Heterocyclic compounds, compositions thereof and methods of treatment therewith

Abstract

Provided herein are compounds having the following structure: # imgabs0 # 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.

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 or prevent cancer or diseases by inhibiting KRAS G12D 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 signal transduction 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 active state, Ras proteins can interact with different downstream proteins and activate related signal transduction pathways (Berndt N, Hamilton AD, Sebti SM. Targeting protein prenylation for cancer therapy. Nat Rev Cancer. 2011; 11 (11): 775-791). The Ras superfamily contains different subfamilies, including Ras, Ral, Rap, Rheb, Rad, Rit and Miro (Wennerberg K, Rossman KL, Der CJ. The Ras superfamily at aglance. 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. Ph armacological 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 signaling (Siveke JT, Schmid RM. Chromosomal instability in mouse metastatic pancreatic cancer--it's Kras and Tp53 after all. Cancer Cell. 2005; 7 (5): 405-407). This suggests that mutant KRas proteins are attractive drug targets for pancreatic cancer, as well as other cancers with KRas mutations. Because Kras proteins are generally considered undruggable targets, there are no clinical treatments that can selectively target G12D mutant Kras proteins.

[0005] Therefore, the KRas G12D mutation is an extremely attractive target for pancreatic cancer and other cancers that harbor this mutation. As such, small molecule therapeutics that can selectively bind to Kras G12D and inhibit its function would be very useful.

[0006] Citation or identification of any reference in this section of the present 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. In one embodiment, the compound is not any of the compounds in Table 1.

[0010] In one embodiment, the compound is selected from Table 2.

[0011] In one embodiment, provided herein is a method for inhibiting the activity of a KRAS mutant protein in a cell, comprising contacting the cell with an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof, optionally wherein the KRAS mutant protein is a KRAS G12D 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 or prodrug thereof, optionally wherein the cancer is mediated by a KRAS mutation; preferably a KRAS G12D 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 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] "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.

[0023] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms having a monocyclic 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.).

[0024] "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 rings, and bridged or spirocyclic ring 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), morpholine 1-H-pyranyl, 1-oxo-2-oxo-3-oxo-1-oxo-4-9-diazaspiro[5.5]decane, 1-oxo-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-oxo-4,9-diazaspiro[5.5]undecane, 2-oxo-1-oxo-3,9-diazaspiro[5.5]undecane, 2-oxo-1-oxo-3,8-diazaspiro[5.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-1-oxo-4,9-diazaspiro[5.5]undecane, 2-oxo-1-oxo-3,9-diazaspiro[5.5]undecane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-1-oxo-4,9-diazaspiro[5.5]undecane, 3-oxo-2,8-diazaspiro[4.5] ...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[1,3]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 heterocyclic 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 heterocyclic groups do not include fused ring species containing fused aromatic groups. Examples of non-aromatic heterocyclic groups include aziridine, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiohexyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclic 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. .

[0025] A "heteroaryl" group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms, and in other embodiments, the ring portion of the group 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.

[0026] 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 the same or different. Each ring in a spirocycle may be substituted or unsubstituted and may have a substituent that is different from each other ring within a set of spirocycles.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] "Halogen" is fluorine, chlorine, bromine or iodine.

[0031] A "hydroxyalkyl" group is an alkyl group as described above substituted with one or more hydroxy groups.

[0032] An "alkoxy" or "alkoxyl" group is an -O-(alkyl) group, wherein alkyl is as defined above.

[0033] An "alkoxyalkyl" group is a -(alkyl)-O-(alkyl) where alkyl is as defined above.

[0034] An "amino" group is a group of the formula: -NH2.

[0035] An "alkylamino" group is a group of the formula: -NH-alkyl or -N(alkyl)2 wherein each alkyl group is independently as defined above.

[0036] A "carboxy" group is a group of the formula: -C(O)OH.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] When groups described herein (other than 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.

[0042] As used herein, the term "one or more pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases (including inorganic acids and bases and organic acids and bases). Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, those well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing, Easton PA (1995).

[0043] 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.

[0044] 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).

[0045] 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.

[0046] 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.

[0047] "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:

[0048]

[0049] It will be readily appreciated by those skilled in the art that 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.

