Oxazepine compounds and their use in the treatment of cancer - Patents.com

Abstract

Provided herein are acyclic oxazepinyl compounds useful for the treatment of cancer. TIFF2024513881001242.tif34170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international patent application claims the benefit of International Patent Application No. PCT / CN2021 / 085959, filed April 8, 2021, which is incorporated by reference in its entirety for all purposes.

[0002] FIELD OF THEINVENTION Provided herein are acyclic compounds useful for treating cancers that contain KRas mutations, compositions of such compounds, and methods of treating cancers that contain KRas mutations. [Background technology]

[0003] background Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch in central growth signaling pathways. In response to extracellular signals, Ras is catalyzed by guanine nucleotide exchange factors (GEFs), in particular the SOS1 protein, to release GDP-bound (Ras GDP ) to GTP-bound (Ras GTP ) state. GTP Ras mediates its diverse growth-stimulatory functions through direct interaction with effectors including Raf, PI3K, and Ral guanine nucleotide dissociation stimulator. The intrinsic GTPase activity of Ras then hydrolyzes GTP to GDP, terminating Ras signaling. Ras GTPase activity can be further accelerated by interaction with GTPase-activating proteins (GAPs), including the neurofibromin 1 tumor suppressor.

[0004] Mutant Ras has reduced GTPase activity, which allows Ras to remain activated, thereby promoting Ras-dependent signaling and cancer cell survival or proliferation. Mutations in Ras that affect its ability to interact with GAPs or convert GTP back to GDP result in sustained activation of the protein, resulting in sustained signals that tell cells to continue to grow and divide. These signals lead to cell growth and division, and thus hyperactive RAS signaling can ultimately lead to cancer. Mutations in any one of the three main isoforms of RAS (HRas, NRas, or KRas) genes are common events in human tumorigenesis. Of the three Ras isoforms (K, N, and H), KRas is the most frequently mutated.

[0005] The most common KRas mutations are found at residues G12 and G13 of the P loop, and at residue Q61. Mutations in Ras in cancer are associated with poor prognosis. Inactivation of oncogenic Ras in mice results in tumor regression. Thus, Ras is widely considered to be an exceptionally important oncological target.

[0006] Thus, there is an urgent need for therapies for mutant KRas-mediated cancers. Summary of the Invention

[0007] overview Solutions to the above problems, as well as other problems in the art, are provided herein.

[0008] In a first aspect, provided herein is a compound of formula (I), or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof as described herein:

[0009] In another aspect, provided herein is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof as described herein.

[0010] In another aspect, provided herein are compounds of Formula (III), (IIIa), (IIIb), (IIIc), (IIId), or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof as described herein.

[0011] In another aspect, provided herein is a compound of Formula (IV), (IVa), (IVb), or (IVc), or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, as described herein.

[0012] In another aspect, provided herein is a compound of Formula (V), (Va), (Vb), or (Vc), or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof as described herein.

[0013] In another aspect, provided herein is a compound as set forth in Table 1, or a pharma- ceutically acceptable salt thereof. Provided herein is a pharmaceutical composition comprising the variant, or a pharma- ceutically acceptable salt thereof.

[0014] In another aspect, the compounds, stereoisomers, atropisomers, tautomers, and the like described herein are

[0015] In another aspect, provided herein is a method of treating a cancer that contains a KRas mutation, comprising administering to a patient having such a cancer a compound, stereoisomer, atropisomer, tautomer, or a pharmaceutically acceptable salt thereof as described herein.

[0016] 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 described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0017] In another aspect, provided herein is a method for inhibiting proliferation of a cell population comprising contacting the cell population with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0018] 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 described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0019] In another aspect, provided herein is a method for preparing a labeled KRas mutant protein, comprising reacting a KRas mutant protein with a labeled compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, to obtain a labeled KRas mutant protein.

[0020] In another aspect, provided herein are methods of synthesizing the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition Disclosed herein are acyclic oxazepine compounds as described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, and pharmaceutical compositions thereof that, in certain embodiments, are inhibitors or modulators of mutant KRas. In certain instances, such compounds and compositions are capable of inhibiting or modulating the mutant KRas provided herein. G12V In certain examples, such compounds and compositions are mutant KRas inhibitors (i.e., pan-KRas inhibitors) or modulators provided herein. The compounds and compositions described herein are useful for treating diseases and disorders mediated by mutant KRas.

[0022] It is understood that while the disclosure herein provides enumerated embodiments, they are not intended to limit the compounds and methods described herein to those embodiments. On the contrary, the disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the disclosure as defined by the claims.

[0023] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0024] The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references mentioned herein are incorporated by reference in their entirety.

[0025] 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.

[0026] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon radical. In one example, an alkyl group is an alkyl group having 1 to 18 carbon atoms (C 1~18 In another embodiment, the alkyl radical is 1~12 , C 1~10 , C 1~8 , C 1~6 , C 1~5 , C 1~4 , or C 1~3 Examples of alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-Butyl (n-Bu, n-Butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-Butyl (s-Bu, s-Butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 , 1-heptyl and 1-octyl.

[0027] The term "oxo" means =O.

[0028] The term "alkoxy" refers to --O-alkyl.

[0029] The term "cyano" or "nitrile" refers to -C≡N or -CN.

[0030] The term "haloalkoxy" refers to -O-haloalkyl.

[0031] The terms "hydroxy" and "hydroxyl" refer to --OH.

[0032] 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 an alkylene radical having 1 to 6 carbons (C 1~6 In another example, the alkylidene radical is C 1~3 , C 1~2 , or C 1 Exemplary alkylidenes include methylidene (=CH 2 ), ethylidene (=CHCH 3 ) and propylidene (=CH-CH 2 -CH 3 ), but are not limited to these.

[0033] The term "alkenyl" means a straight or branched chain monovalent hydrocarbon having at least one carbon-carbon double bond, including groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations. In one example, an alkenyl group is an alkyl group having 2 to 18 carbon atoms (C 2~18 In another embodiment, the alkenyl radical is 2~12 , C 2~10, C 2~8 , C 2~6 , or C 2~3 Examples are ethenyl or vinyl (-CH=CH 2 ), prop-1-enyl (-CH=CHCH 3 ), prop-2-enyl (-CH 2 CH=CH 2 ), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

[0034] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In one example, an alkynyl group is an alkyl group having 2 to 18 carbon atoms (C 2~18 In another embodiment, the alkynyl radical is 2~12 , C 2~10 , C 2~8 , C 2~6 , or C 2~3 Examples include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH 3 ), prop-2-ynyl (propargyl, -CH 2 C≡CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.

[0035] The term "alkylene" refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. In one example, a divalent alkylene group is an alkylene group having 1 to 18 carbon atoms (C 1~18 In another example, the divalent alkylene group is 1~12 , C 1~10 , C 1~8 , C 1~6 , C 1~5 , C 1~4 , or C 1~3An example of an alkylene group is methylene (-CH 2 -), 1,1-ethyl (-CH(CH 3 )-), (1,2-ethyl(-CH 2 CH 2 -), 1,1-propyl (-CH(CH 2 CH 3 )-), 2,2-propyl (-C(CH 3 ) 2 -), 1,2-propyl (-CH(CH 3 )CH 2 -), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,1-dimethyleth-1,2-yl (-C(CH 3 ) 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -) etc.

[0036] The term "cycloalkyl" refers to a saturated hydrocarbon ring group. Cycloalkyl includes monocyclic, bicyclic, tricyclic, spiro and bridged saturated ring systems. In one embodiment, a cycloalkyl group contains 3 to 12 carbon atoms (C 3~12 In another embodiment, the cycloalkyl is 3~4 , C 3~5 , C 3~7 , C 3~8 , C 3~10 , or C 5~10 In another embodiment, the cycloalkyl group, as a single ring, is 3~4 , C 3~8 , C 3~6 , or C 5~6 In another example, the cycloalkyl group, as a bicycle, is 7 ~C 12 In another example, the cycloalkyl group for the spiro system is C 5~12Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary configurations 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.

[0037] The terms "heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl", or "heterocyclo" are used interchangeably and refer to any mono-, bi-, tricyclic, spiro or bridged, saturated, partially saturated, or unsaturated non-aromatic ring system having 3-20 ring atoms, where the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. If any ring atom in the ring system is a heteroatom, the system is a heterocyclic ring, regardless of the point of attachment of the ring system to the rest of the molecule. In one example, a heterocyclyl contains 3-10 ring atoms ("members") and includes mono-, bi-, tricyclic, spiro, and bridged ring systems where the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclyl contains 3-6, 5-9, 4-10, or 5-10 ring atoms. In one example, the heterocyclyl includes 1-4 heteroatoms. In one example, the heterocyclyl includes 1-3 heteroatoms. In another example, the heterocyclyl 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 heterocyclyl 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 heterocyclyl includes a 3-membered monocyclic ring. In another example, the heterocyclyl includes a 4-membered monocyclic ring. In another example, the heterocyclyl includes a 5- to 6-membered monocyclic ring. In another example, the heterocyclyl includes an 8-, 9-, or 10-membered ring. In such examples, the heterocyclyl group can be a 4,5-, 5,5-, 4,6-, 5,6-, or 6,6-fused ring system. In some embodiments, the heterocycloalkyl includes at least one nitrogen. In one example, a heterocyclyl group contains 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO 2 ), any nitrogen heteroatom may be optionally quaternized (e.g., [NR 4 ] + Cl - , [NR 4 ] + OH -Exemplary heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothio ... Dropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, 1,1-dioxoisothiazolyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydro Benzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl , pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranyl.

[0038] As used herein, "aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused or spiro rings (e.g., naphthyl or anthryl) which may or may not be aromatic. Particular aryl groups have from 6 to 14 annular (i.e., ring) carbon atoms ("C 6~14 Aryl groups are groups having a carbon atom, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 120, 132, 140, 141, 152, 163, 170, 171, 182, 193, 194, 195, 196, 197, 198, 199, 102, 103, 104, 1

[0039] The term "heteroaryl" refers to any monocyclic or bicyclic aromatic ring system containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur, and in an exemplary embodiment, at least one heteroatom is nitrogen. Any of the above heteroaryl rings are fused to an aryl ring, and any bicyclic group in which the aryl or heteroaryl ring is attached to the remainder of the molecule is included. Heteroaryl groups can have a single ring (e.g., pyridyl, furyl) or multiple fused or spiro rings (e.g., indolizinyl, benzothienyl) in which the fused or spiro rings may or may not be aromatic. In one embodiment, heteroaryl includes 5- to 6-membered monocyclic aromatic groups in which one or more ring atoms are nitrogen, sulfur, or oxygen. Exemplary heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl, and purinyl, as well as benzo-fused derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indazolyl, and indolyl.

[0040] In certain embodiments, the heterocyclyl or heteroaryl group is bonded at a carbon atom of the heterocyclyl or heteroaryl group. For example, carbon-bonded heterocyclyl groups include bonding arrangements at the 2-, 3-, 4-, 5-, or 6-position of the pyridine ring, the 3-, 4-, 5-, or 6-position of the pyridazine ring, the 2-, 4-, 5-, or 6-position of the pyrimidine ring, the 2-, 3-, 5-, or 6-position of the pyrazine ring, the 2-, 3-, 4-, or 5-position of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, the 2-, 4-, or 5-position of the oxazole, imidazole, or thiazole ring, the 3-, 4-, or 5-position of the isoxazole, pyrazole, or isothiazole ring, the 2-, or 3-position of the aziridine ring, the 2-, 3-, or 4-position of the azetidine ring, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position of the quinoline ring, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position of the isoquinoline ring.

[0041] In certain embodiments, the heterocyclyl or heteroaryl group is N-linked. For example, nitrogen-linked heterocyclyl or heteroaryl groups include attachment at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline.

[0042] "Fused" refers to any ring structure described herein that shares one or more atoms (eg, carbon or nitrogen atoms) with an existing ring structure in the compounds described herein.

[0043] The term "acyl" refers to a carbonyl containing a substituent represented by -C(=O)-R, where R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclyl, where alkyl, cycloalkyl, aryl, and heterocyclyl are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl (e.g., pyridinoyl).

[0044] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogen. Examples of haloalkyl include trifluoromethyl, difluoromethyl, and fluoromethyl. Substituted haloalkyl refers to a haloalkyl having moieties other than halogen.

[0045] As used herein, a wavy line "" crossing a bond in a chemical structure "TIFF2024513881000002.tif2170" shows the attachment point of an atom in a chemical structure where a wavy bond attaches it to the rest of the molecule, or to the rest of a fragment of a molecule.

[0046] In certain embodiments, a divalent group is described generally without a specific bond structure. Unless otherwise specified, it is understood that the general description is meant to include both bond structures. For example, the group R 1 -R 2 -R 3 In the formula, the group R 2 Ga-CH 2 When depicted as C(O)-, unless otherwise specified, the group is R 1 -CH 2 C(O)-R 3 and R 1 -C(O)CH 2 -R 3 It is understood that both are combinable.

[0047] The term "pharmaceutical acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other side reactions when properly administered to an animal, such as a human.

[0048] The compounds described herein may be in the form of salts, such as pharma- ceutically acceptable salts. "Pharmaceutically acceptable salts" includes both acid and base addition salts. "Pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effectiveness and properties of the free base and which are biologically or otherwise desirable, formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like; the organic acids may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0049] The term "pharmaceutically acceptable base addition salts" includes those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Specific base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines including basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0050] In some embodiments, the salt is a 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, saccharate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate, or naphthalene-1(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonic acid), salt, or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulfonate), napsylate (2-naphthalenesulfonate), phthalenesulfonate), camsylate (camphor 10-sulfonate, e.g. (1S)-(+)-10-camphor-sulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

[0051] A "sterile" preparation is aseptic or free of all viable microorganisms and their spores.

[0052] The term "stereoisomers" means compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, atropisomers, conformers, and the like.

[0053] The term "chiral" refers to molecules that have the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0054] The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectroscopic properties, or biological activity. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0055] The term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0056] The term "atropisomers" refers to two conformers resulting from hindered rotation about a single bond, where the steric distortion barrier to rotation can be high enough to allow isolation of each conformer.

[0057] Stereochemical definitions and conventions used herein generally follow 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. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, or (+) and (-), are used to denote the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. 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 called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0058] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0059] Certain compounds described herein can exist in unsolvated and solvated forms, including hydrated forms. "Solvate" refers to an association or complex of one or more solvent molecules and 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 can exist in multiple crystalline or amorphous forms. In general, all physical forms are contemplated herein. The term "hydrate" refers to a complex where the solvent molecule is water.

[0060] The compounds described herein and their pharma- ceutically acceptable salts also include isotopically labeled compounds that are identical to those listed herein due to 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 use are contemplated herein.Exemplary isotopes that can be incorporated into the compounds described herein and their pharma-ceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, e.g., 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 pharma- ceutically acceptable salts thereof (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon 14 ( 14C) isotopes are useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. 15 O. 13 N, 11 C, and 18 Positron emitting isotopes such as F are useful for positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotopically labeled compounds described herein, or pharma- ceutically acceptable salts thereof, can generally be prepared by following procedures similar to those described in the Examples described herein below, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0061] As used herein, the term "amino protecting group" refers to a derivative of a group commonly used to block or protect an amino group while a reaction is carried out at another functional group of the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, and imines, as well as many N-heteroatom derivatives that can be removed to regenerate the desired amine group. Specific amino protecting groups are Pmb (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), and Cbz (carbobenzyloxy). Further examples of these groups can be found in TW Greene and PG M Huts, "Protecting Groups in Organic Synthesis, 3rd ed., 1999, 144:1311-1323, 19 ...0, 1990, 1990, 1991, 1991, 1992, 1992, 1993, 1994, 1994, 1995, 1995, 1996, 1996, 1997, 1998, 1999, 1990, 1991, 1992, rd ed., John Wiley & Sons, Inc., 1999. The term "protected amino" means an amino group substituted with one of the amino-protecting groups described above.

[0062] As used herein, the term "carboxy protecting group" refers to a group that is stable to the conditions of subsequent reaction(s) at other positions on the molecule and can be removed at the appropriate point to give the unprotected carboxy group without destroying the remainder of the molecule. Examples of carboxy protecting groups include ester and heterocyclyl groups. An ester derivative of a carboxylic acid group can be used to block or protect the carboxylic acid group while the reaction is carried out at another functional group of the compound. Examples of such ester groups include substituted aryl alkyl, including substituted benzyl, such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl or substituted alkyl esters, such as methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl (trityl), 4- Examples of protecting groups include methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4''-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as t-butylthioesters, silyl esters such as trimethylsilyl, t-butyldimethylsilyl ester, phenacyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and similar moieties. Another example of a carboxy protecting group is a heterocyclyl group such as 1,3-oxazole. Further examples of these groups can be found in TW Greene and PGM Wuts, "Protecting Groups in Organic Synthesis, 3 rd ed., John Wiley & Sons, Inc., 1999. The term "protected carboxy" means a carboxy group substituted with one of the carboxy-protecting groups described above.

[0063] The compounds described herein and their pharma- ceutically 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 use racemates, diastereomers, or enantiomers as starting materials or intermediates. A mixture of specific diastereomeric compounds may be separated or enriched into one or more specific diastereomers by chromatographic or crystallization techniques. Similarly, the same techniques, or other techniques known in the art, may be used to separate or enantiomerically enrich an enantiomeric mixture. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration, and both of these configurations are contemplated herein.

[0064] In structures depicted herein where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included. Where stereochemistry is specified by a solid wedge or dashed lines representing a specific configuration, that stereoisomer is so specified and defined. Unless otherwise indicated, relative stereochemistry is intended when a solid wedge or dashed lines are used.

[0065] A "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, farm animals (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human. In embodiments involving administering a compound to a patient, the patient is typically in need of administration of the compound.

[0066] The terms "inhibit" and "reduce / diminish" or any variation of these terms include any measurable reduction / decrease or complete inhibition to achieve a desired result. For example, there may be a decrease in activity compared to normal of 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 of these range variables.

[0067] The term "treatment" refers to a clinical intervention designed to change the natural course of the patient or cells being treated during the course of clinical pathology. Desirable effects of treatment include reducing the rate of disease progression, ameliorating or alleviating the disease state, and improving remission or prognosis. For example, a patient is successfully "treated" if one or more symptoms associated with cancer as described herein are reduced or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancerous cells, reducing symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other medications required to treat the disease, and / or prolonging the patient's survival.

[0068] The term "delaying progression" of a disease refers to putting off, preventing, delaying, retarding, stabilizing, and / or postponing the onset of 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 appreciated by those skilled in the art, a sufficient or significant delay can essentially encompass prevention, in that the patient does not develop or recur cancer.

[0069] "Mutant Kras-mediated disease" and the like refers to a disease as described herein (e.g., a cancer as described herein) that has symptoms as described herein or is in need of treatment, that is associated, or a result of, or a function of, or is otherwise correlated, in whole or in part, with mutant Kras activity as described herein. In one such embodiment, mutant KRas is KRas G12VIn another embodiment, the mutant KRas is any G12 mutant (i.e., a pan-KRas inhibitor).

[0070] An "effective amount" or "therapeutically effective amount" is at least the minimum amount necessary to achieve a measurable improvement or prevention of cancer as described herein. The effective amount herein may vary depending on factors such as the disease state, age, sex, and weight of the patient, and the ability of the agent to induce a desired response in the patient. An effective amount is also an amount in which any toxic or adverse effects of the treatment are outweighed by the therapeutically beneficial effects. Beneficial or desired results include results such as eliminating or reducing the risk, reducing the severity, delaying the onset of the disease (including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifested during the development of the disease), reducing one or more symptoms attributable to the disease, improving the quality of life of those 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 the progression of the disease, and / or prolonging survival. In some embodiments, an effective amount of a drug may be effective in reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing or stopping) cancer cell invasion into peripheral organs; inhibiting (i.e., slowing or stopping) tumor metastasis; inhibiting (i.e., slowing or stopping) tumor growth; and / or alleviating one or more symptoms associated with a disorder. An effective amount may be administered in one or more administrations.

[0071] An "administration period" or "cycle" refers to a period that includes administration of one or more compounds described herein or a pharma- ceutically acceptable salt thereof, or an additional therapeutic agent (i.e., a chemotherapeutic agent), and any period that does not include administration of one or more agents or compounds described herein. A "rest period" refers to a period during which at least one of the agents or compounds described herein is not administered. In one embodiment, a rest period refers to a period during which an agent or compound described herein is not administered. The rest periods provided herein can, in some cases, include administration of an additional agent in the absence of a compound described herein or a pharma- ceutically acceptable salt thereof, or vice versa. In such cases, administration of any agent during the rest period should not interfere with or impair administration of a compound described herein or a pharma- ceutically acceptable salt thereof.

[0072] "Dosing regimen" refers to a period of administration of a compound described herein, or a pharma- ceutically acceptable salt thereof, that comprises one or more cycles, and each cycle may comprise administration of a compound described herein, or a pharma- ceutically acceptable salt thereof, at a different time or in a different amount.

[0073] "QD" refers to administration of a compound or a pharma- ceutically acceptable salt thereof once daily.

[0074] "BID" refers to administration of a compound or a pharma- ceutically acceptable salt thereof twice daily.

[0075] The terms "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, 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 subject at the same time. Co-administration includes the simultaneous administration of separate compositions, the administration of separate compositions at different times (i.e., sequential administration), or the administration of a composition in which both agents are present.

[0076] "1L therapy" refers to the first-line therapy administered to treatment-naïve cancer patients. Similarly, 2L, 3L, etc. refer to subsequent therapies administered to patients.

[0077] The term "package insert" is used to refer to instructions customarily included in commercial packaging of a therapeutic agent that contain information about the indications, usage, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic agent.

[0078] 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, whether 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 role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of a target protein by interacting with other elements of a signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with tumor progression, growth, or spread.

[0079] As used herein, the term "agonist" refers to a compound that has the ability to initiate or enhance the biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with the target (e.g., bind to the target), compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other elements of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0080] The terms "cancer" and "cancerous," "neoplasm," and "tumor" and related terms are used interchangeably herein to refer to or describe a physiological condition in a mammal that is typically characterized by uncontrolled cell proliferation. A "tumor" comprises one or more cancer cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinoma), and lung cancers (such as small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma). Other cancers include skin cancer, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral cavity cancer, pharyngeal (mouth) cancer, lip cancer, tongue cancer, mouth cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, gastric cancer, stomach cancer, gastrointestinal cancer, small intestine cancer, large intestine cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary tract cancer, thyroid cancer, papillary cancer, liver cancer, uterine cancer, uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penile cancer, bone cancer, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system, brain cancer, head and neck cancer, Hodgkin's disease, and associated metastases. Other examples of neoplastic disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, myelofibrosis such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

[0081] A "chemotherapeutic agent" is an agent useful in the treatment of a given disorder, such as cancer or an inflammatory disorder. Examples of chemotherapeutic agents are well known in the art. Additionally, chemotherapeutic agents include any pharma- ceutically acceptable salt, acid, or derivative of the chemotherapeutic agent, and combinations of two or more thereof.

[0082] It is specifically contemplated that any limitation described with respect to one embodiment provided herein may be applied to any other embodiment provided herein. Furthermore, any compound described herein and its pharma- ceutically acceptable salts, or any composition 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 its pharma- ceutically acceptable salts, or any composition described herein.

[0083] 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 measure the value.

[0084] compound Provided herein is a compound of formula (I): TIFF2024513881000003.tif34170 (in the formula, X is NR 13 , O, C(R x ) 2 , C(O), SO, SO2, or S; u is 1 or 2; Each R x are independently hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 Is it a haloalkyl? Or, two R's x taken together form a cyclopropyl with the carbon to which they are attached, R 1 is R 7 Substituted or unsubstituted indolyl, R 7 Substituted or unsubstituted benzofuranyl, R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, R 7 Substituted or unsubstituted indenyl, R 7 Substituted or unsubstituted benzothiazolyl, R 7A Substituted or unsubstituted phenyl, or R 7Asubstituted or unsubstituted pyridinyl, Each R 7 are independently hydrogen, halogen, CN, CH 2 OH, -OH, NH 2 , N(Me) 2 , unsubstituted C 1~3 Alkyl, unsubstituted C 2~5 Alkynyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; Each R 7A are independently hydrogen, halogen, NH 2 , N(Me) 2 , unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; R 2 is hydrogen, OL 1 -R 8 , R 8A Substituted or unsubstituted C 1~3 Alkyl or R 8B a substituted or unsubstituted 4- to 10-membered heterocycle; L 1 is a bond or R L1 Substituted or unsubstituted C 1~3 is alkylene, R L1 is halogen or unsubstituted C 1~3 is alkyl, R 8 R containing N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; Each R 9 are independently halogen, oxo, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, R 10 Substituted or unsubstituted C 1~3 Alkylidene or R 10 Substituted or unsubstituted C 3~4 Cycloalkyl or R 10 a substituted or unsubstituted 3- or 4-membered heterocycle; Or, two R's 9 Let's get together and 3~5forming a cycloalkyl or a 3- to 5-membered heterocycle, Hydrogen R 10 is hydrogen or halogen; Each R 8A are independently 9A Substituted or unsubstituted C 1~3 Alkyl, R 9A Substituted or unsubstituted C 1~3 Alkoxy, R 9A Substituted or unsubstituted C 3~4 Cycloalkyl or R 9A a substituted or unsubstituted 4- to 6-membered heterocycle; Each R 9A are independently halogen, oxo, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, unsubstituted C 1~3 Alkylidene, R 9 Substituted or unsubstituted C 3~4 Cycloalkyl or R containing N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 8B are independently halogen, oxo, -NH 2 , unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 is alkylidene, R 3 and R 4 are each independently hydrogen, -CN, halogen, or unsubstituted C 1~3 alkyl, or unsubstituted cyclopropyl; R 5 is R 5A Substituted or unsubstituted C 1~6 Alkyl, R 5A Substituted or unsubstituted C 1~6 Haloalkyl, R 5A Substituted or unsubstituted C 3~10 Cycloalkyl, R 5A Substituted or unsubstituted 3- to 10-membered heterocycle, or R 5A a substituted or unsubstituted 5- to 10-membered heteroaryl; Each R 5A are independently halogen, oxo, CN, OR 11 , S.R. 12 , S.O. 2 R 12 , N.R. 13 R 14 , C(O)N(R 11 ) 2 , C(O)R 11 , R 5B Substituted or unsubstituted C 1~6 Alkyl, R 5B Substituted or unsubstituted C 1~6 Haloalkyl, R 5B Substituted or unsubstituted C 3~6 Cycloalkyl, R 5B Substituted or unsubstituted 3- to 6-membered heterocycle, R 5B Substituted or unsubstituted C 5~8 Aryl or R 5B a substituted or unsubstituted 5- to 9-membered heteroaryl; Or, two R's 5A Let's get together and 3~6 forming a cycloalkyl or a 3- to 6-membered heterocycle; Each R 5B are independently halogen, oxo, CN, OR 11 , N.R. 13 R 14 , S.R. 12 , S.O. 2 R 12 , C(O)N(R 11 ) 2 , C(O)R 11 , R 5C Substituted or unsubstituted C 1~3 Alkyl, R 5C Substituted or unsubstituted C 1~3 Haloalkyl, R 5C Substituted or unsubstituted C 3~6 Cycloalkyl, R 5C Substituted or unsubstituted 3- to 6-membered heterocycle, R 5C Substituted or unsubstituted phenyl, or R 5C a substituted or unsubstituted 5- to 6-membered heteroaryl; Or, two R's 5B Let's get together and 3~6forming a cycloalkyl or a 3- to 6-membered heterocycle; Each R 5C are independently halogen, oxo, CN, C(O)CH 3 , O.H., O.C.H. 3 , C(O)NH 2 , C.F. 3 , CHF 2 , C.H. 2 F, NR 13 R 14 , S.C.H. 3 , S.O. 2 NH 2 , S.O. 2 CH 3 , unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 3~4 cycloalkyl, or an unsubstituted 3- to 4-membered heterocycle; Each R 11 are independently hydrogen, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 3~4 cycloalkyl, or an unsubstituted 3- to 4-membered heterocycle; Each R 12 Independently, NH 2 or unsubstituted C 1~3 is alkyl, Each R 13 and R 14 are independently hydrogen, C(O)N(R 11 ) 2 , C(O)R 11 , R 15 Substituted or unsubstituted C 1~6 Alkyl, R 15 Substituted or unsubstituted C 3~6 Cycloalkyl or R 15 a substituted or unsubstituted 3- to 6-membered heterocycle; Each R 15 are independently halogen, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 )2 , S.O. 2 NH 2 , S.O. 2 CH 3 , R 16 Substituted or unsubstituted C 1~3 Alkyl, R 16 Substituted or unsubstituted C 3~6 Cycloalkyl, R 16 Substituted or unsubstituted 3- to 6-membered heterocycle, R 16 Substituted or unsubstituted 5- to 9-membered aryl, or R 16 It is a substituted or unsubstituted 5- to 9-membered heteroaryl. Each R 16 are independently halogen, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , S.O. 2 CH 3 , R 17 Substituted or unsubstituted C 1~3 Alkyl, R 17 Substituted or unsubstituted C 3~6 Cycloalkyl, R 17 Substituted or unsubstituted 3- to 6-membered heterocycle, R 17 Substituted or unsubstituted 5- to 9-membered aryl, or R 17 It is a substituted or unsubstituted 5- to 9-membered heteroaryl. Each R 17 are independently halogen, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , S.O. 2 CH 3 , or unsubstituted C 1~3is alkyl, R 6 and R 6A are independently hydrogen, halogen, or NR 13 R 14 , or R 6B Substituted or unsubstituted C 1~6 is alkyl, R 6B are halogens, CN, OH, OCH 3 , C.F. 3 , CHF 2 , C.H. 2 F or unsubstituted C 1~3 (It is alkyl) or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0085] In one embodiment, X is O. In another embodiment, X is C(R x ) 2 and R x is as described herein. In one such embodiment, X is C(R x ) 2 If R x is independently hydrogen or methyl. In another such embodiment, X is C(R x ) 2 If R x is independently hydrogen or halogen. In another such embodiment, X is C(R x ) 2 If R x is independently methyl or halogen. In one embodiment, X is NR 13 , C(O), SO, SO 2 or S. In one embodiment, u is 1. In one embodiment, X is O and u is 1.

