4-dimethylaminopyridine (215.6 mg, 1.7 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.0 mmol) in tetrahydrofuran was stirred at 70 °C for 1 hour. After completion, the reaction mixture was diluted with water, extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with methanol / dichloromethane (1:8) to afford the title compound (430.0 mg, 0.3 mmol, 71.6% yield), which was a white solid. LC-MS: (ESI, m / z): 866.3 [M+H] +

[0716] Step 9: N-[3-[13-[(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolo[2,1-c][1,4]oxazin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-2,6-difluoro-5-methyl-4-(trifluoromethyl)phenyl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

[0717]

[0718] Under nitrogen, at -60 °C, bis[(2,2-difluoro-2-fluorosulfonyl-acetyl)oxy]copper (868.0 mg, 3.6 mmol) was added to a solution of N-[3-[13-[(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-2,6-difluoro-4-iodo-5-methyl-phenyl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (430.0 mg, 0.3 mmol) and copper (230.8 mg, 3.6 mmol) in N,N-dimethylformamide (4.5 mL) over 8 minutes. The reaction mixture was then stirred at 90 °C for 1.5 hours. Upon completion, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with methanol / dichloromethane (1:8) to afford the title compound (160.0 mg, 0.14 mmol, 39.1% yield), which was a white solid. LC-MS: (ESI, m / z): 1134.6 [M+H] +

[0719] Step 10: 3-((1R)-1-(5-(3-amino-2,4-difluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyrazin-2-amine

[0720]

[0721] A solution of N-[3-[13-[(1R)-1-[3-[bis[(4-methoxyphenyl)methyl]amino]pyrazin-2-yl]ethyl]-6-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-2,6-difluoro-5-methyl-4-(trifluoromethyl)phenyl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (160.0 mg, 0.1 mmol) in trifluoroacetic acid (1.0 mL) and trifluoromethanesulfonic acid (0.1 mL) was stirred at 25 °C for 30 minutes. After completion, the reaction mixture was diluted with dichloromethane and adjusted to pH = 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10:1) to afford the product. The product was further purified by preparative HPLC under the following conditions (column: XSelect CSH fluorophenyl, 30×150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 4% B to 20% B in 10 min; wavelength: 694 nm) to give the title compound (11.0 mg, 0.01 mmol, 10.5% yield). LC-MS: (ESI, m / z): 694.0 [M+H] +

[0722] Example 13: 1 H NMR (300 MHz, DMSO-d 6, ppm) δ 7.94 (t, J = 2.3 Hz, 1H), 7.78 (t, J = 2.6 Hz, 1H), 6.37 (s, 3H), 6.17 (s, 2H), 5.28 (d, J = 54.4 Hz, 1H), 4.65–4.34 (m, 2H), 4.22–4.02 (m, 2H), 3.99–3.83 (m, 1H), 3.80–3.61 (m, 1H), 3.17–2.97 (m, 2H), 2.98–2.88 (m, 1H), 2.86–2.75 (m, 1H), 2.31 (s, 3H), 2.19–1.93 (m, 3H), 1.89–1.68 (m, 3H), 1.56 (dd, J = 6.9, 2.1 Hz, 3H). LCMS (ESI, m / z): 694.0 [M+H] + .

[0723] Example 14: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[0724] Synthetic route

[0725]

[0726] Step 1: 4-bromo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine

[0727]

[0728] A solution of 4-bromo-6-methylpyridin-2-amine (2.0 g, 10.6 mmol) and potassium tert-butoxide (4.80 g, 42.7 mmol) in N,N-dimethylformamide (20 mL) was stirred at 0 °C for 30 minutes. Then 4-methoxybenzyl chloride (5.02 g, 32.0 mmol) in N,N-dimethylformamide (20 mL) was added and the mixture was stirred at 0 °C for 1.5 hours. After completion, the reaction was quenched with saturated ammonium chloride solution. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:99) to afford the title compound (1.50 g, 3.5 mmol, 32.8% yield), which was a white solid. LCMS (ESI, m / z): 429.1 [M+H] + 。

[0729] Step 2: 4-bromo-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine

[0730]

[0731] A solution of 4-bromo-N,N-bis[(4-methoxyphenyl)methyl]-6-methylpyridin-2-amine (2.09 g, 4.8 mmol) and N-iodosuccinimide (1.10 g, 4.8 mmol) in acetic acid (20 mL) was stirred at 25 °C for 1.5 h. After completion, the reaction was quenched with saturated aqueous sodium carbonate. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:98) to afford the title compound (1.50 g, 2.7 mmol, 55.4% yield), which was a yellow oil. LCMS (ESI, m / z): 554.1 [M+H] + 。

[0732] Step 3: 4-Bromo-N,N-bis(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[0733]

[0734] Under nitrogen, a solution of 4-bromo-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-6-methylpyridin-2-amine (1.50 g, 2.7 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.4 mL, 27.1 mmol), and copper(I) iodide (5.16 g, 27.1 mmol) in N,N-dimethylformamide (15 mL) was stirred at 90 °C for 1.5 h. After completion, the reaction mixture was filtered and the filtrate was diluted with water. The resulting solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate / petroleum ether (1:19) to afford the title compound (1.14 g, 2.3 mmol, 84.9% yield), which was a yellow oil. LCMS (ESI, m / z): 497.2 [M+H] + 。

[0735] Step 4: N,N-Bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine

[0736]