[0050] 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 whose isotopic composition is different from the natural isotopic composition of the atom. "Isotopically enriched" can also refer to a compound containing at least one atom whose isotopic composition is different from the natural isotopic composition of the 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, such as cancer and inflammatory therapeutic agents; research reagents, such as binding assay reagents; and diagnostic agents, such as in vivo imaging agents. All isotopic variations of compounds as described herein (whether or not radioactive) are intended to be covered within the scope of the embodiments provided herein. In some embodiments, isotopologues of compounds are provided, for example, isotopologues are deuterium, carbon-13, or nitrogen-15 enriched compounds.

[0051] 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 disorder, disease or disorder, or symptoms associated with a disorder, wherein the disorder can be treated or prevented by inhibiting KRASG12D.

[0052] 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 G12D.

[0053] 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.

[0054] 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.

[0055] Compound

[0056] Provided herein are compounds having the following formula (I):

[0057]

[0058] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopomers and prodrugs thereof,

[0059] in:

[0060] R 5 is H, -Cl, -CF3 or unsubstituted C 1-4 alkyl;

[0061] R 8 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaralkyl, unsubstituted or substituted spiro, or unsubstituted or substituted -alkyl-spiro;

[0062] R 11 is 3,8-diazabicyclo[3.2.1]oct-3-yl, 3,8-diazabicyclo[3.2.1]oct-8-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl or and

[0063] L 1 It is -O- or bond.

[0064] In one embodiment, the compound is not any of the compounds in Table 1.

[0065] Table 1

[0066]

[0067]

[0068] In one embodiment, L 1 Yes -O-.

[0069] In one embodiment, R 5 Yes - CF3;

[0070] R 11 yes

[0071] R 8 is unsubstituted or substituted heterocyclylalkyl.

[0072] In one embodiment, the heterocyclylalkyl group contains at least one oxygen as a ring member in the heterocyclyl moiety.

[0073] In one embodiment, R 8 Yes-L 8a -R 8a ;

[0074] L 8a Yes - (CH2) n -;

[0075] n is an integer 1, 2 or 3;

[0076] R 8ais 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;

[0077] R 8a is optionally substituted.

[0078] In some embodiments, R 8a Optionally substituted with halogen, cyano, hydroxy, alkoxy or alkyl, the alkyl optionally substituted with halogen, cyano, hydroxy, alkoxy, cycloalkyl or cycloalkoxy.

[0079] In one embodiment, R 8 yes

[0080] In one embodiment, the heterocyclylalkyl group contains at least one nitrogen as a ring member in the heterocyclyl moiety.

[0081] In one embodiment, R 8 Yes-L 8a -R 8a ;

[0082] L 8a Yes - (CH2) n -;

[0083] n is an integer 1, 2 or 3;

[0084] R 8a 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

[0085] R 8a is optionally substituted.

[0086] In some embodiments, R 8a Optionally substituted with halogen, cyano, hydroxy, alkoxy or alkyl, the alkyl optionally substituted with halogen, cyano, hydroxy or alkoxy.

[0087] In one embodiment, R 8 yes

[0088] In one embodiment, L 1 is the key;

[0089] R 5 Yes - CF3;

[0090] R 11 yes

[0091] R 8 is unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclylalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted cycloalkylalkyl.

[0092] In one embodiment, R 8 Yes-L 8a -R 8a ;

[0093] L 8a Yes - (CH2) n -;

[0094] n is an integer 0, 1, 2 or 3;

[0095] R 8a is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or azetidinyl; and

[0096] R 8a is optionally substituted.

[0097] in:

[0098] R 5 is H, -Cl, -CF3 or unsubstituted C 1-4 alkyl;

[0099] R 8 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaralkyl, unsubstituted or substituted spiro, or unsubstituted or substituted -alkyl-spiro;

[0100] R 11 is 3,8-diazabicyclo[3.2.1]oct-3-yl, 3,8-diazabicyclo[3.2.1]oct-8-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl or and

[0101] L 1 It is -O- or bond.

[0102] In one embodiment, L 1 Yes -O-.

[0103] In one embodiment, R 5 Yes - CF3;

[0104] R 11 yes

[0105] R 8 is unsubstituted or substituted heterocyclylalkyl.

[0106] In one embodiment, the heterocyclylalkyl group contains at least one oxygen as a ring member in the heterocyclyl moiety.

[0107] In one embodiment, R 8 Yes-L 8a -R 8a ;

[0108] L 8a Yes - (CH2) n -;

[0109] n is an integer 1, 2 or 3;

[0110] R 8a 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;

[0111] R 8a is optionally substituted.

[0112] In one embodiment, R 8 yes

[0113] In one embodiment, the heterocyclylalkyl group contains at least one nitrogen as a ring member in the heterocyclyl moiety.

