Heterocyclic compounds, compositions thereof and methods of treatment therewith

Abstract

Provided herein are compounds having the structure: wherein the substituents are as defined herein, compositions comprising an effective amount of a compound, and methods for modulating the activity of KRAS G12D and / or G12V. # imgabs0 #

Description

Technical Field

[0001] Provided herein are heterocyclic compounds useful for treating cancer, pharmaceutical compositions comprising these compounds, and methods of using these compounds to treat cancer or a condition treatable or preventable by inhibiting KRAS activity, the methods comprising administering an effective amount of the compound to a subject in need thereof. Background Art

[0002] Ras is a family of proteins that are associated with cell membranes through their C-terminal membrane targeting regions and are well known as molecular switches in intracellular signaling networks (Cox AD, Der CJ. Ras history: The saga continues. Small GTPases. 2010; 1(1): 2-27). Ras proteins bind to GTP or GDP and switch between "on" and "off" states. When Ras protein binds to GDP, it is in the off (or inactive) state. And when Ras is turned on by certain growth-promoting stimuli (such as growth factors), the Ras protein is induced to exchange its bound GDP for GTP and become on (or active) state (Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer 2003; 3(6): 459-465). By switching to an active state, Ras proteins can interact with different downstream proteins and activate related signal transduction pathways (Berndt N, Hamilton AD, Sebti SM. Targeting protein prenylation for cancer therapy. Nat Rev Cancer. 2011; 11(11): 775-791). The Ras superfamily contains different subfamilies, including Ras, Ral, Rap, Rheb, Rad, Rit, and Miro (Wennerberg K, Rossman KL, Der CJ. The Ras superfamily at a glance. J Cell Sci. 2005; 118(Part 5): 843-846). HRAs, NRas, and KRas are the most well-studied proteins in the Ras family, as these proteins are the most common oncogenes in human cancers (O'Bryan JP. Pharmacological targeting of RAS: Recent success with direct inhibitors. Pharmacol Res. 2019; 139: 503-511).

[0003] KRas is one of the most commonly mutated genes in human cancer. Based on data from the Catalog of Somatic Mutations (COSMIC) database, KRas mutations can be found in about 20% of human cancers, including pancreatic cancer, colorectal cancer, lung cancer, skin cancer, etc. (O'Bryan JP. Pharmacological targeting of RAS: Recent success with direct inhibitors [RAS's pharmacological targeting: the latest success of direct inhibitors]. Pharmacol Res [Pharmacological Research]. 2019; 139: 503-511). The most common KRas mutations were found to be located at positions G12 and G13, which block the GTPase activating protein (GAP)-stimulated KRas GTP hydrolysis activity (Wang W, Fang G, Rudolph J. Ras inhibition via direct Ras binding--is there a path forward? [Ras inhibition via direct Ras binding--is there a path forward?] Bioorg Med Chem Lett [Biological Organic Chemistry and Medicinal Chemistry Express]. 2012; 22 (18): 5766-5776). This leads to overactivation of the KRas protein and ultimately to uncontrolled cell proliferation and cancer.

[0004] Among different cancers, pancreatic cancer is considered to be the most KRas-addicted cancer type. KRas mutations are found in 94.1% of pancreatic ductal adenocarcinomas (PDAC). KRas G12D (41%) and G12V (34%) mutations are the two most common mutations in all KRas-mutated PDACs (Waters AM, Der CJ. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med. 2018; 8(9): a031435). In vivo data generated from mouse models demonstrate that the progression and maintenance of pancreatic cancer is highly dependent on constitutive activation of KRas downstream signaling (Siveke JT, Schmid RM. Chromosomal instability in mouse metastatic pancreatic cancer--it's Kras and Tp53 after all. Cancer Cell. 2005; 7(5): 405-407). This suggests that mutant KRas proteins are very attractive drug targets for pancreatic cancer and other cancers with KRas mutations. Because WT KRas proteins also play key roles in the function of normal tissues, and WT KRas function has been shown to be essential for adult hematopoiesis (Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003; 3(6): 459-465). A potential drug molecule that could selectively inhibit mutant Kras proteins in cancer cells and leave its WT partner in normal cells unaffected would be highly desirable.

[0005] Therefore, KRas G12D and G12V mutations are very attractive targets for cancer and other cancers that harbor this mutation. Therefore, small molecule therapeutics that can selectively bind to Kras G12D or G12V and inhibit their function would be very useful.

[0006] Citation or identification of any reference in this section of this application shall not be construed as an admission that such reference is prior art to the present application. Summary of the invention

[0007] Provided herein are compounds having the following formula (II): and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof, wherein the substituents are as defined herein.

[0008] In one embodiment, the compound is selected from Table 1-Table 3.

[0009] In one embodiment, provided herein is a method for inhibiting the activity of a KRAS mutant protein in a cell, the method comprising contacting the cell with an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer or prodrug thereof, optionally wherein the KRAS mutant protein is a KRAS G12D and / or G12V mutant protein.

[0010] In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer or prodrug thereof, optionally wherein the cancer is mediated by a KRAS mutation; preferably a KRAS G12D and / or G12V mutation. DETAILED DESCRIPTION definition

[0011] As used herein, "KRAS gene" refers to a gene selected from the group consisting of DIRAS1, DIRAS2, DIRAS3, ERAS, GEM, HRAS, KRAS, MRAS, NKIRAS1, NKIRAS2, NRAS, RALA, RALB, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, RASD1, RASD2, RASL10A, RASL10B, RASL11A, RASL11B, RASL12, REM1, REM2, RERG, RERGL, RRAD, RRAS, RRAS2, and mutants thereof.

[0012] As used herein, "KRAS protein" refers to the protein expressed by the KRAS gene or its isoforms (Scolnick EM, Papageoege AG, Shih TY (1979), "Guanine nucleotide-binding activity for src protein of rat-derived murine sarcoma viruses," Proc Natl Acad Sci USA. 76(5):5355–5559; Kranenburg O (November 2005) "The KRAS oncogene: past, present, and future," Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1756(2):81–2).

[0013] As used herein, "G12D mutation" refers to a mutation of the 12th amino acid residue located in the G domain of the KRAS protein from glycine to aspartic acid.

[0014] As used herein, "KRAS G12D" or "G12D" refers to a KRAS protein having a G12D mutation.

[0015] As used herein, "G12V mutation" refers to a mutation of the 12th amino acid residue located in the G domain of the KRAS protein from glycine to valine.

[0016] As used herein, "KRAS G12V" or "G12V" refers to a KRAS protein having a G12V mutation.

[0017] As used herein and in the specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents, unless the context clearly dictates otherwise.

[0018] As used herein, unless otherwise indicated, the terms "about" and "approximately", when used with respect to a dose, amount, or weight percentage of an ingredient of a composition or dosage form, mean a dose, amount, or weight percentage known to one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage. In certain embodiments, the terms "about" and "approximately", when used in this context, contemplate a dose, amount, or weight percentage that is within 30%, within 20%, within 15%, within 10%, or within 5% of a specified dose, amount, or weight percentage.

[0019] As used herein and unless otherwise indicated, the terms "about" and "approximately", when used in relation to a value or range of values ​​provided to characterize a particular solid form, for example, in relation to a particular temperature or temperature range, such as, for example, describing a melting, dehydration, desolvation, or glass transition temperature; a change in mass, such as, for example, a change in mass as a function of temperature or humidity; solvent or water content, such as expressed in mass or percentage; or peak position, such as, for example, in analysis by, for example, IR or Raman spectroscopy or XRPD; indicate that the value or range of values ​​may deviate to a degree deemed reasonable by one of ordinary skill in the art while still describing the solid form. Techniques used to characterize crystalline forms and amorphous solids include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy (e.g., infrared (IR) and Raman spectroscopy), solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, high temperature hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In certain embodiments, the terms "about" and "approximately", when used in this context, indicate that a value or range of values ​​can vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the stated value or range of values. For example, in some embodiments, the value of the XRPD peak position may vary by up to ±0.2° 2Θ (or ±0.2 degrees 2Θ) while still describing a specific XRPD peak.

[0020] "Alkyl" groups are saturated, partially saturated or unsaturated straight or branched non-cyclic hydrocarbons having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, or in some embodiments 1 to 6, 1 to 4, or 2 to 6 carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH7CH3), etc. The alkyl group may be substituted or unsubstituted. When alkyl groups described herein are said to be "substituted," they may be substituted with any one or more of the substituents found in the exemplary compounds and examples disclosed herein, as well as the following: halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; amido; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2; or O(alkyl)aminocarbonyl.

[0021] "Alkenyl" group is a straight or branched non-cyclic hydrocarbon with 2 to 10 carbon atoms, usually 2 to 8 carbon atoms, and includes at least one carbon-carbon double bond.Representative straight and branched (C2C8) alkenyl includes-vinyl,-allyl,-1-butenyl,-2-butenyl,-isobutylenyl,-1-pentenyl, 2-pentenyl,-3-methyl-1-butenyl,-2-methyl-2-butenyl,-2,3-dimethyl-2-butenyl,-1-hexenyl, 2-hexenyl,-3-hexenyl,-1-heptenyl,-2-heptenyl,-3-heptenyl,-1-octenyl,-2-octenyl, 3 octenyl etc.The double bond of alkenyl group can be unconjugated or conjugated with another unsaturated group.Alkenyl group can be unsubstituted or substituted.

[0022] An "alkynyl" group refers to a monovalent hydrocarbon moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynyl groups are optionally substituted and can be straight chain, branched or cyclic. Alkynyl groups include, but are not limited to, those having 2-20 carbon atoms, i.e., C2-20 Alkynyl; having 2-12 carbon atoms, i.e. C 2-12 Alkynyl; having 2-8 carbon atoms, i.e. C 2-8 Alkynyl; having 2-6 carbon atoms, i.e. C 2-6 Alkynyl; and having 2-4 carbon atoms, namely C 2-4 Alkynyl. Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and butynyl.

[0023] "Cycloalkyl" group is a saturated, partially saturated or unsaturated cyclic alkyl group with 3 to 10 carbon atoms, which has a single ring or multiple condensed rings or bridged rings that can be optionally substituted by 1 to 3 alkyl groups. In certain embodiments, the cycloalkyl group has 3 to 8 ring members, and in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6 or 3 to 7. The cycloalkyl comprising more than one ring can be fused, spirocyclic or bridged, or a combination thereof. For example, such cycloalkyl groups include monocyclic structures, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or include polycyclic or bridged ring structures, such as 1-bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, adamantyl, etc. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, etc. The cycloalkyl group may be substituted or unsubstituted. For example, such substituted cycloalkyl groups include cyclohexanol, etc.

[0024] "Bridged" bicyclic ring systems include two rings that share three, four or five adjacent ring atoms. As used herein, the term "bridge" refers to an atom or a chain of atoms that connects two different parts of a molecule. The two atoms (usually but not always two tertiary carbon atoms) connected by a bridge are called "bridgehead atoms". In addition to the bridge, the two bridgehead atoms are connected by at least two separate atoms or chains of atoms. Examples of bridged bicyclic ring systems include adamantyl, norbornyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.2..3] nonyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl, and 2,6-dioxa-tricyclo [3.3.1.03,7] nonyl. In one embodiment, the bridge is unsubstituted or substituted -(CH2) n-, wherein n is 1, 2, 3, 4 or 5. In one embodiment, the bridge is -CH2-. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-. A "spiro" bicyclic ring system shares a single ring atom (usually a quaternary carbon atom) between the two rings.

[0025] "Aryl" groups are aromatic carbocyclic groups with 6 to 14 carbon atoms, having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthracenyl). In some embodiments, the aryl group contains 6-14 carbon atoms, in other embodiments, it contains 6 to 12 or even 6 to 10 carbon atoms in the ring portion of the group. Specific aryl groups include phenyl, biphenyl, naphthyl, etc. The aryl group can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0026] "Heterocyclyl" is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl group, wherein one to four ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S and N. In some embodiments, the heterocyclyl group includes 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6 or 3 to 8 ring members. The heterocyclyl group can also be bonded to other groups on any ring atom (i.e., any carbon atom or heteroatom of the heterocycle). The heterocyclyl group can be substituted or unsubstituted. The heterocyclyl group can include multiple condensed rings, including but not limited to bicyclic, tricyclic and tetracyclic, and bridged ring systems or spirocyclic systems. The heterocyclyl group includes unsaturated, partially saturated and saturated ring systems, such as, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidinyl-4-one or imidazolidinyl-2,4-diketo) groups. The phrase heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as, for example, 1- and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidine. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydrofuranyl, pyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, thioxanyl, dioxy, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodisulfinyl, 1,4-dioxaspiro[4.5]decane, 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane, 1-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane, 2-oxo-1-oxa-3,9-diazaspiro[5.5]undecane,5] undecane, homopiperazinyl, quinuclidine, indolyl (e.g., indolyl-2-one or isoindolyl-1-one), indolinyl, isoindolyl, isoindolyl, azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1 H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl , pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), imidazopyridinyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridinyl), triazolopyridinyl, isoxazolopyridinyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolyl, isoquinolyl (e.g., 3,4-dihydroisoquinolin-1(2H)-one), quinolyl, Representative non-aromatic heterocyclyl groups include oxazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thiazinyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridinyl, tetrahydropyrazolopyridinyl, tetrahydroimidazopyridinyl, tetrahydrotriazolopyridinyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species containing fused aromatic groups. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidinyl-4-one or imidazolidinyl-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, thiooxanyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidine-2(1H)-one. Representative substituted heterocyclyl groups may be monosubstituted with various substituents (such as those listed below), or substituted more than once (such as, but not limited to, pyridinyl or morpholinyl groups, 2, 3, 4, 5, or 6 times), or disubstituted. .

[0027] A "heteroaryl" group is an aryl ring system having from one to four heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms, in other embodiments, it contains 6 to 9 or even 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl (e.g., indol-2-one or isoindolin-1-one), azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridinyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridinyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridinyl, thiapyrrolyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-one), tetrahydroquinolinyl, quinoxalinyl and quinazolinyl groups.

[0028] As used herein, "spirocycle" refers to two or more rings in which adjacent rings are attached by a single atom. The individual rings in a spirocycle may be the same or different. The individual rings in a spirocycle may be substituted or unsubstituted and may have different substituents than the other individual rings in a set of spirocycles.

[0029] A "cycloalkylalkyl" group is a group having the formula: -alkyl-cycloalkyl, wherein the alkyl and cycloalkyl are as defined above. The substituted cycloalkylalkyl group may be substituted at both the alkyl, cycloalkyl, or alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include, but are not limited to, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl, etc.

[0030] An "aralkyl" group is a group having the formula: -alkyl-aryl, wherein the alkyl and aryl are as defined above. Substituted aralkyl groups may be substituted on the alkyl, aryl, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups and fused (cycloalkylaryl) alkyl groups, such as 4-ethyl-indanyl.

[0031] A "heterocyclylalkyl" group is a group having the following formula: -alkyl-heterocyclyl, wherein the alkyl and heterocyclyl are as defined above. The substituted heterocyclylalkyl group can be substituted at both the alkyl, heterocyclyl, or alkyl and heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, 4-ethylmorpholinyl, 4-propylmorpholinyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0032] "Halogen" is fluorine, chlorine, bromine or iodine.

[0033] A "hydroxyalkyl" group is an alkyl group as defined above substituted with one or more hydroxy groups.

[0034] An "alkoxy" or "alkoxyl" group is an -O-(alkyl) group wherein alkyl is as defined above.

[0035] An "alkoxyalkyl" group is a -(alkyl)-O-(alkyl) where alkyl is as defined above.

[0036] An "amino" group is a group having the formula: -NH2.

[0037] An "alkylamino" group is a group of the formula: -NH-alkyl or -N(alkyl)2, wherein each alkyl group is independently as defined above.

[0038] A "carboxy" group is a group having the formula: -C(O)OH.

[0039] An "aminocarbonyl" group is a group having the formula: -C(O)N(R # )2、-C(O)NH(R # ) or -C(O)NH2, where each R # Independently is a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl group as defined herein.

[0040] An "amido" group is a group having the formula: -NHC(O)(R # ) or -N(alkyl)C(O)(R # ), wherein each alkyl group and R # Independently as defined above.

[0041] A "sulfonylamino" group is a group having the formula: -NHSO2(R # ) or -N(alkyl)SO2(R # ), wherein each alkyl group and R # As defined above.

[0042] A "urea" group is a group having the formula: -N(alkyl)C(O)N(R # )2, -N(alkyl)C(O)NH(R # )、-N(alkyl)C(O)NH2、-NHC(O)N(R # )2、-NHC(O)NH(R # ), or -NH(CO)NHR # , where each alkyl group and R # Independently as defined above.

[0043] When groups described herein (other than alkyl groups) are referred to as "substituted", they may be substituted with any suitable substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and examples disclosed herein, as well as halogen (chlorine, iodine, bromine, or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; amido; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclic group, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0044] As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, those well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton, Pa. (1990), or Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing, Easton, Pa. (1995).

[0045] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" means one stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. These compounds may have chiral centers and may exist in the form of racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms (including mixtures thereof) are included in the embodiments disclosed herein.

[0046] The use of stereoisomerically pure forms of these compounds and the use of mixtures of these forms are all encompassed in the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. Standard techniques (such as chiral columns or chiral resolving agents) can be used to asymmetrically synthesize or resolve these isomers. See, e.g., Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (ELiel, ed., Univ. of Notre Dame Press, Notre Dame, Indiana, 1972).

[0047] It should also be noted that the compound may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the compound is isolated as an E or Z isomer. In other embodiments, the compound is a mixture of E and Z isomers.

[0048] As used herein and unless otherwise indicated, "atropisomers" refers to stereoisomers resulting from hindered rotation about a single bond axis, where the energy barrier to rotation is high enough to allow separation of the individual rotamers.

[0049] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of these isomeric forms will depend on the environment in which the compound is located, and may differ depending on, for example, whether the compound is a solid or in an organic solution or an aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0050] As will be readily appreciated by those skilled in the art, many functional groups and other structures may exhibit tautomerism, and all tautomers of compounds of formula (I) are within the scope of the present invention.

[0051] It should also be noted that the compounds may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may be radiolabeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 C) labeling, or may be isotopically enriched, for example, with deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15 N). As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of the atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope of a given atom. Radiolabeled and isotopically enriched compounds can be used as therapeutic agents (e.g., cancer and inflammation therapeutic agents), research reagents (e.g., binding assay reagents) and diagnostic agents (e.g., in vivo imaging agents). All isotopic variations of the compounds described herein (whether or not radioactive) should be included within the scope of the embodiments provided herein. In some embodiments, isotopologues of compounds are provided, for example, these isotopologues are deuterium, carbon-13 or nitrogen-15 enriched compounds.

[0052] As used herein, "treatment" means the overall or partial relief of a disorder, disease or condition, or one or more symptoms associated with a disorder, disease or condition, or slowing or stopping the further progression or worsening of these symptoms, or alleviating or eradicating one or more causes of the disorder, disease or symptom itself. In some embodiments, "treatment" means the overall or partial relief of a disorder, disease or condition, or slowing or stopping the further progression or worsening of these symptoms. In another embodiment, "treatment" means the overall or partial relief of a disorder, disease or condition, or symptoms associated with a disorder, wherein the disorder is treatable or preventable by inhibiting KRAS (preferably G12D and / or G12V).

[0053] As used herein, "prevention" means a method that delays and / or prevents the onset, recurrence, or spread of a disorder, disease, or condition in whole or in part; prevents a subject from developing a disorder, disease, or condition; or reduces the risk of a subject developing a disorder, disease, or condition. In one embodiment, the disorder is a disorder that can be treated or prevented by inhibiting KRAS (preferably G12D and / or G12V).

[0054] The term "effective amount" used in connection with a compound means an amount capable of treating or preventing a disorder, disease or condition disclosed herein, or a symptom thereof.

[0055] The term "subject" includes animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment is a mammal, and in another embodiment is a human. Compound

[0056] Aspect 1: Provided herein are compounds having the following formula (I): and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof, in: Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; The moiety B is an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocyclyl, or an unsubstituted or substituted C 2-5 alkyl; X is N or CR 8 ; W is O, NH, NR 9 、NC(=O)-R 10 Or O = S = O; Each R 0 are independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 Alkylamino, carboxyl, nitro, thiol or thioether; or one or more pairs of R 0 The groups, together with the atoms to which they are attached, form unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 alkylamino, carboxyl, nitro, thiol or thioether; or Optionally, R 3a and R 3b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 4a and R 4b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 6b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 7a and R 7b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 8a and R 8b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 6a and R 8a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached they form unsubstituted or substituted bridges; R 8 is H, halogen, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Haloalkyl, unsubstituted or substituted C 3-5 Halogenated cycloalkyl, unsubstituted or substituted C1-4 Haloalkoxy, CN, OH or amino; R 9 is substituted or unsubstituted C 1-4 Alkyl or unsubstituted or substituted C 3-5 Cycloalkyl; R 10 is substituted or unsubstituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl or unsubstituted or substituted 3- to 5-membered heterocyclic group; t is 0 or 1; and m and q are each independently an integer between 0 and the maximum number of substituents permitted on rings A and B, respectively.

[0057] Provided herein are compounds having the following formula (IA): and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof, in: Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; The moiety B is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; X is N or CR 8 ; W is O, NH, NR 9 、NC(=O)-R 10 Or O = S = O; Each R 0 are independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 Alkylamino, carboxyl, nitro, thiol or thioether; or one or more pairs of R 0 The groups, together with the atoms to which they are attached, form unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; R 3a , R 3b , R 4a , R4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 alkylamino, carboxyl, nitro, thiol or thioether; or Optionally, R 3a and R 3b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 4a and R 4b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 6b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 7a and R 7b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 8a and R 8b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 6a and R 8a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached they form unsubstituted or substituted bridges; R 8 is H, halogen, unsubstituted or substituted C1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Haloalkyl, unsubstituted or substituted C 3-5 Halogenated cycloalkyl, unsubstituted or substituted C 1-4 Haloalkoxy, CN, OH or amino; R 9 is substituted or unsubstituted C 1-4 Alkyl or unsubstituted or substituted C 3-5 Cycloalkyl; R 10 is substituted or unsubstituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl or unsubstituted or substituted 3- to 5-membered heterocyclic group; t is 0 or 1; and m and q are each independently an integer between 0 and the maximum number of substituents permitted on rings A and B, respectively.