[0737] Under nitrogen, 4-bromo-N,N-bis[(4-methoxyphenyl)methyl]-6-methyl-5-(trifluoromethyl)pyridin-2-amine (150.0 mg, 0.3 mmol), bis(pinacolato)diboron (115.3 mg, 0.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.4 mg, 0.03 mmol) and potassium acetate (0.04 mL, 0.6 mmol) in 1,4-dioxane (1.5 mL) were added at 100 °C for 1.5 h. After completion, the reaction mixture was used directly for the next step without further purification. LCMS (ESI, m / z): 543.4 [M+H] + 。

[0738] Step 5: tert-Butyl (3-((R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

[0739]

[0740] Under nitrogen, a solution of N,N-bis[(4-methoxyphenyl)methyl]-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (150.0 mg, crude product), tert-butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (170.9 mg, 0.3 mmol), mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (40.2 mg, 0.06 mmol) and potassium phosphate (117.26 mg, 0.55 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) was stirred at 60 °C for 2 h. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with methanol / dichloromethane (1:8) to give the title compound (43.0 mg, 0.04 mmol, yield 15.6%). LCMS (ESI, m / z): 998.5 [M+H]+ 。

[0741] Step 5: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine

[0742]

[0743] A solution of tert-butyl (3-((R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (80.0 mg, 0.08 mmol) in trifluoroacetic acid (0.5 mL) and trifluoromethanesulfonic acid (0.05 mL) was stirred at 25 °C for 30 minutes. After completion, the filtrate was concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane and the reaction mixture was adjusted to pH = 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (10:1) to give a crude solid. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 4), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B to 50% B in 7.5 min; wavelength: 220 nm) to give the title compound (18.0 mg, 0.03 mmol, 34.1% yield), which was a white solid.

[0744] Example 14: 1 1H NMR (300 MHz, DMSO-d 6,ppm) δ 7.96 (dd, J = 4.9, 1.7 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 6.83 (s, 2H), 6.66 (dd, J = 7.5, 4.9 Hz, 1H), 6.33 (q, J = 6.7 Hz, 1H), 6.20 (s, 1H), 5.69 (s, 2H), 5.28 (d, J = 54.4 Hz, 1H), 4.42 (dd, J = 12.9, 6.4 Hz, 1H), 4.28 (dd, J = 12.6, 6.3 Hz, 1H), 4.12 (s, 2H), 3.82–3.60 (m, 2H), 3.17–3.02 (m, 2H), 2.99 (s, 1H), 2.90–2.70 (m, 1H), 2.46 (d, J = 2.3 Hz, 3H), 2.19–2.11 (m, 1H), 2.09–1.95 (m, 2H), 1.92–1.71 (m, 3H), 1.55 (d, J = 6.8 Hz, 3H). LCMS (ESI, m / z): 658.3 [M+H] + 。

[0745] Example 15: 3-((1R)-1-(5-(3-Amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0746] Synthetic route

[0747]

[0748] Step 1: 3-((R)-1-(5-(3-(Bis(4-methoxybenzyl)amino)-2-fluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0749]

[0750] Under nitrogen, a solution of tert-butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (420.0 mg, 0.58 mmol), 2-fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (431.0 mg, 0.88 mmol), potassium carbonate (242.4 mg, 1.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (67.5 mg, 0.06 mmol) in 1,4-dioxane (3 mL) and water (0.60 mL) was stirred at 100 °C for 2 h. After completion, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (1:1) to afford 3-((R)-1-(5-(3-(bis(4-methoxybenzyl)amino)-2-fluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (400.0 mg, 0.47 mmol, 80.8% yield), which was a yellow solid. LC-MS: (ESI, m / z): 847.4 [M+H] + .

[0751] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methylphenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate

[0752]

[0753] A solution of 3-((R)-1-(5-(3-(bis((4-methoxybenzyl)amino))-2-fluoro-5-methylphenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[2,1-c][1,4]diazepin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclotetradecine-10-yl)ethyl)pyridin-2-amine (400.0 mg, 0.47 mmol), di-tert-butyl dicarbonate (515.3 mg, 2.36 mmol), and triethylamine (0.33 mL, 2.36 mmol) in dichloromethane (4 mL) was stirred at 25 °C for 1 h. After completion, the reaction solution was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (1:1) to afford tert-butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methylphenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluorooctahydropyrrolo[2,1-c][1,4]diazepin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate (250.0 mg, 0.22 mmol, 47.3% yield), which was a yellow solid. LC-MS: (ESI, m / z): 1047.5 [M+H] + 。

[0754] Step 3: tert-butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-6-iodo-5-methylphenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluorooctahydropyrrolo[2,1-c][1,4]diazepin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate

[0755]

[0756] To a solution of tert-butyl N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methylphenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate (240.0 mg, 0.23 mmol) in acetic acid (2.5 mL) was added N-iodosuccinimide (61.8 mg, 0.28 mmol), and the mixture was stirred at 25 °C for 0.5 h. Upon completion, the reaction was quenched with saturated sodium thiosulfate solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (1 / 1) to afford tert-butyl N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-6-iodo-5-methylphenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate (140.0 mg, 0.10 mmol, 47.9% yield), which was a yellow solid. LC-MS: (ESI, m / z): 1173.4 [M+H] + 。

[0757] Step 4: tert-Butyl N-[3-[rac-(1R)-1-[7-[3-[bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate

