Heterocyclic compounds, compositions thereof, and methods of treatment thereof

Abstract

Provided herein are compounds having the following structure: wherein the substituents are as defined herein; compositions comprising an effective amount of a compound; and a method 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 the compounds, and methods of using the compounds to treat cancer or disorders that can be treated or prevented 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 associated with the cell membrane through its C-terminal membrane targeting region, and is well known as a molecular switch in the intracellular signaling network (Cox AD, Der CJ. Ras history: The saga continues. Small GTPases. 2010; 1 (1): 2-27). Ras protein binds to GTP or GDP and switches between "on" and "off" states. When Ras protein binds to GDP, it is in a closed (or inactive) state. And when Ras is turned on by certain growth-promoting stimulants such as growth factors, Ras protein will be induced to exchange its bound GDP for GTP and become an open (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 activated state, Ras proteins can interact with different downstream proteins and activate related signaling 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 (Pt 5): 843-846). HRas, NRas, and KRas are the most studied proteins in the Ras family because these proteins are the most common oncogenes in human cancer (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 common 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.Pharmacol Res.2019; 139: 503-511). By blocking the GTP hydrolysis activity stimulated by the GTPase activating protein (GAP) of KRas, the most common KRas mutations were found at positions G12 and G13 (Wang W, Fang G, Rudolph J.Ras inhibition via direct Ras binding--is there a path forward?. Bioorg Med Chem Lett.2012; 22 (18): 5766-5776). This leads to overactivation of KRas protein, and ultimately leads to uncontrolled cell proliferation and cancer.

[0004] Among different cancers, pancreatic cancer is considered to be the most KRas-dependent cancer type. KRas mutations were 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 by mouse models have shown that the progression and maintenance of pancreatic cancer is highly dependent on the constitutive activation of KRas downstream signals (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 attractive drug targets for pancreatic cancer and other cancers with KRas mutations. Since WT KRas proteins also play a key role in the function of normal tissues, and WT KRas function has been shown to be necessary for adult hematopoiesis (Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003; 3(6): 459-465), it is very worthwhile to find a potential drug molecule that can selectively inhibit mutant Kras proteins in cancer cells and retain their WT partners in normal cells.

[0005] Therefore, KRas G12D and G12V mutations are highly 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 (I):

[0008]

[0009] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof, wherein the substituents are as defined herein.

[0010] In one embodiment, the compound is selected from Table 1 to Table 3.

[0011] In one embodiment, provided herein is a method for inhibiting the activity of a KRAS mutant protein or KRAS amplification 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.

[0012] 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

[0013] definition

[0014] 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.

[0015] As used herein, "KRAS protein" refers to a protein expressed by the KRAS gene or an isoform thereof (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).

[0016] 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.

[0017] As used herein, "KRAS G12D" or "G12D" refers to a KRAS protein having a G12D mutation.

[0018] 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.

[0019] As used herein, "KRAS G12V" or "G12V" refers to a KRAS protein having a G12V mutation.

[0020] As used herein, "KRAS amplification" or "KRAS gene amplification" refers to a genetic alteration that increases the number of copies of the KRAS gene in some cancer cells. This can lead to higher expression and activity of the KRAS protein, which is involved in cell growth and survival. KRAS amplification is present in some types of cancer, such as lung cancer, breast cancer, esophageal cancer, ovarian cancer, and testicular cancer.

[0021] As used herein and in the specification and 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.

[0022] As used herein, and unless otherwise indicated, the terms "about" and "approximately" when used in conjunction with the dose, amount, or weight percentage of an ingredient of a composition or dosage form, mean a dose, amount, or weight percentage that one of ordinary skill in the art considers to provide a pharmacological effect equivalent to that obtained from a specified dose, amount, or weight percentage. In certain embodiments, the terms "about" and "approximately" when used herein encompass doses, amounts, or weight percentages within 30%, 20%, 15%, 10%, or 5% of a specified dose, amount, or weight percentage.

[0023] As used herein and unless otherwise indicated, the terms "about" and "approximately" when used in connection with a value or range of values ​​provided to characterize a particular solid form, e.g., a particular temperature or temperature range, such as describing melting, dehydration, desolvation, or glass transition temperature; a change in mass, such as a change in mass as a function of temperature or humidity; solvent or water content, e.g., in mass or percentage; or peak position, such as in analysis by, e.g., IR or Raman spectroscopy or XRPD; indicate that the value or range of values ​​may deviate to an extent that is considered 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, 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 ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. For example, in some embodiments, the value of an XRPD peak position may vary by as much as ±0.2° 2Θ (or ±0.2 degrees 2Θ) while still describing a specific XRPD peak.

[0024] An "alkyl" group is a saturated, partially saturated or unsaturated straight or branched acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbons, 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 referred to as "substituted," they may be substituted with any one or more substituents, such as those present in the exemplary compounds and embodiments disclosed herein, as well as 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; arylalkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0025] "Alkenyl" group is a straight or branched non-cyclic hydrocarbon with 2 to 10 carbon atoms, typically 2 to 8 carbon atoms and including at least one carbon-carbon double bond.Representative straight and branched (C2C8) alkenyl includes-vinyl,-allyl,-1-butenyl,-2-butenyl,-isobutenyl,-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 can be non-conjugated, or conjugated with another unsaturated group.Alkenyl can be unsubstituted or substituted.

[0026] 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 may be straight-chain, branched, or cyclic. Alkynyl groups include, but are not limited to, groups having 2-20 carbon atoms (i.e., C2-20 Alkynyl), 2-12 carbon atoms (i.e., C 2-12 Alkynyl), 2-8 carbon atoms (i.e., C 2-8 Alkynyl), 2-6 carbon atoms (i.e., C 2-6 Alkynyl) and 2-4 carbon atoms (i.e., C 2-4 Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and butynyl.

[0027] "Cycloalkyl" group is a saturated, partially saturated or unsaturated cyclic alkyl group with 3 to 10 carbon atoms of a monocyclic or multiple condensed or bridged rings, which can be optionally substituted by 1 to 3 alkyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, and in other embodiments, the number of ring carbon atoms is in the range of 3 to 5, 3 to 6 or 3 to 7. The cycloalkyl containing more than one ring can be fused, spirocyclic or bridged, or a combination thereof. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or 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. Such substituted cycloalkyl groups include, for example, cyclohexanol, etc.

[0028] "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 "bridgeheads". In addition to the bridge, the two bridgeheads 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. Examples include, but are not limited to, 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.

[0029] "Aryl" groups are aromatic carbocyclic groups of 6 to 14 carbon atoms with a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthracenyl). In some embodiments, the aryl group contains 6-14 carbons, and in other embodiments, the ring portion of the aryl group contains 6 to 12 or even 6 to 10 carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl, etc. The aryl group may be substituted or unsubstituted. The phrase "aryl group" also includes groups containing condensed rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0030] "Heterocyclyl" is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl group in which one to four ring carbon atoms are independently substituted 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 may also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). The heterocyclyl group may be substituted or unsubstituted. The heterocyclyl group may include multiple fused rings, including but not limited to bicyclic, tricyclic and tetracyclic, and bridged or spirocyclic systems. The heterocyclyl group includes unsaturated, partially saturated and saturated ring systems, such as imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-diketo). The phrase heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as 1-aminotetralin 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, tetrahydrothienyl, 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, oxadiazolyl, pyrrolidyl, 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, oxadiazolyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, oxadiazolyl, pyrrolidyl, pyrrolidyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, linyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiolanyl, dioxy, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithienyl, dihydrodisulfide, 1,4-dioxaspiro[4.5]decyl, 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, quinolyl, indolyl (e.g., indolyl-2-one or isoindolyl-1-one), indolyl, 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][1,2,3]triazolyl), 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazolyl-2(3H)-nonyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazininyl, benzodithiazinyl, benzothiazinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolanyl, pyrazolopyridinyl (e.g., 1H-pyrazolo[ 3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), imidazopyridinyl (e.g., azobenzimidazolyl or 1H-imidazo[4,5-b]pyridinyl), triazolopyridinyl, isoxazolopyridinyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolyl, isoquinolyl (e.g., 3,4-dihydroisoquinolin-1(2H)-one), quinolizinyl, quinoxalinyl, quinoline Representative non-aromatic heterocyclyl groups include oxazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thienyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolinyl, dihydrobenzodioxazinyl, tetrahydroindolinyl, 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 aziridine, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidinyl-4-one or imidazolidinyl-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiolanyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be monosubstituted or substituted more than once, such as, but not limited to, pyridinyl or morpholinyl, 2-substituted, 3-substituted, 4-substituted, 5-substituted, or 6-substituted, or disubstituted with various substituents, such as those listed below. .

[0031] 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 the ring portion of the group, and in other embodiments contains 6 to 9 or even 6 to 10 atoms. 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) ), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thionaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolyl, isoquinolyl (e.g., 3,4-dihydroisoquinolin-1(2H)-one), tetrahydroquinolyl, quinoxalinyl, and quinazolinyl.

[0032] As used herein, "spirocycle" refers to two or more rings in which adjacent rings are connected by a single atom. The individual rings within a spirocycle may be identical or different. Each ring in a spirocycle may be substituted or unsubstituted and may have a substituent that is different from that of the other individual rings within a set of spirocycles.

[0033] A "cycloalkylalkyl" group is a group of the formula: -alkyl-cycloalkyl, wherein the alkyl and cycloalkyl groups are as defined above. Substituted cycloalkylalkyl groups may be substituted at the alkyl, cycloalkyl, or both the 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, and the like.

[0034] An "aralkyl" group is a group of the formula: -alkyl-aryl, wherein the alkyl and aryl groups are as defined above. Substituted aralkyl groups may be substituted at 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.

[0035] A "heterocyclylalkyl" group is a group of the formula: -alkyl-heterocyclyl, wherein the alkyl and heterocyclyl groups are defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, heterocyclyl, or both alkyl and heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0036] "Halogen" is fluorine, chlorine, bromine or iodine.

[0037] A "hydroxyalkyl" group is an alkyl group as described above substituted with one or more hydroxy groups.

[0038] An "alkoxy" or "alkoxyl" group is an -O-(alkyl) group, wherein alkyl is as defined above.

[0039] An "alkoxyalkyl" group is a -(alkyl)-O-(alkyl) where alkyl is as defined above.

[0040] An "amino" group is a group of the formula: -NH2.

[0041] An "alkylamino" group is a group of the formula: -NH-alkyl or -N(alkyl)2 wherein each alkyl group is independently as defined above.

[0042] A "carboxy" group is a group of the formula: -C(O)OH.

[0043] An "aminocarbonyl" group is a group of the formula: -C(O)N(R # )2、-C(O)NH(R # ) or -C(O)NH2, where each R # and R is independently substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclic as defined herein.

[0044] An "acylamino" group is a group of the formula: -NHC(O)(R # ) or -N(alkyl)C(O)(R # ), wherein each alkyl group and R # Independently as defined above.

[0045] A "sulfonylamino" group is a group of the formula: -NHSO2(R # ) or -N(alkyl)SO2(R # ), wherein each alkyl group and R # As defined above.

[0046] A "urea" group is a group of 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.

[0047] When groups described herein (except alkyl) 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 embodiments 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; acylamino; phosphonato; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; 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 a monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or a heterocyclic group, which may be a monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl); a 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, pyridyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0048] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base (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 edition, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing, Easton PA (1995).

[0049] Unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" as used herein means that one stereoisomer of a compound is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound with one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound with two chiral centers is substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains 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. Compounds may have chiral centers and may appear as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included in the embodiments disclosed herein, including mixtures thereof.

[0050] The use of stereoisomerically pure forms of such compounds and the use of mixtures of these forms are encompassed in the embodiments disclosed herein. For example, a mixture of enantiomers of a particular compound containing equal or unequal amounts can be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or split using standard techniques such as chiral columns or chiral splitting agents. See, for example, 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, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (ELEliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0051] 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 separated into E or Z isomers. In other embodiments, the compound is a mixture of E and Z isomers.

[0052] As used herein and unless otherwise indicated, "atropisomer" refers to a stereoisomer resulting from hindered rotation about a single bond axis, where the barrier to rotation is sufficiently high to allow separation of the individual rotamers.

[0053] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is located, and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0054]

[0055] As will be readily appreciated by those skilled in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of Formula (I) are within the scope of the present invention.

[0056] It should also be noted that a compound may contain unnatural proportions of atomic isotopes at one or more of its atoms. For example, a compound may contain an isotope such as tritium ( 3 H), iodine-125 ( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 C), or can be radiolabeled with a radioactive isotope such as deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15 N) isotopically enriched. As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom, wherein the atom has an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled and isotopically enriched compounds can be used as therapeutic agents (e.g., cancer and inflammatory therapeutic agents), research reagents (e.g., combined with assay reagents) and diagnostic agents (e.g., in vivo imaging agents). All isotopic variations of compounds as described herein (whether or not radioactive) are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, an isotopologue of a compound is provided, for example, an isotopologue is a deuterium, carbon-13, or nitrogen-15 enriched compound.

[0057] As used herein, "treating" refers to the complete or partial relief of a condition, disease or disorder, or one or more symptoms associated with a condition, disease or disorder, or slowing or stopping the further progression or worsening of those symptoms, or alleviating or eradicating the cause of the condition, disease or disorder itself. In some embodiments, "treating" means the complete or partial relief of a condition, disease or disorder, or slowing or stopping the further progression or worsening of those symptoms. In another embodiment, "treating" means the complete or partial relief of a condition, disease or disorder, or symptoms associated with a condition, wherein the condition can be treated or prevented by inhibiting KRAS, preferably G12D and / or G12V.

[0058] As used herein, "prevention" means a method of completely or partially delaying and / or hindering the onset, recurrence or spread of a disorder, disease or condition; a method of preventing a subject from developing a disorder, disease or condition; or a method of reducing 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.

[0059] The term "effective amount" with respect to a compound refers to an amount capable of treating or preventing a condition, disease or disorder disclosed herein, or a symptom thereof.

[0060] 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, in one embodiment mammals, in another embodiment humans.

[0061] Compound

[0062] Aspect 1: Provided herein are compounds having the following formula (I):

[0063]

[0064] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof,

[0065] in:

[0066] Ring A is an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group;

[0067] Ring B is an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclic group;

[0068] X is N or CR 8 ;

[0069] Each R 0 are independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C1-4 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 an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocyclyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl;

[0070] R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a and R 7b Each of the following is independently H, halogen, unsubstituted or substituted 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, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 4a and R 4b Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 6a and R 6b Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 7a and R 7b Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or optionally, R 3a and R 4a Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 4a and R 5 Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 5 and R6a Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 6a and R 7a together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl;

[0071] 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 Alkyl halides, unsubstituted or substituted C 3-5 Halogenated cycloalkyl, unsubstituted or substituted C 1-4 Halogenated alkoxy, CN, OH or amino;

[0072] t is 0 or 1;

[0073] u is 1, 2, 3, or 4; and

[0074] Each of m and q is independently an integer between 0 and the maximum number of substituent groups permitted on rings A and B, respectively; and

[0075] When u is 2, 3, or 4, each R 6a are independent of each other; and each R 6b Independent of each other.

[0076] 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.

[0077] In one embodiment, when u is 2, 3 or 4, R 6a and R 6b Two of the groups may form a ring or a spiro ring.

[0078] Aspect 2:

[0079] 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 substituents are F, Cl, Br, amino, -CN, OH, -CF3, -CHF2, -CH2F, -CF2CH3, -CF2CF3, -OCHF2, -OCF3, vinyl (-CH=CH), propylene (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, propylene, 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), propylene (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, propylene, allyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy.

[0080] In one embodiment, ring A is a 5- to 7-membered monocyclic heteroaryl or 8- to 12-membered bicyclic heteroaryl group optionally substituted with one or more substituents. In some preferred embodiments, ring A is pyridyl, benzothiazolyl, quinolyl, isoquinolyl, pyrazolopyridinyl, 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.

[0081] In one embodiment, Ring A is

[0082] In one embodiment, Ring A is

[0083] In one embodiment, Ring A is

[0084] In one embodiment, Ring A is

[0085] Aspect 3:

[0086] In one embodiment, Ring B is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl. In one embodiment, the heterocyclyl comprises at least one oxygen as a ring member. In one embodiment, the heterocyclyl comprises at least one nitrogen as a ring member.

[0087] In one embodiment, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 9-membered heterocycle comprising one or two or three nitrogen atoms as ring members. In one embodiment, ring 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 ring B is optionally substituted. In one embodiment, ring 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 ring B is optionally substituted. In one embodiment, ring B is optionally substituted with halogen, cyano, hydroxy, alkoxy, or alkyl optionally substituted with halogen, cyano, hydroxy, alkoxy, heterocyclyl, cycloalkyl or cycloalkoxy.

[0088] In one embodiment, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 9-membered heterocyclic ring containing one or two or three nitrogen atoms as ring members, an 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 1-8 Alkoxy-C 1-8alkyl-, 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.

[0089] In one embodiment, Ring B is

[0090] In one embodiment, Ring 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 Ring B is optionally substituted.

[0091] In one embodiment, Ring B is optionally substituted with halogen, cyano, hydroxy, alkoxy, or alkyl optionally substituted with halogen, cyano, hydroxy or alkoxy.

[0092] In one embodiment, Ring B is

[0093]

[0094] In one embodiment, Ring 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 Ring B is optionally substituted.

[0095] In one embodiment, Ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or azetidinyl; and Ring B is optionally substituted.

[0096] In one embodiment, Ring B is

[0097] In one embodiment, Ring B is

[0098] In one embodiment, Ring B is

[0099] Aspect 4:

[0100] 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.

[0101] In one embodiment, Ring A is

[0102] In one embodiment, Ring A is

[0103] Aspect 5:

[0104] In one embodiment, Ring 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.

[0105] In one embodiment, Ring B is

[0106] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0107] 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.

[0108] In one embodiment, Ring B is In one embodiment, Ring B is In one embodiment, Ring B is In one embodiment, Ring B is In one embodiment, Ring B is In one embodiment, Ring B is In one embodiment, Ring B is In one embodiment, Ring B is In one embodiment, Ring B is

[0109] Aspect 6:

[0110] 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.

[0111] Aspect 7:

[0112] Group 1: In one embodiment, t is 0.

[0113] Group 1.1: In one embodiment, u is 1. In one embodiment, the compound is a compound having formula (II):

[0114]

[0115] In one embodiment, R 3a , R 3b , R 5 , R 7a and R 7b Each of R is independently H or methyl, and R 6a1 , R 6b1 Independently selected from H, halogen, methyl, -CN, -OH, substituted or unsubstituted amino.

