Aza-tetraepoxy aza compounds and uses thereof

Abstract

Provided herein are aza-tetraepoxy aza # imgabs0 #-based compounds that are useful in the treatment of cancer.

Description

Background Art

[0001] Ras is a small GTP-binding protein that acts as a nucleotide-dependent switch in the central growth signaling pathway. In response to extracellular signals, Ras is catalyzed by guanine nucleotide exchange factors (GEFs), particularly SOS1, to switch from GDP-bound (Ras GDP ) state changes to GTP-bound (Ras GTP ) state. Active Ras GTP Its various growth-stimulating functions are mediated through direct interactions with effectors including Raf, PI3K, and Ral guanine nucleotide dissociation stimulator. The intrinsic GTPase activity of Ras subsequently hydrolyzes GTP to GDP, thereby terminating Ras signaling. Ras GTPase activity can be further promoted by its interaction with GTPase-activating proteins (GAPs), including the neurofibromin 1 tumor suppressor.

[0002] The GTPase activity of mutant Ras is reduced, which prolongs its activated state, thereby promoting the survival or growth of Ras-dependent signal transduction and cancer cells. The mutation in Ras affects its ability to interact with GAP or convert GTP back to GDP, which will cause the activation time of the protein to be extended, and then cause the signal that tells the cell to continue to grow and divide to be extended. Because these signals cause cell growth and division, overactivated RAS signal transduction may eventually lead to cancer. Mutations in any one 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 commonly mutated.

[0003] The most common KRas mutations occur at residues G12 and G13 in the P-loop and at residue Q61. G12D (glycine-12 to aspartic acid) is a common mutation in the KRas gene. Ras mutations in cancer are associated with poor prognosis. Inactivation of oncogenic Ras in mice results in tumor regression. Therefore, Ras is widely considered a crucial tumor target.

[0004] Therefore, there is an urgent need for therapies targeting G12D-mutated KRas-mediated cancers. Summary of the Invention

[0005] Solutions to the above-referenced problems and other problems in the art are provided herein.

[0006] In a first aspect, provided herein is a compound of formula (I) as described herein, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0007] In a second aspect, provided herein is a compound of formula (IId) as described herein, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0008] In another aspect, provided herein is a compound as shown in Table 1 or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, provided herein is a pharmaceutical composition comprising a compound as described herein, a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0010] In another aspect, provided herein is a method of treating a cancer comprising a KRas mutation, comprising administering to a patient suffering from such cancer a compound described herein, a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0011] In another aspect, provided herein is a method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a compound as described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0012] In another aspect, provided herein is a method for inhibiting proliferation of a cell population, comprising contacting the cell population with a compound as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0013] In another aspect, provided herein is a method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound as described herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein to a subject in need thereof.

[0014] In another aspect, provided herein is a method for preparing a labeled KRas G12D mutant protein, comprising reacting a KRas G12D mutant protein with a labeled compound as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to produce a labeled KRas G12D mutant protein. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The pharmacokinetic profiles of compounds 6, 7, 81 and 194 and a comparator compound are shown. DETAILED DESCRIPTION

[0016] definition

[0017] Disclosed herein are 6-aza-tetracyclic oxazepines as described herein. Compounds or stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof, which in certain embodiments are inhibitors or modulators of mutant KRas. In some cases, such compounds and compositions are inhibitors or modulators of mutant G12D KRas as provided herein. The compounds and compositions described herein can be used to treat diseases caused by mutant KRas (including KRas G12D mutations)-mediated diseases and disorders.

[0018] Although the disclosure herein provides enumerated embodiments, it should be understood that they are not intended to limit the compounds and methods described herein to those embodiments. On the contrary, this disclosure is intended to cover all alternatives, modifications and equivalents that may be included within the scope of this disclosure as defined by the claims.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety. Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC systematic nomenclature.

[0020] The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of the present disclosure.All references cited herein are incorporated by reference in their entirety.

[0021] 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.

[0022] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. In one embodiment, the alkyl group is one to eighteen carbon atoms (C 1-18 In other examples, the alkyl group is C 1-12 、C 1-10 、C 1-8 、C 1-6 、C 1-5 、C 1-4 or C 1-3Examples of alkyl groups include methyl (Me, –CH3), ethyl (Et, –CH2CH3), 1-propyl (n-Pr, n-propyl, –CH2CH2CH3), 2-propyl (i-Pr, isopropyl, –CH(CH3)2), 1-butyl (n-Bu, n-butyl, –CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, –CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, –CH(CH3)CH 2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, –C(CH3)3), 1-pentyl (n-pentyl, –CH2CH2CH2CH2CH3), 2-pentyl (–CH(CH3)CH2CH2CH3), 3-pentyl (–CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (–CH(CH3)CH(CH3)2), 3-methyl-1-butyl (–CH2 CH2CH(CH3)2), 2-methyl-1-butyl (–CH2CH(CH3)CH2CH3), 1-hexyl (–CH2CH2CH2CH2CH2CH3), 2-hexyl (–CH(CH3)CH2CH2CH2CH3), 3-hexyl (–CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (–C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (–CH(CH3)CH (CH3)CH2CH3), 4-methyl-2-pentyl (–CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (–C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (–CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (–C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (–CH(CH3)C(CH3)3, 1-heptyl, and 1-octyl.

[0023] The term "oxo" refers to =0.

[0024] The term "alkoxy" refers to an -O-alkyl group.

[0025] The term "cyano" or "nitrile" refers to -C≡N or -CN.

[0026] The term "haloalkoxy" refers to an -O-haloalkyl group.

[0027] The terms "hydroxy" and "hydroxyl" refer to the -OH group.

[0028] The term "alkylidene" refers to a linear or branched monovalent hydrocarbon radical having the formula =CR'R", where R' and R' can be the same or different. In one example, an alkylidene radical is 1 to 6 carbon atoms (C1-6 In another example, the alkylidene group is C 1-3 、C 1-2 or C1. Exemplary alkylidene groups include, but are not limited to, methylidene (=CH2), ethylidene (=CHCH3), and propylidene (=CH-CH2-CH3).

[0029] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond, and includes groups having "cis" and "trans" orientations, or alternatively "E" and "Z" orientations. In one example, the alkenyl group is a group of two to eighteen carbon atoms (C 2-18 In other examples, the alkenyl group 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 (-CH=CH2), prop-1-enyl (-CH=CHCH3), prop-2-enyl (-CH2CH=CH2), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

[0030] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. In one example, the alkynyl radical is a radical of two to eighteen carbon atoms (C 2-18 In other examples, the alkynyl group 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°H), prop-1-ynyl (-C°CH3), prop-2-ynyl (propargyl, -CH2C°H), but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0031] The term "alkylene" refers to a saturated, branched or straight chain hydrocarbon radical having two monovalent radical centers, which is derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. In one example, the divalent alkylene group is one to eighteen carbon atoms (C 1-18 In other examples, the divalent alkylene group is C 1-12 、C 1-10 、C 1-8 、C 1-6 、C 1-5 、C 1-4 or C 1-3Exemplary alkylene groups include methylene (–CH2–), 1,1-ethyl (–CH(CH3)–), 1,2-ethyl (–CH2CH2–), 1,1-propyl (–CH(CH2CH3)–), 2,2-propyl (–C(CH3)2–), 1,2-propyl (–CH(CH3)CH2–), 1,3-propyl (–CH2CH2CH2–), 1,1-dimethylethyl-1,2-yl (–C(CH3)2CH2–), 1,4-butyl (–CH2CH2CH2CH2–), and the like.

[0032] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyl encompasses monocyclic, bicyclic, tricyclic, spirocyclic and bridged, saturated ring systems. In one embodiment, a cycloalkyl group is 3 to 12 carbon atoms (C 3-12 In other embodiments, the cycloalkyl group is C 3-4 、C 3-5 、C 3-7 、C 3-8 、C 3-10 or C 5-10 In other embodiments, the cycloalkyl group as a monocyclic ring is C 3-4 、C 3-8 、C 3-6 or C 5-6 In another embodiment, the cycloalkyl group as a bicyclic ring is C7-C 12 In another embodiment, the cycloalkyl group as the 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 spirocycloalkyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane.

[0033] The terms "heterocyclic group," "heterocyclic," "heterocycle," "heterocyclyl," or "heterocyclyl" are used interchangeably and refer to any monocyclic, bicyclic, tricyclic, spirocyclic, 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 of the ring atoms of the ring system is a heteroatom, the system is a heterocycle, regardless of the point of attachment of the ring system to the rest of the molecule. In one example, a heterocyclyl comprises 3-10 ring atoms ("members") and includes monocyclic, bicyclic, tricyclic, spirocyclic, and bridged ring systems, wherein the ring atoms are carbon, and wherein at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclyl comprises 4-10 or 5-10 ring atoms. In one example, a heterocyclyl comprises 1 to 4 heteroatoms. In one example, a heterocyclyl comprises 1 to 3 heteroatoms. In another example, the heterocyclic group includes a 3- to 7-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, 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 example, the heterocyclic group includes a 3-membered monocyclic ring. In another example, the heterocyclic group includes a 4-membered monocyclic ring. In another example, the heterocyclic group includes a 5-6-membered monocyclic ring. In some embodiments, the heterocycloalkyl group includes at least one nitrogen. In one example, the heterocyclic group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may be optionally quaternized (e.g., [NR4] + Cl - 、[NR4] + OH - ). Exemplary heterocycles are oxirane, aziridinyl, thiopyranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thiooxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine 1,4-diazepanyl, diazepanyl, 1,4-diazepanyl, diazepanyl, thiazolinone yl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolinyl, isothiazolidinyl, 1,1-isothiazolidinone, 1,1-dioxaisothiazolyl, oxazolidinone, imidazolinone, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, azinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithienyl, dithiolanyl, pyrimidinone, pyrimidinedione, pyrimidine-2,4-diacyl, piperazinone, piperazinediacyl, pyrazole imidazolinyl, 3-azabis[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]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[3.1.0]hexanyl, [2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonane, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]decan-2-yl, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindolyl, 1,1-dioxahexahydrothiopyranyl.

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

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

[0036] "Fused" refers to any ring structure described herein that shares one or more atoms (eg, carbon or nitrogen atoms) with an existing ring structure in a compound described herein.

[0037] The term "acyl" refers to a carbonyl group containing a substituent represented by the formula -C(=O)-R, where R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl (e.g., pyridyl).

[0038] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Examples of haloalkyls are trifluoromethyl, difluoromethyl, and fluoromethyl. Substituted haloalkyls refer to haloalkyls having moieties other than halogens. Unsubstituted haloalkyls refer to haloalkyls as described herein that are not substituted with moieties other than hydrogen or halogens.

[0039] As used herein, a wavy line that intersects a bond in a chemical structure Indicates the point of attachment of an atom connected by a wavy bond in a chemical structure to the rest of a molecule or molecular fragment.

[0040] In certain embodiments, a divalent group is generally described as having no specific bonding configuration. It should be understood that unless otherwise indicated, 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 -CH2C(O)-, it is understood that this group can be used as R 1 -CH2C(O)-R 3 and R 1 -C(O)CH2-R 3 bonding.

[0041] The term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to animals such as, for example, humans, as appropriate.

[0042] 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 formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid groups, 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, dihydronaphthoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, which retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable.

[0043] The term "pharmaceutically acceptable base addition salts" includes those 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 salts of primary, secondary, and tertiary amines, and substituted amines include 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, hydrazine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline and caffeine.

[0044] In some embodiments, the salt is selected from hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, 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), naphthalene disulfonate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), ethanesulfonate (ethane-1,2-disulfonate).

[0014] Examples of the present invention include benzoate, adipate, oxalate, malonate, methylbenzenesulfonate (2-m-benzenesulfonate), naphthalenesulfonate (2-naphthalenesulfonate), camphorsulfonate (camphor-10-sulfonate, e.g., (1S)-(+)-10-camphorsulfonate), glutamate, glutarate, hippurate (2-(benzamido)acetate), orotate, ditoluate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthomethane-3,3'-dicarboxylate).

[0045] A "sterile" preparation is sterile or free from all viable microorganisms and their spores.

[0046] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, atropisomers, conformers, and the like.

[0047] The term "chiral" refers to a molecule having the property of being non-superimposable on its mirror image partner, whereas the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0048] 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, for example, melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers can be separated under high-resolution analytical procedures (such as electrophoresis) and chromatography (such as HPLC).

[0049] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0050] The term "atropisomers" refers to two conformers resulting from hindered rotation about a single bond, where the steric strain barrier to rotation may be high enough to allow separation of the conformers.

[0051] The stereochemical definitions and conventions used herein generally follow those in S.P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, 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 indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of the rotation of the compound with respect to plane-polarized light, where (-) or 1 indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in the absence of stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that are not optically active.

[0052] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0053] 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 a variety of crystalline or amorphous forms. In general, all physical forms are contemplated herein. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0054] The compounds described herein and their pharmaceutically acceptable salts also encompass isotopically labeled compounds, which are identical to the compounds recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element specified and their uses are contemplated herein. Exemplary isotopes that can be incorporated into the compounds described herein or their pharmaceutically acceptable salts 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 described herein or pharmaceutically acceptable salts thereof (e.g., 3 H and 14 C-labeled compounds) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes are useful because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e., 2 H) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances. 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 described herein, or pharmaceutically acceptable salts thereof, can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0055] The compounds described herein and their pharmaceutically acceptable salts may contain one or more asymmetric carbon atoms. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemates, diastereomers, or enantiomers as starting materials or intermediates. A mixture of specific diastereomeric compounds may be separated or enriched for one or more specific diastereomers by chromatography or crystallization. Similarly, mixtures of enantiomers may be separated or enantiomerically enriched using the same techniques or other techniques known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration, and both of these configurations are contemplated herein.

[0056] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included. When stereochemistry is specified by a solid wedge or dashed line representing a specific configuration, that stereoisomer is specified and defined. Unless otherwise indicated, relative stereochemistry is intended when a solid wedge or dashed line is used.

[0057] "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), sports animals, pets (such as guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human. In embodiments involving administration of a compound to a patient, the patient is typically a patient in need thereof.

[0058] The terms "inhibit" and "reduce," or any variations of these terms, include any measurable reduction or complete inhibition to achieve the desired result. For example, 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 therein, compared to normal.

[0059] The term "treatment" refers to a clinical intervention intended to alter the natural course of the patient or cell being treated during the course of clinical pathology. Desirable therapeutic effects include reducing the rate of disease progression, slowing or alleviating the disease state, and alleviating or improving prognosis. For example, a patient is successfully "treated" if one or more symptoms associated with the cancer described herein are alleviated 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 patients suffering from the disease, reducing the dose of other drugs required to treat the disease, and / or extending the patient's survival.

[0060] The term "delaying progression" of a disease refers to postponing, hindering, slowing, slowing, stabilizing, and / or retarding the progression of a cancer as described herein. This delay can be of varying lengths of time, depending on the history of the cancer and / or the patient being treated. As will be apparent to one skilled in the art, a sufficient or significant delay can actually encompass prevention, in that the patient will not develop the cancer or experience a recurrence.

[0061] "Mutant KRas-mediated disease" and the like refer to a disease as described herein (e.g., a cancer as described herein) having symptoms as described herein or requiring treatment, which symptoms are associated, in whole or in part, as a result of, as a function of, or otherwise related to the activity of a mutant KRas as described herein. In one such embodiment, the mutant KRas is KRas G12D .

[0062] An "effective amount" or "therapeutically effective amount" is the minimum amount required to achieve at least 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, sex, and weight, and the ability of the agent to elicit the desired response in the patient. An effective amount is also an amount in which the beneficial effects of the treatment outweigh any toxic or deleterious effects of the treatment. Beneficial or desired clinical outcomes include results such as: eliminating or reducing risk, reducing severity, delaying the onset of the disease (including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that occur during disease progression), reducing one or more symptoms caused by the disease, improving the quality of life of patients suffering from the disease, reducing the dose of other drugs required to treat the disease, enhancing the effect of another drug (such as by targeting), delaying disease progression, and / or prolonging survival. In some embodiments, an effective amount of a drug may have the following effects: reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing or stopping) the infiltration 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 disease. An effective amount can be administered in one or more administrations.

[0063] As used herein, the terms "co-administration," "combination administration," and their grammatical equivalents encompass the administration of two or more agents to an animal (including a human) such that both agents and / or their metabolites are present in the animal. Co-administration includes simultaneous administration in separate compositions, administration in separate compositions at different times (i.e., sequential administration), or administration in a composition in which both agents are present.

[0064] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0065] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds that have the ability to inhibit the biological function of a target protein by inhibiting the activity or expression of the protein (such as a mutant form of KRas). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological effects of the target protein. Although preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included in the definition. Preferred biological activities inhibited by the antagonist are related to the development, growth, or spread of tumors.

[0066] The term "agonist" as used herein refers to a compound that has the ability to activate or enhance 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 preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that activate 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.

[0067] The terms "cancer" and "cancerous," "neoplasm," and "tumor," and related terms are used interchangeably herein and refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancers include carcinomas, blastomas, sarcomas, seminoma, glioblastomas, melanomas, leukemias, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinomas) and lung cancers, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinomas, and lung squamous cell carcinomas. Other cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral cavity), lips, tongue, mouth, salivary glands, esophagus, larynx, hepatocellular, stomach, gastrointestinal tract, small intestine, large intestine, pancreas, cervix, ovary, liver, bladder, hepatoma, breast, colon, rectum, colorectal, genitourinary system, biliary tract, thyroid, papillary, hepatic, endometrial, uterine, salivary glands, kidney or renal, prostate, testicle, vulva, peritoneum, anus, penis, bone, multiple myeloma, B cell lymphoma, diffuse large B cell lymphoma (DLBCL), central nervous system, brain, head and neck, 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 myeloid leukemia (CML).

[0068] A "chemotherapeutic agent" is a formulation useful for treating a given condition (e.g., cancer or an inflammatory condition). Examples of chemotherapeutic agents are well known in the art. Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any chemotherapeutic agent, and combinations of two or more thereof.

[0069] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds described herein, or pharmaceutically acceptable salts thereof, 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. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled compounds) can be used in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are useful because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e., 2 H) substitution may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds described herein or pharmaceutically acceptable salts thereof, one or more carbon atoms are replaced by a 13 C or 14 Carbon substitution with C. 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. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0070] It is specifically contemplated that any limitation discussed with respect to one embodiment provided herein may apply to any other embodiment provided herein. In addition, any compound described herein, and pharmaceutically acceptable salts thereof, or compositions described herein may be used in any method provided herein, and any method provided herein may be used to produce or utilize any compound described herein, and pharmaceutically acceptable salts thereof, or compositions described herein.

[0071] Throughout this application, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

[0072] The compounds described herein may have the stereochemical structure depicted below:

[0073]

[0074] It is to be understood that all three of the above stereochemical schemes are equivalent as described herein.

[0075] Compound

[0076] Provided herein are compounds having the following formula: A compound of formula (I):

[0077]

[0078] in

[0079] X is O or NR 6

[0080] m is 1 or 2;

[0081] n is 1 or 2;

[0082] wherein n and m together form a 6-membered or 7-membered ring A;

[0083] p is 0, 1, or 2;

[0084] R 1 R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted isoquinolinyl, R 7 Substituted or unsubstituted indazolyl, R 7 Substituted or unsubstituted indanyl, R 7 Substituted or unsubstituted benzothiazolyl, R 7A Substituted phenyl, or R 7A substituted pyridyl;

[0085] Each R 7 are independently halogen, OH, NH2, N(Me)2, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Alkynyl, unsubstituted C1-3 Alkoxy, or unsubstituted C 1-3 Haloalkyl

[0086] Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or unsubstituted cyclopropyl

[0087] R 7B CN, oxo or C 1-3 alkyl;

[0088] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0089] R L1 is halogen, or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl; or

[0090] R 2 R contains one or more heteroatoms selected from N, S or O 9 Substituted or unsubstituted 4- to 10-membered heterocyclic ring

[0091] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0092] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0093] Two R's 9together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0094] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0095] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0096] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0097] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0098] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0099] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0100] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0101] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A Substituted or unsubstituted 3- to 4-membered heterocyclic ring

[0102] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocycle, and

[0103] R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0104] In one embodiment, the present invention further provides a compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0105] X is O or NR 6 ;

[0106] m is 1 or 2;

[0107] n is 1 or 2;

[0108] wherein n and m together form a 6-membered or 7-membered ring A;

[0109] p is 0, 1, or 2;

[0110] R 1 R 7A Substituted phenyl, or R 7A substituted pyridyl;

[0111] Each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 alkyl halide;

[0112] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0113] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0114] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0115] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0116] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0117] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0118] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0119] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0120] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0121] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0122] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0123] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0124] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0125] R 6 is hydrogen, R 6A Substituted or unsubstituted C1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0126] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0127] In another embodiment, is a compound of formula (I-1):

[0128]

[0129] where R 1 、R 3 、R 4 、R 5 , X, m and n are as described herein.

[0130] In one embodiment, each R 4 In another embodiment, one R 4 is hydrogen and one R 4 In another embodiment, one R 4 is hydrogen and one R 4 It is CF3.

[0131] In one embodiment, R 1 R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted isoquinolinyl, R 7 Substituted or unsubstituted indazolyl, R 7 Substituted or unsubstituted indanyl, or R 7 In one embodiment, R 1 R 7 Substituted or unsubstituted naphthyl, R 7Substituted or unsubstituted isoquinolinyl, or R 7 In another embodiment, R 1 R 7 In another embodiment, R 1 R 7 In another embodiment, R 1 R 7A Substituted phenyl or R 7A In one embodiment, R 1 R 7 In one such embodiment, R 1 R 7 substituted isoquinolinyl and each R 4 In another embodiment, R 1 R 7 Substituted naphthyl, R 7 Substituted isoquinolinyl, R 7 Substituted indazolyl, R 7 Substituted indanyl, R 7 Substituted benzothiazolyl, or R 7A In such embodiments, each R 4 is hydrogen, or an R 4 is hydrogen and one R 4 It is a methyl group.

[0132] In one embodiment, each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 In another embodiment, each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 In yet another embodiment, at least one R 7A is NH2. In one such embodiment, wherein at least one R 7A is NH2, at least one other R 7A For unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or halogen.

[0133] In one embodiment, each R 7 are independently halogen, OH, NH2, N(Me)2, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3Alkynyl, unsubstituted C 1-3 Alkoxy, or unsubstituted C 1-3 In one embodiment, each R 7 are independently halogen, OH, NH2, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 In yet another embodiment, at least one R 7 is NH2. In another embodiment, at least one R 7 For OH.

[0134] In one embodiment, R 1 for:

[0135]

[0136] where X 1 N or CR 7C .

[0137] In one such embodiment, X 1 is N or CF, and each R 7A are independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 In one such embodiment, each R 7A are independently hydrogen, Cl, methyl, ethyl or CF3, wherein not more than one R 7A In one embodiment, at least one R 7A is NH2. In one embodiment, each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 In one embodiment, one R 7A In one such embodiment, one R 7A is cyclopropyl and is in the para position relative to the amino group. In another such embodiment, one R 7A Is a cyclopropyl group and is located at the meta position of the amino group. In one embodiment, X 1 is N. In one embodiment, X 1 CR 7C In one such embodiment, R 7C is hydrogen or halogen.