[0758]

[0759] Under nitrogen, to a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-6-iodo-5-methyl-phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (140.0 mg, 0.12 mmol) and copper (75.8 mg, 1.19 mmol) in N,N-dimethylformamide (1 mL) was added copper bis[(2,2-difluoro-2-fluorosulfonyl-acetyl)oxy] (498.8 mg, 1.19 mmol), and the mixture was stirred at -78 °C for 10 minutes, then the mixture was transferred to 90 °C and stirred for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (1 / 1) to give tert-butyl N-tert-butoxycarbonyl-N-[3-[rac-(1R)-1-[7-[3-bis[(4-methoxyphenyl)methyl]amino]-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl]-6-fluoro-3-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridyl]carbamate (110.0 mg, 0.097 mmol, yield 81.8%), which was a yellow solid. LC-MS: (ESI, m / z): 1115.5 [M+H] + 。

[0760] Step 5: 3-((1R)-1-(5-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0761]

[0762] A solution of tert-butyl N-(3-((1R)-1-(7-(3-(bis((4-methoxyphenyl)methyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-6-fluoro-3-(((2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy)-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl)-2-pyridinyl)carbamate (110.0 mg, 0.10 mmol) in 2,2,2-trifluoroacetic acid (1 mL) was stirred at 50 °C for 5 h. After completion, the solvent was removed in vacuo. The resulting solution was diluted with dichloromethane and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse-phase chromatography (acetonitrile / 0.1% aqueous ammonium bicarbonate) to give the crude product. The product was further purified by preparative HPLC using the following conditions: XSelect CSH fluorophenyl, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: B increased from 31% to 56% in 9 min; 254 / 220 nm; RT1: 10.4 min to give 3-((1R)-1-(5-(3-amino-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (6.5 mg, 0.01 mmol, 9.2% yield). LC-MS: (ESI, m / z): 675.2 [M+H] + .

[0763] Example 15: 1 1H NMR (300 MHz, methanol-d 4)δ 8.14–7.89 (m, 1H), 7.95–7.65 (m, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 7.5, 5.1 Hz, 1H), 6.62 (q, J = 6.9 Hz, 1H), 5.33 (d, J = 53.2 Hz, 1H), 4.55–4.42 (m, 1H), 4.42–4.27 (m, 3H), 3.78 (dd, J = 16.1, 6.6 Hz, 1H), 3.63–3.48 (m, 1H), 3.33–3.13 (m, 3H), 3.11–2.94 (m, 1H), 2.42 (d, J = 2.7 Hz, 3H), 2.37–2.12 (m, 3H), 2.13–1.82 (m, 3H), 1.67 (d, J = 7.0 Hz, 3H).

[0764] Example 16: 3 - ((R)-1-(5-(5 - amino - 4 - fluoro - 3 - methyl - 2 - (trifluoromethyl)phenyl)-4 - fluoro - 2 - (((6S,8aS)-hexahydro - 1H - pyrrolo[2,1 - c][1,4]oxazin - 6 - yl)methoxy)-8,9 - dihydro - 10H - 7 - oxa - 1,3,6,10 - tetraazacyclohepta[de]naphthalen - 10 - yl)ethyl)pyridin - 2 - amine

[0765] Synthesis route

[0766]

[0767] Step 1: 3 - ((R)-1-(5-(5 - (bis(4 - methoxybenzyl)amino)-4 - fluoro - 3 - methyl - 2 - (trifluoromethyl)phenyl)-4 - fluoro - 2 - (((6S,8aS)-hexahydro - 1H - pyrrolo[2,1 - c][1,4]oxazin - 6 - yl)methoxy)-8,9 - dihydro - 10H - 7 - oxa - 1,3,6,10 - tetraazacyclohepta[de]naphthalen - 10 - yl)ethyl)pyridin - 2 - amine

[0768]

[0769] Under nitrogen, a solution of tetrakis(triphenylphosphine)palladium (86.8 mg, 0.08 mmol), cesium carbonate (367.0 mg, 1.13 mmol), [5-[bis[(4-methoxyphenyl)methyl]amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]boronic acid (319.2 mg, 0.67 mmol), and tert-butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (240.0 mg, 0.34 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) was stirred at 100 °C for 2 h. After completion, the reaction was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with petroleum ether / ethyl acetate (1:1) to afford 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (240.0 mg, 0.20 mmol, 60.8% yield), which was a yellow solid. LC-MS: (ESI, m / z): 913.4 [M+H] + .

[0770] Step 2: 3-((R)-1-(5-(5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0771]

[0772] A solution of 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (230.0 mg, 0.25 mmol) in trifluoromethanesulfonic acid (0.3 mL) and 2,2,2-trifluoroacetic acid (3 mL) was stirred at 25 °C for 1 h. After completion, the solvent was removed in vacuo. The resulting solution was diluted with dichloromethane and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The resulting solution was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by preparative HPLC using the following conditions: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: B increased from 10% to 40% in 9 min; 254 / 220 nm; RT1: 8.9 min to give 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (81.2 mg, 0.11 mmol, 44.0% yield). LC-MS: (ESI, m / z): 673.1 [M+H] + .