[0058] Provided herein are compounds having the following formula (II): and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof, in: Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; The moiety B is an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocyclyl, or an unsubstituted or substituted C 2-5 alkyl; X is N or CR 8 ; W is O, NH, NR 9 、NC(=O)-R 10 Or O = S = O; Each R 0 are independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 alkylamino, carboxyl, nitro, thiol or thioether; or one or more pairs of R 0 The groups, together with the atoms to which they are attached, form unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 alkylamino, carboxyl, nitro, thiol or thioether; or Optionally, R 3a and R 3b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 4a and R 4b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 6b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 7a and R 7b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 8a and R 8b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 6a and R 8aTogether with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached they form unsubstituted or substituted bridges; R 8 is H, halogen, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Haloalkyl, unsubstituted or substituted C 3-5 Halogenated cycloalkyl, unsubstituted or substituted C 1-4 Haloalkoxy, CN, OH or amino; R 9 is substituted or unsubstituted C 1-4 Alkyl or unsubstituted or substituted C 3-5 Cycloalkyl; R 10 is substituted or unsubstituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl or unsubstituted or substituted 3- to 5-membered heterocyclic group; t is 0 or 1; s and r are each independently 1 or 2; and m and q are each independently an integer between 0 and the maximum number of substituents permitted on rings A and B, respectively.

[0059] Provided herein are compounds having the following formula (IIA): and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof, in: Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; The moiety B is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; X is N or CR 8 ; W is O, NH, NR 9 、NC(=O)-R 10Or O = S = O; Each R 0 are independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 alkylamino, carboxyl, nitro, thiol or thioether; or one or more pairs of R 0 The groups, together with the atoms to which they are attached, form unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 alkylamino, carboxyl, nitro, thiol or thioether; or Optionally, R 3a and R 3b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 4a and R 4b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 6b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 7a and R 7b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R8a and R 8b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 6a and R 8a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached they form unsubstituted or substituted bridges; R 8 is H, halogen, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Haloalkyl, unsubstituted or substituted C 3-5 Halogenated cycloalkyl, unsubstituted or substituted C 1-4 Haloalkoxy, CN, OH or amino; R 9 is substituted or unsubstituted C 1-4 Alkyl or unsubstituted or substituted C 3-5 Cycloalkyl; R 10 is substituted or unsubstituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl or unsubstituted or substituted 3- to 5-membered heterocyclic group; t is 0 or 1; s and r are each independently 1 or 2; and m and q are each independently an integer between 0 and the maximum number of substituents permitted on rings A and B, respectively.

[0060] In one embodiment, s is 1. In one embodiment, s is 2. In some embodiments, m is an integer between 0 and 5. In some embodiments, m is an integer between 1 and 4. In some embodiments, m is an integer between 2 and 3. In some embodiments, m is an integer of 2 or 3. In some embodiments, q is an integer between 0 and 5. In some embodiments, q is an integer between 1 and 4. In some embodiments, q is an integer between 1 and 3. In some embodiments, q is an integer of 1 or 2.

[0061] In one embodiment, X is N. In one embodiment, X is CR 8 In one embodiment, X is CH, CF, C-Cl or C-CF3. In one embodiment, X is C-Cl. In one embodiment, X is C-CF3.

[0062] In some embodiments of any of Formula (I), (IA), (II), or (IIA), R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 6a and R 8a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In some embodiments of any of Formula (I), (IA), (II), or (IIA), R 6a and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In some embodiments of any of Formula (I), (IA), (II), or (IIA), R 6a and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In some embodiments of any of Formula (I), (IA), (II), or (IIA), R 5 and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In some embodiments of any of Formula (I), (IA), (II), or (IIA), R 5 and R 8a Together with the atoms to which they are attached they form unsubstituted or substituted bridges.

[0063] Aspect 2:

[0064] In one embodiment, ring A is an aryl group (e.g., phenyl or naphthyl) optionally substituted with one or more substituents. In one embodiment, the substituent is F, Cl, Br, amino, -CN, OH, -CF3, -CHF2, -CH2F, -CF2CH3, -CF2CF3, -OCHF2, -OCF3, vinyl (-CH=CH), -propenyl (e.g., -C(CH3)=CH), -CF=CH, aryl, heteroaryl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, or hexoxy. In one embodiment, the substituent is F, Cl, Br, amino, -CN, OH, -CF3, -CHF2, -CH2F, -CF2CH3, -CF2CF3, -OCHF2, -OCF3, vinyl (-CH=CH), -propenyl (such as -C(CH3)=CH), -CF=CH, aryl, heteroaryl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, methylcyclopropyl, fluorocyclopropyl, difluorocyclopropyl, fluoromethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy or hexyloxy.

[0065] In one embodiment, ring A is a 5-7 membered monocyclic heteroaryl or 8-12 membered bicyclic heteroaryl group optionally substituted by one or more substituents. In some preferred embodiments, ring A is pyridyl, benzothiazolyl, quinolyl, isoquinolyl, pyrazolopyridyl, benzimidazolyl, quinazolinyl or quinazolinyl. In one embodiment, the substituent is F, Cl, Br, C(CH3)=CH or -CH=CH, -CF=CH, -CN, OH, -NH2, -CF3, -CHF2, -CH2F, -CF2CH3, -CF2CF3, -OCHF2, -OCF3, aryl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy or hexyloxy. In one embodiment, the substituent is F, Cl, Br, C(CH3)=CH or -CH=CH, -CF=CH, -CN, OH, NH2, -CF3, -CHF2, -CH2F, -CF2CH3, -CF2CF3, -OCHF2, -OCF3, aryl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, methylcyclopropyl, fluorocyclopropyl, difluorocyclopropyl, fluoromethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propenyl, allyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy or hexyloxy. In some preferred embodiments, Ring A is pyridyl, benzothiazolyl, quinolyl, isoquinolyl, pyrazolopyridinyl, benzimidazolyl, quinazolinyl or quinazolinyl.

[0066] In one embodiment, Ring A is

[0067] In one embodiment, Ring A is

[0068] In one embodiment, Ring A is

[0069] In one embodiment, Ring A is

[0070] In one embodiment, Ring A is

[0071] Aspect 3:

[0072] In one embodiment, moiety B is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl. In one embodiment, heterocyclyl contains at least one oxygen as a ring member. In one embodiment, heterocyclyl contains at least one nitrogen as a ring member.

[0073] In one embodiment, moiety B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3 to 9 membered heterocycle containing one or two or three nitrogen atoms as ring members. In one embodiment, moiety B is oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, phenyl, tetrahydropyridinyl, azetidinyl, pyrrolidinyl, octahydroindolizinyl, octahydroquinolizinyl, hexahydro-1H-pyrrolizinyl, tetrahydroisoquinolinyl or tetrahydropyridinyl; and moiety B is optionally substituted. In one embodiment, moiety B is oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dihydro-2H-pyranyl, oxabicyclo[2.1.1]hexyl, oxabicyclo[2.2.1]heptyl, oxaspiro[3.3]heptyl, oxabicyclo[3.2.1]octyl, oxabicyclo[2.2.2]octyl, oxaspiro[3.5]nonyl or oxaspiro[3.4]octyl; and moiety B is optionally substituted. In one embodiment, moiety B is optionally substituted with halogen, cyano, hydroxy, alkoxy, or alkyl optionally substituted with halogen, cyano, hydroxy, alkoxy, heterocyclyl, cycloalkyl or cycloalkyloxy.

[0074] In one embodiment, the moiety B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 9-membered heterocycle containing one or two or three nitrogen atoms as ring members, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, phenyl, or tetrahydropyridinyl optionally substituted with one or more substituents. In one embodiment, the substituents are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8Alkoxy-C 1-8 alkyl-, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl or oxo; or the two substituents together with the carbon atoms to which they are attached form a 3- to 8-membered unsaturated or saturated ring containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0075] In one embodiment, portion B is In one embodiment, portion B is In one embodiment, portion B is

[0076] In one embodiment, moiety B is azetidinyl, pyridinyl, isoxazolyl, oxazolyl, dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, pyrrolidonyl, azaspiro[3.3]heptyl, azabicyclo[2.1.1]hexyl, pyrrolidinyl, 1H-pyrazolyl; and moiety B is optionally substituted.

[0077] In one embodiment, part B is C 2-5 Alkyl which is substituted with hydroxy and further substituted with halogen, haloalkyl or alkoxy.

[0078] In one embodiment, the moiety B is optionally substituted with halogen, cyano, hydroxy, alkoxy, or alkyl optionally substituted with halogen, cyano, hydroxy, or alkoxy.

[0079] In one embodiment, portion B is

[0080] In one embodiment, portion B is

[0081] In one embodiment, moiety B is azetidinyl, pyridinyl, isoxazolyl, oxazolyl, dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, pyrrolidonyl, azaspiro[3.3]heptyl, azabicyclo[2.1.1]hexyl, pyrrolidinyl, 1H-pyrazolyl; and moiety B is optionally substituted.

[0082] In one embodiment, moiety B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or azetidinyl; and moiety B is optionally substituted.

[0083] In one embodiment, portion B is

[0084] In one embodiment, portion B is

[0085] In one embodiment, portion B is

[0086] Aspect 4:

[0087] In one embodiment, Ring A is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzo[b]thienyl or substituted or unsubstituted benzo[d]thiazolyl.

[0088] In one embodiment, Ring A is

[0089] In one embodiment, Ring A is

[0090] Aspect 5:

[0091] In some embodiments, portion B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy or C 1-4 Alkoxy-C(O)-.

[0092] In one embodiment, moiety B is substituted or unsubstituted hexahydro-1H-pyrrolazinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted aminomethylcyclopropyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted oxabicyclo[2.1.1]hexanyl, substituted or unsubstituted oxabicyclo[2.2.1]heptanyl.

[0093] In one embodiment, portion B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

[0094] In one embodiment, portion B is In one embodiment, portion B is In one embodiment, portion B is In one embodiment, portion B is In one embodiment, portion B is In one embodiment, portion B is In one embodiment, portion B is In one embodiment, portion B is In one embodiment, portion B is

[0095] Aspect 6:

[0096] In one embodiment, W is O. In one embodiment, W is NH.

[0097] In one embodiment, R 6a and R 7a , or R 6a and R 8a , or R 5 and R 7a , or R 5 and R 8aThe bridge formed is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0098] Aspect 7:

[0099] Group 1 : In one embodiment, t is 0.

[0100] Group 1.1: In one embodiment, X is N.

[0101] In one embodiment, Ring A is and part B is

[0102] In one embodiment, R 1 is methyl or Cl. In one embodiment, R 2 In one embodiment, R 9 It is -NH2.

[0103] Group 1.1.1: In one embodiment, Ring A is

[0104] In one embodiment, portion B is

[0105] Group 1.1.1.1: In one embodiment, portion B is In one embodiment, portion B is

[0106] In one embodiment, W is O. In one embodiment, W is NH.

[0107] In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently H, OH, CN, amino or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently H or unsubstituted or substituted C1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, methyl or ethyl, optionally substituted with OH, CN, amino or methylamino. 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H or methyl.

[0108] In one embodiment, the compound is

[0109] In one embodiment, R 6a and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0110] In one embodiment, R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0111] In one embodiment, the compound is

[0112] Group 1.1.2: In one embodiment, Ring A is

[0113] In one embodiment, portion B is

[0114] Group 1.1.2.1: In one embodiment, portion B is In one embodiment, portion B is

[0115] Group 1.1.3: In one embodiment, Ring A is

[0116] In one embodiment, portion B is

[0117] Group 1.1.3.1: In one embodiment, portion B is In one embodiment, portion B is

[0118] In one embodiment, the compound is

[0119] In one embodiment, the compound is

[0120] Group 1.1.4: In one embodiment, W is O. In one embodiment, Ring A is

[0121] In one embodiment, portion B is

[0122] Group 1.1.4.1: In one embodiment, portion B is In one embodiment, portion B is

[0123] In one embodiment, the compound is

[0124] In one embodiment, the compound is

[0125] In one embodiment, the compound is

[0126] In one embodiment, the compound is

[0127] In one embodiment, the compound is

[0128] In one embodiment, R 6a and R 7aTogether with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0129] In one embodiment, R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0130] In one embodiment, the compound is

[0131] In one embodiment, the compound is

[0132] Group 1.1.4.2: In one embodiment, portion B is

[0133] In one embodiment, portion B is

[0134] In one embodiment, the compound is

[0135] In one embodiment, the compound is

[0136] Group 1.1.4.3: In one embodiment, portion B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N-, O- or S-containing heterocyclic ring.

[0137] In one embodiment, portion B is

[0138] In one embodiment, the compound is

[0139] In one embodiment, the compound is

[0140] In one embodiment, the compound is

[0141] In one embodiment, R 6a and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0142] In one embodiment, R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0143] In one embodiment, the compound is

[0144] Group 1.1.5.1: In one embodiment, Ring A is

[0145] In one embodiment, portion B is

[0146] In one embodiment, portion B is In one embodiment, portion B is

[0147] In one embodiment, the compound is

[0148] In one embodiment, the compound is

[0149] Group 1.2.4.1: In one embodiment, X is CH. In one embodiment, W is O.

[0150] In one embodiment, Ring A is

[0151] In one embodiment, portion B is In one embodiment, portion B is

[0152] In one embodiment, the compound is

[0153] In one embodiment, the compound is

[0154] In one embodiment, the compound is

[0155] Group 1.2.4.3: In one embodiment, X is CH. In one embodiment, W is O.

[0156] In one embodiment, Ring A is

[0157] In one embodiment, portion B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N-, O- or S-containing heterocyclic ring.

[0158] In one embodiment, portion B is

[0159] In one embodiment, the compound is

[0160] Group 1.2.6.1: In one embodiment, X is CH. In one embodiment, W is O.

[0161] In one embodiment, Ring A is

[0162] In one embodiment, portion B is In one embodiment, portion B is

[0163] In one embodiment, the compound is

[0164] In one embodiment, the compound is

[0165] In one embodiment, the compound is

[0166] Group 1.2.6.3: In one embodiment, X is CH. In one embodiment, W is O.

[0167] In one embodiment, Ring A is

[0168] In one embodiment, portion B is Where R aand R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N-, O- or S-containing heterocyclic ring.

[0169] In one embodiment, portion B is

[0170] In one embodiment, the compound is

[0171] Group 1.4.4.1: In one embodiment, X is C-Cl. In one embodiment, W is O.

[0172] In one embodiment, Ring A is

[0173] In one embodiment, portion B is In one embodiment, portion B is

[0174] In one embodiment, the compound is

[0175] In one embodiment, the compound is

[0176] Group 1.4.4.3: In one embodiment, X is C-Cl. In one embodiment, W is O.

[0177] In one embodiment, Ring A is

[0178] In one embodiment, portion B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N-, O- or S-containing heterocyclic ring.

[0179] In one embodiment, portion B is

[0180] In one embodiment, the compound is

[0181] Group 1.4.6.1:In one embodiment, X is C-Cl. In one embodiment, W is O.

[0182] In one embodiment, Ring A is

[0183] In one embodiment, portion B is In one embodiment, portion B is

[0184] In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently H, OH, CN, amino or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently H or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, methyl or ethyl, optionally substituted with OH, CN, amino or methylamino. 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b, R 8a , and R 8b Each is independently H or methyl.

[0185] In one embodiment, the compound is

[0186] In one embodiment, R 6a and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0187] In one embodiment, R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0188] In one embodiment, the compound is

[0189] Group 1.4.6.3: In one embodiment, X is C-Cl. In one embodiment, W is O.

[0190] In one embodiment, Ring A is

[0191] In one embodiment, portion B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N-, O- or S-containing heterocyclic ring.

[0192] In one embodiment, portion B is

[0193] In one embodiment, the compound is

[0194] In one embodiment, R 6a and R 7aTogether with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0195] In one embodiment, R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0196] In one embodiment, the compound is

[0197] Group 1.4.6.6: In one embodiment, X is C-Cl. In one embodiment, W is O.

[0198] In one embodiment, Ring A is

[0199] In one embodiment, portion B is Where R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

[0200] In one embodiment, portion B is

[0201] In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently H, OH, CN, amino or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b are each independently H or unsubstituted or substituted C 1-4In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, methyl or ethyl, optionally substituted with OH, CN, amino or methylamino. 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H or methyl.

[0202] In one embodiment, R 6a and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0203] In one embodiment, R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0204] In one embodiment, the compound is

[0205] Aspect 8:

[0206] Group 2: In one embodiment, t is 1.

[0207] Group 2.1: In one embodiment, X is N.

[0208] In one embodiment, portion B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

[0209] In one embodiment, Ring A is and part B is

[0210] In one embodiment, R 1 is methyl or Cl. In one embodiment, R 2 In one embodiment, R 9 It is -NH2.

[0211] Group 2.1.1: In one embodiment, Ring A is

[0212] In one embodiment, portion B is

[0213] Group 2.1.1.1: In one embodiment, portion B is In one embodiment, portion B is

[0214] In one embodiment, W is O. In one embodiment, W is NH.

[0215] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, methyl or ethyl, optionally substituted with OH, CN, amino or methylamino. 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H or methyl.

[0216] In one embodiment, the compound is

[0217] In one embodiment, the compound is

[0218] In one embodiment, R 6a and R 7aTogether with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0219] In one embodiment, R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0220] In one embodiment, the compound is

[0221] Group 2.1.4: In one embodiment, W is O. In one embodiment, Ring A is

[0222] In one embodiment, portion B is

[0223] Group 2.1.4.1: In one embodiment, portion B is In one embodiment, portion B is

[0224] In one embodiment, the compound is

[0225] In one embodiment, R 6a and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0226] In one embodiment, R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0227] In one embodiment, the compound is

[0228] Group 2.1.4.3: In one embodiment, W is O.

[0229] In one embodiment, Ring A is

[0230] In one embodiment, portion B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N-, O- or S-containing heterocyclic ring.

[0231] In one embodiment, portion B is

[0232] In one embodiment, the compound is

[0233] In one embodiment, R 6a and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0234] In one embodiment, R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0235] In one embodiment, the compound is

[0236] Group 2.1.4.6: In one embodiment, W is O.

[0237] In one embodiment, Ring A is

[0238] In one embodiment, portion B is Where R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

[0239] In one embodiment, portion B is

[0240] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, methyl or ethyl, optionally substituted with OH, CN, amino or methylamino. 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a, and R 8b Each is independently H or methyl.

[0241] In one embodiment, the compound is

[0242] In one embodiment, R 6a and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0243] In one embodiment, R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-.

[0244] In one embodiment, the compound is

[0245] Group 2.2.4.1: In one embodiment, X is CH. In one embodiment, W is O.

[0246] In one embodiment, Ring A is

[0247] In one embodiment, portion B is In one embodiment, portion B is

[0248] In one embodiment, the compound is

[0249] In one embodiment, the compound is

[0250] Group 2.4.6.1: In one embodiment, X is C-Cl. In one embodiment, W is O.

[0251] In one embodiment, Ring A is

[0252] In one embodiment, portion B is In one embodiment, portion B is

[0253] In one embodiment, R 3a , R 3b , R 4a , R 4b, R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H, methyl or ethyl, optionally substituted with OH, CN, amino or methylamino. 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b Each is independently H or methyl.

[0254] In one embodiment, the compound is

[0255] Aspect 9: In some embodiments, the compounds provided herein have one of the following formulae: and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof, in: Ring C is unsubstituted or substituted C 3-6 Cycloalkyl or unsubstituted or substituted 3- to 6-membered heterocyclic group.

[0256] In some embodiments, the compounds provided herein have one of the following formulae: and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof, in: Ring C is unsubstituted or substituted C 3-6 Cycloalkyl or unsubstituted or substituted 3- to 6-membered heterocyclic group.

[0257] In one embodiment, ring C contains Y and is R a Substituted, wherein Y is CH2, O, NH, NR 9 、NC(=O)-R 10 Or O = S = O; R 9 is substituted or unsubstituted C 1-4 Alkyl or unsubstituted or substituted C 3-5 Cycloalkyl; R 10 is substituted or unsubstituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl or unsubstituted or substituted 3- to 5-membered heterocyclyl; and R a is H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy or unsubstituted or substituted C 1-4 Alkylamino.

[0258] In one embodiment, Y is CH2. In one embodiment, Y is O. In one embodiment, Y is NH.

[0259] In one embodiment, R 6a and R 7a Together they form a bridge, wherein the bridge is -CH2-CH2-.

[0260] In one embodiment, R 5 and R 8a Together they form a bridge, wherein the bridge is -CH2-CH2-.

[0261] In one embodiment, Ring C is cyclopropyl. In one embodiment, Ring C is cyclobutyl.

[0262] In one embodiment, Ring C is oxetanyl.

[0263] Aspect 10: In some embodiments, the compounds provided herein have the following formula: and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof.

[0264] In one embodiment, X is N. In one embodiment, X is CH. In one embodiment, W is O. In one embodiment, W is NH.

[0265] In one embodiment, Ring A is In one embodiment, Ring A is

[0266] In one embodiment, portion B is In one embodiment, portion B is

[0267] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a1 , R 8b1 , R 8a2 , and R 8b2 are each independently H, OH, CN, unsubstituted or substituted amino or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R6b , R 7a , R 7b , R 8a1 , R 8b1 , R 8a2 , and R 8b2 are each independently H, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a1 , R 8b1 , R 8a2 , and R 8b2 Each is independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a1 , R 8b1 , R 8a2 , and R 8b2 Each is independently H, methyl or ethyl, optionally substituted with OH, CN, amino or methylamino. 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a1 , R 8b1 , R 8a2 , and R 8b2 Each independently is H or methyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a1 , R 8b1 , R8a2 , and R 8b2 Each independently is H.

[0268] In one embodiment, the compound is

[0269] Aspect 11: In some embodiments, the compounds provided herein have the following formula: and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof.

[0270] In one embodiment, X is N. In one embodiment, X is CH. In one embodiment, W is O. In one embodiment, W is NH.