[0116] In one embodiment, Ring B is

[0117] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0118] 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; and R 3a , R 3b , R 5 , R7a and R 7b Each of R is independently H or methyl, and R 6a1 , R 6b1 Independently selected from H, halogen, methyl, -CN, -OH, substituted or unsubstituted amino.

[0119] Group 1.1.1: In one embodiment, X is N.

[0120] In one embodiment, Ring A is And ring B is

[0121] Group 1.1.1.1: In one embodiment, Ring A is

[0122] In one embodiment, Ring B is

[0123] Group 1.1.1.1.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0124] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of which is independently H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of the 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of R is independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. 3a , R 3b , R 5 , R 6a1 , R 6b1 , R7a and R 7b Each of R is independently H, methyl or ethyl, optionally substituted with OH, CN, amino or methylamino. 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of is independently H or methyl.

[0125] In one embodiment, the compound is

[0126] In one embodiment, R 6a1 and R 6b1 Together with the atoms to which they are attached, they form an unsubstituted or substituted heterocyclyl. In one embodiment, the heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or dioxane. In one embodiment, the heterocyclyl is oxetanyl or tetrahydrofuranyl. In one embodiment, the heterocyclyl is oxetanyl. In one embodiment, the heterocyclyl is tetrahydrofuranyl.

[0127] In one embodiment, the compound is

[0128] Group 1.1.1.4: In one embodiment, Ring A is

[0129] In one embodiment, R 3a , R 3b , R 5 , R 7a and R 7b Each of R is independently H or methyl, and R 6a1 , R 6b1 Independently selected from H, halogen, methyl, -CN, -OH, substituted or unsubstituted amino.

[0130] In one embodiment, Ring A is Ring B is

[0131] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0132] 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; and R 3a , R 3b , R 5 , R 7a and R 7b Each of R is independently H or methyl, and R 6a1 , R 6b1 Independently selected from H, halogen, methyl, -CN, -OH, substituted or unsubstituted amino.

[0133] In one embodiment, Ring B is

[0134] Group 1.1.1.4.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0135] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of which is independently H, OH, CN, amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of the 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of R is independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 7a and R 7bEach of R is independently H, methyl or ethyl, optionally substituted with OH, CN, amino or methylamino. 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of is independently H or methyl.

[0136] In one embodiment, the compound is

[0137] Group 1.2: In one embodiment, u is 2. In one embodiment, the compound is a compound having formula (III):

[0138]

[0139] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of R is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl, or optionally, R 3a and R 5 Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 6a1 and R 5 Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 6a1 and R 6a2 Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 6a2 and R 7a Together with the atoms to which they are attached they form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl.

[0140] In one embodiment, Ring B is

[0141] Where R a and R b Each of which is independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5Cycloalkyl; or R a and R b Together with the N to which they are attached, they form a substituted or unsubstituted heterocyclic ring containing N, O or S; and

[0142] 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0143] Group 1.2.1: In one embodiment, X is N.

[0144] In one embodiment, Ring A is And ring B is

[0145] Group 1.2.1.1: In one embodiment, Ring A is

[0146] In one embodiment, Ring B is

[0147] Group 1.2.1.1.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0148] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0149] In one embodiment, the compound is

[0150] Group 1.2.1.4: In one embodiment, Ring A is

[0151] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0152] In one embodiment, Ring A is Ring B is

[0153] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0154] 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; and R 3a, R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0155] In one embodiment, Ring B is

[0156] Group 1.2.1.4.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0157] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0158] In one embodiment, the compound is

[0159] Group 1.2.2: In one embodiment, X is CH.

[0160] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0161] In one embodiment, Ring A is Ring B is

[0162] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0163] 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0164] In one embodiment, Ring A is And ring B is

[0165] Group 1.2.2.4: In one embodiment, Ring A is

[0166] In one embodiment, Ring B is

[0167] Group 1.2.2.4.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0168] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0169] In one embodiment, the compound is

[0170] In one embodiment, R 6a2 and R 7a Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl. 6a2 and R 7a Together with the atoms to which they are attached, they form unsubstituted or substituted C 3-6 Cycloalkyl, for example to form a fused cyclopropyl, cyclobutyl or cyclopentyl. In one embodiment, the compound is

[0171] Group 1.2.2.6: In one embodiment, Ring A is

[0172] In one embodiment, R 3a , R3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0173] In one embodiment, Ring A is Ring B is

[0174] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0175] 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0176] In one embodiment, Ring B is

[0177] Group 1.2.2.6.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0178] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0179] In one embodiment, the compound is

[0180] Group 1.2.3: In one embodiment, X is CF.

[0181] In one embodiment, Ring A is And ring B is

[0182] Group 1.2.3.4: In one embodiment, Ring A is

[0183] In one embodiment, Ring B is

[0184] Group 1.2.3.4.3: In one embodiment, Ring B is

[0185] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0186] R cis H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 In one embodiment, ring B is

[0187] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0188] In one embodiment, the compound is

[0189] Group 1.2.4: In one embodiment, X is C-Cl.

[0190] In one embodiment, Ring A is And ring B is

[0191] Group 1.2.4.2: In one embodiment, Ring A is

[0192] In one embodiment, Ring B is

[0193] Group 1.2.4.2.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0194] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0195] In one embodiment, the compound is

[0196] Group 1.2.4.6: In one embodiment, Ring A is

[0197] In one embodiment, Ring B is

[0198] Group 1.2.4.6.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0199] In one embodiment, R 3a , R 3b , R 5 , R6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0200] In one embodiment, the compound is

[0201] Group 1.2.5: In one embodiment, X is C-CF3.

[0202] Group 1.2.5.6: In one embodiment, Ring A is

[0203] In one embodiment, Ring B is

[0204] Group 1.2.5.6.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0205] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7bEach of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0206] In one embodiment, the compound is

[0207] Group 1.3: In one embodiment, u is 3. In one embodiment, the compound is a compound having formula (IV):

[0208]

[0209] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0210] In one embodiment, Ring B is

[0211] Where R a and R b Each of which is independently substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl; or Ra and R b Together with the N to which they are attached, they form a substituted or unsubstituted heterocyclic ring containing N, O or S; and

[0212] 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0213] Group 1.3.1: In one embodiment, X is N.

[0214] In one embodiment, Ring A is And ring B is

[0215] Group 1.3.1.1: In one embodiment, Ring A is

[0216] In one embodiment, Ring B is

[0217] Group 1.3.1.1.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0218] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, hydroxymethyl or methyl.

[0219] In one embodiment, the compound is

[0220]

[0221] Group 1.3.1.4: In one embodiment, Ring A is

[0222] In one embodiment, Ring B is

[0223] Group 1.3.1.4.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0224] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0225] In one embodiment, the compound is

[0226] Group 1.3.4: In one embodiment, X is C-Cl.

[0227] In one embodiment, Ring A is And ring B is

[0228] Group 1.3.4.6: In one embodiment, Ring A is

[0229] In one embodiment, Ring B is

[0230] Group 1.3.4.6.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0231] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0232] In one embodiment, the compound is

[0233] Group 1.3.4.7: In one embodiment, Ring A is

[0234] Group 1.3.4.7.3: In one embodiment, Ring B is

[0235] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0236] In one embodiment, the compound is

[0237] Group 1.3.4.7.6: In one embodiment, Ring B is

[0238] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0239] In one embodiment, the compound is

[0240] Group 1.4: In one embodiment, u is 4. In one embodiment, the compound is a compound having formula (V):

[0241]

[0242] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0243] In one embodiment, Ring B is

[0244] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0245] 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2, R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0246] Group 1.4.1: In one embodiment, X is N.

[0247] In one embodiment, Ring A is And ring B is

[0248] Group 1.4.1.1: In one embodiment, Ring A is

[0249] In one embodiment, Ring B is

[0250] Group 1.4.1.1.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0251] In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of the following is independently H, halogen, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0252] In one embodiment, the compound is

[0253] Aspect 8:

[0254] Group 2: In one embodiment, t is 1.

[0255] Group 2.1: In one embodiment, u is 1. In one embodiment, the compound is a compound having formula (VI):

[0256]

[0257] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0258] In one embodiment, Ring B is

[0259] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0260] R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C3-5 Cycloalkyl, substituted or unsubstituted C 1-4 alkoxy; and

[0261] R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0262] Group 2.1.1: In one embodiment, X is N.

[0263] In one embodiment, Ring B is

[0264] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0265] 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.

[0266] In one embodiment, Ring A is And ring B is

[0267] Group 2.1.1.1: In one embodiment, Ring A is

[0268] In one embodiment, Ring B is

[0269] Group 2.1.1.1.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0270] In one embodiment, R 3a , R 3b , R4a , R 4b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of the following is independently H, halogen, 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 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0271] In one embodiment, the compound is

[0272] Group 2.2: In one embodiment, u is 2. In one embodiment, the compound is a compound having formula (VII):

[0273]

[0274] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0275] In one embodiment, Ring B is

[0276] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0277] 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; and

[0278] R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0279] Group 2.2.1: In one embodiment, X is N.

[0280] In one embodiment, Ring B is

[0281] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0282] 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.

[0283] In one embodiment, Ring A is And ring B is

[0284] Group 2.2.1.1: In one embodiment, Ring A is

[0285] In one embodiment, Ring B is

[0286] Group 2.2.1.1.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0287] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, 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 and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, hydroxymethyl or methyl.

[0288] In one embodiment, the compound is

[0289] Group 2.2.1.1.3:In one embodiment, Ring B is

[0290] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, 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 and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0291] In one embodiment, the compound is

[0292] Group 2.2.1.2: In one embodiment, Ring A is

[0293] In one embodiment, Ring B is

[0294] Group 2.2.1.2.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0295] In one embodiment, R3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, 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 and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0296] In one embodiment, the compound is

[0297] Group 2.2.2: In one embodiment, X is CH.

[0298] In one embodiment, Ring B is

[0299] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0300] 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.

[0301] In one embodiment, Ring A is And ring B is

[0302] Group 2.2.2.4: In one embodiment, Ring A is

[0303] In one embodiment, Ring B is

[0304] Group 2.2.2.4.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0305] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, 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 and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0306] In one embodiment, the compound is

[0307] Group 2.2.2.6: In one embodiment, Ring A is

[0308] In one embodiment, Ring B is

[0309] Group 2.2.2.6.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0310] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, 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 and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0311] In one embodiment, the compound is

[0312] Group 2.2.4: In one embodiment, X is C-Cl.

[0313] In one embodiment, Ring B is

[0314] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0315] 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.

[0316] Group 2.2.4.6: In one embodiment, Ring A is

[0317] In one embodiment, Ring B is

[0318] Group 2.2.4.6.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0319] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, 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 , R6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0320] In one embodiment, the compound is

[0321] Group 2.2.4.6.3: In one embodiment, Ring B is

[0322] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, 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 and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0323] In one embodiment, the compound is

[0324] Group 2.2.5: In one embodiment, X is C-CF3.

[0325] In one embodiment, Ring B is

[0326] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0327] 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.

[0328] Group 2.2.5.6: In one embodiment, Ring A is

[0329] In one embodiment, Ring B is

[0330] Group 2.2.5.6.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0331] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R7b Each of the following is independently H, halogen, 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 and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0332] In one embodiment, the compound is

[0333] Group 2.3: In one embodiment, u is 3. In one embodiment, the compound is a compound having formula (VIII):

[0334]

[0335] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0336] In one embodiment, Ring B is

[0337] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0338] 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; and

[0339] R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0340] Group 2.3.1: In one embodiment, X is N.

[0341] In one embodiment, Ring A is And ring B is

[0342] Group 2.3.1.1: In one embodiment, Ring A is

[0343] In one embodiment, Ring B is

[0344] Group 2.3.1.1.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0345] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of the following is independently H, halogen, 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 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0346] In one embodiment, the compound is

[0347] Group 2.3.2: In one embodiment, X is CH.

[0348] In one embodiment, Ring B is

[0349] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0350] 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.

[0351] In one embodiment, Ring A is And ring B is

[0352] Group 2.3.2.4: In one embodiment, Ring A is

[0353] In one embodiment, Ring B is

[0354] Group 2.3.2.4.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0355] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of the following is independently H, halogen, 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 and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0356] In one embodiment, the compound is

[0357] Group 2.4: In one embodiment, u is 4. In one embodiment, the compound is a compound having formula (IX):

[0358]

[0359] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0360] In one embodiment, Ring B is

[0361] Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and

[0362] 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; and

[0363] R 3a , R 3b , R 4a , R 4b , R 5 , R6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

[0364] Group 2.4.1: In one embodiment, X is N.

[0365] In one embodiment, Ring A is And ring B is

[0366] Group 2.4.1.1: In one embodiment, Ring A is

[0367] In one embodiment, Ring B is

[0368] Group 2.4.1.1.1: In one embodiment, Ring B is In one embodiment, Ring B is

[0369] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of the following is independently H, halogen, 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 6a3 , R 6b3 , R6a4 , R 6b4 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino, methyl or ethyl, optionally substituted with OH, CN, amino. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of is independently H, halogen, OH, CN, methylamino or methyl.

[0370] In one embodiment, the compound is

[0371] Aspect 9: In one embodiment, the compound is selected from Table 2 and Table 3.

[0372] Aspect 10: In some embodiments, the compounds provided herein have one of the following formulae:

[0373]

[0374] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof,

[0375] in:

[0376] Ring C is unsubstituted or substituted C 3-6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocyclyl; and

[0377] Each of u and v is independently an integer; and

[0378] The sum of u and v is 1, 2, 3, or 4.

[0379] Aspect 11: In some embodiments, the compounds provided herein have one of the following formulae:

[0380]

[0381] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof,

[0382] in:

[0383] Y is CH2, O, NH, NR 9 、NC(=O)-R 10 Or O = S = O;

[0384] R 9 is substituted or unsubstituted C 1-4 Alkyl, or unsubstituted or substituted C 3-5 Cycloalkyl;

[0385] 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

[0386] R Y 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.

[0387] In one embodiment, Y is O. In one embodiment, Y is N. In one embodiment, Y is CH2.

[0388] Aspect 12: Provided herein is a compound selected from the following table:

[0389] Table 1

[0390]

[0391]

[0392] Aspect 13: 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.

[0393] Aspect 14: In one embodiment, the present invention provides 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. In one embodiment, the present invention provides a method for inhibiting the activity of KRAS amplification 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.

[0394] Aspect 15: 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.

[0395] Aspect 16: 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.

[0396] Aspect 17: Provided herein is a kit 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.

[0397] A more complete understanding of the embodiments of the present invention may be obtained by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

[0398] Methods for preparing compounds

[0399] Compounds can be prepared using conventional organic synthesis and commercially available starting materials. As an example and not limitation, compounds of formula (I) can be prepared as outlined in Schemes 1-2 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.

[0400] Solution 1

[0401]

[0402] As shown in Scheme 1, in some embodiments, provided herein is a method for preparing a compound as defined by formula (I). Under substitution conditions (e.g., if X1 is OH, then HATU, DIEA; if X1 is Cl, then DIEA, DCM), the halogen-substituted compound 1-1 (X2 and X4 are hydrogen, X1 is OH or Cl, and X3 can be a methylthiol group) is converted to compound 1-2; then under substitution conditions (e.g., NaH, THF), compound 1-2 is converted to compound 1-3; then under oxidation conditions (if LG is methylsulfonyl or methylsulfinyl, then m-CPBA oxidation), compound 1-3 is converted to compound 1-4; 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 subjected to 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, borate, metal (such as Zn), tributyltin, etc.; finally, compound 1-6 containing a protecting group is deprotected (e.g., when PG1 and PG2 contain a Boc group, TFA and DCM deprotect the Boc group; when PG1 and PG2 contain a TIPS group, CsF and DMF deprotect the TIPS group) to obtain a compound defined as formula (I).

[0403] Solution 2

[0404]

[0405] As shown in Scheme 2, in some embodiments, provided herein is a method for preparing a compound as defined in formula (I). Under substitution conditions (e.g., NaH, THF), the halogen-substituted compound 2-1 (X2 and X4 are halogens, X1 is OH or Cl, and X3 may be a methylthiol group) is converted to compound 2-2; then under substitution conditions (e.g., if X1 is OH, then HATU, DIEA; if X1 is Cl, then DIEA, DCM), compound 2-2 is converted to compound 2-3; then under oxidation conditions (if LG is methylsulfonyl or methylsulfinyl, then m-CPBA oxidation), compound 2-3 is converted to compound 2-4; then compound 2-4 is converted to compound 2-5, followed by 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 Stille 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 (such as Zn), tributyltin, etc.; finally, compound 2-6 containing a protecting group is deprotected (e.g., when PG1 and PG2 contain a Boc group, TFA and DCM deprotect the Boc group; when PG1 and PG2 contain a TIPS group, CsF and DMF deprotect the TIPS group) to obtain a compound defined as formula (I).

[0406] A more complete understanding of the embodiments of the present invention may be obtained by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

[0407] Example

[0408] The following examples are intended to be exemplary only and should not be considered to be limited in any way. Unless otherwise stated, the experimental methods in the embodiments described below are conventional methods. Unless otherwise stated, reagents and materials are all commercially available. All solvents and chemicals used are of analytical grade or chemical purity. Solvents are all redistilled before use. Anhydrous solvents are all 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 Ocean Chemical Co., Ltd. or Yantai Chemical Co., Ltd. in China; unless otherwise stated, all are eluted with petroleum ether (60°C to 90°C) / ethyl acetate (v / v), and are developed by a solution of iodine or molybdophosphoric acid in ethanol. Unless otherwise stated, all extraction solvents are dried over anhydrous Na2SO4.

[0409] Unless otherwise noted, the reactions described below were performed under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents; reaction flasks were equipped with rubber septa for introduction of substrates and reagents via syringe; glassware was oven-dried and / or heat-dried.

[0410] Unless otherwise stated, column chromatography purifications were performed on a Biotage system (manufacturer: Dyax Corporation) with silica gel columns or on silica SepPak cartridges (Waters), or on a Teledyne Isco Combiflash purification system using pre-packed silica gel cartridges.

[0411] Recorded on a Varian instrument operating at 400 MHz or 500 MHz 1 H NMR spectra were obtained using TMS (tetramethylsilane) as an internal standard using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone or (CD3)2CO 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 peak multiplicities are reported, 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). Coupling constants, when given, are reported in Hertz (Hz).

[0412] 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 from 19.1 generated.

[0413] In the following examples, the following abbreviations are used:

[0414]

[0415]

[0416]

[0417]

[0418] Compound synthesis

[0419] Example 1: 2-amino-7-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepin[5,6,7-de]quinazolin-5-yl)benzo[b]thiophene-3-carbonitrile

[0420]

[0421] Step 1: (S)-Pyrrolidin-2-ylmethanol

[0422]

[0423] (S)-tert-Butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (4 g, 19.9 mmol) was placed in HCl (4M in dioxane) and the mixture was stirred at room temperature for 2 hours until LC-MS indicated that all the starting material was consumed. The mixture was concentrated in vacuo, diluted with MTBE, and then filtered to collect the solid as the title compound (2.2 g). MS (ESI, m / e) [M+H] + 102.2.