[0773] Example 16: 1 1H NMR (400 MHz, DMSO-d 6)δ 7.97 (dd, J = 4.9, 1.7 Hz, 1H), 7.62 (dd, J = 7.5, 1.8 Hz, 1H), 6.67 (dd, J = 7.5, 4.9 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.33 (q, J = 6.8 Hz, 1H), 6.02 (s, 2H), 5.68 (s, 2H), 4.42–4.38 (m, 2H), 4.26–4.22 (m, 2H), 3.72 (dd, J = 15.9, 6.5 Hz, 1H), 3.67–3.36 (m, 5H), 3.14 (t, J = 10.4 Hz, 1H), 3.05–2.78 (m, 3H), 2.32 (s, 3H), 2.22–1.97 (m, 1H), 1.86–1.70 (m, 1H), 1.70–1.48 (m, 4H), 1.43–1.20 (m, 1H).

[0774] Example 17: 4-(10-((R)-1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol

[0775] Synthetic route

[0776]

[0777] Step 1: ((6S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol

[0778]

[0779] To a solution of (6S,8aS)-6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (1.6 g, 9.35 mmol) in tetrahydrofuran (16 mL) at 0 °C was added lithium aluminum hydride (2.1 g, 56.07 mmol), and the mixture was stirred at 65 °C for 1 h. The reaction was quenched with sodium sulfate decahydrate. The solid was filtered off. After filtration, the filtrate was concentrated under reduced pressure to give ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (650 mg, 4.13 mmol, yield 44.2%), which was a pink oil. LC-MS: (ESI, m / z): 158.1 [M+H] +

[0780] Step 2: tert-Butyl (3-((R)-1-(5-chloro-4-fluoro-2-((((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

[0781]

[0782] Under nitrogen, sodium tert-butoxide (497.0 mg, 5.17 mmol) was added to a solution of ((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (812.0 mg, 5.17 mmol) in toluene (11 mL), and the mixture was stirred at 0 °C for 10 minutes. Then tert-butyl N-[3-[(1R)-1-(7-chloro-6-fluoro-3-(methylsulfonyl)-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-2-pyridinyl]carbamate (1.1 g, 1.72 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion, the reaction was quenched with saturated ammonium chloride solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (24:1) to afford tert-butyl (3-((R)-1-(5-chloro-4-fluoro-2-((((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (690.0 mg, 1.12 mmol, 65.1% yield), which was a yellow solid. LC-MS: (ESI, m / z): 616.2 [M+H] +

[0783] Step 3: 3-((R)-1-(4-fluoro-2-((((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-5-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0784]

[0785] Under nitrogen, a solution of tert-butyl (3-((R)-1-(5-chloro-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (500.0 mg, 0.81 mmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (415.0 mg, 0.84 mmol), tetrakis(triphenylphosphine)palladium (162.0 mg, 0.14 mmol), and cesium carbonate (684.0 mg, 2.1 mmol) in water (1 mL) and 1,4-dioxane (5 mL) was stirred at 100 °C for 1 hour. After completion, the resulting solution was quenched with water and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (19:1) to afford 3-((R)-1-(4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-5-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (320 mg, 0.37 mmol, 45.6% yield), which was a yellow solid. LC-MS: (ESI, m / z): 848.4 [M+H] +

[0786] Step 4: 3-((R)-1-(5-(8-Ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0787]

[0788] A solution of 3-((R)-1-(4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-5-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (300.0 mg, 0.35 mmol) and cesium fluoride (304.0 mg, 2 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 1 hour. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (47 / 3) to afford 3-((R)-1-(5-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (240.0 mg, 0.35 mmol, 92% yield), which was a yellow solid. LC-MS: (ESI, m / z): 692.3 [M+H] +

[0789] Step 5: 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol

[0790]

[0791] To a solution of 3-((R)-1-(5-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (220.0 mg, 0.25 mmol) in acetonitrile (1 mL) was added dioxane (1 mL) containing 4 M hydrochloric acid, and the mixture was stirred at room temperature for 30 minutes. After completion, the solvent was removed under vacuum. The pH of the resulting solution was adjusted to 7 with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: within 10 min, B increased from 32% to 54% and maintained 54% B; wavelength: 254 / 220 nm; RT1 (min): 9.6 to obtain 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynylnaphthalen-2-ol (15.3 mg, 0.023 mmol, yield 9.3%). LC-MS: (ESI, m / z): 648.2 [M+H] +

[0792] Example 17: 1 H NMR (300 MHz, methanol-d 4, ppm) δ 7.98–7.96 (m, 1H), 7.81–7.78 (m, 2H), 7.53–7.49 (m, 1H), 7.40–7.38 (m, 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.29–7.15 (m, 1H), 6.82–6.77 (m, 1H), 6.64–6.57 (m, 1H), 4.86–4.65 (m, 2H), 4.55–4.41 (m, 2H), 4.02 (s, 1H), 3.92–3.71 (m, 4H), 3.67–3.60 (m, 4H), 3.31–3.14 (m, 2H), 2.44–2.35 (m, 1H), 2.19–2.07 (m, 3H), 1.70 (d, J = 7.0 Hz, 3H).