[0086] In one embodiment, R 1 is R 7 Substituted or unsubstituted indolyl, R 7 Substituted or unsubstituted benzofuranyl, R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, R7 Substituted or unsubstituted benzothiazolyl, R 7A Substituted or unsubstituted phenyl, or R 7A In one embodiment, R 1 is R 7 Substituted or unsubstituted indolyl, R 7 In another embodiment, R 1 is R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, R 7A Substituted or unsubstituted phenyl, or R 7A In yet another embodiment, R 1 is R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, or R 7 In yet another embodiment, R 1 is R 7 Substituted or unsubstituted naphthyl, or R 7 In another embodiment, R 1 is R 7 In another embodiment, R 1 is R 7A Substituted or unsubstituted phenyl, or R 7A In another embodiment, R 1 is R 7 Substituted or unsubstituted phenyl, R 7 Substituted or unsubstituted indazolyl, or R 7 It is a substituted or unsubstituted pyridinyl.

[0087] In one such embodiment, R 1 is R 7 In another such embodiment, R 1 is R 7 In another such embodiment, R 1 is R 7In another such embodiment, R 1 is R 7 It is a substituted or unsubstituted indolyl.

[0088] In a preferred embodiment, R 1 is expressed by the formula (A): TIFF2024513881000004.tif23170(in the formula, 1 is N, CH or CF, R 7A are as described herein) In one such embodiment, R 7A is hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 It is haloalkyl.

[0089] In one such embodiment, X 1 is N or CF, and each R 7A are independently hydrogen, halogen, or unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 In one such embodiment, R 7A are independently hydrogen, Cl, methyl, ethyl, or CF 3 and no more than one R 7A is hydrogen. In one embodiment, one R 7A is cyclopropyl.

[0090] In one such embodiment, the compound of formula (A1) has the formula: I have TIFF2024513881000005.tif23170.

[0091] In one such embodiment, each R 7A are independently hydrogen, Cl, methyl, or CF 3 In another such embodiment, each R 7A are independently hydrogen, methyl, or CF 3 It is.

[0092] In one such embodiment, R 1 teeth, The file is TIFF2024513881000006.tif21170.

[0093] In another such embodiment, R 1 teeth, The file is TIFF2024513881000007.tif19170.

[0094] In a preferred embodiment, R 1 teeth, The file is TIFF2024513881000008.tif19170.

[0095] In another embodiment, the moiety of formula (A) has the formula: TIFF2024513881000009.tif25170 (in the formula, R 7A is hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl) In one such embodiment, there is no more than one R 7A is hydrogen. In another such embodiment, R 7A is not hydrogen.

[0096] In one such embodiment, R 1 teeth, The file is TIFF2024513881000010.tif23170.

[0097] In one such embodiment, R 1 teeth, The file is TIFF2024513881000011.tif20170.

[0098] In one such embodiment, R 1 teeth, TIFF2024513881000012.tif28170 (in the formula, each R 7 are independently halogen, CN, NH 2 , N(Me) 2 , unsubstituted C 1~3 Alkyl, unsubstituted C 2~3 alkynyl) It is.

[0099] In one embodiment, R 1 teeth, The file is TIFF2024513881000013.tif27170.

[0100] In another embodiment, R 1 teeth, The file is TIFF2024513881000014.tif24170.

[0101] In another embodiment, R 1 teeth, The file is TIFF2024513881000015.tif54170.

[0102] In another embodiment, R 1 teeth, The file is TIFF2024513881000016.tif24170.

[0103] In another embodiment, R 1 teeth, The file is TIFF2024513881000017.tif24170.

[0104] In one embodiment, R 7 are independently hydrogen, halogen, -OH, NH 2 , N(Me) 2 , unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 In one embodiment, R 7 are independently hydrogen, halogen, -OH, NH 2 , N(Me) 2 , unsubstituted C 1~3 Alkyl or unsubstituted C 2~3 In one embodiment, R is alkynyl. 7 are independently hydrogen, halogen, -CN, OH, NH 2 , N(Me) 2 , unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 In another embodiment, R7 are independently halogen, NH 2 , or unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 In one embodiment of the compounds described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, R 7 is not -OH.

[0105] In one embodiment, R 1 is a moiety of formula (B) or (C), R 7 are independently hydrogen, halogen, or unsubstituted C 1~3 In one such embodiment, R 7 are independently hydrogen or unsubstituted C 1~3 In another such embodiment, R 7 are independently halogen (e.g., F) or unsubstituted C 1~3 Alkyl (eg, methyl).

[0106] In one embodiment, R 1 is part of formula (B), and R 7 are independently hydrogen, halogen, -OH, NH 2 , N(Me) 2 , or unsubstituted C 1~3 In one embodiment, R 1 is part of formula (C), R 7 are independently hydrogen, halogen, NH 2 , N(Me) 2 , or unsubstituted C 1~3 In one such embodiment, R 7 are independently halogen or NH 2 It is.

[0107] In one embodiment, R 2 is hydrogen or OL 1 -R 8 In another embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 Alkyl or R 8BIn another embodiment, R 2 is R 8B In yet another embodiment, R 2 OL 1 -R 8 , R 8A Substituted or unsubstituted C 1~3 alkyl or R containing one nitrogen heteroatom 8B It is a substituted or unsubstituted 4- to 6-membered heterocycle.

[0108] In one embodiment, R 2 is hydrogen.

[0109] In one embodiment, the compound of formula (I) has the formula: TIFF2024513881000018.tif34170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 6A and X is as described herein. or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0110] In one such embodiment, the compound of formula (III) has the formula: TIFF2024513881000019.tif70170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 6A and X is as described herein. or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0111] In one embodiment, R 2 OL 1 -R 8 In one embodiment, L 1 is a bond. In one embodiment, L1 is unsubstituted C 1~3 In one preferred embodiment, R 2 Office lady 1 -R 8 If L 1 is methylene. In one such embodiment, R 8 R containing N, S or O 9 It is a substituted or unsubstituted 4- to 10-membered heterocycle.

[0112] In one embodiment, the compound of formula (I) has the formula: TIFF2024513881000020.tif35170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 6A , R 8 and X is as described herein. or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0113] In one such embodiment, the compound of formula (II) has the formula: TIFF2024513881000021.tif71170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 6 , R 6A , R 8 and X is as described herein. or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0114] In one embodiment, R 2 Office lady 1 -R 8 If R 8 R containing N, S or O 9 In another such embodiment, R 8is a 4-10 membered heterocycle containing one N heteroatom. In another such embodiment, R 8 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle containing one N heteroatom. In another such embodiment, R 8 is a 5- or 6-membered monocyclic heterocycle containing one N heteroatom. In another such embodiment, R 8 is a 5- or 6-membered monocyclic heterocycle containing one O heteroatom. In another such embodiment, R 8 is a 6-, 7-, 8-, or 9-membered fused bicyclic heterocycle containing one N heteroatom. In another such embodiment, R 8 is a 7- or 8-membered fused bicyclic heterocycle containing one N heteroatom. In another such embodiment, R 8 is a 7- or 8-membered fused bicyclic heterocycle containing one N heteroatom and one O heteroatom. In one embodiment, R 8 is pyrrolidinyl or tetrahydrofuranyl.

[0115] In such an embodiment, each R 9 are independently halogen, oxo, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy or R 10 Substituted or unsubstituted C 1~3 In another such embodiment, each R 9 are independently halogen, oxo, or R 10 Substituted or unsubstituted C 1~3 In one embodiment, each R 9 are independently unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 In one embodiment, each R 9 is R 10 Substituted or unsubstituted C 3~4 Cycloalkyl or R 10 In one embodiment, two R 9 Together, R 10 Substituted or unsubstituted C3~5 In one such embodiment, two R 9 Together, R 10 In one such embodiment, two R 9 Together, R 10 R is halogen (e.g., F or Cl). 10 In one embodiment, two R 9 Together, R 10 When forming a substituted cyclopropyl, the cyclopropyl is R 8 In one embodiment, two R 9 Together, R 10 Form a substituted cyclopropyl, the cyclopropyl being R 8 In another such embodiment, two R 9 together form an unsubstituted C 3~5 Forming a heterocycle. In one such embodiment, the heterocycle is 1,3-dioxolanyl.

[0116] In one embodiment, R 10 is hydrogen or halogen. In one embodiment, R 10 is hydrogen. In another embodiment, R 10 is halogen. In one such embodiment, R 10 is F.

[0117] In one embodiment, R 2 Office lady 1 -R 8 If R 8 teeth, TIFF2024513881000022.tif19170 (in the formula, R 9 -Halogen, -OCF 3 , -OCHF 2 , -OCH 2 F, R 10 Substituted or unsubstituted C 1~3 Alkylidene or two R 9 Together, R10 Substituted or unsubstituted C 3~5 Forming a cycloalkyl, r is an integer from 0 to 12; j is 1, 2, or 3; k is 1 or 2. It is.

[0118] In one embodiment, R 2 Office lady 1 -R 8 If R 8 teeth, TIFF2024513881000023.tif19170 (in the formula, R 9 is halogen or R 10 Substituted or unsubstituted C 1~3 is alkylidene, r is an integer from 0 to 12; j is 1, 2, or 3; k is 1 or 2. It is.

[0119] In one such embodiment, r is 0, 1, 2, 3, or 4. In another such embodiment, r is 0, 1, 2, or 3. In one embodiment, R 8 teeth, TIFF2024513881000024.tif64170 (in the formula, R 9 , R 10 and r is as described herein and s is 1 or 2. It is.

[0120] In one such embodiment, r is 0, 1, 2, 3, or 4. In another such embodiment, r is 0, 1, 2, or 3. In one embodiment, R 8 teeth, TIFF2024513881000025.tif33170 (in the formula, R 9 , R 10 and r is as described herein. It is.

[0121] In one such embodiment, R 9 are independently halogen or R 10 Substituted or unsubstituted C 1~3 alkylidene, and each R 10 is independently hydrogen or halogen, and r is 1 or 2.

[0122] In one embodiment, R 8 teeth, TIFF2024513881000026.tif23170 and r is 0.

[0123] In another embodiment, R 8 teeth, TIFF2024513881000027.tif33170, r is 0, and each R 10 is independently hydrogen or F. In one such embodiment, r is 0 and each R 10 In another such embodiment, r is 0 and each R 10 is F. In another such embodiment, r is 0 and one R 10 is hydrogen and one R 10 is F. In another such embodiment, each R 10 are independently hydrogen or F; r is 1 or 2; R 9 is F.

[0124] In another embodiment, R 8 teeth, TIFF2024513881000028.tif28170, r is 0, and each R 9 is independently hydrogen or halogen. In one such embodiment, each R 9 is F and r is 0. In one such embodiment, each R 9 is F and r is 1.

[0125] In another embodiment, R 2 Office lady 1 -R 8 If R 8 teeth, TIFF2024513881000029.tif14170. In one such embodiment, r is 1 and R 9 is halogen, oxo, or unsubstituted C 1 In one such embodiment, two R 9 Together, R 10 Substituted or unsubstituted C 3~5 Forms a cycloalkyl.

[0126] In one embodiment, R 8 teeth, TIFF2024513881000030.tif19170, R 10 is halogen and s is 1 or 2. In one such embodiment, R 8 teeth, The file is TIFF2024513881000031.tif21170.

[0127] In another embodiment, R 2 Office lady 1 -R 8 If R 8 teeth, TIFF2024513881000032.tif14170 (in the formula, R 9 is hydrogen or unsubstituted C 1~3 is alkyl, W is O, SO 2 , or NR 12 and R 12 is hydrogen, unsubstituted C1-3 alkyl, or unsubstituted C1-3 haloalkyl. It is.

[0128] In one such embodiment, W is O and R 9 In another such embodiment, W is NR 12 and R 12 is unsubstituted C 1~3 haloalkyl, R 9 is hydrogen. In another such embodiment, W is SO 2 and R 9 is hydrogen.

[0129] In one embodiment of the compounds described herein, or pharma- ceutically acceptable salts thereof, R 8 is azetidinyl, oxetanyl, or thietanedioxide.

[0130] In further embodiments provided herein, R 8 is the expression: TIFF2024513881000033.tif20170 (in the formula, R 9 are independently halogen, oxo or unsubstituted C 1~3 Is it an alkyl group? Or two R's 9 Let's get together and 3~5 Forming a cycloalkyl or a 3- to 5-membered heterocycle, r is 1 or 2) It is a part having the following structure.

[0131] In one such embodiment, R 8 is a moiety having the formula (G), and R 9 and r is as described herein. In one such embodiment, two R 9 Together, R 10 Forms a substituted or unsubstituted cyclopropyl moiety. In one embodiment, the cyclopropyl moiety is unsubstituted. In another embodiment, the cyclopropyl moiety is substituted with halogen (e.g., F). In one such embodiment, two R 9 together, R fused to pyrrolidinyl 10 In another such embodiment, two R 9 together form R, which is spiro for pyrrolidinyl. 10 In one embodiment, R 9 is oxo and r is 1. In another such embodiment, R 9 is F and r is 1 or 2. In one embodiment, NR 9 , R 9 is C 1~3In one such embodiment, R 9 is methyl.

[0132] In another embodiment, R 8 is the expression: TIFF2024513881000034.tif16170 (in the formula, R 10 is a halogen and s is 1 or 2. It is a part having the following structure.

[0133] In another embodiment, R 8 is the expression: TIFF2024513881000035.tif16170 (in the formula, R 9 and r is as described herein. It is a part having the following structure.

[0134] In another embodiment, R 8 is the expression: TIFF2024513881000036.tif24170 (in the formula, R 9 and r is as described herein. It is a part having the following structure.

[0135] In yet another embodiment, R 8 is R 9 Substituted or unsubstituted C 1~3 In one such embodiment, R 8 is the expression: TIFF2024513881000037.tif14170 (in the formula, each R 9 are independently unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 (alkoxy) This is the part.

[0136] In another embodiment, R 8 is the expression: The part with TIFF2024513881000038.tif14170.

[0137] In one embodiment, R8 teeth, The file is TIFF2024513881000039.tif21170.

[0138] In one embodiment, R 8 teeth, The file is TIFF2024513881000040.tif21170.

[0139] In one embodiment, R 8 teeth, The file is TIFF2024513881000041.tif19170.

[0140] In one embodiment, R 8 teeth, The file is TIFF2024513881000042.tif16170.

[0141] In another embodiment, R 8 teeth, The file is TIFF2024513881000043.tif28170.

[0142] In another embodiment, R 8 teeth, The file is TIFF2024513881000044.tif28170.

[0143] In another embodiment, R 8 teeth, The file is TIFF2024513881000045.tif27170.

[0144] In yet another embodiment, R 8 teeth, The file is TIFF2024513881000046.tif23170.

[0145] In yet another embodiment, R 8 teeth, The file is TIFF2024513881000047.tif28170.

[0146] In yet another embodiment, R8 teeth, The file is TIFF2024513881000048.tif14170.

[0147] In yet another embodiment, R 8 teeth, The file is TIFF2024513881000049.tif14170.

[0148] In yet another embodiment, R 2 teeth, TIFF2024513881000050.tif76170 (in the formula, R 9 , R 10 , r, j, and k are as described herein. In one embodiment, R 9 is halogen or R 10 Substituted or unsubstituted C 1~3 In another such embodiment, R 9 is halogen, oxo, R 10 Substituted or unsubstituted C 1~3 alkylidene, and r is independently 0, 1, or 2. It is.

[0149] In one embodiment, R 2 teeth, The file is TIFF2024513881000051.tif19170.

[0150] In another embodiment, R 2 teeth, The file is TIFF2024513881000052.tif58170.

[0151] In another embodiment, R 2 teeth, The file is TIFF2024513881000053.tif28170.

[0152] In yet another embodiment, R 2 teeth, The file is TIFF2024513881000054.tif23170.

[0153] In yet another embodiment, R 2 teeth, The file is TIFF2024513881000055.tif28170.

[0154] In yet another embodiment, R 2 teeth, The file is TIFF2024513881000056.tif14170.

[0155] In yet another embodiment, R 2 teeth, The file is TIFF2024513881000057.tif14170.

[0156] In another embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 Alkyl or R 8B In one embodiment, each R 8A are independently 9A Substituted or unsubstituted C 1~3 Alkyl or R 9A Substituted or unsubstituted C 1~3 In one embodiment, each R 8A are independently 8A are independently 9A Substituted or unsubstituted alkoxy, or R 9A In another embodiment, each R 8A are independently 9A Substituted or unsubstituted C 3~4 Cycloalkyl or R 9A In one embodiment, R 9A is R containing N 9 In another embodiment, R 9 are independently halogen, unsubstituted C 1~3 Alkyl or R 10 Substituted or unsubstituted C 1~3 It is an alkylidene.

[0157] In one embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 is alkyl, R 8A is R 9A Substituted or unsubstituted C 1~3 Alkoxy, R 9A Substituted or unsubstituted C 3~4 Cycloalkyl or R 9A It is a substituted or unsubstituted 4- to 6-membered heterocycle.

[0158] In one embodiment, R 9A are independently halogen, oxo, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 In another such embodiment, R 9A are independently 9A are independently halogen, oxo, or unsubstituted C 1~3 In yet another embodiment, R 9A R containing N, S or O 9 It is a substituted or unsubstituted 4- to 10-membered heterocycle.

[0159] In one embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 is alkyl, R 8A is R 9A Substituted or unsubstituted C 1~3 It is an alkyl.

[0160] In one embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 is alkyl, R 8A is R 9A Substituted or unsubstituted C 1~3 In one such embodiment, R 9A are independently 9 Substituted or unsubstituted C 3~4 Cycloalkyl or R containing one N-heterocycle 9In another such embodiment, R 9A R independently contains one N-heterocycle 9 In such embodiments, R is a substituted or unsubstituted 5- or 6-membered monocyclic heterocycle, or a 7- or 8-membered fused bicyclic heterocycle containing one N-heterocycle. 9 are independently halogen, oxo, unsubstituted C 1~3 Alkyl or R 10 Substituted or unsubstituted C 1~3 alkylidene, and R10 is as defined herein.

[0161] In another embodiment, R 2 is R 8A Substituted or unsubstituted C 1~3 is alkyl, R 8A is R 9A Substituted or unsubstituted C 3~4 In one embodiment, each R 8B are independently halogen, oxo, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 It is an alkylidene.

[0162] In one embodiment, R 2 is R 8B In one such embodiment, R 8B is halogen, oxo, or unsubstituted C 1~3 In one embodiment, R 2 is an R group containing one N heteroatom 8B It is a substituted or unsubstituted 4-, 5- or 7-membered heterocycle.

[0163] In one embodiment, R 3 and R 4 are each independently hydrogen, -CN, halogen, or unsubstituted C 1~3 In one embodiment, R 3 and R 4 are each independently hydrogen, unsubstituted C1~3 In one embodiment, R 3 and R 4 are each independently hydrogen, halogen, or unsubstituted C 1~3 In one embodiment, R 3 and R 4 are each independently hydrogen or halogen. 3 and R 4 In another embodiment, R 3 and R 4 One of R is hydrogen and the other is halogen. In one such embodiment, R 3 is hydrogen, and R 4 is halogen. In one embodiment, R 3 is a halogen. In one such embodiment, R 3 is F or Cl. In another embodiment, R 4 is hydrogen. In another embodiment, R 4 is halogen. In one such embodiment, R 4 is F or Cl.

[0164] In one embodiment, R 5 is R 5A Substituted or unsubstituted C 1~6 Alkyl, R 5A Substituted or unsubstituted C 1~6 Haloalkyl, R 5A Substituted or unsubstituted C 3~10 Cycloalkyl, R 5A Substituted or unsubstituted 3- to 10-membered heterocycle, or R 5A It is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0165] R 5 R 5A Substituted or unsubstituted C 3~10 When it is cycloalkyl, the cycloalkyl may be a single ring, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. R 5 R 5A Substituted or unsubstituted C 3~10When it is a cycloalkyl, the cycloalkyl can be bicyclic, e.g., 3,5-, 3-6, 4,5-, 4-6, 5,5-, or 5,6-, etc., where one or both of the fused rings of the bicyclic moiety are R 5A It includes substituted or unsubstituted cycloalkyl moieties.

[0166] R 5 R 5A In the case of a substituted or unsubstituted 3- to 10-membered heterocycle, the heterocycle may be a single ring, such as, for example, aziridinyl, oxiranyl, or triranyl. 5 R 5A In the case of a substituted or unsubstituted 3- to 10-membered heterocycle, the heterocycle may be a single ring, such as, for example, azetidinyl, oxetanyl, or thietanyl. 5 R 5A In the case of a substituted or unsubstituted 3- to 10-membered heterocycle, the heterocycle may be a single ring, such as, for example, pyrrolidinyl, tetrahydrofuranyl, thiophenyl, imidazolidinyl, oxathiolidinyl, thiazolidinyl, piperidinyl, oxanyl, thianyl, or morpholino. 5 R 5A When a substituted or unsubstituted 3- to 10-membered heterocycle is used, the heterocycle may be bicyclic, e.g., 3,5-, 3-6, 4,5-, 4-6, 5,5-, or 5,6-, and one or both of the fused rings of the bicyclic moiety may be R 5A It includes substituted or unsubstituted heterocyclic moieties.

[0167] R 5 Ga or R 5A When it is a substituted or unsubstituted 5- to 10-membered heteroaryl, the heteroaryl may be, for example, a single ring such as pyrrolyl, imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, triazinyl, pyrazolyl, pyrazinyl, pyridonyl, pyrimidinyl, or pyridazinyl. 5 R 5A When a substituted or unsubstituted 3- to 10-membered heterocycle is used, the heterocycle may be bicyclic, e.g., 3,5-, 3-6, 4,5-, 4-6, 5,5-, or 5,6-, and one or both of the fused rings of the bicyclic moiety may be R 5AIn one such embodiment, R 5 is pyrrolopyridinyl, or pyrazolopyridinyl.

[0168] In another embodiment, R 5 is R 5A Substituted or unsubstituted C 1~6 Alkyl or R 5A Substituted or unsubstituted C 1~6 In another embodiment, R 5 is R 5A Substituted or unsubstituted C 3~10 Cycloalkyl, R 5A Substituted or unsubstituted 3- to 10-membered heterocycle, or R 5A It is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0169] In one embodiment, R 5 is R 5A Substituted or unsubstituted C 1~6 In one such embodiment, R 5 is R 5A Substituted or unsubstituted C 1~3 In one embodiment, R 5 is R 5A is as described herein; R 5A substitution C 1~3 It is an alkyl group. 5 R 5A substitution C 1~3 If it is alkyl, R 5 is the expression: It could be part of TIFF2024513881000058.tif14170.

[0170] In the formula, R 5A is as described herein. 5 R 5A substitution C 1~3 If it is alkyl, R 5 may be a moiety of formula (T1), (T2), (T3), or (T4), where R 5A are halogens, CF3, CHF2, CH2F, CN, OR 11 , S.R.12 , S.O. 2 R 12 , N.R. 13 R 14 , C(O)N(R 11 ) 2 , C(O)R 11 , R 5B Substituted or unsubstituted C 1~6 Alkyl, R 5B Substituted or unsubstituted C 3~6 Cycloalkyl, R 5B Substituted or unsubstituted 3- to 6-membered heterocycle, or R 5B In one such embodiment, at least one R 5A is R 5B Substituted or unsubstituted 3- to 6-membered heterocycle, or R 5B In another such embodiment, two R 5A Together, R 5B Form a substituted or unsubstituted cyclopropyl.

[0171] R 5 R 5A substitution C 1~3 If it is alkyl, R 5 is the expression: TIFF2024513881000059.tif21170 (in the formula, R 5A and R 5B is as described herein; Ring A is a 3- to 6-membered heterocycle or a 5- to 9-membered heteroaryl containing at least one N heteroatom; s is 0, 1, 2, or 3) It may be a part of.