[0138] In another embodiment, provided herein is a compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0139] X is O or NR 6 ;

[0140] m is 1 or 2;

[0141] n is 1 or 2;

[0142] wherein n and m together form a 6-membered or 7-membered ring A;

[0143] p is 0, 1, or 2;

[0144] R 1 With formula where X 1 N or CR 7C And R 7C is hydrogen or halogen; each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 a haloalkyl group or an unsubstituted cyclopropyl group;

[0145] R 7B CN, oxo or C 1-3 alkyl;

[0146] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0147] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0148] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0149] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0150] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0151] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0152] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0153] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0154] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0155] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0156] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0157] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0158] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0159] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0160] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and

[0161] R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0162] In one such embodiment, X 1 is N, and R 7A is hydrogen, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 In another such embodiment, at least one R 7A For unsubstituted C 1-3 In some embodiments, wherein X 1 N, R 1 comprising a moiety having formula (E1);

[0163]

[0164] In another embodiment, is a compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0165] X is O or NR 6 ;

[0166] m is 1 or 2;

[0167] n is 1 or 2;

[0168] wherein n and m together form a 6-membered or 7-membered ring A;

[0169] p is 0, 1, or 2;

[0170] R 1 With formula

[0171] Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3a haloalkyl group or an unsubstituted cyclopropyl group;

[0172] R 7B CN, oxo or C 1-3 alkyl;

[0173] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0174] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0175] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0176] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0177] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0178] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0179] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0180] R 3 is hydrogen, -CN, halogen, unsubstituted C1-3 Alkyl, or unsubstituted cyclopropyl;

[0181] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0182] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0183] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0184] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0185] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0186] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0187] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0188] In one embodiment, wherein R 1 comprising a moiety having formula E1, each R7A is independently hydrogen, Cl, methyl or CF3. In another such embodiment, each R 7A are independently hydrogen, methyl or CF3.

[0189] In one embodiment, wherein R 1 is a moiety having formula (E), and X 1 N, R 1 for:

[0190]

[0191] In another embodiment, R 1 comprising a moiety having formula (E2);

[0192]

[0193] Each R 7A are independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 In one such embodiment, no more than one R 7A In another such embodiment, R 7A is not hydrogen. In one embodiment of parts (E2) and (3), at least one R 7A In one embodiment of parts (E2) and (E3), at least one R 7A is unsubstituted C1-3 haloalkyl (eg, CF3, CHF2, CF2CF3, CHCF3 or CH2CF3).

[0194] In another embodiment, is a compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0195] X is O or NR 6 ;

[0196] m is 1 or 2;

[0197] n is 1 or 2;

[0198] wherein n and m together form a 6-membered or 7-membered ring A;

[0199] p is 0, 1, or 2;

[0200] R 1 is (E2) or (E3)

[0201]

[0202] Each R 7A are independently hydrogen, halogen, unsubstituted C1-3 Alkyl, or unsubstituted C 1-3 alkyl halide;

[0203] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0204] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0205] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0206] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0207] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0208] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0209] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0210] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0211] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0212] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0213] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0214] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0215] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0216] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0217] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and

[0218] R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0219] In one embodiment, R 1 for:

[0220]

[0221] In another embodiment, is a compound of formula (I), or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0222] X is O or NR 6 ;

[0223] m is 1 or 2;

[0224] n is 1 or 2;

[0225] wherein n and m together form a 6-membered or 7-membered ring A;

[0226] p is 0, 1, or 2;

[0227] R 1 for

[0228] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0229] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0230] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0231] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy,

[0232] R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0233] Two R's 9 Together they form R 10 Substituted or unsubstituted C3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0234] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0235] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0236] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0237] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0238] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0239] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0240] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0241] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0242] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0243] R 6AHalogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0244] In one embodiment, R 1 for:

[0245]

[0246]

[0247] In another embodiment, R 1 for:

[0248]

[0249] In another embodiment, is a compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0250] X is O or NR 6 ;

[0251] m is 1 or 2;

[0252] n is 1 or 2;

[0253] wherein n and m together form a 6-membered or 7-membered ring A;

[0254] p is 0, 1, or 2;

[0255] R 1 for

[0256] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0257] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0258] R 2R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0259] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0260] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0261] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0262] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0263] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0264] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0265] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0266] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0267] Two R's5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0268] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0269] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0270] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0271] In another embodiment, R 1 for:

[0272] or a stereoisomer thereof, wherein t is 0, 1, 2, or 3. In one embodiment, t is 1 or 2. In another embodiment, t is 3. In one embodiment of the compounds described herein, R 1 It is not of formula F, F1, F2, F3, F4 or F5, but is a monocyclic ring.

[0273] In another embodiment, R 1 is a moiety having formula (F), (F1), (F2), or (F3), wherein t is 0, 1, 2, or 3. In one embodiment, t is 1 or 2. In another embodiment, t is 3.

[0274] In one embodiment, R 1 for:

[0275]

[0276] or a stereoisomer thereof, wherein R 7 As described in this article.

[0277] In another embodiment, R 1 for:

[0278] or a stereoisomer thereof.

[0279] In another embodiment, R 1 for:

[0280] or a stereoisomer thereof,

[0281] wherein t is 0, 1, 2 or 3. In one embodiment, t is 1 or 2. In one embodiment, R 7 Halogen, NH2, OH, C 1-3 Alkyl or C 2-3 Alkynyl.

[0282] In one embodiment of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, R 2 R contains one or more heteroatoms selected from N or O 9 In another embodiment of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, R 2 R contains one or more nitrogen heteroatoms 9 In another embodiment, R 2 R contains one or more nitrogen heteroatoms 9 a substituted or unsubstituted 5- to 8-membered heterocyclic ring.

[0283] In one embodiment, each R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 In one embodiment, each R9 is independently halogen, CN, OH, OCF3, OCHF2 or OCH2F. In another such embodiment, each R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, or R 10 Substituted or unsubstituted C 1-3 In yet another embodiment, each R 9 Independently R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, or R 10 Substituted or unsubstituted C 1-3 In another embodiment, each R 9 are independently halogen, R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 a substituted or unsubstituted 3- or 4-membered heterocyclic ring.

[0284] In another embodiment, two R 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 In one such embodiment, two R 9 Together they form an unsubstituted cyclopropyl moiety. In another embodiment, two R 9 Together they form an unsubstituted oxetane or azetidine group.

[0285] In another embodiment, two R 9 Together, they form a bridge between two carbon atoms of the cycloalkyl or heterocycle, wherein the bridge comprises 1 to 3 carbon atoms. In one such embodiment, the bridge comprises one carbon atom. In another such embodiment, the bridge comprises 2 carbon atoms.

[0286] In one embodiment, R 9 is halogen, or R 10 Substituted or unsubstituted C 1-3 Alkylene.

[0287] In one embodiment, R2 for

[0288]

[0289] or a stereoisomer thereof, wherein

[0290] R 9 is halogen, or R 10 Substituted or unsubstituted C 1-3 Alkylidene

[0291] r is an integer from 0 to 12;

[0292] j is 1, 2, or 3; and

[0293] k is 1 or 2.

[0294] In one embodiment, R 2 is a portion having the formula:

[0295]

[0296] or a stereoisomer thereof, wherein

[0297] R 9 are independently halogen, or R 10 Substituted or unsubstituted C 1-3 Alkylidene;

[0298] Each R 10 are independently hydrogen or halogen; and

[0299] r is 1 or 2.

[0300] In one embodiment, R 2 is a portion having the formula:

[0301] or a stereoisomer thereof.

[0302] In one embodiment, R 2 is a portion having the formula:

[0303] or a stereoisomer thereof.

[0304] In one embodiment, R 2 is a portion having the formula:

[0305]

[0306] or a stereoisomer thereof, wherein R 9 and r are as described herein. In one such embodiment, r is 1 or 2. In one embodiment, each R 9 are independently halogen, or R 10Substituted or unsubstituted C 1-3 alkyl.

[0307] In one embodiment, R 2 is a portion having the formula:

[0308] or a stereoisomer thereof.

[0309] In another embodiment, R 2 for

[0310]

[0311] or a stereoisomer thereof, wherein

[0312] R 9 are independently halogen, oxo, or unsubstituted C 1-3 alkyl; and

[0313] r is 1 or 2.

[0314] In another embodiment, R 2 for

[0315] or a stereoisomer thereof.

[0316] In another embodiment, R 2 for

[0317] or a stereoisomer thereof.

[0318] In yet another embodiment, R 2 for

[0319] or a stereoisomer thereof.

[0320] In another embodiment, R 2 for

[0321]

[0322] or its stereoisomers, herein X 2 CR 9 Or O. In one embodiment, X 2 It is O.

[0323] In one such embodiment, X 2 is 0 and r is 0.

[0324] In another embodiment, R 2 for

[0325]

[0326] or a stereoisomer thereof, wherein X 3 CR 9 NR 9 or O.

[0327] In one embodiment, R 2 is a moiety having formula (D), wherein X 3 CR 9 , where R 9 As described herein. In one such embodiment, X 3 is CH2 or CF2. In another such embodiment, R 2 is a compound having a major portion of formula (D) or (D1), and X 3 In one embodiment, R 2 is a moiety having formula (D), X 3 is O, and R 9 For unsubstituted C 1-3 In another embodiment, R 2 is a moiety having formula (D), X 3 NR 9 , and R 9 is an oxo group or an unsubstituted C 1-3 alkyl.

[0328] In one embodiment, R 2 for

[0329]

[0330] In one embodiment, r is 0 or 1.

[0331] In one embodiment, L 1 In one embodiment, R 2 As described herein, and L 1 In another embodiment, L 1 R L1 Substituted or unsubstituted C 2-3 In one such embodiment, L 1 For unsubstituted C 2-3 In another such embodiment, L 1 R L1 Substituted C 2-3 Alkylene, where two R L1 Together they form unsubstituted C 3-4 In one such embodiment, L 1 Has the following formula:

[0332]

[0333] In one embodiment of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, R 3 In another embodiment, R 3 It is -CN.

[0334] In one embodiment of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, each R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 In one such embodiment, each R 5 are independently unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 In some embodiments, p is 0 or 1.

[0335] In another embodiment, two R 5 Together, they form a bridge between two carbon atoms of Ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N. In one such embodiment, the two R 5 Together, they form a bridge between the second carbon atoms of Ring A, wherein the bridge comprises 1 to 3 carbon atoms. In one such embodiment, the bridge comprises 1 or 2 carbon atoms. In another such embodiment, the bridge comprises 1 carbon atom. In another such embodiment, the bridge comprises 2 carbon atoms.

[0336] In one embodiment, two R 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 In one embodiment, the bridge comprises an O heteroatom. In another embodiment, the bridge comprises NR 11 , where R 11 is hydrogen or methyl.

[0337] In some embodiments, Ring A is a 6-membered ring (i.e., wherein both m and n are 1). In one embodiment, Ring A is a 7-membered ring, wherein m is 2 and n is 1. In another embodiment, Ring A is a 7-membered ring, wherein m is 1 and n is 2. In one embodiment, X is NR 6 , where R 6 As described in this article.

[0338] In one embodiment, R 6 is hydrogen, or R 6A Substituted or unsubstituted C 1-3 In one embodiment, R 6 R 6A Substituted or unsubstituted C1-3 In one embodiment, R 6 In one embodiment, R 6 It is a methyl group.

[0339] In some embodiments, R 6 R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl.

[0340] In such embodiments, R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B In another embodiment, R 6A Halogen, CN, OH, OMe, OEt, OCF3, SO2Me, unsubstituted C 1-3 Alkyl, or 4-membered heterocyclic ring.

[0341] In one embodiment, each R 6B Independently C 1-3 Alkyl or C 1-3 In one such embodiment, R 6B Independently C 1-3 alkyl.

[0342] Further provided herein are compounds of formula (I) as described herein, which have the formula:

[0343]

[0344] or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 , X, L 1 and p as described herein.

[0345] Further provided herein are compounds of formula (I) as described herein, which have the formula:

[0346]

[0347] or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 , X and p are as described herein.

[0348] Further provided herein are compounds of formula (I) as described herein, which have the formula:

[0349]

[0350] or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 、R 3 、R 4 、R 5 , X and p are as described herein.

[0351] In one embodiment, the compound of formula (IId) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof comprises formula (IId-1),

[0352]

[0353] where R 2 、R 3 、R 4 、R 5 、R 7A ,X,X 1 and p as described herein.

[0354] In one embodiment, the compound of formula (IId) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof comprises formula (IId-2),

[0355]

[0356] where R 2 、R 3 、R 4 、R 5 、R 7A , X and p are as described herein.

[0357] In one embodiment, the compound of formula (IId) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof comprises formula (IId-3),

[0358]

[0359] where R 2、R 3 、R 4 、R 5 、R 7A , X and p are as described herein.

[0360] In one embodiment, the compound of formula (IId) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof comprises formula (IId-4),

[0361]

[0362] where R 2 、R 3 、R 4 、R 5 、R 7A , X and p are as described herein.

[0363] In one embodiment, the compound of formula (IId) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof comprises formula (IId-5),

[0364]

[0365] where R 2 、R 3 、R 4 、R 5 , X and p are as described herein

[0366] In one embodiment, X is NH or N(CH3). In one embodiment, R 1 is a moiety having formula (E), (E1), (E2), (E3), (F), (F1), (F2), (F3), (F4), or (F5) as described herein. In one embodiment, R 2 is a moiety having formula (A), (A-1), (A-2), (A-3), (A-4), (B), (C), (D), or (D1) as described herein.

[0367] In one embodiment of the compounds described herein having Formula (IIa), (IIb), (IIc) or (IId), or stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts thereof, R 2 Contains a portion having the formula:

[0368] or a stereoisomer thereof. In one such embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, comprises Formula (IId) as described herein. In another such embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, comprises Formula (IId-1), (IId-2), (IId-3), (IId-4), or (IId-5) as described herein.

[0369] In one such embodiment, in one embodiment of the compound described herein having Formula (IIa), (IIb), (IIc) or (IId), or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, R 2 Contains a portion having the formula:

[0370]

[0371] In one such embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, comprises Formula (IId) as described herein. In another such embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, comprises Formula (IId-1), (IId-2), (IId-3), (IId-4), or (IId-5), as described herein.

[0372] In another embodiment, the compound of formula (I) as described herein has the formula:

[0373]

[0374] or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 , X and p are as described herein. In one such embodiment, X is NR 6 , where R 6 is hydrogen, or R 6A Substituted or unsubstituted C 1-3 alkyl.

[0375] Table 1:

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450] In one embodiment, it is a compound selected from compounds 1 to 36, 38 to 45, 47 to 62, 64 to 108, 110 to 146, and 149 to 291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0451] In one embodiment, it is a compound selected from compounds 1 to 36, 38 to 45, 47 to 62, 64 to 108, and 110 to 125 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0452] In one embodiment, it is a compound selected from compounds 126 to 146 and 149 to 291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0453] In one embodiment, the compound is selected from compounds 6, 15, 24, 26, 29, 31-32, 57-59, 61-62, 64-66, 75-76, 91, 96, 104, 106, 111, 113, 118-124, 126-146, 149-156, 158-175, 181, 183, 186, 190-192, 195, 200, 204, 224-225, 228-229, 232-239, 241, 244-250, 255, 258-259 and 263 in Table 1, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0454] In one embodiment, the compound is selected from compounds 6, 12-18, 23-24, 26, 29, 31-36, 57-58, 60-62, 64-77, 90-97, 100-102, 104, 108, 111, 113, 115, 118-146, 149-175, 181-183, 186-187, 190, 195, 200, 204, 224-232, 234-239, 241, 244-250, 255, 258-259 and 263 in Table 1, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0455] In one embodiment, the compound is selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 57-62, 64-72, 74, 76, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259 and 263 in Table 1, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0456] In one embodiment, the compound is selected from compounds 6, 12-18, 23-24, 26, 29, 31-36, 42-45, 47-48, 52, 57-58, 60-78, 84-88, 90-97, 100-104, 106, 108, 111-113, 115, 118-146, 149-175, 177-178, 181-183, 185-187, 189-192, 194-195, 197-200, 203-232, 234-250, and 252-291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0457] In one embodiment, the present invention is a compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 42-45, 47-48, 52, 57-62, 64-72, 74, 76, 84-88, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259 and 263 in Table 1, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0458] In one embodiment, it is a compound selected from compounds 42 to 45, 47 to 48 and 52 in Table 1 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0459] In one embodiment, it is a compound selected from compounds 112, 205 to 218, 242 to 243, 252 to 254, 261 to 262, and 264 to 291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0460] Synthesis of compounds

[0461] The compounds of the present disclosure, as described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, can be prepared by a variety of methods depicted in the exemplary synthetic reaction schemes shown and described below. Starting materials and reagents used to prepare these compounds are generally available from commercial suppliers (such as Aldrich Chemical Co.) or are prepared by methods known to those skilled in the art according to methods described in 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. York, 1991, vols. 1-40. The following synthetic reaction schemes are merely illustrative of some of the methods by which the compounds described herein or their pharmaceutically acceptable salts may be synthesized, and various modifications to these synthetic reaction schemes may be made and suggested to those skilled in the art with reference to the disclosure contained herein.

[0462] Synthetic chemistry transformations and protecting group methods (protection and deprotection) that can be used to synthesize the compounds described herein and the necessary reagents and intermediates include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and PGM 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 subsequent editions.

[0463] Compounds as described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, can be prepared individually or as a library of compounds comprising at least two, for example, 5 to 1000 compounds or 10 to 100 compounds. Libraries of compounds as described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, having a formula as described herein, can be prepared by combining split and mix methods or by multiple parallel syntheses using, for example, solution phase or solid phase chemistry. Thus, according to another aspect, provided herein are library of compounds comprising at least two compounds as described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0464] The examples provide exemplary methods for preparing compounds as described herein or stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts thereof. It will be appreciated by those skilled in the art that other synthetic routes may be used to synthesize compounds as described herein or stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts thereof. Although specific starting materials and reagents are described and discussed in the examples, other starting materials and reagents may 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 described may be further modified using conventional chemical methods.

[0465] When preparing a compound as described herein or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, 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-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection can be easily determined. For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0466] In the method for preparing the compounds as described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts, 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 uniformity by techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, 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 apparatus; small scale analytical chromatography; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques.

[0467] Another class of separation methods involves treating the mixture with a reagent that is selected to bind to or otherwise render the desired product, unreacted starting material, reaction by-products, etc. separable. 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 a basic material); a base (in the case of an acidic material); a binding agent 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 an appropriate separation method depends on the properties of the materials involved, such as boiling point and molecular weight for distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of the material in acidic and basic media in multiphase extraction, and the like.

[0468] The diastereomeric mixture can be separated into its individual diastereomers by methods such as by chromatography and / or fractional crystallization, based on the differences in the physicochemical properties of the diastereomers. Enantiomers can be separated as follows: by reacting the enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acyl chloride), the enantiomeric mixture is converted into a diastereomeric mixture, the diastereomers are separated, and each diastereomer is converted (e.g., hydrolyzed) into the corresponding pure enantiomer. In addition, some compounds as described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, can be atropisomers (e.g., substituted biaryls). Enantiomers can also be separated using chiral HPLC columns.

[0469] A single stereoisomer, e.g., an enantiomer substantially free of its stereoisomer, can be obtained by resolving a racemic mixture using a method such as diastereoisomer formation using an optically active resolving agent (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994; Lochmuller, CH, (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of the chiral compounds described herein or pharmaceutically acceptable salts thereof can be separated and isolated by any suitable method, including: (1) forming ionic diastereomeric salts with chiral compounds and separating by fractional crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing agents, separating the diastereomers, and converting to pure stereoisomers; and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See: "Drug Stereochemistry, Analytical Methods and Pharmacology," edited by Irving W. Wainer, Marcel Dekker, Inc., New York (1993).

[0470] According to method (1), diastereomeric salts can be formed by reacting an enantiomerically pure chiral base such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), etc. with an asymmetric compound having an acidic functional group such as a carboxylic acid or a sulfonic acid. The diastereomeric salts can be induced to separate by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds, the addition of a chiral carboxylic acid or sulfonic acid such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can cause the formation of diastereomeric salts.

[0471] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (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 enantiomerically pure chiral derivatizing reagent such as a menthyl derivative, followed by separation of the diastereomers and hydrolysis to obtain the pure or enriched enantiomer. Methods for determining optical purity involve preparing a chiral ester of the racemic mixture, such as a menthyl ester, for example, (-) menthyl chloroformate, or Mosher ester, α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem. (1982) 47: 4165), in the presence of a base, and analyzing 1 H NMR spectroscopy is used to determine the presence of two atropisomers or diastereomers. Stable diastereomers of atropisomers can be separated and isolated by normal and reverse phase chromatography according to the method for separating atropisomers of 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) WJ Lough, ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation or circular dichroism.

[0472] The chemical reactions described herein can be readily adapted to prepare other compounds and pharmaceutically acceptable salts thereof described herein. For example, the synthesis of the non-exemplified compounds and pharmaceutically acceptable salts thereof described herein can be successfully achieved by modifications readily apparent to those skilled in the art, such as by appropriately protecting interfering groups, utilizing other suitable reagents known in the art, or by routinely modifying reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered applicable to the preparation of other compounds and pharmaceutically acceptable salts thereof described herein.

[0473] pharmaceutical preparations

[0474] Also provided herein are pharmaceutical compositions comprising a compound as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0475] The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be formulated into pharmaceutical compositions according to standard pharmaceutical practice. Thus, further provided herein is a pharmaceutical composition comprising a compound described herein, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable excipients.

[0476] Typical formulations are prepared by mixing a compound as described herein or a pharmaceutically acceptable salt thereof 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 specific excipient used will depend on the mode and purpose of administering a compound as described herein or a pharmaceutically acceptable salt thereof. In general, solvents are selected based on generally recognized safe solvents (GRAS) for administration to mammals. Typically, safe solvents are nontoxic aqueous solvents, such as water and other water-soluble or water-miscible nontoxic solvents. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc., and mixtures thereof. The formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, and other known additives to provide an aesthetically pleasing presentation of the drug (i.e., a compound described herein or a pharmaceutical composition thereof) or to aid in the preparation of a pharmaceutical product (e.g., a medicament).

[0477] The formulations can be prepared using conventional dissolution and mixing procedures. For example, the drug substance (i.e., a compound as described herein or a pharmaceutically acceptable salt thereof, or a stable form thereof (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds as described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts are typically formulated into pharmaceutical dosage forms to provide an easily controlled drug dosage and enable patients to comply with the prescription regimen.

[0478] Depending on the method used to administer the drug, the pharmaceutical composition (or formulation) for administration can be packaged in a variety of ways. Typically, the article for distribution includes a container in which the pharmaceutical formulation is deposited in an appropriate 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, the container is provided with a label describing the contents of the container. The label may also include appropriate warnings.

[0479] Pharmaceutical formulations of compounds as described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts can be prepared for various routes of administration and types of administration. For example, a compound or its stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts having a desired purity can be optionally mixed with one or more pharmaceutical excipients (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. ed.) in the form of a lyophilized formulation, a ground powder or an aqueous solution. The formulation can be prepared by mixing with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the receptor at the dose and concentration employed) at an appropriate pH and desired purity at ambient temperature. The pH of the formulation depends primarily 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 embodiment.

[0480] Pharmaceutical compositions can typically be stored as solid compositions, lyophilized formulations, or as aqueous solutions.