[0271] In one embodiment, Ring A is In one embodiment, Ring A is

[0272] In one embodiment, portion B is In one embodiment, portion B is

[0273] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b are each independently H, OH, CN, unsubstituted or substituted amino or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b are each independently H or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b Each is independently H, unsubstituted or substituted methyl or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b Each is independently H, methyl or ethyl, optionally substituted with OH, CN, amino or methylamino. 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b Each independently is H or methyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b Each independently is H.

[0274] In one embodiment, the compound is

[0275] Aspect 12: In some embodiments, the compounds provided herein have the following formula: and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof, wherein the variables are as defined in formula (I) or (II).

[0276] In some embodiments, the compounds provided herein have the formula: and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof, wherein the variables are as defined in formula (I) or (II).

[0277] In one embodiment, R 11 is halogen, deuterium or substituted or unsubstituted C 1-3 In one embodiment, R 11 is deuterium or methyl. In one embodiment, R 11 is methyl. In one embodiment, u is 0, 1, 2, 3, 4 or 5. In one embodiment, u is 0, 1 or 2. In one embodiment, u is 1. In one embodiment, u is 0.

[0278] In one embodiment, ring A is substituted or unsubstituted phenyl or substituted or unsubstituted pyridin-4-yl. In one embodiment, ring A is phenyl or pyridin-4-yl, wherein ring A is optionally selected from halogen, substituted or unsubstituted C 1-3 In one embodiment, ring A is phenyl or pyridin-4-yl, wherein ring A is optionally substituted with one or more groups selected from halogen, CF3, CF2CH3, methyl, ethyl or NH2. In one embodiment, ring A is Where R 12 is H, halogen, substituted or unsubstituted C 1-3 alkyl or cyclopropyl optionally substituted with F; and R 12a is H, deuterium, F or Me. In one embodiment, Ring A is Where R 12 is halogen, substituted or unsubstituted C 1-3 alkyl or cyclopropyl optionally substituted with F. In one embodiment, ring A is Where R 12 is halogen, substituted or unsubstituted C 1-3 alkyl or cyclopropyl optionally substituted with F. In one embodiment, R 12 is F, Cl, methyl or ethyl. In one embodiment, R 12Is Cl or methyl. In one embodiment, Ring A is

[0279] In one embodiment, Ring A is

[0280] In one embodiment, moiety B is an unsubstituted or substituted heterocyclic group, wherein the heterocyclic group does not contain secondary or tertiary amines. In one embodiment, the heterocyclic group contains at least one oxygen as a ring member. In one embodiment, moiety B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy or C 1-4 Alkoxy-C(O)-. In one embodiment, moiety B is In one embodiment, portion B is In one embodiment, moiety B is optionally substituted with halogen, cyano, hydroxyl, C 1-3 Alkoxy or optionally halogen, cyano, hydroxy or C 1-3 Alkoxy substituted C 1-3 In one embodiment, moiety B is substituted or unsubstituted oxabicyclo[2.1.1]hexanyl. In one embodiment, moiety B is 2-oxabicyclo[2.1.1]hexan-4-yl, optionally substituted with halogen, cyano, hydroxyl, C 1-3 Alkoxy or optionally halogen, cyano, hydroxy or C 1-3 Alkoxy substituted C 1-3 Alkyl Substitution In one embodiment, the moiety B is 2-oxabicyclo[2.1.1]hexan-4-yl.

[0281] In one embodiment, the compound is In one embodiment, the compound is In one embodiment, the compound is In one embodiment, the compound is In one embodiment, the compound is In one embodiment, the compound is

[0282] In one embodiment, portion B is In one embodiment, portion B is

[0283] In one embodiment, the compound is In one embodiment, the compound is In one embodiment, the compound is In one embodiment, the compound is In one embodiment, the compound is In one embodiment, the compound is

[0284] In one embodiment, the compound is

[0285] In one embodiment, the compound is

[0286] Aspect 13: Provided herein is a compound selected from the following table:

[0287] Table 1

[0288] Aspect 14: In one embodiment, the compound is selected from Table 1-Table 3.

[0289] Aspect 15: In one embodiment, provided herein is a pharmaceutical composition comprising an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer or prodrug thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

[0290] Aspect 16: In one embodiment, provided herein is a method for inhibiting the activity of a KRAS mutant protein in a cell, the method comprising contacting the cell with an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer or prodrug thereof, optionally wherein the KRAS mutant protein is a KRAS G12D and / or G12V mutant protein.

[0291] Aspect 17: In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer or prodrug thereof, optionally wherein the cancer is mediated by a KRAS mutation; preferably a KRAS G12D and / or G12V mutation. Provided herein is a method for treating or preventing cancer, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein.

[0292] Aspect 18: Provided herein is a method for modulating the activity of KRAS G12D and / or G12V, the method comprising contacting the cell with an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer or prodrug thereof.

[0293] Aspect 19: Provided herein are kits for treating cancer, the kit comprising (a) a pharmaceutical composition comprising a compound provided herein; and (b) instructions for administering an effective amount of a pharmaceutical composition comprising a KRAS G12D and / or G12V inhibitor provided herein to treat cancer in an individual.

[0294] Embodiments of the invention may be more fully understood by reference to the detailed description and examples which are intended to illustrate non-limiting embodiments. Methods for preparing compounds

[0295] The compounds can be prepared using conventional organic synthesis and commercially available starting materials. By way of example and not limitation, compounds of formula (I) can be prepared as outlined in Schemes 1-3 shown below and in the Examples described herein. It should be noted that one skilled in the art will know how to modify the procedures described in the illustrative schemes and Examples to obtain the desired product. Common protecting groups can be used to prevent certain functional groups from undergoing undesirable reactions. Exemplary protecting groups are described in "Protective Groups in Organic Synthesis", 4th edition, PGM Wuts; TW Greene, John Wiley, 2007 and references cited therein.

[0296] Solution 1

[0297] As shown in Scheme 1, in some embodiments, provided herein are methods for preparing compounds as defined in Formula (I). Halogen-substituted compound 1-1 (X2 and X4 are halogens, X1 is OH or Cl, and X3 can be a methylthiol group) is converted to compound 1-2 under substitution conditions (e.g., HATU, DIEA, if X1 is OH; DIEA, DCM, if X1 is Cl); then compound 1-2 is converted to compound 1-3 under substitution conditions (e.g., NaH, THF); then compound 1-3 is converted to compound 1-4 under oxidation conditions (m-CPBA oxidation if LG is methylsulfonyl or methylsulfinyl); then compound 1-4 is converted to compound 1-5, followed by substitution or coupling reaction (e.g., NaH, THF); compound 1-5 is further The step is to carry out a metal-catalyzed cross-coupling reaction, such as Suzuki, Negishi or Stille coupling (e.g., Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water for Suzuki coupling) to obtain compound 1-6, wherein M can be boronic acid, boric acid ester, metal (e.g., Zn), tributyltin, etc.; finally, the compound 1-6 containing a protecting group is deprotected (e.g., when PG1 and PG2 contain a Boc group, the Boc group is deprotected with TFA and DCM; when PG1 and PG2 contain a TIPS group, the TIPS group is deprotected with CsF and DMF) to obtain a compound as defined in formula (I).

[0298] Solution 2

[0299] As shown in Scheme 2, in some embodiments, provided herein is a method for preparing a compound as defined in formula (I). The halogen-substituted compound 2-1 (X2 and X4 are halogens, X1 is OH or Cl, and X3 can be a methylthiol group) is converted to compound 2-2 under substitution conditions (e.g., NaH, THF); then compound 2-2 is converted to compound 2-3 under substitution conditions (e.g., HATU, DIEA, if X1 is OH; DIEA, DCM, if X1 is Cl); then compound 2-3 is converted to compound 2-4 under oxidation conditions (if LG is methylsulfonyl or methylsulfinyl, then m-CPBA oxidation); then compound 2-4 is converted to compound 2-5, followed by a substitution or coupling reaction (e.g., NaH, THF); Compound 2-5 is further subjected to a metal-catalyzed cross-coupling reaction, such as Suzuki, Negishi or Stiller coupling (e.g., Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water, for Suzuki coupling) to obtain compound 2-6, wherein M can be boronic acid, borate, metal (e.g., Zn), tributyltin, etc.; finally, compound 2-6 containing a protecting group is then deprotected (e.g., when PG1 and PG2 contain a Boc group, the Boc group is deprotected with TFA and DCM; when PG1 and PG2 contain a TIPS group, the TIPS group is deprotected with CsF and DMF) to obtain a compound as defined in formula (I).

[0300] Solution 3

[0301] As shown in Scheme 3, in some embodiments, provided herein is a method for preparing a compound as defined by formula (I). The halogen-substituted compound 3-1 (X2 and X4 are halogens, X1 is OH or Cl, and X3 can be a methylthiol group) is converted to compound 3-2 under substitution conditions (e.g., NaH, THF); then compound 3-2 is converted to compound 3-3 under substitution conditions (e.g., HATU, DIEA, if X1 is OH; DIEA, DCM, if X1 is Cl); then compound 3-3 is converted to compound 3-4 under oxidation conditions (if LG is methylsulfonyl or methylsulfinyl, then m-CPBA oxidation); then compound 3-4 is converted to compound 3-5, followed by a substitution or coupling reaction (e.g., NaH, THF). HF); Compound 3-5 is further subjected to a metal-catalyzed cross-coupling reaction, such as Suzuki, Negishi or Stiller coupling (e.g., Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water, for Suzuki coupling) to obtain compound 3-6, wherein M can be boronic acid, boric acid ester, metal (e.g., Zn), tributyltin, etc.; finally, compound 3-6 containing a protecting group is then deprotected (e.g., when PG1 and PG2 contain a Boc group, the Boc group is deprotected with TFA and DCM; when PG1 and PG2 contain a TIPS group, the TIPS group is deprotected with CsF and DMF) to obtain a compound as defined in formula (II). The embodiments of the present invention may be more fully understood by reference to the specific embodiments and examples intended to illustrate non-limiting embodiments. Examples

[0302] The following examples are intended to be purely exemplary and should not be considered to be limiting in any way. Unless otherwise stated, the experimental methods in the examples described below are conventional methods. Unless otherwise stated, reagents and materials are all commercially available. All solvents and chemicals used are analytical grade or chemical purity. Solvents are all redistilled before use. Anhydrous solvents are prepared according to standard methods or reference methods. Silica gel (100-200 mesh) for column chromatography and silica gel (GF254) for thin layer chromatography (TLC) are commercially available from Qingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd. in China; unless otherwise stated, both are eluted with petroleum ether (60°C-90°C) / ethyl acetate (v / v) and visually observed with iodine or phosphomolybdic acid in ethanol. Unless otherwise stated, all extraction solvents are dried over anhydrous Na2SO4.

[0303] Unless otherwise indicated, the reactions described below were performed under a positive pressure of nitrogen or argon or in anhydrous solvents with a drying tube; reaction flasks were equipped with rubber septa for introduction of substrates and reagents via syringe; and glassware was oven-dried and / or heat-dried.

[0304] Unless otherwise indicated, column chromatography purifications were performed on a Biotage system (manufacturer: Dyax Corporation) with silica columns or on silica SepPak columns (Waters), or on a Teledyne Isco Combiflash purification system using pre-packed silica columns.

[0305] 1 H NMR spectra were recorded at 400 MHz or 500 MHz on a Varian instrument with TMS (tetramethylsilane) as internal standard. CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone or (CD3)2CO were used as solvents and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)2CO: 2.05) as reference standards. 1 H-NMR spectra. When reporting the number of multiplets, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (double of doublets), dt (double of triplets). If coupling constants are given, they are reported in Hertz (Hz).

[0306] LC / MS data were recorded by using an Agilent 1100, 1200 high performance liquid chromatography-ion trap mass spectrometer (LC-MSD Trap) equipped with a diode array detector (DAD) detecting at 214 nm and 254 nm and an ion trap (ESI source). All compound names except reagents are 19.1 generated.

[0307] In the following examples, the following abbreviations are used:

[0308] Compound synthesis

[0309] Example 1: 2-amino-7-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine (5,6,7-de)quinazolin-5-yl)benzo[b]thiophene-3-carbonitrile

[0310] Step 1: 7-Bromo-4-chloro-5,8-difluoro-2-(methylthio)quinazoline

[0311] DIPEA (15 mL) was added dropwise to a suspension of 7-bromo-5,8-difluoro-2-(methylthio)quinazolin-4(3H)-one (10 g, 32.6 mmol) in POCl3 (30 mL). The mixture was stirred at 100 ° C overnight. The mixture was then cooled to rt and concentrated in vacuo. The mixture was diluted with DCM, the solid was filtered out to give a crude product, and further purified by silica gel column chromatography (80 g, eluted with PE / EtOAc=100%:0%-75%:25%) to give the title compound (6.9 g). MS (ESI, m / e) [M+H] + 324.4.

[0312] Step 2: (R)-(4-(7-Bromo-5,8-difluoro-2-(methylthio)quinazolin-4-yl)morpholin-3-yl)methanol. To a mixture of (R)-morpholin-3-ylmethanol (0.54 g, 4.6 mmol) and DIPEA (1.2 g, 9.3 mmol) in DCM (20 mL) was added 7-bromo-4-chloro-5,8-difluoro-2-(methylthio)quinazoline (1.5 g, 4.6 mmol) at 0 ° C. The mixture was stirred at room temperature overnight. The mixture was quenched with NH4Cl (10 mL, aq.sat.) solution and extracted with DCM (20 mL*3). The combined organic layers were dried over Na2SO4, concentrated and purified by silica gel chromatography (eluted with PE / EtOAc=2 / 1) to give the title compound (0.93 g). MS (ESI, m / e) [M+H] + 406.2.

[0313] Step 3: (S)-10-Bromo-9-fluoro-7-(methylthio)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine 5,6,7-deoxyquinazoline A mixture of (R)-(4-(7-bromo-5,8-difluoro-2-(methylthio)quinazolin-4-yl)morpholine-3-yl)methanol (0.93 g, 2.3 mmol) was placed in THF. NaH (0.28 g, 6.9 mmol) was added to the solution in batches at 0°C, and the mixture was stirred at room temperature overnight. The mixture was quenched with NH4Cl (10 mL, aq., sat) and extracted with DCM (20 mL*3). The combined organic layers were dried over Na2SO4, concentrated and purified by silica gel chromatography (eluted with PE / EtOAc=1 / 1) to give the title compound (0.87 g). MS (ESI, m / e) [M+H] + 386.2.

[0314] Step 4: (13aS)-10-bromo-9-fluoro-7-(methylsulfinyl)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine 5,6,7-deoxyquinazoline At 0°C, add (S)-10-bromo-9-fluoro-7-(methylthio)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine m-CPBA (0.25 g, 1.43 mmol) was added in portions to a mixture of [5,6,7-de]quinazoline (0.5 g, 1.3 mmol) in DCM (20 mL). The mixture was stirred at 0 °C for 2 hours. The mixture was diluted with DCM (20 mL) and washed 3 times with aqueous NaHCO3 solution (2 M). The resulting organic layer was dried over Na2SO4 and concentrated to give a crude product (480 mg), which was used in the next step without further purification. MS (ESI, m / e) [M+H] + 402.2.

[0315] Step 5: (S)-10-Bromo-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine 5,6,7-deoxyquinazoline ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.55 g, 1.4 mmol) was placed in THF (5 mL). LiHMDS (2.7 mL, 2.7 mmol, 1 M in THF) was added dropwise to the solution at 0°C, and the mixture was stirred at 0°C for another 0.5 h. The resulting solution was added dropwise to (13aS)-10-bromo-9-fluoro-7-(methylsulfinyl)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine at 0°C. [5,6,7-de]quinazoline (0.55 g, 1.36 mmol) in THF (10 mL). The mixture was stirred at 0 ° C for 30 min, then quenched with NH4Cl (aq., sat) and extracted with DCM (20 mL * 3). The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel chromatography (eluted with DCM / MeOH = 10 / 1) to give the title compound (480 mg). MS (ESI, m / e) [M+H] + 497.2.

[0316] Step 6: tert-Butyl(3-cyano-7-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine (5,6,7-de)quinazolin-5-yl)benzo[b]thiophen-2-yl)carbamate

[0317] (S)-10-bromo-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine A mixture of 5,6,7-de]quinazoline (80 mg, 0.16 mmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (67 mg, 0.16 mmol), bis(diphenylphosphinophenyl) ether dichloropalladium(II) (11.5 mg, 0.016 mmol), and NaHCO3 (27 mg, 0.32 mmol) was placed in dioxane / water (5 mL, 9 / 1), and the mixture was stirred at 100°C overnight. The reaction was cooled to room temperature, concentrated in vacuo, and purified by silica gel chromatography (eluted with DCM / MeOH=9 / 1) to give the title compound (60 mg). MS (ESI, m / e) [M+H] + 709.2.

[0318] Step 7: 2-amino-7-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine (5,6,7-de)quinazolin-5-yl)benzo[b]thiophene-3-carbonitrile

[0319] To tert-butyl(3-cyano-7-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine To a mixture of 1,4-dihydro-2-[5,6,7-de]quinazolin-5-yl)benzo[b]thiophen-2-yl)carbamate (60 mg, 0.084 mmol) in dioxane (2 mL) was added HCl (2 mL, 4 M in dioxane). The mixture was stirred at room temperature for 16 hours. The solvent was concentrated in vacuo and the residue was purified by HPLC to give the title product (30 mg). 1H NMR(500MHz,DMSO-d6)δ8.05(s,2H),7.29-7.20(m,1H),7.12-7.03(m,1H),6.77-6.70(m,1H),5.38-5.20(m,1H),4.84-4.76(m,1H),4.46-4.2 6(m,2H),4.19-3.91(m,4H),3.65–3.45(m,2H),3.27-3.17(m,1H),3.16 -3.00(m,3H),2.27-2.24(m,1H),2.15-1.96(m,3H),1.95-1.70(m,3H). MS(ESI,m / e)[M+H] + 609.2.

[0320] Example 2: 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine 5-[5,6,7-de]quinazolin-5-yl)naphthalen-2-ol

[0321] Step 1: (S)-4-Fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine 5,6,7-deoxyquinazoline (S)-10-bromo-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine A mixture of 5,6,7-de]quinazoline (80 mg, 0.16 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (82 mg, 0.16 mmol), Pd(dtbpf)Cl2 (10.4 mg, 0.016 mmol), and NaHCO3 (27 mg, 0.32 mmol) was placed in dioxane / water (5 mL, 9 / 1), and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by silica gel chromatography (eluted with DCM / MeOH=9 / 1) to give the title compound (60 mg, crude product), which was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 803.4.

[0322] Step 2: (S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine 5,6,7-deoxyquinazoline (S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine A mixture of [5,6,7-de]quinazoline (60 mg, crude) and CsF (22 mg, 0.15 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give a crude product (60 mg, crude), which was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 647.2.

[0323] Step 3: 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine 5-[5,6,7-de]quinazolin-5-yl)naphthalen-2-ol

[0324] To (S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine To a mixture of [5,6,7-de]quinazoline (60 mg, 0.093 mmol) in dioxane (3 mL) was added HCl (1 mL, 4 M in dioxane) in portions. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and purified by HPLC to give the title product (6 mg). 1 H NMR(500MHz,DMSO-d6)δ10.11(s,1H),7.96-7.93(m,1H),7.48-7.41(m,1H),7.37 -7.30(m,1H),7.10-7.00(m,1H),6.77-6.69(m,1H),5.37-5.18(m,1H),4.87-4.7 6(m,1H),4.47-4.34(m,2H),4.13-4.04(m,2H),4.04-3.91(m,6H),3.66-3.40(m, 2H),3.14-3.04(m,2H),2.88-2.79(m,1H),2.18-1.96(m,3H),1.88-1.70(m,3H). MS(ESI,m / e)[M+H] + 603.2.

[0325] Example 3: 3-Chloro-5-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)-4-(trifluoromethyl)aniline

[0326] Step 1: (S)-7-Chloro-8-fluoro-2-(methylthio)-5-(morpholin-3-ylmethoxy)pyrido[4,3-d]pyrimidin-4-ol

[0327] To a stirred solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (200 mg, 0.72 mmol) and (R)-morpholin-3-ylmethanol (85 mg, 0.72 mmol) in THF (6 mL) was added NaH (100 mg, 2.5 mmol, 60%) at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with H2O, and the pH was adjusted to 6 with 1N aq HCl. The mixture was filtered and the filter cake was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 361.2.

[0328] Step 2: (S)-2-Chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0329] To a stirred solution of (S)-7-chloro-8-fluoro-2-(methylthio)-5-(morpholin-3-ylmethoxy)pyrido[4,3-d]pyrimidin-4-ol (0.72 mmol) in MeCN (50 mL) was added DIEA (186 mg, 1.4 mmol) and HATU (410 mg, 1.1 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (PE / EA=4:1 to 1:3) to give the title product (220 mg). MS (ESI, m / e) [M+H] + 343.0.

[0330] Step 3: (5aS)-2-Chloro-1-fluoro-11-(methylsulfinyl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0331] To a stirred solution of (S)-2-chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (220 mg, 0.64 mmol) in DCM (15 mL) at 0°C was added m-CPBA (156 mg, 0.77 mmol, 85%) and the resulting mixture was stirred at 0°C for 10 min. The reaction was quenched with aq.Na2S2O3 and then extracted with DCM. The organic layer was washed with Sat.aq NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 359.0.

[0332] Step 4: (S)-2-Chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0333] To a stirred solution of (5aS)-2-chloro-1-fluoro-11-(methylsulfinyl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (0.64 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (206 mg, 1.3 mmol) in THF (15 mL) was added LiHMDS (1.3 mL, 1.3 mmol, 1 M in THF) at 0 °C, and the resulting mixture was stirred at 0 °C for 20 min. The reaction was quenched with Sat.aq NH4Cl and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the title product (78 mg). MS (ESI, m / e) [M+H] + 454.2.