[0114] In one embodiment, R 8 Yes-L 8a -R 8a ;

[0115] L 8a Yes - (CH2) n -;

[0116] n is an integer 1, 2 or 3;

[0117] R8a 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

[0118] R 8a is optionally substituted.

[0119] In one embodiment, R 8 yes

[0120] In one embodiment, L 1 is the key;

[0121] R 5 Yes - CF3;

[0122] R 11 yes

[0123] R 8 is unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclylalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted cycloalkylalkyl.

[0124] In one embodiment, R 8 Yes-L 8a -R 8a ;

[0125] L 8a Yes - (CH2) n -;

[0126] n is an integer 0, 1, 2 or 3;

[0127] R 8a is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or azetidinyl; and

[0128] R 8a is optionally substituted.

[0129] In one embodiment, R 8 yes

[0130] In one embodiment, R 5 Yes - CF3;

[0131] L 1 is-O-;

[0132] R 11 is 3,8-diazabicyclo[3.2.1]oct-8-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl or

[0133] R 8 yes and

[0134] R 8 is optionally substituted.

[0135] In one embodiment, the compound is

[0136]

[0137] In one embodiment, R 5 is -Cl;

[0138] L 1 is-O-;

[0139] R 8 yes and

[0140] R 8 is optionally substituted.

[0141] In one embodiment, the compound is

[0142]

[0143] In one embodiment, R 5 is unsubstituted C 1-4 alkyl;

[0144] R 11 yes

[0145] L 1 is-O-;

[0146] R 8 yes and

[0147] R 8 is optionally substituted.

[0148] In one embodiment, the compound is

[0149]

[0150] In one embodiment, R 5 Yes - CF3;

[0151] R 11is 3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl;

[0152] L 1 is-O-;

[0153] R 8 yes and

[0154] R 8 is optionally substituted.

[0155] In one embodiment, the compound is

[0156]

[0157] Aspect 2: In one embodiment, the compound is selected from Table 2.

[0158] Aspect 3: 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 or prodrug thereof and a pharmaceutically acceptable carrier, excipient or vehicle.

[0159] Aspect 4: In one embodiment, provided herein is a method for inhibiting the activity of a KRAS mutant protein in a cell, comprising contacting the cell with an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof, optionally wherein the KRAS mutant protein is a KRAS G12D mutant protein.

[0160] Aspect 5: 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 or prodrug thereof, optionally wherein the cancer is mediated by a KRAS mutation; preferably a KRAS G12D mutation.

[0161] Aspect 6: Provided herein is a method for regulating KRAS G12D activity, comprising contacting the cell with an effective amount of a compound provided herein or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof.

[0162] Aspect 7: Provided herein is a method for treating or preventing cancer, the method comprising administering an effective amount of a compound provided herein to a subject in need thereof.

[0163] Aspect 8: 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 inhibitor provided herein to treat cancer in an individual.

[0164] 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.

[0165] Methods for preparing compounds

[0166] The compound can be prepared using conventional organic synthesis and commercially available starting materials. As an example and not limitation, the compound of formula (I) can be prepared as outlined in the schemes 1-3 shown below and in the examples described herein. It should be noted that those 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.

[0167] Solution 1

[0168]

[0169] As shown in Scheme 1, in some embodiments, provided herein is a method for preparing a compound as defined in formula (I). Compound 1-1 substituted with LG (leaving group) (LG is Cl, F, methylsulfonyl or methylsulfinyl) is converted to compound 1-2 under substitution conditions (e.g., NaH, THF) or Buchwald coupling conditions (e.g., RuPhos Pd catalyst, Cs2CO3, 1,4-dioxane); then compound 1-2 is deprotected (e.g., when PG1 and PG2 are Boc, TFA and DCM are used to deprotect the Boc group) to obtain a compound as defined in formula (I).

[0170] Solution 2

[0171]

[0172] As shown in Scheme 2, in some embodiments, provided herein is a method for preparing a compound as defined in formula (I). The halogen-substituted compound 2-1 (X1, X2, X3 are halogens) is converted to compound 2-2 under alkaline conditions (e.g., NaH, THF); then compound 2-2 is converted to compound 2-3 under substitution conditions (e.g., if LG is F, KF, DMSO; or if LG is methylsulfonyl or methylsulfinyl, MeSNa, MeOH, then m-CPBA oxidation); compound 2-3 is further subjected to metal-catalyzed cross-coupling reactions such as Suzuki, Negishi or Stille coupling (e.g., Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water for Suzuki coupling) to obtain compound 2-4, wherein M can be boronic acid, boric acid ester, metal (such as Zn), tributyltin, etc.; under substitution conditions (e.g., NaH, THF) or Buchwald coupling conditions (e.g., RuPhos Pd catalyst, Cs2CO3, 1,4-dioxane) to convert compound 2-4 into compound 2-5; then deprotect compound 2-5 (for example, when PG1 and PG2 are Boc, use TFA and DCM to deprotect the Boc group) to obtain a compound as defined in formula (I).