[0481] The pharmaceutical compositions described herein can be formulated, dosed, and administered in a manner consistent with good medical practice, i.e., dosage, concentration, schedule, course of treatment, vehicle, and route of administration. Factors that need to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to practitioners. The effective amount of the compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to be administered will be influenced by these considerations and is the minimum amount necessary to ameliorate or treat the hyperproliferative disorder.

[0482] Generally, the initial pharmaceutically effective amount per dose of the compound, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, administered parenterally will be in the range of about 0.01 mg / kg to 100 mg / kg (i.e., about 0.1 mg / kg to 20 mg / kg of patient body weight) per day, with a typical initial range of 0.3 mg / kg / day to 15 mg / kg / day of the compound used. In another embodiment, the pharmaceutical compositions described herein comprise an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in an amount of 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.

[0483] Acceptable pharmaceutical excipients are nontoxic to recipients 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 octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; 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 dextrins; 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 or polyethylene glycol (PEG). Active pharmaceutical ingredients can also be encapsulated in microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively) prepared, for example, by coacervation techniques or by interfacial polymerization, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition (Osol, A., ed., 1980).

[0484] Sustained-release formulations of the compounds as described herein or pharmaceutically acceptable salts thereof can be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds as described herein or pharmaceutically acceptable salts thereof, in the form of shaped articles such as films 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®. (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.

[0485] The formulation includes formulations suitable for the routes of administration detailed herein. The formulation can be conveniently presented in the form of a unit dose and can be prepared by any method. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of associating the active ingredient with a carrier that constitutes one or more auxiliary ingredients. In general, the formulation is prepared by uniformly and tightly combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, molding the product.

[0486] Formulations of compounds suitable for oral administration as described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be prepared as discrete units, such as pills, capsules, cachets, or tablets, each containing a predetermined amount of such compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (e.g., powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant) in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. The tablets can optionally be coated or scored and can optionally be formulated to provide slow or controlled release of the active ingredient therefrom. Tablets, buccal tablets, lozenges, 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 administration. Formulations of the compounds or pharmaceutically acceptable salts thereof for oral administration as described herein can be prepared according to any method used to prepare pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavorings, colorants, and preservatives, to provide a palatable formulation. Tablets containing the active ingredient admixed with non-toxic pharmaceutical excipients suitable for tablet preparation are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate, alone or with a wax, may be used.

[0487] For the treatment of the eye or other external tissues (e.g., oral cavity and skin), the preparation is preferably applied in the form of a topical ointment or cream containing, for example, an active ingredient in an amount of 0.075% W / W to 20% W / W. When formulated as an ointment, the active ingredient can be used with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with an oil-in-water cream base. If desired, the aqueous phase of the cream base can include a polyol, i.e., an alcohol with two or more hydroxyl groups, such as propylene glycol, 1,3-butylene glycol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400) and mixtures thereof. Topical preparations can desirably include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs. The oil phase of the emulsion of the composition provided herein can be composed of known ingredients in a known manner. Although this phase can contain only an emulsifier, it is desirable to include a mixture of at least one emulsifier with a fat or oil or with both 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 oil and fat. The emulsifier with or without a stabilizer together constitutes the so-called emulsifying wax, and the wax together with the oil and fat constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. Emulsifiers and emulsion stabilizers suitable for the formulations described herein include 60. 80, Cetearyl Alcohol, Benzyl Alcohol, Myristyl Alcohol, Glyceryl Monostearate and Sodium Lauryl Sulfate.

[0488] Aqueous suspensions comprising a compound as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, may contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic, and dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecanethoxycetyl alcohol), condensation products of ethylene oxide with partial esters and hexitol anhydrides derived from fats (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl 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.

[0489] Pharmaceutical compositions of the compounds described herein or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts can be in the form of sterile injectable preparations, such as sterile injectable aqueous or oily suspensions. The suspensions can be formulated using suitable dispersants or wetting agents and suspending agents as mentioned above. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or prepared as lyophilized powders. Acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injections.

[0490] The amount of active component that can be combined with carrier material to produce single dosage form will change according to the host being treated and specific mode of administration.For example, the time-release preparation for oral administration of people can contain the active substance of about 1 to 1000mg and the carrier material compound of suitable and convenient amount, and this carrier material can account for about 5% to about 95% (weight: weight (w / w)) of total composition.Pharmaceutical composition can be prepared to provide the dosage that is easy to measure.For example, the aqueous solution for intravenous infusion can comprise about 3 to 500 μ g of active component with every milliliter of solution, so that suitable volume can be infused at the rate of about 30mL / hr.

[0491] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes to render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0492] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations 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.

[0493] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; lozenges comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0494] Formulations for rectal administration may be presented as a suppository with a suitable base containing for example cocoa butter or a salicylate.

[0495] Preparations suitable for intrapulmonary or nasal administration have, for example, a particle size in the range of 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns with increments such as 0.5 microns, 1 micron, 30 microns, 35 microns, etc.), which can be rapidly inhaled through the nasal cavity or inhaled through the mouth to reach the alveolar sacs. 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 to treat or prevent diseases as described herein.

[0496] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are deemed appropriate.

[0497] Preparation can be packaged in unit dose or multidose container, for example in sealed ampoule and bottle, and can be stored under freeze drying (lyophilization) condition, only need to add sterile liquid carrier for injection, for example water before use. Extemporaneous injection solution and suspension are prepared by sterile powder, granule and tablet of the aforementioned type. Preferred unit dose formulation is containing daily dose or unit daily subdose as described herein above, or those of the active ingredient of its appropriate fraction.

[0498] In one embodiment, compound or its stereoisomer, atropisomer, tautomer or pharmaceutical 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 cracked to provide the compound or its stereoisomer, atropisomer, tautomer or pharmaceutical salt under biological conditions. Prodrugs as defined herein include derivatives comprising one or more parts that regulate 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 class of drug properties) and are converted into bioactive substances as provided herein or more biologically active substances. In one embodiment, the prodrug herein does not have biological activity before releasing the compound or its pharmaceutical salt.

[0499] Application method

[0500] The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous (IV), intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal. In one embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are administered orally or by IV administration. For local immunosuppressive therapy, the compounds can be administered by intralesional administration, including pre-transplant perfusion or otherwise contacting the graft with the inhibitor. It should be understood that the preferred route may vary, for example, depending on the condition of the recipient. In the case of oral administration of the compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, the compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be formulated with a pharmaceutically acceptable carrier or excipient into pills, capsules, tablets, and the like. In cases where the compound or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof is administered parenterally, the compound or pharmaceutically acceptable salt thereof can be formulated with a pharmaceutically acceptable parenteral vehicle in a unit dosage injection form, as described in detail below.

[0501] Thus, in one aspect, provided herein is a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, the compound as described herein, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, is administered as a pharmaceutical composition that can be administered orally or parenterally to a subject. The compound as described herein, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be formulated for topical or parenteral use, wherein the compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, is dissolved or otherwise suspended in a solution suitable for injection, suspension, syrup, cream, ointment, gel, spray, solution, and emulsion.

[0502] Oral administration can promote patient compliance in taking the compound (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 to delay or extend release.

[0503] The dosage range for treating human patients can be about 10 mg to about 1000 mg of the compound described herein. The typical dose of the compound can be about 100 mg to about 300 mg. A 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 frequency of administration, rather than the number of independent units that a patient, such as those described herein, must take in one dose. Therefore, in some embodiments, a patient can take two or more dosage units (e.g., two or more pills / tablets / capsules) QD. In addition, toxicity factors may affect the dosage and administration regimen. When administered orally, the pills, capsules, or tablets can be taken daily or at a lower frequency within a specified time period. This regimen can be repeated for multiple treatment cycles.

[0504] Treatment methods and uses

[0505] 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. On the other hand, the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts can be used as NRas inhibitors. On the other hand, the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts can be used as HRas inhibitors. In one embodiment, the compounds described herein or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts can be used as G12D Ras inhibitors and G12D KRas inhibitors.

[0506] Provided herein are methods of contacting a cell, such as an isolated cell, with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to inhibit Ras activity (e.g., KRas activity) in the cell. In another embodiment, the activity is mutant G12D KRas activity.

[0507] Further provided herein are methods for treating cancers comprising KRas mutations, comprising administering to a patient suffering from such cancer an effective amount of a compound as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the KRas mutation is KRas G12D mutation.

[0508] In one embodiment, the method further comprises targeting KRas prior to administering the compound described herein or a pharmaceutically acceptable salt thereof. G12DThe absence or presence of a mutation in a patient sample is tested (e.g., as described herein). In one such embodiment, after a patient sample is identified as KRas G12D After testing positive for a mutation (eg, presence), the patient is administered a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0509] The methods of treating cancer described herein relate to the treatment of cancers such as acute myeloid leukemia, juvenile cancers, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumors, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumors, embryonal tumors, germ cell tumors, primary lymphomas, cervical cancer, childhood cancers, chordomas, heart tumors, chronic lymphocytic leukemia (CLL), chronic Myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesia neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, skeletal fibrous histiocytoma, 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, pancreatic 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 neoplasms, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC) , oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic cancer, 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 virally induced cancers.

[0510] 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, appendix cancer, or pancreatic cancer. In one embodiment, the cancer is pancreatic cancer, lung cancer, or colon cancer. Lung cancer may 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.

[0511] The methods provided herein can also include targeting KRas prior to administering a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. G12D In one embodiment, a sample from a patient is tested for the presence or absence of a mutation. G12D After mutation, the compound, its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, or pharmaceutical composition is administered to the patient. In one embodiment, unless the patient sample contains KRas G12D The compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, are not administered unless the compounds are mutated.

[0512] In one embodiment, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In another embodiment, the cancer is of uncharacterized tissue (comprising KRas G12D In one such embodiment, pancreatic cancer, lung cancer, or colorectal cancer comprises KRas G12D mutation.

[0513] Further provided herein are methods for treating a patient with a KRas-containing G12D In one such embodiment, a method for treating a patient with a lung cancer comprising a KRas G12D Methods for treating lung cancer in patients with a mutation in a lung cancer of the type described herein (M1), comprising administering 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). In one embodiment, the lung cancer is adenocarcinoma, NSCLC, squamous cell lung cancer (SCLC), or large cell lung cancer. In one embodiment, the lung cancer is adenocarcinoma, NSCLC, or SCLC. In another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is an adenoma, a carcinoid tumor, or an undifferentiated carcinoma. The lung cancer may 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 an IL therapy.

[0514] The present invention further provides a method for treating a patient with KRas G12D In one such embodiment, a method for treating a patient with pancreatic cancer comprising a KRas G12D A method of treating pancreatic cancer in a patient with a pancreatic cancer mutation (M2), 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. In one embodiment, the patient has previously received radiation therapy and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is at stage 0, stage I, or stage II. In another embodiment, the pancreatic cancer is at stage III or stage IV.

[0515] The present invention further provides a method for treating a patient with KRas G12D In one such embodiment, a method for treating a patient with a KRas G12D A method (M3) for treating a patient with a colorectal cancer that has a colorectal cancer mutation, 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. In one embodiment, the colorectal cancer is at stage I or stage II. In another embodiment, the colorectal cancer is at stage III or stage IV.

[0516] In one embodiment of methods M1, M2 and M3 as described herein, the method further comprises:

[0517] (a) Determining the absence or presence of KRas in a sample obtained from a patient suspected of being diagnosed with cancer G12D mutations; and

[0518] (b) administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0519] Further provided herein are methods for treating KRas G12D In one embodiment of the method, the method comprises:

[0520] (a) Determining the absence or presence of KRas in a sample obtained from a patient suspected of being diagnosed with cancer G12D mutations; and

[0521] (b) administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0522] In one embodiment of such methods, the patient is diagnosed with a cancer as described herein. In another embodiment of such methods, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is collected before any therapy is administered. In another such embodiment, the sample is collected before administering a compound as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and after administering another chemotherapeutic agent. In another embodiment of such methods, the compound as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered as provided herein (e.g., orally or IV).

[0523] Also provided herein are compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts for use as therapeutically active substances. In one such embodiment, the compounds or their stereoisomers, atropisomers, tautomers or pharmaceutically acceptable salts can be used to therapeutically treat a disease comprising Kras. G12D Mutated cancer.

[0524] Further provided herein are methods for the therapeutic and / or prophylactic treatment of KRas G12D In one embodiment, the compound or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt is used to prepare a method for treating a cancer comprising KRas G12D Further provided herein is the use of a compound as described herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting tumor metastasis.

[0525] Further provided herein is a method for inhibiting tumor metastasis, comprising administering to a patient suffering from a tumor a therapeutically effective amount of a compound as described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the inhibition is directed against a KRas G12D In another embodiment, the inhibition of a patient's tumor metastasis as described herein results in a decrease in tumor size. In another embodiment, the inhibition of a patient's tumor metastasis as described herein results in a stabilization of tumor size (e.g., no further growth). In another embodiment, the inhibition of a patient's tumor metastasis as described herein results in a remission of cancer and / or its symptoms.

[0526] Further provided herein are methods for inhibiting proliferation of a cell population comprising contacting the cell population with a compound described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the cell population is in a human patient. In another embodiment, the cell population comprises KRas G12D mutation.

[0527] Further provided herein are methods of inhibiting KRas in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the KRas inhibited is KRas G12D In another embodiment, inhibiting KRas results in reduced tumor size. In another embodiment, inhibiting KRas results in remission of cancer and / or its symptoms.

[0528] Further provided herein are methods for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a compound described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the mutant protein comprises KRas G12D Mutation. In one embodiment, upon contact with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, KRas activity is reduced. In another embodiment, downregulation of KRas mutant protein activity treats a cancer described herein in a patient described herein. In another embodiment, downregulation of KRas mutant protein activity results in reduced tumor size. In another embodiment, downregulation of KRas mutant protein activity results in alleviation of a cancer described herein and / or its symptoms.

[0529] In some embodiments, the methods provided herein comprise contacting a cell with a protein sufficient to inhibit Kras in said cell. G12D An active amount of a compound described herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof is contacted to inhibit KRas in the cell G12D In some embodiments, the methods provided herein comprise contacting a tissue with a KRas G12D An active amount of a compound described herein or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof is contacted to inhibit KRas in the tissue G12D In some embodiments, the methods provided herein comprise administering to a patient as described herein a combination of a drug sufficient to inhibit KRas activity in said patient. G12D An active amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, is contacted to inhibit KRas in the patient G12D active.

[0530] Further provided herein are methods for preparing labeled KRas G12D A method for mutating a protein, the method comprising: G12D The mutant protein is reacted with a labeled compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, to produce a labeled KRas G12DIn one embodiment, the marker is an imaging agent. In one embodiment, the labeled KRas G12D It can be used to detect the absence or presence of G12D mutant KRas in a patient sample, thereby detecting the presence or absence of cancer mediated by mutant KRas.

[0531] Further provided herein is a method for inhibiting cell signaling mediated by Ras. In one embodiment, the method includes contacting the cell with an effective amount of one or more compounds disclosed herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. Inhibition of Ras-mediated signal transduction can be assessed and demonstrated in a variety of ways known in the art. Non-limiting examples include showing that (a) the GTPase activity of Ras is reduced; (b) GTP binding affinity is reduced or GDP binding affinity is improved; (c) K off of GTP is increased or K off of GDP is reduced; (d) the level of signal transduction molecules downstream of the Ras pathway is reduced, such as reduced pMEK levels; and / or (e) the binding of the Ras complex to downstream signaling molecules (including but not limited to Raf) is reduced. Kits and commercially available assays can be used to determine one or more of the above.

[0532] KRas mutations, including G12D mutants, have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, certain embodiments relate to administering a compound disclosed herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof (e.g., in the form of a pharmaceutical composition), to a patient in need of treatment for a hematological malignancy. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the presently disclosed compounds 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 described herein, or pharmaceutically acceptable salts thereof, can be used to treat lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0533] Whether a tumor or cancer contains KRas can be determined by evaluating the nucleotide sequence encoding the KRas protein, by evaluating the amino acid sequence of the KRas protein, or by evaluating the characteristics of a putative KRas mutant protein. G12D Mutations. The sequence of wild-type human KRas (eg, accession number NP203524) is known in the art.

[0534] Methods for detecting mutations in KRas nucleotide sequences 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) assays, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In certain embodiments, the G12d KRas mutation of a sample is assessed by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRas G12D mutation is used. When a mutation is present, the probe binds and detects fluorescence. In certain embodiments, the KRas G12D mutation is identified using a direct sequencing method of a specific region (e.g., exon 2 and / or exon 3) in the KRas gene. This technology will identify all possible mutations in the sequencing region.

[0535] To determine whether a tumor or cancer contains KRas G12D The methods for mutation detection can be used with a variety of samples. In some embodiments, the sample is obtained from a subject suffering from 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.

[0536] Further provided herein are uses of the compounds described herein or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof 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 (e.g., IV administration). In some embodiments, the cancer comprises KRas G12D mutation. 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, 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, there is provided the use of a compound as described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0537] Combination therapy

[0538] The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be used alone or in combination with other therapeutic agents to treat the diseases or conditions described herein. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound described herein, or its pharmaceutically acceptable salt, such that they do not adversely affect each other. Combination therapies can provide "synergy" and be demonstrated to be "synergistic," i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by the individual compounds when used alone.

[0539] Combination therapy can be administered simultaneously or sequentially. When administered sequentially, the composition can be administered twice or more. Co-administration includes co-administration using separate formulations or single pharmaceutical formulations, as well as continuous administration in any order, wherein preferably both (or all) active agents exert their biological activity simultaneously over a certain period of time.

[0540] The combination therapies herein comprise the administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and at least one other therapeutic method. The amounts of the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and the one or more other pharmaceutically active agents, and the relative timing of administration, will be selected to achieve the desired combined therapeutic effect.

[0541] In various embodiments of this method, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC 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 (such as an antimicrotubule agent, including paclitaxel and docetaxel), an antimetabolite (such as 5-FU or gemcitabine), or an alkylating agent (such as cisplatin or cyclophosphamide) or a taxane.

[0542] 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 GFR inhibitor is a dual or full 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-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine or a salt thereof (eg, dimethanesulfonate).

[0543] 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 a neutralizing monoclonal antibody specific for IGF1R, such as AMG-479 (ganitumab), CP-751,871 (figitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (robatumumab).

[0544] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor. In some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, lestaurtinib, momelotinib, pacritinib, ruxolitinib, or TG101348.

[0545] In some other embodiments, the additional therapeutic agent is an anti-glypican 3 antibody. In some embodiments, the anti-glypican 3 antibody is codrituzumab.

[0546] In some other embodiments, the additional therapeutic agent is an antibody drug conjugate (ADC). In some embodiments, the ADC is polatuzumab vedoti, RG7986, RG7882, RG6109, or RO7172369.

[0547] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist. In some embodiments, the MDM2 antagonist is idasanutlin.

[0548] In some other embodiments, the additional therapeutic agent is an anti-CD40 agonist antibody. In some embodiments, the anti-CD40 agonist antibody is selicrelumab (RG7876).

[0549] 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.

[0550] In some other embodiments, the additional therapeutic agent is a targeted immunocytokine. In some embodiments, the targeted immunocytokine is RG7813 or RG7461.

[0551] In some other embodiments, the additional therapeutic agent is an antibody that targets colony stimulating factor-1 receptor (CSF-1R). In some embodiments, the (CSF-1R) antibody is emactuzumab.

[0552] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine. In some embodiments, the personalized cancer vaccine is RG6180.

[0553] In some other embodiments, the additional therapeutic agent is an inhibitor of BET (bromodomain and extraterminal family) proteins (BRD2 / 3 / 4 / T). In some embodiments, the BET inhibitor is RG6146.

[0554] In some other embodiments, the additional therapeutic agent is an antibody designed to bind TIGIT. In some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0555] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor degrader (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545, giredestrant).

[0556] 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 MET neutralizing monoclonal antibody, such as onartuzumab.

[0557] 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 the SRC family non-receptor tyrosine kinase subfamily. In this regard, exemplary inhibitors include dasatinib. Other examples in this regard include ponatinib, saracatinib, and bosutinib.

[0558] In yet 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.

[0559] In yet 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.

[0560] 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, nilotinib, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pegaptanib sodium, ranibizumab, ruxolitinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib or vemurafenib. In other more embodiments, the additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is irinotecan. In some other embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include paclitaxel and docetaxel.

[0561] 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 described herein or pharmaceutically acceptable salts thereof. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

[0562] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as (imatinib mesylate), (bortezomib), Casodex (bicalutamide), (gefitinib) and doxorubicin as well as a range of 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; ethylenimine and methylamelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide, and trimethylol melamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as aclacinomycins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex TM, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, 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, thiamiprine, thioguanine, ioguanine); pyrimidine analogs such as ancitabine, azacitidine, 6-azaguanosine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadreners such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; and aceglatone;Aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitraerine; pentostatin; phenamet; pirarubicin; podophyllinic acid acid; 2-ethylhydrazine; procarbazine; polysaccharide K; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; cytarabine ("Ara-C"); cyclophosphamide; thiotepa; taxanes, for example, paclitaxel (TAXOL; TM , Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE TM , Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicins; capecitabine; and any pharmaceutically acceptable salts, acids, or derivatives thereof. Also included as suitable chemotherapeutic cell modulators are antihormonal agents that modulate or inhibit hormonal effects on tumors, such as antiestrogens, including, for example, tamoxifen (Nolvadex TM), raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, raloxifene (keoxifene), LY 117018, onapristone, and toremifene; 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; navelbine; novantrone; teniposide; daunomycin; aminopterin; Ibandronate; Camptothecin-11 (CPT-11); topoisomerase inhibitor RFS2000; and difluoromethylornithine (DMFO). If necessary, the compounds described herein or their pharmaceutically acceptable salts or pharmaceutical compositions 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 thiosemiurea, Amonafide, Anthracenedione, Anti-CD22 immunotoxin, Antineoplastic drug, Antineoplastic herbal remedy, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine Sulfoximine, CBV (chemotherapy), Calyculin, Cell Cycle Nonspecific Antineoplastic Agents, 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 Inhibitors, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, swainsonine, talaporfin, tariquidar, tegafur-uracil, temozolomide, tesetaxel, triplatinium tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, 2,5-hexanoxtheobromine (Vadimezan), vinflunine, ZD6126, or zosuquidar.

[0563] The exact method of administering the compound and other therapeutic agent will be apparent to those of ordinary skill in the art. In some exemplary embodiments, the compound and other therapeutic agent can be co-administered. In other embodiments, the compound and other therapeutic agent are administered separately.

[0564] In some embodiments, the compound and the additional therapeutic agent are administered simultaneously or separately with the second agent. Such combined administration can include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound described herein and any other therapeutic agent can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound and any other therapeutic agent described herein can be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, the compound can be administered after any additional therapeutic agent described herein, or vice versa. In some embodiments of the separate administration regimen, the compound described herein and any other therapeutic agent are administered a few minutes apart, a few hours apart, or a few days apart.

[0565] Products

[0566] Also provided herein are articles or "kits" containing materials useful for treating cancers provided herein. In one embodiment, the kit includes a container containing a compound described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. The kit may also include a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound described herein or a pharmaceutically acceptable salt thereof, or a formulation thereof, that is 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 include a second container containing a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's injection, or dextrose solution. It may further include other materials required from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0567] 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 capsule. Such a kit can include a plurality 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 to package pharmaceutical unit dosage forms.

[0568] Example

[0569] Exemplary embodiments of the present invention are provided below.