[0334] Step 5: 3-Chloro-5-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)-4-(trifluoromethyl)aniline

[0335] At 90°C, (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (45 mg, 0.10 mmol), 3-chloro-5-(4 A mixture of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (72 mg, 0.20 mmol, 89%), Pd(dtbpf)Cl2 (13 mg, 0.02 mmol), NaHCO3 (26 mg, 0.30 mmol), dioxane (5.0 mL) and H2O (1.0 mL) was stirred for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 5:1) and then prep-HPLC to give the title product (15.6 mg). 1 H NMR(500MHz,CD3OD)δ6.91–6.85(m,1H),6.51–6.45(m,1H),5.48–5.25(m,1H),5.18–5.08(m,1H),4.56–4.46(m,2H),4.44–4.29(m,2H) ,4.13–4.10(m,1H),4.10–3.95(m,2H),3.74–3.56(m,2H),3.56–3.39(m,3H),3.38–3.33(m,1H),3.20–3.10(m,1H),2.49–1.89(m,6H). MS(ESI,m / e)[M+H] + 613.4.

[0336] Example 4: 5-ethynyl-6-fluoro-4-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)naphthalen-2-ol

[0337] Step 1: (S)-1-Fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0338] At 90°C, (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (30 mg, 0.07 mmol), ((2-fluoro-6-(methoxymethoxy)- A mixture of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (72 mg, 0.14 mmol), Pd(dtbpf)Cl2 (9.0 mg, 0.014 mmol), NaHCO3 (18 mg, 0.21 mmol), dioxane (4.0 mL), and H2O (0.8 mL) was stirred for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 10:1) to give the title product (37 mg). MS (ESI, m / e) [M+H] + 804.6.

[0339] Step 2: (S)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0340] To a stirred solution of (S)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (37 mg, 0.046 mmol) in DMF (3 mL) was added CsF (70 mg, 0.46 mmol) and the resulting mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc and H2O and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 648.4.

[0341] Step 3: 5-ethynyl-6-fluoro-4-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-2-yl)naphthalen-2-ol

[0342] To a stirred solution of (S)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (0.046 mmol) in DCM (4.0 mL) at 0°C was added 4N HCl in dioxane (0.8 mL) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and basified with DIEA and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) followed by Prep-HPLC to give the title product (10.2 mg). 1H NMR(500MHz,CD3OD)δ7.87–7.79(m,1H),7.37–7.14(m,3H),5.44–5.24(m,1H),5.23–7.12(m,1H),4.63–4.46(m,2H),4.42–4.24(m,2H) ,4.23–4.14(m,1H),4.10–3.99(m,2H),3.75–3.60(m,2H),3.55–3.50(m,1H),3.46–3.33(m,3H),3.14–3.03(m,1H),2.43–1.85(m,6H). MS(ESI,m / e)[M+H] + 604.5.

[0343] Example 5: 5-ethyl-6-fluoro-4-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)naphthalen-2-ol

[0344] Step 1: (S)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0345] At 90°C, (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (35 mg, 0.08 mmol), 2-(8-ethyl-7- A mixture of fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (56 mg, 0.16 mmol), Pd(dtbpf)Cl2 (10 mg, 0.02 mmol), NaHCO3 (20 mg, 0.24 mmol), dioxane (4.0 mL), and H2O (0.8 mL) was stirred for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 10:1) to give the title product (31 mg). MS (ESI, m / e) [M+H] + 652.1.

[0346] Step 2: 5-ethyl-6-fluoro-4-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-2-yl)naphthalen-2-ol

[0347] To a stirred solution of (S)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (0.05 mmol) in DCM (3.0 mL) at 0° C. was added 4N HCl in dioxane (0.5 mL) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and basified with DIEA and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) followed by Prep-HPLC to give the title product (8.3 mg). 1H NMR (500MHz, CD3OD) δ7.71–7.60(m,1H),7.33–7.02(m,3H),5.47–5.26(m,1H),5.24–5.10(m,1H),4.62–4.47(m,2H),4.45–4.28(m,2H) ,4.26–4.12(m,1H),4.10–3.98(m,2H),3.76–3.56(m,2H),3.54–3.34(m,4H),3.20–3.06(m,1H),2.57–1.87(m,8H),0.92–0.78(m,3H). MS(ESI,m / e)[M+H] + 608.5.

[0348] Example 6: 3-Chloro-4-cyclopropyl-5-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)phenol

[0349] Step 1: (S)-2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0350] A mixture of (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (35 mg, 0.08 mmol), 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54 mg, 0.16 mmol), Pd(dtbpf)Cl2 (10 mg, 0.02 mmol), NaHCO3 (20 mg, 0.24 mmol), dioxane (4.0 mL), and H2O (0.8 mL) was stirred at 90°C for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 10:1) to give the title product (42 mg). MS (ESI, m / e) [M+H] + 630.1.

[0351] Step 2: 3-Chloro-4-cyclopropyl-5-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)phenol

[0352] To a stirred solution of (S)-2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (30 mg, 0.05 mmol) in DCM (3.0 mL) at 0° C. was added TFA (1.0 mL) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and basified with DIEA, and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) followed by Prep-HPLC to give the title product (5.2 mg). 1H NMR (500MHz, CD3OD) δ6.97–6.90(m,1H),6.78–6.70(m,1H),5.47–5.25(m,1H),5.22–5.10(m,1H),4.56–4.45(m,2H),4.40–4.27(m,2H),4.23–4. 13(m,1H),4.10–3.94(m,2H),3.73–3.57(m,2H),3.55–3.32(m,4H),3.1 8–3.06(m,1H),2.47–1.77(m,7H),0.75–0.55(m,2H),0.23–0.05(m,2H). MS(ESI,m / e)[M+H] + 586.4.

[0353] Example 7: 5-ethynyl-6-fluoro-4-((S)-1-fluoro-11-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthol-2-yl)naphthalen-2-ol Step 1: (5aS)-2-Chloro-1-fluoro-11-(methylsulfinyl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0354] To a stirred solution of (S)-2-chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (68 mg, 0.20 mmol) in DCM (3.0 mL) was added m-CPBA (48 mg, 0.24 mmol, 85%) at 0°C and the resulting mixture was stirred at 0°C for 10 min. The reaction was quenched with aq.Na2S2O3 and then extracted with DCM. The organic layer was washed with Sat.aq NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0355] Step 2: (S)-2-Chloro-1-fluoro-11-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0356] To a stirred solution of (5aS)-2-chloro-1-fluoro-11-(methylsulfinyl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (0.20 mmol) and ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (53 mg, 0.40 mmol) in THF (3.0 mL) was added LiHMDS (0.40 mL, 0.40 mmol, 1 M in THF) dropwise at 0°C, and the resulting mixture was stirred at 0°C for 20 min. The solvent was evaporated, and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the title product (32 mg). MS (ESI, m / e) [M+H] + 428.3.

[0357] Step 3: (S)-1-Fluoro-11-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0358] At 100°C, (S)-2-chloro-1-fluoro-11-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (32 mg, 0.075 mmol), ((2-fluoro-6-(methoxymethoxy)-8- A mixture of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (77 mg, 0.15 mmol), Pd(dtbpf)Cl2 (10 mg, 0.015 mmol), NaHCO3 (19 mg, 0.23 mmol), dioxane (3.0 mL), and H2O (0.6 mL) was stirred for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 20:1) to give the title product (46 mg). MS (ESI, m / e) [M+H] + 778.4.

[0359] Step 4: (S)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-11-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0360] To a stirred solution of (S)-1-fluoro-11-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (46 mg, 0.06 mmol) in DMF (3.0 mL) was added CsF (46 mg, 0.30 mmol) and the resulting mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc and H2O and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 622.4.

[0361] Step 5: 5-ethynyl-6-fluoro-4-((S)-1-fluoro-11-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-2-yl)naphthalen-2-ol

[0362] To a stirred solution of (S)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-11-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (0.06 mmol) in DCM (5.0 mL) at 0° C. was added 4N HCl in dioxane (1.0 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and basified with DIEA, and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) followed by Prep-HPLC to give the title product (14.2 mg). 1H NMR (500MHz, CD3OD) δ7.88–7.78(m,1H),7.39–7.16(m,3H),5.34–5.10(m,2H),4.62–4.44(m,4H),4.25–4.13(m,1H),4.12–3. 98(m,2H),3.75–3.50(m,4H),3.42–3.33(m,1H),3.29–3.21(m,1H),2.83–2.55(m,4H),2.40–2.24(m,1H),2.15–1.95(m,1H). MS(ESI,m / e)[M+H] + 578.5.

[0363] Example 8: (S)-5-ethynyl-6-fluoro-4-(1-fluoro-11-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)naphthalen-2-ol

[0364] Step 1: (5aS)-2-Chloro-1-fluoro-11-(methylsulfinyl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0365] To a stirred solution of (S)-2-chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (200 mg, 0.58 mmol) in DCM (8.0 mL) was added m-CPBA (142 mg, 0.70 mmol, 85%) at 0°C and the resulting mixture was stirred at 0°C for 10 min. The reaction was quenched with aq.Na2S2O3 and then extracted with DCM. The organic layer was washed with Sat.aq NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0366] Step 2: (S)-2-Chloro-1-fluoro-11-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0367] To a stirred solution of (5aS)-2-chloro-1-fluoro-11-(methylsulfinyl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (0.58 mmol) and (1-(morpholinomethyl)cyclopropyl)methanol (205 mg, 1.2 mmol) in THF (8.0 mL) was added LiHMDS (1.2 mL, 1.2 mmol, 1 M in THF) dropwise at 0°C, and the resulting mixture was stirred at 0°C for 20 min. The residue was purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the title product (128 mg). MS (ESI, m / e) [M+H] + 466.5.

[0368] Step 3: (S)-1-Fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-11-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0369] A mixture of (S)-2-chloro-1-fluoro-11-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (128 mg, 0.27 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (211 mg, 0.41 mmol), Pd(dtbpf)Cl2 (35 mg, 0.054 mmol), NaHCO3 (68 mg, 0.81 mmol), dioxane (10 mL), and H2O (2.0 mL) was stirred at 100°C for 3 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the title product (90 mg). MS (ESI, m / e) [M+H] + 816.6.

[0370] Step 4: (S)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-11-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0371] To a stirred solution of (S)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-11-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (90 mg, 0.11 mmol) in DMF (4.0 mL) was added CsF (167 mg, 1.1 mmol) and the resulting mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc and H2O and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 660.4.

[0372] Step 5: (S)-5-ethynyl-6-fluoro-4-(1-fluoro-11-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)naphth-2-ol

[0373] To a stirred solution of (S)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-11-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (0.11 mmol) in DCM (5.0 mL) at 0° C. was added 4N HCl in dioxane (1.0 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and basified with DIEA, and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 20:1) followed by Prep-HPLC to give the title product (19.5 mg). 1HNMR(500MHz,CD3OD)δ7.88–7.78(m,1H),7.36–7.18(m,3H),5.21–5.12(m,1H),4.62–4.47(m,2H),4.44–4.35(m,2H),4.22–4 .13(m,1H),4.10–3.97(m,2H),3.76–3.50(m,7H),3.41–3.33(m,1H),2.81–2.44(m,6H),0.82–0.67(m,2H),0.64–0.45(m,2H). MS(ESI,m / e)[M+H] + 616.4.

[0374] Example 9: (S)-4-(11-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-1-fluoro-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)-5-ethynyl-6-fluoronaphth-2-ol

[0375] Step 1: (5aS)-2-Chloro-1-fluoro-11-(methylsulfinyl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0376] To a stirred solution of (S)-2-chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (68 mg, 0.20 mmol) in DCM (3.0 mL) was added m-CPBA (48 mg, 0.24 mmol, 85%) at 0°C and the resulting mixture was stirred at 0°C for 10 min. The reaction was quenched with aq.Na2S2O3 and then extracted with DCM. The organic layer was washed with Sat.aq NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0377] Step 2: (S)-11-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-chloro-1-fluoro-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0378] To a stirred solution of (5aS)-2-chloro-1-fluoro-11-(methylsulfinyl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (0.20 mmol) and (2-oxabicyclo[2.1.1]hexan-4-yl)methanol (46 mg, 0.40 mmol) in THF (3.0 mL) was added LiHMDS (0.40 mL, 0.40 mmol, 1 M in THF) dropwise at 0°C, and the resulting mixture was stirred at 0°C for 20 min. The solvent was removed, and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the title product (45 mg). MS (ESI, m / e) [M+H] + 409.2.

[0379] Step 3: (S)-11-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0380] At 100°C, (S)-11-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-chloro-1-fluoro-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (45 mg, 0.11 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4 A mixture of (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (113 mg, 0.22 mmol), Pd(dtbpf)Cl2 (13 mg, 0.02 mmol), NaHCO3 (28 mg, 0.33 mmol), dioxane (4.0 mL), and H2O (0.8 mL) was stirred for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the title product (60 mg). MS (ESI, m / e) [M+H] + 759.4.

[0381] Step 4: (S)-11-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene

[0382] To a stirred solution of (S)-11-((2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (60 mg, 0.08 mmol) in DMF (3.0 mL) was added CsF (60 mg, 0.40 mmol), and the resulting mixture was stirred for 2 hours. The reaction mixture was diluted with EtOAc and H2O, then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 603.4.

[0383] Step 5: (S)-4-(11-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-1-fluoro-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)-5-ethynyl-6-fluoronaphth-2-ol

[0384] To a stirred solution of (S)-11-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (0.08 mmol) in DCM (5.0 mL) at 0° C. was added 4N HCl in dioxane (1.0 mL) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and basified with DIEA and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 20:1) followed by Prep-HPLC to give the product (15.6 mg). 1HNMR(500MHz,CD3OD)δ7.89–7.78(m,1H),7.36–7.12(m,3H),5.22–5.12(m,1H),4.81–4.70(m,2H),4.59–4.46(m,3H),4.22–4 .12(m,1H),4.09–3.98(m,2H),3.77–3.60(m,4H),3.56–3.50(m,1H),3.42–3.32(m,1H),2.01–1.90(m,2H),1.67–1.56(m,2H). MS(ESI,m / e)[M+H] + 559.4.

[0385] Example 10: 3-Chloro-5-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline

[0386] Step 1: tert-Butyl 2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanaphtho[1,8-ab]heptalene-14-carboxylate

[0387] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.5 g, crude) and DIPEA (1.49 g, 11.57 mmol) in DCM (15 mL) was added tert-butyl 2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.06 mmol) (Wuxi LabNetwork catalog number QC50004035) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. Upon completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaCl (15 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in petroleum ether to give the title product (400 mg). MS (ESI, m / e) [M+H] + 468.1.

[0388] Step 2: tert-Butyl 2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methano[1,8-ab]heptalene-14-carboxylate

[0389] To a solution of tert-butyl 2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-carboxynaphtho[1,8-ab]heptalene-14-carboxylate (250.0 mg, 0.53 mmol) in DCM (5 mL) was added m-CPBA (115.1 mg, 0.53 mmol, 80%) at room temperature, and the resulting mixture was stirred at room temperature for 1 hour to give mixture 1. To another mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (253.0 mg, 1.59 mmol) in THF (5 mL) was added LiHMDS (2.0 mL, 2.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Then, mixture 1 was added to the above reaction mixture. The resulting mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaCl (15 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography, eluted with a petroleum ether solution of 0-100% ethyl acetate to obtain the title product (60 mg). MS (ESI, m / e) [M+H] + 579.2.

[0390] Step 3: tert-Butyl 2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methano[1,8-ab]heptalene-14-carboxylate

[0391] A mixture of tert-butyl 2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanaphtho[1,8-ab]heptene-14-carboxylate (60 mg, 0.10 mmol), (5-amino-3-chloro-2-(trifluoromethyl)phenyl)boronic acid (71.7 mg, 0.30 mmol), NaHCO3 (25.2 mg, 0.30 mmol), Pd(dppf)Cl2 (36.5 mg, 0.05 mmol), dioxane (5 mL), and water (1 mL) was stirred at 100°C for 4 hours. After completion, the reaction mixture was diluted with DCM (20 mL) and washed with saturated NaCl (10 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by Prep-TLC (DCM: MeOH = 10: 1) to give the title product (30 mg). MS (ESI, m / e) [M+H] + 738.4.

[0392] Step 4: 3-Chloro-5-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline

[0393] To a solution of tert-butyl 2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanaphtho[1,8-ab]heptene-14-carboxylate (30.0 mg, 0.04 mmol) in DCM (2 mL) was added TFA (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. Upon completion, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC to give the title product (1.48 mg). 1H NMR(500MHz,CD3OD)δ6.94–6.86(m,1H),6.53–6.40(m–1H),5.44-5.20(m,1H),5.05–4. 99(m,1H),4.69–4.00(m–4H),3.80-3.60(m–2H),3.32-3.00(m–5H),2.72-2.03(m,10H). MS(ESI,m / e)[M+H] + 638.1.

[0394] Example 11: 5-ethynyl-6-fluoro-4-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methano[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0395] Step 1: tert-Butyl 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methano[1,8-ab]heptene-14-carboxylate

[0396] Tert-butyl 2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanaphtho[1,8-ab]heptalene-14-carboxylate (60 mg, 0.10 mmol), ((2-fluoro-6-(methoxymethoxy) A mixture of 4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-( + 929.5.

[0397] Step 2: tert-Butyl 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methano[1,8-ab]heptene-14-carboxylate

[0398] To a solution of tert-butyl 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanaphtho[1,8-ab]heptene-14-carboxylate (25.0 mg, 0.03 mmol) in DMF (2 mL) was added CsF (45.6 mg, 0.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. Upon completion, the reaction mixture was diluted with EtOAc (20 mL) and washed with saturated NaCl (10 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain a crude product (25 mg). MS (ESI, m / e) [M+H] + 773.3.

[0399] Step 3: 5-ethynyl-6-fluoro-4-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methano[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0400] To tert-butyl 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methano[1,8-ab]heptene-14-carboxylate (25 mg crude) was added HCl in EtOAc (1M, 2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC to give the title product (3.3 mg). 1 H NMR(500MHz,DMSO-d6)δ10.15(s–1H),7.97-7.94(m–1H),7.50-7.40(m,1H),7.37(s–1H),7.25-7.05(m,1H),5.4 2–5.20(m–1H),4.87-4.78(m–1H),4.54-4.49(m–1H),4.38-3.95(m,4H),3.32-3.00(m,5H),2.20–1.57(m,10H). MS(ESI,m / e)[M+H]+ 629.5.

[0401] Example 12: 3-Chloro-5-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)-4-(trifluoromethyl)aniline

[0402] Step 1: tert-Butyl (S)-4-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

[0403] Tert-butyl (S) -3- (hydroxymethyl) piperazine -1- carboxylate (648.3 mg, 3.0 mmol) was added to a solution of 4,5,7-trichloro-8-fluoro-2- (methylthio) pyrido [4,3-d] pyrimidine (1.5 g crude) and DIPEA (1.49 g, 11.57 mmol) in DCM (15 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaCl (15 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography and eluted with 0-60% ethyl acetate in petroleum ether to obtain the title product (500 mg). MS (ESI, m / e) [M+H] + 478.1.

[0404] Step 2: tert-Butyl (S)-2-chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene-7(5H)-carboxylate

[0405] To a solution of tert-butyl (S)-4-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (500 mg, 1.05 mmol) in THF (15 mL) was added LiHMDS (1.05 mL, 1.05 mmol, 1 M) at room temperature. The resulting mixture was stirred at room temperature for 0.5 hours. Upon completion, the reaction mixture was directly concentrated to give a residue. The residue was purified by silica gel column chromatography, eluting with 0-100% ethyl acetate in petroleum ether to give the title product (300 mg). MS (ESI, m / e) [M+H] + 442.1.

[0406] Step 3: tert-Butyl (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene-7(5H)-carboxylate

[0407] To a solution of tert-butyl (S)-2-chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene-7(5H)-carboxylate (234.0 mg, 0.53 mmol) in DCM (5 mL) was added m-CPBA (115.1 mg, 0.53 mmol, 80%) at room temperature. The resulting mixture was stirred at room temperature for 1 hour to give mixture 1. To another mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (253.0 mg, 1.59 mmol) in THF (5 mL) was added LiHMDS (2.0 mL, 2.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Then, mixture 1 is added to the reaction mixture, and the resulting mixture is stirred at room temperature for 1h. After completion, the reaction mixture is diluted with EtOAc (30mL), and washed with saturated NaCl (15mL × 3). The organic layer is dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated to obtain a residue. The residue is purified by silica gel column chromatography, eluted with a petroleum ether solution of 0-100% ethyl acetate, to obtain the title product (100mg). MS (ESI, m / e) [M+H] + 553.2.

[0408] Step 4: tert-Butyl (S)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene-7(5H)-carboxylate

[0409] A mixture of tert-butyl (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene-7(5H)-carboxylate (55.2 mg, 0.10 mmol), (5-amino-3-chloro-2-(trifluoromethyl)phenyl)boronic acid (71.7 mg, 0.30 mmol), Pd(dppf)Cl2 (36.5 mg, 0.05 mmol), NaHCO3 (25.2 mg, 0.30 mmol), dioxane (5 mL), and water (1 mL) was stirred at 100°C for 4 hours. After completion, the reaction mixture was diluted with DCM (20 mL) and washed with saturated NaCl (10 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by Prep-TLC (DCM: MeOH = 10: 1) to give the title product (35 mg). MS (ESI, m / e) [M + H] + 712.2.

[0410] Step 5: 3-Chloro-5-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)-4-(trifluoromethyl)aniline

[0411] To a solution of tert-butyl (S)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene-7(5H)-carboxylate (35.0 mg, 0.05 mmol) in DCM (4 mL) was added TFA (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC to give the title product (6.6 mg). 1 H NMR(500MHz,CD3OD)δ6.94–6.85(m,1H),6.53–6.43(m,1H),5.59-5.40(m,1H),5.35-5.26(m,1H),4.65–4. 50(m,4H),4.18-4.10(m,1H),3.80-3.65(m,3H),3.43-3.33(m,3H),3.30-2.88(m,3H),2.64-2.05(m,6H). MS(ESI,m / e)[M+H] + 612.4.