[0424] Step 2: (S)-(1-(7-bromo-5,8-difluoro-2-(methylthio)quinazolin-4-yl)pyrrolidin-2-yl)methanol

[0425]

[0426] A mixture of (S)-pyrrolidin-2-ylmethanol (610 mg, 6.0 mmol) and 7-bromo-5,8-difluoro-2-(methylthio)quinazolin-4-ol (2.0 g, 6.6 mmol), HATU (3.8 g, 9.9 mmol), DIEA (1.3 g, 9.9 mmol) and DCM (10 mL) was stirred at room temperature for 16 hours. The mixture was quenched with NH4Cl (10 mL, saturated aqueous solution) solution and extracted with DCM (20 mL*3). The combined organic layers were dried over Na2SO4. The mixture was filtered and the filtrate was concentrated to give a residue, which was then purified by silica gel chromatography (eluted with PE / EtOAc=2 / 1) to give the title compound (610 mg). MS (ESI, m / e) [M+H] + 389.2.

[0427] Step 3: (S)-5-Bromo-4-fluoro-2-(methylthio)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0428]

[0429] To a mixture of (S)-(1-(7-bromo-5,8-difluoro-2-(methylthio)quinazolin-4-yl)pyrrolidin-2-yl)methanol (570 mg, 1.5 mmol) in THF was added NaH (114 mg, 3.0 mmol) in batches at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was quenched with NH4Cl (10 mL, saturated aqueous solution), extracted with DCM (20 mL*3), and the combined organic layers were dried over Na2SO4. The filtrate was concentrated and purified by silica gel chromatography (eluted with PE / EtOAc=1 / 1) to give the title compound (480 mg). MS (ESI, m / e) [M+H] + 370.2.

[0430] Step 4: (8aS)-5-Bromo-4-fluoro-2-(methylsulfinyl)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0431]

[0432] To a mixture of (S)-5-bromo-4-fluoro-2-(methylthio)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline (480 mg, 1.3 mmol) in DCM (10 mL) at 0°C was added m-CPBA (321 mg, 1.3 mmol, 70%) in portions. 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 the crude product (480 mg) which was used in the next step without further purification. MS (ESI, m / e) [M+H] + 386.2.

[0433] Step 5: (S)-5-Bromo-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0434]

[0435] To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (480 mg, 1.3 mmol) in THF (5 mL) was added NaH (99 mg, 2.6 mmol) in portions at 0°C. The mixture was stirred for 0.5 hours and then added in portions to a solution of (8aS)-5-bromo-4-fluoro-2-(methylsulfinyl)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline (480 mg, 1.3 mmol) in THF (10 mL) at 0°C. The mixture was stirred at 50°C for 2 hours. The mixture was quenched with NH4Cl (saturated aqueous solution), extracted with DCM (20 mL*3), and the combined organic layers were dried over Na2SO4. The filtrate was 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] + 481.4.

[0436] Step 6: tert-butyl (3-cyano-7-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)benzo[b]thiophen-2-yl)carbamate

[0437]

[0438] (S)-5-bromo-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline (100 mg, 0.2 mmol), (3-cyano-7-fluoro-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamic acid tert-butyl ester (251 mg, 0.6 mmol), bis(diphenylphosphinophenyl) ether dichloropalladium(II) (15 mg, 0.02 mmol), Cs2CO3 (195 mg, 0.6 mmol) and dioxane / water (5 mL, 9 / 1) were stirred at 100°C for 4 hours. The mixture was cooled to room temperature, concentrated in vacuo, and the residue was purified by silica gel chromatography (eluted with DCM / MeOH=9 / 1) to give the title compound (120 mg). MS (ESI, m / e) [M+H] + 693.4.

[0439] Step 7: 2-amino-7-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)benzo[b]thiophene-3-carbonitrile

[0440] To a mixture of tert-butyl (3-cyano-7-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)benzo[b]thiophen-2-yl)carbamate (120 mg, 0.17 mmol) in dioxane (2 mL) was added HCl (2 mL, 4 M in dioxane) in one portion. The mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title product (54 mg). 1H NMR(500MHz,DMSO-d6)δ8.03(s,2H),7.25-7.21(m,1H),7.10-7.08(m,1H),6.71-6.63(m,1H),5.42-5.21(m,1H),4.63-4.61(m,1H), 4.22-3.96(m,4H),3.82-3.80(m,2H),3.16-3.13(m,2H),2.90-2.86(m,1H),2.28-2.13(m,2H),2.08-1.99(m,3H),1.95-1.64(m,5H). MS(ESI,m / e)[M+H] + 593.4.

[0441] Example 2: 5-ethynyl-6-fluoro-4-((R)-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]oxazepino[5,6,7-de]quinazolin-9-yl)naphthalen-2-ol

[0442]

[0443] Example 2 was prepared by a procedure analogous to that described in Example 1 to give the title product (3.17 mg). 1 H NMR(500MHz,DMSO-d6)δ10.11(s,1H),8.01-7.87(m,1H),7.48-7.44(m,1H),7.35-7.32(m, 1H),7.10-7.02(m,1H),6.68-6.45(m,1H),5.38-5.20(m,1H),4.65-4.56(m,1H),4.12-4.0 8(m,3H),3.98-3.94(m,2H),3.84-3.82(m,2H),3.11-3.00(m,3H),2.84-2.81(m,1H),2.36 -2.16(m,2H),2.15-2.07(m,2H),2.06-1.97(m,3H),1.91-1.82(m,2H),1.80-1.74(m,2H). MS(ESI,m / e)[M+H] + 587.6.

[0444] Example 3: 5-ethynyl-6-fluoro-4-((R)-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazolin-9-yl)naphthalen-2-ol

[0445]

[0446] Example 3 was prepared by a procedure analogous to that described in Example 1 to give the title product (0.78 mg). 1 H NMR(500MHz,DMSO-d6)δ10.13(s,1H),7.96(s,1H),7.51-7.42(m,1H),7.35(s,1H),7.11-7.01(m,1H),6.76(s,1H),5.63-5.40(m,1H) ,4.65-4.45(m,3H),4.34-4.10(m,3H),4.03-3.93(m,1H),3.88-3.68(m,6H),2.20-2.10(m,4H),2.05-1.95(m,4H),1.94-1.85(m,3H). MS(ESI,m / e)[M+H] + 601.6.

[0447] Example 4: 5-ethynyl-6-fluoro-4-((S)-2,2,8-trifluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,12,12a-tetrahydro-1H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-9-yl)naphthalen-2-ol

[0448]

[0449] Example 4 was prepared by a procedure analogous to that described in Example 1, substituting (S)-(4,4-difluoropyrrolidin-2-yl)methanol for 3-(methylamino)propan-1-ol to give the title product (2.25 mg). 1H NMR(500MHz,DMSO-d6)δ10.13(s,1H),7.98-7.92(m,1H),7.53-7.40(m,1H), 7.37-7.31(m,1H),7.09-7.02(m,1H),6.83-6.70(m,1H),5.38-5.15(m,1H), 4.70-3.89(m,8H),3.12-3.06(m,2H),3.04-3.01(m,1H),2.86-2.69(m,2H), 2.14-2.07(m,1H),2.05-1.99(m,2H),1.87-1.82(m,1H),1.80-1.72(m,2H). MS (ESI, m / e) [M+H] + 623.3.

[0450] Example 5: 2-amino-7-fluoro-4-((R)-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazolin-9-yl)benzo[b]thiophene-3-carbonitrile

[0451]

[0452] Example 5 was prepared by a procedure analogous to that described in Example 1, replacing (S)-5-bromo-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,10,11-tetrahydro-8H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline with (R)-9-bromo-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline to give the title product (58 mg). 1H NMR(500MHz,DMSO-d6)δ8.10-8.03(m,2H),7.31-7.15(m,1H),7.15-7.05(m,1H),6.70-6.62(m,1H),5.41-5.20(m,1H),4.48-4.40(m ,1H),4.28-3.99(m,4H),3.84-3.80(m,1H),3.73-3.63(m,1H),3.20-3.10(m,3H),2.89(s,1H),2.23-1.94(m,6H),1.93-1.74(m,5H). MS(ESI,m / e)[M+H] + 607.1.

[0453] Example 6: 5-ethynyl-6-fluoro-4-(1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazolin-2-yl)naphthalen-2-ol

[0454]

[0455] Step 1: 7-Bromo-8-fluoro-2-(methylthio)-5-(2-(piperidin-2-yl)ethoxy)quinazolin-4(3H)-one

[0456]

[0457] To a solution of tert-butyl 2-(2-hydroxyethyl)piperidine-1-carboxylate (2.2 g, 9.8 mmol) in THF (50 mL) was added NaH (60%, 536 mg, 13.4 mol). The mixture was stirred at room temperature for 10 minutes, and then 7-bromo-5,8-difluoro-2-(methylthio)quinazolin-4(3H)-one (2.0 g, 7.5 mol) was added to the mixture. The resulting mixture was stirred at 55 ° C overnight. The mixture was cooled to room temperature and quenched with ice. The mixture was extracted with DCM (30 mL*3) and washed with brine (50 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo, and the residue was purified by silica gel column chromatography (20 g, eluted with PE / EtOAc=100%:0%~0%:100%) to give the title compound (1.2 g). MS (ESI, m / e) [M+H] + 416.2.

[0458] Step 2: 2-Bromo-1-fluoro-13-(methylthio)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline

[0459]

[0460] HATU (2.9 g, 7.3 mmol), DIEA (1.1 g, 8.7 mmol) were placed in a suspension of 7-bromo-8-fluoro-2-(methylthio)-5-(2-(piperidin-2-yl)ethoxy)quinazolin-4(3H)-one (1.2 g, 2.9 mmol) in DCM / DMF (20 mL / 20 mL). The mixture was stirred at room temperature overnight. Then, the mixture was extracted with DCM (30 mL*2) and washed with brine (50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The mixture was purified by silica gel chromatography (20 g, eluted with PE / EtOAc=100%:0% to 65%:35%) to give the title compound (650 mg). MS (ESI, m / e) [M+H] + 398.2.

[0461] Step 3: 2-Bromo-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline

[0462]

[0463] 2-Bromo-1-fluoro-13-(methylthio)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline (620 mg, 1.56 mmol) was placed in DCM (10 mL). At 0°C, m-CPBA (309 mg, 1.796 mmol) was added to the solution in batches. The mixture was stirred at 0°C for 1 hour. The mixture was then extracted with DCM (10 mL*2), washed with Na2CO3 (20 mL, saturated aqueous solution), washed with brine (20 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a crude product, which was used directly. ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (744 mg, 4.7 mmol) was placed in THF (10 mL), and LiHMDS (3.1 mL, 3.1 mmol) was added to the solution in batches at 0°C. The mixture was stirred at 0°C for 1 hour, and the above crude product was added. The mixture was stirred from 0°C to room temperature and stirred at room temperature for 1 hour. Then, the mixture was quenched with MeOH (5 mL) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with DCM / MeOH=80%:20%) to give the title compound (213 mg). MS (ESI, m / e) [M+H] + 509.3.

[0464] Step 4: 1-Fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline

[0465]

[0466] 2-Bromo-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline (100 mg, 0.2 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline (100 mg, 0.2 mmol), A mixture of 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (18 mg, 0.03 mmol) and NaHCO3 (50 mg, 0.6 mmol) in dioxane / water (10 mL / 2 mL) was stirred at 100°C overnight. The cooled reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (4 g, eluted with PE / EtOAc=100%:0% to 0%:100%, DCM / MeOH=90%:10%) to give the title compound (140 mg). MS (ESI, m / e) [M+H] + 815.7.

[0467] Step 5: 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline

[0468]

[0469] To a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline (70 mg, 0.09 mmol) in DMF (5 mL) was added CsF (65 mg, 0.4 mmol). The mixture was stirred at room temperature overnight. Then, the mixture was filtered and the filtrate was concentrated in vacuo to give the crude product which was used in the next step without further purification (80 mg, crude). MS (ESI, m / e) [M+H] + 659.5.

[0470] Step 6: 5-ethynyl-6-fluoro-4-(1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazolin-2-yl)naphthalen-2-ol

[0471] To a solution of 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline (80 mg, 0.1 mmol) in dioxane (4 mL) was added HCl (2 mL, 4 M in dioxane). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give the title product (22 mg). 1 H NMR(500MHz,DMSO-d6)δ10.14(br,1H),7.96-7.92(m,1H),7.44-7.40(m,1H),7.36-7. 30(m,1H),7.13-6.96(m,1H),6.69-6.57(m,1H),5.36-5.18(m,1H),4.95-4.65(m,1H), 4.38-4.26(m,1H),4.17-4.01(m,2H),3.99-3.87(m,3H),3.13-3.05(m,2H),3.04-3.0 0(m,1H),2.84-2.80(m,1H),2.34-2.30(m,1H),2.20-1.97(m,3H),1.92-1.49(m,10H). MS(ESI,m / e)[M+H] + 615.5.

[0472] Example 7: 2-amino-4-((13aR)-10-chloro-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0473]

[0474] Step 1: 7-Bromo-4,6-dichloro-5,8-difluoro-2-(methylthio)quinazoline

[0475]

[0476] DIPEA (5 mL) was added dropwise to a suspension of 7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazoline-4-ol (900 mg, 2.8 mmol) in POCl3 (10 mL). The mixture was stirred at 100 ° C overnight. Then, the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (20 g, eluted with PE / EtOAc=100%:0% to 70%:30%) to give the title compound (700 mg). MS (ESI, m / e) [M+H] + 359.0.

[0477] Step 2: (R)-2-(1-(7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-yl)pyrrolidin-2-yl)ethan-1-ol

[0478]

[0479] To a solution of 7-bromo-4,6-dichloro-5,8-difluoro-2-(methylthio)quinazoline (700 mg, 2.0 mmol) and (R)-2-(pyrrolidin-2-yl)ethan-1-ol (337 mg, 2.9 mmol) in DCM (20 mL) was added DIPEA (756 mg, 5.9 mmol). The mixture was stirred from 0 ° C to room temperature for 1 hour. Then, the mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (12 g, eluted with PE / EtOAc=100%:0% to 0%:100%) to give the title compound (600 mg). MS (ESI, m / e) [M+H] + 438.1.

[0480] Step 3: (R)-9-Bromo-10-chloro-8-fluoro-6-(methylthio)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline

[0481]

[0482] To a solution of (R)-2-(1-(7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-yl)pyrrolidin-2-yl)ethan-1-ol (600 mg, 1.4 mmol) in THF was added LiHMDS (2.8 mL, 2.8 mmol, 1 M in THF) in portions at 0°C. The mixture was stirred from 0°C to room temperature and stirred at room temperature for 1 hour. The mixture was quenched with MeOH (5 mL), then concentrated in vacuo, and the residue was purified by silica gel column chromatography (12 g, eluted with PE / EtOAc=100%:0% to 0%:100%) to give the title compound (540 mg). MS (ESI, m / e) [M+H] + 418.7.

[0483] Step 4: (R)-9-Bromo-10-chloro-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline

[0484]

[0485] To a mixture of (R)-9-bromo-10-chloro-8-fluoro-6-(methylthio)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline (540 mg, 1.3 mmol) in DCM (10 mL) at 0°C was added m-CPBA (256 mg, 1.5 mmol, 70%) in portions. The mixture was stirred at 0°C for 2 hours to give mixture A. To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (617 mg, 3.385 mmol) in THF (10 mL) at 0°C was added LiHMDS (2.6 mL, 2.6 mmol) in portions. The mixture was stirred at room temperature for 30 minutes and added to the above mixture A. The resulting mixture was stirred at room temperature for 2 hours, quenched with MeOH (5 mL) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with DCM / MeOH=90%:10%) to give the title compound (500 mg). MS (ESI, m / e) [M+H] + 529.3.

[0486] Step 5: tert-Butyl (4-((13aR)-10-chloro-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate

[0487]

[0488] (R)-9-bromo-10-chloro-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazoline (70 mg, 0.132 mmol), (3-cyano-7-fluoro-4-(4,4,5,5 A mixture of tert-butyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (220 mg, 0.53 mmol), bis(diphenylphosphinophenyl) ether dichloropalladium(II) (19 mg, 0.026 mmol), Cs2CO3 (171 mg, 0.53 mmol) in dioxane / water (10 mL / 2 mL) was stirred overnight at 100°C. The mixture was cooled to room temperature, concentrated in vacuo, and the residue was purified by silica gel chromatography (4 g, eluted with DCM / MeOH=90%:10%) to give a crude product, which was further purified by preparative TLC (DCM / MeOH=20 / 1 and EtOAc) to give the title compound (25 mg, crude). MS (ESI, m / e) [M+H] + 741.5.

[0489] Step 6: 2-amino-4-((13aR)-10-chloro-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0490] To a solution of tert-butyl (4-((13aR)-10-chloro-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,3,12,13,13a-hexahydropyrrolo[1',2':5,6][1,5]oxazolidinone[4,3,2-de]quinazolin-9-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (25 mg, 0.034 mmol) in dioxane (5 mL) was added HCl (4M) / dioxane (5 mL). The mixture was stirred at room temperature for 3 hours. The mixture was then concentrated in vacuo to give the crude product, which was further purified by preparative HPLC to give the desired product (0.99 mg). 1 H NMR(500MHz,DMSO-d6)δ8.06(s,2H),7.26-7.05(m,2H),5.36-5.18(m,1H),4.54-5.38(m,1H),4.26-4.13(m,2H), 4.10-3.98(m,2H),3.87-3.67(m,2H),3.14-2.98(m,3H),2.84-2.80(m,1H),2.18-2.10(m,6H),1.80-1.71(m,4H). MS(ESI,m / e)[M+H] + 641.5.

[0491] Example 8: 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-3,10a,11,13-tetraazabenzo[4,5]cyclooctane[1,2,3-de]naphthalen-2-yl)-4-(trifluoromethyl)aniline

[0492]

[0493] Step 1: 7-Chloro-8-fluoro-2-(methylthio)-5-(2-(piperidin-2-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-ol

[0494]

[0495] To a solution of 2-(piperidin-2-yl)ethan-1-ol (129 mg, 1 mmol) in THF (10 mL) was added NaH (40 mg, 1 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Then, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (280 mg, 1 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by a flash silica gel column (DCM:MeOH=10:1) to give the title product (240 mg). MS (ESI, m / e) [M+H] + 373.1.