[0793] Example 18: 3 - ((R)-1-(5-(5-Ethynylisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0794] Synthetic route

[0795]

[0796] Step 1: 5-Chloro-4-(trimethylstannyl)isoquinoline

[0797]

[0798] Under nitrogen, a solution of 4-bromo-5-chloroisoquinoline (1.5 g, 6.19 mmol), hexamethylditin (6.1 g, 18.62 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.72 g, 0.62 mmol) in toluene (15 mL) was stirred at 100 °C for 48 h. After completion, the resulting solution was quenched with saturated potassium fluoride solution and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was purified by reverse-phase chromatography (acetonitrile / water containing 0.1% NH 4 HCO 3 to give 5-chloro-4-(trimethylstannyl)isoquinoline (1.0 g, 3.06 mmol, 49.5% yield) as a colorless oil. LC-MS: (ESI, m / z): 328.0 [M + H] +

[0799] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolinyl)-6-fluoro-3-methylthio-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate

[0800]

[0801] Under nitrogen, a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-(7-chloro-6-fluoro-3-methylthio-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-2-pyridinyl]carbamate (800.0 mg, 1.32 mmol), (5-chloro-4-isoquinolinyl)-trimethyl-stannane (860.0 mg, 2.63 mmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (164.0 mg, 0.26 mmol), copper(I) iodide (76.0 mg, 0.40 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (107.0 mg, 0.13 mmol) in toluene (8 mL) was stirred at 90 °C for 1 h. After completion, the resulting solution was quenched with saturated potassium fluoride solution and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (97:3) to afford tert-butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolinyl)-6-fluoro-3-methylthio-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate (653 mg, 0.89 mmol, 67.5% yield), which was a yellow solid. LC-MS: (ESI, m / z): 734.2 [M+H] +

[0802] Step 3: tert-Butyl N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolinyl)-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate

[0803]

[0804] To a solution of tert-butyl N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolinyl)-6-fluoro-3-methylthio-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate (633.0 mg, 0.86 mmol) in dichloromethane (7 mL) was added 3-chloroperoxybenzoic acid (374.0 mg, 2.17 mmol), and the mixture was stirred at room temperature for 0.5 h. After completion, the resulting solution was quenched with saturated sodium bisulfite solution and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (97:3) to afford tert-butyl N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolinyl)-6-fluoro-3-methylsulfonyl-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamate (493.0 mg, 0.64 mmol, 74.6% yield), which was a yellow solid. LC-MS: (ESI, m / z): 766.2 [M+H] +

[0805] Step 4: tert-Butyl (3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

[0806]

[0807] Under nitrogen, sodium tert-butoxide (181.0 mg, 1.88 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (300.0 mg, 1.88 mmol) in toluene (5 mL), and the mixture was stirred at 0 °C for 10 minutes. Then N-tert-butoxycarbonyl-N-[3-[(1R)-1-[7-(5-chloro-4-isoquinolinyl)-6-fluoro-3-methanesulfonyl-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl]ethyl]-2-pyridinyl]carbamic acid tert-butyl ester (480.0 mg, 0.63 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. After completion, the resulting solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (91:9) to afford tert-butyl (3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (170 mg, 0.23 mmol, 36.4% yield), which was a yellow solid. LC-MS: (ESI, m / z): 745.3 [M+H] +

[0808] Step 5: 3-((R)-1-(4-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(5-((triisopropylsilyl)ethynyl)isoquinolin-4-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0809]

[0810] Under nitrogen, (tert-butyl (3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate) (150.0 mg, 0.18 mmol), ethynyltriisopropylsilane (367.0 mg, 2.01 mmol), bis(acetonitrile)palladium(II) dichloride (6.0 mg, 0.02 mmol), X-phos (58.0 mg, 0.12 mmol), and cesium carbonate (197.0 mg, 0.60 mmol) in acetonitrile (2 mL) were added at 90 °C for 4 h. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (89:11) to afford 3-((R)-1-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(5-((triisopropylsilyl)ethynyl)isoquinolin-4-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (70 mg, 0.09 mmol, 49.1% yield), which was a yellow solid. LC-MS: (ESI, m / z): 791.4 [M+H] +

[0811] Step 6: 3-((R)-1-(5-(5-Ethynylisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0812]

[0813] A solution of 3-((R)-1-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(5-((triisopropylsilyl)ethynyl)isoquinolin-4-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (65.0 mg, 0.08 mmol) and cesium fluoride (39.0 mg, 0.26 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 1.5 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 25 mL / min; gradient: within 7 min, B increased from 50% to 80% and maintained 80% B; wavelength: 254 / 220 nm; RT1 (min): 6.4 to obtain 3-((R)-1-(5-(5-ethynylisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (8.4 mg, 0.01 mmol, yield 15.7%). LC-MS: (ESI, m / z): 635.3 [M+H] +

[0814] Example 18: 1 1H NMR (300 MHz, methanol-d 6 6, ppm) δ 9.41 (s, 1H), 8.50 (s, 1H), 8.28 (dd, J = 8.1, 1.3 Hz, 1H), 8.04–7.96 (m, 2H), 7.78–7.68 (m, 2H), 6.82–6.76 (m, 1H), 6.62 (q, J = 6.7 Hz, 1H), 5.31 (d, J = 53.5 Hz, 1H), 4.87–4.36 (m, 4H), 3.49–3.37 (m, 1H), 3.32–3.30 (m, 2H), 3.25–3.17 (m, 3H), 3.03–2.98 (m, 1H), 2.24–2.02 (m, 3H), 2.00–1.95 (m, 3H), 1.69 (d, J = 6.6 Hz, 3H).