[0570] Example 0. A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0571] X is O or NR 6

[0572] m is 1 or 2;

[0573] n is 1 or 2;

[0574] wherein n and m together form a 6-membered or 7-membered ring A;

[0575] p is 0, 1, or 2;

[0576] R 1 R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted isoquinolinyl, R 7 Substituted or unsubstituted indazolyl, R 7 Substituted or unsubstituted indanyl, R 7 Substituted or unsubstituted benzothiazolyl, R7A Substituted phenyl, or R 7A substituted pyridyl;

[0577] Each R 7 are independently halogen, OH, NH2, N(Me)2, unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Alkynyl, unsubstituted C 1-3 Alkoxy, or unsubstituted C 1-3 Haloalkyl

[0578] Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or unsubstituted cyclopropyl

[0579] R 7B CN, oxo or C 1-3 alkyl;

[0580] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0581] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0582] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0583] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0584] Two R's 9 Together they form R10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0585] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0586] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0587] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0588] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0589] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0590] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0591] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0592] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0593] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl; R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A Substituted or unsubstituted 3- to 4-membered heterocyclic ring

[0594] R6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring, and

[0595] R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0596] Example 1. A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0597] X is O or NR 6 ;

[0598] m is 1 or 2;

[0599] n is 1 or 2;

[0600] wherein n and m together form a 6-membered or 7-membered ring A;

[0601] p is 0, 1, or 2;

[0602] R 1 Having formula (E), wherein X 1 N or CR 7C And R 7C is hydrogen or halogen;

[0603] Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 a haloalkyl group or an unsubstituted cyclopropyl group;

[0604] R 7B CN, oxo or C 1-3 alkyl;

[0605] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0606] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4Cycloalkyl;

[0607] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0608] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0609] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0610] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0611] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0612] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0613] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0614] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0615] Two R's 5together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0616] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0617] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0618] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0619] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and

[0620] R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0621] Embodiment 2. The compound according to embodiment 1 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X 1 CR 7C And R 7C is hydrogen or halogen.

[0622] Embodiment 3. The compound according to embodiment 1 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X 1 is N.

[0623] Example 4. A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0624] X is O or NR 6 ;

[0625] m is 1 or 2;

[0626] n is 1 or 2;

[0627] wherein n and m together form a 6-membered or 7-membered ring A;

[0628] p is 0, 1, or 2;

[0629] R 1 is a moiety having formula (E2) or (E3)

[0630] Each R 7A are independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 alkyl halide;

[0631] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0632] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0633] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0634] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0635] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0636] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0637] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0638] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0639] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0640] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0641] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0642] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0643] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0644] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0645] R 6A Halogen, CN, OR 6B SR 6C、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0646] Embodiment 5. The compound according to embodiment 4, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein not more than one R 7A For hydrogen.

[0647] Embodiment 6. The compound according to embodiment 4, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 7A Not hydrogen.

[0648] Embodiment 7. The compound according to embodiment 4 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein at least one R 7A It is a halogen.

[0649] Embodiment 8. The compound according to embodiment 4 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein at least one R 7A For unsubstituted C 1-3 Halogenated alkyl.

[0650] Example 9. A compound of formula (I): or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0651] X is O or NR 6 ;

[0652] m is 1 or 2;

[0653] n is 1 or 2;

[0654] wherein n and m together form a 6-membered or 7-membered ring A;

[0655] p is 0, 1, or 2;

[0656] R 1 for

[0657]

[0658] L 1 R L1 Substituted or unsubstituted C1-4 alkylene;

[0659] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0660] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0661] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0662] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0663] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0664] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0665] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0666] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0667] R 5 are independently halogen, oxo, unsubstituted C1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0668] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0669] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0670] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0671] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0672] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and

[0673] R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0674] Example 10. A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0675] X is O or NR 6 ;

[0676] m is 1 or 2;

[0677] n is 1 or 2;

[0678] wherein n and m together form a 6-membered or 7-membered ring A;

[0679] p is 0, 1, or 2;

[0680] R 1 R 7A Substituted phenyl, or R 7A substituted pyridyl;

[0681] Each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 alkyl halide;

[0682] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0683] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0684] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0685] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0686] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0687] Two R's 9together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0688] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0689] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0690] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0691] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0692] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0693] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0694] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0695] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0696] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and

[0697] R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0698] Example 11. A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0699] X is O or NR 6 ;

[0700] m is 1 or 2;

[0701] n is 1 or 2;

[0702] wherein n and m together form a 6-membered or 7-membered ring A;

[0703] p is 0, 1, or 2;

[0704] R 1 for

[0705] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0706] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0707] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0708] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0709] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0710] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0711] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0712] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0713] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0714] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0715] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0716] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0717] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0718] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0719] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and

[0720] R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0721] Example 12. A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0722] X is O or NR 6 ;

[0723] m is 1 or 2;

[0724] n is 1 or 2;

[0725] wherein n and m together form a 6-membered or 7-membered ring A;

[0726] p is 0, 1, or 2;

[0727] R 1 Having formula (E1);

[0728] Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 a haloalkyl group or an unsubstituted cyclopropyl group;

[0729] R 7B CN, oxo or C 1-3 alkyl;

[0730] L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0731] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1Together they form unsubstituted C 3-4 Cycloalkyl;

[0732] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0733] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0734] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0735] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0736] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0737] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0738] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0739] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0740] Two R's 5together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0741] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0742] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0743] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0744] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0745] Example 13. A compound of formula (I) or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

[0746] X is O or NR 6 ;

[0747] m is 1 or 2;

[0748] n is 1 or 2;

[0749] wherein n and m together form a 6-membered or 7-membered ring A;

[0750] p is 0, 1, or 2;

[0751] R 1 for L 1 R L1 Substituted or unsubstituted C 1-4 alkylene;

[0752] R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl;

[0753] R 2 R contains one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle;

[0754] R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or wherein

[0755] Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or wherein

[0756] Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons;

[0757] Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl;

[0758] R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl;

[0759] Each R 4 are independently hydrogen, methyl or C 1-3 alkyl halide;

[0760] R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein

[0761] Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbon atoms and optionally one heteroatom selected from O and N; or

[0762] Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of;

[0763] R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl;

[0764] R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocycle;

[0765] R 6A Halogen, CN, OR 6B SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and

[0766] R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0767] Embodiment 14. The compound according to any one of Embodiments 1 to 13, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R 4 For hydrogen.

[0768] Embodiment 15. The compound according to any one of Embodiments 1 to 13, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein one R 4 is hydrogen and one R 4 It is a methyl group.

[0769] Embodiment 16. The compound according to any one of Embodiments 1 to 13, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen and one R 4 It is -CF3.

[0770] Embodiment 17. The compound according to any one of Embodiments 1 to 3 and 12, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 Halogenated alkyl.

[0771] Embodiment 18. The compound according to any one of Embodiments 1 to 3, 10, 12 and 14 to 17, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein at least one R 7A is NH2.

[0772] Embodiment 19. The compound according to any one of Embodiments 1 to 18, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L 1 For methylene.

[0773] Embodiment 20. The compound of any one of Embodiments 1 to 18, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L 1 R L1 Substituted or unsubstituted C 2-3 Alkylene.

[0774] Embodiment 21. The compound according to any one of Embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is a moiety having formula (A) or a stereoisomer thereof, wherein,

[0775] R 9 is halogen, or R 10 Substituted or unsubstituted C 1-3 Alkylidene

[0776] r is an integer from 0 to 12;

[0777] j is 1, 2, or 3; and

[0778] k is 1 or 2.

[0779] Embodiment 22. The compound according to any one of Embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is a moiety having formula (B) or a stereoisomer thereof, wherein

[0780] R 9 are independently halogen, or unsubstituted C 1-3 alkyl; and

[0781] r is 1 or 2.

[0782] Embodiment 23. The compound according to any one of Embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 for:

[0783] or a stereoisomer thereof.

[0784] Embodiment 24. The compound according to any one of Embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 for:

[0785] or a stereoisomer thereof, wherein

[0786] R 9 are independently halogen, or R 10 Substituted or unsubstituted C 1-3 Alkylidene;

[0787] Each R 10 are independently hydrogen or halogen; and

[0788] r is 1 or 2.

[0789] Embodiment 25. The compound according to any one of Embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 for:

[0790] or a stereoisomer thereof.

[0791] Embodiment 26. The compound of any one of Embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is a moiety having formula (C) or a stereoisomer thereof, wherein X 2 CR 9 or O.

[0792] Embodiment 27. The compound according to any one of Embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is a moiety having formula (D) or (D1) or a stereoisomer thereof, wherein X 3 CR 9 NR 9 or O.

[0793] Embodiment 28. The compound according to any one of Embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 for:

[0794] or a stereoisomer thereof.

[0795] Embodiment 29. The compound according to any one of Embodiments 1 to 20, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 for:

[0796]

[0797] Embodiment 30. The compound of any one of Embodiments 1 to 29, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3 It is a halogen.

[0798] Embodiment 31. The compound according to any one of Embodiments 1 to 30, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein both R 5 Together they form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbons.

[0799] Embodiment 32. The compound of embodiment 31 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the bridge comprises 2 carbon atoms.

[0800] Embodiment 33. The compound of embodiment 31 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the bridge comprises 1 carbon atom.

[0801] Embodiment 34. The compound according to any one of Embodiments 1 to 33, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is NR 6 .

[0802] Embodiment 35. The compound according to embodiment 34, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, or R 6ASubstituted or unsubstituted C 1-3 alkyl.

[0803] Embodiment 36. The compound according to embodiment 34, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 6 R 6A Substituted or unsubstituted C 1-3 alkyl.

[0804] Embodiment 37. The compound according to any one of Embodiments 34 to 36, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 6A Halogen, CN, OH, OMe, OEt, OCF3, SO2Me, unsubstituted C 1-3 Alkyl, or 4-membered heterocyclic ring.

[0805] Embodiment 38. The compound according to embodiment 34, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 6 For hydrogen.

[0806] Embodiment 39. The compound according to any one of Embodiments 1 to 38, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is azetidine, oxetanyl or thietane dioxide.

[0807] Embodiment 40. A compound according to any one of Embodiments 1 to 13, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) comprises Formula (IIa), (IIb), (IIc) or (IId), or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0808] Embodiment 41. A compound according to any one of Embodiments 1 to 13, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) comprises Formula (IIIa) or (IIIb), or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0809] Embodiment 42. A compound selected from compounds 1 to 36, 38 to 45, 47 to 62, 64 to 108, 110 to 146, and 149 to 291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0810] Embodiment 43. A compound selected from compounds 1 to 36, 38 to 45, 47 to 62, 64 to 108, and 110 to 125 of Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0811] Embodiment 44. A compound selected from compounds 126 to 146 and 149 to 291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0812] Embodiment 45. A compound selected from compounds 6, 15, 24, 26, 29, 31-32, 57-59, 61-62, 64-66, 75-76, 91, 96, 104, 106, 111, 113, 118-124, 126-146, 149-156, 158-175, 181, 183, 186, 190-192, 195, 200, 204, 224-225, 228-229, 232-239, 241, 244-250, 255, 258-259, and 263 of Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0813] Embodiment 46. A compound selected from compounds 6, 12-18, 23-24, 26, 29, 31-36, 57-58, 60-62, 64-77, 90-97, 100-102, 104, 108, 111, 113, 115, 118-146, 149-175, 181-183, 186-187, 190, 195, 200, 204, 224-232, 234-239, 241, 244-250, 255, 258-259, and 263 of Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0814] Embodiment 47. A compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 57-62, 64-72, 74, 76, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259, and 263 of Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0815] Embodiment 48. A compound selected from compounds 6, 12-18, 23-24, 26, 29, 31-36, 42-45, 47-48, 52, 57-58, 60-78, 84-88, 90-97, 100-104, 106, 108, 111-113, 115, 118-146, 149-175, 177-178, 181-183, 185-187, 189-192, 194-195, 197-200, 203-232, 234-250, and 252-291 of Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0816] Embodiment 49. A compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 42-45, 47-48, 52, 57-62, 64-72, 74, 76, 84-88, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259, and 263 of Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0817] Embodiment 50. A compound selected from compounds 42 to 45, 47 to 48 and 52 in Table 1 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0818] Embodiment 51. A compound selected from compounds 112, 205 to 218, 242 to 243, 252 to 254, 261 to 262, and 264 to 291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0819] Embodiment 52. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0820] Embodiment 53. A method for treating cancer, comprising administering an effective amount of the compound according to any one of Embodiments 1 to 51 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to Embodiment 52.

[0821] Embodiment 54. The method of embodiment 53, wherein the cancer is characterized by comprising a KRas mutation.

[0822] Embodiment 55. The method of embodiment 54, wherein the KRas mutation corresponds to KRas G12D mutation.

[0823] Example 56. The method according to any one of Examples 53 to 55, further comprising targeting KRas G12D Samples from patients are tested for the absence or presence of mutations.

[0824] Example 57. The method of Example 56, wherein the patient sample shows the presence of KRas G12D Following mutation, the compound, a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition is administered to the patient.

[0825] Embodiment 58. The method of any one of embodiments 53 to 57, wherein the cancer is histologically uncharacterized.

[0826] Embodiment 59. The method of any one of embodiments 53 to 57, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0827] Example 60. The method of Example 59, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

[0828] Example 61. The method of Example 59, wherein the cancer is pancreatic cancer.

[0829] Example 62. The method of Example 59, wherein the cancer is colorectal cancer.

[0830] Embodiment 63. The method of any one of embodiments 53 to 62, further comprising administering at least one additional therapeutic agent.

[0831] Example 64. The method of Example 63, 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.

[0832] Embodiment 65. The compound according to any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0833] Embodiment 66. A compound according to any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use in the therapeutic treatment of a KRas-containing G12D Uses for cancer mutations.

[0834] Embodiment 67. Use of the compound of any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0835] Embodiment 68. Use of a compound according to any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a KRas-containing G12D Mutated cancer.

[0836] Embodiment 69. A compound according to any one of embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of a KRas-containing G12D Mutated cancer.

[0837] Embodiment 70. A method for modulating the activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound according to any one of embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

[0838] Embodiment 71. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound according to any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0839] Embodiment 72. The method of embodiment 71, wherein inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0840] Embodiment 73. A method for inhibiting tumor metastasis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0841] Embodiment 74. The compound of any one of embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use in modulating the activity of a KRas mutant protein.

[0842] Embodiment 75. A compound according to any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use in inhibiting the proliferation of a cell population.

[0843] Embodiment 76. The compound, stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt of embodiment 75, wherein the inhibition of proliferation is measured as a decrease in cell viability of a cell population.

[0844] Embodiment 77. A compound according to any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use in inhibiting tumor metastasis.

[0845] Embodiment 78. Use of the compound of any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating the activity of a KRas mutant protein.

[0846] Embodiment 79. Use of a compound according to any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the proliferation of a cell population.

[0847] Embodiment 80. The use according to embodiment 79, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0848] Embodiment 81. Use of a compound according to any one of Embodiments 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0849] Examples

[0850] The following examples are offered by way of illustration only and not limitation.

[0851] intermediates

[0852] Intermediate 1: 4-amino-2,6-dichloro-5-fluoronicotinic acid

[0853]

[0854] Step 1: 2,6-Dichloro-3-fluoropyridin-4-amine

[0855] Under nitrogen, a solution of 2,6-dichloropyridin-4-amine (9.01 g, 55.3 mmol) and SelectFlour (23.6 g, 66.6 mmol) in DMF (90 mL) and acetonitrile (90 mL) was stirred at 80 ° C for 30 min. The mixture was concentrated under vacuum. The crude product was purified by reverse phase chromatography (gradient: water containing 0% to 40% acetonitrile (0.1% formic acid)) to give the title compound (4.62 g, 46.2% yield) as a light brown solid. LC-MS: (ESI, m / z): [M + H] + =181. 1 H NMR (300MHz, DMSO-d6, ppm) δ6.99 (s, 2H), 6.70 (d, J = 5.4Hz, 1H).

[0856] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-(2,6-dichloro-3-fluoro-4-pyridinyl)carbamate

[0857] Under nitrogen, NaHMDS (53.1 mL, 2M in THF) was added to a solution of 2,6-dichloro-3-fluoropyridin-4-amine (4.82 g, 26.6 mmol) in THF (100 mL) at 0 ° C. The resulting solution was stirred at 0 ° C for 30 min. THF (450 mL) containing Boc2O (29.0 g, 133 mmol) was then added at 0 ° C. and stirred at room temperature overnight. The reaction was quenched with NH4Cl aqueous solution. Most of the THF was removed under vacuum, and the resulting solution was extracted with EtOAc. The combined organic layers were concentrated under vacuum to give the title compound (9.11 g, crude product) as a white solid that was used without further purification. LC-MS: (ESI, m / z): [M + H] + =381. 1 H NMR (300MHz, DMSO-d6, ppm) δ6.13 (s, 1H), 1.42 (s, 9H), 1.38 (d, J = 2.4Hz, 9H).

[0858] Step 3: tert-Butyl 4-((tert-Butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate

[0859] Under nitrogen, LDA (41.9 mL, 1 M in THF) was added to a solution of tert-butyl N-(2,6-dichloro-3-fluoro-4-pyridyl)carbamate (9.11 g, 23.9 mmol) in THF (180 mL) at -78 ° C. The resulting solution was stirred at -78 ° C for 0.5 h. The reaction was quenched with aqueous NH4Cl solution and extracted with EtOAc (300 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 10%) to give the title compound (4.18 g, 45.9% yield) as a white solid. LC-MS: (ESI, m / z): [M + H] + =381. 1 H NMR (300MHz, DMSO-d6, ppm) δ10.07(s,1H),1.54(s,9H),1.45(s,9H).

[0860] Step 4: 4-Amino-2,6-dichloro-5-fluoronicotinic acid

[0861] A solution of tert-butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate (4.18 g, 11.0 mmol) in TFA (15 mL) and DCM (15 mL) was stirred at 40° C. for 3 hours. The solvent was concentrated under vacuum to give the title compound (2.86 g, crude) as a brown solid, which was used without further purification. LC-MS: (ESI, m / z): [M+H] + =225.

[0862] Intermediate 2: 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0863]

[0864] Step 1: 5,7-dichloro-8-fluoro-2-thio-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one

[0865] To a solution of 4-amino-2,6-dichloro-5-fluoronicotinic acid (2.01 g, 8.92 mmol, intermediate 1) in MeCN (60 mL) / pyridine (20 mL) was added ethoxycarbonyl isothiocyanate (4.20 mL, 35.6 mmol). The resulting solution was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was purified by reverse phase chromatography (gradient: water containing 0% to 40% acetonitrile (0.1% formic acid)) to give the title compound 1.58 g (yield 46.6%) as a yellow solid. LC-MS: (ESI, m / z): [M + H] + =264. 1 H NMR (400MHz, DMSO-d6, ppm) δ13.30 (s, 1H), 12.86 (s, 1H).

[0866] Step 2: 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0867] Under nitrogen, to a solution of 5,7-dichloro-8-fluoro-2-sulfanyl-2,3-dihydropyrido[4,3-d]pyrimidin-4(1H)-one (1.58 g, 5.93 mmol) in DMF (20 mL) was added ChONa (320 mg, 5.93 mmol) at 0 ° C. The resulting solution was stirred at room temperature for 10 min. Then CHI (842 mg, 5.93 mmol) was slowly added at room temperature. Stirred overnight at room temperature. The reaction solution was slowly added to cold water with stirring. The solid was collected by filtration and dried in an oven to give the title compound (2.07 g, crude product) as a yellow solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =280. 1 H NMR (300MHz, DMSO-d6, ppm) δ13.35 (br, 1H), 2.61 (s, 3H).

[0868] Intermediate 3: tert-Butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0869]

[0870] Step 1: tert-Butyl (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0871] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (50.0 g, 236 mmol) in DMF (800 mL) was added K2CO3 (65.1 g, 472 mmol) and BnBr (60.1 g, 353.53 mmol). Stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water (500 mL × 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 10%)) to give the title compound (69 g, 96.9% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =303.

[0872] Step 2: 3-(tert-butyl)2-methyl (1R,2S,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-2,3-dicarboxylate and 3-(tert-butyl)2-methyl (1R,2R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-2,3-dicarboxylate

[0873]

[0874] Under N2, s-BuLi (117mL, 1.3M in hexane) was added dropwise to a solution of 8-benzyl-3,8-diazabicyclo [3.2.1] octane-3-tert-butyl formate (23.0g, 76.06mmol) and TMEDA (17.7g, 152.59mmol) in ether (500mL) at -78°C, and the mixture was stirred for 1.5 hours at -78°C. 40mL Et2O containing methyl chloroformate (17.9g, 189mmol) was then added dropwise at -78°C. The reaction was warmed to room temperature and stirred for an additional 16 hours. The reaction was quenched with saturated NaHCO3 (aqueous solution), diluted with water, and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0% to 10%) to give 16 g of a racemic mixture (mixture of cis isomers) as a yellow oil. The mixture was separated by chiral SFC (column: 5 μm Cellulose-2, 5×25 cm, 5 μm; Mobile phase A: CO 2 , Mobile phase B: MeOH (0.1% 2M NH 3 -MeOH); Flow rate: 180 mL / min; Gradient: 18% B; 220 nm; RT1: 5.07; RT2: 5.57) to obtain 5.9 g of the faster peak and 5.6 g of the slower peak as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =361.

[0875] Step 3: tert-Butyl (1R,2S,5S)-8-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0876] Under nitrogen, to a solution of (1R, 2S, 5S) -8-benzyl -3,8- diazabicyclo [3.2.1] octane -2,3- dicarboxylic acid 3- (tert-butyl) 2-methyl ester (20.0 g, 55.5 mmol, faster peak of the previous operation) in THF (300 mL) was added LiAlH4 (4.20 g, 111 mmol) at 0 ° C. The resulting solution was stirred at 0 ° C for 30 min and quenched with Na2SO4.10H2O. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (using EtOAc / petroleum ether (0% to 20%)) to give the title compound (14.3 g, 77.5% yield) as a white solid. LC-MS: (ESI, m / z): [M + H] + =333.

[0877] Step 4: (6S,9R,9aS)-10-Benzylhexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine -3-Keto

[0878] Under nitrogen, to a solution of tert-butyl 8-benzyl-4-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.1 g, 15.34 mmol) in THF (100 mL) was added NaH (1.35 g, 33.75 mmol, 60% in mineral oil) at 0 ° C. The resulting solution was stirred at room temperature for 3 hours, quenched with NH4Cl (aqueous solution) and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluted with EtOAc / petroleum ether (0% to 40%) to give the title compound (3.5 g, 88.3% yield) as a white solid. LC-MS: (ESI, m / z): [M + H] + =259.

[0879] Step 5: (6S,9R,9aS)-Hexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine -3-Keto

[0880] (6S,9R,9aS)-10-benzylhexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine A mixture of -3-ketone (10.0 g, 38.7 mmol) and Pd / C (3.0 g, 10%, anhydrous) in methanol (200 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was filtered off. The filtrate was concentrated under reduced pressure to give 6 g of crude product, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =169.

[0881] Step 6: (6S,9R,9aS)-3-oxohexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine -10-tert-Butyl formate

[0882] (6S,9R,9aS)-hexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine A solution of -3-ketone (6.00 g, 35.7 mmol), (Boc)2O (12.6 g, 57.8 mmol) and DIPEA (10.0 g, 77.5 mmol) in dichloromethane (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated sodium chloride solution. The organic phase was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 40%)) to give the title compound 7.50 g (yield 78.4%) as a white solid. LC-MS: (ESI, m / z): [M+H] + =269.