[0412] Example 13: 3-Chloro-5-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,8,10a,11,13-pentazabenzo[4,5]cyclooctane[1,2,3-de]naphth-2-yl)-4-(trifluoromethyl)aniline

[0413] Step 1: tert-Butyl 3-(2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)piperazine-1-carboxylate

[0414] At room temperature, NaH (200 mg, 5 mmol, 60%) was added to a solution of tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (460.4 mg, 2.0 mmol) in THF (15 mL). The resulting mixture was stirred at room temperature for 1 h. Then, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (500 mg, 1.79 mmol) was added to the reaction mixture, and the mixture was stirred at 60 ° C for 16 hours. After completion, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (40 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography, eluted with 0-100% ethyl acetate in petroleum ether to obtain the title product (350 mg). MS (ESI, m / e) [M+H] + 474.1.

[0415] Step 2: tert-Butyl 2-chloro-1-fluoro-12-(methylthio)-5,6,6a,7,9,10-hexahydro-8H-4-oxa-3,8,10a,11,13-pentazabenzo[4,5]cyclooctane[1,2,3-de]naphthalene-8-carboxylate

[0416] To a solution of tert-butyl 3-(2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)piperazine-1-carboxylate (350 mg, 0.74 mmol) and DIPEA (193.8 mg, 1.5 mmol) in DMF (150 mL) was added HATU (570.4 mg, 1.5 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was diluted with EtOAc (150 mL) and washed with saturated NaCl (50 mL x 5). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in petroleum ether to give the title product (100 mg). MS (ESI, m / e) [M+H] + 456.1.

[0417] The following steps of Example 13 followed a similar procedure to the synthesis of Example 12. 1H NMR(500MHz,CD3OD)δ6.94–6.85(m,1H),6.58–6.37(m,1H),5.55-5.37(m,1H),5.30-5.20(m,1H),4.65–4.40(m,3H),4.30 -4.22(m,1H),4.07-3.96(m,1H),3.77-3.55(m,3H),3.30–2.98(m,4H),2.91-2.80(m,1H),2.64-2.02(m,8H). MS(ESI,m / e)[M+H] + 626.5.

[0418] Example 14: 2-amino-4-((S)-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine (5,6,7-de)quinazolin-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0419] Step 1: (R)-(4-(7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-yl)morpholin-3-yl)methanol

[0420] To a mixture of (R)-morpholin-3-ylmethanol (3 g, 8.4 mmol) and DIPEA (2.2 g, 17.1 mmol) in DCM (30 mL) was added 7-bromo-4,6-dichloro-5,8-difluoro-2-(methylthio)quinazoline (1.0 g, 8.4 mmol) at 0°C. The mixture was stirred at room temperature overnight. NH4Cl (10 mL, aq.sat.) solution was added to the mixture, and the aqueous phase was extracted with DCM (20 mL*3). The combined organic layers were dried over Na2SO4, concentrated and purified by silica gel chromatography (eluted with PE / EtOAc=2 / 1) to give the title compound (1.4 g). MS (ESI, m / e) [M+H] + 440.2.

[0421] Step 2: (S)-10-bromo-11-chloro-9-fluoro-7-(methylthio)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine 5,6,7-deoxyquinazoline

[0422] A mixture of (R)-(4-(7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-yl)morpholin-3-yl)methanol (1.4 g, 3.16 mmol) was placed in THF. NaH (0.38 g, 9.5 mmol) was added to the solution in batches at 0°C, and the mixture was stirred at RT overnight. It was quenched with NH4Cl (10 mL, aq, sat.) and extracted with DCM (20 mL*3). The combined organic layers were dried over Na2SO4, concentrated and purified by silica gel chromatography (eluted with PE / EtOAc=1 / 1) to give the title compound (1.2 g). MS (ESI, m / e) [M+H] + 420.2.

[0423] Step 3: (13aS)-10-bromo-11-chloro-9-fluoro-7-(methylsulfinyl)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine 5,6,7-deoxyquinazoline

[0424] At 0°C, add (S)-10-bromo-11-chloro-9-fluoro-7-(methylthio)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine To a mixture of [5,6,7-de]quinazoline (0.6 g, 1.41 mmol) in DCM (20 mL) was added m-CPBA (0.26 g, 1.5 mmol). The mixture was stirred at 0 °C for 2 hours. The mixture was diluted with DCM (20 mL) and washed three times with aqueous NaHCO3 solution (2 M). The resulting organic layer was dried over Na2SO4 and concentrated to give a crude product (0.5 g), which was used in the next step without further purification. MS (ESI, m / e) [M+H] + 435.9.

[0425] Step 4: (S)-10-bromo-11-chloro-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine 5,6,7-deoxyquinazoline

[0426] To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.33 g, 0.66 mmol) in THF (10 mL) was added LiHMDS (1.4 ml, 1.38 mmol) in portions at 0 °C to (13aS)-10-bromo-11-chloro-9-fluoro-7-(methylsulfinyl)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine And [5,6,7-de]quinazoline (0.3 g, 0.69 mmol) in THF (10 mL). The mixture was stirred at RT for 30 min. It was quenched with NH4Cl (aq., sat) and extracted with DCM (20 mL*3). The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel chromatography (eluted with DCM / MeOH=10 / 1) to give the title compound (200 mg). MS (ESI, m / e) [M+H] + 531.2.

[0427] Step 5: tert-Butyl(4-((S)-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine (5,6,7-de)quinazolin-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate

[0428] (S)-10-bromo-11-chloro-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepine A mixture of 5,6,7-de]quinazoline (70 mg, 0.132 mmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (130 mg, 0.132 mmol), Pd(dtbpf)Cl2 (42 mg, 0.066 mmol), and K3PO4 (84 mg, 0.396 mmol) was placed in dioxane / water (5 mL, 9 / 1), and the mixture was stirred at 100°C overnight. The reaction was cooled to room temperature, concentrated in vacuo, and purified by silica gel chromatography (eluted with DCM / MeOH=9 / 1) to give the title compound (50 mg). MS (ESI, m / e) [M+H] + 744.2.

[0429] Step 6: 2-amino-4-((S)-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine (5,6,7-de)quinazolin-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0430] To tert-butyl (4-((S)-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydro-8H-[1,4]oxazino[3',4':3,4][1,4]oxazepine To a mixture of 5-[5,6,7-de]quinazolin-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (50 mg, 0.067 mmol) in dioxane (2 mL) was added HCl (2 mL, 4 M in dioxane). The mixture was stirred at room temperature for 16 hours. Concentrated in vacuo and purified by Prep-HPLC to give the title product (isomer 1 = 4 mg, isomer 2 = 5 mg). Isomer 1: 1H NMR(500MHz,DMSO-d6)δ8.09(s,2H),7.24-7.21(m,1H),7.18-7.10(m,1H),5.38-5.1 8(m,1H),4.80-4.70(m,1H),4.57-4.49(m,1H),4.43-4.34(m,1H),4.16-4.03(m,2H), 4.02-3.94(m,2H),3.64-3.53(m,2H),3.31-3.23(m,4H),3.15-3.07(m,1H),3.05-2.9 9(m,1H),2.85-2.79(m,1H),2.16-2.09(m,1H),2.08-1.96(m,1H),1.91-1.71(m,3H). MS(ESI,m / e)[M+H] + 643.3. Isomer 2: 1 H NMR(500MHz,DMSO-d6)δ8.09(s,2H),7.22-7.21(m,1H),7.16-7.12(m,1H), 5.37-5.17(m,1H),4.80-4.70(m,1H),4.50-4.37(m,2H),4.14-4.07(m,2H), 4.01-3.94(m,3H),3.61-3.52(m,2H),3.29-3.19(m,2H),3.12-3.05(m,2H), 3.04-3.00(m,1H),2.88-2.78(m,1H),2.16-1.95(m,2H),1.89-1.70(m,3H). MS (ESI, m / e) [M+H] + 643.3.

[0431] Example 15: 2-amino-4-(11-chloro-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3,4-dihydro-1H,13H-4,13a-ethano[1,4]oxazino[3',4':3,4][1,4]oxazepine (5,6,7-de)quinazolin-10-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0432] Example 15 was prepared by an analogous procedure as described in Example 14 by replacing (R)-morpholin-3-ylmethanol with (3-oxa-8-azabicyclo[3.2.1]octan-1-yl)methanol to give the title product (16 mg). 1H NMR(500MHz,DMSO-d6)δ8.09(s,2H),7.26-7.12(m,2H),5.50-5.30(m,1H),4.82-4.70(m,1H),4.19-4.16(m,1H),3.96-3.83(m,2H),3.82-3.7 5(m,1H),3.72-3.65(m,1H),3.33-3.30(m,4H),2.55-2.50(m,3H),2.27 -2.13(m,2H),2.08-1.97(m,4H),1.92-1.78(m,3H),1.20-1.06(m,1H). MS(ESI,m / e)[M+H] + 669.4.

[0433] Example 16: 3-Chloro-5-((S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,6a,7,9,10-hexahydro-4,8-dioxa-3,10a,11,13-tetraazabenzo[4,5]cyclooctane[1,2,3-de]naphth-2-yl)-4-(trifluoromethyl)aniline

[0434] Example 16 was prepared by an analogous procedure as described in Example 3 by replacing (R)-morpholin-3-ylmethanol with tert-butyl (S)-3-(2-hydroxyethyl)morpholine-4-carboxylate to give the title product (0.4 mg). 1 H NMR(500MHz,CD3OD)δ6.89-6.87(m,1H),6.60-6.34(m,1H),5.44-5.39(m,1H ),5.18-5.12(m,1H),4.62-4.54(m,2H),4.43-4.37(m,1H),4.32-4.21(m,2H) ,4.10-4.04(m,1H),3.94-3.82(m,2H),3.79-3.71(m,1H),3.65-3.56(m,1H) ,3.49-3.33(m,4H),3.18-3.08(m,1H),2.65-2.56(m,1H),2.46-1.89(m,6H). MS (ESI, m / e) [M+H] + 627.4.

[0435] Example 17: 3-Chloro-5-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline

[0436] Step 1: Methyl (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate

[0437] Me3OBF4 (32.6 g, 0.44 mol) was added to a solution of methyl (R)-5-oxopyrrolidine-2-carboxylate (24.6 g, 0.20 mol) in DCM (300 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was quenched with saturated NaHCO3 aqueous solution (200 mL) and extracted with DCM (150 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography, eluted with 0-10% MeOH in DCM to obtain the title product (16.0 g). MS (ESI, m / e) [M+H] + 158.1.

[0438] Step 2: Methyl (R)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate

[0439] Ethyl 2-nitroacetate (21.6 g, 0.16 mmol) was added to methyl (R)-5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (8.5 g, 0.05 mol) at room temperature. The resulting mixture was stirred at 60 ° C for 16 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by silica gel column chromatography, eluting with 0-100% ethyl acetate in petroleum ether to obtain the title product (6.0 g). MS (ESI, m / e) [M+H] + 259.2.

[0440] Step 3: Ethyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate

[0441] To a mixture of methyl (R)-5-(2-ethoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate (6.0 g, 23.2 mmol) in ethanol (600 mL) was added wet palladium on carbon (6 g) at room temperature. The resulting mixture was stirred at room temperature under a (0.4 MPa) H2 atmosphere for 72 hours. After completion, the reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography, eluted with 0-10% MeOH in DCM to give the title product (2.3 g). MS (ESI, m / e) [M+H] + 199.1.

[0442] Step 4: 8-(tert-butyl) 2-ethyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate

[0443] At room temperature, di-tert-butyl dicarbonate (2.52 g, 11.6 mmol) and triethylamine (2.34 g, 23.2 mmol) were added to a solution of ethyl (1S, 2S, 5R)-4-oxo-3,8-diazabicyclo [3.2.1] octane-2-carboxylate (2.3 g, 11.6 mmol) in DCM (50 mL). The resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography, eluted with 0-100% EtOAc in petroleum ether to give the title product (2.8 g). MS (ESI, m / e) [M+H] + 299.2.

[0444] Step 5: tert-Butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0445] At room temperature, LiAlH4 (760 mg, 20 mmol) was added to a solution of 8-(tert-butyl) 2-ethyl (1S, 2S, 5R) -4-oxo-3, 8-diazabicyclo [3.2.1] octane-2, 8-dicarboxylate (1.4 g, 7.1 mmol) in THF (30 mL). The resulting mixture was stirred at room temperature for 4 hours. After completion, the reaction mixture was quenched with NaSO4·10H2O, filtered, and the filtrate was concentrated to give a crude product (900 mg). MS (ESI, m / e) [M+H] + 243.2.

[0446] Step 6: 3-Chloro-5-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methanaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline

[0447] Example 17 was prepared by a similar procedure as described in Example 10 by replacing tert-butyl (1S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate with tert-butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate to give the title product (2.8 mg). 1 H NMR(500MHz,DMSO-d6)δ6.90-6.85(m,1H),6.55-6.25(m,3H),5.41-5.20(m,1H),4.98-4.78(m,1H),4.60-4.35(m,2H ),4.20–3.98(m,3H),3.85-3.70(m,2H),3.24-3.00(m,4H),2.90–2.80(m,1H),2.22–1.98(m,3H),1.97-1.55(m,7H). MS(ESI,m / e)[M+H] + 638.4.

[0448] Example 18: 2-amino-4-((S)-10-chloro-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,12,12a-tetrahydro-1H-pyrrolo[2',1':3,4][1,4]oxazepine (5,6,7-de)quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0449] Step 1: tert-Butyl (S)-3-(2-((7-bromo-6-chloro-8-fluoro-4-hydroxy-2-(methylthio)quinazolin-5-yl)oxy)ethyl)morpholine-4-carboxylate

[0450] To a solution of 7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazoline-4-ol (500 mg, 1.47 mmol) in THF (10 mL) was added tert-butyl (S)-3-(2-hydroxyethyl)morpholine-4-carboxylate (509 mg, 2.20 mmol) and NaH (60%, 176 mg, 4.41 mmol). The mixture was stirred at 50 ° C for 3 hours. The mixture was cooled to rt and quenched by MeOH (5 mL). The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (12 g, PE: EtOAc = 100%: 0% - 0%: 100%) to give the title compound (441 mg). MS (ESI, m / e) [M + H] + 552.2.

[0451] Step 2: (S)-7-Bromo-6-chloro-8-fluoro-2-(methylthio)-5-(2-(morpholin-3-yl)ethoxy)quinazolin-4-ol

[0452] A mixture of tert-butyl (S)-3-(2-((7-bromo-6-chloro-8-fluoro-4-hydroxy-2-(methylthio)quinazolin-5-yl)oxy)ethyl)morpholine-4-carboxylate (440 mg, 0.673 mmol) in HCl (4M) / dioxane (10 mL) was stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo to give the crude product (493 mg, crude). MS (ESI, m / e) [M+H] + 452.2.

[0453] Step 3: (S)-10-bromo-11-chloro-9-fluoro-7-(methylthio)-1,3,4,13,14,14a-hexahydro-[1,4]oxazino[4',3':5,6][1,5]oxazolo[4,3,2-de]quinazoline

[0454] To a solution of (S)-7-bromo-6-chloro-8-fluoro-2-(methylthio)-5-(2-(morpholin-3-yl)ethoxy)quinazolin-4-ol (490 mg, 1.08 mmol) in DMF (10 mL) was added HATU (1.23 g, 3.24 mmol) and DIEA (700 mg, 5.4 mmol). The mixture was then stirred at room temperature overnight. The mixture was extracted with EtOAc (20 mL*2), washed with brine (20 mL), dried over Na2SO4, and the combined organic phases were concentrated in vacuo. The residue was purified by silica gel column chromatography (12 g, eluted with PE / EtOAc=100%:0%-0%:100%) to give the title compound (300 mg). MS (ESI, m / e) [M+H] + 434.1.

[0455] Step 4: (S)-10-bromo-11-chloro-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,4,13,14,14a-hexahydro-[1,4]oxazino[4',3':5,6][1,5]oxazolo[4,3,2-de]quinazoline

[0456] At 0°C, (S)-9-bromo-10-chloro-8-fluoro-6-(methylthio)-2,3,12,12a-tetrahydro-1H-pyrrolo[2',1':3,4][1,4]oxazepine m-CPBA (45 mg, 0.266 mmol) was added in batches to a mixture of [5,6,7-de]quinazoline (100 mg, 0.231 mmol) in DCM (10 mL). The mixture was stirred at 0 ° C for 2 hours. ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methanol (110 mg, 0.693 mmol) was placed in THF (10 mL). At 0 ° C, LiHMDS (0.46 mL, 0.46 mmol) was added to the solution in batches. The mixture was stirred at room temperature for 30 min, and the mixture was added to the above DCM solution. The mixture was stirred at room temperature overnight, quenched with MeOH (5 mL), and concentrated in vacuo. The residue was purified by silica gel chromatography (12 g, eluted with DCM / MeOH=90%:10%) to give the title compound (100 mg). MS (ESI, m / e) [M+H] + 545.3.

[0457] Step 5: tert-Butyl (4-((S)-11-chloro-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,4,13,14,14a-hexahydro-[1,4]oxazino[4',3':5,6][1,5]oxazolo[4,3,2-de]quinazolin-10-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate

[0458] A solution of K3PO4 (97 mg, 0.46 mmol) in dioxane / water (10 mL / 2 mL) was stirred at 80°C for 10 min. (S)-10-bromo-11-chloro-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,4,13,14,14a-hexahydro-[1,4]oxazino[4',3':5,6][1,5]oxazolo[4,3,2-de]quinazoline (100 mg, 0.184 mmol), tert-butyl(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzo[b]thiophen-2-yl)carbamate (153 mg, 0.367 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (60 mg, 0.092 mmol) were added. The mixture was stirred at 80°C for 1 hour, then the reaction was cooled to room temperature, concentrated in vacuo, and purified by silica gel chromatography (12 g, eluted with DCM / MeOH=90%:10%) to give a crude product (70 mg, crude). MS (ESI, m / e) [M+H] + 757.4.

[0459] Step 6: 2-amino-4-((S)-11-chloro-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,3,4,13,14,14a-hexahydro-[1,4]oxazino[4',3':5,6][1,5]oxazolo[4,3,2-de]quinazolin-10-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0460] To a solution of tert-butyl(4-((S)-11-chloro-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,3,4,13,14,14a-hexahydro-[1,4]oxazino[4',3':5,6][1,5]oxazolo[4,3,2-de]quinazolin-10-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (70 mg, 0.092 mmol) in dioxane (5 mL) was added HCl (4M) / dioxane (5 mL). The mixture was stirred at room temperature overnight. The mixture was then concentrated in vacuo and purified by prep-HPLC to give the title compound (8.33 mg). 1 H NMR(500MHz,DMSO-d6)δ8.08(s,2H),7.34-7.07(m,2H),5.37-5.20(m,1H),4.58-4.36(m,2H),4.35-4.18(m,1H),4.10-3.91(m,3H), 3.85–3.75(m,1H),3.71-3.48(m,4H),3.14-2.98(m,3H),2.84-2.81(m,1H),2.37-2.25(m,1H),2.17-1.95(m,4H),1.94-1.70(m,3H). MS(ESI,m / e)[M+H] + 657.4.

[0461] Example 19: 3-Chloro-5-((S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline

[0462] Step 1: tert-Butyl (R)-3-(hydroxymethyl)-1,4-oxazepane-4-carboxylate

[0463] To a stirred solution of (S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-3-carboxylic acid (245 mg, 1 mmol) in THF (10 mL) was added BH3·THF (3.5 mL, 3.5 mmol, 1 M in THF) at 0°C, and the resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at 0°C and then concentrated in vacuo. The crude product was purified by flash chromatography (CH2Cl2 / EA=1:1) to give the desired product (217 mg).

[0464] Step 2: (R)-(1,4-oxazepan-3-yl)methanol

[0465] To a stirred solution of tert-butyl (R)-3-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (217 mg, 0.9 mmol) in CH2Cl2 (5 mL) was added HCl (5 mL, 4 M in dioxane) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and used in the next step without further purification.

[0466] Example 19 was prepared by a similar procedure as described in Example 3 by replacing (R)-morpholin-3-ylmethanol with (R)-(1,4-oxazepan-3-yl)methanol to give the title product (3.5 mg). 1 H NMR(500MHz,CD3OD)δ6.90–6.86(m,1H),6.55–6.41(m,1H),5.41–5.24(m,1H ),5.23–5.15(m,1H),4.76–4.65(m,1H),4.63–4.47(m,4H),4.39–4.24(m,3H) ,4.22–4.12(m,1H),4.04–3.91(m,1H),3.82–3.70(m,1H),3.59–3.49(m,1H) ,3.48–3.36(m,3H),3.14–3.03(m,1H),2.43–2.10(m,4H),2.09–1.87(m,4H). [M+H] + 627.3.

[0467] Example 20: 5-ethynyl-6-fluoro-4-((S)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,9,10-tetrahydro-5H,8H-4,7-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0468] Example 20 was prepared by a similar procedure as described in Example 3 / 4 by replacing (R)-morpholin-3-ylmethanol with (R)-(1,4-oxazepan-3-yl)methanol to give the title product (38 mg). 1 H NMR(500MHz,CD3OD)δ7.90–7.78(m,1H),7.40–7.15(m,3H),5.60–5.40(m,1H),5.30–5.15(m,1H),4.77–4.51(m,4H),4.48–4.29(m,1H) ,4.24–4.05(m,1H),4.00–3.64(m,6H),3.63–3.46(m,1H),3.45–3.34(m,2H),2.74–2.46(m,2H),2.43–2.22(m,3H),2.22–1.87(m,3H). MS(ESI,m / e)[M+H] + 618.5.

[0469] Example 21: 3-Chloro-5-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,9,10-hexahydro-4,8-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline

[0470] Example 21 was prepared by a similar procedure as described in Example 19 by replacing tert-butyl (R)-3-(hydroxymethyl)-1,4-oxazepane-4-carboxylate with tert-butyl 5-(hydroxymethyl)-1,4-oxazepane-4-carboxylate to give the title product (6.3 mg). 1 H NMR (500MHz, CD3OD) δ6.90–6.86(m,1H),6.59–6.40(m,1H),5.44–5.15(m,2H),4.73–4.64(m,1H),4.63–4.47(m,1H),4.40–4. 21(m,3H),4.05–3.82(m,3H),3.66–3.54(m,1H),3.54–3.42(m,2H),3.42–3.32(m,3H),3.16–3.05(m,1H),2.46–1.87(m,8H). [M+H] + 627.3.