[0496] Step 2: 2-Chloro-1-fluoro-12-(methylthio)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazabenzo[4,5]cyclooctano[1,2,3-de]naphthalene

[0497]

[0498] To a solution of 7-chloro-8-fluoro-2-(methylthio)-5-(2-(piperidin-2-yl)ethoxy)pyrido[4,3-d]pyrimidin-4-ol (240 mg, 0.645 mmol) in 20 mL of N,N-dimethylformamide was added N,N-diisopropylethylamine (166.4 mg, 1.29 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (490.2 mg, 1.29 mmol) at room temperature and stirred at room temperature for 1 hour. Another batch of N, N-diisopropylethylamine (1.66 g, 12.9 mmol) and 2-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (4.9 g, 12.9 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water, extracted with EA, and the organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (PE: EtOAc = 1: 5) to give the title product (75 mg). MS (ESI, m / e) [M + H] + 355.1.

[0499] Step 3: 2-Chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazabenzo[4,5]cyclooctano[1,2,3-de]naphthalene

[0500]

[0501] To a solution of 2-chloro-1-fluoro-12-(methylthio)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazabenzo[4,5]cycloocta[1,2,3-de]naphthalene (75 mg, 0.212 mmol) in 10 mL of dichloromethane was added 3-chloroperoxybenzoic acid (44 mg, 0.254 mmol) at room temperature, and stirred at room temperature for 2 hours as mixture 1. Meanwhile, LiHMDS (1N THF solution, 0.3 mL) was added to a THF (10 mL) solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (101 mg, 0.635 mmol) at room temperature, and stirred at room temperature for 2 hours as mixture 2. Then, mixture 2 was added to mixture 1 at room temperature, and the mixture was stirred at room temperature for 2 hours. Then, the solvent was evaporated, and the residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the title product (73 mg). MS (ESI, m / e) [M+H] + 466.2.

[0502] Step 4: 3-Chloro-5-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazabenzo[4,5]cyclooctane[1,2,3-de]naphthalen-2-yl)-4-(trifluoromethyl)aniline

[0503] 2-Chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazabenzo[4,5]cyclooctane[1,2,3-de]naphthalene (73 mg, 0.157 mmol), 3-chloro-5-(4,4,5,5 A mixture of 1-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (101 mg, 0.314 mmol), K3PO4 (66.6 mg, 0.314 mmol) and Pd(dtbpf)Cl2 (20.4 mg, 0.0314 mmol) in dioxane (10 mL) and water (2 mL) was stirred at 95° C. for 3 hours. The resulting mixture was cooled, concentrated, and the residue was purified by column chromatography (DCM / MeOH=10 / 1) to give a crude product, which was further purified by preparative HPLC to give the title product (1.75 mg). 1H NMR(500MHz,CD3OD)δ6.89–6.85(m,1H),6.60–6.36(m,1H),5.40–5.26(m,2H),4.55–4. 48(m,1H),4.39–4.16(m,3H),4.13–4.01(m,1H),3.18–3.03(m,2H),2.49–1.56(m,16H). MS(ESI,m / e)[M+H] + 625.2.

[0504] Example 9: 3-Chloro-5-((S)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-4-(trifluoromethyl)aniline

[0505]

[0506] Step 1: 4,5,7-Trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0507]

[0508] To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (280 mg, 1.0 mmol) in acetonitrile (10 mL) was added DIPEA (194 mg, 1.5 mmol) and POCl3 (184 mg, 1.2 mmol), and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated in vacuo and used in the next step without further purification.

[0509] Step 2: (S)-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol

[0510]

[0511] To a stirred solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.0 mmol) in CH2Cl2 (10 mL) was added DIPEA (387 mg, 3.0 mmol) and (S)-pyrrolidin-2-ylmethanol (101 mg, 1.0 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc=4:1 to 1:2) to give the desired product (210 mg). MS (ESI, m / e) [M+H] + 363.1.

[0512] Step 3: (S)-8-Chloro-7-fluoro-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0513]

[0514] To a stirred solution of (S)-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (162 mg, 0.45 mmol) in THF (5 mL) was added LiHMDS (1 mL, 1 mmol, 1 M in THF) at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (PE / EtOAc=10:1 to 2:1) to give the product (104 mg). MS (ESI, m / e) [M+H] + 327.0.

[0515] Step 4: (11aS)-8-Chloro-7-fluoro-5-(methylsulfinyl)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0516]

[0517] To a stirred solution of (S)-8-chloro-7-fluoro-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (104 mg, 0.32 mmol) in CH2Cl2 (2.5 mL) at 0°C was added m-CPBA (78 mg, 0.38 mmol, 85%) and the resulting mixture was stirred at 0°C for 10 minutes. The reaction mixture was used in the next step without further purification. MS (ESI, m / e) [M+H] + 343.3.

[0518] Step 5: (S)-8-Chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0519]

[0520] To a stirred solution of (11aS)-8-chloro-7-fluoro-5-(methylsulfinyl)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (0.32 mmol) was added dropwise a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (102 mg, 0.64 mmol) in THF (2.5 mL) and LiHMDS (0.96 mL, 0.96 mmol, 1 M in THF) at 0°C, and the resulting mixture was stirred at 0°C for 20 minutes. The reaction was quenched with H2O and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2 / MeOH=100:1 to 30:1) to give the product (92 mg). MS (ESI, m / e) [M+H] + 438.5.

[0521] Step 6: 3-Chloro-5-((S)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-4-(trifluoromethyl)aniline

[0522] A mixture of (S)-8-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (30 mg, 0.07 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (50 mg, 0.14 mmol, 89%), Pd(dtbpf)Cl2 (9.0 mg, 0.014 mmol), NaHCO3 (18 mg, 0.21 mmol), dioxane (5.0 mL) and H2O (1.0 mL) was stirred at 90°C for 3 h. The reaction mixture was concentrated and purified by flash chromatography (CH2Cl2 / MeOH=100:1 to 5:1) and then further purified by preparative HPLC to give the title product (12.2 mg). 1 H NMR(500MHz,CD3OD)δ6.92–6.83(m,1H),6.58–6.40(m,1H),5.52–5.25(m,1H),4.77–4. 70(m,2H),4.50–3.85(m,6H),3.52–3.40(m,1H),3.20–3.03(m,2H),2.43–1.75(m,10H). MS(ESI,m / e)[M+H] + 597.4.

[0523] Example 10: 5-ethynyl-6-fluoro-4-((S)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)naphthalen-2-ol

[0524]

[0525] Step 1: (S)-7-Fluoro-8-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0526]

[0527] (S)-8-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (50 mg, 0.11 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- A mixture of (1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-1 ...2-yl, 1,4-dioxaborolan-1-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan-2-yl, 1,4-dioxaborolan- + 788.8.

[0528] Step 2: (S)-8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0529]

[0530] To a stirred solution of (S)-7-fluoro-8-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (65 mg, 0.08 mmol) in DMF (4 mL) was added CsF (122 mg, 0.8 mmol) and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo and the crude product was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 632.5.

[0531] Step 3: 5-ethynyl-6-fluoro-4-((S)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)naphthalen-2-ol

[0532] To a stirred solution of (S)-8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (0.08 mmol) in CH2Cl2 (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 hour. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (CH2Cl2 / MeOH=100:1 to 10:1) and then further purified by preparative HPLC to give the title product (3.5 mg). 1 H NMR(500MHz,CD3OD)δ7.92–7.72(m,1H),7.41–7.09(m,3H),5.49–5.29(m,1H) ,4.79–4.71(m,1H),4.50–3.87(m,6H),3.62–3.33(m,5H),2.53–1.78(m,10H). MS(ESI,m / e)[M+H] + 588.4.

[0533] Example 11: 3-Chloro-5-((R)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,3,11,12,12a-hexahydro-10-oxa-3a,4,6,9-tetraazacyclopenta[4,5]cyclooctane[1,2,3-de]naphthalen-8-yl)-4-(trifluoromethyl)aniline

[0534]

[0535] Step 1: 4,5,7-Trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0536]

[0537] To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (280 mg, 1.0 mmol) in acetonitrile (10 mL) was added DIPEA (194 mg, 1.5 mmol) and POCl3 (184 mg, 1.2 mmol), and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification.

[0538] Step 2: (R)-2-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)ethan-1-ol

[0539]

[0540] To a stirred solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.0 mmol) in CH2Cl2 (5 mL) was added DIPEA (1.94 mg, 1.5 mmol) and (R)-2-(pyrrolidin-2-yl)ethan-1-ol hydrochloride (11 mg, 1.0 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc=4:1 to 1:2) to give the desired product (262 mg). MS (ESI, m / e) [M+H] + 377.1.

[0541] Step 3: (R)-8-Chloro-7-fluoro-5-(methylthio)-1,2,3,11,12,12a-hexahydro-10-oxa-3a,4,6,9-tetraazacyclopenta[4,5]cyclooctano[1,2,3-de]naphthalene

[0542]

[0543] To a stirred solution of (R)-2-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)ethan-1-ol (262 mg, 0.70 mmol) in THF (5 mL) was added LiHMDS (1 mL, 1 mmol, 1 M in THF) at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O and concentrated in vacuo. The residue was purified by flash chromatography (PE / EtOAc=10:1 to 2:1) to give the product (210 mg). MS (ESI, m / e) [M+H] + 340.8.

[0544] Step 4: (12aR)-8-chloro-7-fluoro-5-(methylsulfinyl)-1,2,3,11,12,12a-hexahydro-10-oxa-3a,4,6,9-tetraazacyclopenta[4,5]cyclooctane[1,2,3-de]naphthalene

[0545]

[0546] To a stirred solution of (R)-8-chloro-7-fluoro-5-(methylthio)-1,2,3,11,12,12a-hexahydro-10-oxa-3a,4,6,9-tetraazacyclopenta[4,5]cycloocta[1,2,3-de]naphthalene (210 mg, 0.62 mmol) in CH2Cl2 (5 mL) at 0°C was added m-CPBA (150 mg, 0.74 mmol, 85%) and the resulting mixture was stirred at 0°C for 10 min. The reaction mixture was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 357.1.

[0547] Step 5: (R)-8-Chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,3,11,12,12a-hexahydro-10-oxa-3a,4,6,9-tetraazacyclopenta[4,5]cyclooctane[1,2,3-de]naphthalene

[0548]

[0549] To a stirred solution of (12aR)-8-chloro-7-fluoro-5-(methylsulfinyl)-1,2,3,11,12,12a-hexahydro-10-oxa-3a,4,6,9-tetraazacyclopenta[4,5]cyclooctane[1,2,3-de]naphthalene (0.62 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (128 mg, 0.80 mmol) in THF (2.5 mL) was added LiHMDS (1.0 mL, 1.0 mmol, 1 M in THF) dropwise at 0°C and the resulting mixture was stirred at 0°C for 20 min. The reaction was quenched with H2O and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2 / MeOH=100:1 to 30:1) to give the product (223 mg). MS (ESI, m / e) [M+H] + 452.2.

[0550] Step 6: 3-Chloro-5-((R)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,3,11,12,12a-hexahydro-10-oxa-3a,4,6,9-tetraazacyclopenta[4,5]cyclooctane[1,2,3-de]naphthalen-8-yl)-4-(trifluoromethyl)aniline

[0551] (R)-8-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,3,11,12,12a-hexahydro-10-oxa-3a,4,6,9-tetraazacyclopenta[4,5]cyclooctane[1,2,3-de]naphthalene (25 mg, 0.055 mmol), 3-chloro-5-(4,4,5,5- A mixture of tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (40 mg, 0.11 mmol, 89%), Pd(dtbpf)Cl2 (7.0 mg, 0.011 mmol), NaHCO3 (14 mg, 0.17 mmol), dioxane (5.0 mL) and H2O (1.0 mL) was stirred at 90°C for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (CH2Cl2 / MeOH=100:1 to 5:1), and then further purified by preparative HPLC to give the title product (1.2 mg). 1 H NMR(500MHz,CD3OD)δ6.93–6.81(m,1H),6.60–6.36(m,1H),5.50–5.27(m,1H),4.65–4.50(m,1H) ,4.50–4.24(m,4H),4.09–3.95(m,1H),3.85–3.70(m,1H),3.19–3.05(m,1H),2.47–1.82(m,12H). MS(ESI,m / e)[M+H] + 611.3.

[0552] Example 12: 3-((R)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,3,11,12,12a-hexahydro-10-oxa-3a,4,6,9-tetraazacyclopenta[4,5]cyclooctane[1,2,3-de]naphthalen-8-yl)-5-methyl-4-(trifluoromethyl)aniline

[0553]

[0554] (R)-8-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,3,11,12,12a-hexahydro-10-oxa-3a,4,6,9-tetraazacyclopenta[4,5]cyclooctane[1,2,3-de]naphthalene (25 mg, 0.055 mmol), 3-methyl-5-(4,4,5,5 A mixture of 4-(trifluoromethyl)aniline (34 mg, 0.11 mmol, 89%), Pd(dtbpf)Cl2 (7.0 mg, 0.011 mmol), NaHCO3 (14 mg, 0.17 mmol), dioxane (5.0 mL) and H2O (1.0 mL) was stirred at 90°C for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (CH2Cl2 / MeOH=100:1 to 5:1), and then further purified by preparative HPLC to give the title product (1.5 mg, 4%). 1 H NMR (500MHz, CDCl3) δ6.70–6.50(m,2H),5.44–5.25(m,1H),4.66–4.24(m,5H),4.10–3.22(m,6H),3.13–3.01(m,1H),2.54–2.00(m,14H). MS(ESI,m / e)[M+H] + 591.5.

[0555] Example 13: 3-Chloro-5-((R)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-4-(trifluoromethyl)aniline

[0556]

[0557] Step 1: 4,5,7-Trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0558]

[0559] To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (280 mg, 1.0 mmol) in ACN (10 mL) was added DIEA (194 mg, 1.5 mmol) and POCl3 (184 mg, 1.2 mmol), and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification.

[0560] Step 2: (R)-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol

[0561]

[0562] To a stirred solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.0 mmol) in DCM (10 mL) was added DIEA (387 mg, 3.0 mmol) and (R)-pyrrolidin-2-ylmethanol (101 mg, 1.0 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc=4:1 to 1:2) to give the desired product (276 mg). MS (ESI, m / e) [M+H] + 363.1.

[0563] Step 3: (R)-8-Chloro-7-fluoro-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0564]

[0565] To a stirred solution of (R)-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)methanol (178 mg, 0.49 mmol) in THF (6 mL) was added NaH (40 mg, 0.98 mmol, 60%) at 0°C, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O 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 (PE / EtOAc=10:1 to 2:1) to give the product (154 mg). MS (ESI, m / e) [M+H] + 327.0.

[0566] Step 4: (11aR)-8-chloro-7-fluoro-5-(methylsulfinyl)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0567]

[0568] To a stirred solution of (R)-8-chloro-7-fluoro-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (154 mg, 0.47 mmol) in DCM (8 mL) at 0°C was added m-CPBA (115 mg, 0.56 mmol, 85%) and the resulting mixture was stirred at 0°C for 10 minutes. The reaction was quenched with aqueous Na2S2O3 and then extracted with DCM. The organic layer was washed with saturated aqueous 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] + 343.3.

[0569] Step 5: (R)-8-Chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0570]

[0571] At 0 ° C, to (11aR) -8- chloro-7-fluoro-5- (methylsulfinyl) -2,3,11,11a- tetrahydro -1H-10- oxa-3a,4,6,9- tetraazanaphtho [1,8-ef] azulene (0.47mmol) and ((2R,7aS) -2-fluorotetrahydro -1H- pyrrolazine -7a (5H) -yl) methanol (149mg, 0.94mmol) in THF (8mL) in a stirred solution was added LiHMDS (0.94mL, 0.94mmol, 1M in THF), and the resulting mixture was stirred at 0 ° C for 20 minutes. The reaction was quenched with saturated NH4Cl aqueous solution 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 product (110 mg, 53%). MS (ESI, m / e) [M+H] + 438.5.

[0572] Step 6: 3-Chloro-5-((R)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-4-(trifluoromethyl)aniline

[0573] A mixture of (R)-8-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (30 mg, 0.07 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (50 mg, 0.14 mmol, 89%), Pd(dtbpf)Cl2 (9.0 mg, 0.014 mmol), NaHCO3 (18 mg, 0.21 mmol), dioxane (2.0 mL) and H2O (0.4 mL) was stirred at 90°C for 2 h. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100: 1 to 5: 1) and then by preparative HPLC to give the title product (12.6 mg). 1 H NMR(500MHz,CD3OD)δ6.90–6.83(m,1H),6.56–6.40(m,1H),5.43–5.21(m,1H),4.76–4. 66(m,2H),4.41–4.09(m,4H),4.03–3.85(m,2H),3.27–3.03(m,2H),2.43–1.80(m,10H). MS(ESI,m / e)[M+H] + 597.4.

[0574] Example 14: 5-ethynyl-6-fluoro-4-((R)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)naphthalen-2-ol

[0575]

[0576] Step 1: (R)-7-Fluoro-8-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0577]

[0578] (R)-8-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (50 mg, 0.11 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- A mixture of (1,4-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (113 mg, 0.22 mmol), Pd(dtbpf)Cl2 (14 mg, 0.022 mmol), NaHCO3 (28 mg, 0.33 mmol), dioxane (3.0 mL) and H2O (0.6 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 (65 mg). MS (ESI, m / e) [M+H] + 788.8.

[0579] Step 2: (R)-8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0580]

[0581] To a stirred solution of (R)-7-fluoro-8-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (65 mg, 0.08 mmol) in DMF (4 mL) was added CsF (122 mg, 0.8 mmol) and the resulting mixture was stirred at room temperature 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] + 632.5.

[0582] Step 3: 5-ethynyl-6-fluoro-4-((R)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)naphthalen-2-ol

[0583]

[0584] To a stirred solution of (R)-8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (0.08 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 hour. The reaction mixture was concentrated and basified with DIEA, and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) and then by preparative HPLC to give the product (18.2 mg). 1 H NMR (500MHz, CD3OD) δ7.93–7.72(m,1H),7.41–7.12(m,3H),5.49–5.31(m,1H),4.79–4. 72(m,1H),4.54–3.88(m,6H),3.65–3.41(m,5H),3.23–3.13(m,1H),2.53–1.78(m,10H). MS(ESI,m / e)[M+H] + 588.6.

[0585] Example 15: 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-3,9a,10,12-tetraazabenzo[4,5]cycloheptyl[1,2,3-de]naphthalen-2-yl)-4-(trifluoromethyl)aniline

[0586]

[0587] Step 1: (S)-7-Chloro-8-fluoro-2-(methylthio)-5-(piperidin-2-ylmethoxy)pyrido[4,3-d]pyrimidin-4-ol

[0588]

[0589] 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 (S)-piperidin-2-ylmethanol (82 mg, 0.72 mmol) in THF (6 mL) at 0°C was added NaH (100 mg, 2.5 mmol, 60%), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with H2O, and the pH was then adjusted to 6 with 1N aqueous 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] + 359.1.