[0883] Step 7: tert-Butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0884] (6S,9R,9aS)-3-oxohexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine A solution of tert-butyl-10-formate (7.50 g, 28.0 mmol) and NaOH (16.8 g, 420 mmol) in ethanol (200 mL) and water (70 mL) was stirred at 80 ° C for 16 hours. Most of the EtOH was removed under reduced pressure. The residual solution was adjusted to pH = 8 with HCl aqueous solution (1 M) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with DCM / MeOH (5 / 1)) to give the title compound (5 g, 73.8% yield) as an off-white solid. LC-MS: (ESI, m / z): [M+H] + =243. 1 H NMR(400MHz,DMSO-d6,ppm)δ4.72-4.57(m,1H),4.02-3.90(m,2H),3.25-3.15(m,2H),2 .82-2.68(m,2H),2.64-2.53(m,1H),1.85-1.61(m,3H),1.61-1.47(m,1H),1.41(s,9H).

[0885] Intermediate 4: tert-Butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0886]

[0887] Step 1: tert-Butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0888] Under nitrogen, to a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.00 g, 23.5 mmol) in N,N-dimethylformamide (50 mL) was added K2CO3 (6.51 g, 47.1 mmol) and (bromomethyl)benzene (6.01 g, 35.1 mmol) at 0 ° C. It was stirred at room temperature for 1 h. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 30% EtOAc / petroleum ether) to obtain 7 g (yield 98.3%) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =303.

[0889] Step 2: (1S,6S,9R,9aS)-10-Benzyl-1-methylhexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine -3-Keto

[0890]

[0891] Under nitrogen, s-BuLi (35.6 mL, 46.3 mmol, 1.3 M in hexane) was added dropwise to a solution of 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (7.0 g, 23.1 mmol) and TMEDA (5.38 g, 46.3 mmol) in diethyl ether (70 mL) at -78 ° C. The resulting solution was stirred at -78 ° C for 1.5 h. Acetaldehyde (2.55 g, 57.8 mmol) was then added at -78 ° C. The reaction was gradually warmed to room temperature and stirred overnight. The mixture was quenched with NH4Cl (aqueous solution) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (petroleum ether containing 0% to 50% EtOAc) to obtain 5.1 g of a mixture of 4 diastereomers. The mixture was separated by preparative SFC (column: CHIRALPAK IH, 3×25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: IPA (0.5% 2M NH 3 -MeOH); flow rate: 70 mL / min; gradient: isocratic 35% B; column temperature (° C.): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 6.31; RT2 (min): 8.33; sample solvent: MeOH-----preparative grade; injection volume: 1.9 mL; number of runs: 50) to obtain compound a (1.39 g, yield 22%) (first peak) and compound d (1.47 g, yield 23.3%) (third peak) and a mixture of compounds b and c (second peak). The mixture of compounds b and c was separated again by preparative SFC (column: CHIRALPAK IH, 5×25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: IPA (0.5% 2 M NH 3 -MeOH); flow rate: 200 mL / min; gradient: isocratic 50% B; column temperature (° C.): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 5.73; RT2 (min): 8.44; sample solvent: MeOH—preparative grade; injection volume: 10 mL; number of runs: 6) to obtain compound b (0.500 g, yield 7.9%) (faster peak) and compound c (0.430 g, yield 6.8%) (slower peak) as yellow solids. LC-MS: (ESI, m / z): [M+H] + =273.

[0892] Step 3: (1S,6S,9R,9aS)-1-methylhexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine -3-Keto

[0893] (1S,6S,9R,9aS)-10-benzyl-1-methylhexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine A solution of -3-ketone (1.00 g, 3.67 mmol) (compound a from the previous step) and Pd / C (500 mg, 10%) in methanol (15 mL) was stirred at room temperature under a hydrogen atmosphere for 1 h. The catalyst was filtered off. The filtrate was concentrated under vacuum to give 658 mg (crude product) of the title compound as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =183.

[0894] Step 4: (1S,6S,9R,9aS)-1-methyl-3-oxohexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine -10-tert-Butyl formate

[0895] (1S,6S,9R,9aS)-1-methylhexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine A solution of -3-ketone (658 mg, 3.61 mmol), (Boc)2O (1.18 g, 5.41 mmol) and DIPEA (1.4 g, 10.8 mmol) in dichloromethane (10 mL) was stirred at room temperature for 30 min. The reaction system was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 100% EtOAc / petroleum ether) to give the title compound (920 mg, 90.2% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =283.

[0896] Step 5: tert-Butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0897] (1S,6S,9R,9aS)-1-methyl-3-oxohexahydro-1H,3H-6,9-imidooxazolo[3,4-a]azepine A solution of tert-butyl-10-formate (900 mg, 3.19 mmol) and NaOH (1.28 g, 32.0 mmol) in ethanol (12 mL) and water (4 mL) was stirred at 80 ° C for 1 h. The reaction solution was cooled to room temperature and diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to give 815 mg (crude product) as an oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M + H] + =257. 1 H NMR (300MHz, DMSO-d6) δ4.54(s,1H),3.94(d,J=5.1Hz,1H),3.82(s,1H),2.73(d,J=11.3Hz,1H),2.60(d,J=11. 5Hz,1H),2.41(d,J=8.1Hz,1H),2.15(s,1H),179–1.67(m,3H),1.56(s,1H),1.40(s,9H),1.04(d,J=6.3Hz,3H).

[0898] Intermediate 5: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol

[0899]

[0900] Step 1: (S)-2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester and (R)-2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester

[0901]

[0902] 20.0 g of ethyl 2,5-dioxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (20.0 g, 94.6 mmol) was separated by SFC (column: AD 2.12×25 cm, 5 μm; mobile phase A: CO2, mobile phase B: EtOH:ACN=1:1; flow rate: 200 mL / min; gradient: 50% B; 220nm; RT1: 2.44; RT2: 3.58; injection volume: 10ml; number of runs: 15) to give (S)-2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (8.21g, faster peak) (which is a yellow oil) and (R)-2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (7.92g, slower peak) (which is a yellow oil). LC-MS: (ESI, m / z): [M+H] + =212. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.22 (q, J = 7.2 Hz, 2H), 4.14–4.05 (m, 1H), 3.54 (d, J = 18.6 Hz, 1H), 3.02–2.91 (m, 2H), 2.87–2.72 (m, 1H), 2.60–2.38 (m, 2H), 2.23–2.11 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H).

[0903] Step 2: (7aS)-2-Hydroxy-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester

[0904] Under nitrogen, to a solution of (S)-2,5-dioxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (1.22 g, 5.68 mmol) in tetrahydrofuran (100 mL) was added NaBH4 (70.3 mg, 1.85 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 30 min. The reaction was quenched with water and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 6% MeOH / DCM) to give the title compound (0.631 g, 62% yield) as a light yellow oil. LC-MS: (ESI, m / z): [M+H] + =214.

[0905] Step 3: (2R,7aS)-2-Fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester and (2S,7aS)-2-Fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester

[0906]

[0907] To a solution of (7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (809 mg, 3.80 mmol) was added DAST (923 mg, 5.74 mmol, dissolved in 20 mL of DCM) at -15°C under nitrogen. The mixture was stirred at room temperature for 3 hours. The mixture was quenched with EtOH. The solvent was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0% to 100% EtOAc / petroleum ether) to afford 425 mg (52% yield) of ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate as a colorless oil and 219 mg (26.9% yield) of ethyl (2S,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate as a white solid. LC-MS: (ESI, m / z): [M+H] + =216.

[0908] (2R,7aS)-2-Fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (faster peak). 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.32 (d, J = 19.2 Hz, 1H), 4.26–4.11 (m, 3H), 3.25–3.12 (m, 1H), 2.85–2.59 (m, 3H), 2.48–2.39 (m, 1H), 2.37–2.07 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H).

[0909] (2S,7aS)-2-Fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (slower peak). 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.47–5.32 (m, 1H), 4.29–4.24 (m, 2H), 4.08–3.96 (m, 1H), 3.46–3.35 (m, 1H), 2.98–2.78 (m, 2H), 2.53–2.42 (m, 2H), 2.20–2.12 (m, 1H), 1.91–1.76 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H).

[0910] Step 4: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol

[0911] Under nitrogen, to a solution of (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester (310 mg, 1.44 mmol) in tetrahydrofuran (7 mL) was added LiAlH4 (3.1 mL, 1 M in THF) at 0 ° C. The reaction mixture was stirred at 70 ° C for 0.5 h. The mixture was quenched with Na2SO4.10H2O and filtered. The solvent was removed by blowing N2, and the title compound 124 mg (crude) was obtained as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M + H] + =160.

[0912] Intermediate 6: (3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-yl)methanol

[0913]

[0914] Step 1. 1-(tert-Butyl)2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate

[0915] Under nitrogen, to a solution of 1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (2.0 g, 7.54 mmol) in tetrahydrofuran (30 mL) was added LiHMDS (10 mL, 10 mmol) at -78 ° C and stirred at -78 ° C for 0.5 hours. 1-Chloro-2-iodoethane (2.87 g, 15.1 mmol) was then added and stirred at room temperature for 1 hour. The reaction was quenched with NH4Cl (aqueous solution) and extracted with EtOAc. The combined organic layers were dried over NaSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel and eluted with EtOAc / petroleum ether (0% to 60%) to give the title compound 900 mg (yield 36.4%) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =328

[0916] Step 2. Methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate

[0917] Under nitrogen, TFA (1 mL) was added to a solution of 1-(tert-butyl) 2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (470 mg, 1.43 mmol) in dichloromethane (5 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The solvent was concentrated under vacuum to give 300 mg of the title compound (crude product) as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =228

[0918] Step 3. Methyl 3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate

[0919] Under nitrogen, to a solution of 2-(2-chloroethyl)-4,4-difluoro-pyrrolidine-2-carboxylic acid methyl ester (300 mg, 1.32 mmol) in acetonitrile (5 mL) was added Et3N (1 mL) at room temperature and stirred at 85 ° C for 12 hours. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluting with DCM / MeOH (0% to 6%) to give the title compound 150 mg (yield 59.5%) as a yellow solid. LC-MS: (ESI, m / z): [M + H] + =192

[0920] Step 4. (3,3-Difluoro-1-azabicyclo[3.2.0]hept-5-yl)methanol

[0921] To a solution of methyl 3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate (150 mg, 0.780 mmol) in tetrahydrofuran (3 mL) was added LiAlH4 (2.4 mL, 2.4 mmol, 1 M in THF) at 0°C under nitrogen. The solution was stirred at 0°C for 0.5 hours. The solvent was removed by nitrogen blowing to give 110 mg (crude) of the title compound as a yellow oil, which was used in the next reaction without further purification. LC-MS: (ESI, m / z): [M+H] + = 164. Purification.

[0922] Intermediate 6A: (3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-yl)methanol

[0923]

[0924] Step 1. 1-(tert-Butyl)2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate

[0925] Under nitrogen, to a solution of 1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (2.0 g, 7.54 mmol) in tetrahydrofuran (30 mL) was added LiHMDS (10 mL, 10 mmol) at -78 ° C, and the mixture was stirred at -78 ° C for 0.5 hours. 1-Chloro-2-iodoethane (2.87 g, 15.1 mmol) was then added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with NH4Cl (aqueous solution) and then extracted with EtOAc. The combined organic layers were dried over NaSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluted with EtOAc / petroleum ether (0% to 60%) to obtain the title compound 900 mg (yield 36.4%) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =328

[0926] Step 2. Methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate

[0927] Under nitrogen, TFA (1 mL) was added to a solution of 1-(tert-butyl) 2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (470 mg, 1.43 mmol) in dichloromethane (5 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The solvent was concentrated under vacuum to give 300 mg of the title compound (crude product) as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =228

[0928] Step 3. Methyl 3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate

[0929] Under nitrogen, to a solution of 2-(2-chloroethyl)-4,4-difluoro-pyrrolidine-2-carboxylic acid methyl ester (300 mg, 1.32 mmol) in acetonitrile (5 mL) was added Et3N (1 mL) at room temperature, and the mixture was stirred at 85 ° C for 12 hours. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel, eluted with DCM / MeOH (0% to 6%) to give the title compound 150 mg (yield 59.5%) as a yellow solid. LC-MS: (ESI, m / z): [M + H] + =192

[0930] Step 4. (3,3-Difluoro-1-azabicyclo[3.2.0]hept-5-yl)methanol

[0931] Under nitrogen, to a solution of methyl 3,3-difluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate (150 mg, 0.780 mmol) in tetrahydrofuran (3 mL) was added LiAlH4 (2.4 mL, 2.4 mmol, 1 M in THF) at 0 ° C. The solution was stirred at 0 ° C for 0.5 hours. The solvent was removed by blowing nitrogen through the solvent to give 110 mg of the crude title compound as a yellow oil, which was used in the next reaction without further purification. LC-MS: (ESI, m / z): [M + H] + = 164. Purification.

[0932] Intermediate 7: (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0933]

[0934] Step 1: tert-Butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0935] Under nitrogen, to a solution of (1S, 2S, 5R) -2- (hydroxymethyl) -3, 8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (289 mg, 1.19 mmol, intermediate 3) in THF (20 mL) was added NaH (191 mg, 4.78 mmol, 60% in mineral oil) at 0 ° C. The resulting solution was stirred at room temperature for 0.5 h. 5,7- dichloro -8- fluoro -2- (methylthio) pyrido [4,3-d] pyrimidin -4 (3H) -one (803 mg, 1.43 mmol, intermediate 2) was then added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with NH4Cl aqueous solution, diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (1.05 g crude) as a white solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =486.

[0936] Step 2: (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-ethylnaphtho[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0937] To a solution of tert-butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.05 g, 2.15 mmol) in DCM (10 mL) was added DIPEA (4.16 g, 32.3 mmol) and BOPCl (2.20 g, 8.61 mmol). The resulting solution was stirred at room temperature for 2 hours, diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0% to 40%) to give the title compound (381 mg, 37.8% yield) as a light yellow solid. LC-MS:(ESI,m / z):[M+H] + =469

[0938] Intermediate 8: (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0939]

[0940] To a solution of (5aS, 6S, 9R) -2- chloro-1-fluoro-12- (methylthio) -5a, 6,7,8,9,10- hexahydro -5H-4-oxa-3,10a, 11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester (381 mg, 0.816 mmol, intermediate 7) in EtOAc (5 mL) was added mCPBA (423 mg, 2.45 mmol) at 0 ° C. The solution was stirred at room temperature for 1 hour, diluted with saturated NaHCO solution (20 mL), and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 60%)) to afford the title compound 372 mg (91.3% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =500. 1 H NMR (300MHz, DMSO-d6, ppm) δ4.99(d,J=13.5Hz,1H),4.77(dd,J=13.5,1.9Hz,1H),4.59(dd,J=13.5,7.4Hz,1H),4.38(d,J=8 .3Hz, 2H), 4.20 (d, J = 7.1Hz, 1H), 3.42 (s, 3H), 3.22 (d, J = 13.6Hz, 1H), 1.93 (d, J = 6.7Hz, 1H), 1.86–1.64 (m, 3H), 1.45 (s, 9H).

[0941] Intermediate 9: (5aS,6S,9R)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0942]

[0943] To a mixture of (5aS,6S,9R)-2-chloro-1-fluoro-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester (201 mg, 0.401 mmol, Intermediate 8) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (128 mg, 0.802 mmol, Intermediate 5) in toluene (2 mL) was added t-BuONa (77.1 mg, 0.802 mmol) under nitrogen at 0° C. The solution was stirred at room temperature for 1 hour, diluted with water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with CH 3 OH / DCM (0% to 10%)) to give the title compound (151 mg, 64.8% yield) as a light yellow solid. LC-MS: (ESI, m / z): [M + H] + =579. 1 H NMR(300MHz,DMSO-d6,ppm)δ5.29(d,J=54.2Hz,1H),4.89(d,J=13.4Hz,1H),4.72–4.62(m,1H),4.48(dd,J=13.3,7.3Hz,1H),4.40–4.25 (m,2H),4.19–3.95(m,3H),3.15–2.97(m,4H),2.89–2.76(m,1H),2.17–2.11(m,1H),2.07–2.02(m,1H),1.94–1.62(m,8H),1.45(s,9H).

[0944] Intermediate 10: (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0945]

[0946] Step 1: (1S,2S,5R)-tert-Butyl 2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0947] Under nitrogen, to a solution of (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (769 mg, 3.00 mmol, intermediate 4) in THF (10 mL) was added NaH (480 mg, 12.0 mmol, 60% in mineral oil) at 0 ° C. The resulting solution was stirred at room temperature for 0.5 h. 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (1.01 g, 3.60 mmol, intermediate 2) was then added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with NH4Cl aqueous solution, diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (1.61 g crude) as a white solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =500.

[0948] Step 2: (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0949] To a solution of tert-butyl (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.61 g, 3.21 mmol) in DCM (15 mL) was added DIPEA (6.22 g, 48.2 mmol) and BOPCl (3.28 g, 12.9 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0% to 55%) to give the title compound (1.21 g, 77.9% yield) as a light yellow solid. LC-MS: (ESI, m / z): [M+H] + =482.

[0950] Intermediate 11: (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0951]

[0952] To a solution of (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester (1.21 g, 2.5 mmol, intermediate 10) in EtOAc (20 mL) was added mCPBA (1.30 g, 7.52 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour, diluted with NaHCO3 and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0% to 60%) to afford the title compound (931 mg, 72.4% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =514. 1 H NMR (300MHz, DMSO-d6, ppm) δ5.32–5.16 (m, 1H), 4.74 (t, J = 7.7Hz, 1H), 4.35 (d, J = 5.2Hz, 1H), 4.30–4. 10(m,2H),3.42(s,3H),3.20(d,J=13.4Hz,1H),1.93–1.70(m,4H),1.53(d,J=6.3Hz,3H),1.47(s,9H).

[0953] Intermediate 12: (5S,5aS,6S,9R)-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0954]

[0955] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (37.5 mg, 0.240 mmol, Intermediate 5) and (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester (60.6 mg, 0.120 mmol, Intermediate 11) in toluene (1.5 mL) was added t-BuONa (22.6 mg, 0.240 mmol) under nitrogen at 0° C. The reaction mixture was stirred at room temperature for 1 hour, quenched with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with CH 3 OH / DCM (0% to 10%)) to give the title compound (40.6 mg, 58.1% yield) as a light yellow solid. LC-MS: (ESI, m / z): [M + H] + =593.

[0956] Intermediate 13: tert-Butyl (5S,5aS,6S,9R)-2-chloro-12-((3,3-difluoro-1-azabicyclo[3.2.0]hept-5-yl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylate

[0957]

[0958] To a solution of tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]cycloheptatriene-14-carboxylate (3.50 g, 6.81 mmol, Intermediate 11) and (3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl)methanol (1.30 g, 7.97 mmol, Intermediate 6) in toluene (35 mL) was added t-BuONa (1.30 g, 13.5 mmol) under nitrogen at 0° C. The resulting solution was stirred at room temperature for 1 h, quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 6% MeOH / DCM) to give a mixture of two diastereomers as a white solid 2.06 g (yield 50.7%). The diastereomers were separated by chiral preparative HPLC (column: CHIRALPAK IE-3, 4.6×50 mm, 3 μm; mobile phase A: Hex (0.1% DEA): EtOH=50:50; flow rate: 1 mL / min; gradient: 0% B to 0% B; injection volume: 5 ul mL) to give 643 mg of a faster peak and 676 mg of a slower peak as a white solid. LC-MS: (ESI, m / z): [M+H] + =597.

[0959] Faster peak (desired isomer): 1 H NMR (300MHz, DMSO-d6, ppm): δ5.18 (d, J=13.2Hz, 1H), 4.64 (t, J=7.6Hz, 1H), 4.44–4. 29(m,3H),4.16(s,1H),3.99(d,J=9.0Hz,1H),3.54(dd,J=9.0,4.7Hz,1H),3.33–3.1 5(m,1H),3.15(d,J=4.4Hz,1H),3.13–2.98(m,2H),2.75–2.52(m,1H),2.50–2.38(m, 1H), 2.41–2.25 (m, 1H), 1.87 (s, 3H), 1.73 (s, 1H), 1.50 (d, J = 6.3Hz, 3H), 1.47 (s, 9H).

[0960] Slower peak: 1 H NMR (300 MHz, DMSO-d6, ppm): 1H NMR (300MHz, DMSO-d6, ppm): δ5.18 (d, J=13.2Hz, 1H), 4.64 (t, J=7.6Hz, 1H), 4.44–4. 29(m,3H),4.16(s,1H),3.99(d,J=9.0Hz,1H),3.54(dd,J=9.0,4.7Hz,1H),3.33–3.1 5(m,1H),3.15(d,J=4.4Hz,1H),3.13–2.98(m,2H),2.75–2.52(m,1H),2.50–2.38(m, 1H), 2.41–2.25 (m, 1H), 1.87 (s, 3H), 1.73 (s, 1H), 1.50 (d, J = 6.3Hz, 3H), 1.47 (s, 9H).

[0961] Intermediate 14: (5aS,6S,9R)-2-chloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0962]

[0963] Step 1: 4-Amino-2,6-dichloro-5-fluoronicotinamide

[0964] A solution of 4-amino-2,6-dichloro-5-fluoronicotinic acid (2.86 g, 12.7 mmol), NH4Cl (3.38 g, 63.8 mmol), HATU (7.25 g, 19.1 mmol) and DIPEA (16.5 g, 127 mmol) in DMA (28 mL) was stirred at room temperature for 0.5 hours. The resulting solution was diluted with EtOAc (80 mL) and washed with water (60 mL×4). The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with CH3OH / DCM (0% to 5%) to give the title compound (1.61 g, 56.5% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =224. 1 H NMR (400MHz, DMSO-d6, ppm) δ8.06(s,1H),7.81(s,1H),6.87(s,2H).

[0965] Step 2: 5,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one

[0966] A solution of 4-amino-2,6-dichloro-5-fluoronicotinamide (1.51 g, 6.74 mmol) in triethoxymethane (30 mL) was stirred at 150 ° C for 3 hours. The mixture was then concentrated under vacuum. The residue was triturated with EtOAc / petroleum ether (1: 1, 10 mL). The solid was collected by filtration to give the title compound (1.04 g, crude product) as a yellow solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M + H] + =234. 1 H NMR (400MHz, DMSO-d6, ppm) δ13.02 (br s, 1H), 8.41 (s, 1H).

[0967] Step 3: tert-Butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0968] Under nitrogen, to a solution of (1S, 2S, 5R) -2- (hydroxymethyl) -3, 8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (624 mg, 2.58 mmol, intermediate 3) in DMF (6 mL) was added NaH (134 mg, 3.35 mmol, 60% in mineral oil) at 0 ° C. The resulting solution was stirred at room temperature for 30 min. 5,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4 (3H) -one (601 mg, 2.57 mmol) was then added and stirred at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature and quenched with NH4Cl aqueous solution. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL × 4). 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 CH3OH / DCM (0% to 10%) to afford the title compound (452 ​​mg, 40% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =440. 1 H NMR(400MHz,d6,ppm)δ8.32(s,1H),4.25–4.05(m,3H),3.98(d,J=6.4Hz,1H),3.20-3.11(m,1H),2.80(d,J=11.5Hz,1H),2.60(s,1H),2.03 -1.92(m,1H),1.82–1.57(m,3H),1.37(t,J=9.6Hz,9H).