[0172] R 5 R 5A substitution C 1~3 If it is alkyl, R 5 may be a moiety of formula (T5) or (T6); R 5B is halogen, oxo, CN, OH, OCH 3 , N.R. 13 R14 , S.R. 12 , R 5C Substituted or unsubstituted C 1~3 Alkyl, R 5C Substituted or unsubstituted C 1~3 Haloalkyl, R 5C Substituted or unsubstituted 3- to 6-membered heterocycle, or R 5C In another embodiment, R 5B is halogen, oxo, CN, OH, OCH 3 , N.R. 13 R 14 , S.R. 12 , or R 5C Substituted or unsubstituted C 1~3 In another embodiment, R 5B is oxo, CN, OH, NR 13 R 14 , S.R. 12 , or R 5C Substituted or unsubstituted C 1~3 It is an alkyl group. 5B R 5C Substituted or unsubstituted C 1~3 In such embodiments, when R is alkyl, 5C is halogen, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, NR 13 R 14 , S.C.H. 3 , S.O. 2 NH 2 , S.O. 2 CH 3 , or unsubstituted C 1~3 In one particular embodiment, R 5B is NR 13 R 14 and R13 and R14 are as described herein. In one such embodiment, at least one of R13 and R14 is hydrogen. In another such embodiment, at least one of R13 and R15 is R 15 Substituted or unsubstituted C 1~6 Alkyl, R 15Substituted or unsubstituted C 3~6 Cycloalkyl or R 15 It is a substituted or unsubstituted 3- to 6-membered heterocycle.

[0173] In one embodiment, R 5 R 5A substitution C 1~3 If it is alkyl, R 5 may be a moiety of formula (T5) or (T6); R 5B is NR 13 R 14 and NR 13 R 14 is NH2. In another embodiment, R 5 R 5A substitution C 1~3 If it is alkyl, R 5 may be a moiety of formula (T5) or (T6); R 5B is NR 13 R 14 and NR 13 R 14 NHR 14 and R14 is R 15 Substituted or unsubstituted C 1~6 Alkyl, R 15 Substituted or unsubstituted C 3~6 Cycloalkyl or R 15 It is a substituted or unsubstituted 3- to 6-membered heterocycle.

[0174] In one embodiment, each R 5A are independently halogen, oxo, CN, OR 11 , S.R. 12 , S.O. 2 R 12 , N.R. 13 R 14 , C(O)N(R 11 ) 2 , or C(O)R 11 In one embodiment, each R 5A are independently 5B Substituted or unsubstituted C 1~6 Alkyl, R 5B Substituted or unsubstituted 1~6 haloalkyl. In one embodiment, each R 5A are independently 5BSubstituted or unsubstituted C 3~6 Cycloalkyl, R 5B Substituted or unsubstituted 3- to 6-membered heterocycle, R 5B Substituted or unsubstituted phenyl, or R 5B It is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0175] In one embodiment, each R 5A OR 11 and R 11 is hydrogen, methyl, ethyl, CH 2 F, CHF 2 , C.F. 3 , cyclopropyl, cyclopropylmethyl, oxetanyl, or oxetanylmethyl. In one embodiment, each R 5A are independently halogen, oxo, CN, OH, OCH 3 , SH, SO 2 NH 2 , N.H. 2 , NH(CH 3 ), N(CH3) 2 , N(CH 3 )(CH 2 CH 3 ), C(O)NH 2 , or C(O)CH 3 It is.

[0176] Each R 5A But independently, R 5B When substituted or unsubstituted 5- to 9-membered heteroaryl, the heteroaryl moiety can be a 5-, 6-, or 7-membered monocyclic heteroaryl. In one such embodiment, the heteroaryl moiety is a 5-, 6-, or 7-membered moiety that contains at least one N heteroatom. In another such embodiment, the heteroaryl moiety is a 5-, 6-, or 7-membered moiety that contains at least one O heteroatom. In yet another embodiment, the heteroaryl moiety is a 5-, 6-, or 7-membered moiety that contains an S heteroatom.

[0177] Each R 5A But independently, R 5BWhen a substituted or unsubstituted 5- to 9-membered heteroaryl, the heteroaryl moiety can be a 7-, 8-, or 9-membered bicyclic heteroaryl. In one such embodiment, the heteroaryl moiety is a 7-, 8-, or 9-membered moiety that contains at least one N heteroatom. In another such embodiment, the heteroaryl moiety is a 7-, 8-, or 9-membered moiety that contains at least one O heteroatom. In yet another embodiment, the heteroaryl moiety is a 7-, 8-, or 9-membered moiety that contains an S heteroatom.

[0178] In one embodiment, each R 5B are independently halogen, oxo, CN, OH, OCH 3 , N.R. 13 R 14 , S.R. 12 , S.O. 2 R 12 , C(O)N(R 11 ) 2 , or C(O)R 11 In one embodiment, each R 5B are independently 5C Substituted or unsubstituted C 1~3 In one embodiment, each R 5B are independently 5C Substituted or unsubstituted C 1~3 haloalkyl. In one embodiment, each R 5B are independently 5C Substituted or unsubstituted C 3~6 In one such embodiment, each R 5B is independently cyclopropyl or cyclobutyl. In one embodiment, each R 5B are independently 5C In one such embodiment, each R 5B are independently a 4-, 5-, or 6-membered heterocycle. In another such embodiment, the 4-, 5-, or 6-membered heterocycle contains at least one N heteroatom. In another such embodiment, the 4-, 5-, or 6-membered heterocycle contains at least one O heteroatom. In one embodiment, each R 5B are independently 5CIn one embodiment, each R 5B are independently or R 5C It is a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0179] In one embodiment, R 5C are independently halogen, oxo, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, NR 13 R 14 , S.C.H. 3 , S.O. 2 NH 2 , or SO 2 CH 3 In one embodiment, R 5B is R 5C substitution C 1~3 is alkyl, R 5C are independently halogen, oxo, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, NR 13 R 14 , S.C.H. 3 , S.O. 2 NH 2 , or SO 2 CH 3 In another embodiment, R 5B is R 5C substitution C 1~3 is alkyl, R 5C are independently halogen, oxo, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, NR 13 R 14 , S.C.H. 3 , S.O. 2 NH 2 , S.O. 2 CH 3 or unsubstituted C 1~3In another such embodiment, R 5C are independently unsubstituted C 1~3 In one embodiment, R 5C are independently unsubstituted C 3~4 It is a cycloalkyl or an unsubstituted 3- to 4-membered heterocycle.

[0180] In one embodiment, R 11 is hydrogen or unsubstituted C 1~3 -alkyl. R 11 R may be hydroxy. 11 R may be methyl. 11 may be ethyl.

[0181] In one embodiment, R 12 NH 2 , N.H.C.H. 3 , or N(CH 3 ) 2 , or unsubstituted C 1~3 It is an alkyl group. 12 NH 2 or unsubstituted C 1~3 In one such embodiment, R 12 NH 2 In another such embodiment, R 12 is methyl.

[0182] In one embodiment, R 13 and R 14 are independently hydrogen, C(O)R 11 , R 15 Substituted or unsubstituted C 1~6 Alkyl, R 15 Substituted or unsubstituted C 3~6 Cycloalkyl, R 15 Substituted or unsubstituted 3- to 6-membered heterocycle, or R 15 It is a substituted or unsubstituted 3- to 6-membered heteroaryl.

[0183] In one embodiment, each R 13 and R 14 are independently hydrogen, C(O)R 11 , or R15 Substituted or unsubstituted C 1~6 In one embodiment, each R 13 and R 14 are independently 15 Substituted or unsubstituted C 3~6 Cycloalkyl or R 15 R is a substituted or unsubstituted 3- to 6-membered heterocycle. 13 and R 14 are each independently hydrogen or R 15 Substituted or unsubstituted C 1~6 In another embodiment, each independently is hydrogen or R 15 Substituted or unsubstituted C 1~3 In one embodiment, R 13 and R 14 is hydrogen. In another embodiment, R 13 and R 14 One of them is R 15 Substituted or unsubstituted C 1~6 It is an alkyl.

[0184] In one embodiment, R 15 is halogen, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , or SO 2 CH 3 In one embodiment, R 15 CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , or SO 2 CH3 In another embodiment, R 15 is R 16 Substituted or unsubstituted C 1~3 In yet another embodiment, R 15 is R 16 Substituted or unsubstituted C 3~6 Cycloalkyl, R 16 Substituted or unsubstituted 3- to 6-membered heterocycle, R 16 Substituted or unsubstituted 5- to 9-membered aryl, or R 16 In one embodiment, R is a substituted or unsubstituted 5- to 9-membered heteroaryl. 15 is R 16 substitution C 1~3 alkyl, and each R16 is independently

[0185] In one embodiment, each R 16 is halogen, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , S.O. 2 CH 3 , unsubstituted C 1~3 Alkyl, unsubstituted C 3~6 It is cycloalkyl, an unsubstituted 3- to 6-membered heterocycle, an unsubstituted 5- to 9-membered aryl, or an unsubstituted 5- to 9-membered heteroaryl.

[0186] In one embodiment, R 16 are independently halogen, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , or SO 2 CH3 In one embodiment, each R 16 are independently 17 Substituted or unsubstituted C 1~3 In one embodiment, each R 16 are independently 17 Substituted or unsubstituted C 3~6 In one embodiment, each R 16 are independently 17 In one embodiment, each R 16 are independently 17 In one such embodiment, the 4-, 5-, or 6-membered heterocycle contains at least one N heteroatom. In one embodiment, each R 16 are independently 17 In one embodiment, each R 16 are independently or R 17 In one embodiment, each R 16 are independently 17 It is a substituted or unsubstituted 4-, 5- or 6-membered heteroaryl. In one such embodiment, the 4-, 5- or 6-membered heteroaryl contains at least one N or O heteroatom. In another such embodiment, the 4-, 5- or 6-membered heteroaryl contains at least one N heteroatom. In another such embodiment, the 4-, 5- or 6-membered heteroaryl contains at least one O heteroatom.

[0187] In one embodiment, R 17 are independently halogen, CN, C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , or SO 2 CH 3In another embodiment, each R 17 are independently CN, NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , S.O. 2 CH 3 , or unsubstituted C 1~3 In one such embodiment, each R 17 are independently CN, NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , S.O. 2 CH 3 , or methyl.

[0188] In one embodiment, ring A is a 3-6 membered heterocycle. In one such embodiment, ring A is a 4-, 5- or 6-membered ring containing one or more N heteroatoms. In another embodiment, the ring is a 5- to 9-membered heteroaryl containing at least one N heteroatom. In one such embodiment, ring A is a 6-membered heteroaryl containing at least one N heteroatom. In one embodiment, ring A is azetidinyl, thietanyl 1,1-dioxide, imidazolyl, thiazolyl, isothiazolyl, triazolyl, pyrazolyl, pyrazinyl, pyridonyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolopyridinyl, or pyrazolopyridinyl. In another embodiment, ring A is imidazolyl, isothiazolyl, or triazolyl. In another embodiment, ring A is pyrazolyl, pyridonyl, pyridinyl, pyrimidinyl, or pyridazinyl.

[0189] In one embodiment, R 5 R 5A substitution C 1~3 If it is alkyl, R 5 may be a moiety of formula (T5) or (T6), which moiety is of formula Contains part TIFF2024513881000060.tif74170.

[0190] In one embodiment, R 5 R 5A substitution C 1~3 If it is alkyl, R 5 may be a moiety of formula (T5) or (T6), which moiety is of formula Contains part TIFF2024513881000061.tif77170.

[0191] In one embodiment, R 5 R 5A substitution C 1~3 If it is alkyl, R 5 can be a part of (T1), and R 5A is as described herein. 5 When is a moiety of (T1), in one embodiment, R 5A CN, OH, C(O)N(R 11 ) 2 , C(O)R 11 , S.O. 2 R 12 , N.R. 13 R 14 , R 5B Substituted or unsubstituted azetidinyl, or R 5B R is a substituted or unsubstituted oxetanyl. 5 When is a moiety of (T1), in one embodiment, R 5A is NR 13 R 14 and R 13 and R 14 are independently hydrogen, R 15 Substituted or unsubstituted C 1~6 Alkyl, R 15 Substituted or unsubstituted C 3~6 Cycloalkyl or R 15 In one embodiment, R 13 and R 14 is hydrogen. In another embodiment, R 13 and R 14 At least one of the following is R 15 Substituted or unsubstituted C 1~6 In one such embodiment, R 13 and R 14In another embodiment, at least one of R 13 and R 14 At least one of the following is R 15 Substituted or unsubstituted C 1~3 It is an alkyl group. 13 and R 14 At least one of the following is R 15 Substituted or unsubstituted C 1~3 When R15 is alkyl, R15 is C(O)CH 3 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , R 16 Substituted or unsubstituted C 1~3 Alkyl, R 16 Substituted or unsubstituted C 3~6 Cycloalkyl, R 16 Substituted or unsubstituted 3- to 6-membered heterocycle, R 16 Substituted or unsubstituted 5- to 9-membered aryl, or R 16 It can be a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0192] In one embodiment of the compounds described herein, or pharma- ceutically acceptable salts thereof, R 5 is R 5A Substituted or unsubstituted C 3~10 In one such embodiment, R 5 is R 5A In another such embodiment, R 5 R is an alkyl group in which at least one of the rings is a cycloalkyl moiety. 5A In one embodiment, the C3-5 cycloalkyl is spiro-bonded to a carbon of another ring.

[0193] In one embodiment, R 5 is R 5A In one such embodiment, R 5is R 5A In another such embodiment, R 5 R is an alkyl group in which at least one of the rings is a heterocyclic moiety. 5A A substituted 7- to 10-membered bicyclic heterocycle. In one embodiment, a 3- to 5-membered heterocycle is spiro-bonded to a carbon of another ring.

[0194] In one embodiment, R 5 is R 5A In one such embodiment, R 5 is R 5A In another such embodiment, R 5 is an R in which at least one of the rings is a heteroaryl moiety. 5A It is a substituted 7- to 10-membered bicyclic heteroaryl.

[0195] In one embodiment, R 5 is R 5A Substituted or unsubstituted cyclopentapyridinyl, R 5A It is a substituted or unsubstituted pyrrolopyridinyl, pyrazolopyridinyl, or imidazopyridinyl.

[0196] In one embodiment, R 6 and R 6A are independently hydrogen or R 6B Substituted or unsubstituted C 1~6 In another embodiment, R 6 and R 6A are independently hydrogen, NR 13 R 14 , or R 6B Substituted or unsubstituted C 1~6 In yet another embodiment, R 6 and R 6A are independently hydrogen, halogen, or R 6B Substituted or unsubstituted C 1~6 In one embodiment, R 6 is R 6B Substituted or unsubstituted C 1~3 In one embodiment, R6 is R 6B substitution C 1~3 In one embodiment, R 6A is R 6B Substituted or unsubstituted C 1~3 In one embodiment, R 6A is R 6B substitution C 1~3 In one embodiment, R 6 and R 6A At least one of is independently hydrogen. 6 is hydrogen. In another embodiment, R 6 and R 6A At least one of the following is independently R 6B Substituted or unsubstituted C 1~3 is alkyl, R 6B is halogen, CN, or OH. In one such embodiment, R 6 and R 6A One of them is hydrogen and the other is R 6B Substituted or unsubstituted C 1~3 In one such embodiment, R 6B is halogen, CN or OH. In one embodiment, R 6 is methyl, CHCN or CHOH, R 6A is hydrogen. In one embodiment, R 6A is methyl, CHCN or CHOH, R 6 is hydrogen.

[0197] In one embodiment, R 6B is halogen, CN, OH or OCH 3 In one embodiment, R 6B CF 3 , CHF 2 , or C.H. 2 F. In one embodiment, R 6B or unsubstituted C 1~3 In one embodiment, R 6B is CN.

[0198] In one such embodiment, R 1is as described herein. In another such embodiment, R 1 is a moiety of formula (A1), (A2), or (B). In another such embodiment, R 2 is a moiety of formula (H), (J), (K), (L), (M), (N), (O), or (P).

[0199] In another such embodiment, the compound is a compound of formula (II) having the formula:

[0200] In one embodiment, the compound of formula (I) is TIFF2024513881000062.tif34170 (in the formula, R 1 is a moiety of formula (A1), (A2), or (B); R 8 is a moiety of formula (D1), (D2), (D3), (E), (G), or (G1), and X is O. or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof. In another embodiment of the compound of formula (II), R 1 is a moiety of formula (A1) or (A2), R 8 is a moiety of formula (D1), (D2), (D3), (E), (G) or (G1) and X is O. In yet another embodiment, R 1 is part of formula (B), and R 8 is a moiety of formula (D1), (D2), (D3), (E), (G), or (G1), and X is O. In some such embodiments, R 5 is a portion of (T1), (T2), (T3), (T4), (T5), or (T6).

[0201] In one embodiment, the compound of formula (I) is TIFF2024513881000063.tif35170 (in the formula, R 1 is a moiety of formula (A1), (A2), or (B), and X is O. or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof. In another embodiment of the compound of formula (III), R1 is a moiety of formula (A1) or (A2) and X is O. In yet another embodiment, R 1 is a moiety of formula (B) and X is O. In some such embodiments, R 5 is a portion of (T1), (T2), (T3), (T4), (T5), or (T6).

[0202] In one embodiment, R of the compounds described herein 8 teeth, The file is TIFF2024513881000064.tif27170.

[0203] In one embodiment, R of the compounds described herein 8 teeth, The file is TIFF2024513881000065.tif33170.

[0204] In another embodiment, R of the compounds described herein 8 teeth, The file is TIFF2024513881000066.tif27170.

[0205] In one embodiment, R of the compounds described herein 8 teeth, The file is TIFF2024513881000067.tif19170.

[0206] Further provided herein is a compound of the formula: TIFF2024513881000068.tif84170 (in the formula, R 1 , R 3 , R 4 , R 5 , R 5A , R 5B , R 6 , R 6A , R 8 , X and ring A are as defined herein. or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof. In one embodiment of the compound of formula (II), (IIa), (IIb), (IIc), (IId), (IV), (IVa), (IVb), or (IVc), R 8 teeth, The file is TIFF2024513881000069.tif71170.

[0207] In another embodiment of the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IV), (IVa), (IVb) or (IVc), R 8 teeth, TIFF2024513881000070.tif21170 (wherein R9, W, W1, q, j, and k are as described herein) It is.

[0208] In another embodiment of the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IV), (IVa), (IVb) or (IVc), R 8 teeth, TIFF2024513881000071.tif33170 (wherein R9 and R10 are as described herein) It is.

[0209] In another embodiment of the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IV), (IVa), (IVb) or (IVc), R 8 teeth, The file is TIFF2024513881000072.tif19170.

[0210] formula: TIFF2024513881000073.tif84170(in the formula, R1, R 3 , R 4 , R 5 , R 5A , R 5B , R 6 , R 6A , R 8, X and ring A are as defined herein. Further provided herein is a compound of the formula: or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0211] In one embodiment, the compound of Formula (I), (II) or (III), or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, is a compound of Table 1.

[0212] Table 1 TIFF2024513881000074.tif213170TIFF2024513881000075.tif249170TIFF2024513881000076.tif23 9170TIFF2024513881000077.tif242170TIFF2024513881000078.tif238170TIFF2024513881000079.t if221170TIFF2024513881000080.tif203170TIFF2024513881000081.tif155170TIFF20245138810000 82.tif235170TIFF2024513881000083.tif228170TIFF2024513881000084.tif232170TIFF20245138810 00085.tif237170TIFF2024513881000086.tif245170TIFF2024513881000087.tif216170TIFF2024513 881000088.tif239170TIFF2024513881000089.tif253170TIFF2024513881000090.tif253170TIFF202 4513881000091.tif233170TIFF2024513881000092.tif212170TIFF2024513881000093.tif237170TIF F2024513881000094.tif243170TIFF2024513881000095.tif237170TIFF2024513881000096.tif162170

[0213] In one embodiment, the compound of Formula (I), (II) or (III), or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, is a compound of Table 1.

[0214] Table 2: G12D compounds TIFF2024513881000097.tif238170TIFF2024513881000098.tif213170TIFF2024513881000099.tif253170TIFF2024513881000100.tif49170

[0215] Compound synthesis The compounds described herein of the present disclosure, or the stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, can be made by a variety of methods illustrated in the exemplary synthetic reaction schemes shown and described below. The starting materials and reagents used in the preparation of these compounds are generally available from commercial suppliers such as Aldrich Chemical Co., or may be purchased from other sources, such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley and Sons: New York, vol. 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley and Sons: New The compounds are prepared by methods known to those skilled in the art, according to the procedures described in references such as, for example, John Wiley & Sons, Inc., New York, 1991, vol. 1-40. The synthetic reaction schemes provided herein are merely illustrative of some of the methods by which the compounds described herein or pharma- ceutically acceptable salts thereof can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to those skilled in the art in view of the disclosure contained herein.

[0216] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein and the requisite reagents and intermediates include those described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGM Huts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0217] The compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, can be prepared singly or as a compound library comprising at least two, e.g., 5-1,000 compounds, or 10-100 compounds. Libraries of compounds described herein of the formulas described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, can be prepared by combinatorial split and mix approaches, or by multiple parallel synthesis, e.g., using either solution phase or solid phase chemistry. Thus, according to a further aspect, there is provided herein a compound library comprising at least two compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof.

[0218] The examples provide exemplary methods for preparing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts. Although specific starting materials and reagents are described and discussed in the examples, other starting materials and reagents can be substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the exemplary compounds prepared by the methods described can be further modified in light of the present disclosure using conventional chemistry.

[0219] In preparing the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, protection of remote functionality (e.g., primary or secondary amines) of intermediates may be necessary. The need for such protection will vary with the nature of the remote functionality and the conditions of the preparation method. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethylenoxycarbonyl (Fmoc). The need for such protection is readily 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).

[0220] In the process for preparing the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma-ceutically acceptable salts thereof, it may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or sequence of steps are separated and / or purified to the desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods, including, for example, reversed-phase and normal-phase, size exclusion, ion exchange, high-, medium-, and low-pressure liquid chromatography methods and equipment, small-scale analytical, simulated moving bed (SMB) and preparative thin- or thick-layer chromatography, and small-scale thin-layer and flash chromatography techniques.

[0221] Another class of separation methods involves treating the mixture with a selected reagent to bind or otherwise render separable the desired product, unreacted starting materials, reaction by-products, etc. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, etc. Alternatively, the reagent may be an acid in the case of basic substances, a base in the case of acidic substances, a binding reagent such as an antibody, a binding protein, a selective chelating agent such as crown ethers, liquid-liquid ion extraction reagents (LIX), etc. The selection of an appropriate separation method depends on the properties of the materials involved, such as boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of the materials in acidic and basic media in multiphase extraction, etc.

[0222] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences, for example, by methods such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Moscha acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharma-ceutically acceptable salts, may also be atropisomers (e.g., substituted biaryls). Enantiomers can also be separated using chiral HPLC columns.

[0223] A single stereoisomer, e.g., an enantiomer, can be obtained substantially free of its stereoisomer by resolving the racemic mixture using methods such as the formation of diastereomers with optically active resolving agents (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley and Sons, Inc., New York, 1994; Lochmuller, CH, (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds described herein or pharma- ceutically acceptable salts thereof can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional recrystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers under chiral conditions. See Drug Stereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

[0224] In method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), with asymmetric compounds bearing acidic functional groups, such as carboxylic and sulfonic acids. The diastereomeric salts can be induced to separate by fractional recrystallization or ionic chromatography. To separate the optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can form diastereomeric salts.

[0225] 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 the asymmetric compound with an enantiomerically pure chiral derivatizing agent such as a menthyl derivative, followed by separation and hydrolysis of the diastereomers to obtain the pure or enriched enantiomer. A method for determining optical purity involves making a chiral ester such as a menthyl ester, e.g., (-)-menthyl chloroformate, or Mosher's ester, α-methoxy-α-(trifluoromethyl)phenylacetate (Jacob III. J. Org. Chem. (1982) 47:4165), in the presence of a base of the racemic mixture, and testing for the presence of the enantiomers or diastereomers of the two atropisomers. 1This involves analyzing the H NMR spectrum. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal and reverse phase chromatography following the method for separating atropisomeric naphthyl-isoquinolines (WO 96 / 15111). Racemic mixtures of the two enantiomers can be separated by chromatography using chiral stationary phases according to method (3) ("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 separated by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[0226] The chemical reactions described herein can be easily adapted to prepare other compounds described herein and their pharmaceutically acceptable salts. For example, the synthesis of compounds not exemplified herein and their pharmaceutically acceptable salts can be successfully carried out by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications to reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds described herein and their pharmaceutically acceptable salts.

[0227] Pharmaceutical preparations Also provided herein are pharmaceutical compositions comprising a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

[0228] The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be formulated according to standard pharmaceutical practice as pharmaceutical compositions.Thus, further provided herein are pharmaceutical compositions comprising the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable excipients.

[0229] A typical formulation is prepared by mixing the compound described herein or its pharma- ceutically acceptable salt with an additive. Suitable carriers, diluents and additives include, but are not limited to, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and other materials. The particular additives used depend on the means and purpose for which the compound described herein or its pharma- ceutically acceptable salt is applied. Solvents are generally selected based on solvents that are recognized as safe (GRAS) for administration to mammals. In general, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, and other known additives to provide proper presentation of the drug (i.e., a compound described herein or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0230] The formulations can be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., the compound described herein or a pharma- ceutically acceptable salt thereof, or a stabilized 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 additives. The compound described herein or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof described herein is typically formulated into a pharmaceutical dosage form to provide an easily controllable drug dosage and allow patient compliance with a prescribed regimen.

[0231] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, the article for distribution includes a container having the pharmaceutical formulation disposed therein in a suitable form. Suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, and metal cylinders. The container may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, the container has disposed thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0232] Pharmaceutical formulations of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts, can be prepared for various routes and types of administration. For example, the compounds, or their stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts, having the desired degree of purity, can be mixed with one or more pharma- ceutical acceptable excipients (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), optionally in the form of a lyophilized formulation, a ground powder, or an aqueous solution. Formulation may be performed by mixing with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dose and concentration employed, at ambient temperature, at an appropriate pH, and at the desired degree of purity. The pH of the formulation depends primarily on the specific application and the concentration of the compound, but may range from about 3 to about 8. For example, formulation in acetate buffer at pH 5 may be a preferred embodiment.

[0233] The pharmaceutical compositions may generally be stored as a solid composition, a lyophilized formulation or an aqueous solution.

[0234] The pharmaceutical compositions described herein can be formulated, prescribed and administered in a manner consistent with full medical practicality, i.e., amount, concentration, schedule, course, vehicle and route of administration.Factors to be considered in this regard include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the drug, the method of administration, the administration schedule, and other factors known to medical practitioners.The effective amount of the compound to be administered, or its stereoisomer, atropisomer, tautomer or pharmaceutically acceptable salt, is governed by such considerations and is the minimum amount necessary to improve or treat the hyperproliferative disorder.

[0235] As a general proposition, an initial pharma- ceutically effective amount of a parenterally administered compound, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, will be in the range of about 0.01-100 mg / kg, i.e., about 0.1-20 mg / kg of the patient's body weight per day, with a typical initial range of the compound used being 0.3-15 mg / kg / day. In another embodiment, the pharmaceutical compositions described herein comprise an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, in an amount of about: 1 mg to 10 mg; 10 mg to 25 mg; 20 mg to 50 mg; 50 mg to 75 mg; 70 mg to 100 mg; 100 mg to 150 mg; 100 mg to 200 mg; 100 mg to 500 mg; 200 mg to 500 mg; 250 mg to 500 mg; 500 mg to 1000 mg; or 750 mg to 1000 mg.