[0590] Step 2: (S)-2-Chloro-1-fluoro-11-(methylthio)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene

[0591]

[0592] To a stirred solution of (S)-7-chloro-8-fluoro-2-(methylthio)-5-(piperidin-2-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 / EtOAc=4:1 to 1:3) to give the desired product (184 mg). MS (ESI, m / e) [M+H] + 341.1.

[0593] Step 3: (5aS)-2-Chloro-1-fluoro-11-(methylsulfinyl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene

[0594]

[0595] To a stirred solution of (S)-2-chloro-1-fluoro-11-(methylthio)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (184 mg, 0.54 mmol) in DCM (15 mL) at 0°C was added m-CPBA (120 mg, 0.59 mmol, 85%) and the resulting mixture was stirred at 0°C for 10 minutes. The reaction was quenched with aqueous Na2S2O3 and then extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0596] Step 4: (S)-2-Chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene

[0597]

[0598] To a stirred solution of (5aS)-2-chloro-1-fluoro-11-(methylsulfinyl)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (0.54 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (172 mg, 1.1 mmol) in THF (15 mL) was added LiHMDS (1.1 mL, 1.1 mmol, 1 M in THF) dropwise at 0°C and the resulting mixture was stirred at 0°C for 20 minutes. The reaction was quenched with saturated aqueous 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 product (96 mg). MS (ESI, m / e) [M+H] + 452.3.

[0599] 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-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)-4-(trifluoromethyl)aniline

[0600] A mixture of (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (32 mg, 0.07 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (45 mg, 0.14 mmol, 89%), Pd(dtbpf)Cl2 (9 mg, 0.014 mmol), NaHCO3 (18 mg, 0.21 mmol), dioxane (3.0 mL) and H2O (0.6 mL) was stirred at 90°C for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100: 1 to 5: 1) and then by preparative HPLC to give the title product (10.6 mg). 1 H NMR(500MHz,CD3OD)δ6.91–6.84(m,1H),6.53–6.42(m,1H),5.49–5.22(m,2H),4.57–4.42(m,2H) ,4.41–4.20(m,2H),4.02–3.85(m,1H),3.56–3.33(m,3H),3.15–3.00(m,2H),2.46–1.51(m,12H). MS(ESI,m / e)[M+H] + 611.4.

[0601] Example 16: 5-ethynyl-6-fluoro-4-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)naphthalen-2-ol

[0602]

[0603] 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)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene

[0604]

[0605] (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (60 mg, 0.13 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4, A mixture of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (133 mg, 0.26 mmol), Pd(dtbpf)Cl2 (18 mg, 0.03 mmol), NaHCO3 (33 mg, 0.39 mmol), dioxane (5.0 mL) and H2O (1.0 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 (95 mg).

[0606] 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)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene

[0607]

[0608] 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)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (95 mg, 0.11 mmol) in DMF (4 mL) was added CsF (152 mg, 1.1 mmol) and the resulting mixture was stirred at room temperature 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] + 646.1.

[0609] Step 3: 5-ethynyl-6-fluoro-4-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)naphthalen-2-ol

[0610] 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)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[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 hour. The reaction mixture was concentrated and basified with DIEA and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) and then by preparative HPLC to give the product (38.6 mg). 1 H NMR(500MHz,CD3OD)δ7.90–7.77(m,1H),7.37–7.13(m,3H),5.48–5.27(m,2H),4.61–4.47(m,2H) ,4.46–4.26(m,2H),4.05–3.89(m,1H),3.58–3.35(m,4H),3.20–3.02(m,2H),2.51–1.55(m,12H). MS(ESI,m / e)[M+H] + 602.5.

[0611] Example 17: 3-Chloro-5-(1,7-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-4-(trifluoromethyl)aniline

[0612]

[0613] Step 1: 1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)pyrrolidin-3-ol

[0614]

[0615] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (299 mg, 1.0 mmol) in DCM (30 mL) was added DIPEA (322 mg, 2.5 mmol) and 2-(hydroxymethyl)pyrrolidin-3-ol (118 mg, 1.17 mmol) at 0°C. The resulting mixture was stirred at 0°C to room temperature for 1 hour. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel column (PE: EtOAc = 1: 1) to give the title product (156 mg). MS (ESI, m / e) [M+H] + 379.0.

[0616] Step 2: 8-Chloro-7-fluoro-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-1-ol

[0617]

[0618] To a solution of 1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)pyrrolidin-3-ol (156 mg, 0.42 mmol) in THF (15 mL) was added NaH (34 mg, 0.85 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. After completion, the mixture was evaporated. The residue was purified by silica gel chromatography (PE:EtOAc=1:1) to give the title product (227 mg, crude). MS (ESI, m / e) [M+H] + 343.0.

[0619] Step 3: 8-Chloro-1,7-difluoro-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0620]

[0621] At room temperature, DAST (159 mg, 0.99 mmol) was added to a solution of 8-chloro-7-fluoro-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulen-1-ol (227 mg, 0.66 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was evaporated. The residue was purified by silica gel chromatography (DCM: MeOH = 20: 1) to give the title product (46 mg). MS (ESI, m / e) [M + H] +345.0.

[0622] Step 4: 8-Chloro-1,7-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0623]

[0624] To a solution of 8-chloro-1,7-difluoro-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (46 mg, 0.16 mmol) in DCM (10 mL) was added m-CPBA (28 mg, 0.16 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour as mixture 1. Meanwhile, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (78 mg, 0.49 mmol) in 15 mL of THF was added LiHMDS (1N in THF, 0.3 mL, 0.3 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour as mixture 2. Then, mixture 2 was added to mixture 1 at room temperature, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was evaporated. The residue was purified by silica gel column chromatography (DCM: MeOH = 10: 1) to give the title product (23 mg, crude product). MS (ESI, m / e) [M+H] + 456.1.

[0625] Step 5: 3-Chloro-5-(1,7-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-4-(trifluoromethyl)aniline

[0626] 3-Chloro-5-(1,7-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-4-(trifluoromethyl)aniline (23 mg, 0.05 mmol), 3-chloro-5-( A mixture of 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (64 mg, 0.2 mmol), NaHCO (13 mg, 0.15 mmol), Pd(dtbpf)Cl (3.3 mg, 0.005 mmol) in dioxane / H2O (10 / 2 mL) was stirred at 95°C for 3 hours. The resulting mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give a residue, which was further purified by preparative HPLC to give the title product (1.6 mg). 1 H NMR(500MHz,CD3OD)δ6.91-6.85(m,1H),6.55-6.41(m,1H),5.45-5.06(m,2H),4.91-4. 88(m,1H),4.42-3.98(m,6H),3.49-3.33(m,3H),3.13-3.08(m,1H),2.50-1.89(m,8H). MS(ESI,m / e)[M+H] + 615.1.

[0627] Example 18: 5-ethynyl-6-fluoro-4-((R)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalen-7-yl)naphthalen-2-ol

[0628]

[0629] Step 1: 4,5,7-Trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0630]

[0631] To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (280 mg, 1.0 mmol) in ACN (10 mL) was added DIEA (194 mg, 1.5 mmol) and POCl3 (184 mg, 1.2 mmol), and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification.

[0632] Step 2: (R)-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methanol

[0633]

[0634] To a stirred solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (200 mg, crude) in DCM (5.0 mL) was added DIEA (129 mg, 1.0 mmol) and (R)-azetidin-2-ylmethanol (44 mg, 0.5 mmol) at 0 °C, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc=4:1 to 1:2) to give the desired product (90 mg). MS (ESI, m / e) [M+H] + 349.2.

[0635] Step 3: (R)-7-Chloro-6-fluoro-4-(methylthio)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalene

[0636]

[0637] To a stirred solution of (R)-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methanol (90 mg, 0.26 mmol) in THF (3.0 mL) at 0°C was added NaH (31 mg, 0.78 mmol, 60%) and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O and then extracted with EtOAc. The organic layer was washed with 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] + 313.1.

[0638] Step 4: (10aR)-7-chloro-6-fluoro-4-(methylsulfinyl)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalene

[0639]

[0640] To a stirred solution of (R)-7-chloro-6-fluoro-4-(methylthio)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalene (0.26 mmol) in DCM (5.0 mL) was added m-CPBA (63 mg, 0.31 mmol, 85%) at 0°C and the resulting mixture was stirred at 0°C for 10 minutes. The reaction was quenched with aqueous Na2S2O3 and then extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0641] Step 5: (R)-7-Chloro-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacycloti[4,5]cyclohepta[1,2,3-de]naphthalene

[0642]

[0643] To a stirred solution of (10aR)-7-chloro-6-fluoro-4-(methylsulfinyl)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutan[4,5]cyclohepta[1,2,3-de]naphthalene (0.26 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (83 mg, 0.52 mmol) in THF (5.0 mL) was added LiHMDS (0.52 mL, 0.52 mmol, 1 M in THF) dropwise at 0°C and the resulting mixture was stirred at 0°C for 20 minutes. The mixture was evaporated and purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the title product (56 mg). MS (ESI, m / e) [M+H] + 424.1.

[0644] Step 6: (R)-6-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacycloti[4,5]cyclohepta[1,2,3-de]naphthalene

[0645]

[0646] (R)-7-chloro-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalene (28 mg, 0.07 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4, A mixture of 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (72 mg, 0.14 mmol), Pd(dtbpf)Cl2 (9 mg, 0.014 mmol), NaHCO3 (18 mg, 0.21 mmol), dioxane (3.0 mL) and H2O (0.6 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 (32 mg). MS (ESI, m / e) [M+H] + 774.2.

[0647] Step 7: (R)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutan[4,5]cyclohepta[1,2,3-de]naphthalene

[0648]

[0649] To a stirred solution of (R)-6-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalene (32 mg, 0.043 mmol) in DMF (3.0 mL) was added CsF (65 mg, 0.43 mmol) and the resulting mixture was stirred at room temperature 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] + 618.3.

[0650] Step 8: 5-ethynyl-6-fluoro-4-((R)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutan[4,5]cyclohepta[1,2,3-de]naphthalen-7-yl)naphthalen-2-ol

[0651] To a stirred solution of (R)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacycloti[4,5]cyclohepta[1,2,3-de]naphthalene (0.043 mmol) in DCM (3.0 mL) at 0°C was added 4N HCl (in dioxane) (1.0 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and basified with DIEA, and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) and then by preparative HPLC to give the product (6.5 mg). 1 H NMR(500MHz,CD3OD)δ7.96–7.73(m,1H),7.50–7.10(m,3H),5.45–5.26(m,1H),5.23–5.06(m,1H) ,4.74–4.62(m,1H),4.57–4.26(m,5H),3.61–3.35(m,4H),3.19–3.06(m,1H),2.70–1.85(m,8H). MS(ESI,m / e)[M+H] + 574.1.

[0652] Example 19: 4-((2R,11aS)-2,7-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0653]

[0654] Step 1: ((2S,4R)-1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-4-fluoropyrrolidin-2-yl)methanol

[0655]

[0656] A solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (200 mg) and ((2S,4R)-4-fluoropyrrolidin-2-yl)methanol hydrochloride (115 mg, 0.74 mmol) in DIEA (0.5 mL) and CH3CN (10 mL) was stirred at room temperature for 2 hours. After completion, the mixture was concentrated in vacuo, and the crude product was purified by silica gel column (eluted with PE / EtOAc=1 / 1) to give the title product (140 mg). MS (ESI, m / e) [M+H] + 381.1

[0657] Step 2: (2R,11aS)-8-chloro-2,7-difluoro-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0658]

[0659] To a solution of ((2S,4R)-1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-4-fluoropyrrolidin-2-yl)methanol (140 mg) in THF (10 mL) was added NaH (40 mg). The mixture was stirred at room temperature for 1 hour. After completion, the reaction was quenched with water. The resulting mixture was evaporated and the crude product was purified by silica gel column (eluted with PE / EtOAc=1 / 9) to give the title product (120 mg). (ESI, m / e)[M+H] + 346.2.

[0660] Step 3: (2R,11aS)-8-chloro-2,7-difluoro-5-(methylsulfinyl)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0661]

[0662] To a mixture of (2R, 11aS)-8-chloro-2,7-difluoro-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (120 mg, 0.35 mmol) in DCM (20 mL) was added m-CPBA (60 mg, 0.35 mmol). The mixture was stirred at room temperature for 1 hour. After completion, the resulting mixture was used directly in the next step. MS (ESI, m / e) [M+H] + 361.1.

[0663] Step 4: (2R,11aS)-8-chloro-2,7-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0664]

[0665] To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (100 mg, 0.63 mmol) in THF (20 mL) was added LiHMDS (0.4 mL), and the mixture was stirred at room temperature for 1 hour. Then, (2R,11aS)-8-chloro-2,7-difluoro-5-(methylsulfinyl)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (20 mL of the mixture from the previous step) was added. After completion, the resulting mixture was concentrated. The crude product was then further purified by silica gel column (eluted with DCM / MeOH=9 / 1) to give the title product (84 mg). MS (ESI, m / e) [M+H] + 456.1.

[0666] Step 5: (2R,11aS)-2,7-difluoro-8-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0667]

[0668] (2R,11aS)-8-chloro-2,7-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (40 mg, 0.088 mmol), Pd(dtbpf)Cl2 A mixture of (20 mg), K3PO4 (30 mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (50 mg, 0.097 mmol) in dioxane (20 mL) and H2O (4 mL) was stirred at 100°C for 6 hours. After completion, the solvent was evaporated and the crude product was purified by silica gel column (eluted with DCM / MeOH=5 / 1) to give the title product (10 mg). MS (ESI, m / e) [M+H] + 806.1

[0669] Step 6: (2R,11aS)-8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,7-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0670]

[0671] To a solution of (2R, 11aS)-2,7-difluoro-8-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (10 mg, 0.012 mmol) in DMF (5 mL) was added CsF (20 mg). The mixture was stirred at room temperature for 3 hours. After completion, the reaction was poured into water and extracted with DCM. The organic layer was concentrated and used directly in the next step. MS (ESI, m / e) [M+H] + 832.4.

[0672] Step 7: 4-((2R,11aS)-2,7-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0673] A mixture of (2R, 11aS)-8-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2,7-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (10 mg crude) in dioxane / HCl (4M) (2 mL) was stirred at room temperature for 2 hours. After completion, the resulting mixture was evaporated and the residue was adjusted to pH=9 with DIPEA. The residue was then further purified by preparative HPLC to give the title product (1.5 mg). 1H NMR(500MHz,DMSO-d6)δ10.14(s,1H),8.00-7.91(m,1H),7.48-7.41(m,1H),7.37(s,1H),7.20-7.11( m,1H),5.54-5.19(m,2H),4.78-4.68(m,1H),4.30-3.95(m,7H),3.31-3.04(m,3H),2.29-1.64(m,7H). MS(ESI,m / e)[M+H] + 606.3.

[0674] Example 20: 5-ethynyl-6-fluoro-4-((S)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalen-7-yl)naphthalen-2-ol

[0675]

[0676] Step 1: 4,5,7-Trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0677]

[0678] To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (200 mg, 0.71 mmol) in MeCN (10 mL) was added DIEA (120 mg, 0.92 mmol) and POCl3 (130 mg, 0.85 mmol), and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification.

[0679] Step 2: (S)-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methanol

[0680]

[0681] To a stirred solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (0.71 mmol) in DCM (10 mL) was added DIEA (271 mg, 2.1 mmol) and (S)-azetidin-2-ylmethanol (62 mg, 0.71 mmol) at 0 ° C., and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc=4:1 to 1:2) to give the desired product (135 mg). MS (ESI, m / e) [M+H] + 349.0.

[0682] Step 3: (S)-7-Chloro-6-fluoro-4-(methylthio)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalene

[0683]

[0684] To a stirred solution of (S)-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)methanol (135 mg, 0.39 mmol) in THF (6.0 mL) at 0°C was added NaH (48 mg, 1.2 mmol, 60%) and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O and then extracted with EtOAc. The organic layer was washed with 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] + 313.1.

[0685] Step 4: (10aS)-7-Chloro-6-fluoro-4-(methylsulfinyl)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalene

[0686]

[0687] To a stirred solution of (S)-7-chloro-6-fluoro-4-(methylthio)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalene (0.39 mmol) in DCM (8.0 mL) was added m-CPBA (83 mg, 0.48 mmol, 85%) at 0°C and the resulting mixture was stirred at 0°C for 10 minutes. The reaction was quenched with aqueous Na2S2O3 and then extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0688] Step 5: (S)-7-Chloro-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacycloti[4,5]cyclohepta[1,2,3-de]naphthalene

[0689]

[0690] To a stirred solution of (10aS)-7-chloro-6-fluoro-4-(methylsulfinyl)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclotitan[4,5]cyclohepta[1,2,3-de]naphthalene (0.39 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (127 mg, 0.80 mmol) in THF (8.0 mL) was added LiHMDS (0.80 mL, 0.80 mmol, 1 M in THF) dropwise at 0°C and the resulting mixture was stirred at 0°C for 20 minutes. The residue was purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the title product (56 mg). MS (ESI, m / e) [M+H] + 424.2.

[0691] Step 6: (S)-6-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacycloti[4,5]cyclohepta[1,2,3-de]naphthalene

[0692]

[0693] (S)-7-chloro-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalene (28 mg, 0.07 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4, A mixture of (5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (72 mg, 0.14 mmol), Pd(dtbpf)Cl2 (9 mg, 0.014 mmol), NaHCO3 (18 mg, 0.21 mmol), dioxane (3.0 mL) and H2O (0.6 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 (12 mg). MS (ESI, m / e) [M+H] + 774.6.

[0694] Step 7: (S)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutan[4,5]cyclohepta[1,2,3-de]naphthalene

[0695]

[0696] To a stirred solution of (S)-6-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclohepta[1,2,3-de]naphthalene (12 mg, 0.016 mmol) in DMF (3.0 mL) was added CsF (24 mg, 0.16 mmol) and the resulting mixture was stirred at room temperature 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] + 618.0.