[0969] Step 4: (5aS,6S,9R)-2-chloro-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0970] Under nitrogen, a solution of tert-butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (452 ​​mg, 1.03 mmol), BOP-Cl (1.05 g, 4.12 mmol) and DIPEA (1.99 g, 15.5 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. The mixture was then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 40%) to give the title compound (315 mg, 72.6% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =422.

[0971] Intermediate 15: (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0972]

[0973] Step 1: tert-Butyl (1R,2S,5S)-2-((S)-1-((7-chloro-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0974] Under nitrogen, to a solution of (1R, 2S, 5S) -2- ((S) -1- hydroxyethyl) -3, 8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester (229 mg, 0.890 mmol, intermediate 4) in DMF (6 mL) was added NaH (71.6 mg, 1.79 mmol, 60% in mineral oil) at 0 ° C. The resulting solution was stirred at room temperature for 30 min. 5,7- dichloro -8- fluoropyrido [4,3-d] pyrimidin -4 (3H) -one (251 mg, 1.07 mmol, intermediate 14, step 2) was then added and stirred at 80 ° C for 1 hour. The reaction mixture was quenched with NH4Cl aqueous solution, diluted with EtOAc (20 mL) and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (476 mg, crude) as a white solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =454.

[0975] Step 2: (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]cycloheptatriene-14-carboxylic acid tert-butyl ester

[0976] To a solution of tert-butyl (1R,2R,5S)-2-((S)-1-((7-chloro-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (476 mg, 1.05 mmol) in DCM (20 mL) was added DIPEA (2.03 g, 15.71 mmol) and BOPCl (1.07 g, 4.19 mmol). The solution was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0% to 50%) to give the title compound (221 mg, 48.3% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =436.

[0977] Intermediate 16: 6-Fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0978]

[0979] Step 1: 7-Bromo-6-fluoro-1-methyl-1H-indazole

[0980] Under nitrogen, a solution of 3-bromo-2,4-difluoro-benzaldehyde (500 mg, 2.26 mmol), 1-methylhydrazine sulfate (1.63 g, 11.3 mmol) and K2CO3 (3.12 g, 22.6 mmol) in NMP (15 mL) was stirred at 200 ° C for 2 h under microwave irradiation. The reaction system was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 10%) to obtain 7-bromo-6-fluoro-1-methyl-indazole (333.2 mg, 64.3% yield) as a white solid. LC-MS: (ESI, m / z): [M + H] + =229 / 231; 1 H NMR (400MHz, DMSO-d6) δ8.13 (s, 1H), 7.80 (dd, J = 8.7, 5.0Hz, 1H), 7.15 (t, J = 8.9Hz, 1H), 4.31 (s, 3H).

[0981] Step 2: 6-Fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0982] Under nitrogen, a solution of 7-bromo-6-fluoro-1-methyl-1H-indazole (150 mg, 0.660 mmol), Pin2B2 (836 mg, 3.29 mmol), Pd(dppf)Cl (48.2 mg, 0.0700 mmol), and KOAc (258 mg, 2.63 mmol) in DMF (5 mL) was stirred at 80° C. overnight. The resulting solution was purified by reverse phase chromatography (gradient: 0% to 60% acetonitrile in water (0.05% NH4HCO3)) to give the title compound (49.9 mg, 27.5% yield) as a white solid. LC-MS: (ESI, m / z): [M+H] + =277. 1 H-NMR (300MHz, DMSO-d6, ppm): δ8.07(s,1H),7.88(dd,J=8.8,5.6Hz,1H),6.98(dd,J=9.5,8.8Hz,1H),4.05(s,3H),1.38(s,12H)

[0983] Intermediate 17: 6-(allylsulfonyl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0984]

[0985] Step 1: 6-(allylthio)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0986] Under nitrogen, to a solution of allyl mercaptan (3.74 g, 50.5 mmol) and K2CO3 (2.79 g, 20.2 mmol) in DMF (20 mL) was added 6-bromo-N, N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (5.01 g, 10.1 mmol). The solution was stirred at room temperature overnight and diluted with acetonitrile (20 ml). The solid was filtered off. The filtrate was concentrated under reduced pressure to give 5.05 g (crude) of the title compound as a dark red oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =489.

[0987] Step 2: 6-(allylsulfonyl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0988] To a solution of 6-allylsulfanyl-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (5.05 g, 10.3 mmol) in DCM (150 mL) was added mCPBA (14.3 g, 82.7 mmol). The reaction mixture was stirred at room temperature overnight, quenched with saturated NaHCO3 aqueous solution (100 mL) and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on silica gel (gradient: 0% to 65% ethyl acetate / petroleum ether) to give 1.70 g (yield 31.6%) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =521. 1 H NMR (400MHz, DMSO-d6, ppm) δ7.16 (d, J = 8.6 Hz, 4H), 7.01 (s, 1H), 6.90 (d, J = 8.7 Hz, 4H), 5.61 (ddt, J = 18.8, 9.4, 7. 1Hz,1H),5.30(s,1H),5.27(dd,J=6.0,1.7Hz,1H),4.76(s,4H),4.15(d,J=7.2Hz,2H),3.72(s,6H),2.38(s,3H).

[0989] Intermediate 18: ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0990]

[0991] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol

[0992] Under nitrogen, to 7-fluoronaphthalene-1-ol (2.50g, 15.4mmol) and (bromoethynyl) triisopropylsilane (4.82g, 18.4mmol) in DCE (24mL) solution, add dichloro (p-cymene) ruthenium (II) dimer (1.42g, 2.31mmol), K2CO3 (2.13g, 15.4mmol) and NaOAc (253mg, 3.09mmol). The mixture is stirred at 40 ° C overnight and concentrated under vacuum. The residue is purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 15%) to obtain 5.01g (yield 94.7%) title compound, which is a yellow oil. 1 H-NMR (300MHz, CDCl3, ppm) δ9.00 (s, 1H), 7.68 (dd, J = 9.1, 5.8Hz, 1H), 7.30–7.21 (m, 2H), 7.18–7.06 (m, 1H), 6.96–6.88 (m, 1H), 1.13–1.06 (m, 21H).

[0993] Step 2: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate

[0994] Under nitrogen, to a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (8.95 g, 26.1 mmol) and DIPEA (6.75 g, 52.3 mmol) in DCM (90 mL) was added trifluoromethanesulfonic anhydride (11.1 g, 39.2 mmol) dropwise at -40 ° C over 15 min. The solution was stirred at -40 ° C for 1 h and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 15%) to obtain 10.4 g (83.5% yield) as a yellow oil. 1 H-NMR (300MHz, CDCl3, ppm) δ7.90–7.81(m,2H),7.58(d,J=7.8Hz,1H),7.48(t,J=8.0Hz,1H),7.43–7.35(m,1H),1.33–1.15(m,21H).

[0995] Step 3: ((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane

[0996] Under nitrogen, a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (3.01 g, 6.32 mmol), Pin2B2 (3.22 g, 12.7 mmol), Pd(dppf)Cl2 (486 mg, 0.630 mmol) and KOAc (1.24 g, 12.7 mmol) in 1,4-dioxane (12 mL) was stirred at 110 ° C overnight. The resulting reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 13%)) to give 1.61 g (55.9% yield) of the title compound as a yellow solid. 1 H-NMR (300MHz, CDCl3, ppm) δ7.87–7.71(m,3H),7.48–7.37(m,1H),7.32–7.18(m,1H),1.44(s,12H),1.26–1.07(m,21H).

[0997] Intermediate 19: 2-Fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0998]

[0999] Step 1: 3-Bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-5-methylaniline

[1000] Under nitrogen, NaH (6.06 g, 151 mmol, 60% in mineral oil) was added to a solution of 3-bromo-2-fluoro-5-methylaniline (10.3 g, 50.4 mmol) in THF (90 mL) at 0 ° C. The resulting solution was stirred at room temperature for 20 min. PMBCl (19.7 g, 125 mmol) was then added at 0 ° C. and stirred at room temperature for 1.5 hours. The reaction was quenched with NH4Cl aqueous solution and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 9% EtOAc / DCM) to obtain 20.4 g (yield 90.9%) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] +=443.

[1001] Step 2: 2-Fluoro-N,N-bis(4-methoxybenzyl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[1002] Under nitrogen, a solution of 3-bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-5-methylaniline (5.01 g, 11.2 mmol), Pin2B2 (5.72 g, 22.5 mmol), Pd(dppf)Cl2 (1.73 g, 2.25 mmol) and KOAc (3.31 g, 33.7 mmol) in 1,4-dioxane (55 mL) was stirred at 120 ° C for 5 h. The resulting solution was concentrated under vacuum. The residue was purified by silica gel flash chromatography (gradient: 0% to 20% EtOAc / petroleum ether) to give 4.81 g (yield 79.2%) of the title compound as a yellow syrup. LC-MS: (ESI, m / z): [M + H] + =492. 1 H NMR (300MHz, DMSO-d6, ppm): δ7.28 (s, 6H), 7.24-7.10 (m, 4H), 6.80 (d, J = 30.0Hz, 4H), 3.78 (s, 6H), 2.12 (s, 3H), 1.40 (s, 12H).

[1003] Intermediate 20: (5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid

[1004]

[1005] Step 1: 5-Bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methylaniline

[1006] Under nitrogen, NaH (2.82 g, 70.5 mmol, 60% in mineral oil) was added to a solution of 5-bromo-2-fluoro-3-methylaniline (4.81 g, 23.5 mmol) in DMF (40 mL) at 0 ° C. The resulting solution was stirred at room temperature for 20 min. PMBCl (7.42 g, 47.3 mmol) was then added. It was stirred at room temperature for 1 hour and quenched with NH4Cl aqueous solution. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×80 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was slurried with ethanol to give 6.50 g (crude) of the title compound as an off-white solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] +=444

[1007] Step 2: 5-Bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)-3-methylaniline

[1008] Under nitrogen, NIS (3.20 g, 14.2 mmol) was added to a solution of 5-bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-3-methylaniline (5.70 g, 12.8 mmol) in acetic acid (50 mL) at room temperature. The solution was stirred at room temperature for 20 min. The reaction was quenched with an aqueous solution of Na2S2O3 and diluted with EtOAc (150 mL). The phases were separated. The organic layer was washed with water (4 × 100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 30%)) to give 7.21 g (yield 98.5%) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =570.

[1009] Step 3: 5-Bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)aniline

[1010] Under nitrogen, 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (15.2 mL, 119 mmol) and CuI (23.4 g, 123 mmol) were added to a solution of 5-bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)-3-methylaniline (7.08 g, 12.4 mmol) in DMF (80 mL) at room temperature. The reaction mixture was stirred at 75 ° C for 6 hours, washed with H2O (40 mL) and extracted with EtOAc (70 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with EtOAc / petroleum ether (0% to 50%) to obtain 3.47 g (yield 54.5%) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =512.

[1011] Step 4: (5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid

[1012] Under nitrogen, n-BuLi (2.2 mL, 2.5 M in THF) was added to a solution of 5-bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)aniline (2.40 g, 4.68 mmol) and triisopropyl borate (1.60 mL, 6.91 mmol) in THF (35 mL) at -78 ° C. The resulting solution was stirred at -78 ° C for 1 h. The reaction was quenched with NH4Cl aqueous solution, diluted with H2O (20 mL) and extracted with EtOAc (50 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluted with EtOAc (0.1% TEA) / petroleum ether (10% DCM) (0% to 30%) to obtain 1.22 g (yield 54.4%) of the title compound as a yellow syrup. LC-MS:(ESI,m / z):[M+H] + =477.

[1013] Intermediate 21: 5-chloro-4-(trimethylstannyl)isoquinoline

[1014]

[1015] Under nitrogen, a solution of 4-bromo-5-chloroisoquinoline (450 mg, 1.86 mmol), Sn2Me6 (2.00 g, 6.10 mmol) and Pd(PPh3)4 (215 mg, 0.190 mmol) in toluene (5 mL) was stirred at 100 ° C for 48 h. The reaction system was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by reverse phase chromatography (gradient: 0% to 78% acetonitrile / water (0.1% FA)) to give 341 mg (yield 56.3%) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M + H] + =328. 1 H NMR (400 MHz, chloroform-d, ppm) δ 9.22 (s, 1H), 8.71 (s, 1H), 7.95–7.88 (m, 1H), 7.85–7.78 (m, 1H), 7.58–7.50 (m, 1H), 0.47 (s, 9H).

[1016] Intermediate 22: 2-Fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[1017]

[1018] Step 1: 5-Bromo-2-fluoro-N,N-bis(4-methoxybenzyl)aniline

[1019] Under nitrogen, NaH (6.40 g, 160 mmol, 60% in mineral oil) was added to a solution of 5-bromo-2-fluoro-aniline (10.1 g, 53.2 mmol) in DMF (70 mL) at 0 ° C. Stir at room temperature for 30 min. PMBCl (18.2 g, 117 mmol) was then added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with NH4Cl aqueous solution (20 mL), diluted with EtOAc (250 mL) and washed with water (200 mL × 4). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 17% EtOAc / petroleum ether) to obtain 24.1 g of the title compound as a yellow syrup. LC-MS: (ESI, m / z): [M+H] + =430.

[1020] Step 2: 5-Bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)aniline

[1021] Under nitrogen, a solution of 5-bromo-2-fluoro-N, N-bis(4-methoxybenzyl)aniline (23.9 g, 55.5 mmol) and NIS (14.9 g, 66.5 mmol) in acetic acid (150 mL) was stirred at room temperature for 1.5 hours. The reaction was quenched with Na2S2O3 (15 mL), diluted with EtOAc (300 mL) and washed with water (250 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 22% EtOAc / petroleum ether) to obtain 16.7 g (yield 54.0%) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =556.

[1022] Step 3: 5-Bromo-2-fluoro-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline

[1023] Under nitrogen, a solution of 5-bromo-2-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)aniline (1.01 g, 1.82 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.46 g, 18.0 mmol) and CuI (3.42 g, 18.0 mmol) in DMF (10 mL) was stirred at 90 ° C for 24 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (35 mL × 4). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by C18 column (solvent gradient: water containing 0% to 85% ACN (0.05% NH4HCO3)) to obtain 460 mg (yield 51.3%) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =498.

[1024] Step 4: 2-Fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[1025] Under nitrogen, a solution of 5-bromo-2-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)aniline (321 mg, 0.640 mmol), Pin2B2 (327 mg, 1.29 mmol), Pd(dppf)Cl2 (99.1 mg, 0.131 mmol) and KOAc (189 mg, 1.93 mmol) in 1,4-dioxane (2 mL) was stirred at 110 ° C for 1 h. The mixture was then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 12% EtOAc / petroleum ether) to give 160 mg (yield 45.5%) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M + H] + =546.

[1026] Intermediate 23: 2-Fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[1027]

[1028] Under nitrogen, a solution of 5-bromo-2-fluoro-3-methyl-aniline (101 mg, 0.493 mmol), Pin2B2 (253 mg, 0.996 mmol), KOAc (145 mg, 1.48 mmol) and Pd(dppf)Cl2 (38.4 mg, 0.0500 mmol) in 1,4-dioxane (3 mL) was stirred at 110 ° C for 3 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0% to 8%) to give 184 mg (crude, containing some Pin2B2) of the title compound as a yellow oil that was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =251.

[1029] Intermediate 24: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol

[1030]

[1031] Under nitrogen, a solution of 4-bromonaphthalene-2-ol (400 mg, 1.79 mmol), Pin2B2 (911 mg, 3.59 mmol), Pd(dppf)Cl2 (275 mg, 0.360 mmol) and KOAc (527 mg, 5.38 mmol) in 1,4-dioxane (2 mL) was stirred at 110 ° C for 2 h. The mixture was then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 15% EtOAc / petroleum ether) to give 335 mg (yield 92%) of the title compound as a white solid. LC-MS: (ESI, m / z): [M + H] + =271. 1 H NMR (300MHz, DMSO-d6, ppm): δ9.66 (s, 1H), 8.49 (d, J = 8.3Hz, 1H), 7.70 (d, J = 9Hz, 1H), 7.5 (d, J = 3Hz, 1H), 7.42-7.24 (m, 3H), 1.38 (s, 12H).

[1032] Intermediate 25: 2-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[1033]

[1034] Step 1: N-(5-bromonaphthalen-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine

[1035] Under nitrogen, LiHMDS (451 mL, 1 M in THF) was added to a solution of 5-bromonaphthalene-1-amine (45.3 g, 204 mmol) in THF (500 mL) at -78 ° C and stirred at 20 ° C for 3 h. The solution was then cooled back to -78 ° C. TMSCl (48.7 g, 448 mmol) was added at -78 ° C. The mixture was naturally warmed to 20 ° C and stirred at 20 ° C for 3 h. The mixture was then concentrated under vacuum. The residue was treated with hexane. The solid was filtered out. The filtrate was concentrated under vacuum to obtain 87.1 g (crude) of the title compound as a red oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M + H] + = 443. 1 H-NMR (300MHz, CDCl3, ppm) δ8.21–8.16(m,1H),7.97–7.84(m,2H),7.63–7.55(m,1H),7.49–7.41(m,1H),7.22–7.17(m,1H),0.04(s,21H).

[1036] Step 2: N-(5-fluoronaphthalen-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silylamine

[1037] Under nitrogen, n-BuLi (148 mL, 2.5 M in n-hexane) was added to a solution of N-(5-bromonaphthalene-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silaneamine (87.2 g, 238 mmol) in THF (800 mL) at -78 ° C and stirred for 20 min at -78 ° C. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (121 g, 382 mmol) was then added at this temperature. The reaction mixture was naturally warmed to room temperature and stirred at this temperature for 1 h. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 100% petroleum ether) to obtain 45.1 g (62.1%) of the title compound as a light red syrup. LC-MS:(ESI,m / z):[M+H] + =203.

[1038] Step 3: 5-Fluoronaphthalen-1-amine

[1039] To a solution of N-(5-fluoronaphthalen-1-yl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine (45.1 g, 148 mmol) in MeOH (300 mL) was added aqueous HCl (40 mL, 1 M) and stirred at room temperature for 10 min. The mixture was then concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (gradient: water (0.1% TFA) containing 0% to 65% acetonitrile) to give 23.4 g (98.4% yield) of the title compound as a brown solid. LC-MS: (ESI, m / z): [M+H] + =162. 1 H-NMR (300MHz, CDCl3, ppm) δ7.69–7.55(m,2H),7.47–7.26(m,2H),7.20–7.11(m,1H),6.88–6.83(m,1H),4.20(s,2H).

[1040] Step 4: 2,4-Dibromo-5-fluoronaphthalen-1-amine

[1041] To a solution of 5-fluoronaphthalene-1-amine (10.0 g, 62.0 mmol) in HOAc (100 mL) was added a solution of bromine (21.4 g, 134 mmol) in HOAc (100 mL) at 0 ° C. The mixture was then stirred at 70 ° C for 3 h. Cooled to room temperature. The solid was collected by filtration and washed with HOAc (300 mL). The solid was then suspended in NaOH (15%, 200 mL) and stirred for 20 min. The solid was collected by filtration and washed with water (200 mL) and dried under vacuum to give 20.1 g (crude) of the title compound as a black solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M + H] + =318. 1 H-NMR (300MHz, CDCl3, ppm) δ7.85(s,1H),7.65–7.59(m,1H),7.51–7.39(m,1H),7.32–7.22(m,1H),4.67(br s,2H).

[1042] Step 5: 5-Bromo-6-fluoronaphtho[1,2-d][1,2,3]oxadiazole

[1043] To a solution of 2,4-dibromo-5-fluoronaphthalen-1-amine (18.0 g, 56.4 mmol) in propionic acid (45.0 mL, 603 mmol) and HOAc (360 mL) was added NaNO2 (5.84 g, 84.6 mmol) at 0°C. The mixture was then stirred at 0°C for 50 min, warmed to 20°C and stirred for 1.5 h. The solid was collected by filtration, washed with water (200 mL), and dried under vacuum to give 10.9 g (crude) of the title compound as a brown solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =269. 1 H-NMR (300MHz, CDCl3, ppm) δ7.59–7.50(m,1H),7.20(s,1H),7.14–6.99(m,2H).

[1044] Step 6: 4-Bromo-5-fluoronaphthalen-2-ol

[1045] To a solution of 5-bromo-6-fluoronaphtho[1,2-d][1,2,3]oxadiazole (10.9 g, 40.8 mmol) in EtOH (150 mL) and THF (75 mL) was added NaBH4 (3.15 g, 82.9 mmol) at 0°C. The mixture was then stirred at room temperature for 1.5 h and quenched with NaHSO4 (125 mL, 10% in water). Most of the EtOH was removed under vacuum. The residual reaction mixture was extracted with EtOAc (3×150 mL). The combined organic phases were washed with water (150 mL), brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 55% EtOAc / petroleum ether) to give 5.10 g (yield 51.8%) of the title compound as a brown solid. LC-MS: (ESI, m / z): [M+H] + =241. 1 H-NMR (300MHz, CDCl3, ppm) δ7.56–7.43(m,2H),7.42–7.33(m,1H),7.22–7.02(m,2H).

[1046] Step 7: 1-Bromo-8-fluoro-3-(methoxymethoxy)naphthalene

[1047] To a solution of 4-bromo-5-fluoronaphthalene-2-ol (4.11 g, 17.0 mmol) in DCM (42.0 mL) was added MOMBr (3.82 g, 30.6 mmol) and DIPEA (5.52 g, 42.7 mmol) at 0 ° C. It was stirred for 0.5 h at 0 ° C. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 15% EtOAc / petroleum ether) to obtain 4.12 g (yield 84.4%) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M + H] + =299. 1 H-NMR (300MHz, CDCl3, ppm) δ7.64–7.50(m,2H),7.45–7.34(m,2H),7.15–7.05(m,1H),5.29(s,2H),3.54(s,3H).

[1048] Step 8: 2-(8-Fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[1049] Under nitrogen, a solution of 1-bromo-8-fluoro-3-(methoxymethoxy)naphthalene (5.1 g, 17.9 mmol), Pin2B2 (11.4 g, 44.9 mmol), Pd(dppf)Cl2 (1.38 g, 1.80 mmol) and KOAc (5.28 g, 53.8 mmol) in 1,4-dioxane (100 mL) was stirred at 110 ° C for 4 h. Cooled to room temperature. The resulting reaction mixture was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 25% EtOAc / petroleum ether) to give 7.60 g (containing 45% Pin2B2) of the title compound as a white solid, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M + H] + =333. 1 H-NMR (300MHz, CDCl3, ppm) δ7.54–7.49(m,1H),7.45–7.24(m,3H),7.07–6.99(m,1H),5.31(s,2H),3.52(s,3H),1.46(s,12H).

[1050] Intermediate 26: Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane

[1051]

[1052] Step 1: 3-(Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate

[1053] To a solution of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol (1.00g, 2.60mmol) and N-(4-chlorophenyl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.23g, 3.13mmol) in THF (10mL) was added NaH (114.6mg, 2.86mmol, 60% in oil) at 0°C. The reaction mixture was stirred at room temperature for 1h. The resulting reaction mixture was diluted with water (30mL) and extracted with EtOAc (150mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 15% EtOAc / petroleum ether) to obtain the title compound (1.41g, 92.7% yield) as a yellow oil. LC-MS:(ESI,m / z):[M+H] + =580. 1 H-NMR (300MHz, CDCl3, ppm) δ7.81–7.70(m,2H),7.51–7.39(m,2H),7.35–7.31(m,1H),5.31(s,2H),3.54(s,3H),1.27–1.13(m,21H).