[0236] Acceptable pharma- ceutically acceptable additives are nontoxic to recipients at the dosages and concentrations employed and include, but are not limited to, buffers (such as phosphate, citric acid, 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; amino acids (such as glycine, glutamine, asparagine, histidine, arginine, or lysine); monosaccharides, disaccharides, and other sugar chains (including glucose, mannose, or dextrin); chelating agents (such as EDTA); sugars (such as sucrose, mannitol, trehalose, or sorbitol); salt-forming counterions (such as sodium); metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants (such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG)). The active pharmaceutical ingredient may also be incorporated into microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, respectively, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0237] The compound described herein or its pharmaceutically acceptable salt may be prepared as a sustained release preparation.Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound described herein or its pharmaceutically acceptable salt, and the matrices are 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)), polylactides (US Pat. No. US3773919), copolymers of L-glutamic acid and γ-L-ethyl glutamate, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT (injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0238] Formulations include those suitable for the routes of administration detailed herein. Formulations may conveniently be presented in unit dosage form and may 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 bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0239] Formulations of the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof suitable for oral administration can be prepared as discrete units, such as pills, capsules, cachets, or tablets, each containing a predetermined amount of such a compound, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent, and the like. Molded tablets can be made by molding in a suitable machine a mixture of moistened powdered active ingredient and an inert liquid diluent. The tablets can be optionally coated or grooved, and are optionally formulated to provide a slow or controlled release of the active ingredient therefrom. Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, such as gelatin capsules, syrups, or elixirs may be prepared for oral use. Formulations of the compounds described herein or their pharma- ceutically acceptable salts intended for oral use may be prepared according to any method for preparing pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient mixed with non-toxic pharma-ceutically acceptable additives suitable for the manufacture of tablets may be acceptable. These additives may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, for example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0240] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of 0.075-20% w / w. When formulated in an ointment, the active ingredient may be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG400), and mixtures thereof. The topical formulations may optionally contain a compound that enhances 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 analogues. The oily phase of the emulsions of the compositions provided herein may be composed of known ingredients in a known manner. A phase may simply comprise an emulsifier, but desirably comprises 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 included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Taken together, the emulsifier(s) with or without the stabilizer(s) constitute the so-called emulsifying wax, and the wax together with the oil and fat constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. Emulsifiers and emulsion stabilizers suitable for use in the formulations described herein include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0241] Aqueous suspensions containing the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts, can contain the active material in admixture with additives suitable for the manufacture of aqueous suspensions, such as suspending agents, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, dispersing or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example 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.

[0242] The pharmaceutical compositions of the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharma-ceutically acceptable salts, may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. The suspension may be formulated using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be conventionally used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables as well.

[0243] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans may contain approximately 1-1000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions may be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3-500 μg of active ingredient per milliliter of solution to result in infusion of a suitable volume at a rate of about 30 mL / hour.

[0244] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which 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.

[0245] Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5-20% w / w, for example about 0.5-10% w / w, for example about 1.5% w / w.

[0246] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth, pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia, and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0247] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0248] Formulations suitable for pulmonary 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 in increments of microns such as 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nostrils to reach the alveolar sacs, or by inhalation through the mouth. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered together with other therapeutic agents, such as compounds previously used in the treatment or prevention of disorders described below.

[0249] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations which contain, in addition to the active ingredient, such carriers as are deemed appropriate.

[0250] The formulations may be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or daily unit sub-dose of the active ingredient, as herein above recited, or an appropriate fraction thereof.

[0251] In one embodiment, the compound or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt is formulated as a prodrug. As used herein, the term prodrug refers to a derivative of a compound that can be hydrolyzed, oxidized, or cleaved under biological conditions to provide the compound or its stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt. Prodrugs as defined herein include derivatives that contain one or more moieties that modulate or improve one or more physical, physiological, or pharmaceutical properties, such as solubilization, permeability, uptake, biodistribution, metabolic stability, onset of action, or any other drug-like property, and are converted to a bioactive or more biologically active substance as provided herein. In one embodiment, the prodrugs herein have no biological activity until the release of the compound or its pharmaceutically acceptable salt.

[0252] Method of administration The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, can be administered by any route appropriate to the condition being treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), intravaginal, intraperitoneal, intrapulmonary, and intranasal. For localized immunosuppressive treatment, the compounds can be administered by intralesional administration, including perfusing or otherwise contacting the graft with an inhibitor prior to transplantation. It will be understood that the preferred route may vary, for example, with the condition of the recipient. When the compound, or its stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are administered orally, they can be formulated as pills, capsules, tablets, and the like, together with pharmaceutically acceptable carriers or excipients. When the compound, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, is administered parenterally, it may be formulated in a unit dosage injectable form, as detailed below, with a pharma- ceutically acceptable parenteral vehicle.

[0253] Thus, in one aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable additives.In one embodiment, the compound described herein or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof is administered as a pharmaceutical composition that can be administered orally or parenterally to a subject.The compound described herein or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof can be formulated for topical or parenteral use, and the compound or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof is dissolved or otherwise suspended in a solution suitable for injection, suspension, syrup, cream, ointment, gel, spray, solution, and emulsion.

[0254] Oral administration can facilitate 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, tablets (e.g., coated, uncoated, chewing), and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric-coated capsules, and sustained release capsules). Tablets can be prepared by direct compression, wet granulation, or dry granulation. Oral pharmaceutical compositions comprising the compounds described herein can be formulated for delayed or extended release.

[0255] Doses for treating human patients can range from about 10 mg to about 1000 mg of the compounds described herein. A typical dose can be from about 100 mg to about 300 mg of the compound. Doses can be administered once a day (QID), twice a day (BID), or more frequently depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion, of the particular compound. Dosing, as used herein, refers to the frequency of administration and not the number of individual units that a patient must take for administration, for example, as described herein. Thus, in some embodiments, a patient may take two or more dosage units (e.g., two or more pills / tablets / capsules) QD. In addition, toxicity factors can affect the dose and administration regimen. When administered orally, pills, capsules, or tablets may be taken orally every day for a specified time period, or more spaced apart. This regimen can be repeated for a given number of treatment cycles.

[0256] Treatment Methods and Uses The compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as Ras inhibitors. In one aspect, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as KRas inhibitors. In another embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as KRasG12V inhibitors. In yet another embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as pan-KRas inhibitors (i.e., compounds that inhibit the activity of mutant KRas proteins). In one embodiment, the compounds of Table 2 described herein, or their stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts, are useful as KRasG12D inhibitors. In such embodiments, such compounds are useful in the methods described herein, where such cancer or disease is mediated by KRasG12D.

[0257] Provided herein is a method of contacting a cell, such as an ex vivo cell, with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, to inhibit KRas activity in the cell. In another embodiment, the activity is mutant KRasG12V activity. In another embodiment, the activity is mutant KRas activity (e.g., mutant pan-KRas activity).

[0258] As used herein, inhibition of the activity of two or more KRas mutants is referred to as pan-KRas inhibition. In such cases, the compounds described herein or pharma- ceutically acceptable salts thereof inhibit the activity of two or more mutant KRas proteins. In certain examples, such compounds or pharma- ceutically acceptable salts thereof selectively inhibit two or more mutant KRas proteins compared to wild-type (WT) KRas protein activity. In such an embodiment, the pan-KRas inhibitors described herein and used in the methods provided herein inhibit mutant KRas proteins at least 5-fold, 8-fold, 10-fold, 12-fold, 15-fold, 20-fold, 24-fold, 27-fold, 50-fold, 100-fold, 500-fold, 700-fold, 1000-fold, 1300-fold, 1700-fold, 2000-fold, 5000-fold, or more than WT KRas protein. In one embodiment, such KRas mutations are in the SWII domain. In one embodiment, such KRas mutations correspond to changes in the native amino acid at positions corresponding to G12, G13, Q61, or A146. In some embodiments, the mutations correspond to G12A, G12C, G12D, G12R, G12S, G12V, G13A, G13C, G13D, G13R, G13S, G13V, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, A146T, A146P, A146V, or A146T.

[0259] Further provided herein is a method of treating a cancer containing a KRas mutation, comprising administering to a patient having such a cancer an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the KRas mutation is KRas G12V In yet another embodiment, the mutation is a known KRas mutation (e.g., treatment with a compound described herein that exhibits pan-KRas inhibition, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt, or pharmaceutical composition thereof).

[0260] In one embodiment, the method comprises administering G12V The method further comprises testing a sample from the patient (e.g., as described herein) for the absence or presence of a mutation prior to administration of a compound described herein or a pharma- ceutically acceptable salt thereof. In one such embodiment, a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition is administered to the patient after the patient sample is determined to be positive for a KRas mutation (e.g., a Kras mutation is present). In one embodiment, the method further comprises testing a sample from the patient (e.g., as described herein) for the absence or presence of a KRas mutation prior to administration of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition is administered to the patient after the patient sample is determined to be positive for such a KRas mutation (e.g., a Kras mutation is present).

[0261] The methods of treating cancer described herein include, but are not limited to, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical atypical teratoid / rhabdoid tumors, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML ... ML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, uterine cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, Pancreatic neuroendocrine tumors, Kidney cancer, Laryngeal cancer, Lip and oral cavity cancer, Lobular carcinoma in situ (LCIS), Lung cancer, Lymphoma, Occult primary metastatic squamous neck cancer, Midline carcinoma, Oral cancer, Multiple endocrine neoplasia syndrome, Multiple myeloma / plasma cell neoplasm, Mycosis fungoides, Myelodysplastic syndrome, Myelodysplasia / myeloproliferative neoplasia, Multiple myeloma, Merkel cell carcinoma, Malignant mesothelioma, Malignant fibrous histiocytoma and osteosarcoma of bone, Nasal cavity and paranasal sinus cancer, Nasopharyngeal cancer, Neuroblastoma, Non-Hodgkin's lymphoma, Non-small cell lung cancer (NSCLC), Oral cavity cancer, Oropharyngeal cancer, For the treatment of cancers such as head cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, abnormal cancer of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.

[0262] In some embodiments, the cancer is 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. The lung cancer can be adenocarcinoma, non-small cell lung cancer (NSCLC), or small cell lung cancer (SCLC). In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is lung adenocarcinoma.

[0263] The methods provided herein may also include testing a sample from a patient prior to administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, for the absence or presence of a KRas mutation corresponding to position 12 of KRas (e.g., Gly12). In one embodiment, the compound, a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, or pharmaceutical composition is administered to a patient after a patient sample indicates the presence of a KRas mutation corresponding to position 12 of KRas (e.g., Gly12). In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, is not administered unless the patient sample contains a KRas mutation corresponding to position 12 of KRas (e.g., Gly12).

[0264] The methods provided herein also include methods for detecting KRas G12V This may include testing a sample from the patient prior to administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, for the absence or presence of a mutation. In one embodiment, the compound, stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, or pharmaceutical composition is administered to a patient sample prior to administration of a compound described herein, or a ... for the absence or presence of a mutation. G12V In one embodiment, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, is administered to the patient after the patient sample indicates the presence of a KRas mutation. G12V It will not be administered unless it contains a mutation.

[0265] The methods provided herein can further include testing a sample from the patient prior to administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, for the absence or presence of a KRas mutation, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, has pan-KRas inhibition. In one embodiment, the compound, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, or pharmaceutical composition is administered to the patient after the patient sample indicates the presence of a KRas mutation, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, has pan-KRas inhibition. In one embodiment, the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, are not administered unless the patient sample contains a KRas mutation, and the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, have pan-KRas inhibition.

[0266] In one embodiment, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In another embodiment, the pancreatic cancer, lung cancer, or colorectal cancer is a cancer that is associated with a KRas G12V In yet another embodiment, the cancer is tissue independent but includes a KRas G12V Includes mutations.

[0267] In another embodiment, the pancreatic cancer, lung cancer, or colorectal cancer contains a KRas mutation. In one such embodiment, the cancer is tissue independent but contains a KRas mutation. In such an embodiment, the cancer can be treated as described herein with a compound having pan-KRas inhibition, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0268] KRas G12VFurther provided herein is a method of treating a lung cancer comprising a mutation in a patient having such a lung cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof (or a pharmaceutical composition comprising the same). In one embodiment, the lung cancer is a non-small cell lung carcinoma (NSCLC). The NSCLC can be, for example, an adenocarcinoma, a squamous cell lung carcinoma, or a large cell lung carcinoma. In another embodiment, the lung cancer is a small cell lung carcinoma. In yet another embodiment, the lung cancer is an adenocarcinoma, a carcinoid tumor, or an undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is a stage III or stage IV lung cancer. The methods provided herein include administering the compound as a 1L treatment.

[0269] Further provided herein is a method of treating a lung cancer comprising a KRas mutation (e.g., corresponding to position Gly12) in a patient having such a lung cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof (or a pharmaceutical composition comprising the same), wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof has pan-KRas inhibition. In one embodiment, the lung cancer is a non-small cell lung carcinoma (NSCLC). The NSCLC can be, for example, an adenocarcinoma, a squamous cell lung carcinoma, or a large cell lung carcinoma. In another embodiment, the lung cancer is a small cell lung carcinoma. In yet another embodiment, the lung cancer is an adenocarcinoma, a carcinoid tumor, or an undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer. The methods provided herein include administering the compounds as a 1L treatment.

[0270] KRas G12VFurther provided herein is a method of treating a pancreatic cancer comprising a mutation in a patient having such a pancreatic cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof. In one embodiment, the patient has previously been treated with radiation and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is stage 0, stage I, or stage II. In another embodiment, the pancreatic cancer is stage III or stage IV.

[0271] Further provided herein is a method of treating a pancreatic cancer comprising a KRas mutation (e.g., corresponding to position Gly12) in a patient having such pancreatic cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition. In one embodiment, the patient has previously been treated with radiation and one or more chemotherapeutic agents. In one embodiment, the pancreatic cancer is stage 0, stage I, or stage II. In another embodiment, the pancreatic cancer is stage III or stage IV.

[0272] KRas G12V Still further provided herein is a method for treating a colon cancer comprising a mutation in a patient having such a colon cancer, comprising administering to the patient an effective amount of a compound as described herein, or a stereoisomer, atropisomer, tautomer, or pharma-ceutically acceptable salt thereof. In one embodiment, the colon cancer is stage I or stage II. In another embodiment, the colon cancer is stage III or stage IV.

[0273] Still further provided herein is a method for treating colon cancer comprising a KRas mutation (e.g., corresponding to position Gly12) in a patient having such colon cancer, comprising administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition. In one embodiment, the colon cancer is stage I or stage II. In another embodiment, the colon cancer is stage III or stage IV.

[0274] KRas G12V Further provided herein is a method for treating a tissue-independent cancer comprising a mutation. In one embodiment of such a method, method (Ag2) comprises: (a) KRas expression in samples from patients diagnosed with suspected cancer G12V Measuring the presence or absence of mutations; (b) administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof; Includes.

[0275] Further provided herein is a method for treating a tissue-independent cancer comprising a KRas mutation (e.g., corresponding to position Gly12). In one embodiment of such a method, method (Ag3) comprises: (a) determining the presence or absence of KRas mutations in samples taken from patients diagnosed with suspected cancer; (b) administering to the patient an effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, has pan-KRas inhibition. Includes.

[0276] In one embodiment of the methods of Ag1, Ag2, and Ag3, the patient is diagnosed with a cancer as described herein. In another embodiment of the methods of Ag1, Ag2, and Ag3, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is taken before administration of any therapy. In another such embodiment, the sample is taken before administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, and after administration of another chemotherapeutic agent. In another embodiment of the methods of Ag1, Ag2, and Ag3, the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, is administered (e.g., orally) as provided herein.

[0277] Also provided herein are compounds, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, for use as therapeutically active substances. In another such embodiment, the compounds, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, inhibit KRas. G12V In yet another such embodiment, the compounds, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, may be for the therapeutic treatment of cancers that contain KRas mutations (e.g., corresponding to position Gly12), and the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma-ceutically acceptable salts thereof, have pan-KRas inhibition.

[0278] KRas G12VFurther provided herein are compounds, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, for the therapeutic and / or prophylactic treatment of cancers that contain a KRas mutation (e.g., corresponding to position Gly12). Still further provided herein are compounds, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, for the therapeutic and / or prophylactic treatment of cancers that contain a KRas mutation (e.g., corresponding to position Gly12), wherein the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharmaceutically acceptable salts thereof, have pan-KRas inhibition.

[0279] In one embodiment, the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, inhibit KRas G12V In one embodiment, the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts, are used in the preparation of a medicament for the therapeutic treatment of a cancer that contains a KRas mutation (e.g., corresponding to position Gly12), and the compounds described herein, or their stereoisomers, atropisomers, tautomers, or pharma-ceutically acceptable salts, have pan-KRas inhibition.

[0280] Still further provided herein is the use of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0281] Further provided herein is a method for inhibiting tumor metastasis, comprising administering to a patient having a tumor a therapeutically effective amount of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof. In one embodiment, the inhibition is via activation of KRas G12VIn one embodiment, the inhibition is of tumors that contain a KRas mutation (e.g., corresponding to position Gly12), and the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, have pan-KRas inhibition. In another embodiment, the inhibition of tumor metastasis in a patient described herein results in a reduction in tumor size. In another embodiment, the inhibition of tumor metastasis in a patient described herein results in stabilization of tumor size (e.g., no further growth). In another embodiment, the inhibition of tumor metastasis in a patient described herein results in remission of cancer and / or its symptoms.

[0282] Further provided herein is a method for inhibiting proliferation of a cell population, comprising contacting the cell population with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof. In one embodiment, the cell population is present in a human patient. In another embodiment, the cell population is a cell population that is expressing KRas G12V In another embodiment, the cell population comprises a KRas mutation (e.g., corresponding to position Gly12), and the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, have pan-KRas inhibition.

[0283] Further provided herein is a method 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 pharma- ceutically acceptable salt thereof. In one embodiment, the KRas inhibited is KRas G12V In one embodiment, the KRas inhibited is a mutant KRas protein (e.g., corresponding to position Gly12), and the compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts thereof, have pan-KRas inhibition. In another embodiment, inhibiting KRas reduces tumor size. In another embodiment, inhibiting KRas results in the amelioration of cancer and / or its symptoms.

[0284] Further provided herein is a method 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 pharma- ceutically acceptable salt thereof. In one embodiment, the mutant protein is a KRas G12V In one embodiment, the mutant protein comprises a KRas mutation, and the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, has pan-KRas inhibition. In one embodiment, the activity of KRas is decreased after contact with the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof. In another embodiment, downregulation of the activity of the KRas mutant protein treats the cancer described herein in the patient described herein. In another embodiment, downregulation of the activity of the KRas mutant protein results in a reduction in tumor size. In another embodiment, downregulation of the activity of the KRas mutant protein results in the amelioration of the cancer described herein and / or symptoms thereof.

[0285] In some embodiments, the methods provided herein include inhibiting KRas in a cell. G12V and inhibiting KRas in the cell by contacting the cell with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of KRas. G12V In some embodiments, the methods provided herein include inhibiting KRas activity in a tissue. G12V and inhibiting KRas in the tissue by contacting the tissue with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of KRas in the tissue. G12V In some embodiments, the methods provided herein include inhibiting KRas activity in a patient as described herein. G12Vand inhibiting KRas in the patient by contacting the patient with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, in an amount sufficient to inhibit the activity of KRas. G12V This includes inhibiting activity.

[0286] In some embodiments, the methods provided herein include inhibiting mutant KRas (e.g., a mutation at Gly12) activity in a cell by contacting the cell with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, in an amount sufficient to inhibit activity of mutant KRas (e.g., a mutation at Gly12) in the cell. In some embodiments, the methods provided herein include inhibiting mutant KRas (e.g., a mutation at Gly12) activity in a tissue by contacting the tissue with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, in an amount sufficient to inhibit activity of mutant KRas (e.g., a mutation at Gly12) in the tissue. In some embodiments, the methods provided herein include inhibiting mutant KRas (e.g., a mutation at Gly12) activity in a patient by contacting the patient with a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, in an amount sufficient to inhibit activity of mutant KRas (e.g., a mutation at Gly12) in the patient. In such embodiments, the compounds described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, are understood to have pan-KRas inhibition.

[0287] In another embodiment, the labeled KRas G12V A method for preparing a mutant protein comprising: G12V The mutant protein is reacted with a labeled compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, to produce a labeled KRas protein. G12VFurther provided herein is a method for preparing a labeled KRas mutant protein, comprising obtaining the mutant protein. In one embodiment, the label is an imaging agent. In one embodiment, the labeled KRas G12V Using G12V The absence or presence of the mutant protein can be detected, thereby detecting the presence or absence of cancer mediated by mutant KRas.

[0288] Further provided herein is a method for preparing a labeled KRas mutant protein (e.g., mutated at Gly12), comprising reacting the KRas mutant protein with a labeled compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, has pan-KRas inhibition, resulting in a labeled KRas mutant protein. In one embodiment, the label is an imaging agent. In one embodiment, the labeled mutant KRas protein can be used to detect the absence or presence of mutant KRas in a patient sample, thereby detecting the presence or absence of cancer mediated by mutant KRas.

[0289] Further provided herein is a method of inhibiting Ras-mediated cell signaling. In one embodiment, the method comprises contacting a cell with an effective amount of one or more compounds disclosed herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof. Inhibition of Ras-mediated signaling can be assessed and demonstrated by various methods known in the art. Non-limiting examples include: (a) a decrease in the GTPase activity of Ras; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in Koff of GTP or a decrease in Koff of GDP; (d) a decrease in the amount of signaling molecules downstream of the Ras pathway, such as a decrease in the amount of pMEK; and / or (e) a decrease in binding of the Ras complex to downstream signaling molecules, including but not limited to Raf. Kits and commercially available assays can be utilized to measure one or more of the above.

[0290] KRas mutations have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments relate to the administration of the disclosed compounds described herein, or stereoisomers, atropisomers, tautomers, or pharma- ceutically acceptable salts 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 compounds disclosed herein can be used for the treatment of diseases such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the compounds described herein, or pharma- ceutically acceptable salts thereof, are useful for the treatment of all subtypes of lymphomas, such as Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0291] Determining whether a tumor or cancer contains a KRas mutation as described herein can be made 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. The sequence of wild-type human KRas (e.g., Accession No. NP203524) is known in the art.

[0292] 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 PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays, and microarray analysis. In some embodiments, samples are evaluated for KRas mutations as described herein by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRas mutation is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRas mutations are identified using direct sequencing of specific regions of the KRas gene (e.g., exon 2 and / or exon 3). The method identifies all possible mutations within the sequenced region.

[0293] The methods for determining whether a tumor or cancer contains a KRas mutation described herein can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0294] Further provided herein is the use of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt 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. In some embodiments, the cancer is a KRas G12V In some embodiments, the cancer comprises a KRas mutation (e.g., a mutation at Gly12) in which a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, has pan-KRas inhibition. In some embodiments, the cancer is 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, the use of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0295] Further provided herein is a compound as described herein, or a pharma- ceutically acceptable salt thereof, for use in a method of treating cancer. In one embodiment, the cancer is a cancer characterized by a KRas G12VIn one embodiment, the cancer comprises a KRas mutation (e.g., a mutation at Gly12) for which a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, has pan-KRas inhibition. In one such embodiment, the cancer is a hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one such embodiment, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In one such embodiment, the cancer is colorectal cancer. In one such embodiment, the cancer is pancreatic cancer. In one such embodiment, the cancer is lung adenocarcinoma.

[0296] Combination therapy 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 disorders described herein. The second compound of the combined pharmaceutical formulation or administration regimen preferably has complementary activity to the compounds described herein, or their pharmaceutically acceptable salts, so that they do not adversely affect each other. Combination therapy can provide "synergy" and prove "synergistic", i.e., an effect achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately.

[0297] Combination therapy can be administered as a simultaneous regimen or as a sequential regimen. When administered sequentially, the combination is administered in two or more doses. Co-administration includes co-administration using separate formulations or a single pharmaceutical formulation, and sequential administration in any order, preferably with time for both (or all) active agents to exert their biological activity simultaneously.

[0298] The combination therapy herein includes the administration of a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and the use of at least one other therapeutic method. The amounts and relative timing of administration of the compound described herein, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, and the other pharmaceutically active agent(s) will be selected to achieve the desired combined therapeutic effect.

[0299] In various embodiments of the method, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor (such as irinotecan, or such as etoposide, or such as doxorubicin), a taxane (such as anti-microtubule inhibitors, including paclitaxel and docetaxel), an antimetabolite (such as 5-FU, or such as gemcitabine), or an alkylating agent (such as cisplatin, or such as cyclophosphamide), or a taxane.

[0300] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, such as erlotinib, or such as afatinib. In some embodiments, the additional therapeutic agent is gefitinib, osimertinib, or dacomitinib. In some embodiments, the additional therapeutic agent is a monoclonal antibody, such as cetuximab (Erbitux) or panitumumab (Vectibix). In some embodiments, the EGFR inhibitor is a dual or pan-HER inhibitor. In another embodiment, 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 means 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, or a salt thereof (e.g., the bismesylate salt).

[0301] In yet 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 (fizitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (lovatumumab).

[0302] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor, hi some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, lestaurtinib, momelotinib, pacritinib, ruxolitinib, or TG101348.

[0303] In some other embodiments, the additional therapeutic agent is an anti-glypican 3 antibody. In some embodiments, the anti-glypican 3 antibody is codrituzumab.

[0304] In some other embodiments, the additional therapeutic agent is an antibody drug conjugate (ADC). In some embodiments, the ADC is polatuzumab vetotin, RG7986, RG7882, RG6109, or RO7172369.

[0305] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist. In some embodiments, the MDM2 antagonist is idasanutulin.

[0306] In some other embodiments, the additional therapeutic agent is an agonistic antibody against CD40. In some embodiments, the agonistic antibody against CD40 is celicrelumab (RG7876).

[0307] In some other embodiments, the additional therapeutic agent is a bispecific antibody, hi some embodiments, the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP-DR5), RG6160, RG6026, ERY974, or anti-HER2 / CD3.

[0308] In some other embodiments, the additional therapeutic agent is a targeted immunocytokine, hi some embodiments, the targeted immunocytokine is RG7813 or RG7461.

[0309] 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.

[0310] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine, hi some embodiments, the personalized cancer vaccine is RG6180.

[0311] 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.

[0312] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT, hi some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0313] 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).

[0314] In some other embodiments, the additional therapeutic agent is crizotinib, tivantinib, AMG337, cabozantinib, or foretinib, hi other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody against methionine, such as onartuzumab.

[0315] In further embodiments, the additional therapeutic agent is an SRC family non-tyrosine kinase inhibitor. For example, in some embodiments, the additional therapeutic agent is an inhibitor of the SRC family non-receptor tyrosine kinase subfamily. Exemplary inhibitors of this aspect include dasatinib. Other examples in this regard include ponatinib, saracatinib, and bosutinib.

[0316] 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, COTELLIC® (cobimetinib), PD0325901, or RO5126766. In other embodiments, the MEK inhibitor is GSK-1120212, also known as trametinib.

[0317] 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.

[0318] In other embodiments, the protein kinase inhibitor is taselisib, ipataselitib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, afatinib, axitinib, atezolizumab, bevacizumab, bosutinib, cetuximab, crizotinib, dasatinib, erlotinib, erythropoietin ... The additional therapeutic agent is selected from the group consisting of rotinibe, fostamatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, ruxolitinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, and vemurafenib. In still further embodiments, the additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is irinotecan. In some further embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include taxol and docetaxel.