[0697] Step 8: 5-ethynyl-6-fluoro-4-((S)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacyclobutan[4,5]cyclohepta[1,2,3-de]naphthalen-7-yl)naphthalen-2-ol

[0698] To a stirred solution of (S)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,2,10,10a-tetrahydro-9-oxa-2a,3,5,8-tetraazacycloti[4,5]cyclohepta[1,2,3-de]naphthalene (0.016 mmol) in DCM (2.0 mL) at 0°C was added 4N HCl (in dioxane) (0.4 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and basified with DIEA, and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) and then by preparative HPLC to give the product (0.92 mg). 1H NMR (500MHz, CD3OD) δ7.92–7.73(m,1H),7.37–7.11(m,3H),5.44–5.26(m,1H),5.20–5. 03(m,1H),4.72–4.25(m,6H),3.49–3.34(m,4H),3.19–3.05(m,1H),2.69–1.85(m,8H). MS(ESI,m / e)[M+H] + 574.4.

[0699] Example 21: 5-ethynyl-6-fluoro-4-((S)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalen-7-yl)naphthalen-2-ol

[0700]

[0701] Step 1: 4,5,7-Trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0702]

[0703] To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (200 mg, 0.71 mmol) in MeCN (10 mL) was added DIEA (120 mg, 0.92 mmol) and POCl3 (130 mg, 0.85 mmol), and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification.

[0704] Step 2: (S)-2-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)ethan-1-ol

[0705]

[0706] To a stirred solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (0.71 mmol) in DCM (10 mL) was added DIEA (271 mg, 2.1 mmol) and (S)-2-(azetidin-2-yl)ethan-1-ol (72 mg, 0.71 mmol) at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc=4:1 to 1:2) to give the desired product (216 mg). MS (ESI, m / e) [M+H] + 363.2.

[0707] Step 3: (S)-7-Chloro-6-fluoro-4-(methylthio)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalene

[0708]

[0709] To a stirred solution of (S)-2-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)azetidin-2-yl)ethan-1-ol (216 mg, 0.60 mmol) in THF (6.0 mL) at 0°C was added NaH (72 mg, 1.8 mmol, 60%) and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O and then extracted with EtOAc. The organic layer was washed with 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] + 327.1.

[0710] Step 4: (11aS)-7-Chloro-6-fluoro-4-(methylsulfinyl)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalene

[0711]

[0712] To a stirred solution of (S)-7-chloro-6-fluoro-4-(methylthio)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalene (0.60 mmol) in DCM (8.0 mL) was added m-CPBA (146 mg, 0.72 mmol, 85%) at 0°C and the resulting mixture was stirred at 0°C for 10 minutes. The reaction was quenched with aqueous Na2S2O3 and then extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0713] Step 5: (S)-7-Chloro-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalene

[0714]

[0715] To a stirred solution of (11aS)-7-chloro-6-fluoro-4-(methylsulfinyl)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalene (0.60 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (190 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 minutes. The residue was purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the title product (64 mg). MS (ESI, m / e) [M+H] + 438.3.

[0716] Step 6: (S)-6-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalene

[0717]

[0718] (S)-7-chloro-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalene (32 mg, 0.073 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4, A mixture of (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (77 mg, 0.15 mmol), Pd(dtbpf)Cl2 (10 mg, 0.02 mmol), NaHCO3 (19 mg, 0.22 mmol), dioxane (3.0 mL) and H2O (0.6 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 (32 mg). MS (ESI, m / e) [M+H] + 788.1.

[0719] Step 7: (S)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutan[4,5]cyclooctane[1,2,3-de]naphthalene

[0720]

[0721] To a stirred solution of (S)-6-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalene (32 mg, 0.04 mmol) in DMF (3.0 mL) was added CsF (60 mg, 0.40 mmol) and the resulting mixture was stirred at room temperature 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] + 632.4.

[0722] Step 8: 5-ethynyl-6-fluoro-4-((S)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutan[4,5]cyclooctane[1,2,3-de]naphthalen-7-yl)naphthalen-2-ol

[0723] To a stirred solution of (S)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutan[4,5]cycloocta[1,2,3-de]naphthalene (0.04 mmol) in DCM (3.0 mL) at 0°C was added 4N HCl (in dioxane) (0.4 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and basified with DIEA, and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) and then by preparative HPLC to give the product (6.5 mg). 1 H NMR(500MHz,CD3OD)7.91–7.75(m,1H),7.39–7.14(m,3H),5.45–5.27(m,1H), 4.54–4.24(m,6H),3.66–3.33(m,4H),3.19–3.04(m,1H),2.73–1.85(m,10H). MS(ESI,m / e)[M+H] + 588.3.

[0724] Example 22: 3-Chloro-5-((S)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalen-7-yl)-4-(trifluoromethyl)aniline

[0725]

[0726] A mixture of (S)-7-chloro-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cycloocta[1,2,3-de]naphthalene (32 mg, 0.073 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (48 mg, 0.15 mmol), Pd(dtbpf)Cl2 (10 mg, 0.02 mmol), NaHCO3 (19 mg, 0.22 mmol), dioxane (3.0 mL) and H2O (0.6 mL) was stirred at 90°C 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 (10.8 mg). 1 H NMR(500MHz,CD3OD)δ6.92–6.85(m,1H),6.58–6.39(m,1H),5.48–5.22(m,1H) ,4.56–4.23(m,6H),3.50–3.32(m,3H),3.15–3.01(m,1H),2.75–1.84(m,10H). MS(ESI,m / e)[M+H] + 597.4.

[0727] Example 23: 3-Chloro-5-((R)-6-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,10,11,11a-tetrahydro-2H-9-oxa-2a,3,5,8-tetraazacyclobutane[4,5]cyclooctane[1,2,3-de]naphthalen-7-yl)-4-(trifluoromethyl)aniline

[0728]

[0729] Step 1: (R)-tert-butyl 2-(2-hydroxyethyl)azetidine-1-carboxylate

[0730]

[0731] At 0 ° C, to (R) -2- (1- (tert-butoxycarbonyl) azetidine -2- base) acetic acid (250 mg, 1.16 mmol) in THF (10 mL) in a stirred solution of BH .THF (3.5 mL, 3.5 mmol, 1 M THF solution), and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with CH OH at 0 ° C and then concentrated under reduced pressure. The crude product was purified by flash chromatography (PE / EtOAc = 5: 1 to 1: 1) to give the desired product (225 mg).

[0732] Step 2: (R)-2-(azetidin-2-yl)ethan-1-ol

[0733]

[0734] To a stirred solution of (R)-tert-butyl 2-(2-hydroxyethyl)azetidine-1-carboxylate (225 mg, 1.12 mmol) in DCM (4.0 mL) was added TFA (1.0 ml) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and used in the next step without further purification.

[0735] Example 23 was prepared by a procedure analogous to that described in Example 21 / Example 22, substituting (R)-2-(azetidin-2-yl)ethan-1-ol for (S)-2-(azetidin-2-yl)ethan-1-ol to give the title product (8.7 mg). 1 H NMR(500MHz,CD3OD)δ6.93–6.85(m,1H),6.59–6.39(m,1H),5.48–5.22(m,1H) ,4.56–4.23(m,6H),3.52–3.33(m,3H),3.20–3.05(m,1H),2.75–1.80(m,10H). MS(ESI,m / e)[M+H] + 597.5.

[0736] Example 24: 3-Chloro-5-((11aS)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-methyl-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-4-(trifluoromethyl)aniline

[0737]

[0738] Step 1: (S)-tert-Butyl 2-Formylpyrrolidine-1-carboxylate

[0739]

[0740] At -78 ° C, DMSO (1.2 g, 15 mmol) was added dropwise to a stirred solution of (COCl) (1.3 g, 10 mmol) in DCM (25 mL), and the resulting mixture was stirred at -78 ° C for 30 minutes. Then a solution of (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (3.0 mL) was added dropwise to the above mixture, and the reaction mixture was stirred at -78 ° C for 1 hour. Et3N (2.5 g, 25 mmol) was subsequently added to the above mixture, and the mixture was stirred for another 30 minutes. The reactant was allowed to warm to room temperature and then extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0741] Step 2: tert-Butyl (2S)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate

[0742]

[0743] At -78 ° C, CH was added to a stirred solution of (S)-2-formylpyrrolidine-1-formic acid tert-butyl ester (5.0mmol) in THF (20mL) MgBr (2.5mL, 7.5mmol, 3M), and the resulting mixture was stirred at -78 ° C for 15 minutes, then warmed to room temperature. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (PE / EtOAc=8:1 to 2:1) to obtain the desired product (940mg).

[0744] Step 3: 1-((S)-Pyrrolidin-2-yl)ethan-1-ol

[0745]

[0746] To a stirred solution of (2S)-tert-butyl 2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (4.4 mmol) in DCM (10 mL) was added 4N HCl (in dioxane) (5.0 mL) at room temperature and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The crude product was used in the next step without further purification.

[0747] Step 4: 1-((S)-1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)ethan-1-ol

[0748]

[0749] To a stirred solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (3.2 mmol) in DCM (30 mL) was added DIEA (1.2 g, 9.6 mmol) and 1-((S)-pyrrolidin-2-yl)ethan-1-ol (3.2 mmol) at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc=4:1 to 1:2) to give the desired product (1.1 g). MS (ESI, m / e) [M+1] + 377.1.

[0750] Step 5: (11aS)-8-Chloro-7-fluoro-11-methyl-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0751]

[0752] To a stirred solution of 1-((S)-1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-2-yl)ethan-1-ol (630 mg, 1.67 mmol) in THF (25 mL) at 0°C was added NaH (200 mg, 5.01 mmol, 60%) and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with H2O and then extracted with EtOAc. The organic layer was washed with 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] + 341.1.

[0753] Step 6: (11aS)-8-Chloro-7-fluoro-11-methyl-5-(methylsulfinyl)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0754]

[0755] To a stirred solution of (11aS)-8-chloro-7-fluoro-11-methyl-5-(methylthio)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (1.67 mmol) in DCM (10 mL) was added m-CPBA (340 mg, 1.67 mmol) at 0 ° C and the resulting mixture was stirred at 0 ° C for 10 minutes. The reaction was quenched with aqueous Na2S2O3 and then extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0756] Step 7: (11aS)-8-Chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11-methyl-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene

[0757]

[0758] To a stirred solution of (11aS)-8-chloro-7-fluoro-11-methyl-5-(methylsulfinyl)-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (1.67 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (531 mg, 3.34 mmol) in THF (20 mL) was added LiHMDS (3.3 mL, 3.34 mmol, 1 M in THF) at 0 °C and the resulting mixture was stirred at 0 °C for 20 minutes. The reaction was quenched with saturated aqueous 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 desired product (320 mg). MS (ESI, m / e) [M+H] + 452.2.

[0759] Step 8: 3-Chloro-5-((11aS)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-methyl-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene-8-yl)-4-(trifluoromethyl)aniline

[0760] To a mixture of (11aS)-8-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-11-methyl-2,3,11,11a-tetrahydro-1H-10-oxa-3a,4,6,9-tetraazanaphtho[1,8-ef]azulene (60 mg, 0.13 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (84 mg, 0.26 mmol), Pd(dtbpf)Cl2 (17 mg, 0.03 mmol) and NaHCO3 (33 mg, 0.39 mmol) were added dioxane (4.0 mL) and H2O (0.8 mL). The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 5:1) and then by preparative HPLC to give the title product (25.3 mg). 1 H NMR(500MHz,CD3OD)δ6.90–6.85(m,1H),6.57–6.41(m,1H),5.47–5.26(m,1H),4.47–4.23(m,3H) ,4.06–3.85(m,3H),3.44–3.24(m,3H),3.13–3.02(m,1H),2.41–1.80(m,10H),1.60–1.48(m,3H). MS(ESI,m / e)[M+H] + 611.3.

[0761] Example 25: 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-tetraazanaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline

[0762]

[0763] Step 1: 5-(Azepan-2-ylmethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0764]

[0765] To a stirred solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (280 mg, 1.0 mmol) and azepan-2-ylmethanol (130 mg, 1.0 mmol) in THF (10 mL) was added NaH (140 mg, 3.5 mmol, 60%) at 0°C, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with H2O, and the pH was adjusted to 6 with 1N aqueous 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] + 372.9.

[0766] Step 2: 2-Chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalene

[0767]

[0768] To a stirred solution of 5-(azepan-2-ylmethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.0 mmol) in MeCN (50 mL) was added DIEA (323 mg, 2.5 mmol) and HATU (570 mg, 1.5 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc=4:1 to 1:3) to give the desired product (243 mg). MS (ESI, m / e) [M+H] + 355.2.

[0769] Step 3: 2-Chloro-1-fluoro-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalene

[0770]

[0771] To a stirred solution of 2-chloro-1-fluoro-12-(methylthio)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalene (243 mg, 0.68 mmol) in DCM (10 mL) at 0°C was added m-CPBA (138 mg, 0.68 mmol, 85%) and the resulting mixture was stirred at 0°C for 10 minutes. The reaction was quenched with aqueous Na2S2O3 and then extracted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0772] Step 4: 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-tetraazanaphtho[1,8-ab]heptalene

[0773]

[0774] To a stirred solution of 2-chloro-1-fluoro-12-(methylsulfinyl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptalene (0.68 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (222 mg, 1.4 mmol) in THF (15 mL) was added LiHMDS (1.1 mL, 1.1 mmol, 1 M in THF) dropwise at 0°C and the resulting mixture was stirred at 0°C for 20 minutes. The reaction was quenched with saturated aqueous 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 product (240 mg) as a white solid. MS (ESI, m / e) [M+H] + 466.3.

[0775] Step 5: 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-tetraazanaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline

[0776] To a mixture of 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-tetraazanaphtho[1,8-ab]heptalene (70 mg, 0.15 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (96 mg, 0.30 mmol, 89%), Pd(dtbpf)Cl2 (20 mg, 0.03 mmol) and NaHCO3 (38 mg, 0.45 mmol) was added dioxane (5.0 mL) and H2O (1.0 mL). The reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100: 1 to 5: 1) and then by preparative HPLC to give the product (24.2 mg). 1 H NMR(500MHz,CD3OD)δ6.90–6.85(m,1H),6.57–6.41(m,1H),5.41–5.21(m,1H),5.14–5.02(m,1H),4.67–4.55(m,1H) ,4.50–4.40(m,1H),4.32–4.08(m,3H),3.28–3.15(m,3H),3.06–2.97(m,1H),2.40–1.56(m,13H),1.42–1.26(m,3H). MS(ESI,m / e)[M+H] + 625.5.

[0777] Example 26: 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-tetraazanaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0778]

[0779] Step 1: 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-tetraazanaphtho[1,8-ab]heptalene

[0780]

[0781] To the reaction mixture were 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-tetraazanaphtho[1,8-ab]heptalene (70 mg, 0.15 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4 To a mixture of (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (154 mg, 0.30 mmol), Pd(dtbpf)Cl2 (20 mg, 0.03 mmol) and NaHCO3 (38 mg, 0.45 mmol) was added dioxane (5.0 mL) and H2O (1.0 mL). The reaction mixture 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 (100 mg).

[0782] Step 2: 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-tetraazanaphtho[1,8-ab]heptalene

[0783]

[0784] To a solution of 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-tetraazanaphtho[1,8-ab]heptalene (100 mg, 0.12 mmol) in DMF (4 mL) was added CsF (93 mg, 0.60 mmol) and the resulting mixture was stirred at room temperature for 1 hour. 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] + 660.5.

[0785] 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-tetraazanaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol

[0786] To a solution of 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-tetraazanaphtho[1,8-ab]heptalene (0.12 mmol) in DCM (4.0 mL) at 0°C was added 4N HCl (in dioxane) (1.0 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and basified with DIEA and the residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) and then by preparative HPLC to give the product (32.8 mg). 1 H NMR (500MHz, CD3OD) δ7.86–7.80(m,1H),7.36–7.12(m,3H),5.41–5.22(m,1H),5.18–5.05(m,1H),4.68–4.60(m,1H),4.54–4. 44(m,1H),4.28–4.20(m,2H),4.20–4.06(m,1H),3.53–3.32(m,2H),3.29–3.19(m,3H),3.10–2.98(m,1H),2.45–1.32(m,14H). MS(ESI,m / e)[M+H] + 616.5.

[0787] Example 27: 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]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0788]

[0789] Step 1: (S)-Pyrrolidin-2-ylmethanol

[0790]

[0791] A mixture of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 4.98 mmol) in HCl (4 M) / dioxane (10 mL) was stirred at room temperature for 3 hours. The mixture was then concentrated in vacuo to give the crude product (1.1 g, crude), which was used directly without further purification. MS (ESI, m / e) [M+H] + 102.2.

[0792] Step 2: (S)-(1-(7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-yl)pyrrolidin-2-yl)methanol

[0793]

[0794] To a solution of 7-bromo-4,6-dichloro-5,8-difluoro-2-(methylthio)quinazoline (800 mg, 2.23 mmol), (S)-pyrrolidin-2-ylmethanol (338 mg, 3.35 mmol) in DCM (15 mL) was added DIEA (863 mg, 6.69 mmol). The mixture was stirred at room temperature overnight. Then, the mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (12 g, eluted with PE / EtOAc=100%:0% to 50%:50%) to give the title compound (735 mg). MS (ESI, m / e) [M+H] + 424.1.

[0795] Step 3: (S)-9-Bromo-10-chloro-8-fluoro-6-(methylthio)-2,3,12,12a-tetrahydro-1H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline

[0796]

[0797] To a solution of (S)-(1-(7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-yl)pyrrolidin-2-yl)methanol (735 mg, 1.737 mmol) in THF (10 mL) was added LiHMDS (4.34 mL, 4.34 mmol, 1 M in hexane) at 0°C. The mixture was then stirred at room temperature overnight. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (12 g, eluted with PE / EtOAc=100%:0% to 0%:100%) to give the title compound (486 mg). MS (ESI, m / e) [M+H] + 404.1.

[0798] Step 4: (S)-9-Bromo-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]oxazepino[5,6,7-de]quinazoline

[0799]

[0800] (S)-9-Bromo-10-chloro-8-fluoro-6-(methylthio)-2,3,12,12a-tetrahydro-1H-pyrrolo[2',1':3,4][1,4]oxazepin[5,6,7-de]quinazoline (486 mg, 1.21 mmol) was placed in DCM (10 mL). At 0°C, m-CPBA (237 mg, 1.38 mmol) was added to the solution in batches. The mixture was stirred at 0°C for 2 hours. ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methanol (575 mg, 3.60 mmol) was placed in THF (10 mL). At 0°C, LiHMDS (2.4 mL, 2.40 mmol) was added to the solution in batches. The mixture was stirred at room temperature for 30 minutes, and the mixture was added to the above DCM solution. The mixture was stirred at room temperature overnight, quenched with MeOH (5 mL), and the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with DCM / MeOH=90%:10%) to give the title compound (450 mg). MS (ESI, m / e) [M+H] + 515.1.