[0471] Example 22: 5-ethynyl-6-fluoro-4-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,9,10-hexahydro-4,8-dioxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0472] Example 22 was prepared by a similar procedure as described in Example 20 by replacing tert-butyl (R)-3-(hydroxymethyl)-1,4-oxazepane-4-carboxylate with tert-butyl 5-(hydroxymethyl)-1,4-oxazepane-4-carboxylate to give the title product (18 mg). 1 H NMR (500MHz, CD3OD) δ7.88–7.78(m,1H),7.41–7.12(m,3H),5.49–5.15(m,2H),4.73–4.63(m,1H),4.63–4. 50(m,1H),4.47–4.24(m,3H),4.05–3.86(m,3H),3.73–3.36(m,7H),3.22–3.09(m,1H),2.54–1.88(m,8H). MS(ESI,m / e)[M+H] + 618.5.

[0473] Example 23: 3-((7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphth-2-yl)-5-chloro-4-(trifluoromethyl)aniline

[0474] From a synthetic point of view, Example 23 is different from Example 17 in that it has an 8-membered ring. The synthesis of Example 23 having an 8-membered ring requires the key intermediate tert-butyl (1S, 5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. The synthesis of Example 23 requires a specific synthetic procedure and complex functional group transformations to avoid stereochemical isomerization.

[0475] Intermediate 23-0 (tert-butyl (1S,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) was prepared by the following general route (Scheme 4).

[0476] Scheme 4: Synthesis of intermediate 23-0

[0477] As described in Scheme 4, three different synthetic pathways can be used to produce intermediate 23-0 (tert-butyl (1S,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) from commercially available starting materials. In pathway 1, amine 23-1 undergoes protecting group manipulation and ester hydrolysis to generate carboxylic acid 23-3, which is further converted to diazo ketone 23-5 via mixed anhydride 23-4, followed by Wolff rearrangement to produce ester 23-6. Ester reduction followed by deprotection affords the desired intermediate alcohol 23-0. Alternatively, in pathway 2, alcohol 23-11 is converted to mesylate 23-13 after amine protection, which is then converted to ester 23-6 via S N 2 is further converted to the corresponding cyanide 23-14. Cyanide 23-14 is hydrolyzed to ester 23-15, which is further reduced to alcohol 23-16, which is deprotected to give the desired intermediate alcohol 23-0. Alternatively, in route 3, alcohol 23-21 is oxidized to the corresponding aldehyde 23-22 by conventional methods known in the art, which undergoes a Wittig reaction to give olefin 23-23. Olefin 23-23 undergoes a hydroboration reaction to produce alcohol 23-24, which is deprotected to give the desired intermediate 23-0.

[0478] Step 1: 3-Benzyl 8-(tert-butyl) 2-ethyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-2,3,8-tricarboxylate

[0479] A mixture of 8-(tert-butyl) 2-ethyl (1S, 5R) -3,8-diazabicyclo [3.2.1] octane-2,8-dicarboxylate (6.5 g, 22.89 mmol) and TEA (11.66 g, 114.44 mmol) and Cbz-Cl (7.8 g, 45.88 mmol) in DCM (65 mL) was stirred at 0 ° C for 12 h under nitrogen. The reaction mixture was quenched by adding 5 mL of water, then diluted with water (100 mL) and extracted with EA. The combined organic layers were washed with solvent brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EA = 100: 1 to 5: 1) to give the title product (7.5 g, 78% yield) as a colorless oil. MS (ESI, m / e) [M + H + 22] + =441.

[0480] Step 2: (1S,5R)-3-((Benzyloxy)carbonyl)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid

[0481] 3-Benzyl 8-(tert-butyl) 2-ethyl (1S, 5R) -3,8-diazabicyclo [3.2.1] octane-2,3,8-tricarboxylate (7 g, 16.74 mmol), EtOH (6 mL) and H2O (1.5 mL) and LiOH (1.93 g, 83.70 mmol) were added to a 25 mL sealed tube. After stirring at 50 °C for 3 h, the mixture was adjusted to pH = 5 with 1M HCl, then diluted with water (25 mL) and extracted with EtOAc. The combined organic layers were concentrated. The crude product (5.5 g) was used directly in the next step without further purification. (ESI, m / e) [M+H] + =391.

[0482] Step 3: (1S,5R)-3-((benzyloxy)carbonyl)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (isobutylcarbonic acid) anhydride

[0483] A mixture of (1S,5R)-3-((benzyloxy)carbonyl)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-2-carboxylic acid (2 g, 5.13 mmol) and DIPEA (3.3 g, 25.60 mmol) in THF (20 mL) was stirred at -50 °C for 10 min under nitrogen, then isobutyl chloroformate (3.50 g, 25.60 mmol) was added, the reaction mixture was stirred at -50 °C for 1 h, and the resulting mixture was used directly in the next step without further purification.

[0484] Step 4: 3-Benzyl 8-(tert-butyl)(1S,5R)-2-(2-diazoacetyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0485] To the crude mixture of step 3 was added CH2N2 (25.60 mmol in Et2O, 250 mL) at 0°C. After stirring at room temperature for 12 h, the mixture was concentrated. The residue was purified by silica gel chromatography (PE:EA=100:1 to 5:1) to give the title product (1.2 g). MS (ESI, m / e) [M+Na] + =437.

[0486] Step 5: 3-Benzyl 8-(tert-butyl)(1S,5R)-2-(2-methoxy-2-oxoethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0487] To a solution of 3-benzyl 8-(tert-butyl)(1R,5S)-2-(2-diazoacetyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (1.2 g, 2.9 mmol) and TEA (178 mg, 1.77 mmol) in MeOH (15 mL) was added AgOAc (47 mg, 0.29 mmol) at 0°C. After stirring at 60°C for 30 min, the mixture was concentrated and purified by silica gel chromatography (PE:EA=100:0 to 50:50) to give the title product (800 mg). (ESI, m / e)[M+H] + =419.

[0488] Step 6: 3-Benzyl 8-(tert-butyl)(1S,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0489] At 0°C, to a solution of 3-benzyl 8-(tert-butyl)(1S,5R)-2-(2-methoxy-2-oxoethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (750 mg, 1.86 mmol) in THF (15 mL) was added LiBH4 (164.2 mg, 7.46 mmol). After stirring overnight at room temperature, the mixture was quenched with NH4Cl(aq) at 0°C and extracted with EA. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (PE:EA=100:0 to 50:50) to give the title product (480 mg). (ESI, m / e)[M+H] + =392.

[0490] Step 7: tert-Butyl (1S,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0491] To a solution of 3-benzyl 8-(tert-butyl)(1S,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (400 mg, 1.03 mmol) in MeOH (10 mL) was added Pd / C (400 mg, 10% w) at room temperature. After stirring for 3 h at room temperature under H2(g) atmosphere, the resulting mixture was filtered and the filter cake was washed with DCM / MeOH (3:1). The filtrate was concentrated to give the title product (187 mg), designated as Isomer 1 of Intermediate 23-0: 1 H NMR (400MHz, CDCl3) δ4.27–3.94(m,2H),3.89–3.74(m,2H),3.46–3.14(m,1H),2.99–2.72(m, 1H),2.46–2.41(m,1H),2.10–2.08(m,1H),2.07–1.87(m,2H),1.86–1.62(m,3H),1.47(s,9H). MS(ESI,m / e)[M+H] + =257.15.

[0492] Intermediate 23-0 was also produced by route 3 in Scheme 4 and was named Isomer 2: 1 H NMR (500MHz, CDCl3) δ4.16-3.94(m,2H),3.83-3.74(m,2H),3.11-2.97(m,2H),2.73-2.46(m, 2H),2.00-1.93(m,1H),1.84-1.79(m,2H),1.70-1.64(m,1H),1.60-1.59(m,1H),1.48(s,9H). MS(ESI,m / e)[M+H] + 257.3.

[0493] Step 8: tert-Butyl (1S,5R)-2-(2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0494] To a mixture of tert-butyl (1S, 5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (737 mg, 2.9 mmol, isomer 2 of intermediate 23-0) and 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (803 mg, 2.9 mmol) in THF (75 mL) was added NaH (576 mg, 14.4 mmol, 60% w / w) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride solution (50 mL) was then added to the mixture, followed by H2O (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 3 times). The organic phases were combined, dried over Na2SO4 and concentrated in vacuo to give the crude title product (1.8 g). MS (ESI, m / e) [M+H] + 500.3.

[0495] Step 9: tert-Butyl (7S,10R)-2-chloro-1-fluoro-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate

[0496] To a solution of tert-butyl (1S,5R)-2-(2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.27 g, 2.5 mmol) in MeCN (70 mL) was added BOP-Cl (1.29 g, 5.1 mmol) and DIPEA (980 mg, 7.6 mmol). The resulting mixture was stirred at 70 °C for 1 hour. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by flash chromatography (DCM / EtOAc=5 / 1) to give the title product (630 mg). MS (ESI, m / e) [M+H] + 482.2.

[0497] Step 10: Tert-butyl (7S,10R)-2-chloro-1-fluoro-13-(methylsulfinyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate

[0498] To a solution of tert-butyl (7S, 10R) -2-chloro-1-fluoro-13- (methylthio) -5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocycloheptane [4,5] cyclooctane [1,2,3-de] naphthalene-15-carboxylate (392 mg, 0.8 mmol) in DCM (40 mL) was added mCPBA (140 mg, 0.8 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo. The crude product was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 498.2.

[0499] Step 11: Tert-butyl (7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-chloro-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylate

[0500] To a solution of (2-oxabicyclo[2.1.1]hexane-4-yl)methanol (137 mg, 1.2 mmol) in THF (15 mL) was added LiHMDS (1 M in THF, 1.12 mL, 1.12 mmol). The resulting mixture was stirred at 0 ° C for 30 minutes. Tert-butyl (7S, 10R) -2-chloro-1-fluoro-13- (methylsulfinyl) -5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-bridged methylcycloheptane [4,5] cyclooctane [1,2,3-de] naphthalene-15-carboxylate (crude, 0.4 mmol) was then added to the reaction mixture at 0 ° C and further stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The crude product was purified by Prep-TLC (DCM / MeOH=10 / 1) to give the title product (78 mg). MS (ESI, m / e) [M+H] + 548.3.

[0501] Step 12: Tert-butyl (7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methanocyclohepta[4,5]cyclooctano[1,2,3-de]naphthalene-15-carboxylate

[0502] Tert-butyl (7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-chloro-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocycloheptane[4,5]cyclooctane[1,2,3-de]naphthalene-15-carboxylate (78 mg, 0.14 mmol), 3- A mixture of chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (114 mg, 0.36 mmol), Pd(dppf)Cl2 (52 mg, 0.07 mmol) and NaHCO3 (36 mg, 0.43 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was vacuum degassed and refilled with nitrogen three times. The mixture was stirred at 95 ° C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by pre-TLC (DCM / MeOH / NH4OH=12 / 1 / 0.1) to give the title product (99 mg). MS (ESI, m / e) [M+H] + 707.4.

[0503] Step 13: 3-((7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphth-2-yl)-5-chloro-4-(trifluoromethyl)aniline

[0504] To a solution of tert-butyl (7S, 10R) -13- ((2-oxabicyclo [2.1.1] hexane-4-yl) methoxy) -2- (5-amino-3-chloro-2- (trifluoromethyl) phenyl) -1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10- methanocycloheptane [4,5] cyclooctane [1,2,3- de] naphthalene-15-carboxylate (99 mg, 0.14 mmol) in DCM (10 mL) was added TFA (5 mL). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated in vacuo. The crude product was purified by prep-HPLC to give the title product (30 mg, formate). MS (ESI, m / e) [M+H] + 607.6. 1HNMR(500MHz,CD3OD)δ8.49(s,1H),6.89(s,1H),6.54-6.51(m,1H),4.86-4.78(m,2H),4.58(s,1H),4.40-4.23(m ,3H),4.19-4.06(m,1H),4.04-3.98(m,1H),3.95-3.81(m,2H),3.74(s,2H),2.47-1.75(m,8H),1.64-1.60(m,2H).

[0505] Example 24: 3-Chloro-5-((7S,10R)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphth-2-yl)-4-(trifluoromethyl)aniline

[0506] Example 24 was prepared by replacing (2-oxabicyclo[2.1.1]hexan-4-yl)methanol with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol by a similar procedure as described in Example 23. Tert-butyl (1S,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (isomer 2 of intermediate 23-0) was used.

[0507] MS (ESI, m / e) [M+H] + :652.4

[0508] 1 H NMR(500MHz,CD3OD)δ6.91(s,1H),6.52(s,1H),5.59-5.48(m,1H),4.63(s,2H),4.46-4.29(m,2H),4.27-4.01(m, 3H),3.92-3.75(m,4H),3.44-3.38(m,1H),3.31(s,1H),2.68-2.53(m,2H),2.51-2.21(m,5H),2.20-1.93(m,5H).

[0509] Example 25: 3-Chloro-5-((7S,10R)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphth-2-yl)-4-(trifluoromethyl)aniline

[0510] Example 25 was prepared by a similar procedure as described in Example 23 by replacing (2-oxabicyclo[2.1.1]hexan-4-yl)methanol with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol. Tert-butyl (1S,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (isomer 1 of intermediate 23-0) was used.

[0511] MS (ESI, m / e) [M+H] + :652.7

[0512] 1 H NMR(500MHz,CD3OD)δ6.90(s,1H),6.60-6.38(m,1H),5.62-5.52(m,1H),5.42-5.39(m,1H),4.69-4.59(m,4H),4.32-4.28(m,1H),4.14-4.00 (m,3H),3.95-3.82(m,2H),3.50-3.43(m,2H),2.76-2.54(m,2H),2.50 -2.45(m,1H),2.41-2.25(m,4H),2.20-2.00(m,3H),1.85-1.72(m,2H).

[0513] Intermediate 26-0: tert-Butyl (1S, 2R, 5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0514] Synthetic pathway

[0515] Step 1: tert-Butyl (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0516] To a 250-mL round-bottom flask was added tert-butyl (1S, 2S, 5R) -3-benzyl -2- (hydroxymethyl) -3, 8- diazabicyclo [3.2.1] octane -8- carboxylate (1.55 g, 4.65 mmol), DMP (2.37 g, 5.58 mmol), and DCM (50 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The crude product was purified by column chromatography (PE / EA = 0-12%) to give the title product (1.02 g, 68% yield) as a colorless oil.

[0517] Step 2: tert-Butyl (1S,2R,5R)-3-benzyl-2-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0518]

[0519] PPh3MeBr (748 mg, 2.11 mmol), THF (6 mL), and KHMDS (1 M, 1.76 mL, 1.76 mmol) were added to a 50-mL round-bottom flask. The reaction mixture was stirred at room temperature for 30 min, and then a THF (6 mL) solution of tert-butyl (1S, 2S, 5R)-3-benzyl-2-formyl-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (580 mg, 1.76 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was then quenched by adding sat.NH4Cl (50 mL). The mixture was extracted 3 times with EtOAc (20 mL). The organic phases were combined, dried with Na2SO4 and filtered through diatomaceous earth. The mixture was concentrated in vacuo. The resulting crude product was purified by column chromatography (PE / EA=0-12%) to give the title compound (400 mg, 69% yield) as a white solid.

[0520] Step 3: tert-Butyl (1S, 2R, 5R)-3-benzyl-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0521] Tert-butyl (1S, 2R, 5R) -3- benzyl -2- vinyl -3, 8- diazabicyclo [3.2.1] octane -8- carboxylate (1 g, 0.0030 mol), 9-BBN (0.5 M, 36.5 mL, 0.018 mol), and THF (10 mL) were added to a 100-mL round-bottom flask. The reaction mixture was stirred at 50 ° C for 2 h under N2 atmosphere. After the reaction was completed (as shown by LCMS), aq. NaOH (3 M, 7 ml) and H2O2 (7 mL) were added dropwise at 0 ° C. The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with H2O (50 mL) and extracted 3 times with EtOAc (30 mL). The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (PE / EA=0-23%) to give the title compound (900 mg, 85% yield) as a colorless oil.

[0522] Step 4: tert-Butyl (1S, 2R, 5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0523] To a 100-mL round-bottom flask was added tert-butyl (1S, 2R, 5R) -3-benzyl -2- (2-hydroxyethyl) -3, 8-diazabicyclo [3.2.1] octane -8-carboxylate (1.7 g, 4.91 mmol), Pd / C (10wt%, 1.7 g), and MeOH (15 mL). Under H2 atmosphere, the reaction solution was stirred at room temperature for 3 h. The reaction mixture was then filtered through celite and concentrated in vacuo to give the title compound (1.1 g, 91% yield) as a colorless oil. MS (ESI, m / e) [M + H] + =257.10. 1 H NMR(300MHz,DMSO-d6)δ4.45(d,J=4.8Hz,1H),4.06–3.80(m,1H),3.73(d,J=6.6Hz,1H),3.42(q ,J=11.1,8.8Hz,2H),3.06–2.63(m,2H),2.09(t,J=33.2Hz,1H),1.87–1.48(m,4H),1.39(s,9H).

[0524] Example 26: 3-((6aR,7S,10R)-13-((3-(difluoromethyl)oxetan-3-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline

[0525] Synthetic pathway

[0526] Step 1: tert-Butyl (1S,2R,5R)-2-(2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0527] To a mixture of tert-butyl (1S, 2R, 5R) -2- (2-hydroxyethyl) -3, 8- diazabicyclo [3.2.1] octane -8- carboxylate (1.53 g, 6 mmol) and 5,7- dichloro-8-fluoro-2- (methylthio) pyrido [4,3-d] pyrimidin-4-ol (1.68 g, 6 mmol) in THF (150 mL) was added NaH (1.2 g, 30 mmol). The mixture was stirred at room temperature for 20 hours. The reaction was then quenched by adding saturated aqueous ammonium chloride solution (50 mL) and water (50 mL). The resulting mixture was extracted 3 times with EtOAc (50 mL). The organic phases were combined, dried over Na2SO4, and concentrated in vacuo to give the crude title product (4 g). MS (ESI, m / e) [M+H] + 499.8.

[0528] Step 2: tert-Butyl (6aR,7S,10R)-2-chloro-1-fluoro-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate

[0529] To a solution of tert-butyl (1S, 2R, 5R)-2-(2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 g, 8 mmol) in MeCN (220 mL) was added BOP-Cl (4.1 g, 5.1 mmol) and DIPEA (980 mg, 7.6 mmol). The resulting mixture was stirred at 70 °C for 1 hour. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography (DCM / EtOAc=5 / 1) to give the title product (1.6 g). MS (ESI, m / e) [M+H] + 481.9.

[0530] Step 3: tert-Butyl (6aR,7S,10R)-2-chloro-1-fluoro-13-(methylsulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate

[0531] To a solution of tert-butyl (6aR, 7S, 10R) -2-chloro-1-fluoro-13- (methylthio) -5,6,6a, 7,8,9,10,11-octahydro-4-oxa-3,11a, 12,14,15-pentaaza-7,10-bridged methanocycloheptane [4,5] cyclooctane [1,2,3-de] naphthalene-15-carboxylate (378 mg, 0.8 mmol) in THF (28 mL) and water (7 mL) was added NaIO4 (505 mg, 2.4 mmol) and RuCl3 (16 mg, 0.08 mmol). The resulting mixture was stirred at 0 ° C for 1 hour. The mixture was diluted by adding water (20 mL) and extracted 3 times with EtOAc (20 mL). The organic phases were combined and concentrated in vacuo to give the crude title compound (335 mg), which was used in the next step without treatment. MS (ESI, m / e) [M+H] + 514.2.

[0532] Step 4: tert-Butyl (6aR,7S,10R)-2-chloro-13-((3-(difluoromethyl)oxetan-3-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate

[0533] To a solution of (3-(difluoromethyl)oxetan-3-yl)methanol (27.6 mg, 0.2 mmol) in THF (5 mL) was added LiHMDS (1 M in THF, 0.2 mL, 0.2 mmol) and the resulting solution was stirred at room temperature for 0.5 h. Tert-butyl (6aR,7S,10R)-2-chloro-1-fluoro-13-(methylsulfonyl)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate (100 mg, 0.2 mmol) was then added to the reaction mixture and stirred at room temperature for another 1 h. After the reaction was completed (as shown by LCMS), the reaction mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give the title product (85.7 mg, 0.15 mmol). MS (ESI, m / e) [M+H] + 572.2.

[0534] Step 5: tert-Butyl (6aR,7S,10R)-2-(5-amino-3-methyl-2-(trifluoromethyl)phenyl)-13-((3-(difluoromethyl)oxetan-3-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxetan-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate

[0535] Tert-butyl (6aR,7S,10R)-2-chloro-13-((3-(difluoromethyl)oxetan-3-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocycloheptane[4,5]cyclooctane[1,2,3-de]naphthalene-15-carboxylate (85.7 mg, 0.15 mmol), 3-methyl-5-(4,4, A mixture of 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (135.5 mg, 0.45 mmol), Pd(dtbpf)Cl2 (19.5 mg, 0.03 mmol) and K3PO4 (127.1 mg, 0.60 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was degassed by bubbling nitrogen for 5 min and then stirred at 95 ° C for 4 hours. The resulting mixture was cooled to room temperature, concentrated in vacuo, and purified by prep-TLC (DCM / MeOH=15 / 1) to give the title product (71.0 mg, 0.10 mmol). MS (ESI, m / e) [M+H] + 711.3.

[0536] Step 6: 3-((6aR,7S,10R)-13-((3-(difluoromethyl)oxetan-3-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphth-2-yl)-5-methyl-4-(trifluoromethyl)aniline

[0537] To a solution of tert-butyl (6aR, 7S, 10R) -2- (5-amino-3-methyl-2- (trifluoromethyl) phenyl) -13- ((3- (difluoromethyl) oxetan-3-yl) methoxy) -1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10- methanocycloheptane [4,5] cyclooctane [1,2,3- de] naphthalene-15-carboxylate (71.0 mg, 0.10 mmol) in DCM (14 mL) was added TFA (7 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The crude product was purified by prep-HPLC to give the title product (22 mg). MS (ESI, m / e) [M+H] + 611.3. 1H NMR(500MHz,DMSO)δ6.61(s,1H),6.52-6.30(m,2H),5.87(s,2H),4.73–4.58( m,6H),4.30–3.94(m,5H),3.55-3.32(m,2H),2.36(s,3H),2.13–1.57(m,6H).