[1054] Step 2: Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane

[1055] Under nitrogen, a solution of 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (1.12 g, 2.17 mmol), Pin2B2 (1.65 g, 6.50 mmol), Pd(dppf)Cl2 (166.7 mg, 0.22 mmol) and KOAc (745 mg, 7.59 mmol) in toluene (11 mL) was stirred at 110 ° C overnight. The mixture was partitioned between EtOAc and water. The organic phase was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% EtOAc / petroleum ether) to give 833 mg (yield 77.7%) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M + H] + =558. 1 H-NMR (300MHz, CDCl3, ppm) δ7.76–7.66 (m, 2H), 7.49 (d, J = 2.6Hz, 1H), 7.42 –7.32(m,2H),5.30(s,2H),3.52(s,3H),1.45(s,12H),1.23–1.15(m,21H).

[1056] Intermediate 27: 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[1057]

[1058] Step 1: 8-Ethyl-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate

[1059] Under nitrogen, DIPEA (2.22 g, 17.2 mmol) and Tf2O (1.82 g, 6.45 mmol) were added to a solution of 8-ethyl-3-(methoxymethoxy)naphthalene-1-ol (1.00 g, 4.31 mmol) in DCM (15 mL) at -40 ° C. The resulting solution was stirred for 1 h at -40 ° C. and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 15% EtOAc / petroleum ether) to obtain 1.41 g (89.3% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + = 365. 1 H-NMR (300MHz, CDCl3, ppm) δ7.69–7.63(m,1H),7.50–7.39(m,2H),7.37–7. 25(m,2H),5.32(s,2H),3.55(s,3H),3.32–3.22(m,2H),1.35–1.28(m,3H).

[1060] Step 2: 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[1061] Under nitrogen, a solution of 8-ethyl-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (1.41 g, 3.87 mmol), Pin2B2 (2.95 g, 11.6 mmol), Pd(dppf)Cl2 (298 mg, 0.390 mmol) and KOAc (949 mg, 9.67 mmol) in 1,4-dioxane (15 mL) was stirred at 110 ° C overnight. The mixture was partitioned between EtOAc and water. The organic phase was concentrated under vacuum. The residue was purified by silica gel flash chromatography (gradient: 0% to 15% EtOAc / petroleum ether) to give 872 mg (65.8% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M + H] + = 343. 1 H-NMR (300MHz, CDCl3, ppm) δ7.65–7.58(m,1H),7.46–7.34(m,3H),7.30–7.25(m,1 H),5.31(s,2H),3.53(s,3H),3.26–3.16(m,2H),1.46(s,12H),1.42–1.34(m,3H).

[1062] Intermediate 28: N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[1063]

[1064] Step 1: 3-Bromo-N,N-bis(4-methoxybenzyl)-5-methylaniline

[1065] Under nitrogen, NaH (324 mg, 8.10 mmol, 60% in mineral oil) was added to a solution of 3-bromo-5-methyl-aniline (500 mg, 2.69 mmol) in DMF (5 mL) at 0 ° C. Stir for 0.5 hours. PMBCl (1.05 g, 6.69 mmol) was then added and stirred at room temperature for 12 hours. The reaction was quenched with NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% ethyl acetate / petroleum ether) to obtain the title compound (441 mg, 87.8% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =426 / 428.

[1066] Step 2: 3-Bromo-4-iodo-N,N-bis(4-methoxybenzyl)-5-methylaniline

[1067] To a solution of 3-bromo-N, N-bis[(4-methoxyphenyl)methyl]-5-methyl-aniline (2.00 g, 4.69 mmol) in DMF (20 mL) was added NIS (1.58 g, 7.03 mmol) and TsOH (96.0 mg, 0.560 mmol) in portions at room temperature. The resulting solution was stirred at room temperature for 20 min and then quenched with a Na2S2O3 aqueous solution. The solution was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 18% ethyl acetate / petroleum ether) to give the title compound (1.58 g, 50.6% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =552 / 554.

[1068] Step 3: 3-Bromo-N,N-bis(4-methoxybenzyl)-5-methyl-4-(trifluoromethyl)aniline

[1069] Under nitrogen, a solution of 3-bromo-4-iodo-N,N-bis[(4-methoxyphenyl)methyl]-5-methyl-aniline (1.58 g, 2.86 mmol), 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (1.82 mL, 14.3 mmol) and CuI (547 mg, 2.86 mmol) in DMF (15 mL) was stirred at 90 ° C for 1 hour. The reaction mixture was partitioned between EtOAc and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% ethyl acetate / petroleum ether) to give the title compound (695 mg, 43.2% yield) as a yellow solid. LC-MS: (ESI, m / z): [M + H] + =494 / 496.

[1070] Step 4: N,N-bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[1071] Under nitrogen, a solution of 3-bromo-N,N-bis[(4-methoxyphenyl)methyl]-5-methyl-4-(trifluoromethyl)aniline (100 mg, 0.2 mmol), Pin2B2 (153.6 mg, 0.600 mmol), PdCl2(dppf) (15.0 mg, 0.0200 mmol) and KOAc (59.3 mg, 0.610 mmol) in 1,4-dioxane (10 mL) was stirred at 100 ° C for 3 hours. The mixture was then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% ethyl acetate / petroleum ether) to give the title compound (33.0 mg, 22.7% yield) as a yellow solid. LC-MS: (ESI, m / z): [M + H] + =542.

[1072] Intermediate 29: 2,3-Difluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[1073]

[1074] Step 1: 5-Bromo-2,3-difluoro-N,N-bis(4-methoxybenzyl)aniline

[1075] Under nitrogen, NaH (384 mg, 9.6 mmol, 60% in mineral oil) was added to a solution of 5-bromo-2,3-difluoro-aniline (500 mg, 2.40 mmol) in DMF (10 mL) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. PMBCl (1.13 g, 7.21 mmol) was then added and stirred at room temperature for 4 hours. The reaction was quenched with NH4Cl aqueous solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 5% ethyl acetate / petroleum ether) to obtain the title compound (900 mg, 84.6% yield) as an oil. LC-MS: (ESI, m / z): [M+H] + =448.

[1076] Step 2: 5-Bromo-2,3-difluoro-4-iodo-N,N-bis(4-methoxybenzyl)aniline

[1077] A solution of 5-bromo-2,3-difluoro-N,N-bis[(4-methoxyphenyl)methyl]aniline (900 mg, 2.01 mmol) and NIS (676 mg, 3.02 mmol) in acetic acid (10 mL) was stirred at room temperature for 2 hours. The mixture was then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 5% ethyl acetate / petroleum ether) to give the title compound (800 mg, 69.4% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =574.

[1078] Step 3: 5-Bromo-2,3-difluoro-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline

[1079] Under nitrogen, to a solution of 5-bromo-2,3-difluoro-4-iodo-N,N-bis[(4-methoxyphenyl)methyl]aniline (900mg, 1.57mmol) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (1.50g, 7.85mmol) in DMA (9mL) was added CuI (300mg, 1.57mmol) at room temperature. The reaction mixture was stirred for 4 hours at 90°C. The reaction mixture was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% ethyl acetate / petroleum ether) to give the title compound (600mg, 74.1% yield) as a brown oil. LC-MS: (ESI, m / z): [M+H] + =516.

[1080] Step 4: 2,3-Difluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[1081] Under nitrogen, a solution of 5-bromo-2,3-difluoro-N,N-bis[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)aniline (500 mg, 0.970 mmol), Pin2B2 (739 mg, 2.91 mmol), PdCl2(dppf) (71.0 mg, 0.100 mmol) and KOAc (285 mg, 2.91 mmol) in 1,4-dioxane (5 mL) was stirred at 100 ° C for 4 hours. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% ethyl acetate / petroleum ether) to give the title compound (260 mg, 47.7% yield) as a white solid. LC-MS: (ESI, m / z): [M + H] + =564.

[1082] Intermediate 30: 3-Fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[1083]

[1084] Step 1: 3-Bromo-5-fluoro-4-iodo-N,N-bis(4-methoxybenzyl)aniline

[1085] To a solution of 3-bromo-5-fluoro-N,N-bis[(4-methoxyphenyl)methyl]aniline (600 mg, 1.39 mmol) and NIS (484 mg, 2.16 mmol) in DMF (5 mL) was added TsOH (29.0 mg, 0.170 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with a Na2S2O3 aqueous solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 25% ethyl acetate / petroleum ether) to give 200 mg (yield 25.5%) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =556.

[1086] Step 2: 3-Bromo-5-fluoro-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline

[1087] Under nitrogen, to a solution of 3-bromo-5-fluoro-4-iodo-N,N-bis[(4-methoxyphenyl)methyl]aniline (100 mg, 0.180 mmol) and CuI (46.0 mg, 0.240 mmol) in DMF (1 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (0.16 mL, 1.19 mmol) at room temperature. The resulting solution was stirred at 90 ° C for 2 hours. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient: 0% to 25% ethyl acetate / petroleum ether) to give 125 mg (crude) of the title compound as a light yellow solid. LC-MS: (ESI, m / z): [M + H] + =498.

[1088] Step 3: 3-Fluoro-N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline

[1089] Under nitrogen, a solution of 3-bromo-5-fluoro-N,N-bis[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)aniline (129 mg, 0.260 mmol), PdCl2(dppf) (19.0 mg, 0.0300 mmol), KOAc (76.0 mg, 0.780 mmol) and Pin2B2 (198 mg, 0.780 mmol) in 1,4-dioxane (2 mL) was stirred at 110 ° C overnight. The resulting solution was diluted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (solvent gradient: water containing 0% to 60% ACN (0.05% NH4HCO3)) to give 50 mg (yield 35.4%) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H] + =546.

[1090] Intermediate 31: 2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[1091]

[1092] Step 1: 3-Bromo-2,6-difluoro-5-methylbenzoic acid

[1093] Under nitrogen, LDA (3.14 mL, 6.28 mmol, 2 mol / L in THF) was added to a stirred solution of 1-bromo-2,4-difluoro-5-methylbenzene (1.00 g, 4.83 mmol) in THF (25 mL) at -85 ° C. The solution was stirred for 2 h at -85 ° C. The reaction mixture was then poured into a solution of dry ice (250 g) in THF (25 mL). The resulting solution was stirred at room temperature for 1 h. The reaction was quenched with NH4Cl solution (100 mL). THF was removed under reduced pressure, and the residual solution was acidified to pH = 1 with 1 mol / L HCl solution. The solid was collected by filtration and washed with H2O to obtain the title compound (980 mg, 80.8% yield) as a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ14.14(s,1H),7.90–7.77(m,1H),2.23(s,3H).

[1094] Step 2: tert-Butyl (3-bromo-2,6-difluoro-5-methylphenyl)carbamate

[1095] A solution of 3-bromo-2,6-difluoro-5-methyl-benzoic acid (2.00 g, 7.97 mmol), diphenylphosphoryl azide (3.28 g, 11.9 mmol) and triethylamine (1.62 g, 16.0 mmol) in 2-methyl-2-propanol (50 mL) was stirred at 90 ° C overnight and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% EtOAc / petroleum ether) to give (2.00 g, 77.9% yield) the title compound as a white solid. LC-MS: (ESI, m / z): [MH] + =320.

[1096] Step 3: 3-Bromo-2,6-difluoro-5-methylaniline

[1097] A solution of tert-butyl N-(3-bromo-2,6-difluoro-5-methyl-phenyl)carbamate (2.00 g, 6.21 mmol) and HCl (30 mL, 4 mol / L in dioxane) in dichloromethane (30 mL) was stirred at room temperature for 5 h. The mixture was then concentrated under reduced pressure. The residue was distributed between saturated NaHCO (aqueous solution) and EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 20% EtOAc / petroleum ether) to obtain (1 g, 77.9% yield) the title compound as a white solid. LC-MS: (ESI, m / z): [M+1+MeCN] + =263.

[1098] Step 4: 2,6-difluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[1099] Under nitrogen, Pin2B2 (515 mg, 2.03 mmol), Pd(dppf)Cl2 (98.9 mg, 0.140 mmol) and KOAc (265 mg, 2.70 mmol) were added to a stirred solution of 3-bromo-2,6-difluoro-5-methyl-aniline (300 mg, 1.35 mmol) in 1,2-dimethoxyethane (DME) (10 mL) at room temperature. The resulting solution was stirred at 90 ° C. overnight. The mixture was then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0% to 20% EtOAc / petroleum ether) to give the title compound (310 mg, 85.3% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+1+MeCN] + =311.

[1100] Intermediate 32: ((3S)-3-Fluoro-1-azabicyclo[3.2.0]heptane-5-yl)methanol

[1101]

[1102] Step 1: 1-(tert-Butyl)2-methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-1,2-dicarboxylate

[1103] Under nitrogen, to a solution of (2S, 4R)-4-fluoropyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (5.00 g, 20.2 mmol) and HMPA (10.9 g, 60.9 mmol) in tetrahydrofuran (70 mL) was added THF (60.7 mL, 60.7 mmol, 1 M) containing LiHMDS at -78 ° C. The resulting solution was stirred at -78 ° C for 1 h. 1-bromo-2-chloroethane (8.36 mL, 100 mmol) was then added. The resulting solution was stirred at room temperature for 1 h. The mixture was quenched with NH4Cl (aqueous solution) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 100% EtOAc / petroleum ether) to obtain 1.26 g (yield 20.1%) of the title compound as a colorless oil. LC-MS:(ESI,m / z):[M+H] + =310.

[1104] Step 2: Methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-2-carboxylate

[1105] To a solution of 1-(tert-butyl)-2-methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-1,2-dicarboxylate (1.26 g, 3.87 mmol) in dichloromethane (10 mL) was added TFA (5 mL). The resulting solution was stirred at room temperature for 30 min. The solvent was evaporated under vacuum to give 2 g (crude) of the title compound as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =210.

[1106] Step 3: Methyl (3S)-3-fluoro-1-azabicyclo[3.2.0]heptane-5-carboxylate

[1107] A solution of methyl (4R)-2-(2-chloroethyl)-4-fluoropyrrolidine-2-carboxylate (2.00 g, 3.82 mmol) and KCO (1.60 g, 11.6 mmol) in acetonitrile (30 mL) was stirred at 85° C. for 1 h. The solid was filtered off. The filtrate was concentrated under vacuum to give 2.9 g (crude) of the title compound as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =174.

[1108] Step 4: ((3S)-3-Fluoro-1-azabicyclo[3.2.0]hept-5-yl)methanol

[1109] Under nitrogen, to a solution of (3S)-3-fluoro-1-azabicyclo[3.2.0]heptane-5-carboxylic acid methyl ester (2.90 g, 16.7 mmol) in tetrahydrofuran (20 mL) was added LiAlH4 in THF (16.7 mL, 16.7 mmol, 1 M) at 0°C. The resulting solution was stirred at 0°C for 30 min. The mixture was quenched with Na2SO4.10H2O and filtered. The solvent was removed by blowing N2 (volatiles) to give 2 g (crude product) as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =146.

[1110] Intermediate 33: ((7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine]-7a'(5'H)-yl)methanol.

[1111] Step 1: (R)-2-Methylene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester and (S)-2-Methylene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid ethyl ester

[1112]

[1113] Ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (19.9 g) was separated by chiral SFC (column: CHIRALPAK 1H, 50×250 mm; mobile phase A: CO 2 , mobile phase B: EtOH; flow rate: 150 mL / min; gradient: 26% B; 220 nm; RT1: 4.8; RT2: 6.43; injection volume: 1.8 ml; run number: 122) to give (R)-ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (7.61 g, faster peak) and (S)-ethyl 2-methylene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-carboxylate (7.29 g, slower peak). LC-MS: (ESI, m / z): [M+H] + =210. 1 H NMR (400 MHz, chloroform-d) δ 5.12–5.00 (m, 2H), 4.32–4.28 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.73 (d, J = 15.7 Hz, 1H), 3.06 (d, J = 15.7 Hz, 1H), 2.85–2.72 (m, 1H), 2.66–2.57 (m, 1H), 2.53–2.41 (m, 2H), 2.19–2.08 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H). The H NMR spectra of the two isomers were identical.

[1114] Step 2: (7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester

[1115]

[1116] Under nitrogen, to a solution of (S)-2-methylene-5-oxotetrahydro-1H-pyrrolazine-7a(5H)-ethyl carboxylate (200 mg, 0.960 mmol) and NaI (71.7 mg, 0.480 mmol) in THF (5 mL) was added TMSCF3 (476 mg, 3.35 mmol) at room temperature. The resulting solution was stirred at 65 ° C for 2.5 h. The solution was diluted with DCM, washed with sodium thiosulfate solution, and dried over Na2SO4. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 35% ethyl acetate / petroleum ether) to obtain a faster peak 95.0 mg (yield 38.3%) and (gradient: 35% to 90% ethyl acetate / petroleum ether) to obtain a slower peak 108 mg (yield 43.6%) as a yellow solid. LC-MS:(ESI,m / z):[M+H] + = 260. Faster peak: 1 H NMR (300 MHz, DMSO-d6, ppm) δ 4.25-4.19 (m, 2H), 3.80–3.70 (m, 1H), 3.04 (d, J = 12.1, 3.5 Hz, 1H), 2.62-2.58 (m, 1H), 2.51–2.12 (m, 5H), 1.60 (t, J = 9.3 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H). Slower peaks: 1 H NMR(300MHz,DMSO-d6,ppm)δ4.24–4.08(m,2H),3.61(d,J=11.7,2.7Hz,1H),3.11(d,J=11 .6Hz,1H),2.72–2.54(m,1H),2.44–2.13(m,5H),1.79-1.58(m,2H),1.22(t,J=7.1Hz,3H).

[1117] Step 2: ((7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-yl)methanol

[1118] To a solution of (7a'S)-2,2-difluoro-5'-oxodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'H)-carboxylic acid ethyl ester (95.0 mg, 0.370 mmol, faster peak from the previous step) in THF (2.5 mL) was added LiAlH4 (1.1 mL, 1 M in THF) under nitrogen. The solution was stirred at 65 ° C for 1 hour. The reaction was cooled to room temperature and quenched with Na2SO4·10H2O. After filtration, the filtrate was concentrated under reduced pressure to give 42.0 mg (yield 56.4%) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M + H] + =204.

[1119] Intermediate 34: (Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (mixture of trans isomers)

[1120]

[1121] Step 1: Diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (mixture of trans isomers)

[1122] To a solution of cis-1-benzylpyrrolidine-2,5-dicarboxylic acid diethyl ester (8.60 g, 28.2 mmol) in tetrahydrofuran (120 mL) was added LiHMDS (43.4 mL, 56.4 mmol) at -35 ° C. After 1 h, the reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 15% ethyl acetate / petroleum ether) to obtain 1.27 g (yield 14%) of the title compound as a light yellow oil. The cis isomer (6.3 g) was recovered. LC-MS: (ESI, m / z): [M+H] + =306.2. 1 H NMR (300MHz, DMSO-d6, ppm) δ7.32–7.20(m,5H),4.13–3.87(m,6H),3.75–3.60(m,3H),2.25–2.11(m,2H),1.91–1.75(m,2H),1.25–1.06(m,3H).

[1123] Step 2: (1-Benzylpyrrolidine-2,5-diyl)dimethanol (mixture of trans isomers)

[1124] To an ice-cooled solution of trans-1-benzylpyrrolidine-2,5-dicarboxylic acid diethyl ester (2.30 g, 7.53 mmol) in tetrahydrofuran (30 mL) under nitrogen was added LiAlH4 (716 mg, 18.8 mmol) in several batches. The reaction was warmed to room temperature. After 2 h, the mixture was quenched with Na2SO4·10H2O. The solid was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% MeOH / DCM) to give 1.65 g (yield 99%) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =222.1. 1 H NMR(400MHz,DMSO-d6,ppm)δ7.38–7.15(m,5H),4.34(s,2H),3.95–3.82(m,2H),3.46–3 .36(m,2H),3.28–3.20(m,2H),3.01–2.90(m,2H),1.90–1.75(m,2H),1.71–1.58(m,2H).

[1125] Step 3: Pyrrolidine-2,5-diyldimethanol (mixture of trans isomers)

[1126] A solution of (1-benzylpyrrolidine-2,5-diyl)dimethanol (0.60 g, 2.7 mmol) and Pd / C (180 mg, 10% w / w) in methanol (10 mL) was stirred at room temperature for 2 h under hydrogen (1 atm). The catalyst was filtered and the filtrate was concentrated to give 405 mg (crude) of the title compound as a light yellow oil. LC-MS: (ESI, m / z): [M+H] + = 132.1. The crude product was used directly without further purification.

[1127] Step 4: 1-(2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-2-bromoethan-1-one (mixture of trans isomers)

[1128] To an ice-cooled solution of pyrrolidine-2,5-diyldimethanol (355 mg, 2.71 mmol) and N-methylmorpholine (410 mg, 4.06 mmol) in tetrahydrofuran (10 mL) was added 2-bromoacetyl bromide (539 mg, 2.67 mmol). After 1 h, the reaction was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% MeOH / DCM) to give 130 mg (yield 19%) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =252.1. 1H NMR (400MHz, DMSO-d6, ppm) δ5.03 (s, 1H), 4.71 (s, 1H), 4.24 (d, J = 11.4Hz, 1H), 4. 09–3.99(m,1H),3.92–3.87(m,2H),3.69(s,2H),3.17(s,2H),2.04–1.72(m,4H).

[1129] Step 5: 6-(Hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (mixture of trans isomers)

[1130] To an ice-cooled suspension of NaH (65.0 mg, 1.63 mmol, 60% in mineral oil) in tetrahydrofuran (5 mL) was added 1 mL of THF containing 1-(2,5-bis(hydroxymethyl)pyrrolidin-1-yl)-2-bromoethyl-1-one (130 mg, 0.517 mmol). After 1 h, the resulting solution was warmed to room temperature for 3 h. The reaction was diluted with water and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% MeOH / DCM) to give the title compound as an oil (37.0 mg, 42% yield). LC-MS: (ESI, m / z): [M+H] + =172.2. 1 H NMR (400MHz, DMSO-d6, ppm) δ4.88–4.82(m,1H),4.14–3.97(m,3H),3.84(d,J=16Hz,1H),3.71–3.61(m ,1H),3.59–3.48(m,2H),3.23–3.15(m,1H),2.03–1.87(m,2H),1.82–1.66(m,1H),1.39–1.19(m,1H).

[1131] Step 6: (Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (mixture of trans isomers)

[1132] To a suspension of ice-cold LiAlH4 (27.3 mg, 0.720 mmol) in tetrahydrofuran (5 mL) under nitrogen was added 0.5 mL of THF containing 6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (60.0 mg, 0.350 mmol). The resulting solution was warmed to 60 ° C for 2 h. The reaction was cooled to room temperature and quenched with Na2SO4·10H2O. The solid was filtered and the filtrate was concentrated to give the title compound as a light yellow oil (60 mg, crude product). LC-MS: (ESI, m / z): [M + H] + = 158.1 The crude product was used in the next step without further purification.