[0815] Example 19: 3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0816] Synthetic route

[0817]

[0818] Step 1: 3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0819]

[0820] A solution of tert-butyl (3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (60.0 mg, 0.07 mmol) in dioxane (1 mL) containing 4 M hydrochloric acid was stirred at room temperature for 0.5 h. After completion, the resulting solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: from 28% B to 52% B in 8.5 min; Wavelength: 220 nm; RT1 (min): 6.6; Number of runs: 2 to obtain 3-((R)-1-(5-(5-chloroisoquinolin-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (13.9 mg, 0.02 mmol, yield 30.2%). LC-MS: (ESI, m / z): 645.3 [M+H] +

[0821] Example 19: 1 H NMR (300 MHz, DMSO-d 6 , ppm) δ 9.53 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.99–7.92 (m, 2H), 7.80–7.74 (m, 1H), 7.65–7.63 (m, 1H), 6.66 (dd, J = 7.5, 4.9 Hz, 1H), 6.36 (q, J = 6.8 Hz, 1H), 5.74 (d, J = 20.0 Hz, 2H), 5.27 (d, J = 54.0 Hz, 1H), 4.46–4.43 (m, 2H), 4.12 (d, J = 1.7 Hz, 2H), 3.75–3.71 (m, 1H), 3.54–3.38 (m, 1H), 3.18–2.94 (m, 3H), 2.84–2.82 (m, 1H), 2.22–2.04 (m, 3H), 1.85–1.78 (m, 3H), 1.60 - 1.56 (m, 3H).

[0822] Example 20: 3-((R)-1-(5-(5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0823] Synthetic route

[0824]

[0825] Step 1: tert-Butyl (3-((R)-1-(5-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate

[0826]

[0827] Under nitrogen, sodium tert-butoxide (180.0 mg, 1.87 mmol) was added to a solution of [(2S)-4,4-difluoro-1-methyl-pyrrolidin-2-yl]methanol (280.0 mg, 1.85 mmol) in toluene (4 mL), and the resulting solution was stirred at 0 °C for 10 min. Then N-tert-butoxycarbonyl-N-[3-[(1R)-1-(7-chloro-6-fluoro-3-methanesulfonyl-10-oxa-2,4,8,13-tetraazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-13-yl)ethyl]-2-pyridinyl]carbamate tert-butyl ester (400.0 mg, 0.63 mmol) was added, and the mixture was stirred at room temperature for 1 h. After completion, the resulting solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (97:3) to give tert-Butyl (3-((R)-1-(5-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (320 mg, 0.32 mmol, 52.6% yield), which was a yellow solid. LC-MS: (ESI, m / z): 610.2 [M+H] +

[0828] Step 2: 3-((R)-1-(5-(5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine

[0829]

[0830] Under nitrogen, a solution of tert-butyl (3-((R)-1-(5-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (300.0 mg, 0.42 mmol), [5-[bis((4-methoxyphenyl)methyl)amino]-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]boronic acid (465.0 mg, 0.97 mmol), tetrakis(triphenylphosphine)palladium (105.0 mg, 0.0900 mmol), and cesium carbonate (420.0 mg, 1.29 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL) was stirred at 100 °C for 2 hours. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. Then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane / methanol (96:4) to afford 3-((R)-1-(5-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8,9-dihydro-10H-7-oxa-...

Claims

1. A compound of formula (I) or its atropisomer, stereoisomer, tautomer or pharmaceutically acceptable salt, wherein: Ring A is R 8 a substituted or unsubstituted 3- to 10-membered heterocyclic ring, or R 8 a substituted or unsubstituted 5- to 10-membered heteroaryl; R 8 independently a halogen, CN, NH 2 , NHC 1-3 alkyl, R 8A substituted or unsubstituted C 1-6 alkyl, or R 8A substituted or unsubstituted C 1-6 haloalkyl; R 8A is halogen, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl; n is 1 or 2; R 1 is R 7 substituted or unsubstituted indolyl, R 7 substituted or unsubstituted benzofuranyl, R 7 substituted or unsubstituted naphthyl, R 7 substituted or unsubstituted indazolyl, R 7 substituted or unsubstituted indenyl, R 7 substituted or unsubstituted benzothiazolyl, R 7 substituted or unsubstituted isoquinolinyl, R 7A substituted or unsubstituted phenyl or R 7A substituted or unsubstituted pyridyl; Each R 7 is independently hydrogen, halogen, CN, CH 2 OH, -OH, NH 2 , N(Me) 2 , unsubstituted C 1-3 alkyl, unsubstituted C 2-5 alkynyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; Each R 7a is independently hydrogen, halogen, NH 2 , N(Me) 2 , unsubstituted C 1-3 alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 2 is OH, unsubstituted C 1-3 alkoxy, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl; R 3 is R 9 a 4- to 10-membered heterocycle containing N, S or O, which is substituted or unsubstituted; R 9 independently a halogen, oxo, unsubstituted C 1-3 alkyl, unsubstituted C 1-3 haloalkyl, unsubstituted C 1-3 alkoxy, R 10 substituted or unsubstituted C 1-3 alkylidene, or R 10 substituted or unsubstituted C 3-4 cycloalkyl, or R 10 substituted or unsubstituted 3- or 4-membered heterocycle; or two of the Rs 9 together form C 3-5 cycloalkyl or a 3- to 5-membered heterocycle; R 10 is hydrogen or a halogen; R 4 is hydrogen, halogen, unsubstituted C 1-3 alkyl, unsubstituted C 1-3 alkoxy, or unsubstituted C 1-3 haloalkyl; and R 5 and R 6 each independently is hydrogen or unsubstituted C 1-3 alkyl group.