[0801] Step 5: 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]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0802] K3PO4 (237 mg, 1.12 mmol), dioxane / water (10 mL / 2 mL), (S)-9-bromo-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]oxazepin[5,6,7-deoxy ] Quinazoline (230mg, 0.447mmol), (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)benzo[b]thiophene-2-yl)carbamic acid tert-butyl ester (374mg, 0.895mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (146mg, 0.223mmol) were stirred at 80°C for 2 hours. The reaction was cooled to room temperature, concentrated in vacuo, and purified by silica gel chromatography (12g, eluted with DCM / MeOH=90%:10%) to give a crude product, which was dissolved in HCl (4M) / dioxane (10mL) and stirred at room temperature for 3 hours. Then, the mixture was concentrated in vacuo and further purified by preparative HPLC to give the title compound (16.2mg). 1 H NMR(500MHz,DMSO-d6)δ8.07(s,2H),7.26-7.11(m,2H),5.37-5.17(m,1H),4.80-4.65(m,1H),4.23-4.17 (m,1H),4.13-3.98(m,3H),3.91-3.75(m,2H),3.13-2.99(m,3H),2.86-2.79(m,1H),2.27-1.66(m,10H). MS(ESI,m / e)[M+H] + 627.3.

[0803] Example 28: 2-amino-4-((2R,12aS)-10-chloro-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-methyl-2,3,12,12a-tetrahydro-1H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0804]

[0805] Example 28 was prepared by a procedure analogous to that described in Example 27, substituting ((2S,4R)-4-methylpyrrolidin-2-yl)methanol for (S)-pyrrolidin-2-ylmethanol to give the title product (14.5 mg). 1H NMR(500MHz,DMSO-d6)δ8.07(s,2H),7.28-7.12(m,2H),5.33-5.12(m,1H),4.79-4.65(m,1H),4.33-4.18(m,2H), 4.14-3.95(m,3H),3.45-3.40(m,1H),3.12-2.97(m,3H),2.85-2.79(m,1H),2.15-1.69(m,8H),1.13-1.02(m,3H). MS(ESI,m / e)[M+H] + 641.3.

[0806] Example 29: 2-amino-4-((2R,12aS)-10-chloro-8-fluoro-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2-hydroxy-2,3,12,12a-tetrahydro-1H-pyrrolo[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-9-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0807] Example 29 was prepared by a procedure analogous to that described in Example 27, substituting (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol for (S)-pyrrolidin-2-ylmethanol to give the title product (5.8 mg). 1 H NMR(500MHz,DMSO-d6)δ8.07(s,2H),7.28–7.07(m,2H),5.35–5.12(m,1H),4.80–4.72(m,1H), 4.47–3.95(m,6H),3.78–3.63(m,1H),3.13–2.98(m,3H),2.90–2.75(m,1H),2.45-1.47(m,8H). MS(ESI,m / e)[M+H] + 643.3.

[0808] Example 30: (8aS)-5-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrido[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10-carbonitrile

[0809]

[0810] Example 30 was prepared by a procedure analogous to that described in Example 27, substituting (2S)-tert-butyl 4-cyano-2-(hydroxymethyl)piperidine-1-carboxylate for (S)-pyrrolidin-2-ylmethanol to give the title product (5 mg). 1 H NMR(500MHz,DMSO-d6)8.09(s,2H),7.25–7.11(m,2H),5.35–5.15(m,1H),5.10-4.95(m,1H),4.64-4.39(m,2H),4.20-3.93(m,3H),3 .58-3.48(m,1H),3.23-3.15(m,1H),3.11-2.98(m,2H),2.90-2.79(m,1H),2.19-1.97(m,5H),1.91-1.74(m,4H),1.29-1.07(m,2H). MS(ESI,m / e)[M+H] + 666.4.

[0811] Example 31: 2-amino-4-((8aS,10R)-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-10-hydroxy-8,8a,9,10,11,12-hexahydropyrido[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0812]

[0813] Step 1: (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)piperidine-1-carboxylate

[0814]

[0815] At 0 ° C, LiBH4 (2M in THF, 7ml, 14mmol) was added to a solution of (2S, 4R)-4-hydroxypiperidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (2.6g, 10mmol) in THF (40mL). The mixture was stirred at room temperature overnight. The mixture was quenched with NH4Cl (aqueous solution) and extracted with EtOAc. Then, the organic phase was concentrated in vacuo to give a crude product. The residue was purified by silica gel column chromatography (20g, eluted with DCM / MeOH=100%:0% to 90%:10%) to give the title compound (2.0g).

[0816] Step 2: (2S,4R)-2-(Hydroxymethyl)piperidin-4-ol

[0817]

[0818] To a suspension of (2S, 4R)-4-hydroxy-2-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 6.5 mmol) in DCM (10 mL) was added TFA (10 mL) dropwise. The mixture was stirred at room temperature for 1 hour. Then, the mixture was concentrated in vacuo to give a crude product (1.6 g, crude product) which was used directly without further purification.

[0819] Example 31 was prepared by a procedure analogous to that described in Example 27, substituting (2S,4R)-2-(hydroxymethyl)piperidin-4-ol for (S)-pyrrolidin-2-ylmethanol to give the title product (5 mg). 1 H NMR(500MHz,DMSO-d6)δ8.08(s,2H),7.33-7.09(m,2H),5.39-5.18(m,1H),4.98-4.89(m,1H),4.48-4.39(m,2H ),4.16-3.77(m,4H),3.06-2.96(m,3H),2.84(m,1H),2.15-1.95(m,6H),1.88-1.74(m,3H),1.45-1.35(m,1H). MS(ESI,m / e)[M+H] + 657.3.

[0820] Example 32: 5-ethynyl-6-fluoro-4-((5aS,6aS,7aS)-1-fluoro-9-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,6a,7,7a-hexahydro-4-oxa-3,7b,8,10-tetraazirido[a]naphtho[1,8-gh]azulene-2-yl)naphthalen-2-ol

[0821]

[0822] Example 32 was prepared by a procedure analogous to that described in Example 21, substituting ((1S,3S,5S)-2-azabicyclo[3.1.0]hexan-3-yl)methanol for (S)-2-(azetidin-2-yl)ethan-1-ol to give the title product (21 mg). 1HNMR(500MHz,CD3OD)δ7.89–7.78(m,1H),7.38–7.17(m,3H),5.49–5.30(m,1H),4.81–4.73(m,1 H),4.59–4.49(m,2H),4.46–4.34(m,1H),4.26–4.14(m,1H),3.92–3.82(m,1H),3.69–3.42(m,4H ),3.26–3.15(m,1H),2.87–2.73(m,1H),2.56–2.34(m,2H),2.33–2.21(m,1H),2.20–2.08(m,2H) ,2.08–1.92(m,1H),1.92–1.82(m,1H),1.81–1.71(m,1H),1.39–1.26(m,1H),0.74–0.63(m,1H). MS(ESI,m / e)[M+1] + 600.8.

[0823] Example 33: 3-Chloro-5-((5S,5aS)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)-4-(trifluoromethyl)aniline

[0824]

[0825] Example 33 was prepared by a procedure analogous to that described in Example 23, substituting (S)-1-((S)-piperidin-2-yl)ethan-1-ol for (R)-2-(azetidin-2-yl)ethan-1-ol to give the title product (4.8 mg). 1 H NMR(500MHz,DMSO-d6)δ6.85(s,1H),6.48-6.30(m,3H),5.36-5.20(m,1H),5.01-4.96(m,1H),4.54-4.49(m,1H),4.15-4.09(m,1H), 4.03-3.97(m,1H),3.91-3.84(m,1H),3.18-3.01(m,4H),2.84-2.76(m,1H),2.20-1.95(m,3H),1.89-1.53(m,8H),1.48-1.29(m,4H). MS(ESI,m / e)[M+H] + 625.5.

[0826] Example 34: 5-ethynyl-6-fluoro-4-((5S,5aS)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)naphthalen-2-ol

[0827]

[0828] Example 34 was prepared by a procedure analogous to that described in Example 21, substituting (S)-1-((S)-piperidin-2-yl)ethan-1-ol for (S)-2-(azetidin-2-yl)ethan-1-ol to give the title product (8.8 mg). 1 H NMR(500MHz,DMSO-d6)δ10.31-10.01(m,1H),8.01-7.94(m,1H),7.52-7.46(m,1H),7.23-7.20(m,1H),7.16- 7.07(m,1H),5.37-4.43(m,3H),4.15-3.76(m,4H),3.21-2.98(m,4H),2.87-2.80(m,1H),2.21-1.37(m,15H). MS(ESI,m / e)[M+H] + 616.6.

[0829] Example 35: (5aS,8S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-8-ol

[0830]

[0831] Example 35 was prepared by a procedure analogous to that described in Examples 15 / 16, substituting (3S,6S)-6-(hydroxymethyl)piperidin-3-ol for (S)-piperidin-2-ylmethanol to give the title product (3.5 mg). 1H NMR(500MHz,CD3OD)δ7.86–7.81(m,1H),7.33–7.15(m,3H),5.50–5.34(m,2H),4.62-4.55(m,2H),4.50–4.10(m,1H),4.39–4.27(m,1H) ,4.16–4.08(m,1H),4.00–3.92(m,1H),3.61–3.35(m,4H),3.21–3.11(m,1H),2.53–2.18(m,4H),2.17–1.90(m,5H),1.81–1.70(m,1H). MS(ESI,m / e)[M+H] + 618.5.

[0832] Determination

[0833] KRAS WT and KRAS G12V probe replacement assay

[0834] The assay is used to identify compounds that bind to GDP-loaded KRAS proteins and are able to displace biotinylated probes that occupy KRAS binding sites. GST-labeled GDP-loaded WT KRAS (amino acids 1-169) and GST-labeled GDP-loaded KRAS G12V (amino acids 1-169) were expressed in Escherichia coli and purified in-house. All proteins and reaction solutions were prepared in an 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 for WT KRAS (60 nM final assay concentration) and biotinylated probe 2 for KRAS G12V (2.5 nM final assay concentration) were added to the assay plate, respectively. After incubation for 1 hour at 24°C, MabAnti-GST-Tb cryptate (Cisbio) and streptavidin-XL665 (Cisbio) were added and incubated for another 1 hour at 24°C. TR-FRET signals (ex337nm, em665nm / 620nm) were read on a BMG PHERAstar FSX instrument. The percentage of inhibition of KRAS protein binding to the biotinylated probe in the presence of increasing concentrations of compound was calculated based on the ratio of fluorescence at 665nm to fluorescence at 620nm. The data were fitted to a four-parameter logistic model by Dotmatics to calculate the IC for each compound. 50 value.

[0835] KRAS WT and KRAS G12D probe displacement assay

[0836] The assay is used to identify compounds that bind to GDP-loaded KRAS proteins and are able to displace biotinylated probes that occupy KRAS binding sites. GST-labeled GDP-loaded WT KRAS (amino acids 1-188) and GST-labeled GDP-loaded KRAS G12D (amino acids 1-188) were expressed in Escherichia coli and purified in-house. All proteins and reaction solutions were prepared in an 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 for WT KRAS (60 nM final assay concentration) and biotinylated probe 2 for KRAS G12D (4 nM final assay concentration) were added to the assay plate, respectively. After incubation for 1 hour at 24°C, Mab Anti-GST-Tb cryptate (Cisbio) and streptavidin-XL665 (Cisbio) were added and incubated for another 1 hour at 24°C. TR-FRET signals (ex337nm, em665nm / 620nm) were read on a BMG PHERAstar FSX instrument. The percentage of inhibition of KRAS protein binding to the biotinylated probe in the presence of increasing concentrations of compound was calculated based on the ratio of fluorescence at 665nm to fluorescence at 620nm. The data were fitted to a four-parameter logistic model by Dotmatics to calculate the IC for each compound. 50 value.

[0837] KRAS G12V pERK assay

[0838] The SW620 cell line was used in this study. The cells were maintained in RP MI 1640 supplemented with 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin and streptomycin (Thermo Fisher) and maintained at 37°C in a humidified atmosphere with 5% CO2 in the air. The cells were revived from frozen cells within 30 passages of the purchased original cells. 40,000 cells per well were seeded in a 96-well plate and incubated overnight. The cells were treated with a 10-point dilution series. The final compound concentration was 0 μM to 10 μM. After 2 hours of compound treatment, the cells were lysed and the pERK1 / 2 (THR 202 / TYR204) level in the cell lysate was detected by HTRF kit (Cisbio). 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. 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 (Cisbio) at room temperature in the dark 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 the inhibitor concentration using Dotmatics.

[0839] KRAS G12D pERK assay

[0840] AsPC-1 cell line was used in this study. Cells were maintained in RP MI-1640 supplemented with 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin and streptomycin (Thermo Fisher) and maintained at 37°C in a humid atmosphere containing 5% CO2 in the air. Cells were revived from frozen cells within 30 passages of the purchased original cells. 30,000 cells per well were seeded in a 96-well plate and incubated overnight. Cells were treated with a 10-point dilution series. The final compound concentration was 0 μM to 10 μM. After 2 hours of compound treatment, cells were lysed and pERK1 / 2 (THR202 / TYR204) levels in cell lysates were detected by HTRF kit (Cisbio). 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. 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 (Cisbio) at room temperature overnight in the dark. When the donor and acceptor are in close proximity, excitation of the donor with a laser 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). IC was performed by fitting a curve of percent inhibition versus the logarithm of the inhibitor concentration using Dotmatics 50 Determination.

[0841] KRAS G12D protein preparation and crystallization

[0842] KRAS G12D protein purification

[0843] KRAS G12D 1-169aa was cloned into pET28a vector. The gene was placed in frame with N-terminal 6Xhis tag and Sumo tag. The construct was transformed into BL21(DE3) cells. When the cells reached OD 600When the pH was 0.6, protein expression was induced by adding 1-thio-β-D-galactopyranoside (IPTG) to a final concentration of 200uM, and then incubated overnight at 16°C. Bacteria were harvested by centrifugation (4000rpm, 20 minutes, 4°C), and 1 liter of cell paste was resuspended in 30ml of 50mMTris pH 8.0, 300mM NaCl, 20mM imidazole, 5mM MgCl2, supplemented with 2 stacks of EDTA-free protease inhibitor cocktail tablets (Roche Diagnostics). Proteins were purified using His-trap HP columns (Cytiva) according to standard protocols. The N-terminal His-sumo tag was cleaved by digestion with ULP1 protease overnight, and the UPL1 and His-sumo tags were removed by reloading into the His-trap HP columns (Cytiva). The protein was further purified by gel filtration on HiLoad 16 / 600 Superdex 75 pg (Cytiva) equilibrated with 20 mM Tris pH 8.0, 100 mM NaCl, 5 mM MgCl2. The protein solution was concentrated to 30-40 mg / ml for crystallization experiments.

[0844] KRAS G12D crystallization

[0845] KRAS G12D with small molecule inhibitor co-crystals were grown at 20°C by mixing 1 ul of protein (40 mg / ml) with an equal volume of crystallization buffer using sitting drop vapor diffusion. Crystals emerged as droplets containing 1.0 M LiCl, 0.1 M citric acid pH 5.0, 20% PEG 6000. Diffraction data were collected at beamline BL10U2 of the Shanghai Synchrotron Radiation Source.

[0846] Metabolic stability of different types of liver microsomes

[0847] First, liver microsomes were mixed with NADPH to obtain final concentrations of 0.5 mg / mL and 1 mM microsomes and NADPH, 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. 20 μL aliquots were taken out of the incubation system at 0, 15, 30, 45 and 60 minutes after the start of incubation. The reaction solution was stopped by adding cold acetonitrile with analytical IS. The sample was centrifuged at 4000 rpm for 5 minutes and then analyzed on LC-MS / MS.

[0848] The peak areas of samples from different time points were determined from the extracted ion chromatograms; these were then plotted to calculate metabolic stability. The slope value k was determined by linear regression of the natural logarithm of the percentage of parent drug remaining versus the incubation time curve. The in vitro half-life (in vitro t 1 / 2 ):

[0849] In vitro 1 / 2 =-(0.693 / k)

[0850] In vitro t 1 / 2 (in minutes) converted to in vitro intrinsic clearance (in vitro CL int , in μL / min / mg protein) using the following formula (average of duplicate determinations):

[0851]

[0852] 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.

[0853] CYP (Cytochrome P450) Enzyme Inhibition Assay in Human Liver Microsomes

[0854] 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 substrates for 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). The incubation plates were preheated in a 37°C water bath for 5 minutes before starting the reaction by adding 20 μL of 10 mM NADPH solution. The reactions were performed in a 37°C water bath.

[0855] At predetermined time points, the reaction was stopped by adding 300 μL of quenching solution (acetonitrile with internal standard) to each well. The sample plate was vortexed for 1 minute and centrifuged at 3000 g for 10 minutes. 100 μL of supernatant was transferred to a new 96-well plate and then mixed with 100 μL of water to be analyzed by LC-MS / MS, followed by data processing (i.e., inhibition percentage or IC50 determination at 10 uM).

[0856] Time-dependent Cytochrome P450 (CYP) Enzyme Inhibition Assay (TDI) in Human Liver Microsomes

[0857] The TDI assay involves preincubation of 0.1 mg·mL-1 human liver microsomes with 10 uM test compound and positive control in the presence or absence of 1 mM NADPH at 37°C ("inactivation incubation") for 30 minutes. After the pre-incubation 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 pre-incubation mixture, and an additional 20 minutes of "active incubation" for CYP1A2, 2B6, 2C19, 2D6, 10 minutes for CYP2C8, CYP3A (testosterone), 6 minutes for CYP2C9, and 5 minutes for 3A (midazolam). All reactions were terminated by the addition of ice-cold acetonitrile with internal standard and then centrifuged for LC-MS / MS analysis.

[0858] Bidirectional permeability assay in MDCKII-MDR1 cell monolayers

[0859] First, MDCKII-MDR1 cells were prepared in cell seeding medium. 50 μL of cultured cell suspension was added to each well of the previously prepared Transwell plate. The plate was incubated for 4-8 days. The medium was replaced every other day. Before permeability measurement, the integrity of the cell monolayer was assessed via the resistance method.

[0860] To determine the transport rate of drugs in the apical to basolateral direction, 125 μL of the test compound working solution was added to the Transwell chamber (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 transport rate of drugs in the basolateral to apical direction, 285 μL of the compound working solution was added to the receiving 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 well and the basolateral well and transferred to a new plate. Then 200 μL of cold acetonitrile containing internal standards (IS: 2 μM ketoprofen, 200 nM labetalol, 200 nM caffeine and 100 nM alprazolam) was added to the plate. Vortex for 5 minutes. The samples were centrifuged at 3,220 g for 20 minutes. An aliquot of 100 μL of supernatant was diluted with 100 μL ultrapure H2O and the mixture was used for LC / MS / MS analysis. All incubations were performed in duplicate. For MDCKII-MDR1 drug transport assays, the apparent permeability (Papp) (in cm / sec) can be calculated using the following formula:

[0861]

[0862] where VA is the volume in mL in the acceptor 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 scaffolds). 2 ), and time is the total transit time in seconds.