[0538] Examples 27-68: The following compounds were prepared in a similar manner as described in Example 26:

[0539] Example 68: 3-((6aR,7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphth-2-yl)-5-ethyl-4-(trifluoromethyl)aniline

[0540] Synthetic pathway

[0541] Step 1: tert-Butyl (6aR,7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-(5-amino-2-(trifluoromethyl)-3-vinylphenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate

[0542] Tert-butyl (6aR,7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cyclooctane[1,2 A mixture of 1,4-dioxane (12.5 mL) and water (2.5 mL) was degassed in vacuo and refilled with N2 three times. The resulting mixture was stirred at 95 ° C for 2 hours. The resulting cooled mixture was concentrated in vacuo and dissolved in DCM (20 mL). After filtration, the filtrate was concentrated to give the title product, which was used in the next step without further purification. MS (ESI, m / e) [M + H] + 700.1.

[0543] Step 2: tert-Butyl (6aR,7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-(5-amino-3-ethyl-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate

[0544] To a solution of tert-butyl (6aR, 7S, 10R) -13- ((2-oxabicyclo [2.1.1] hexan-4-yl) methoxy) -2- (5-amino-2- (trifluoromethyl) -3-vinylphenyl) -1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaza-7,10-methanocycloheptane [4,5] cyclooctane [1,2,3-de] naphthalene-15-carboxylate (crude, 0.08 mmol) in MeOH (30 mL) was added Pd / C (10% w / w, 100 mg). The reaction mixture was stirred at 25 ° C for 1 hour under a balloon of H2. The resulting mixture was filtered and the filtrate was concentrated to give the title product, which was used in the next step without further purification. MS (ESI, m / e) [M + H] + 701.4.

[0545] Step 3: 3-((6aR,7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphth-2-yl)-5-ethyl-4-(trifluoromethyl)aniline

[0546] To a solution of tert-butyl (6aR, 7S, 10R) -13- ((2-oxabicyclo [2.1.1] hexane-4-yl) methoxy) -2- (5-amino-3-ethyl-2- (trifluoromethyl) phenyl) -1-fluoro-5,6,6a, 7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocycloheptane [4,5] cyclooctane [1,2,3-de] naphthalene-15-carboxylate (crude, 0.08 mmol) in DCM (15 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 0.5 hours, then concentrated and further purified by prep-HPLC to give the title product (14 mg, FA salt). MS (ESI, m / e) [M+H] + 601.45. 1 H NMR(500MHz,CD3OD)δ8.48(s,1H),6.89-6.76(m,1H),6.47-6.44(m,1H),4.82-4.75(m,2H),4.58(s,1H),4.50 -3.80(m,7H),3.74(s,2H),2.76(q,J=7.1Hz,2H),2.35-1.90(m,8H),1.65-1.60(m,2H),1.26(t,J=7.5Hz,3H). Determination

[0547] KRAS WT and KRAS G12V probe replacement assay

[0548] This assay is used to identify compounds that bind to GDP-loaded KRAS protein and can displace the biotinylated probe occupying the KRAS binding site. WT KRAS (amino acids 1-169) loaded with GST tag and KRAS G12V (amino acids 1-169) loaded with GDP with GST tag were expressed in E. coli and purified in-house. All proteins and reaction solutions were prepared in assay buffer containing 50mM HEPES pH7.5, 50mM NaCl, 1mM MgCl2, 1mM TCEP, 0.01% BSA, and 0.008% Brij-35. Purified WT KRAS (3nM final concentration) or KRAS G12V protein (2nM final concentration) was incubated with 3-fold serial dilutions of the compound in an assay plate (384-well microplate, black, Corning). The plate was incubated at 24°C for 1 hour. After incubation, biotinylated probe 1 of WT KRAS (60 nM final assay concentration) and biotinylated probe 2 of KRASG12V (2.5 nM final assay concentration) were added to the assay plate, respectively. After incubation at 24°C for 1 hour, Mab anti-GST-Tb cryptate (Cisbio) and streptavidin-XL665 (Cisbio) were added and further incubated at 24°C for another 1 hour. TR-FRET signals (ex337 nm, em665nm / 620nm) were read on a BMG PHERAstar FSX instrument. Based on the fluorescence ratio at 665nm to 620nm, the percentage of inhibition of KRAS protein binding to the biotinylated probe was calculated with increasing compound concentrations. The IC of each compound was calculated by fitting the data to a four-parameter logistic model using Dotmatics. 50 value.

[0549] KRAS WT and KRAS G12D probe displacement assay

[0550] This assay is used to identify compounds that bind to GDP-loaded KRAS protein and can displace the biotinylated probe occupying the KRAS binding site. GST-tagged GDP-loaded WT KRAS (amino acids 1-188) and GST-tagged GDP-loaded KRAS G12D (amino acids 1-188) were expressed in E. coli and purified in-house. All proteins and reaction solutions were prepared in assay buffer containing 50mM HEPES pH7.5, 50mM NaCl, 1mM MgCl2, 1mM TCEP, 0.01% BSA, and 0.008% Brij-35. Purified WT KRAS (3nM final concentration) or KRAS G12D protein (0.5nM final concentration) was incubated with 3-fold serial dilutions of the compound in an assay plate (384-well microplate, black, Corning). The plate was incubated at 24°C for 1 hour. After incubation, biotinylated probe 1 of WT KRAS (60nM final assay concentration) and biotinylated probe 2 of KRAS G12D (4nM final assay concentration) were added to the assay plate, respectively. After incubation at 24°C for 1 hour, Mab anti-GST-Tb cryptate (Xisi Biotechnology Co., Ltd.) and streptavidin-XL665 (Xisi Biotechnology Co., Ltd.) were added and further incubated at 24°C for another 1 hour. TR-FRET signals (ex337 nm, em665 nm / 620nm) were read on a BMG PHERAstar FSX instrument. Based on the fluorescence ratio at 665nm to 620nm, the percentage of inhibition of KRAS protein binding to the biotinylated probe was calculated with increasing compound concentrations. The IC of each compound was calculated by fitting the data to a four-parameter logistic model using Dotmatics. 50 value.

[0551] KRAS G12V pERK assay

[0552] The SW620 cell line was used in this study. The cells were maintained in RPMI 1640 supplemented with 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin and streptomycin (Thermo Fisher), and stored in a humidified atmosphere containing 5% CO2 in air at 37°C. The cell line was revived from a frozen stock solution that was stored within 30 generations of the purchased original cells. 40,000 cells per well were seeded into a 96-well plate and incubated overnight. The cells were treated with a 10-point dilution series. The final compound concentration was 0 to 10 μM. After 2 hours of compound treatment, the cells were lysed and the pERK1 / 2 (THR202 / TYR204) level in the cell lysate was detected by HTRF kit (Xisi Biotechnology Co., Ltd.). In brief, a total of 16 μL of cell lysate from each well of the 96-well plate was transferred to a 384-well white assay plate. The lysate from each well was incubated with 2 μL of Eu3+-cryptate (donor) labeled anti-phospho-ERK1 / 2 and 2 μL of D2 (acceptor) labeled anti-phospho-ERK1 / 2 antibody (Xisi Biotech) in the dark at room temperature overnight. When the donor and acceptor are in close proximity, laser excitation of the donor triggers fluorescence resonance energy transfer (FRET) toward the acceptor, which then fluoresces at a wavelength of 655 nm. The FRET signal was measured using a PHERAstar FSX reader (BMG Labtech). IC50 determinations were performed by fitting a curve of percent inhibition versus the logarithm of inhibitor concentration using Dotmatics.

[0553] KRAS G12D pERK assay

[0554] AsPC-1 cell line was used in this study. Cells were maintained in RPMI-1640 supplemented with 10% fetal bovine serum (Thermo Fisher Scientific), 50 units / mL penicillin and streptomycin (Thermo Fisher Scientific), and stored in a humidified atmosphere containing 5% CO2 in air at 37°C. Cell lines were revived from frozen stock solutions that were stored within 30 generations of the purchased original cells. 30,000 cells per well were seeded into 96-well plates and incubated overnight. Cells were treated with a 10-point dilution series. The final compound concentration was 0 to 10 μM. After 2 h of compound treatment, cells were lysed and pERK1 / 2 (THR202 / TYR204) levels in cell lysates were detected by HTRF kit (Xisi Biotechnology Co., Ltd.). In brief, a total of 16 μL of cell lysate from each well of a 96-well plate was transferred to a 384-well white assay plate. The lysate from each well was incubated with 2 μL of Eu3+-cryptate (donor) labeled anti-phospho-ERK1 / 2 and 2 μL of D2 (acceptor) labeled anti-phospho-ERK1 / 2 antibody (Xisi Biotech) in the dark at room temperature overnight. When the donor and acceptor are in close proximity, laser excitation of the donor triggers fluorescence resonance energy transfer (FRET) toward the acceptor, which in turn emits fluorescence at a wavelength of 655 nm. The FRET signal was measured using a PHERAstar FSX reader (BMG Laboratory Technology). IC 50 The assay was performed by fitting a curve of percent inhibition versus the logarithm of inhibitor concentration using Dotmatics.

[0555] Preparation and crystallization of KRAS G12D protein

[0556] KRAS G12D protein purification

[0557] KRAS G12D 1-169aa was cloned into the pET28a vector. The gene was placed in frame with an N-terminal 6Xhis tag and a Sumo tag. The construct was transformed into BL21 (DE3) cells. The cells were cultured by adding 1-thio-β-D-galactopyranoside (IPTG) to a final concentration of 200uM and then incubated at 16°C overnight. When the cells reached OD 600When the pH is 0.6, protein expression is induced. Bacteria are harvested by centrifugation (4000rpm, 20min, 4°C), and 1 liter of cell paste is resuspended in 30ml of 50mM Tris pH 8.0, 300mM NaCl, 20mM imidazole, 5mM MgCl2, wherein 2 piles of EDTA-free protease inhibitor mixed tablets (Roche Diagnostics) are supplied. Proteins are purified using His-trap HP columns (Cytiva) according to standard protocols. The N-terminal His-sumo tag is cut by overnight digestion with ULP1 protease, and UPL1 and His-sumo tags are removed by reloading into the His-trap HP column (Cytiva). The HiLoad 16 / 600Superdex 75pg (Cytiva) balanced with 20mMTris pH 8.0, 100mM NaCl, 5mM MgCl2 is used to further purify the protein by gel filtration. The protein solution was concentrated to 30-40 mg / ml for crystallization experiments.

[0558] KRAS G12D crystallization

[0559] KRAS G12D co-crystals with small molecule inhibitors were grown using sitting drop vapor diffusion by mixing 1 ul of protein (40 mg / ml) with an equal volume of crystallization buffer at 20°C. Crystals appeared in droplets containing 1.0 M LiCl, 0.1 M citric acid pH 5.0, 20% PEG 6000. Diffraction data were collected on beamline BL10U2 at the Shanghai Synchrotron Radiation Facility.

[0560] Metabolic stability of different types of liver microsomes

[0561] First, liver microsomes were mixed with NADPH to obtain final concentrations of microsomes and NADPH of 0.5 mg / mL and 1 mM, respectively. The test compound was added to the incubation system at a final concentration of 1 μM and incubated at 37°C. Incubation was started by adding NADPH to the system. At 0, 15, 30, 45 and 60 minutes after the start of incubation, 20 μL aliquots were taken out from the incubation system. The reaction solution was terminated by adding cold acetonitrile and analyzing IS. The sample was centrifuged at 4000 rpm for 5 minutes and then analyzed on LC-MS / MS.

[0562] The peak areas of the samples at different time points were determined from the extracted ion chromatograms; the metabolic stability was then calculated by plotting the slope value k. The slope value k was determined by linear regression of the natural logarithm of the parent drug remaining percentage versus the incubation time curve. The in vitro half-life (in vitro t 1 / 2 ) is determined according to the slope value: In vitro 1 / 2 =-(0.693 / k) In vitro 1 / 2 (in minutes) to the in vitro intrinsic clearance (in vitro CL int The conversion to μL / min / mg protein was done using the following equation (average of replicates):

[0563] A control compound (verapamil) was included in the assay to ensure data consistency. A negative control (same experimental setup but without NADPH in the incubation system) was used to exclude misleading factors caused by the instability of the chemical itself.

[0564] Human liver microsomal CYP (cytochrome P450) enzyme inhibition assay

[0565] Incubations were performed in 96-well plates. 1 μL of the test compound working solution or vehicle was added to 179 μL of human liver microsomes fortified with CYP1A2 (40 μM phenacetin), 2C9 (6 μM diclofenac), 2C19 (50 μM (S)-mephenytoin), 2D6 (10 μM dextromethorphan), and 3A4 (1 μM midazolam or 50 μM testosterone) substrates. The incubation plates were preheated in a 37°C water bath for 5 min, and then 20 μL of 10 mM NADPH solution was added to start the reaction. The reaction was performed in a 37°C water bath.

[0566] At predetermined time points, the reaction was stopped by adding 300 μL of quenching solution (acetonitrile containing internal standard) to each well. The sample plate was vortexed for 1 min and centrifuged at 3000 g for 10 min. 100 μL of supernatant was transferred to a new 96-well plate and then mixed with 100 μL of water and analyzed by LC-MS / MS, followed by data processing (i.e., percent inhibition at 10 uM or IC50 determination).

[0567] Time-dependent Cytochrome P450 (CYP) Enzyme Inhibition Assay (TDI) in Human Liver Microsomes

[0568] The TDI assay involves preincubation of 0.1 mg·mL-1 human liver microsomes with 10 uM test compound and positive control at 37°C for 30 min in the presence or absence of 1 mM NADPH ("inactivation incubation"). After the preincubation period, the remaining CYP activity was determined by the subsequent addition of substrate (1A2, 40 μM phenacetin; CYP2B6, 50 μM bupropion; CYP2C8, 5 μM paclitaxel; CYP2C9, 6 μM diclofenac; CYP2C19, 50 μM (S)-mephenytoin; CYP2D6, 10 μM dextromethorphan; CYP3A, 1 μM midazolam or 50 μM testosterone) and NADPH to the preincubation mixture and an additional 20 min "activity incubation" for CYP1A2, 2B6, 2C19, 2D6, 10 min "activity incubation" for CYP2C8, CYP3A (testosterone), 6 min "activity incubation" for CYP2C9, and 5 min "activity incubation" for 3A (midazolam). All reactions were terminated by the addition of ice-cold acetonitrile with internal standard followed by centrifugation for LC-MS / MS analysis.

[0569] Bidirectional permeability assay of MDCKII-MDR1 cell monolayer

[0570] First, prepare MDCKII-MDR1 cells in cell seeding medium. Add 50 μL of cultured cell suspension to each well of the pre-prepared Transwell plate. Incubate the plate for 4-8 days. Change the medium every other day. Prior to permeability measurement, assess the integrity of the cell monolayer by electrical resistance method.

[0571] To determine the rate of drug transport from the apical to the basolateral direction. 125 μL of the test compound working solution was added to the Transwell insert (apical compartment), and 50 μL of the sample (D0 sample) was immediately transferred from the apical compartment to a new 96-well plate. To determine the rate of drug transport from the basolateral to the apical direction. 285 μL of the compound working solution was added to the receiver plate well (basolateral compartment), and 50 μL of the sample (D0 sample) was immediately transferred from the basolateral compartment to a new 96-well plate. The plate was incubated at 37°C for 2 hours. At the end of the transport period, 50 μL was transferred directly from the apical and basolateral wells and transferred to a new plate. Then 200 μL of cold acetonitrile containing internal standards (IS: 2 μM ketorolac, 200 nM labetalol, 200 nM caffeine and 100 nM alprazolam) was added to the plate. Vortex for 5 minutes. The sample was centrifuged at 3,220 g for 20 minutes. An aliquot of 100 μL of the supernatant was diluted with 100 μL of ultrapure H2O and the mixture was used for LC / MS / MS analysis. All incubations were performed in duplicate. For the MDCKII-MDR1 drug transport assay, the apparent permeability (Papp) in centimeters per second can be calculated using the following equation: where VA is the volume in mL in the receptor pore (0.235 mL for Ap→Bl flux and 0.075 mL for Bl→Ap flux), and Area is the surface area of ​​the membrane (0.143 cm for Transwell-96 permeable supports). 2 ), time is the total transit time (in seconds). The outflow ratio can be determined using the following equation: Where P app(B-A) represents the apparent permeability from the basolateral to the apical direction, and P app(A-B) Represents the apparent permeability in the apical to basolateral direction. The recovery can be determined using the following equation:

[0572] Where V A is the volume in the acceptor pore (in mL) (0.235 mL for Ap→Bl flux and 0.075 mL for Bl→Ap), V D is the volume in the donor well (in mL) (0.075 mL for Ap→Bl flux and 0.235 mL for Bl→Ap).

[0573] Intrinsic clearance of different hepatocyte types

[0574] Prepare 10 mM stock solutions of test compounds and positive controls in appropriate solvents (DMSO). Place incubation medium (Williams' E Medium supplemented with GlutaMAX) in a 37°C water bath and warm for at least 15 minutes before use. In separate conical tubes, dilute 10 mM test compounds and positive controls to 100 μM by mixing 198 μL of 50% acetonitrile / 50% water and 2 μL of 10 mM stock solutions. Pipette 198 μL of cryopreserved hepatocytes (0.5×10 6 2 μL of 100 μM test compound or positive control was pipetted into each well of a 96-well uncoated plate. The reaction was started with a pipette. The final concentration of the test compound or control compound was 1 μM. The plate was returned to the incubator and placed on an orbital shaker. 25 μL aliquots of the well contents were taken out at 0, 15, 30, 60, 90 and 120 minutes. The aliquots were then mixed with 6 volumes (150 μL) of cold acetonitrile and IS (2 μM ketorolac, 200 nM salamide, 200 nM caffeine and 100 nM alprazolam) to terminate the reaction. Centrifuged at 3,220 g for 30 minutes. 100 μL aliquots of the supernatant will be used for LC / MS / MS analysis. Depending on the LC-MS signal response and peak shape, the supernatant can be diluted with ultrapure water. All incubations will be repeated.

[0575] All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. In vitro half-lives (t 1 / 2 ).

[0576] In vitro half-life (in vitro t 1 / 2 ) is determined by the slope value: In vitro 1 / 2 =0.693 / k In vitro 1 / 2 (in minutes) to the in vitro intrinsic clearance (in vitro CL int , unit is μL / min / 10 6 The conversion of cells) is done using the following equation: In vitro CL int =kV / N

[0577] V = incubation volume (0.2 mL); N = number of hepatocytes per well (0.1 × 10 6 cells).

[0578] Mouse and rat PK studies

[0579] The pharmacokinetics of the compound were evaluated in male CD-1 mice or SD-JVC rats by intravenous and oral administration. For intravenous administration studies, the test compound was dissolved in DMA: 30% Solutol HS 15 (w / v): saline (volume ratio of 20: 20: 60) and injected with 1mg / kg dose by tail vein. For oral administration studies, the test compound was dissolved in 0.5% MC or PEG400 / Phosal 50 PG / EtOH (volume ratio of 30 / 60 / 10) and administered to mice by gavage with a dosage of 10mg / kg or 30mg / kg. Animals will be grouped and processed according to body weight. At the time point after administration (5 minutes (IV only), 15 and 30 minutes after administration and 1, 2, 4, 8 and 24h after administration), rat blood samples will be collected from JVC, mice will be anesthetized by isoflurane, and blood samples will be collected from orbital bleeding. Blood samples will be collected in 1.5mL EDTA.K2 coated EP tubes. Approximately 50 μL of blood (mouse) and 150 μL of blood (rat) were collected at each time point and placed on ice, then centrifuged at 5600 rpm for 7 min at 4°C to obtain plasma. Plasma will be transferred to a new tube and temporarily stored at -20°C or in dry ice. Samples will be stored at -80°C until ex vivo PK assays are performed.

[0580] Plasma concentration was determined by the following sample preparation method and measurement conditions. To an aliquot of 10 μL of sample was added 200 μL of IS (Terfenadine, 5 ng / mL) in ACN. The mixture was vortexed for 1 min and centrifuged at 4000 rpm for 10 min at 4°C. An aliquot of 80 μL of supernatant was diluted with 80 μL of water, and the mixed sample was injected into liquid chromatography-tandem mass spectrometry (LC-MS / MS, Triple Quad 5500) for analysis. Amount of sample injected: 2 μL. Monitor: MRM; Column: Advanced Materials Technology, HALO AQ-C18 2.7 μm 50*2.1mm; column temperature: 40℃; mobile phase A: H2O-0.1% FA, mobile phase B: ACN-0.1% FA, gradient program: 15% B-15% B (0min-0.3min), 15% B-90% B (0.3min-1.0min), 90% B-90% B (1.0min-1.8min), 90% B-30% B (1.8min-2.0min), 30% B-30% B (2.0min-2.5min).

[0581] SW1990 PD Study:

[0582] 5×10 6 SW1990 cells / 200 μL PBS / Matrigel were implanted subcutaneously into the right flank of female NCG mice. After inoculation, when the tumor size reached approximately 350-450 mm 3 The mice were randomly divided into treatment groups when the average volume of MC was 0.5%. The randomized mice will receive a single dose of vehicle consisting of 0.5% MC or different doses (e.g., 30, 50, or 100 mg / kg) of the test compound by oral administration. Plasma was collected at 0.5, 2, 4, and 7 hours after administration, and tumors were collected at 7 hours to determine the exposure level. Tumor fragments were quickly frozen in homogenization tubes with liquid nitrogen, homogenized with T-PER tissue protein extraction buffer, and fresh protease and phosphatase inhibitors were added before use. Tumor lysates were then analyzed for ERK1 / 2 phosphorylation.