2. The compound according to claim 1, wherein R 1 is R 7 substituted or unsubstituted indolyl, R 7 substituted or unsubstituted benzofuranyl, R 7 substituted or unsubstituted naphthyl, R 7 substituted or unsubstituted indazolyl, R 7 substituted or unsubstituted indenyl, R 7 substituted or unsubstituted benzothiazolyl, or R 7 substituted or unsubstituted isoquinolinyl.

3. The compound according to claim 1 or 2, wherein R 1 is R 7 a substituted or unsubstituted naphthyl group, or R 7 a substituted or unsubstituted isoquinolinyl group.

4. The compound according to any one of claims 1 to 3, wherein R 1 is 5. The compound according to any one of claims 1 to 4, wherein R 1 is 6. The compound according to any one of claims 1 to 5, wherein R 1 is 7. The compound according to claim 1, wherein R 1 is R 7A substituted or unsubstituted phenyl, or R 7A substituted or unsubstituted pyridyl.

8. The compound according to claim 1 or 7, wherein R 1 is wherein X 1 is N, CH, CF or CCl; and R 7A is hydrogen, a halogen, an unsubstituted C 1-3 alkyl group, or an unsubstituted C 1-3 haloalkyl group.

9. A compound according to any one of claims 1, 7 or 8, wherein R 1 is wherein, X 1 is N, CH, CF or CCl; and R 7A is hydrogen, a halogen, an unsubstituted C 1-3 alkyl group, or an unsubstituted C 1-3 haloalkyl group.

10. The compound according to claim 9, wherein X 1 is N.

11. A compound according to any one of claims 1 or 9 to 10, wherein R 1 is wherein R 7A is hydrogen, halogen, unsubstituted C 1-3 alkyl, or unsubstituted C 1-3 haloalkyl.

12. A compound according to any one of claims 1 or 9 to 11, R 1 is 13. The compound according to claim 9, wherein X 1 is CH, CF or CCl.

14. The compound according to claim 9 or 13, wherein R 1 is wherein R 7A is hydrogen, F or Cl.

15. The compound according to claim 9 or 13, wherein R 1 is wherein R 7A is hydrogen, F or Cl.

16. The compound according to any one of claims 1, 7 or 8, wherein R 1 is wherein R 7A is hydrogen, a halogen, an unsubstituted C 1-3 alkyl, or an unsubstituted C 1-3 haloalkyl.

17. A compound according to any one of claims 1 or 7 to 16, wherein R 1 is 18. A compound according to any one of claims 1 or 7 to 17, wherein R 1 is 19. The compound according to any one of claims 1 or 7 to 18, R 1 is 20. The compound according to any one of claims 1 to 19, wherein R 4 is Cl or F.

21. The compound according to any one of claims 1 to 20, wherein R 4 is F.

22. The compound according to any one of claims 1 to 21, wherein R 4 is Cl.

23. The compound according to any one of claims 1 to 22, wherein R 4 is OCH 3 .

24. The compound according to any one of claims 1 to 23, wherein R 3 is wherein: Z is C(R 9 ) 2 or O; R 9 is hydrogen, a halogen, or R 10 substituted or unsubstituted C 1-3 alkylidene; or two of the Rs 9 together form C 3-5 cycloalkyl or a 3- to 5-membered heterocycle r is an integer from 0 to 12; j is 1, 2 or 3; and k is 1 or 2.

25. The compound according to any one of claims 1 to 24, R 3 is where R 9 is halogen, -OCF 3 , -OCHF 2 , -OCH 2 F, R 10 substituted or unsubstituted C 1-3 alkylidene, or two Rs 9 together form an R 10 substituted or unsubstituted C 3-5 cycloalkyl; r is an integer from 0 to 12; j is 1, 2 or 3; and k is 1 or 2.

26. The compound according to any one of claims 1 to 25, wherein R 3 is: wherein: Each R 9 is independently a halogen, or R 10 is a substituted or unsubstituted C 1-3 alkylidene; Each R 10 is independently hydrogen or halogen; r is 0, 1 or 2; and s is 0, 1 or 2.

27. The compound according to any one of claims 1 to 26, wherein R 3 is (D1), (D2) or (D3), wherein: Each R 9 is independently a halogen, or R 10 substituted or unsubstituted C 1-3 alkylidene; Each R 10 is independently hydrogen or halogen; r is 0, 1 or 2; and s is 0, 1 or 2.

28. The compound according to any one of claims 1 to 27, wherein R 3 is:

29. The compound according to any one of claims 1 to 27, wherein R 3 is (D1), where r is 1.

30. A compound according to any one of claims 1 to 27, wherein R 3 is (D2), where r is 0 and each R 10 is independently hydrogen or F.

31. A compound according to any one of claims 1 to 27, wherein R 3 is (D3), where r is 0, and each R 9 is independently hydrogen or halogen.

32. A compound according to any one of claims 1 to 26, wherein R 3 is (D4), wherein R 10 is a halogen, and s is 0, 1 or 2.

33. A compound according to any one of claims 1 to 25, wherein R 3 is wherein R 10 is a halogen and s is 0, 1 or 2.

34. A compound according to any one of claims 1 to 25, wherein R 3 is wherein, Each R 9 is independently halogen, oxo, or unsubstituted C 1-3 alkyl; and r is 0, 1 or 2.