[0319] In addition to the additional therapeutic agents listed above, other chemotherapeutic agents are currently known in the art and can be used in combination with the compounds described herein and their pharma- ceutically acceptable salts. In some embodiments, the chemotherapy 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, antihormones, angiogenesis inhibitors, and antiandrogens.

[0320] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; chlorambucil, tetracycline ... Nitrogen mustards such as cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; aclacinomycin, actinomycin, anthramycin, azaserine, and bleomycin. mycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, puromycin, kerama Antibiotics such as isin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,Pyrimidine analogues such as dideoxyuridinene, doxifluridine, enocitabine, and floxiridine;androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone;antiadrenal drugs such as aminoglutethimide, mitotein, and trilostane;folic acid supplements such as folinic acid;aceglatone;aldophosphamide glycosides;aminolevulinic acid;amsacrine;bestrabul;bisantrene;edatrexate;defofamine;demecolcine;diaziquone;elfomitine;elliptinium acetate;ethoglucide;gallium nitrate;hydroxyurea;lentinan ;lonidamine;mitoguazone;mitoxantrone;mopidamol;nitracrine;pentostatin;phenamet;pirarubicin;podophyllic acid;2-ethylhydrazide;procarbazine;polysaccharide K;razoxane;sizofiran;spirogermanium;tenuazonic acid;triaziquone;2,2',2''-trichlorotriethylamine;urethane;vindesine;dacarbazine;mannomustine;mitobronitol;mitolactol;pipobroman;gacytosine;arabinoside ("Ara-C");cyclophosphamide;thiotepa;taxanes (e.g. paclitaxel (TAXOL(TM), Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin; capecitabine; and pharma- ceutically acceptable salts, acids, or derivatives of any of the above. Suitable chemotherapeutic cell modulating agents include, for example, tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxyphene, keoxyphene, LY117018, onapristone, and toremifene (Farestone); flutamide, nilutamide, bicalutamide, leuprolide,Also included are anti-hormonal agents which act to regulate or inhibit hormone action in tumors, such as anti-androgens, including but not limited to goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues, including cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda™; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS 2000; and anti-estrogens, including difluoromethylornithine (DMFO). If desired, the compounds described herein or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions thereof can be administered in combination with other medicaments, such as Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, Venclexta™, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxot®, or other medicaments. ere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic drugs, tumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricoder, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific anticancer drug, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exilin, ferruginol, forodesine, fosfestol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucansone, lurtotecan, mafosfamide,It can be used in combination with commonly prescribed anticancer drugs such as mitozolomide, nafoximide, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosquidar.

[0321] The exact method for administering the compound and additional therapeutic agent will be apparent to one of skill in the art. In some exemplary embodiments, the compound and additional therapeutic agent are administered simultaneously. In other embodiments, the compound and additional therapeutic agent are administered separately.

[0322] In some embodiments, the compound and the additional therapeutic agent are administered simultaneously with the second agent or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound described herein and any of the additional therapeutic agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound described herein and any of the additional therapeutic agents can be administered simultaneously, where both agents are in separate formulations. In another embodiment, the compound can be administered immediately after administration of any of the additional therapeutic agents described herein, or vice versa. In some embodiments of the separate administration protocol, the compound described herein and any of the additional therapeutic agents are administered minutes apart, or hours apart, or days apart.

[0323] manufactured goods Also provided herein is an article of manufacture or "kit" containing materials useful for treating cancer as provided herein. In one embodiment, the kit comprises a container containing a compound described herein, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof. The kit may further comprise a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister packs, 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 pharma- ceutically acceptable salt thereof, or a formulation thereof, that is effective for treating a condition, and may have a sterile access port (e.g., the container may be an intravenous fluid bag or a vial with a stopper that can be pierced by a hypodermic needle). At least one active agent in the composition is a compound described herein, or a pharma- ceutically acceptable salt thereof. Alternatively, or additionally, the article of manufacture may further comprise a second container containing a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextrose solution. The article of manufacture may further comprise other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0324] In another embodiment, the kit is suitable for delivery of a solid oral form (e.g., tablet or capsule) of the compound described herein or a pharma- ceutically acceptable salt thereof. Such a kit can include a number of unit doses. An example of such a kit is a "blister pack." Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms.

[0325] Embodiment Embodiment No. 1: Formula (I): TIFF2024513881000101.tif34170 (in the formula, X is NR 13 , O, C(R x ) 2 , C(O), SO, SO 2 , or S, u is 1 or 2; Each R x are independently hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 Is it a haloalkyl? Or, two R's x taken together form a cyclopropyl with the carbon to which they are attached, R 1 is R 7 Substituted or unsubstituted indolyl, R 7 Substituted or unsubstituted benzofuranyl, R 7 Substituted or unsubstituted naphthyl, R 7 Substituted or unsubstituted indazolyl, R 7 Substituted or unsubstituted indenyl, R 7 Substituted or unsubstituted benzothiazolyl, R 7A Substituted or unsubstituted phenyl, or R 7A substituted or unsubstituted pyridinyl, Each R 7 are independently hydrogen, halogen, CN, CH 2 OH, -OH, NH 2 , N(Me) 2 , unsubstituted C 1~3 Alkyl, unsubstituted C 2~5 Alkynyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; Each R 7A are independently hydrogen, halogen, NH 2 , N(Me) 2 , unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 haloalkyl, or unsubstituted cyclopropyl; R 2 is hydrogen, OL 1 -R 8 , R 8A Substituted or unsubstituted C 1~3 Alkyl or R 8B a substituted or unsubstituted 4- to 10-membered heterocycle; L 1 is a bond or R L1 Substituted or unsubstituted C 1~3 is alkylene, R L1 is halogen or unsubstituted C 1~3 is alkyl, R 8 R containing N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; Each R 9 are independently halogen, oxo, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, R 10 Substituted or unsubstituted C 1~3 Alkylidene or R 10 Substituted or unsubstituted C 3~4 Cycloalkyl or R 10 a substituted or unsubstituted 3- or 4-membered heterocycle; Or, two R's 9 Let's get together and 3~5 forming a cycloalkyl or a 3- to 5-membered heterocycle, Hydrogen R 10 is hydrogen or halogen; Each R 8A are independently 9A Substituted or unsubstituted C 1~3 Alkyl, R 9A Substituted or unsubstituted C 1~3 Alkoxy, R 9A Substituted or unsubstituted C 3~4 Cycloalkyl or R 9A a substituted or unsubstituted 4- to 6-membered heterocycle; Each R 9A are independently halogen, oxo, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy, unsubstituted C 1~3 Alkylidene, R 9 Substituted or unsubstituted C 3~4 Cycloalkyl or R containing N, S or O 9 a substituted or unsubstituted 4- to 10-membered heterocycle; R 8B are independently halogen, oxo, -NH 2 , unsubstituted C1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 1~3 Alkoxy or unsubstituted C 1~3 is alkylidene, R 3 and R 4 are each independently hydrogen, -CN, halogen, or unsubstituted C 1~3 alkyl, or unsubstituted cyclopropyl; R 5 is R 5A -Substituted or unsubstituted C 1~6 Alkyl, R 5A -Substituted or unsubstituted C 1~6 Haloalkyl, R 5A -Substituted or unsubstituted C 3~10 Cycloalkyl, R 5A -Substituted or unsubstituted 3- to 10-membered heterocycle or R 5A -substituted or unsubstituted 5- to 10-membered heteroaryl, Each R 5A are independently halogen, oxo, CN, OR 11 , S.R. 12 , S.O. 2 R 12 , N.R. 13 R 14 , C(O)N(R 11 ) 2 , C(O)R 11 , R 5B Substituted or unsubstituted C 1~6 Alkyl, R 5B Substituted or unsubstituted C 1~6 Haloalkyl, R 5B Substituted or unsubstituted C 3~6 Cycloalkyl, R 5B Substituted or unsubstituted 3- to 6-membered heterocycle, R 5B Substituted or unsubstituted C 5~8 Aryl or R 5B a substituted or unsubstituted 5- to 9-membered heteroaryl; Or, two R's 5A Let's get together and 3~6 forming a cycloalkyl or a 3- to 6-membered heterocycle; Each R 5Bare independently halogen, oxo, CN, OR 11 , N.R. 13 R 14 , S.R. 12 , S.O. 2 R 12 , C(O)N(R 11 ) 2 , C(O)R 11 , R 5C Substituted or unsubstituted C 1~3 Alkyl, R 5C Substituted or unsubstituted C 1~3 Haloalkyl, R 5C Substituted or unsubstituted C 3~6 Cycloalkyl, R 5C Substituted or unsubstituted 3- to 6-membered heterocycle, R 5C Substituted or unsubstituted phenyl, or R 5C a substituted or unsubstituted 5- to 6-membered heteroaryl; Or, two R's 5B Let's get together and 3~4 forming a cycloalkyl or a 3- to 6-membered heterocycle; Each R 5C are independently halogen, oxo, CN, C(O)CH 3 , C(O)NH 2 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, NR 13 R 14 , S.C.H. 3 , S.O. 2 NH 2 , S.O. 2 CH 3 , unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 3~4 cycloalkyl, or an unsubstituted 3- to 4-membered heterocycle; Each R 11 are independently hydrogen, unsubstituted C 1~3 Alkyl, unsubstituted C 1~3 Haloalkyl, unsubstituted C 3~4 cycloalkyl, or an unsubstituted 3- to 4-membered heterocycle; Each R 12 Independently, NH2 or unsubstituted C 1~3 is alkyl, Each R 13 and R 14 are independently hydrogen, C(O)R 11 , C(O)N(R 11 ) 2 , R 15 Substituted or unsubstituted C 1~6 Alkyl, R 15 Substituted or unsubstituted C 3~6 Cycloalkyl or R 15 a substituted or unsubstituted 3- to 6-membered heterocycle; Each R 15 is halogen, CN, C(O)CH 3 , C(O)NH 2 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , S.O. 2 CH 3 , R 16 Substituted or unsubstituted C 1~3 Alkyl, R 16 Substituted or unsubstituted C 3~6 Cycloalkyl, R 16 Substituted or unsubstituted 3- to 6-membered heterocycle, R 16 Substituted or unsubstituted 5- to 9-membered aryl, or R 16 a substituted or unsubstituted 5- to 9-membered heteroaryl; Each R 16 are independently halogen, CN, C(O)CH 3 , C(O)NH 2 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , S.O.2 CH 3 , R 17 Substituted or unsubstituted C 1~3 Alkyl, R 17 Substituted or unsubstituted C 3~6 Cycloalkyl, R 17 Substituted or unsubstituted 3- to 6-membered heterocycle, R 17 Substituted or unsubstituted 5- to 9-membered aryl, or R 17 a substituted or unsubstituted 5- to 9-membered heteroaryl; Each R 17 are independently halogen, CN, C(O)CH 3 , C(O)NH 2 , O.H., O.C.H. 3 , C.F. 3 , CHF 2 , C.H. 2 F, N.H. 2 , N.H.C.H. 3 , N(CH 3 ) 2 , S.O. 2 NH 2 , S.O. 2 CH 3 , or unsubstituted C 1~3 is alkyl, R 6 and R 6A are independently hydrogen, halogen, or NR 13 R 14 , or R 6B Substituted or unsubstituted C 1~6 is alkyl, R 6B are halogens, CN, OH, OCH 3 , C.F. 3 , CHF 2 , C.H. 2 F or unsubstituted C 1~3 (It is alkyl) or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0326] Embodiment No. 2: R 1 But R 7A Substituted or unsubstituted phenyl, R 7 Substituted or unsubstituted indazolyl, or R 7AThe compound of embodiment 1, which is a substituted or unsubstituted pyridinyl.

[0327] Embodiment No. 3: R 1 But R 7A The compound of embodiment 1, which is substituted or unsubstituted phenyl.

[0328] Embodiment No. 4: R 1 But R 7 The compound of embodiment 1, which is a substituted or unsubstituted indazolyl.

[0329] Embodiment No. 5: R 1 But R 7A The compound of embodiment 1, which is a substituted or unsubstituted pyridinyl.

[0330] Embodiment No. 6: Each R 7A are independently halogen, NH 2 , unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 The compound of any one of embodiments 1-5, wherein the compound is haloalkyl.

[0331] Embodiment No. 7: R 1 but, TIFF2024513881000102.tif22170 (in the formula, X 1 is N, CH, or CF; R 7A is hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl) The compound of embodiment 1 or embodiment 2, wherein

[0332] Embodiment No. 8: R 1 but, The compound of any one of embodiments 1, 2, 5, or 7, wherein the compound is TIFF2024513881000103.tif22170.

[0333] Embodiment No. 9: R 1 but, The compound of any one of embodiments 1, 2, 5, 7, or 8, which is TIFF2024513881000104.tif21170.

[0334] Embodiment No. 10: R 1 but, TIFF2024513881000105.tif24170 (in the formula, R 7A is hydrogen, halogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl) The compound of any one of embodiments 1-3 or 7, wherein

[0335] Embodiment No. 11: R 1 but, 12. The compound of any one of embodiments 1-4, 8, or 11, which is TIFF2024513881000106.tif23170.

[0336] Embodiment No. 12: R 1 but, TIFF2024513881000107.tif27170 (in the formula, each R 7 are independently halogen, NH 2 , N(Me) 2 , unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl) 2. The compound of embodiment 1, wherein

[0337] Embodiment No. 13: R 2 But, OL 1 -R 8 , R 8A Substituted or unsubstituted C 1~3 Alkyl or R 8B The compound of any one of embodiments 1 to 12, which is a substituted or unsubstituted 4- to 6-membered heterocycle.

[0338] Embodiment No. 14: R 2 But, OL 1 -R 8 The compound of any one of embodiments 1-13, wherein

[0339] Embodiment No. 15: L 1 But non-substituted C 1~3 The compound of any one of embodiments 13-14, wherein the compound is alkylene.

[0340] Embodiment No. 16:R 8 The compound of any one of embodiments 13-15, wherein is a 4-10 membered heterocycle containing one N heteroatom.

[0341] Embodiment No. 17:R 8 but, TIFF2024513881000108.tif17170 (in the formula, R 9 is halogen or R 10 Substituted or unsubstituted C 1~3 is alkylidene, r is an integer from 0 to 12; j is 1, 2, or 3; k is 1 or 2. 17. The compound of any one of embodiments 13-16, wherein

[0342] Embodiment No. 18: A compound according to embodiment 17, wherein r is 0, 1, 2 or 3.

[0343] Embodiment No. 19:R 8 but, TIFF2024513881000109.tif33170 (in the formula, R 9 are independently halogen or R 10 Substituted or unsubstituted C 1~3 is alkylidene, Each R 10 are independently hydrogen or halogen; r is 1 or 2) The compound of any one of embodiments 13-18, wherein

[0344] Embodiment No. 20:R 8 but, TIFF2024513881000110.tif19170 (in the formula, R 9 are independently halogen, oxo or unsubstituted C 1~3 Is it an alkyl group? Or two R's 9 Let's get together and 3~5 Forming a cycloalkyl or a 3- to 5-membered heterocycle, r is 1 or 2) 17. The compound of any one of embodiments 13-16, wherein

[0345] Embodiment No. 21:R 8 but, TIFF2024513881000111.tif13170 (in the formula, R 9 is hydrogen or unsubstituted C 1~3 is alkyl, W is O, SO 2 , or NR 12 and R 12 is hydrogen, unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 haloalkyl) 17. The compound of any one of embodiments 13-16, wherein Embodiment No. 22:R 8 The compound of any one of embodiments 13-16 or 21, wherein is azetidinyl, oxetanyl, or thietanedioxide.

[0346] Embodiment No. 23:R 2 but, The compound of any one of embodiments 1 to 22, wherein the compound is TIFF2024513881000112.tif64170.

[0347] Embodiment No. 24:R 9 is halogen or R 10 Substituted or unsubstituted C 1~3 The compound of embodiment 23, wherein the compound is an alkylidene.

[0348] Embodiment No. 25:R 2 The compound of any one of embodiments 1-12, wherein is hydrogen.

[0349] Embodiment No. 26:R 3 The compound of any one of embodiments 1-25, wherein is hydrogen or halogen.

[0350] Embodiment No. 27:R 4 The compound of any one of embodiments 1-26, wherein is halogen.

[0351] Embodiment No. 28:R 5 But R 5A Substituted or unsubstituted C 1~6 The compound of any one of embodiments 1-27, wherein is alkyl.

[0352] Embodiment No. 29:R 5 but, TIFF2024513881000113.tif14170 The compound of any one of embodiments 1-28, wherein

[0353] Embodiment No. 30:R 5 but, TIFF2024513881000114.tif21170 (in the formula, Ring A is a 3- to 6-membered heterocycle or a 5- to 9-membered heteroaryl containing at least one N heteroatom; s is 0, 1, 2, or 3) The compound of any one of embodiments 1-29, wherein

[0354] Embodiment No. 31: A compound according to embodiment 30, wherein Ring A is azetidinyl, thietanyl 1,1-dioxide, imidazolyl, thiazolyl, isothiazolyl, triazolyl, pyrazolyl, pyrazinyl, pyridonyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolopyridinyl, or pyrazolopyridinyl.

[0355] Embodiment No. 32: A compound according to embodiment 30 or 31, wherein Ring A is imidazolyl, isothiazolyl, or triazolyl.

[0356] Embodiment No. 33: A compound according to embodiment 30 or 31, wherein Ring A is pyrazolyl, pyridonyl, pyridinyl, pyrimidinyl, or pyridazinyl.

[0357] Embodiment No. 34: Formula: The compound of embodiment 30, having TIFF2024513881000115.tif72170.

[0358] Embodiment No. 35: Two R's 5A But together, C 3~4 The compound according to any one of the embodiments 1 to 34, which forms a cycloalkyl or a 3- to 4-membered heterocycle.

[0359] Embodiment No. 36:R 5 but, TIFF2024513881000116.tif12170 (in the formula, R 5A CN, OH, COR 11 , S.O. 2 R 12 , N.R. 13 R 14 , R 5B Substituted or unsubstituted azetidinyl, or R 5B substituted or unsubstituted oxetanyl The compound of any one of embodiments 1-29, wherein Embodiment No. 37:R 5 But R 5A The compound of any one of embodiments 1 to 27, which is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0360] Embodiment No. 38: Formula: The compound of embodiment 1 having the formula: TIFF2024513881000117.tif34170, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0361] Embodiment No. 39: Formula: The compound of embodiment 1 having TIFF2024513881000118.tif70170, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0362] Embodiment No. 40: Formula: The compound of embodiment 1 having TIFF2024513881000119.tif70170, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0363] Embodiment No. 41: Formula: The compound of embodiment 1 having TIFF2024513881000120.tif84170, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0364] Embodiment No. 42: Formula: The compound of embodiment 1 having TIFF2024513881000121.tif84170, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0365] Embodiment No. 43:R 8 but, The compound of any one of embodiments 1 to 42, wherein the compound is TIFF2024513881000122.tif27170.

[0366] Embodiment No. 44:R 8 but, The compound of any one of embodiments 1 to 42, wherein the compound is TIFF2024513881000123.tif33170.

[0367] Embodiment No. 45:R 8 but, The compound of any one of embodiments 1 to 42, wherein the compound is TIFF2024513881000124.tif19170.

[0368] Embodiment No. 46: A compound according to any one of embodiments 1 to 45, wherein X is O.

[0369] Embodiment No. 47: X is C(R x ) 2 The compound of any one of embodiments 1-45, wherein

[0370] Embodiment No. 48:R 6 But R 6A Substituted or unsubstituted C 1~3 The compound of any one of embodiments 1-47, wherein is alkyl.

[0371] Embodiment No. 49:R 6 But R 6A substitution C 1~3 The compound of any one of embodiments 1-47, wherein is alkyl.

[0372] Embodiment No. 50:R 6A The compound according to embodiment 48 or 49, wherein is halogen, CN, or OH.

[0373] Embodiment No. 51:R 6 The compound of any one of embodiments 1-47, wherein is hydrogen.

[0374] Embodiment No. 52: A compound of Table 1, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0375] Embodiment No. 53: A compound of Table 2, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0376] Embodiment No. 54: A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable additives.

[0377] Embodiment No. 55: A method for treating cancer, comprising administering an effective amount of a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 54.

[0378] Embodiment No. 56: The method according to embodiment 55, wherein the cancer comprises a KRas mutation.

[0379] Embodiment No. 57: The KRas mutation is KRas G12D Mutation or KRas G12V 57. The method of embodiment 56, corresponding to a mutation.

[0380] Embodiment No. 58: The method according to embodiment 56, further comprising testing a sample from the patient prior to administration for the absence or presence of a KRas mutation.

[0381] Embodiment No. 59: The method according to embodiment 58, wherein the compound, its stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt, or pharmaceutical composition is administered to the patient after the patient sample indicates the presence of a KRas mutation.

[0382] Embodiment No. 60: The method of any one of embodiments 55 to 59, wherein the cancer is tissue-independent.

[0383] Embodiment No. 61: The method according to any one of embodiments 55 to 59, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0384] Embodiment No. 62: The method of embodiment 61, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

[0385] Embodiment No. 63: The method of embodiment 61, wherein the cancer is pancreatic cancer.

[0386] Embodiment No. 64: The method of embodiment 61, wherein the cancer is colorectal cancer.

[0387] Embodiment No. 65: The method according to any one of embodiments 55 to 64, further comprising administering at least one additional therapeutic agent.

[0388] Embodiment No. 66: The method of embodiment 65, 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.

[0389] Embodiment No. 67: A compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0390] Embodiment No. 68: Use of a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, for the therapeutic treatment of cancers that contain KRas mutations.

[0391] Embodiment No. 69: Use of a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer or pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a cancer that contains a KRas mutation.

[0392] Embodiment No. 70: Use of a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharmaceutical salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0393] Embodiment No. 71: A compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer or pharmaceutical salt thereof, for the therapeutic and / or prophylactic treatment of cancers that contain KRas mutations.

[0394] Embodiment No. 72: A method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0395] Embodiment No. 73: A method for inhibiting the proliferation of a cell population, comprising contacting said cell population with a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

[0396] Embodiment No. 74: The method of embodiment 73, wherein said inhibition of proliferation is measured as a decrease in cell viability of said cell population.

[0397] Embodiment No. 75: A method for preparing a labeled KRas mutant protein, comprising reacting a KRas mutant protein with a labeled compound according to any one of embodiments 1 to 56, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, to obtain the labeled KRas mutant protein.

[0398] Embodiment No. 76: A method for inhibiting tumor metastasis, comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1 to 53, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 54.

[0399] Embodiment No. 77: A method for synthesizing a compound of formula (I) as described herein. EXAMPLES

[0400] Working Example The following examples describe the preparation and biological evaluation of compounds within the scope of the present invention. These examples and the preparations which follow are provided to enable those skilled in the art to more clearly understand and practice the present invention. They should not be construed as limiting the scope of the present invention, but should be understood as merely illustrative and representative thereof.

[0401] Intermediate 1A: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024513881000125.tif28170

[0402] Step 1: Ethyl (2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024513881000126.tif29170

[0403] To a solution of ethyl (8S)-3,6-dioxo-1,2,5,7-tetrahydropyrrolidine-8-carboxylate (10.00 g, 47.3 mmol) in tetrahydrofuran (10 mL) was added L-selectride (1M in THF) (23.6 mL, 23.6 mmol) and the resulting mixture was stirred at -78°C for 20 minutes. Additional lithium L-selectride (1M in THF) (23.6 mL, 23.6 mmol) was then added and the resulting mixture was stirred at -78°C for 40 minutes. The reaction was quenched with saturated sodium bicarbonate solution. The solution was concentrated under vacuum to remove THF. The residue was then diluted with dichloromethane / methanol (20 / 1). After filtration, the solids were removed and the filtrate was collected and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (97 / 3) to give ethyl (2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (4 g, 18.759 mmol, 39.6% yield) as a yellow oil.

[0404] LC-MS: (ESI, m / z): [M+H] + =214.1.

[0405] Step 2: Ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024513881000127.tif29170

[0406] To a solution of ethyl (2S,7aS)-2-hydroxy-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (4 g, 18.6 mmol) in dichloromethane (40 mL) under nitrogen, diethylaminosulfur trifluoride (4.2 mL, 37.2 mmol) was added at −15° C. The solution was stirred at room temperature for 16 h. Upon completion, the reaction was quenched with ethanol and the solvent was concentrated under vacuum. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (7 / 3) to give ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (2.2 g, 10.1 mmol, 54.3% yield) as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =216.1.

[0407] Step 3: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024513881000128.tif17170

[0408] To a solution of ethyl (2R,7aS)-2-fluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (10.0 g, 46.2 mmol) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (1 M in THF) (138.6 mL, 138.6 mmol) at 0° C. The mixture was then stirred at 70° C. for 30 min (extending the reaction time gives the F-removal by-product). Upon completion, the reaction was quenched with sodium sulfate decahydrate and diluted with tetrahydrofuran. After filtration, the filtrate was collected and the solid was washed three times with tetrahydrofuran. The tetrahydrofuran in the filtrate was blown out with nitrogen gas (concentration under vacuum causes loss of products with low boiling points) to give ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (5.3 g, 33.1 mmol, 71.6% yield) as a pale yellow oil. LC-MS: (ESI, m / z): [M+H] + =160.1.

[0409] Intermediate 2A: 7-Bromo-6-chloro-5-fluoroquinazolin-4(3H)-one TIFF2024513881000129.tif21170

[0410] Step 1: 2-Amino-4-bromo-6-fluorobenzonitrile TIFF2024513881000130.tif20170

[0411] A solution of 4-bromo-2,6-difluorobenzonitrile (4000.0 g, 435.7 mmol) in i-PrOH (40.0 L) was treated with NH 3 .H 2 O (20.0 L) was added and stirred in a high pressure tank at 80° C. for 6 h. The resulting solution was evaporated until 20 L remained. The solid was collected by filtration and dried to give 3625 g (91%) of the title compound as a white solid. LCMS (ESI): [MH] + =213.

[0412] Step 2: 6-Amino-4-bromo-3-chloro-2-fluorobenzonitrile TIFF2024513881000131.tif20170

[0413] To a solution of 2-amino-4-bromo-6-fluorobenzonitrile (450.0 g, 2102.8 mmol) in DMF (2.5 L) was added NCS (280.7 g, 2102.8 mmol) at 0° C. and stirred at 60° C. for 2 h. The resulting solution was cooled to room temperature and poured into 25 L of water. The solid was collected by filtration. The solid was added to 3.0 L of ethyl acetate / petroleum ether (1:5) and stirred at 25° C. for 30 min. The solid was collected by filtration to give 350 g of crude title compound. The 350 g of crude compound was added to 1.5 L of ethyl acetate / petroleum ether (1:10) and stirred at 25° C. for 30 min. The solid was collected by filtration to give 210 g (40% yield) of the title compound as a yellow solid. LCMS (ESI): [MH] + =247.