[1133] Intermediate 34A: ((6S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol

[1134]

[1135] Step 1: Diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (mixture of trans isomers)

[1136] To a solution of cis-1-benzylpyrrolidine-2,5-dicarboxylic acid diethyl ester (8.60 g, 28.2 mmol) in tetrahydrofuran (120 mL) was added LiHMDS (43.4 mL, 56.4 mmol) at -35 ° C. After 1 h, the reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 15% ethyl acetate / petroleum ether) to obtain 1.27 g (yield 14%) of the title compound as a light yellow oil. The cis isomer (6.3 g) was recovered. LC-MS: (ESI, m / z): [M+H] + =306.2. 1 H NMR (300MHz, DMSO-d6, ppm) δ7.32–7.20(m,5H),4.13–3.87(m,6H),3.75–3.60(m,3H),2.25–2.11(m,2H),1.91–1.75(m,2H),1.25–1.06(m,3H).

[1137] Step 2: (1-Benzylpyrrolidine-2,5-diyl)dimethanol (mixture of trans isomers)

[1138] To an ice-cooled solution of trans-1-benzylpyrrolidine-2,5-dicarboxylic acid diethyl ester (2.30 g, 7.53 mmol) in tetrahydrofuran (30 mL) under nitrogen was added LiAlH4 (716 mg, 18.8 mmol) in several batches. The reaction was warmed to room temperature. After 2 h, the mixture was quenched with Na2SO4·10H2O. The solid was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% MeOH / DCM) to give 1.65 g (yield 99%) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =222.1. 1 H NMR(400MHz,DMSO-d6,ppm)δ7.38–7.15(m,5H),4.34(s,2H),3.95–3.82(m,2H),3.46–3 .36(m,2H),3.28–3.20(m,2H),3.01–2.90(m,2H),1.90–1.75(m,2H),1.71–1.58(m,2H).

[1139] Step 3: Pyrrolidine-2,5-diyldimethanol (mixture of trans isomers)

[1140] A solution of (1-benzylpyrrolidine-2,5-diyl)dimethanol (0.60 g, 2.7 mmol) and Pd / C (180 mg, 10% w / w) in methanol (10 mL) was stirred at room temperature for 2 h under hydrogen (1 atm). The catalyst was filtered and the filtrate was concentrated to give 405 mg (crude) of the title compound as a light yellow oil. LC-MS: (ESI, m / z): [M+H] + = 132.1. The crude product was used directly without further purification.

[1141] Step 4: (6R,8aR)-6-(Hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one and (6S,8aS)-6-(Hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one

[1142]

[1143] To a solution of pyrrolidine-2,5-diyldimethanol (7.9 g, 60.305 mmol) in IPA (300.0 mL) was added potassium trimethylsilanol (16.98 g, 132.671 mmol) at 0 ° C. 2-bromoacetyl bromide (13.27 g, 66.336 mmol) was then added. The solution was stirred at 0 ° C for 1 min. The reaction was quenched with MeOH (20 mL). The solid was filtered off and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 10% MeOH / dichloromethane) to obtain 3.9 g (a mixture of trans isomers) of the title compound as a yellow oil. The enantiomers were separated by chiral SFC using the following conditions (column: CHIRAL ART Amylose-SA, 3×25 cm, 5 μm; mobile phase: CO 2 (70%) and MeOH (0.1% 2M NH 3 -MeOH) (30%)) to give the faster peak 1.98 g and the slower peak 1.9 g (desired isomer) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =172. H-NMR-PH-GNE-VINT-073-0: 1 H NMR(300MHz, DMSO-d6)δ4.85(t,J=5.7Hz,1H),4.14-3.99(m,3H),3.84(d,J=16.5Hz,1H),3.67-3.56( m,1H),3.67-3.51(m,2H),3.23-3.16(m,1H),2.00-1.89(m,2H),1.80-1.69(m,1H),1.34-1.25(m,1H).

[1144] Step 5: ((6S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol

[1145] To a suspension of LiAlH4 (27.3 mg, 0.720 mmol) in tetrahydrofuran (5 mL) under ice-cooling nitrogen was added 0.5 mL of THF containing (6S,8aS)-6-(hydroxymethyl)tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one (60.0 mg, 0.350 mmol). The resulting solution was warmed to 60 ° C for 2 h. The reaction was cooled to room temperature and quenched with Na2SO4·10H2O. The solid was filtered and the filtrate was concentrated to give the title compound as a light yellow oil (60 mg, crude product). LC-MS: (ESI, m / z): [M + H] + = 158.1 The crude product was used in the next step without further purification.

[1146] Intermediate 35: ((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methanol

[1147]

[1148] To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (60.0 g, 257 mmol) in tetrahydrofuran (1000 mL) was added LiAlH4 (19.6 g, 515 mmol) at 0°C under nitrogen. The reaction mixture was stirred at room temperature for 1 h and then at 60°C for 2 h. The reaction mixture was cooled in an ice bath and water (20 mL) was slowly added to quench the reaction, followed by addition of 20% aqueous NaOH solution (20 mL) and 20 mL of water. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was redissolved in DCM, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: DCM (0.1% TEA) containing 0% to 15% MeOH) to obtain 12.4 g (36% yield) of the title compound as a yellow oil. LC-MS:(ESI,m / z):[M+H] + =134. 1 H NMR (300 MHz, DMSO-d 6, ppm)δ5.25–4.97(m,1H),4.44(dd,J=6.0,5.0Hz,1H),3.50–3.22(m,3H),2.57-2. 50(m,1H),2.46–2.31(m,1H),2.30(s,3H),2.07-1.87(m,1H),1.87-1.60(m,1H).

[1149] Intermediate 36: (R)-(2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol and (S)-(2-methylenetetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol

[1150]

[1151] To a solution of (S)-2-methylene-5-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid ethyl ester (110 mg, 0.510 mmol, intermediate 33, step 1) in tetrahydrofuran (5 mL) was added LiAlH4 (1.1 mL, 1 M in THF) at 0°C under nitrogen. The mixture was stirred at 70°C for 0.5 hours. The mixture was quenched with Na2SO4.10H2O and filtered. The solvent was removed by nitrogen blowing (the product had a low boiling point) to give the title compound (62.8 mg, crude product), which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =154.

[1152] Intermediate 37: 4'-((((2R,7aS)-7a-(Hydroxymethyl)hexahydro-1H-pyrrolizin-2-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile

[1153]

[1154] Step 1: 4'-(Hydroxymethyl)-[1,1'-biphenyl]-2-carbonitrile

[1155] Under nitrogen, a solution of 2-bromobenzonitrile (1.25 g, 6.87 mmol), Pd(PPh 3 ) 4 (793 mg, 0.690 mmol), 4-(hydroxymethyl)phenylboronic acid (1.15 g, 7.55 mmol), K 2 CO 3 (1.90 g, 13.8 mmol) and water (5 mL) in 1,2-dimethoxyethane (50 mL) was stirred at 100 ° C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 30% EtOAc / petroleum ether) to obtain the title compound (1.26 g, 87.7% yield) as a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ8.00–7.90(m,1H),7.85–7.75(m,1H),7.69–7.51(m,6H),5.75(s,1H),4.69(s,2H).

[1156] Step 2: Methanesulfonic acid (2'-cyano-[1,1'-biphenyl]-4-yl)methyl ester

[1157] Under nitrogen, to a solution of 2-[4-(hydroxymethyl)phenyl]benzonitrile (235 mg, 1.12 mmol)] and N,N-diisopropylethylamine (0.58 mL, 3.36 mmol) in dichloromethane (10 mL) at 0°C was added methanesulfonic anhydride (254 mg, 1.46 mmol). The resulting solution was stirred at room temperature for 2 h, diluted with CH2Cl2 and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (320 mg, crude product) as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+Na] + =310.

[1158] Step 3: 4'-((((2R,7aS)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidin-2-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile

[1159] Under nitrogen, to a solution of (2R,8S)-8-(trityloxymethyl)-1,2,3,5,6,7-hexahydropyrrolizin-2-ol (448 mg, 1.12 mmol) in tetrahydrofuran (4 mL) at 0°C was added NaH (269 mg, 6.73 mmol, 60% in mineral oil). The resulting solution was stirred at room temperature for 0.5 h. Then, tetrahydrofuran (4 mL) containing [4-(2-cyanophenyl)phenyl]methyl methanesulfonate (322 mg, 1.12 mmol) was added at room temperature and stirred at 50°C for 12 hours. The reaction was quenched with saturated NH4Cl solution (20 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0% to 30% EtOAc / petroleum ether) to afford the title compound (440 mg, 66.5% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =591.

[1160] Step 4: 4'-((((2R,7aS)-7a-(Hydroxymethyl)hexahydro-1H-pyrrolizin-2-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile

[1161] A solution of 4'-((((2R,7aS)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolazin-2-yl)oxy)methyl)-[1,1'-biphenyl]-2-carbonitrile (440 mg, 0.740 mmol) in 2,2,2-trifluoroacetic acid (5 mL) was stirred at room temperature for 1 h and then concentrated under vacuum. The crude product was purified by reverse phase chromatography (gradient: 0% to 60% acetonitrile in water (0.05% TFA)) to give the title compound (220 mg, 84.8% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =349.

[1162] Intermediate 38: tert-Butyl 5-(hydroxymethyl)-1,4-diazepane-1-carboxylate

[1163]

[1164] A solution of 1-tert-butoxycarbonyl-1,4-diazepane-5-carboxylic acid (200 mg, 0.820 mmol) and BH 3 ·THF (4.91 mL, 4.91 mmol, 1 M in THF) in THF (5 mL) was stirred at 40° C. for 18 hours. The reaction system was quenched with MeOH and concentrated under vacuum to give the title compound 130 mg (crude) as a yellow oil, which was used in the next step without further purification. LC-MS: (ESI, m / z): [M+H] + =231.

[1165] Intermediate 39: tert-Butyl (1R,2S,5R)-2-(hydroxymethyl)-3,6-diazabicycl...

Claims

1. A compound of formula (I): or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together form a 6-membered or 7-membered ring A; p is 0, 1, or 2; R 1 With formula Where X 1 N or CR 7C And R 7C is hydrogen or halogen; Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B CN, oxo or C 1-3 alkyl; L 1 For R L1 Substituted or unsubstituted C 1-4 Alkylene; R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl; R 2 is R containing one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 Haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbons and optionally one heteroatom selected from O and N; or Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of; R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocyclic ring; R 6A Halogen, CN, OR 6B , SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

2. The compound according to claim 1 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, wherein X 1 CR 7C And R 7C is hydrogen or halogen.

3. The compound according to claim 1 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, wherein X 1 is N.

4. A compound of formula (I): or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together form a 6-membered or 7-membered ring A; p is 0, 1, or 2; R 1 is (E2) or (E3) Each R 7A are independently hydrogen, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 Haloalkyl; L 1 For R L1 Substituted or unsubstituted C 1-4 Alkylene; R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl; R 2 is R containing one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or two R 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 Haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbons and optionally one heteroatom selected from O and N; or Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of; R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocyclic ring; R 6A Halogen, CN, OR 6B , SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

5. The compound according to claim 4 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, wherein no more than one R 7A For hydrogen.

6. The compound according to claim 4 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, wherein R 7A Not hydrogen.

7. The compound according to claim 4 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, wherein at least one R 7A It is a halogen.

8. The compound according to claim 4 or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, wherein at least one R 7A It is an unsubstituted C1-3 haloalkyl group.

9. A compound of formula (I): or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together form a 6-membered or 7-membered ring A; p is 0, 1, or 2; R 1 for L 1 For R L1 Substituted or unsubstituted C 1-4 Alkylene; R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl; R 2 is R containing one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or two R 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 Haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbons and optionally one heteroatom selected from O and N; or Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of; R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocyclic ring; R 6A Halogen, CN, OR 6B , SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

10. A compound of formula (I): or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together form a 6-membered or 7-membered ring A; p is 0, 1, or 2; R 1 For R 7A Substituted phenyl, or R 7A substituted pyridyl; Each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 Haloalkyl; L 1 For R L1 Substituted or unsubstituted C 1-4 Alkylene; R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl; R 2 is R containing one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 Haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbons and optionally one heteroatom selected from O and N; or Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of; R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocyclic ring; R 6A Halogen, CN, OR 6B , SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

11. A compound of formula (I): or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together form a 6-membered or 7-membered ring A; p is 0, 1, or 2; R 1 for L 1 For R L1 Substituted or unsubstituted C 1-4 Alkylene; R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl; R 2 is R containing one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or two R 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 Haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbons and optionally one heteroatom selected from O and N; or Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of; R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocyclic ring; R 6A Halogen, CN, OR 6B , SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

12. A compound of formula (I): or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together form a 6-membered or 7-membered ring A; p is 0, 1, or 2; R 1 With formula Each R 7A are independently halogen, CN, NH2, N(Me)2, R 7B Substituted or unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 haloalkyl, or unsubstituted cyclopropyl; R 7B CN, oxo or C 1-3 alkyl; L 1 For R L1 Substituted or unsubstituted C 1-4 Alkylene; R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl; R 2 is R containing one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or Two R's 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 Haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbons and optionally one heteroatom selected from O and N; or Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of; R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocyclic ring; R 6A Halogen, CN, OR 6B , SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

13. A compound of formula (I): or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in X is O or NR 6 ; m is 1 or 2; n is 1 or 2; wherein n and m together form a 6-membered or 7-membered ring A; p is 0, 1, or 2; R 1 for L 1 For R L1 Substituted or unsubstituted C 1-4 Alkylene; R L1 is halogen or unsubstituted C 1-3 Alkyl, or two R L1 Together they form unsubstituted C 3-4 Cycloalkyl; R 2 is R containing one or more heteroatoms selected from N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 9 are independently halogen, CN, OH, OCF3, OCHF2, OCH2F, R 10 Substituted or unsubstituted C 1-3 Alkyl, R 10 Substituted or unsubstituted C 1-3 Haloalkyl, unsubstituted C 1-3 Alkoxy, R 10 Substituted or unsubstituted C 1-3 Alkylene, or R 10 Substituted or unsubstituted C 3-4 Cycloalkyl, or R 10 Substituted or unsubstituted 3-membered or 4-membered heterocyclic ring; or Two R's 9 Together they form R 10 Substituted or unsubstituted C 3-5 Cycloalkyl, or R containing one or more oxygen atoms 10 Substituted or unsubstituted C 3-5 Heterocyclic ring; or two R 9 together forming a bridge between two carbon atoms of said cycloalkyl or heterocyclic ring, wherein said bridge comprises 1 to 3 carbons; Each R 10 are independently hydrogen, oxo, CN, halogen, or C 1-3 unsubstituted alkyl; R 3 is hydrogen, -CN, halogen, unsubstituted C 1-3 Alkyl, or unsubstituted cyclopropyl; Each R 4 are independently hydrogen, methyl or C 1-3 Haloalkyl; R 5 are independently halogen, oxo, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 haloalkyl; or wherein Two R's 5 together form a bridge between two carbon atoms of ring A, wherein the bridge comprises 1 to 3 carbons and optionally one heteroatom selected from O and N; or Two R's 5 Together, they form a bridge between two carbon atoms of ring A, wherein the bridge comprises O or NR 11 one of; R 11 is hydrogen, C(O)CH3, or unsubstituted C 1-3 alkyl; R 6 is hydrogen, R 6A Substituted or unsubstituted C 1-6 Alkyl, R 6A Substituted or unsubstituted C 1-6 Haloalkyl, R 6A Substituted or unsubstituted C 1-6 Alkenyl, R 6A Substituted or unsubstituted C 1-6 Alkynyl, or R 6A a substituted or unsubstituted 3- to 4-membered heterocyclic ring; R 6A Halogen, CN, OR 6B , SR 6C 、S(O)2R 6C 、C(O)R 6B , unsubstituted C 1-3 Alkyl, unsubstituted C 1-3 Haloalkyl, or R 6B a substituted or unsubstituted 3- to 4-membered heterocyclic ring; and R 6B and R 6C Each independently is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

14. A compound according to any one of claims 1 to 13, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein each R 4 For hydrogen.

15. A compound according to any one of claims 1 to 13, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein one R 4 is hydrogen and one R 4 It is methyl.

16. A compound according to any one of claims 1 to 13, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen and one R 4 It is -CF3.

17. The compound according to any one of claims 1 to 3 and 12, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein each R 7A are independently halogen, NH2, unsubstituted C 1-3 Alkyl, or unsubstituted C 1-3 Halogenated alkyl.

18. A compound according to any one of claims 1 to 3, 10, 12 and 14 to 17, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein at least one R 7A is NH2.

19. A compound according to any one of claims 1 to 18, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L 1 For methylene.

20. A compound according to any one of claims 1 to 18, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L 1 For R L1 Substituted or unsubstituted C 2-3 Alkylene.

21. A compound according to any one of claims 1 to 20, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 for or a stereoisomer thereof, wherein R 9 is halogen, or R 10 Substituted or unsubstituted C 1-3 Alkylene r is an integer from 0 to 12; j is 1, 2 or 3; and k is 1 or 2.

22. A compound according to any one of claims 1 to 20, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 for or a stereoisomer thereof, wherein R 9 are independently halogen, or unsubstituted C 1-3 Alkyl; and r is 1 or 2.

23. A compound according to any one of claims 1 to 20, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 for: or a stereoisomer thereof.

24. A compound according to any one of claims 1 to 20, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 for: or a stereoisomer thereof, wherein R 9 are independently halogen, or R 10 Substituted or unsubstituted C 1-3 Alkylene; Each R 10 are independently hydrogen or halogen; and r is 1 or 2.

25. A compound according to any one of claims 1 to 20, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 for: or a stereoisomer thereof.

26. A compound according to any one of claims 1 to 20, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 for: or a stereoisomer thereof, Where X 2 CR 9 or O.

27. A compound according to any one of claims 1 to 20, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 for: or its stereoisomers, wherein X 3 CR 9 NR 9 or O.

28. A compound according to any one of claims 1 to 20, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 for: or a stereoisomer thereof.

29. A compound according to any one of claims 1 to 20, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 for:

30. A compound according to any one of claims 1 to 29, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 3 It is a halogen.

31. A compound according to any one of claims 1 to 30, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein two R 5 Together they form a bridge between two carbon atoms of ring A, wherein the bridge contains 1 to 3 carbons.

32. The compound of claim 31, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the bridge comprises 2 carbon atoms.

33. The compound of claim 31 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the bridge comprises 1 carbon atom.

34. A compound according to any one of claims 1 to 33, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is NR 6 .

35. The compound according to claim 34, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, or R 6A Substituted or unsubstituted C 1-3 alkyl.

36. The compound according to claim 34, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 6 For R 6A Substituted or unsubstituted C 1-3 alkyl.

37. A compound according to any one of claims 34 to 36, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 6A Halogen, CN, OH, OMe, OEt, OCF3, SO2Me, unsubstituted C 1-3 Alkyl, or a 4-membered heterocyclic ring.

38. The compound according to claim 34, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 6 For hydrogen.

39. A compound according to any one of claims 1 to 38, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 2 is azetidine, oxetanyl or thietane dioxide.

40. A compound according to any one of claims 1 to 13, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) comprises the following formula: or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

41. A compound according to any one of claims 1 to 13, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) comprises the following formula: or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

42. A compound selected from compounds 1 to 36, 38 to 45, 47 to 62, 64 to 108, 110 to 146 and 149 to 291 in Table 1, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

43. A compound selected from compounds 1 to 36, 38 to 45, 47 to 62, 64 to 108 and 110 to 125 in Table 1, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

44. A compound selected from compounds 126 to 146 and 149 to 291 in Table 1 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

45. A compound selected from compounds 6, 15, 24, 26, 29, 31-32, 57-59, 61-62, 64-66, 75-76, 91, 96, 104, 106, 111, 113, 118-124, 126-146, 149-156, 158-175, 181, 183, 186, 190-192, 195, 200, 204, 224-225, 228-229, 232-239, 241, 244-250, 255, 258-259 and 263 of Table 1, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

46. ​​A compound selected from compounds 6, 12-18, 23-24, 26, 29, 31-36, 57-58, 60-62, 64-77, 90-97, 100-102, 104, 108, 111, 113, 115, 118-146, 149-175, 181-183, 186-187, 190, 195, 200, 204, 224-232, 234-239, 241, 244-250, 255, 258-259 and 263 of Table 1, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

47. A compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 57-62, 64-72, 74, 76, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259 and 263 of Table 1, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

48. A compound selected from compounds 6, 12-18, 23-24, 26, 29, 31-36, 42-45, 47-48, 52, 57-58, 60-78, 84-88, 90-97, 100-104, 106, 108, 111-113, 115, 118-146, 149-175, 177-178, 181-183, 185-187, 189-192, 194-195, 197-200, 203-232, 234-250, and 252-291 of Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

49. A compound selected from compounds 6, 13-14, 16-18, 23-24, 26, 29, 31-34, 36, 42-45, 47-48, 52, 57-62, 64-72, 74, 76, 84-88, 91-104, 106-108, 111, 113, 115, 117-146, 149-154, 157, 159-174, 199, 200, 224-229, 234-241, 244-249, 255, 258-259 and 263 of Table 1, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

50. A compound selected from compounds 42 to 45, 47 to 48 and 52 in Table 1 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

51. A compound selected from compounds 112, 205 to 218, 242 to 243, 252 to 254, 261 to 262, and 264 to 291 in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

52. A pharmaceutical composition comprising a compound according to any one of claims 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

53. A method for treating cancer, the method comprising administering an effective amount of a compound according to any one of claims 1 to 51 or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52.

54. The method of claim 53, wherein the cancer is characterized by comprising a KRas mutation.

55. The method of claim 54, wherein the KRas mutation corresponds to KRas G12D mutation.

56. The method according to any one of claims 53 to 55, further comprising targeting KRas G12D Samples from patients are tested for the absence or presence of mutations.

57. The method of claim 56, wherein the patient sample shows the presence of KRas G12D After mutation, the compound, its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, or pharmaceutical composition is administered to the patient.

58. The method of any one of claims 53 to 57, wherein the cancer is histologically uncharacterized.

59. The method of any one of claims 53 to 57, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

60. The method of claim 59, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

61. The method of claim 59, wherein the cancer is pancreatic cancer.

62. The method of claim 59, wherein the cancer is colorectal cancer.

63. The method of any one of claims 53 to 62, further comprising administering at least one additional therapeutic agent.

64. The method of claim 63, 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.

65. A compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

66. A compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use in the therapeutic treatment of a disease comprising KRas G12D Uses for cancer mutations.

67. Use of a compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

68. Use of a compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a KRas G12D Mutation cancer.

69. A compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of a disease comprising KRas G12D Mutation cancer.

70. A method for modulating the activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

71. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof.

72. The method of claim 71, wherein inhibition of proliferation is measured as a decrease in cell viability of the cell population.

73. A method for inhibiting tumor metastasis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof to a subject in need thereof.

74. A compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use in modulating the activity of a KRas mutant protein.

75. A compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use in inhibiting the proliferation of a cell population.

76. The compound, stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt of claim 75, wherein inhibition of proliferation is measured as a decrease in cell viability of the cell population.

77. A compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, for use in inhibiting tumor metastasis.

78. Use of a compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating the activity of a KRas mutant protein.

79. Use of a compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the proliferation of a cell population.

80. The use of claim 79, wherein inhibition of proliferation is measured as a decrease in cell viability of the cell population.

81. Use of a compound according to any one of claims 1 to 51, or a stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

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