35. A compound according to any one of claims 1 to 25, wherein R 3 is wherein, Each R 9 is independently halogen, oxo, or unsubstituted C 1-3 alkyl; and r is 0, 1 or 2.

36. A compound according to any one of claims 1 to 23, wherein R 3 is wherein, Each R 9 is independently halogen, oxo, or unsubstituted C 1-3 alkyl; or two of the Rs 9 together form C 3-5 cycloalkyl or a 3- to 5-membered heterocycle; and r is 1 or 2.

37. A compound according to any one of claims 1 to 23, wherein R 3 is 38. A compound according to any one of claims 1 to 23, wherein R 3 is 39. A compound according to any one of claims 1 to 38, wherein R 2 is methyl.

40. A compound according to any one of claims 1 to 38, wherein R 2 is CHF 2 , CH 2 F or CF 3 .

41. The compound according to any one of claims 1 to 40, wherein ring A is R 8 a substituted or unsubstituted 3- to 10-membered heterocycle, or R 8 a substituted or unsubstituted 5- to 10-membered heteroaryl.

42. The compound according to any one of claims 1 to 41, wherein ring A is R 8 a substituted or unsubstituted 3- to 6-membered heterocycle, or R 8 a substituted or unsubstituted 5- to 6-membered heteroaryl.

43. The compound according to any one of claims 1 to 42, wherein ring A is R 8 a 3- to 6-membered heterocycle containing at least 1 heterocyclic ring nitrogen atom, which is substituted or unsubstituted, or R 8 a 5- to 6-membered heteroaryl containing at least 1 heterocyclic ring nitrogen atom, which is substituted or unsubstituted.

44. The compound according to any one of claims 1 to 43, wherein ring A is R 8 a 5- or 6-membered heterocycle which is substituted or unsubstituted and contains at least 1 heterocyclic ring nitrogen atom.

45. The compound according to any one of claims 1 to 44, wherein ring A is R 8 a 6-membered heteroaryl group which is substituted or unsubstituted and contains at least 1 heterocyclic ring nitrogen atom.

46. The compound according to any one of claims 1 to 45, wherein ring A is R 8 a substituted or unsubstituted pyridyl group, R 8 a substituted or unsubstituted pyrimidinyl group or R 8 a substituted or unsubstituted pyrazinyl group.

47. The compound according to any one of claims 1 to 46, wherein ring A is a moiety having the following formula; where X is CH or N, and n is 1 or 2.

48. The compound according to any one of claims 1 to 47, wherein ring A is a moiety having the following formula; where X is CH or N.

49. A compound according to any one of claims 1 to 48, wherein R 5 and R 6 are each hydrogen.

50. The compound according to any one of claims 1 to 49, R 5 is CH 3 and R 6 is hydrogen.

51. A compound of Table 1 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt.

52. A compound of Table 2 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt.

53. A compound of Table 3 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt.

54. A pharmaceutical composition comprising the compound according to any one of claims 1 to 53 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, and one or more pharmaceutical excipients.

55. A method for treating cancer, the method comprising administering an effective amount of the compound according to any one of claims 1 to 53 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 54.

56. A method for treating cancer, the method comprising administering an effective amount of the compound according to any one of claims 1 to 53 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt.

57. The method according to claim 56, wherein the cancer is characterized by the presence of a KRas mutation.

58. The method according to claim 57, wherein the KRas mutation corresponds to a KRas G12D mutation or a KRas G12V mutation.

59. The method according to claim 57, further comprising testing a sample from a patient for the absence or presence of a KRas mutation prior to administration.

60. The method according to claim 59, wherein after the patient sample shows the presence of a KRas mutation, the compound, its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition is administered to the patient.

61. The method according to any one of claims 56 to 60, wherein the cancer is of undetermined histology.

62. The method according to any one of claims 56 to 60, wherein the cancer is pancreatic cancer, lung cancer or colorectal cancer.

63. The method according to claim 62, wherein the lung cancer is adenocarcinoma of the lung, NSCLC or SCLC.

64. The method according to claim 62, wherein the cancer is pancreatic cancer.

65. The method according to claim 62, wherein the cancer is colorectal cancer.

66. The method according to any one of claims 56 to 65, further comprising administering at least one additional therapeutic agent.

67. The method according to claim 66, wherein the additional therapeutic agent comprises an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an antimetabolite, or an alkylating agent.

68. The compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use as a therapeutic agent.

69. Use of the compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for the therapeutic treatment of cancer comprising a KRas mutation.

70. Use of the compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of cancer comprising a KRas mutation.

71. Use of the compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting tumor metastasis.

72. The compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of cancer comprising a KRas mutation.

73. A method of modulating the activity of a KRas mutant protein, the method comprising reacting the mutant protein with the compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

74. A method of inhibiting the proliferation of a cell population, the method comprising contacting the cell population with the compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

75. The method according to claim 74, wherein inhibition of proliferation is measured by a decrease in the cell viability of the cell population.

76. A method of preparing a labeled KRas mutant protein, the method comprising reacting a KRas mutant protein with a labeled compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, to produce the labeled KRas mutant protein.

77. A method of inhibiting tumor metastasis, the method comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 53, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 55, to a subject in need thereof.

78. A method of synthesizing the compounds as described herein.

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