[0414] Step 3: 7-Bromo-6-chloro-5-fluoroquinazolin-4(3H)-one TIFF2024513881000132.tif19170

[0415] A solution of 6-amino-4-bromo-3-chloro-2-fluorobenzonitrile (15.0 g, 150.5 mmol) in formic acid (75.0 mL) was added to H 2 SO 4 (7.5 mL) was added at 25° C. and stirred at 100° C. for 30 min. The resulting solution was cooled to room temperature and poured into 250 mL of ice / water. The solid was collected by filtration and dried to give 12.24 g (73%) of the title compound as an off-white solid. LCMS (ESI): [MH] + =277. 1 H NMR (300 MHz, DMSO-d 6 )δ 12.55(s,1H),8.14(s,1H),7.92(d,J=2.1 Hz,1H).

[0416] Intermediate 3A: 7-Bromo-2,6-dichloro-5-fluoroquinazolin-4(3H)-one TIFF2024513881000133.tif24170

[0417] Step 1: 6-Amino-4-bromo-3-chloro-2-fluorobenzamide TIFF2024513881000134.tif20170

[0418] To a solution of 6-amino-4-bromo-3-chloro-2-fluorobenzonitrile (600 g, 2405 mmol) in DMSO (3.0 L), 2 CO 3 (665 g, 4810 mmol) was then added. 2 O 2 (30%) (1091 g, 9620 mmol) was added dropwise at 15° C. and stirred at 25° C. for 30 min. The reaction was then quenched by adding 3 L of saturated aqueous sodium sulfite solution. The solid was collected by filtration and washed with water. The solid was dried to give 512 g (79%) of the title compound as a yellow solid. LCMS (ESI): [M+H] + =267.

[0419] Step 2: 7-Bromo-2,6-dichloro-5-fluoroquinazolin-4(3H)-one TIFF2024513881000135.tif20170

[0420] To a solution of 6-amino-4-bromo-3-chloro-2-fluorobenzamide (16.5 g, 61.7 mmol) in dioxane (100.0 mL) was added thiophosgene (14.9 g, 129.6 mmol) dropwise at 0° C. and then stirred at room temperature for 1 h. The mixture was then stirred at 105° C. for 50 min. The reaction mixture was cooled to room temperature and concentrated in vacuo. To the solid was added dioxane (40 mL) and MTBE (50 mL) and then stirred for 15 min. The solid was collected by filtration to give 9.22 g (47%) of the title compound as an off-white solid. LCMS (ESI): [MH] + =309.1 H NMR (300 MHz, DMSO-d 6 )δ 7.90(d,J=1.8 Hz,1H).

[0421] Intermediate 4A. 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-fluoroquinazolin-4(3H)-one TIFF2024513881000136.tif134170

[0422] Step 1: 7-Bromo-6-chloro-5-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one TIFF2024513881000137.tif19170

[0423] A solution of 7-bromo-6-chloro-5-fluoro-3H-quinazolin-4-one (20.00 g, 72.1 mmol), tetrabutylazanium iodide (2.66 g, 7.2 mmol) and cesium carbonate (46.97 g, 144.2 mmol) in N,N-dimethylformamide (160 mL) was stirred at 0° C. for 5 minutes. Then, 2-2-(trimethylsilyl)ethoxymethyl chloride (20.4 mL, 115.3 mmol) was added and stirred at 25° C. for 1.5 hours. After completion, the reaction mixture was diluted with water (300 mL). The resulting solution was extracted with ethyl acetate (3×200 mL) and the organic layers were combined. The organic layers were washed again with water (3×150 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 / 9) to give 7-bromo-6-chloro-5-fluoro-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (24.00 g, 58.86 mmol, 81.7% yield) as a white solid. LC-MS: (ESI, m / z): 407.0 [M+H] +

[0424] Step 2: 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-fluoro-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one TIFF2024513881000138.tif30170

[0425] To a solution of 7-bromo-6-chloro-5-fluoro-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (10.00 g, 24.5 mmol) in tetrahydrofuran (80 mL) under nitrogen, isopropylmagnesium chloride lithium chloride complex (1.3 M in tetrahydrofuran) (22.6 mL, 29.4 mmol) was added at −78° C. and stirred for 0.5 h at −78° C. Zinc chloride (2 M in tetrahydrofuran) (14.7 mL, 29.4 mmol) was then added and stirred at 25° C. for 1 h. The mixture was transferred to a degassed solution of 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (10.93 g, 22.1 mmol), tris(dibenzylideneacetone)dipalladium (2.25 g, 2.4 mmol) and tri(2-furyl)phosphine (1.14 g, 4.9 mmol) in N,N-dimethylformamide (20 mL). The solution was then stirred at 80° C. for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and then diluted with water (100 mL). The resulting solution was extracted with ethyl acetate (3×200 mL) and the organic layers were combined. The organic layers were washed again with water (3×50 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 / 8) to give 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5-fluoro-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (7.00 g, 9.4 mmol) as a white solid. LC-MS: (ESI, m / z): 743.3 [M+H] +

[0426] Step 3: 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-fluoroquinazolin-4(3H)-one TIFF2024513881000139.tif30170

[0427] A solution of 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5-fluoro-3-(2-trimethylsilylethoxymethyl)quinazolin-4-one (14.00 g, 18.8 mmol) and tetrabutylammonium fluoride (19.70 g, 75.3 mmol) in tetrahydrofuran (90 mL) was stirred at 50° C. for 5 hours. After completion, the reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with ethyl acetate (300 mL). The resulting solution was washed with water (10×60 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / dichloromethane (1 / 5) to give 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5-fluoro-3H-quinazolin-4-one (7.50 g, 9.6 mmol) as a white solid. LC-MS: (ESI, m / z): 613.2 [M+H] +

[0428] Intermediate 5A. 6-(8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000140.tif107170

[0429] Step 1: 5-(2-aminoethoxy)-7-bromo-6-chloroquinazolin-4(3H)-one TIFF2024513881000141.tif29170

[0430] A solution of 2-aminoethan-1-ol (2.20 g, 36.04 mmol) and NaH (60% purity) (2.88 g, 72.08 mmol) in tetrahydrofuran (30 mL) was stirred at 0° C. for 5 min. Then, 7-bromo-6-chloro-5-fluoro-3H-quinazolin-4-one (5.00 g, 18.02 mmol) was added and stirred at 65° C. for 1 h. After completion, the reaction mixture was adjusted to PH=7-8 with 1N hydrochloric acid. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography eluting with acetonitrile / water (1:4) to give 5-(2-aminoethoxy)-7-bromo-6-chloro-3H-quinazolin-4-one (5.70 g, 17.89 mmol, 99.3% yield) as a white solid. LC-MS: (ESI, m / z): 318.5 [M+H] + .

[0431] Step 2: 9-Bromo-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000142.tif22170

[0432] To a solution of 5-(2-aminoethoxy)-7-bromo-6-chloro-3H-quinazolin-4-one (5.80 g, 18.21 mmol) in acetonitrile (70 mL) was added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (11.37 g, 21.85 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.32 g, 54.62 mmol) and stirred for 2 hours at 25° C. After completion, the reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give 9-bromo-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (2.80 g, 9.31 mmol, 51.2% yield) as a yellow solid. LC-MS: (ESI, m / z): 300.5 [M+H] + .

[0433] Step 3: 8-Chloro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000143.tif32170

[0434] A solution of 9-bromo-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (1.0 g, 3.33 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (271.7 mg, 0.33 mmol), potassium acetate (65.3 mg, 0.67 mmol) and bis(pinacolato)diboron (2.53 g, 9.98 mmol) in 1,4-dioxane (25 mL) under nitrogen was stirred at 100° C. for 1.5 h. After completion, the solvent was concentrated under vacuum. The reaction mixture was diluted with dichloromethane. After filtration, the reaction mixture was concentrated under vacuum to give the crude product, which was used directly in the next step without purification. LC-MS: (ESI, m / z): 347.6 [M+H] + .

[0435] Step 4: 6-(8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000144.tif34170

[0436] A solution of 8-chloro-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (3.00 g, crude), potassium fluoride (703.6 mg, 12.12 mmol), bis(triphenylphosphine)palladium(II) chloride (283.4 mg, 0.40 mmol) and 6-bromo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (2.00 g, 4.04 mmol) in acetonitrile (25 mL) and water (5 mL) under nitrogen was stirred for 3 hours at 80° C. After completion, the reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give 6-(8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (1.04 g, 0.81 mmol, 40.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 636.0 [M+H] + .

[0437] Intermediate 6A: (S)-2-(9-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-5-yl)acetonitrile TIFF2024513881000145.tif48170

[0438] Synthetic Route TIFF2024513881000146.tif91170

[0439] Step 1: (S)-3-Amino-4-hydroxybutanenitrile hydrochloride TIFF2024513881000147.tif24170

[0440] A solution of tert-butyl S)-(1-cyano-3-hydroxypropan-2-yl)carbamate (2.30 g, 11.49 mmol) in hydrochloric acid (20.0 mL, 1M in 1,4-dioxane) and dichloromethane (5.0 mL) was stirred at 25° C. for 4 h. After completion, the solvent was concentrated under vacuum. The crude product is used directly in the next step without purification. LC-MS: (ESI, m / z): 101.1 [M+H] + .

[0441] Step 2: (S)-3-amino-4-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)butanenitrile TIFF2024513881000148.tif52170

[0442] To a solution of (S)-3-amino-4-hydroxybutanenitrile hydrochloride (2.5 g, crude) in tetrahydrofuran (25 mL) was added sodium hydride (812.5 mg, 20.3 mmol, 60% purity) at 0° C. Then 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-fluoroquinazolin-4(3H)-one (2.5 g, 4.07 mmol) was added and stirred at 0° C. for 5 min. The resulting solution was stirred at 65° C. for 2 h. After completion, the residue was diluted with dichloromethane and the pH was adjusted to 7-8 with 2N hydrochloric acid. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give (S)-3-amino-4-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)butanenitrile (1.4 g, 2.02 mmol, 49.6% yield) as a yellow solid. LC-MS: (ESI, m / z): 693.2 [M+H] + .

[0443] Step 3: (S)-2-(9-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-5-yl)acetonitrile TIFF2024513881000149.tif48170

[0444] A solution of (S)-3-amino-4-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)butanenitrile (1.4 g, 2.02 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.54 g, 10.10 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.58 g, 3.03 mmol) in acetonitrile (14.0 mL) was stirred at 25° C. for 0.5 h. After completion, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10:1) to give (S)-2-(9-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-5-yl)acetonitrile (1 g, 1.48 mmol, 73.3% yield) as a yellow solid. LC-MS: (ESI, m / z): 675.2 [M+H] + .

[0445] Intermediate 7A: (S)-(dihydro-1H,3H-spiro[pyrrolidine-2,2'-[1,3]dioxolane]-7a(5H)-yl)methanol TIFF2024513881000150.tif18170

[0446] Synthetic Route TIFF2024513881000151.tif33170

[0447] Step 1: Ethyl (S)-5-oxodihydro-1H,3H-spiro[pyrrolidine-2,2'-[1,3]dioxolane]-7a(5H)-carboxylate TIFF2024513881000152.tif29170

[0448] A solution of ethyl ((S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (1.00 g, 4.73 mmol), ethylene glycol (450.1 mg, 7.25 mmol) and p-toluenesulfonic acid (158.0 mg, 0.92 mmol) in toluene (50 mL) was stirred at 110° C. for 1 h. After completion, the reaction was concentrated under vacuum, diluted with dichloromethane, washed with water and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give ethyl (S)-5-oxodihydro-1H,3H-spiro[pyrrolidine-2,2′-[1,3]dioxolane]-7a(5H)-carboxylate (1.17 g, 4.58 mmol, 96.8% yield) as a brown oil. LC-MS: (ESI, m / z): 256.1 [M+H] +

[0449] Step 2: (S)-(Dihydro-1H,3H-spiro[pyrrolidine-2,2'-[1,3]dioxolane]-7a(5H)-yl)methanol TIFF2024513881000153.tif18170

[0450] To a solution of ethyl (S)-5-oxodihydro-1H,3H-spiro[pyrrolidine-2,2'-[1,3]dioxolane]-7a(5H)-carboxylate (700.0 mg, 2.74 mmol) in tetrahydrofuran (35 mL) under nitrogen, diisobutylaluminum hydride (8.23 mL, 8.23 ​​mmol, 1M in toluene) was added at 0° C. and stirred at room temperature for 30 minutes. After completion, the reaction was quenched with ammonium chloride solution, diluted with dichloromethane, washed with water and the organic layers were combined. The aqueous phase was concentrated under vacuum to give (S)-(dihydro-1H,3H-spiro[pyrrolidine-2,2'-[1,3]dioxolane]-7a(5H)-yl)methanol (180.1 mg, crude) as a yellow oil. LC-MS: (ESI, m / z): 200.1 [M+H] +

[0451] Intermediate 8A: 9-Bromo-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000154.tif29170

[0452] Synthetic Route TIFF2024513881000155.tif71170

[0453] Step 1: 7-Bromo-2,6-dichloro-5-(2-(methylamino)ethoxy)quinazolin-4(3H)-one TIFF2024513881000156.tif34170

[0454] To a solution of 2-(methylamino)ethanol (1.32 g, 17.63 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (1.92 g, 48.09 mmol) and the mixture was stirred at 0° C. for 1 h. Then 7-bromo-2,6-dichloro-5-fluoro-3H-quinazolin-4-one (5.00 g, 16.03 mmol) was added and stirred at 25° C. for 1 h. After completion, the reaction was quenched with 1N hydrochloric acid solution. After filtration, the solid was collected to give 7-bromo-2,6-dichloro-5-(2-(methylamino)ethoxy)quinazolin-4(3H)-one (8.40 g crude) as a brown solid. LC-MS: (ESI, m / z): 366.0 [M+H] +

[0455] Step 2: 9-Bromo-2,8-dichloro-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000157.tif22170

[0456] A mixture of 7-bromo-2,6-dichloro-5-[2-(methylamino)ethoxy]-3H-quinazolin-4-one (8.30 g, 22.61 mmol), N,N-diisopropylethylamine (5.84 g, 45.23 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (6.89 g, 27.14 mmol) in chloroform (80 mL) was stirred at 65° C. for 1 h. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 / 1) to give 9-bromo-2,8-dichloro-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7de]quinazoline (3.74 g, 9.64 mmol, 42.6% yield) as a yellow solid. LC-MS: (ESI, m / z): 348.0 [M+H] +

[0457] Step 3: 9-Bromo-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000158.tif29170

[0458] To a solution of [rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (638.6 mg, 4.0 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (343.8 mg, 8.6 mmol) and the mixture was stirred at 0° C. for 0.5 h. Then 9-bromo-2,8-dichloro-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (1.00 g, 2.87 mmol) was added and stirred at 40° C. for 1 h. After completion, the reaction was quenched with 1N hydrochloric acid solution. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 25) to give 9-bromo-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (1.10 g, 2.19 mmol, 76.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 471.1 [M+H] +

[0459] Example 1: 6-(4-((1H-pyrazol-5-yl)methyl)-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000159.tif43170

[0460] Synthetic Route TIFF2024513881000160.tif147170

[0461] Step 1: 1-Trityl-1H-pyrazole-3-carbaldehyde TIFF2024513881000161.tif18170

[0462] A solution of 1H-pyrazole-3-carbaldehyde (4.00 g, 41.62 mmol), trityl chloride (17.41 g, 62.40 mmol) and triethylamine (17.4 mL, 124.96 mmol) in N,N-dimethylformamide (40 mL) was stirred at 25° C. for 8 h. After completion, the reaction mixture was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layers were washed with water again. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 / 30) to give 1-tritylpyrazole-3-carbaldehyde (11.00 g, 32.55 mmol) as a white solid. LC-MS: (ESI, m / z): 339.1 [M+H] +

[0463] Step 2: 2-(((1-trityl-1H-pyrazol-3-yl)methyl)amino)ethan-1-ol TIFF2024513881000162.tif27170

[0464] A solution of 1-tritylpyrazole-3-carbaldehyde (6.00 g, 17.70 mmol), 2-aminoethanol (3.2 mL, 53.20 mmol) and acetic acid (0.11 g, 1.87 mmol) in methyl alcohol (50 mL) was stirred at 25° C. for 3 h. Sodium cyanoborohydride (2.23 g, 35.53 mmol) was then added and stirred at 25° C. for 4 h. After completion, the reaction was quenched with water. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 20) to give 2-[(1-tritylpyrazol-3-yl)methylamino]ethanol (1.20 g, 3.12 mmol) as a colorless oil. LC-MS: (ESI, m / z): 384.2 [M+H] +

[0465] Step 3: 7-Bromo-2,6-dichloro-5-(2-(((1-trityl-1H-pyrazol-3-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one TIFF2024513881000163.tif42170

[0466] A solution of 2-[(1-tritylpyrazol-3-yl)methylamino]ethanol (1.12 g, 2.9 mmol) and sodium hydride (292.4 mg, 7.3 mmol) in tetrahydrofuran (10 mL) was stirred at 0° C. for 15 minutes. Then, 7-bromo-2,6-dichloro-5-fluoro-3H-quinazolin-4-one (760.0 mg, 2.4 mmol) was added and stirred at 65° C. for 1 hour. After completion, the reaction mixture was adjusted to pH=6 with hydrochloric acid (1N). The solution was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 20) to give 7-bromo-2,6-dichloro-5-(2-(((1-trityl-1H-pyrazol-3-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one.

[0467] (1.60 g, 2.37 mmol) was obtained as a white solid. LC-MS: (ESI, m / z): 674.1 [M+H]+

[0468] Step 4: 9-Bromo-2,8-dichloro-4-((1-trityl-1H-pyrazol-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000164.tif34170

[0469] A solution of 7-bromo-2,6-dichloro-5-(2-(((1-trityl-1H-pyrazol-3-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one (1.60 g, 2.37 mmol), bis(2-oxo-3-oxazolidinyl)phosphine chloride (0.90 g, 3.55 mmol) and N,N-diisopropylethylamine (0.61 g, 4.75 mmol) in chloroform (15 mL) was stirred at 70° C. for 1 h. After completion, the reaction mixture was diluted with dichloromethane. The resulting solution was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 50) to give 7-bromo-3,8-dichloro-13-[(1-tritylpyrazol-3-yl)methyl]-10-oxa-2,4,13-triazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaene (700.0 mg, 1.06 mmol) as a white solid. LC-MS: (ESI, m / z): 656.1 [M+H] +

[0470] Step 5: 9-Bromo-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000165.tif42170

[0471] A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (181.6 mg, 1.12 mmol) and sodium hydride (152.1 mg, 3.81 mmol) in tetrahydrofuran (5 mL) was stirred at 0° C. for 15 minutes. Then, 7-bromo-3,8-dichloro-13-[(1-tritylpyrazol-3-yl)methyl]-10-oxa-2,4,13-triazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaene (500.0 mg, 0.81 mmol) was added and stirred at 40° C. for 5 hours. After completion, the reaction mixture was adjusted to pH=6 with saturated ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (60 mL). The resulting solution was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 / 8) to give 9-bromo-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (400.0 mg, 0.51 mmol) as a white solid. LC-MS: (ESI, m / z): 779.3 [M+H] +

[0472] Step 6: (8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)boronic acid TIFF2024513881000166.tif43170

[0473] A solution of 9-bromo-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (380.0 mg, 0.51 mmol), bis(pinacolato)diboron (247.4 mg, 0.92 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35.6 mg, 0.051 mmol) and potassium acetate (95.6 mg, 0.92 mmol) in 1,4-dioxane (3 mL) under nitrogen was stirred at 100° C. for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The reaction mixture was then diluted with dichloromethane. After filtration, the organics were collected and concentrated under vacuum. The crude product (8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)boronic acid (600.0 mg, crude) was used directly in the next step without further purification. LC-MS: (ESI, m / z): 745.3 [M+H] +

[0474] Step 7: 6-(8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000167.tif44170

[0475] A solution of (8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)boronic acid (597.4 mg, crude), 6-bromo-4-methyl-5(trifluoromethyl)pyridin-2-amine (170.4 mg, 0.73 mmol), bis(triphenylphosphine)palladium(II) chloride (46.9 mg, 0.073 mmol) and sodium carbonate (141.6 mg, 1.36 mmol) in acetonitrile (4 mL) and water (1 mL) under nitrogen was stirred at 80° C. for 1 h. After completion, the reaction mixture was concentrated under reduced pressure. The reaction mixture was then diluted with dichloromethane. After filtration, the organic phase was collected and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 20) to give 6-(8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (250.0 mg, 0.28 mmol) as a brown solid. LC-MS: (ESI, m / z): 875.4 [M+H] +

[0476] Step 8: 6-(4-((1H-pyrazol-5-yl)methyl)-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000168.tif43170

[0477] A solution of 6-(8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (150.0 mg, 0.171 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) and dichloromethane (0.5 mL) was stirred at 25° C. for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified using the following conditions (Column: XBridge Prep OBD C18 column, 30×150 mm 5 μm; Mobile phase A: water (10 mmol / L) NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 39B to 49B in 8 min, 254 / 220 nm; RT1:7.6; RT2;) to give 6-(4-((1H-pyrazol-5-yl)methyl)-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (29.7 mg, 0.059 mmol, 34.5% yield). LC-MS: (ESI, m / z): 633.3 [M+H] +

[0478] Example 1: 1 H NMR (300 MHz, DMSO-d 6 )δ 12.65(s,1H),7.64(s,1H),6.93(s,1H),6.75(s,2H),6.44(s,1H),6.25(d,J=2.2 Hz,1H),5.27(d,J=54.1 Hz,1H),5.13-4.93(m,2H),4.68-4.43(m,2H),4.16-3.87(m,4H),3.10(s,2H),3.00(s,1H),2.90-2.72(m,1H),2.35(d,J=2.3 Hz,3H),2.19-2.09(m,1H),2.06-1.92(m,2H),1.91-1.64(m,3H).

[0479] Example 2: 6-(4-((1H-pyrazol-4-yl)methyl)-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000169.tif47170

[0480] Synthetic Route TIFF2024513881000170.tif152170

[0481] Step 1: 1-Trityl-1H-pyrazole-4-carbaldehyde TIFF2024513881000171.tif23170

[0482] A solution of 1H-pyrazole-4-carbaldehyde (3.00 g, 31.22 mmol), triethylamine (13 mL, 93.66 mmol) and trityl chloride (13.10 g, 46.84 mmol) in N,N-dimethylformamide (30 mL) was stirred at 25° C. for 4 h. After completion of the reaction, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (10 / 1) to give 1-trityl-1H-pyrazole-4-carbaldehyde (2.40 g, 7.07 mmol) as a white solid. LC-MS: (ESI, m / z): 339.4 [M+H] + Step 2: 2-(((1-trityl-1H-pyrazol-4-yl)methyl)amino)ethan-1-ol TIFF2024513881000172.tif14170

[0483] A solution of 1-tritylpyrazole-4-carbaldehyde (1.50 g, 4.42 mmol), 2-aminoethanol (0.54 mL, 8.84 mmol) and acetic acid (0.03 mL, 0.03 mmol) in methyl alcohol (1 mL) was stirred at 25° C. for 2 h. Then sodium cyanoborohydride (0.56 g, 8.84 mmol) was added and stirred at 25° C. for 2 h. After completion of the reaction, the solvent was quenched with water and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give 2-(((1-trityl-1H-pyrazol-4-yl)methyl)amino)ethan-1-ol (630.0 mg, 1.64 mmol) as a white solid. LC-MS: (ESI, m / z): 384.4 [M+H] +

[0484] Step 3: 7-Bromo-2,6-dichloro-5-(2-(((1-trityl-1H-pyrazol-4-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one TIFF2024513881000173.tif44170

[0485] A solution of 2-((((1-trityl-1H-pyrazol-4-yl)methyl)amino)ethan-1-ol (991.4 mg, 2.58 mmol) and sodium hydride (258.5 mg, 6.45 mmol, 60% purity) in tetrahydrofuran (10 mL) was stirred at 0° C. for 5 min. Then 7-bromo-2,6-dichloro-5-fluoro-3H-quinazolin-4-one (10.0 mg, 0.03 mmol) was added and stirred at 65° C. for 4 h. The medium was quenched with 1M hydrochloric acid and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give 7-bromo-2,6-dichloro-5-(2-(((1-trityl-1H-pyrazol-4-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one (550 mg, 0.81 mmol) as a white solid. LC-MS: (ESI, m / z): 674.4 [M+H] +

[0486] Step 4: 9-Bromo-2,8-dichloro-4-((1-trityl-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000174.tif38170

[0487] A solution of 7-bromo-2,6-dichloro-5-(2-(((1-trityl-1H-pyrazol-4-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one (1.10 g, 1.53 mmol), bis(2-oxo-3-oxazolidinyl)phosphine chloride (0.57 g, 2.24 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.99 mmol) in chloroform (100 mL) was stirred at 70° C. for 4 hours. After completion of the reaction, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 10) to give 9-bromo-2,8-dichloro-4-((1-trityl-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (300.0 mg, 0.45 mmol) as a white solid. LC-MS: (ESI, m / z): 656.1 [M+H] +

[0488] Step 5: 9-Bromo-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000175.tif44170

[0489] A solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (108.9 mg, 0.6 mmol) and sodium hydride (91.2 mg, 2.3 mmol, 60% purity) in tetrahydrofuran (4 mL) was stirred at 0° C. for 10 min. Then, 7-bromo-3,8-dichloro-13-[(1-tritylpyrazol-4-yl)methyl]-10-oxa-2,4,13-triazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaene (300.0 mg, 0.4 mmol) was added and stirred at 40° C. for 2 h. After completion, the reaction was quenched with dilute hydrochloric acid. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 50) to give 9-bromo-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (200.0 mg, 0.25 mmol) as a white solid. LC-MS: (ESI, m / z): 779.2 [M+H] +

[0490] Step 6: (8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)boronic acid TIFF2024513881000176.tif44170

[0491] A solution of 9-bromo-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (165.0 mg, 0.23 mmol), bis(pinacolato)diboron (107.4 mg, 0.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.48 mg, 0.02 mmol) and potassium acetate (0.03 mL, 0.46 mmol) in 1,4-dioxane (3 mL) under nitrogen was stirred at 100° C. for 1.5 hours. After completion, the reaction mixture was concentrated under reduced pressure. The reaction mixture was then diluted with dichloromethane (20 mL). After filtration, the organics were collected and concentrated under vacuum. The crude product ((8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)boronic acid (340.0 mg, crude) (brown oil) was used directly in the next step without further purification. LC-MS: (ESI, m / z): 745.4 [M+H] +

[0492] Step 7: 6-(8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000177.tif49170

[0493] A solution of (8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)boronic acid (315.5 mg, crude), 6-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-amine (90.0 mg, 0.46 mmol), bis(triphenylphosphine)palladium(II) chloride (24.8 mg, 0.04 mmol) and sodium carbonate (74.8 mg, 0.79 mmol) in acetonitrile (4 mL) / water (1 mL) was added under nitrogen and stirred at 80° C. for 1 h. After completion, the reaction mixture was diluted with dichloromethane. The resulting solution was washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 20) to give 6-(8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((1-trityl-1H-pyrazol-4-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (130.0 mg, 0.15 mmol) as a brown solid. LC-MS: (ESI, m / z): 875.4 [M+H] +

[0494] Step 8: 6-(4-((1H-pyrazol-4-yl)methyl)-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000178.tif47170

[0495] A solution of 6-(4-((1H-pyrazol-4-yl)methyl)-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (100.0 mg, 0.12 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) / dichloromethane (0.5 mL) was stirred at 25° C. for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified using the following conditions (Column: XBridge Prep OBD C18 column, 30×150 mm 5 μm; Mobile phase A: water (10 mmol / L) NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 37B to 46B in 9 min, 254 / 220 nm; RT1: 8.17; RT2:) to give 6-(4-((1H-pyrazol-4-yl)methyl)-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (24.7 mg, 0.04 mmol, 33.3% yield). LC-MS: (ESI, m / z): 633.3 [M+H] +

[0496] Example 2: 1 H NMR (300 MHz, DMSO-d 6 )δ 12.79(s,1H),7.68(s,2H),6.94(s,1H),6.74(s,2H),6.44(s,1H),5.26(d,J=53.7 Hz 1H),4.96-4.76(m,2H),4.64-4.40(m,2H),4.18-3.95(m,2H),3.95-3.78(m,2H),3.16-2.91(m,3H),2.89-2.72(m,1H),2.34(d,J=2.2 Hz,3H),2.20-2.08(m,1H),2.08-1.90(m,2H),1.90-1.62(m,3H).