[0863] The outflow ratio can be determined using the following formula:

[0864]

[0865] Where P app(B-A) represents the apparent permeability coefficient in the basolateral to apical direction, and P app(A-B) Represents the apparent permeability coefficient in the apical to basolateral direction.

[0866] Recovery can be determined using the following formula:

[0867]

[0868] Where V A is the volume in mL in the acceptor pore (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).

[0869] Intrinsic clearance of different hepatocyte types

[0870] Prepare 10 mM stock solutions of test compounds and positive controls in appropriate solvents (DMSO). Place incubation medium (William's 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 combining 198 μL of 50% acetonitrile / 50% water and 2 μL of 10 mM stock solutions. Pipette 198 μL of cryopreserved hepatocytes (0.5×10 62 μL of 100 μM test compound or positive control was transferred to the corresponding well of the 96-well non-coated plate to start the reaction. 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. At 0, 15, 30, 60, 90 and 120 minutes, the well contents were removed in 25 μL aliquots. The aliquots were then mixed with 6 volumes (150 μL) of cold acetonitrile and IS (2 μM ketoprofen, 200 nM labetalol, 200 nM caffeine and 100 nM alprazolam) to terminate the reaction. Centrifuged at 3,220 g for 30 minutes. An aliquot of 100 μL supernatant was 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 performed in duplicate.

[0871] All calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. In vitro half-lives (t ) of the parent compounds were determined by regression analysis of the parent disappearance percentage versus time curves. 1 / 2 ).

[0872] In vitro half-life (in vitro t 1 / 2 ) is determined by the slope value:

[0873] In vitro 1 / 2 =0.693 / k

[0874] In vitro 1 / 2 (in minutes) to the in vitro intrinsic clearance (in vitro CL int , in μL / min / 10 6 The conversion of cells into cells was performed using the following formula:

[0875] In vitro CL int =kV / N

[0876] V = incubation volume (0.2 mL); N = number of hepatocytes per well (0.1 × 10 6 cells).

[0877] Mouse and rat PK studies

[0878] The pharmacokinetics of the compound were evaluated in male CD-1 mice or SD-JVC rats via intravenous and oral administration. For intravenous administration studies, the test compound was dissolved in DMA: 30% Solutol HS15 (w / v): saline (20: 20: 60, volume ratio), and 1mg / kg dose was injected via tail vein. For oral administration studies, the test compound was dissolved in 0.5% MC or PEG400 / Phosal 50PG / EtOH (30 / 60 / 10, volume ratio), and was administered to mice by gavage at 10mg / kg or 30mg / kg. Animals were grouped and processed according to body weight. At each time point after administration (5 minutes (only IV), 15 minutes and 30 minutes after administration and 1 hour, 2 hours, 4 hours, 8 hours and 24 hours), rat blood samples were collected from JVC, mice were anesthetized with isoflurane, and blood samples were collected from orbital bleeding. Blood samples were collected in 1.5 mL EDTA.K2 coated EP tubes. About 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 minutes at 4°C to obtain plasma. Plasma was transferred to a new tube and temporarily stored at -20°C or on dry ice. Samples were stored at -80°C until in vitro PK determination was performed.

[0879] Plasma concentrations were determined via the following sample treatment method and measurement conditions. 200 μL of IS (terfenadine, 5 ng / mL) in ACN was added to an aliquot of 10 μL of sample. The mixture was vortexed for 1 minute and centrifuged at 4000 rpm for 10 minutes 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. Injection volume: 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).

[0880] SW1990 PD Study:

[0881] Female NCG mice were implanted subcutaneously in the right flank with 5×10 6SW1990 cells / 200 μL PBS / Matrigel. After inoculation, when the tumor size reaches about 350-450 mm 3 The mice were randomly divided into treatment groups when the average volume of MC was 1.5% MC. The randomized mice will receive a single dose of a vehicle consisting of 0.5% MC or a test compound at different doses (e.g., 30, 50, or 100 mg / kg) by oral administration. Plasma was collected at 0.5, 2, 4, and 7 hours after administration, and tumors were collected 7 hours after administration to determine the exposure level. Tumor fragments were quickly frozen in a homogenization tube with liquid nitrogen and homogenized with T-PER tissue protein extraction buffer with freshly added protease and phosphatase inhibitors before use. Tumor lysates were then analyzed for ERK1 / 2 phosphorylation.

[0882] SW1990 Efficacy Study:

[0883] Female NCG mice were implanted subcutaneously in the right flank with 5×10 6 SW1990 cells / 200 μL PBS / Matrigel. After inoculation, when the tumor size reaches about 150-250 mm 3 The mice were randomized into treatment groups when the mean volume of the tumor reached 1.5 % MC. The randomized mice received either vehicle consisting of 0.5% MC or different doses (e.g., 30, 50, or 100 mg / kg BID) of the test compound by oral administration. The animals were monitored daily, and tumor volumes were measured twice a week in two dimensions using calipers 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 starting tumor volume on the first day of dosing 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:

[0884]

[0885] Treatment t = volume of tumor treated at time t

[0886] Treatment t0 = volume of tumor treated at time 0

[0887] Placebo t = Placebo tumor volume at time t

[0888] Placebo t0 = placebo tumor volume at time 0

[0889] SW620 PD Study:

[0890] Female NOD / SCID mice were implanted subcutaneously in the right flank with 5×10 6 SW620 cells / 200 μL PBS / Matrigel. After inoculation, when the tumor size reaches about 350-450 mm 3 The mice were randomly divided into treatment groups when the average volume of MC was 1.5% MC. The randomized mice will receive a single dose of a vehicle consisting of 0.5% MC or a test compound at different doses (e.g., 30, 50, or 100 mg / kg) 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 after administration to determine the exposure level. Tumor fragments were quickly frozen in a homogenization tube with liquid nitrogen and homogenized with T-PER tissue protein extraction buffer with freshly added protease and phosphatase inhibitors before use. Tumor lysates were then analyzed for ERK1 / 2 phosphorylation.

[0891] SW620 efficacy study:

[0892] Female NOD / SCID mice were implanted subcutaneously in the right flank with 5×10 6 SW620 cells / 200 μL PBS / Matrigel. After inoculation, when the tumor size reaches about 150-250 mm 3 The mice were randomized into treatment groups when the mean volume of the tumor reached 1.5 % MC. The randomized mice received either vehicle consisting of 0.5% MC or different doses (e.g., 30, 50, or 100 mg / kg BID) of the test compound by oral administration. The animals were monitored daily, and tumor volumes were measured twice a week in two dimensions using calipers 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 starting tumor volume on the first day of dosing 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:

[0893]

[0894] Treatment t = volume of tumor treated at time t

[0895] Treatment t0 = volume of tumor treated at time 0

[0896] Placebo t = Placebo tumor volume at time t

[0897] Placebo t0 = placebo tumor volume at time 0

[0898] RKN PD Study:

[0899] Female NOD / SCID mice were implanted subcutaneously in the right flank with 5×10 6 RKN cells / 200 μL PBS / Matrigel. After inoculation, when the tumor size reached about 350-450 mm 3 The mice were randomly divided into treatment groups when the average volume of MC was 1.5% MC. The randomized mice will receive a single dose of a vehicle consisting of 0.5% MC or a test compound at different doses (e.g., 30, 50, or 100 mg / kg) 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 after administration to determine the exposure level. Tumor fragments were quickly frozen in a homogenization tube with liquid nitrogen and homogenized with T-PER tissue protein extraction buffer with freshly added protease and phosphatase inhibitors before use. Tumor lysates were then analyzed for ERK1 / 2 phosphorylation.

[0900] SW620 efficacy study:

[0901] Female NOD / SCID mice were implanted subcutaneously in the right flank with 5×10 6 RKN cells / 200 μL PBS / matrigel. After inoculation, when the tumor size reaches about 150-250 mm 3 The mice were randomized into treatment groups when the mean volume of the tumor was 2.5 wt% (100 μg / kg) / day. The randomized mice received either vehicle consisting of 0.5% MC or different doses (e.g., 30, 50, or 100 mg / kg BID) of the test compound by oral administration. The animals were monitored daily, and tumor volumes were measured twice a week in two dimensions using calipers 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 starting tumor volume on the first day of dosing 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:

[0902]

[0903] Treatment t = volume of tumor treated at time t

[0904] Treatment t0 = volume of tumor treated at time 0

[0905] Placebo t = Placebo tumor volume at time t

[0906] Placebo t0 = Placebo tumor volume at time 0

[0907] AsPC-1PD Study:

[0908] 3×10 6 AsPC-1 cells / 200 μL PBS / matrigel. 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 1.5% MC. The randomized mice will receive a single dose of a vehicle consisting of 0.5% MC or a test compound at different doses (e.g., 30, 50, or 100 mg / kg) 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 after administration to determine the exposure level. Tumor fragments were quickly frozen in a homogenization tube with liquid nitrogen and homogenized with T-PER tissue protein extraction buffer with freshly added protease and phosphatase inhibitors before use. Tumor lysates were then analyzed for ERK1 / 2 phosphorylation.

[0909] AsC-1 efficacy research:

[0910] 3×10 6 AsPC-1 cells / 200 μL PBS / matrigel. After inoculation, when the tumor size reaches about 150-250 mm 3 The mice were randomized into treatment groups when the mean volume of the tumor was 2.5 wt% (100 μg / kg) / day. The randomized mice received either vehicle consisting of 0.5% MC or different doses (e.g., 30, 50, or 100 mg / kg BID) of the test compound by oral administration. The animals were monitored daily, and tumor volumes were measured twice a week in two dimensions using calipers 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 starting tumor volume on the first day of dosing 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:

[0911]

[0912] Treatment t = volume of tumor treated at time t

[0913] Treatment t0 = volume of tumor treated at time 0

[0914] Placebo t = Placebo tumor volume at time t

[0915] Placebo t0 = Placebo tumor volume at time 0

[0916] hERG assay

[0917] hERG (human Ether-à-go-go related gene) encodes a rapidly activated potassium channel (I Kr ). Blockade of the hERG channel can lead to QT prolongation in the electrocardiogram known as long QT syndrome. In some cases, drug-induced delayed ventricular repolarization can trigger a fatal arrhythmia - torsades de pointes. About 25-40% of lead drug compounds show varying degrees of potential risk of hERG dependence, and many drugs have been withdrawn from the market due to the risk of QT prolongation.

[0918] Prior to testing hERG currents, the blank control was diluted with an appropriate volume of extracellular solution to prepare a control working solution. Positive control and test article stock solutions were taken from -20°C, thawed, and diluted with an appropriate volume of extracellular solution to prepare working solutions.

[0919] The highest concentration of the test article working solution will be diluted from the stock solution with the extracellular solution, or the stock solution should be diluted with DMSO first. For the test articles of other test concentrations, DMSO will be used for serial dilution and then prepared into working solutions with 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 form. Finally, all working solutions of the test articles were ultrasonicated for 20 minutes before performing the patch clamp experiment.

[0920] Keep the blank control (DMSO) stock solution at room temperature. Prepare the blank control working solution on the day of testing and keep it at room temperature. Positive control stock solution and test article stock solution will be stored at -20°C. Prepare the positive control and test article working solutions on the day of testing and keep them at room temperature.

[0921] Test article concentrations will be automatically set to 30, 10, 3, 1, and 0.3 μM. Blank controls will be 0.3% DMSO, and positive control (cisapride) concentrations will be 1000, 100, 10, 1, 0.1 nM.

[0922] In this study, electrophysiological recordings will be performed using the automated patch clamp system QPatch 48X (Sophion).

[0923] The prepared cells are placed on a centrifuge on the Qpatch work surface, the cells are washed by multiple centrifugation / suspension, and the cell culture medium is replaced with an extracellular solution. An MTP-96 plate is taken out and placed in the MTP source position. The QPlate chip is taken out and placed in the Qplate source position. The barcode reader scans the barcodes of the MTP-96 plate and the QPlate chip, and the clamping arm grabs them to the measurement position. The intracellular and extracellular solutions in the saline container are added to the intracellular saline wells, cells and compound wells of the QPlate chip. For measurement, all measurement points of the QPlate will be under initial quality control. The quality control process includes drawing the cell suspension from the cell container of the centrifuge, positioning the cells on the chip wells through a pressure controller, establishing a high barrier seal, and forming a whole-cell recording mode. Once a stable control current baseline is obtained, the test article will be applied to the cell by sequentially drawing from the MTP-96 plate in order of concentration. hERG currents were recorded using the whole-cell patch clamp technique at a holding potential of -80mV, then depolarized to -50mV for 0.5 seconds to test leakage currents. The voltage was then depolarized to 30mV for 2.5 seconds. Peak tail current was induced to -50mV by a repolarization pulse for 4 seconds. The protocol was repeated at 10 second intervals to observe the effects of the test article on hERG tail currents. The data will be collected by the QPatch screening station and stored in the QPatch database server.

[0924] In the experiment, each drug concentration will be applied twice with a recording period of at least 5 minutes. Control and test solutions will be applied to cells sequentially from low to high concentrations. The current detected for each cell in the extracellular solution without compound will serve as its own blank control.

[0925] Calculation IC 50 The dose-response curves were fitted using the nonlinear regression equation above, where IC 50 The IC values ​​were calculated using GraphPad Prism software. 50 Calculation and curve fitting.

[0926] Active Table

[0927] Each compound in Table 2 and Table 3 was tested in one or more of the biochemical assays provided herein and found to be active therein.

[0928] Table 2

[0929]

[0930]

[0931] Table 3

[0932]

[0933] As shown by the data in Tables 2-3, the present inventors surprisingly and unexpectedly discovered that the exemplary compounds in Tables 2-3 can modulate or inhibit the activity of KRAS G12D and / or G12V.

[0934] 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 an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group; Ring B is an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclic group; X is N or CR 8 ; 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 said R 0 The groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocyclyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl; R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a and R 7b Each of the following is independently H, halogen, unsubstituted or substituted 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, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 4a and R 4b Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 6a and R 6b Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 7a and R 7b Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or optionally, R 3a and R 4a Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 4a and R 5 Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 5 and R 6a Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 6a and R 7a together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; 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 Alkyl halides, unsubstituted or substituted C 3-5 Halogenated cycloalkyl, unsubstituted or substituted C 1-4 Halogenated alkoxy, CN, OH or amino; t is 0 or 1; u is 1, 2, 3, or 4; and Each of m and q is independently an integer between 0 and the maximum number of substituent groups 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 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 Ring 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, or substituted or unsubstituted oxabicyclo[2.2.1]heptanyl.

4. The compound as claimed in claim 3, wherein ring A is 5. The compound as claimed in claim 4, wherein ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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.

6. The compound of claim 5, wherein the compound is a compound having formula (II):

7. The compound as claimed in claim 6, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 7a and R 7b Each of R is independently H or methyl, and R 6a1 , R 6b1 Independently selected from H, halogen, methyl, -CN, -OH, substituted or unsubstituted amino.

8. The compound as claimed in claim 6, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; R 3a , R 3b , R 5 , R 7a and R 7b Each of R is independently H or methyl; and R 6a1 and R 6b1 Together with the atoms to which they are attached they form an unsubstituted or substituted heterocyclyl.

9. The compound as claimed in claim 6, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 7a and R 7b Each of R is independently H or methyl, and R 6a1 , R 6b1 Independently selected from H, halogen, methyl, -CN, -OH, substituted or unsubstituted amino.

10. The compound of claim 5, wherein the compound is a compound having formula (III):

11. The compound according to claim 10, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

12. The compound according to claim 10, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of R is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl; or optionally, R 3a and R 5 Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 6a1 and R 5 Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 6a1 and R 6a2 Together with the atoms to which they are attached, they form an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted heterocyclyl group; or R 6a2 and R 7a Together with the atoms to which they are attached they form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl.

13. The compound of claim 10, wherein X is CH; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

14. The compound of claim 10, wherein X is CH; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

15. The compound of claim 10, wherein X is CF; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

16. The compound as claimed in claim 10, wherein X is C-Cl; Ring A is And ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

17. The compound as claimed in claim 10, wherein X is C-Cl; Ring A is And ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

18. The compound of claim 10, wherein X is C-CF3; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

19. The compound of claim 5, wherein the compound is a compound having formula (IV):

20. The compound of claim 19, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, hydroxymethyl or methyl.

21. The compound of claim 19, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

22. The compound according to claim 19, wherein X is C-Cl; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

23. The compound according to claim 19, wherein X is C-Cl; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

24. The compound of claim 19, wherein X is C-Cl; Ring A is And ring 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

25. The compound of claim 5, wherein the compound is a compound having formula (V):

26. The compound of claim 25, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

27. The compound of claim 5, wherein the compound is a compound having formula (VI):

28. The compound of claim 27, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

29. The compound of claim 5, wherein the compound is a compound having formula (VII):

30. The compound of claim 29, wherein X is N; Ring A is Ring 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; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

31. The compound of claim 29, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

32. The compound of claim 29, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

33. The compound of claim 29, wherein X is CH; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

34. The compound of claim 29, wherein X is CH; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

35. The compound of claim 29, wherein X is C-Cl; Ring A is Ring 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; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

36. The compound of claim 29, wherein X is C-Cl; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

37. The compound of claim 29, wherein X is C-CF3; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

38. The compound of claim 5, wherein the compound is a compound having formula (VIII):

39. The compound of claim 38, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

40. The compound of claim 38, wherein X is CH; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

41. The compound of claim 5, wherein the compound is a compound having formula (IX):

42. The compound of claim 41, wherein X is N; Ring A is Ring B is Where R a and R b Each of which is 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 heterocyclic ring containing N, O or S; 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; and R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 6a3 , R 6b3 , R 6a4 , R 6b4 , R 7a and R 7b Each of is independently H, halogen, OH, CN, substituted or unsubstituted amino, or methyl.

43. The compound of claim 5, wherein the compound is a compound having formula (Ia): 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; Each of u and v is independently an integer; and The sum of u and v is 1, 2, 3, or 4.

44. The compound of any one of claims 1 to 43, wherein the compound is selected from Table 1 to Table 3.

45. A pharmaceutical composition comprising an effective amount of a compound as described in any one of claims 1 to 44, or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer, enantiomer, atropisomer or prodrug thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

46. ​​A method for inhibiting the activity of a KRAS mutant protein or KRAS amplification in a cell, the method comprising contacting the cell with an effective amount of a compound as described in any one of claims 1 to 44, 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.

47. 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 to 44, 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.

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