[0583] SW1990 Efficacy Study:

[0584] 5×10 6 SW1990 cells / 200 μL PBS / Matrigel were implanted subcutaneously into the right flank of female NCG mice. After inoculation, when the tumor size reached approximately 150-250 mm 3 The mice were randomly divided into treatment groups when the mean volume of the tumor reached 1.5% MC. The randomized mice received the vehicle consisting of 0.5% MC or the test compound at different doses (e.g., 30, 50, or 100 mg / kg BID) by oral administration. The animals were monitored daily, and the tumor volume was determined twice a week using a vernier caliper in two dimensions and expressed in mm using the following formula: 3 Meaning: V = 0.5 (a × b 2 ), where a and b are the long and short diameters of the tumor, respectively. Partial regression (PR) was defined as a tumor volume less than 50% of the initial tumor volume on the first day of administration in three consecutive measurements, and complete regression (CR) was defined as a tumor volume less than 14 mm in three consecutive measurements. 3 Data are presented as mean tumor volume ± standard error of the mean (SEM). Tumor growth inhibition (TGI) was calculated using the following formula: Treatment t = treated tumor volume at time t Treatment t0 = treated tumor volume at time 0 Placebo t = Placebo tumor volume at time t Placebo t0 = Placebo tumor volume at time 0

[0585] It has been found that Example 23, as a monobasic G12D inhibitor, shows improved KRas WT selectivity, enhanced oral exposure, reduced gastrointestinal accumulation and reduced toxicity compared to dibasic G12D inhibitors (e.g., Example 17). It has also been found that Examples 26, 27, 29, 32, 35, 40, 41 and other Examples show enhanced oral pharmacodynamic effects.

[0586] SW620 PD Study:

[0587] 5×10 6 SW620 cells / 200 μL PBS / Matrigel were implanted subcutaneously into the right flank of female NOD / SCID mice. After inoculation, when the tumor size reached approximately 350-450 mm 3 The mice were randomly divided into treatment groups when the average volume of MC was 0.5%. The randomized mice will receive a single dose of vehicle consisting of 0.5% MC or different doses (e.g., 30, 50, or 100 mg / kg) of the test compound by oral administration. Plasma was collected at 0.5, 2, 4, and 8 hours after administration, and tumors were collected at 4 and 8 hours to determine the exposure level. Tumor fragments were quickly frozen in homogenization tubes with liquid nitrogen, homogenized with T-PER tissue protein extraction buffer, and fresh protease and phosphatase inhibitors were added before use. Tumor lysates were then analyzed for ERK1 / 2 phosphorylation.

[0588] SW620 efficacy study:

[0589] 5×10 6 SW620 cells / 200 μL PBS / Matrigel were implanted subcutaneously into the right flank of female NOD / SCID mice. After inoculation, when the tumor size reached approximately 150-250 mm 3 The mice were randomly divided into treatment groups when the mean volume of the tumor reached 1.5% MC. The randomized mice received the vehicle consisting of 0.5% MC or the test compound at different doses (e.g., 30, 50, or 100 mg / kg BID) by oral administration. The animals were monitored daily, and the tumor volume was determined twice a week in two dimensions using a vernier caliper and expressed in mm using the following formula: 3 Meaning: V = 0.5 (a × b 2 ), where a and b are the long and short diameters of the tumor, respectively. Partial regression (PR) was defined as a tumor volume less than 50% of the initial tumor volume on the first day of administration in three consecutive measurements, and complete regression (CR) was defined as a tumor volume less than 14 mm in three consecutive measurements. 3 Data are presented as mean tumor volume ± standard error of the mean (SEM). Tumor growth inhibition (TGI) was calculated using the following formula: Treatment t = treated tumor volume at time t Treatment t0 = treated tumor volume at time 0 Placebo t = Placebo tumor volume at time t Placebo t0 = Placebo tumor volume at time 0

[0590] RKN PD Study:

[0591] 5×10 6 RKN cells / 200 μL PBS / Matrigel were implanted subcutaneously into the right flank of female NOD / SCID mice. After inoculation, when the tumor size reached approximately 350-450 mm 3 The mice were randomly divided into treatment groups when the average volume of MC was 0.5%. The randomized mice will receive a single dose of vehicle consisting of 0.5% MC or different doses (e.g., 30, 50, or 100 mg / kg) of the test compound by oral administration. Plasma was collected at 0.5, 2, 4, and 8 hours after administration, and tumors were collected at 4 and 8 hours to determine the exposure level. Tumor fragments were quickly frozen in homogenization tubes with liquid nitrogen, homogenized with T-PER tissue protein extraction buffer, and fresh protease and phosphatase inhibitors were added before use. Tumor lysates were then analyzed for ERK1 / 2 phosphorylation.

[0592] SW620 efficacy study:

[0593] 5×10 6 RKN cells / 200 μL PBS / Matrigel were implanted subcutaneously into the right flank of female NOD / SCID mice. After inoculation, when the tumor size reached approximately 150-250 mm 3 The mice were randomly divided into treatment groups when the mean volume of the tumor reached 1.5% MC. The randomized mice received the vehicle consisting of 0.5% MC or the test compound at different doses (e.g., 30, 50, or 100 mg / kg BID) by oral administration. The animals were monitored daily, and the tumor volume was determined twice a week using a vernier caliper in two dimensions and expressed in mm using the following formula: 3 Meaning: V = 0.5 (a × b 2 ), where a and b are the long and short diameters of the tumor, respectively. Partial regression (PR) was defined as a tumor volume less than 50% of the initial tumor volume on the first day of administration in three consecutive measurements, and complete regression (CR) was defined as a tumor volume less than 14 mm in three consecutive measurements. 3 Data are presented as mean tumor volume ± standard error of the mean (SEM). Tumor growth inhibition (TGI) was calculated using the following formula: Treatment t = treated tumor volume at time t Treatment t0 = treated tumor volume at time 0 Placebo t = Placebo tumor volume at time t Placebo t0 = Placebo tumor volume at time 0

[0594] AsPC-1PD Study:

[0595] 3×10 6 AsPC-1 cells / 200 μL PBS / Matrigel were implanted subcutaneously into the right flank of female BALB / c nude mice. After inoculation, when the tumor size reached approximately 350-450 mm 3 The mice were randomly divided into treatment groups when the average volume of MC was 0.5%. The randomized mice will receive a single dose of vehicle consisting of 0.5% MC or different doses (e.g., 30, 50, or 100 mg / kg) of the test compound by oral administration. Plasma was collected at 0.5, 2, 4, and 8 hours after administration, and tumors were collected at 4 and 8 hours to determine the exposure level. Tumor fragments were quickly frozen in homogenization tubes with liquid nitrogen, homogenized with T-PER tissue protein extraction buffer, and fresh protease and phosphatase inhibitors were added before use. Tumor lysates were then analyzed for ERK1 / 2 phosphorylation.

[0596] AsC-1 efficacy research:

[0597] 3×10 6 AsPC-1 cells / 200 μL PBS / Matrigel were implanted subcutaneously into the right flank of female BALB / c nude mice. After inoculation, when the tumor size reached approximately 150-250 mm 3 The mice were randomly divided into treatment groups when the mean volume of the tumor reached 1.5% MC. The randomized mice received the vehicle consisting of 0.5% MC or the test compound at different doses (e.g., 30, 50, or 100 mg / kg BID) by oral administration. The animals were monitored daily, and the tumor volume was determined twice a week in two dimensions using a vernier caliper and expressed in mm using the following formula: 3 Meaning: V = 0.5 (a × b 2 ), where a and b are the long and short diameters of the tumor, respectively. Partial regression (PR) was defined as a tumor volume less than 50% of the initial tumor volume on the first day of administration in three consecutive measurements, and complete regression (CR) was defined as a tumor volume less than 14 mm in three consecutive measurements. 3 Data are presented as mean tumor volume ± standard error of the mean (SEM). Tumor growth inhibition (TGI) was calculated using the following formula: Treatment t = treated tumor volume at time t Treatment t0 = treated tumor volume at time 0 Placebo t = Placebo tumor volume at time t Placebo t0 = Placebo tumor volume at time 0

[0598] hERG assay

[0599] hERG (human ether-à-go-go related gene) encodes a rapidly activated potassium channel (I Kr ), which helps repolarize the cardiac action potential. Blockade of hERG channels can lead to QT prolongation in the electrocardiogram, known as long QT syndrome. Drug-induced delay of ventricular repolarization may in some cases trigger a fatal arrhythmia, torsades de pointes. About 25%-40% of major pharmaceutical compounds exhibit varying degrees of potential risk of hERG dependence, and many drugs have been withdrawn from the market due to the risk of QT prolongation.

[0600] Before testing hERG current, the blank control was diluted with an appropriate volume of extracellular solution to prepare a control working solution. The positive control and test article stock solutions were taken out from -20°C, thawed and diluted with an appropriate volume of extracellular solution to prepare a working solution.

[0601] The highest concentration of the test article working solution will be diluted with the extracellular solution from the stock solution, or the stock solution should be diluted with DMSO first. For other tested concentrations of the test article, serial dilutions will be made with DMSO and then prepared into working solutions with the extracellular solution. The DMSO concentration in the final working solution will be 0.3%. The specific preparation information will be recorded in the compound working solution preparation sheet. Finally, all test article working solutions will be sonicated for 20 minutes before performing the patch clamp experiment.

[0602] The blank control (DMSO) stock solution will be kept at room temperature. The blank control working solution will be prepared on the day of testing and kept at room temperature. The positive control stock solution and the test article stock solution will be stored at -20°C. The positive control and test article working solutions will be prepared on the day of testing and kept at room temperature.

[0603] The test article concentration will be automatically set to 30, 10, 3, 1, and 0.3 μM. The blank control will be 0.3% DMSO, and the positive control (cisapride) concentration will be 1000, 100, 10, 1, 0.1 nM.

[0604] In this study, electrophysiological recordings will be performed using the automated patch clamp system QPatch 48X (Sophion).

[0605] The prepared cells are placed on the centrifuge of the Qpatch work surface, the cells are washed with multiple centrifugation / suspension, and the cell culture medium is replaced with the extracellular solution. The MTP-96 plate is removed and placed in the MTP source position. The QPlate chip is removed and placed in the Qplate source position. The barcode reader scans the barcodes of the MTP-96 plate and QPlate chip, and the gripper arm grabs them to the measurement position. The intracellular and extracellular solutions from the saline reservoir will be added to the intracellular saline wells, cells, and compound wells of the QPlate chip. For the measurement, all measurement points of the QPlate will be under initial quality control. The quality control process includes aspirating the cell suspension from the cell container of the centrifuge, positioning the cells on the chip wells through the pressure controller, establishing a high-resistance seal, and forming a whole-cell recording mode. Once a stable control current baseline is obtained, the test articles will be continuously aspirated from the MTP-96 plate in a concentration order and applied to the cells. hERG currents will be recorded using the whole-cell patch clamp technique at a holding potential of -80mV, followed by depolarization to -50mV for 0.5 seconds to test for leak current. The voltage will then be depolarized to 30mV for 2.5 seconds. Peak tail currents will be induced by a repolarization pulse to -50mV for 4 seconds. This protocol will be repeated at 10s intervals to observe the effect of the test article on the hERG tail current. Data will be collected by the QPatch Screening Station and stored in the QPatch Database Server.

[0606] In the experiment, each drug concentration will be applied twice, with a recording period of at least 5 min. The control solution and the test solution will be applied to the cells sequentially from low to high concentrations. The current of each cell detected in the extracellular solution without the compound will serve as its own blank control.

[0607] The IC will be calculated 50 values, and the dose-response curves were fitted using the above nonlinear regression equation, where IC 50 is half of the maximum inhibitory concentration. IC 50 Calculations and curve fitting will be performed using GraphPad Prism software. Active Table

[0608] Each of the compounds in Tables 2 and 3 was tested in one or more of the biochemical assays provided herein and was found to be active therein.

[0609] Table 2

[0610] Table 3

[0611] As shown by the data in Tables 2-3, the inventors surprisingly and unexpectedly discovered that the exemplary compounds in Tables 2-3 modulate or inhibit the activity of KRAS G12D and / or G12V.

[0612] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer, or prodrug thereof, in Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; The moiety B is an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocyclyl, or an unsubstituted or substituted C 2-5 alkyl; X is N or CR 8 ; W is O, NH, NR 9 , NC(=O)-R 10 Some O=S=O; Each R 0 are independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 Alkylamino, carboxyl, nitro, thiol or thioether; or one or more pairs of R 0 The groups, together with the atoms to which they are attached, form unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 Alkylamino, carboxyl, nitro, thiol or thioether; Optionally, R 3a and R 3b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 4a and R 4b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 6b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 7a and R 7b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 8a and R 8b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 6a and R 8a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached they form unsubstituted or substituted bridges; R 8 is H, halogen, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Haloalkyl, unsubstituted or substituted C 3-5 Halogenated cycloalkyl, unsubstituted or substituted C 1-4 Haloalkoxy, CN, OH or amino; R 9 is substituted or unsubstituted C 1-4 Alkyl or unsubstituted or substituted C 3-5 Cycloalkyl; R 10 is substituted or unsubstituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl or unsubstituted or substituted 3- to 5-membered heterocyclic group; t is 0 or 1; and m and q are each independently an integer between 0 and the maximum number of substituents permitted on rings A and B, respectively.

2. The compound of claim 1, wherein X is N, CH, C-Cl or C-CF3.

3. The compound of claim 2, wherein W is O or NH.

4. The compound of claim 3, wherein ring A is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzo[b]thienyl, or substituted or unsubstituted benzo[d]thiazolyl; and moiety B is substituted or unsubstituted hexahydro-1H-pyrrolizinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted aminomethylcyclopropyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted oxabicyclo[2.1.1]hexanyl, substituted or unsubstituted oxabicyclo[2.2.1]heptanyl.

5. The compound as claimed in claim 3, wherein ring A is 6. The compound of claim 5, wherein part B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy or C 1-4 Alkoxy-C(O)-.

7. The compound of claim 6, wherein the bridge is -(CH2)2-, -(CH2)3-, or -CH2-O-CH2-.

8. The compound of claim 7, wherein t is 0; X is N; Ring A is Part B is and W is O or NH.

9. The compound of claim 7, wherein t is 0; X is N; Ring A is Part B is and W is O or NH.

10. The compound of claim 7, wherein t is 0; X is N; Ring A is and part B is and W is O or NH.

11. The compound of claim 7, wherein t is 0; X is N; Ring A is W is O or NH; or part B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N-, O- or S-containing heterocyclic ring.

12. The compound of claim 7, wherein t is 0; X is N; Ring A is W is O or NH; and the moiety B is 13. The compound of claim 7, wherein t is 0; X is CH; Ring A is W is O or NH; and the moiety B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N-, O- or S-containing heterocyclic ring.

14. The compound of claim 7, wherein t is 0; X is CH; Ring A is W is O or NH; and the moiety B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N-, O- or S-containing heterocyclic ring.

15. The compound of claim 7, wherein t is 0; X is C-Cl; Ring A is W is O or NH; and the moiety B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N-, O- or S-containing heterocyclic ring.

16. The compound of claim 7, wherein t is 0; X is C-Cl; Ring A is W is O or NH; and the moiety B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

17. The compound of claim 7, wherein t is 1; X is N; Ring A is W is O or NH; and the moiety B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

18. The compound of claim 7, wherein t is 1; X is N; Ring A is W is O or NH; and the moiety B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

19. The compound of claim 7, wherein t is 1; X is CH; Ring A is W is O or NH; and the moiety B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

20. The compound of claim 7, wherein t is 1; X is C-Cl; Ring A is W is O or NH; and the moiety B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

21. The compound of claim 7, wherein R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 6a and R 8a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge; and the bridge is -(CH2)2-, -(CH2)3- or -CH2-O-CH2-.

22. The compound of claim 21, wherein t is 0; X is N; Ring A is and part B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

23. The compound of claim 22, wherein R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge; and the bridge is -(CH2)2-, -(CH2)3- or -CH2-O-CH2-.

24. The compound of claim 21, wherein t is 0; X is N; Ring A is and part B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

25. The compound of claim 24, wherein R 6a and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge; and the bridge is -(CH2)2-, -(CH2)3- or -CH2-O-CH2-.

26. The compound of claim 21, wherein t is 0; X is C-Cl; Ring A is and part B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

27. The compound of claim 26, wherein R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge; and the bridge is -(CH2)2-, -(CH2)3- or -CH2-O-CH2-.

28. The compound of claim 21, wherein t is 1; X is N; Ring A is and part B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

29. The compound of claim 28, wherein R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge; and the bridge is -(CH2)2-, -(CH2)3- or -CH2-O-CH2-.

30. The compound of claim 21, wherein t is 1; X is N; Ring A is and part B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy.

31. The compound of claim 30, wherein R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached, they form an unsubstituted or substituted bridge; and the bridge is -(CH2)2-, -(CH2)3- or -CH2-O-CH2-.

32. The compound of claim 3, wherein the compound has one of the following formulas: or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopomer, or prodrug thereof, in: Ring C is unsubstituted or substituted C 3-6 Cycloalkyl or unsubstituted or substituted 3- to 6-membered heterocyclic group.

33. The compound of claim 32, wherein ring C contains Y and is replaced by R a Substituted, wherein Y is CH2, O, NH, NR 9 、NC(=O)-R 10 Or O = S = O; R 9 is substituted or unsubstituted C 1-4 Alkyl or unsubstituted or substituted C 3-5 Cycloalkyl; R 10 is substituted or unsubstituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl or unsubstituted or substituted 3- to 5-membered heterocyclyl; and R a is H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy or unsubstituted or substituted C 1-4 Alkylamino.

34. The compound of claim 33, wherein Y is CH2, O or NH.

35. The compound of claim 33, wherein R 6a and R 7a Together they form a bridge, and the bridge is -CH2-CH2-.

36. The compound of claim 33, wherein R 5 and R 8a Together they form a bridge, and the bridge is -CH2-CH2-.

37. The compound of claim 33, wherein Ring C is cyclopropyl or cyclobutyl.

38. The compound of claim 33, wherein Ring C is oxetanyl.

39. A compound having formula (II): or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer, or prodrug thereof, in Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; The moiety B is an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocyclyl, or an unsubstituted or substituted C 2-5 alkyl; X is N or CR 8 ; W is O, NH, NR 9 , NC(=O)-R 10 Some O=S=O; Each R 0 are independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 Alkylamino, carboxyl, nitro, thiol or thioether; or one or more pairs of R 0 The groups, together with the atoms to which they are attached, form unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclic group, unsubstituted or substituted C 1-4 Alkylamino, carboxyl, nitro, thiol or thioether; Optionally, R 3a and R 3b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 4a and R 4b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 6b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 7a and R 7b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 8a and R 8b together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl; or R 6a and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 6a and R 8a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 7a Together with the atoms to which they are attached, form an unsubstituted or substituted bridge; or R 5 and R 8a Together with the atoms to which they are attached they form unsubstituted or substituted bridges; R 8 is H, halogen, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Haloalkyl, unsubstituted or substituted C 3-5 Halogenated cycloalkyl, unsubstituted or substituted C 1-4 Haloalkoxy, CN, OH or amino; R 9 is substituted or unsubstituted C 1-4 Alkyl or unsubstituted or substituted C 3-5 Cycloalkyl; R 10 is substituted or unsubstituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl or unsubstituted or substituted 3- to 5-membered heterocyclic group; t is 0 or 1; s and r are each independently 1 or 2; and m and q are each independently an integer between 0 and the maximum number of substituents permitted on rings A and B, respectively.

40. The compound of claim 39, wherein the compound has formula (IIf): or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer, or prodrug thereof, wherein X is N or CH; W is O or NH; Ring A is Part B is and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a1 , R 8b1 , R 8a2 , and R 8b2 are each independently H, OH, CN, unsubstituted or substituted amino or unsubstituted or substituted C 1-4 alkyl.

41. The compound of claim 39, wherein the compound has formula (IIg): or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer, or prodrug thereof, wherein X is N or CH; W is O or NH; Ring A is Part B is and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b are each independently H, OH, CN, unsubstituted or substituted amino or unsubstituted or substituted C 1-4 alkyl.

42. The compound of claim 39, wherein the compound has formula (IIh): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopomer, or prodrug thereof, Where R 11 is deuterium or substituted or unsubstituted C 1-3 Alkyl; and u is 0, 1, 2, 3, 4, or 5.

43. The compound of claim 42, wherein Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted pyridin-4-yl.

44. The compound of claim 42, wherein Ring A is Where R 12 is H, halogen, substituted or unsubstituted C 1-3 alkyl or cyclopropyl optionally substituted with F; and R 12a is H, deuterium, F or Me.

45. The compound of claim 42, wherein Ring A is 46. ​​The compound of claim 44, wherein moiety B is an unsubstituted or substituted heterocyclic radical, wherein the heterocyclic radical does not contain a secondary or tertiary amine and comprises at least one oxygen as a ring member.

47. The compound of claim 44, wherein part B is Where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted N, O or S-containing heterocyclic ring; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxy or C 1-4 Alkoxy-C(O)-.

48. The compound of claim 44, wherein moiety B is 49. The compound of claim 44, wherein moiety B is oxabicyclo[2.1.1]hexane, optionally substituted with halogen, cyano, hydroxyl, C 1-3 Alkoxy or optionally halogen, cyano, hydroxy or C 1-3 Alkoxy substituted C 1-3 Alkyl substitution.

50. The compound of claim 44, wherein moiety B is or 2-oxabicyclo[2.1.1]hexan-4-yl.

51. The compound of claim 44, wherein moiety B is 52. The compound of any one of claims 1-51, wherein the compound is selected from Table 1-Table 3.

53. A pharmaceutical composition comprising an effective amount of a compound as described in any one of claims 1 to 51 or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer or prodrug thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

54. A method for inhibiting the activity of a KRAS mutant protein in a cell, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer or prodrug thereof, optionally wherein the KRAS mutant protein is a KRAS G12D and / or G12V mutant protein.

55. A method for treating or preventing cancer, the method comprising administering to a subject in need thereof an effective amount of a compound as described in any one of claims 1-51 or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer or prodrug contact thereof, optionally wherein the cancer is mediated by KRAS mutations, preferably KRAS G12D and / or G12V mutations.

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