[0497] Example 3: 6-(4-((5-aminopyridin-3-yl)methyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000179.tif49170

[0498] Synthetic Route TIFF2024513881000180.tif92170

[0499] Step 1: 6-(4-((5-bromopyridin-3-yl)methyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000181.tif49170

[0500] A solution of 3-bromo-5-(bromomethyl)pyridine (236.6 mg, 0.96 mmol) and sodium hydride (60% purity) (25.1 mg, 0.64 mmol) in N,N-dimethylacetamide (1 mL) was stirred at 25° C. for 10 minutes. Then, 6-(8-chloro-10-oxa-2,4,13 triazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (200.0 mg, 0.32 mmol) was added and stirred for 2 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride solution, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give 6-(4-((5-bromopyridin-3-yl)methyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (150.0 mg, 0.18 mmol, 51.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 805.1 [M+H] +

[0501] Step 2: 6-(4-((5-aminopyridin-3-yl)methyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000182.tif49170

[0502] A solution of 6-(4-((5-bromopyridin-3-yl)methyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (150.0 mg, 0.18 mmol), tris(dibenzylideneacetone)dipalladium (17.0 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21.5 mg, 0.04 mmol), diphenylmethanimine (261.35 mg, 1.44 mmol) and cesium carbonate (121.2 mg, 0.36 mmol) in toluene (3 mL) was stirred at 90° C. for 16 h under nitrogen. After completion, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The resulting solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give 6-(4-((5-aminopyridin-3-yl)methyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (100.0 mg, 0.13 mmol, 73.8% yield) as a black solid. LC-MS: (ESI, m / z): 742.2 [M+H] +

[0503] Step 3: 6-(4-((5-aminopyridin-3-yl)methyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000183.tif49170

[0504] A solution of 6-(4-((5-aminopyridin-3-yl)methyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (100.0 mg, 0.13 mmol) and trifluoroacetic acid (5 mL) was stirred at 50° C. for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified using the following conditions: Column: XBridge Prep OBD C18 column, 30×150 mm 5 um; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Detector, UV 254 nm. Purification by prep-HPLC at RT: 8.5 gave 6-(4-((5-aminopyridin-3-ylmethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (20.7 mg, 0.04 mmol, 30.3% yield). LC-MS: (ESI, m / z): 502.1 [M+H] +

[0505] Example 3: 1 H NMR (300 MHz, DMSO-d 6 ,ppm)δ 8.43(s,1H),7.83(d,J=2.6 Hz,1H),7.75(d,J=1.9 Hz,1H),7.20(s,1H),6.85(t,J=2.3 Hz,1H),6.77(s,2H),6.46(s,1H),5.30(brs,2H),5.11-4.93(m,2H),4.61(q,J=3.4 Hz,2H),3.95-3.86(m,2H),2.36(d,J=2.3 Hz,3H).

[0506] Example 4: (S)-6-(4-(1-(5-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000184.tif50170

[0507] Synthetic Route TIFF2024513881000185.tif106170

[0508] Step 1: (S)-5-(2-((1-(5-aminopyridin-3-yl)ethyl)amino)ethoxy)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4(3H)-one TIFF2024513881000186.tif55170

[0509] A solution of 2-[[rac-(1S)-1-(5-amino-3-pyridyl)ethyl]amino]ethanol (133.0 mg, 0.73 mmol) and sodium hydride (60% purity) (46.9 mg, 1.94 mmol) in tetrachloroethylene (5 mL) was stirred at 0° C. for 20 minutes. Then, 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-fluoroquinazolin-4(3H)-one (300.0 mg, 0.49 mmol) was added and stirred at 65° C. for 1 hour. After completion, the reaction mixture was quenched with saturated ammonium chloride, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give (S)-5-(2-((1-(5-aminopyridin-3-yl)ethyl)amino)ethoxy)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4(3H)-one (200.0 mg, 0.24 mmol, 48% yield) as a yellow solid. LC-MS: (ESI, m / z): 774.3 [M+H] +

[0510] Step 2: (S)-6-(4-(1-(5-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000187.tif49170

[0511] A solution of (S)-5-(2-((1-(5-aminopyridin-3-yl)ethyl)amino)ethoxy)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4(3H)-one (200.0 mg, 0.24 mmol), N,N-diisopropylethylamine (66.7 mg, 0.51 mmol) and bis(2-oxo-3-oxazolidinyl)phosphine chloride (85.4 mg, 0.32 mmol) in chloroform (3 mL) was stirred at 70° C. for 6 hours. After completion, the reaction mixture was diluted with dichloromethane. The resulting solution was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give (S)-6-(4-(1-(5-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (90.0 mg, 0.11 mmol, 44.7% yield) as a yellow solid. LC-MS: (ESI, m / z): 756.3 [M+H] +

[0512] Step 3: (S)-6-(4-(1-(5-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000188.tif49170

[0513] A solution of (S)-6-(4-(1-(5-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (90.0 mg, 0.11 mmol) and trifluoroacetic acid (2 mL) was stirred for 24 hours at 25° C. After completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative-HPLC under the following conditions: column: YMC-Actus Triart C18 ExRS, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; detector, UV 254 nm. RT: 8.32 to give (S)-6-(4-(1-(5-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (18.1 mg, 0.03 mmol, 29.5% yield). LC-MS: (ESI, m / z): 516.2 [M+H] +

[0514] Example 4: 1 H NMR (300 MHz, DMSO-d 6 ,ppm)δ 8.47(d,J=1.7 Hz,1H),7.91-7.84(m,1H),7.84-7.77(m,1H),7.20(d,J=1.1 Hz,1H),6.88(d,J=8.4 Hz,1H),6.75(s,2H),6.60-6.50(m,1H),6.45(s,1H),5.30(s,2H),4.67-4.35(m,2H),3.80-3.41(m,2H),2.36(d,J=2.3 Hz,3H),1.59(dd,J=7.1,2.4 Hz,3H).

[0515] Example 5: (R)-6-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000189.tif46170

[0516] Synthetic Route TIFF2024513881000190.tif101170

[0517] Step 1: (R)-5-(2-((1-(2-aminopyridin-3-yl)ethyl)amino)ethoxy)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4(3H)-one TIFF2024513881000191.tif54170

[0518] A solution of (R)-2-((1-(2-aminopyridin-3-yl)ethyl)amino)ethan-1-ol (133.0 mg, 0.73 mmol) and sodium hydride (46.9 mg, 1.92 mmol, 60% purity) in tetrachloroethylene (5 mL) was stirred at 0° C. for 20 minutes. Then 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-fluoroquinazolin-4(3H)-one (300.0 mg, 0.48 mmol) was added and stirred at 65° C. for 1 hour. After completion, the reaction mixture was quenched with saturated ammonium chloride, concentrated under vacuum, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give (R)-5-(2-((1-(2-aminopyridin-3-yl)ethyl)amino)ethoxy)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloroquinazolin-4(3H)-one (200.0 mg, 0.23 mmol, 48% yield) as a yellow solid. LC-MS: (ESI, m / z): 774.3 [M+H] +

[0519] Step 2: (R)-6-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000192.tif46170

[0520] A solution of (R)-6-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (250.0 mg, 0.32 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL, 0.97 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (252.0 mg, 0.48 mmol) in acetonitrile (3 mL) was stirred for 1 hour. After completion, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give (R)-6-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (90.0 mg, 0.12 mmol, 37.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 756.3 [M+H] +

[0521] Step 3: (R)-6-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000193.tif38170

[0522] A solution of (R)-6-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (90.0 mg, 0.1 mmol) and trifluoroacetic acid (2 mL) was stirred at 65° C. for 24 hours. After completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative-HPLC under the following conditions: column: YMC-Actus Triart C18 ExRS, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; detector, UV 254 nm. RT: 8.32 to give (R)-6-(4-(1-(2-aminopyridin-3-yl)ethyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (18.1 mg, 0.03 mmol, 29.5% yield). LC-MS: (ESI, m / z): 516.2 [M+H] +

[0523] Example 5: 1 H NMR (400 MHz, DMSO-d 6 ,ppm)δ 8.51(s,1H),7.99-7.92(m,1H),7.67-7.60(m,1H),7.19(s,1H),6.75(s,2H),6.70-6.62(m,1H),6.45(s,2H), 5.80(s,1H),5.73(s,1H),4.59-4.45(m,1H),4.36-4.24(m,1H),3.93(s,1H),3.74-3.60(m,1H),2.35(d,J=2.5 Hz,3H),1.59-1.51(m,3H).

[0524] Example 6: 6-(8-chloro-4-((5-(methylamino)pyridin-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000194.tif54170

[0525] Synthetic Route TIFF2024513881000195.tif147170

[0526] Step 1: tert-Butyl (5-formylpyridin-3-yl)carbamate TIFF2024513881000196.tif18170

[0527] A solution of 5-bromonicotinaldehyde (2000.0 mg, 10.75 mmol), tert-butyl carbamate (1.89 g, 16.12 mmol), tris(dibenzylideneacetone)dipalladium-chloroformal adduct (1.11 g, 1.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.24 g, 2.150 mmol) and cesium carbonate (7.05 g, 21.50 mmol) in 1,4-dioxane (40 mL) under nitrogen was stirred at 85° C. for 3 h. LC-MS showed that the product was formed and SM was consumed. After completion, the solution was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (70 / 30) to give tert-butyl N-(5-formyl-3-pyridyl)carbamate (1.88 g, 8.45 mmol, 78.7% yield) as a colorless solid. LC-MS: (ESI, m / z): 223.1 [M+H] + Step 2: tert-Butyl (5-formylpyridin-3-yl)(methyl)carbamate TIFF2024513881000197.tif18170

[0528] A solution of tert-butyl N-(5-formyl-3-pyridyl)carbamate (1.88 g, 8.46 mmol), iodomethane (1.32 g, 9.31 mmol) and cesium carbonate (5.54 g, 16.92 mmol) in N,N-dimethylformamide (20 mL) was stirred at 25° C. for 1 h. After completion, the reaction mixture was diluted with ethyl acetate. The resulting solution was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (80 / 20) to give tert-butyl (5-formylpyridin-3-yl)(methyl)carbamate (1.19 g, 5.03 mmol, 59.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 237.1 [M+H] +

[0529] Step 3: tert-Butyl (5-(((2-hydroxyethyl)amino)methyl)pyridin-3-yl)(methyl)carbamate TIFF2024513881000198.tif29170

[0530] A solution of tert-butyl (5-formylpyridin-3-yl)(methyl)carbamate (1.19 g, 5.04 mmol), 2-aminoethanol (0.9 mL, 15.11 mmol) and sodium cyanoborohydride (1.19 g, 18.94 mmol) in titanium(iv) isopropoxide (10.0 mL, 5.04 mmol) and methyl alcohol (10 mL) was stirred at 80° C. for 16 h. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (95 / 5) to give the crude product. The residue was purified by flash chromatography on C18 gel eluted with methanol / water (25 / 75) to give tert-butyl (5-(((2-hydroxyethyl)amino)methyl)pyridin-3-yl)(methyl)carbamate (1.10 g, 3.72 mmol, 73.9% yield) as a yellow oil. LC-MS: (ESI, m / z): 282.1 [M+H] +

[0531] Step 4: tert-Butyl (5-(((2-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)amino)methyl)pyridin-3-yl)(methyl)carbamate TIFF2024513881000199.tif54170

[0532] A solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-fluoroquinazolin-4(3H)-one (400.0 mg, 0.65 mmol), tert-butyl N-[5-[(2-hydroxyethylamino)methyl]-3-pyridyl]-N-methyl-carbamate (275.3 mg, 0.97 mmol) and sodium hydride (60%) (78.3 mg, 1.95 mmol) in tetrahydrofuran (3 mL) was stirred at 65° C. for 2 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. 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 dichloromethane / methanol (10 / 1) to give tert-butyl (5-(((2-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)amino)methyl)pyridin-3-yl)(methyl)carbamate (280.0 mg, 0.32 mmol, 49.1% yield) as a yellow solid. LC-MS: (ESI, m / z): 874.3 [M+H] +

[0533] Step 5: tert-Butyl (5-((9-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)methyl)pyridin-3-yl)(methyl)carbamate TIFF2024513881000200.tif54170

[0534] A solution of tert-butyl (5-(((2-((7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)amino)methyl)pyridin-3-yl)(methyl)carbamate (280.0 mg, 0.32 mmol), b1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL, 1.28 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.0 mL, 1.44 mmol) in acetonitrile (3 mL) was stirred at 25° C. for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The resulting solution was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give tert-butyl (5-((9-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)methyl)pyridin-3-yl)(methyl)carbamate (230.0 mg, 0.27 mmol, 85.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 856.3 [M+H] +

[0535] Step 6: 6-(8-chloro-4-((5-(methylamino)pyridin-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000201.tif54170

[0536] A solution of tert-butyl (5-((9-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)methyl)pyridin-3-yl)(methyl)carbamate (230.0 mg, 0.27 mmol) and trifluoroacetic acid (3 mL) was stirred at 50° C. for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (10 / 1) to give the crude product. The crude product was purified by prep-HPLC under the following conditions: Column: XBridge Prep OBD C18 column, 30x150mm 5um; Mobile phase A: water (10MMOL / L NH4HCO3), Mobile phase B: ACN; Detector, UV 254nm.RT: 6.5 to give 6-(8-chloro-4-((5-(methylamino)pyridin-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (27.8mg, 0.05mmol, 13% yield). LC-MS: (ESI,m / z):516.1[M+H] +

[0537] Example 6: 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 8.44(s,1H),7.84(d,J=2.6 Hz,1H),7.79(d,J=1.8 Hz,1H),7.19(s,1H),6.89-6.81(m,1H),6.78(s,2H),6.46(s,1H),5.91(s, 1H),5.14-4.98(m,2H),4.71-4.55(m,2H),3.97-3.88(m,2H),2.67(d,J=3.6 Hz,3H),2.36(d,J=2.3 Hz,3H).

[0538] Example 7: (R)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000202.tif33170

[0539] Synthetic Route TIFF2024513881000203.tif105170

[0540] Step 1: Ethyl (R)-2,2-difluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024513881000204.tif27170

[0541] A solution of ethyl (R)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (20.00 g, 94.6 mmol) in dichloromethane (200 mL) was stirred at 0° C. for 5 min. Then diethylaminosulfur trifluoride (37.5 mL, 284.0 mmol) was added and stirred at room temperature for 6 h. After completion of the reaction, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 / 10) to give (R)-2,2-difluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (15.70 g, 67.3 mmol, 71.1% yield) as a white solid. LC-MS: (ESI, m / z): 234.1 [M+H] +

[0542] Step 2: (R)-(2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024513881000205.tif22170

[0543] A solution of ethyl (R)-2,2-difluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (750.0 mg, 3.2 mmol) and lithium aluminum hydride (9.5 mL in THF, 9.5 mol, 1 mol / L) in tetrahydrofuran (8 mL) was stirred at 0° C. for 2 h. Upon completion, the reaction mixture was quenched with sodium sulfate decahydrate and diluted with tetrahydrofuran. After filtration, the filtrate was concentrated under reduced pressure to give (R)-(2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (450 mg, crude). LC-MS: (ESI, m / z): 178.1 [M+H] +

[0544] Step 3: (R)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000206.tif34170

[0545] A solution of (R)-(2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (99.4 mg, crude) and sodium hydride (59.8 mg, 1.49 mmol, 60% purity) in tetrahydrofuran (3 mL) was stirred at 0° C. for 20 minutes. Then, 6-(8-chloro-2-fluoro-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (250.0 mg, 0.37 mmol) was added and stirred at 25° C. for 2 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give (R)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (150.0 mg, 0.18 mmol, 48.6% yield) as a yellow solid. LC-MS: (ESI, m / z): 825.3 [M+H] +

[0546] Step 4: (R)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000207.tif33170

[0547] A solution of (R)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (150.0 mg, 0.18 mmol) in trifluoroacetic acid (2 mL) was stirred at 50° C. for 8 hours. After completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by prep-HPLC under the following conditions: Column: XBridge Prep OBD C18 column, 30x150mm 5um; Mobile phase A: water (10MMOL / L NH4HCO3), Mobile phase B: ACN; Detector, UV 254nm.RT: 6.5 to give (R)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (64.1mg, 0.12mmol, 60.3% yield). LC-MS: (ESI,m / z):535.1[M+H] +

[0548] Example 7: 1 H NMR (300 MHz, DMSO-d 6,ppm)δ 6.93(s,1H),6.74(d,J=2.1 Hz,2H),6.44(s,1H),4.67-4.49(m,2H),4.17-3.98(m,2H),3.98-3.84(m,2H),3.41(s,1H),3.29(s,3H),3.19-3.01(m,2H),2.72(d,J=8.6 Hz,1H),2.45-2.24(m,5H),2.02(d,J=5.1 Hz,1H),1.93-1.70(m,3H).

[0549] Example 8: 8-Chloro-9-(6-fluoro-1-methyl-1H-indazol-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000208.tif34170

[0550] Synthetic Route TIFF2024513881000209.tif42170

[0551] Step 1: 8-chloro-9-(6-fluoro-1-methyl-1H-indazol-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline TIFF2024513881000210.tif34170

[0552] A solution of 9-bromo-8-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (200.0 mg, 0.42 mmol), 6-fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (117.0 mg, 0.42 mmol), potassium phosphate (179.7 mg, 0.84 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31.4 mg, 0.042 mmol) in tetrahydrofuran (2.0 mL) and water (0.4 mL) was stirred at 60°C for 1 h under nitrogen. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (25 / 1) to give 100 mg of crude product. The crude product was purified by elution with the following conditions: Column: XBridge Prep C18 OBD column, 30×100 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 50B to 80B in 7 min, 254 / 220 nm; RT1: 6.53 to give 8-chloro-9-(6-fluoro-1-methyl-1H-indazol-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazoline (29.1 mg, 0.05 mmol, 12.7% yield). LC-MS: (ESI, m / z): 541.2 [M+H] + .

[0553] Example 8: 1H NMR(300 MHz,DMSO-d6)δ 8.26(s,1H),7.21(d,J=8.2 Hz,2H),7.02(dd,J=9.9,7.9 Hz,1H),5.29(d,J=54.3 Hz,1H),4.81-4.50(m,2H),4.13-3.90(m,4H),3.56(s,3H),3.08(d,J=28.7 Hz,3H),3.20-3.00(m,3H),2.90-2.80(m,1H),2.15(d,J=5.2 Hz,1H),2.03(d,J=11.7 Hz,2H),1.91-1.68(m,3H).

[0554] Example 9: 5-((9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)methyl)pyridin-3-ol TIFF2024513881000211.tif48170

[0555] Synthetic Route TIFF2024513881000212.tif127170

[0556] Step 1: 5-((2-(trimethylsilyl)ethoxy)methoxy)nicotinaldehyde TIFF2024513881000213.tif19170

[0557] A solution of 5-hydroxynicotinaldehyde (2.00 g, 16.2 mmol) and cesium carbonate (10.6 g, 32.5 mmol) in tetrahydrofuran (20.0 mL) was stirred at 25° C. for 10 min. Then, 2-(trimethylsilyl)ethoxymethyl chloride (2.8 mL, 16.2 mmol) was added and stirred at 25° C. for 3 h. After completion of the reaction, the solvent was diluted with water and extracted with ethyl acetate. The organic layers were then combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 10) to give 5-((2-(trimethylsilyl)ethoxy)methoxy)nicotinaldehyde (1.96 g, 7.2 mmol, 44.6% yield) as a yellow solid. LC-MS: (ESI, m / z): 254.1 [M+H] +

[0558] Step 2: 2-(((5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)methyl)amino)ethan-1-ol TIFF2024513881000214.tif14170

[0559] A solution of 2-aminoethanol (0.8 mL, 14.6 mmol) and acetic acid (0.1 mL, 0.7 mmol) in methyl alcohol (200.0 mL) was stirred at room temperature for 5 minutes. Then, 5-((2-(trimethylsilyl)ethoxy)methoxy)nicotinaldehyde (1.86 g, 7.3 mmol) was added and stirred at room temperature for 2 hours. Then, sodium cyanoborohydride (922.6 mg, 14.6 mmol) was added at 0° C. and stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 10) to give 2-(((5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)methyl)amino)ethan-1-ol (2.0 g, 6.4 mmol, 88.2% yield) as a colorless oil. LC-MS: (ESI, m / z): 299.2 [M+H] +

[0560] Step 3: 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-(2-(((5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one TIFF2024513881000215.tif63170

[0561] A solution of 2-(((5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)methyl)amino)ethan-1-ol (400.0 mg, 1.30 mmol) and sodium hydride (64.3 mg, 2.60 mmol, 60% purity) in tetrahydrofuran (4.0 mL) was stirred at 0° C. for 5 minutes. Then, 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5-fluoro-3H-quinazolin-4-one (410.7 mg, 0.65 mmol) was added and stirred at 65° C. for 1 hour. After completion of the reaction, the reaction was quenched by saturated ammonium chloride solution. The solvent was diluted with water and extracted with ethyl acetate. The organic layers were then combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 10) to give 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-(2-(((5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one (464.0 mg, 0.52 mmol, 38.8% yield) as a white solid. LC-MS: (ESI, m / z): 891.5 [M+H] +

[0562] Step 4: 6-(8-chloro-4-((5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000216.tif49170

[0563] A solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-(2-(((5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one (176.0 mg, 0.20 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (154.1 mg, 0.30 mmol) and 1,8-diazabicycloundec-7-ene (0.1 mL, 0.57 mmol) in acetonitrile (2 mL) was stirred at room temperature for 1 h. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 15) to give 6-(8-chloro-4-((5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (54.0 mg, 0.061 mmol, 28.9% yield). LC-MS: (ESI, m / z): 873.4 [M+H] +

[0564] Step 5: 5-((9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)methyl)pyridin-3-ol TIFF2024513881000217.tif49170

[0565] A solution of 6-(8-chloro-4-((5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-3-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (200.0 mg, 0.22 mmol) in 2,2,2-trifluoroacetic acid (3.0 mL) was stirred at 50° C. for 3 hours. After completion of the reaction, the solvent was concentrated under vacuum. The product was purified using the following conditions (column, XBridge Prep C18 OBD column 19×15 mm 5 um C-0013; mobile phase, A: 1 mmol TFA in water, B: ACN and NH 4 Purification by prep-HPLC with Cl% (51% to 73% in 7 min; detector, UV 254 nm) gave 5-((9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)methyl)pyridin-3-ol (36.8 mg, 0.073 mmol, 32% yield). LC-MS: (ESI, m / z): 503.0 [M+H] +

[0566] Example 9: 1 H NMR (300 MHz, DMSO-d 6 ,ppm)δ 10.03-9.70(m,1H),8.60-8.35(m,1H),8.15-7.84(m,2H),7.19(s,1H),7.16-7.09(m,1H),6.76(s,2H),6.44(d,J=1.5 Hz,1H),5.08(s,2H),4.79-4.48(m,2H),3.94(d,J=5.1 Hz,2H),2.40-2.30(m,3H).

[0567] Example 10: (S)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000218.tif31170

[0568] Synthetic Route TIFF2024513881000219.tif115170

[0569] Step 1: Ethyl (S)-2,2-difluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate TIFF2024513881000220.tif27170

[0570] A solution of ethyl (S)-2,5-dioxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (15.00 g, 71.0 mmol) in dichloromethane (150.0 mL) was stirred at 0° C. for 10 min under nitrogen. Diethylaminosulfur trifluoride (28.1 mL, 213.0 mmol) was then added and stirred at 25° C. for 6 h. After completion of the reaction, the reaction was quenched with ethanol and the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 / 10) to give (S)-2,2-difluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.29 g, 31.2 mmol, 44% yield) as a white solid. LC-MS: (ESI, m / z): 234.2 [M+H] +

[0571] Step 2: (S)-(2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol TIFF2024513881000221.tif22170

[0572] A solution of ethyl (S)-2,2-difluoro-5-oxotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (7.2 g, 30.8 mmol) in tetrahydrofuran (100.0 mL) was stirred at 0° C. for 10 min. Then diisobutylaluminum hydride (13.10 g, 92.6 mmol, 1M in THF) was added and stirred at 70° C. for 30 min. After completion of the reaction, the reaction was quenched by sodium sulfate decahydrate (1.00 g). The resulting solution was filtered and the filtrate was concentrated under reduced pressure to give (S)-(2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (4.70 g, crude) as a white oil. LC-MS: (ESI, m / z): 178.2 [M+H] +

[0573] Step 3: (S)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000222.tif33170

[0574] A solution of (S)-(2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (99.4 mg, 0.55 mmol) and sodium hydride (74.0 mg, 1.85 mmol, 60% purity) in tetrahydrofuran (4.0 mL) was stirred at room temperature for 5 minutes. Then, 6-(8-chloro-3-fluoro-13-methyl-10-oxa-2,4,13-triazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl)-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (250.0 mg, 0.35 mmol) was added and stirred at room temperature for 2 hours. After completion, the reaction was quenched by saturated ammonium chloride solution. The solvent was diluted with water and extracted with ethyl acetate. The organic layers were then combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 10) to give (S)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (263.0 mg, 0.31 mmol, 88.5% yield) as a yellow solid. LC-MS: (ESI, m / z): 825.3 [M+H] +

[0575] Step 4: (S)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000223.tif33170

[0576] A solution of (S)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (250.0 mg, 0.30 mmol) in 2,2,2-trifluoroacetic acid (4.0 mL) was stirred at 50° C. for 5 h. After completion, the solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile in water 0-40 / 0.1% NH 4 Cl) to give (S)-6-(8-chloro-2-((2,2-difluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (93.0 mg, 0.15 mmol, 52.5% yield). LC-MS: (ESI, m / z): 585.0 [M+H] +

[0577] Example 10: 1 H NMR (300 MHz, DMSO-d 6 )δ 6.80(s,1H),6.62(d,J=2.1 Hz,2H),6.39-6.21(m,1H),4.57-4.32(m,2H),4.08-3.68(m,4H),3.28-3.17(m,4H),3.0 8-2.84(m,2H),2.66-2.49(m,1H),2.36-2.09(m,5H),1.96-1.83(m,1H),1.71(d,J=34.1 Hz,3H).

[0578] Example 11: 6-(4-(1-(2-aminopyridin-3-yl)cyclopropyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000224.tif43170

[0579] Synthesis Route: TIFF2024513881000225.tif171170

[0580] Step 1: Ethyl 1-(2-chloropyridin-3-yl)cyclopropane-1-carboxylate TIFF2024513881000226.tif17170

[0581] To a solution of ethyl 2-(2-chloro-3-pyridyl)acetate (1.00 g, 5.02 mmol) in N,N-dimethylformamide (25.0 mL) was added sodium hydride (800.0 mg, 20.08 mmol, 60% purity) and 1,2-dibromoethane (1.40 g, 7.48 mmol) at 0° C. The solution was then stirred at 0° C. for 2 h. Upon completion, the reaction was quenched with saturated ammonium chloride. The resulting solution was diluted with water, extracted with ethyl acetate, washed with brine, and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (4 / 1). This afforded ethyl 1-(2-chloropyridin-3-yl)cyclopropane-1-carboxylate (660.0 mg, 2.92 mmol, 58.4% yield) as a colorless oil. LC-MS: (ESI, m / z): 226.1 [M+H] +

[0582] Step 2: 1-(2-chloropyridin-3-yl)cyclopropane-1-carboxylic acid TIFF2024513881000227.tif17170

[0583] A solution of ethyl 1-(2-chloropyridin-3-yl)cyclopropane-1-carboxylate (660.0 mg, 2.92 mmol) and sodium hydroxide (590.0 mg, 14.7 mmol) in ethanol (15.0 mL) and water (10.0 mL) was stirred at 80° C. for 24 hours. After completion, ethanol was removed under vacuum. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 1-(2-chloropyridin-3-yl)cyclopropane-1-carboxylic acid (570.0 mg, 2.87 mmol, 98.6% yield) as a white solid. LC-MS: (ESI, m / z): 198.0 [M+H] +

[0584] Step 3: tert-Butyl (1-(2-chloropyridin-3-yl)cyclopropyl)carbamate TIFF2024513881000228.tif17170

[0585] A mixture of 1-(2-chloropyridin-3-yl)cyclopropane-1-carboxylic acid (2.50 g, 12.62 mmol), triethylamine (4.00 g, 39.54 mmol) and diphenylphosphoryl azide (5.00 g, 18.16 mmol) in 2-methyl-2-propanol (50.0 mL) was stirred at 85° C. for 16 h. After completion, the resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (7 / 3). This afforded tert-butyl (1-(2-chloropyridin-3-yl)cyclopropyl)carbamate (3.00 g, 11.15 mmol, 88.2% yield) as a white solid. LC-MS: (ESI, m / z): 269.1 [M+H] +

[0586] Step 4: tert-Butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(1-(2-chloropyridin-3-yl)cyclopropyl)carbamate TIFF2024513881000229.tif17170

[0587] To a mixture of tert-butyl N-[1-(2-chloro-3-pyridyl)cyclopropyl]carbamate (3.20 g, 11.90 mmol) in N,N-dimethylformamide (50.0 mL) was added sodium hydride (1.50 g, 37.58 mmol, 60% purity) at room temperature and stirred for 1 h, then (2-bromoethoxy)-tert-butyldimethylsilane (3.8 mL, 17.85 mmol) was added and stirred for 4 h. After completion, the reaction was quenched with saturated ammonium chloride. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (80 / 20). This gave tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(1-(2-chloropyridin-3-yl)cyclopropyl)carbamate (4.00 g, 9.36 mmol, 78.7% yield) as a yellow oil. LC-MS: (ESI, m / z): 427.1 [M+H] +

[0588] Step 5: tert-Butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)carbamate TIFF2024513881000230.tif24170

[0589] A mixture of 4-methoxybenzylamine (0.3 mL, 2.30 mmol), tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-n-[1-(2-chloro-3-pyridyl)cyclopropyl]carbamate (500.0 mg, 1.15 mmol), tris(dibenzylideneacetone)dipalladium (110.0 mg, 0.1 mmol), 1.1'-binaphthyl-2.2'-diphenylphosphine (150.0 mg, 0.23 mmol) and sodium tert-butoxide (340.0 mg, 3.51 mmol) in toluene (8.0 mL) was stirred at 100° C. for 2 hours. After completion, the resulting solution was diluted with water. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (4 / 1). This gave tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)carbamate (560.0 mg, 1.06 mmol, 90.6% yield) as a yellow oil. LC-MS: (ESI, m / z): 528.3 [M+H] +

[0590] Step 6: 2-((1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)amino)ethan-1-ol TIFF2024513881000231.tif23170

[0591] A solution of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)carbamate (500.0 mg, 1.06 mmol) and hydrochloric acid (1 M in 1,4-dioxane) (6.0 mL) was stirred at room temperature for 4 h. After completion, LC-MS showed that the product was formed and SM was consumed. The crude product (600 mg, crude) is used directly in the next step without purification. LC-MS: (ESI, m / z): 314.2 [M+H] +

[0592] Step 7: 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-(2-((1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)amino)ethoxy)quinazolin-4(3H)-one TIFF2024513881000232.tif44170

[0593] A solution of 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5-fluoro-3H-quinazolin-4-one (300.0 mg, 0.49 mmol), 2-((1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)amino)ethan-1-ol (153.37 mg, 0.49 mmol) and sodium hydride (58.7 mg, 2.45 mmol, 60% purity) in tetrahydrofuran (4.0 mL) was stirred at 65° C. for 5 hours. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 10) to give 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-(2-((1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)amino)ethoxy)quinazolin-4(3H)-one (300.0 mg, 0.33 mmol, 51.4% yield) as a yellow solid. LC-MS: (ESI, m / z): 906.4 [M+H] +

[0594] Step 8: 6-(8-chloro-4-(1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000233.tif43170

[0595] A solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-(2-((1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)amino)ethoxy)quinazolin-4(3H)-one (400.0 mg, 0.44 mmol), bis(2-oxo-3-oxazolidinyl)phosphine chloride (168.5 mg, 0.66 mmol) and N,N-diisopropylethylamine (171.1 mg, 1.32 mmol) in chloroform (2.0 mL) was stirred at 70° C. for 3 hours. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (2 / 1) to give 6-(8-chloro-4-(1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (230.0 mg, 0.26 mmol, 58.7% yield) as a yellow solid. LC-MS: (ESI, m / z): 888.4 [M+H] +

[0596] Step 9: 6-(4-(1-(2-aminopyridin-3-yl)cyclopropyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000234.tif43170

[0597] A solution of 6-(8-chloro-4-(1-(2-((4-methoxybenzyl)amino)pyridin-3-yl)cyclopropyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (220.0 mg, 0.2 mmol) in 2,2,2-trifluoroacetic acid (4.0 mL) was stirred for 4 hours at 70° C. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 10) to give 6-(4-(1-(2-aminopyridin-3-yl)cyclopropyl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (46.3 mg, 0.087 mmol, 35.3% yield). LC-MS: (ESI, m / z): 528.1 [M+H] + .

[0598] Example 11: 1 H NMR(300 MHz,DMSO-d6)δ 8.52(s,1H),7.91(dd,J=4.9,1.8 Hz,1H),7.78(dd,J=7.4,1.9 Hz,1H),7.19(s,3H),6.77(s,2H),6.55(dd,J=7.4,4.8 Hz,1H),6.45(s,1H),4.61(dd,J=32.8,11.4 Hz,2H),4.05(d,J=21.5 Hz,2H),2.35(q,J=2.1 Hz,3H),1.56(s,2H),1.40-1.20(m,2H).

[0599] Example 12: 6-((9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)methyl)pyridin-2(1H)-one TIFF2024513881000235.tif38170

[0600] Synthesis Route: TIFF2024513881000236.tif158170

[0601] Step 1: 2-(((6-methoxypyridin-2-yl)methyl)amino)ethan-1-ol TIFF2024513881000237.tif17170

[0602] A solution of ethanolamine (1.3 mL, 21.78 mmol) and 6-methoxy-2-pyridinecarbaldehyde (1.7 mL, 14.54 mmol) in toluene (20.0 mL) was stirred at 120° C. for 6 hours in a Dean-Stark separator. The reaction solvent was then concentrated under vacuum. Sodium borohydride (1.9 g, 52.54 mmol) and methyl alcohol (20.0 mL) were then added to the reaction mixture at 0° C. and stirred for 1 hour. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 10) to give 2-(((6-methoxypyridin-2-yl)methyl)amino)ethan-1-ol (1.12 g, 6.12 mmol, 41.6% yield) as a white solid. LCMS(ESI,m / z):183.2[M+H] + .

[0603] Step 2: 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-(2-(((6-methoxypyridin-2-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one TIFF2024513881000238.tif54170

[0604] A solution of 2-(((6-methoxypyridin-2-yl)methyl)amino)ethan-1-ol (178.3 mg, 0.95 mmol) and sodium hydride (78.3 mg, 3.2 mmol, 60% purity) in tetrahydrofuran (5.0 mL) was stirred at 60° C. for 5 minutes. 7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-5-fluoro-3H-quinazolin-4-one (400.0 mg, 0.65 mmol) was then added and stirred at 60° C. for 3 hours. After completion, the reaction was quenched with dilute hydrochloric acid. The solvent was diluted with water and extracted with ethyl acetate. The organic layers were then combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with methanol / dichloromethane (1 / 30) to give 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-(2-(((6-methoxypyridin-2-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one (430.0 mg, 0.55 mmol, 81.6% yield) as a white solid. LCMS (ESI, m / z): 775.2 [M+H] + .

[0605] Step 3: 6-(8-chloro-4-((6-methoxypyridin-2-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000239.tif46170

[0606] A solution of 7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-5-(2-(((6-methoxypyridin-2-yl)methyl)amino)ethoxy)quinazolin-4(3H)-one 420.0 mg, 0.52 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (422.9 mg, 0.81 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL, 1.64 mmol) in chloroform (5.0 mL) was stirred at 60° C. for 2 hours. After completion, the solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / petroleum ether (1 / 3) to give 6-(8-chloro-4-((6-methoxypyridin-2-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (317.0 mg, 0.41 mmol, 76.5% yield) as a white solid. LCMS (ESI, m / z): 757.2 [M+H] + .

[0607] Step 4: 6-(8-chloro-4-((6-methoxypyridin-2-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine TIFF2024513881000240.tif46170

[0608] A solution of 6-(8-chloro-4-((6-methoxypyridin-2-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (300.0 mg, 0.39 mmol) in 2,2,2-trifluoroacetic acid (4.0 mL) was stirred at 50° C. for 3 h. After completion, the solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile 0-40 / 0.1% NH 4 HCO 3 aqueous solution) to give 6-(8-chloro-4-((6-methoxypyridin-2-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (172.0 mg, 0.33 mmol, 84% yield) as a white solid. LCMS (ESI, m / z): 517.1 [M+H] +

[0609] Step 5: 6-((9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)methyl)pyridin-2(1H)-one TIFF2024513881000241.tif46170

[0610] A solution of 6-(8-chloro-4-((6-methoxypyridin-2-yl)methyl)-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (150.0 mg, 0.29 mmol) and boron tribromide (726.9 mg, 2.92 mmol) in 1,2-dichloroethane (3.0 mL) was stirred at 80° C. for 10 h. After completion, the reaction was quenched with water. The solvent was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography (acetonitrile 0-40 / 0.1% NH 4Cl (aq.) to give 6-((9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)methyl)pyridin-2(1H)-one (68.2 mg, 0.13 mmol, 46.3% yield). LCMS (ESI, m / z): 503.1 [M+H] + .

[0611] Example 12: 1 H NMR(300 MHz,DMSO-d6)δ 11.62(s,1H),8.40(s,1H),7.40-7.23(m,1H),7.19(s,1H),6.75(s,2H),6.44(s,1H),6.20(d,J=9.1 Hz,1H),6.06(s,1H),4.96-4.78(m,2H),4.75-4.60(m,2H),4.07-3.90(m,2H),2.34(d,J=2.4 Hz,3H).

[0612] Example 13: 3-(9-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)propanenitrile TIFF2024513881000242.tif38170

[0613] Synthetic Route TIFF2024513881000243.tif107170

[0614] Step 1: 3-((2-((7-bromo-6-chloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)amino)propanamide TIFF2024513881000244.tif45170

[0615] A solution of 7-bromo-6-chloro-5-fluoro-3H-quinazolin-4-one (1.50 g, 5.41 mmol) in tetrahydrofuran (40 mL) was stirred at 65° C. for 5 minutes. Sodium hydride (0.65 g, 16.22 mmol, 60% purity) and 3-(2-hydroxyethylamino)propanamide (1.43 g, 10.82 mmol) were then added and stirred at 65° C. for 3 hours. After completion, the reaction mixture was adjusted to pH 7-8 with hydrochloric acid (1N). The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with acetonitrile / water (1 / 4) to give 3-((2-((7-bromo-6-chloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)amino)propanamide (1.50 g, 3.85 mmol, 71.2% yield) as a white solid. LC-MS: (ESI, m / z): 389.6 [M+H] + .

[0616] Step 2: 3-(9-bromo-8-chloro-5,6-dihydro-4H-[1,4]oxazepino[5,6,7-de]quinazolin-4-yl)propanamide TIFF2024513881000245.tif30170

[0617] A solution of 3-((2-((7-bromo-6-chloro-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)amino)propanamide (1.50 g, 3.85 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.7 g, 11.11 mmol) in acetonitrile (20 mL) was stirred at 25° C. for 5 minutes. Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (2.40 g, 4.66 mmol) was then added and stirred at 25° C. for 2 hours. After completion, the reaction mixture was diluted with ethyl acetate, washed with water and the organic layers were combined. The organic layers were dried over anhydrous so...

Claims

1. Formula (I): (In the formula, X is NR １３ , O, C(R ｘ ) ２ ,C(O),SO,SO ２ , or S, u is 1 or 2; Each R ｘ are independently hydrogen, halogen, unsubstituted C １～３ Alkyl or unsubstituted C １～３ Is it a haloalkyl? Or, two R ｘ taken together form a cyclopropyl with the carbon to which they are attached, R １ is R ７ Substituted or unsubstituted indolyl, R ７ Substituted or unsubstituted benzofuranyl, R ７ Substituted or unsubstituted naphthyl, R ７ Substituted or unsubstituted indazolyl, R ７ Substituted or unsubstituted indenyl, R ７ Substituted or unsubstituted benzothiazolyl, R ７Ａ Substituted or unsubstituted phenyl, or R ７Ａ substituted or unsubstituted pyridinyl, Each R ７ are independently hydrogen, halogen, CN, CH ２ OH, -OH, NH ２ , N(Me) ２ , unsubstituted C １～３ Alkyl, unsubstituted C ２～５ Alkynyl, unsubstituted C １～３ haloalkyl, or unsubstituted cyclopropyl; Each R ７Ａ are independently hydrogen, halogen, NH ２ , N(Me) ２ , unsubstituted C １～３ Alkyl, unsubstituted C １～３ haloalkyl, or unsubstituted cyclopropyl; R ２ is hydrogen, O-L １ -R ８ , R ８Ａ Substituted or unsubstituted C １～３ Alkyl, or R ８Ｂ a substituted or unsubstituted 4- to 10-membered heterocycle; L １ is a bond or R Ｌ１ Substituted or unsubstituted C １～３ is alkylene, R Ｌ１ is halogen or unsubstituted C １～３ is alkyl, R ８ R containing N, S or O ９ a substituted or unsubstituted 4- to 10-membered heterocycle; Each R ９ are independently halogen, oxo, unsubstituted C １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C １～３ Alkoxy, R １０ Substituted or unsubstituted C １～３ Alkylidene, or R １０ Substituted or unsubstituted C ３～４ Cycloalkyl, or R １０ a substituted or unsubstituted 3- or 4-membered heterocycle; Or, two R ９ Let's join together and ３～５ forming a cycloalkyl or 3- to 5-membered heterocycle; R １０ is hydrogen or halogen, Each R ８Ａ are independently R ９Ａ Substituted or unsubstituted C １～３ Alkyl, R ９Ａ Substituted or unsubstituted C １～３ Alkoxy, R ９Ａ Substituted or unsubstituted C ３～４ Cycloalkyl, or R ９Ａ a substituted or unsubstituted 4- to 6-membered heterocycle; Each R ９Ａ are independently halogen, oxo, unsubstituted C １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C １～３ Alkoxy, unsubstituted C １～３ Alkylidene, R ９ Substituted or unsubstituted C ３～４ Cycloalkyl or R containing N, S or O ９ a substituted or unsubstituted 4- to 10-membered heterocycle; R ８Ｂ are independently halogen, oxo, -NH ２ , unsubstituted C １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C １～３ Alkoxy or unsubstituted C １～３ is alkylidene, R ３ and R ４ are each independently hydrogen, —CN, halogen, unsubstituted C １～３ alkyl, or unsubstituted cyclopropyl; R ５ is R ５Ａ Substituted or unsubstituted C １～６ Alkyl, R ５Ａ Substituted or unsubstituted C １～６ Haloalkyl, R ５Ａ Substituted or unsubstituted C ３～１０ Cycloalkyl, R ５Ａ A substituted or unsubstituted 3- to 10-membered heterocycle, or R ５Ａ a substituted or unsubstituted 5- to 10-membered heteroaryl; Each R ５Ａ are independently halogen, oxo, CN, OR １１ , S.R. １２ , S.O. ２ R １２ , N.R. １３ R １４ , C(O)N(R １１ ) ２ , C(O)R １１ , R ５Ｂ Substituted or unsubstituted C １～６ Alkyl, R ５Ｂ Substituted or unsubstituted C １～６ Haloalkyl, R ５Ｂ Substituted or unsubstituted C ３～６ Cycloalkyl, R ５Ｂ Substituted or unsubstituted 3- to 6-membered heterocycle, R ５Ｂ Substituted or unsubstituted C ５～８ Aryl, or R ５Ｂ a substituted or unsubstituted 5- to 9-membered heteroaryl; Or, two R ５Ａ Let's join together and ３～６ forming a cycloalkyl or 3- to 6-membered heterocycle; Each R ５Ｂ are independently halogen, oxo, CN, OR １１ , N.R. １３ R １４ , S.R. １２ , S.O. ２ R １２ , C(O)N(R １１ ) ２ , C(O)R １１ , R ５Ｃ Substituted or unsubstituted C １～３ Alkyl, R ５Ｃ Substituted or unsubstituted C １～３ Haloalkyl, R ５Ｃ Substituted or unsubstituted C ３～６ Cycloalkyl, R ５Ｃ Substituted or unsubstituted 3- to 6-membered heterocycle, R ５Ｃ Substituted or unsubstituted phenyl, or R ５Ｃ a substituted or unsubstituted 5- to 6-membered heteroaryl; Or, two R ５Ｂ Let's join together and ３～４ forming a cycloalkyl or 3- to 6-membered heterocycle; Each R ５Ｃ are independently halogen, oxo, CN, C(O)CH ３ , C(O)NH ２ , O.H., O.C.H. ３ , C.F. ３ , C.H.F. ２ , C.H. ２ F, N.R. １３ R １４ , S.C.H. ３ , S.O. ２ N.H. ２ , S.O. ２ CH ３ , unsubstituted C １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C ３～４ cycloalkyl, or an unsubstituted 3- to 4-membered heterocycle; Each R １１ are independently hydrogen, unsubstituted C １～３ Alkyl, unsubstituted C １～３ Haloalkyl, unsubstituted C ３～４ cycloalkyl, or an unsubstituted 3- to 4-membered heterocycle; Each R １２ is independently NH ２ or unsubstituted C １～３ is alkyl, Each R １３ and R １４ are independently hydrogen, C(O)R １１ , C(O)N(R １１ ) ２ , R １５ Substituted or unsubstituted C １～６ Alkyl, R １５ Substituted or unsubstituted C ３～６ Cycloalkyl, or R １５ a substituted or unsubstituted 3- to 6-membered heterocycle; Each R １５ is halogen, CN, C(O)CH ３ , C(O)NH ２ , O.H., O.C.H. ３ , C.F. ３ , C.H.F. ２ , C.H. ２ F, N.H. ２ , N.H.H. ３ , N(CH ３ ) ２ , S.O. ２ N.H. ２ , S.O. ２ CH ３ , R １６ Substituted or unsubstituted C １～３ Alkyl, R １６ Substituted or unsubstituted C ３～６ Cycloalkyl, R １６ Substituted or unsubstituted 3- to 6-membered heterocycle, R １６ Substituted or unsubstituted 5- to 9-membered aryl, or R １６ a substituted or unsubstituted 5- to 9-membered heteroaryl; Each R １６ are independently halogen, CN, C(O)CH ３ , C(O)NH ２ , O.H., O.C.H. ３ , C.F. ３ , C.H.F. ２ , C.H. ２ F, N.H. ２ , N.H.H. ３ , N(CH ３ ) ２ , S.O. ２ N.H. ２ , S.O. ２ CH ３ , R １７ Substituted or unsubstituted C １～３ Alkyl, R １７ Substituted or unsubstituted C ３～６ Cycloalkyl, R １７ Substituted or unsubstituted 3- to 6-membered heterocycle, R １７ Substituted or unsubstituted 5- to 9-membered aryl, or R １７ a substituted or unsubstituted 5- to 9-membered heteroaryl; Each R １７ are independently halogen, CN, C(O)CH ３ , C(O)NH ２ , O.H., O.C.H. ３ , C.F. ３ , C.H.F. ２ , C.H. ２ F, N.H. ２ , N.H.H. ３ , N(CH ３ ) ２ , S.O. ２ N.H. ２ , S.O. ２ CH ３ , or unsubstituted C １～３ is alkyl, R ６ and R ６Ａ are independently hydrogen, halogen, NR １３ R １４ , or R ６Ｂ Substituted or unsubstituted C １～６ is alkyl, R ６Ｂ is halogen, CN, OH, OCH ３ , C.F. ３ , C.H.F. ２ , C.H. ２ F, or unsubstituted C １～３ is alkyl) or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

2. R １ But, R ７Ａ substituted or unsubstituted phenyl, R ７ Substituted or unsubstituted indazolyl, or R ７Ａ 2. The compound of claim 1, which is a substituted or unsubstituted pyridinyl, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

3. Each R ７Ａ are independently halogen, NH ２ , unsubstituted C １～３ Alkyl or unsubstituted C １～３ 2. The compound of claim 1, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, which is haloalkyl.

4. R １ but, (In the formula, X １ is N, CH, or CF; R ７Ａ is hydrogen, halogen, unsubstituted C １～３ Alkyl or unsubstituted C １～３ haloalkyl) 2. The compound of claim 1, wherein:

5. R １ but, 2. The compound of claim 1, wherein:

6. R １ but, (In the formula, R ７Ａ is hydrogen, halogen, unsubstituted C １～３ Alkyl or unsubstituted C １～３ haloalkyl) 2. The compound of claim 1, wherein:

7. R １ but, 2. The compound of claim 1, wherein:

8. R １ but, (In the formula, each R ７ are independently halogen, NH ２ , N(Me) ２ , unsubstituted C １～３ Alkyl or unsubstituted C １～３ haloalkyl) 2. The compound of claim 1, wherein:

9. R ２ But O-L １ -R ８ , R ８Ａ Substituted or unsubstituted C １～３ Alkyl, or R ８Ｂ The compound according to any one of claims 1 to 8, which is a substituted or unsubstituted 4- to 6-membered heterocycle, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

10. R ２ But O-L １ -R ８ 9. The compound of any one of claims 1 to 8, wherein: L 1 is unsubstituted C 1-3 alkylene and R 8 is a 4- to 10-membered heterocycle containing one N heteroatom, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

11. R 2 is OL 1 -R 8 , L 1 is an unsubstituted C 1-3 alkylene, and R ８ but, (In the formula, R ９ is halogen or R １０ Substituted or unsubstituted C １～３ is alkylidene, r is an integer from 0 to 12; j is 1, 2, or 3; k is 1 or 2.

9. The compound of any one of claims 1 to 8, wherein:

12. R 2 is OL 1 -R 8 , L 1 is an unsubstituted C 1-3 alkylene, and R ８ but, (In the formula, R ９ are independently halogen or R １０ Substituted or unsubstituted C １～３ is alkylidene, Each R １０ are independently hydrogen or halogen; r is 1 or 2.

9. The compound of any one of claims 1 to 8, wherein:

13. R 2 is OL 1 -R 8 , L 1 is an unsubstituted C 1-3 alkylene, and R ８ but, (In the formula, R ９ are independently halogen, oxo or unsubstituted C １～３ Is it an alkyl group? Or two R's ９ Let's join together and ３～５ forming a cycloalkyl or 3- to 5-membered heterocycle; r is 1 or 2.

9. The compound of any one of claims 1 to 8, wherein:

14. R 2 is OL 1 -R 8 , L 1 is an unsubstituted C 1-3 alkylene, and R ８ but, (In the formula, R ９ is hydrogen or unsubstituted C １～３ is alkyl, W is O, SO ２ , or NR １２ and R １２ is hydrogen, unsubstituted C １～３ Alkyl or unsubstituted C １～３ haloalkyl) 9. The compound of any one of claims 1 to 8, wherein:

15. R ２ The compound of any one of claims 1 to 8, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein is hydrogen.

16. R ３ The compound of any one of claims 1 to 8, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein R is hydrogen or halogen and R 4 is halogen.

17. R ５ But, R ５Ａ Substituted or unsubstituted C １～６ 9. The compound of any one of claims 1 to 8, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

18. R ５ but, 9. The compound of any one of claims 1 to 8, wherein:

19. R ５ but, (In the formula, Ring A is a 3- to 6-membered heterocycle or a 5- to 9-membered heteroaryl containing at least one N heteroatom; s is 0, 1, 2, or 3.

9. The compound of any one of claims 1 to 8, wherein:

20. 20. The compound of claim 19, wherein Ring A is azetidinyl, thietanyl 1,1-dioxide, imidazolyl, thiazolyl, isothiazolyl, triazolyl, pyrazolyl, pyrazinyl, pyridonyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolopyridinyl, or pyrazolopyridinyl, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof.

21. formula:

20. The compound of claim 19, having the formula:

22. R ５ but, (In the formula, R ５Ａ CN, OH, COR １１ , S.O. ２ R １２ , N.R. １３ R １４ , R ５Ｂ Substituted or unsubstituted azetidinyl, or R ５Ｂ substituted or unsubstituted oxetanyl) 9. The compound of any one of claims 1 to 8, wherein:

23. 9. The compound of any one of claims 1 to 8, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, wherein X is O and R 6 is hydrogen.

24. below; or a pharma- ceutically acceptable salt thereof.

25. The following; or a pharma- ceutically acceptable salt thereof.

26. 3. A pharmaceutical composition comprising a compound according to claim 1 or 2, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

27. ​​A pharmaceutical for treating cancer in a subject in need of such treatment, comprising an effective amount of a compound according to claim 1 or 2, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to claim 1 or 2, or a stereoisomer, atropisomer, tautomer, or pharma- ceutically acceptable salt thereof, and one or more pharma- ceutical acceptable additives.

28. The pharmaceutical according to claim 27 , wherein the cancer is characterized by comprising a KRas mutation, the KRas mutation corresponding to a KRas G12D mutation or a KRas G12V mutation.

29. The method of claim 28, wherein the cancer is tissue-independent.

30. The pharmaceutical composition of claim 28 , wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

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