[0173] Solution 3

[0174]

[0175] As shown in Scheme 3, in some embodiments, provided herein is a method for preparing a compound as defined by formula (I). The halogen-substituted compound 3-1 (X1, X2, X3 are halogens) is converted to compound 3-2 under alkaline conditions (e.g., NaH, THF); then compound 3-2 is converted to compound 3-3 under substitution conditions (e.g., if LG is F, KF, DMSO; or if LG is methylsulfonyl or methylsulfinyl, MeSNa, MeOH, then m-CPBA oxidation); under substitution conditions (e.g., NaH, THF) or Buchwald coupling conditions (e.g., RuPhos Pd catalyst, Cs2CO3, 1,4-dioxane) to convert compound 3-3 into compound 3-4; compound 3-4 further undergoes 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 3-5, wherein M can be boronic acid, boric acid ester, metal (such as Zn), tributyltin, etc.; compound 3-5 is then deprotected (e.g., when PG1 and PG2 are Boc, TFA and DCM are used to deprotect the Boc group) to obtain a compound as defined in formula (I).

[0176] 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.

[0177] Example

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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. 1H-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).

[0182] 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.

[0183] In the following examples, the following abbreviations are used:

[0184]

[0185]

[0186]

[0187] Compound synthesis

[0188] Example 1: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0189]

[0190] Step 1: 1-(Iodomethyl)-4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane

[0191]

[0192] At room temperature, NaH (1.20g, 30.0mmol) was added to a solution of (1-(iodomethyl)-2-oxabicyclo [2.1.1] hexane-4-yl) methanol (2.54g, 10.0mmol) in THF (20mL). The resulting mixture was stirred at room temperature for 1 hour. Then, 1-(chloromethyl)-4-methoxybenzene was added to the reaction, and the mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was quenched with water (30mL), extracted with EtOAc (100mL), and washed with saturated NaCl (50mLx3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain residue. The residue was purified by silica gel column chromatography, and eluted with 0-30% ethyl acetate in petroleum ether to obtain title product (1.87g, 5.0mmol).

[0193]

[07] Step 2: (4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexan-1-yl)methanol

[0194]

[0195] To a solution of 1-(iodomethyl)-4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane (1.87 g, 5.0 mmol) in DMSO (30 mL) was added KOAc (2.45 g, 25 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 16 hours. Upon completion, the reaction mixture was diluted with EtOAc (200 mL) and washed with saturated aqueous NaCl (50 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. Sodium ethoxide (680 mg, 10 mmol) and EtOH (10 mL) were added to the residue. Then, the reaction mixture was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was directly concentrated to obtain a residue. The residue was purified by silica gel column chromatography and eluted with 0-80% ethyl acetate in petroleum ether to obtain the title product (528.2 mg, 2.0 mmol).

[0196] Step 3: 4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane-1-carbaldehyde

[0197]

[0198] To a solution of (4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane-1-yl)methanol (528.2 mg, 2.0 mmol) in DCM (10 mL) was added DMP (848 mg, 2.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NaCl (50 mL×3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give the crude title product (1.0 g).

[0199] Step 4: 1-(Difluoromethyl)-4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane

[0200]

[0201] To a solution of 4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane-1-carbaldehyde (1.0 g crude) in DCM (10 mL) was added DAST (483.6 mg, 3.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was directly concentrated to give a residue. The residue was purified by silica gel column chromatography and eluted with 0-20% ethyl acetate in petroleum ether to give the title product (284.1 mg, 1.0 mmol).

[0202] Step 5: (1-(Difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol

[0203]

[0204] To a solution of 1-(difluoromethyl)-4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane (284.1 mg, 1.0 mmol) in DCM (10 mL) and water (1 mL) was added DDQ (454.0 mg, 2.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with water (30 mL), extracted with DCM (100 mL) and washed with saturated NaCl (20 mLx3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography and eluted with 0-60% ethyl acetate in petroleum ether to obtain the title product (60.0 mg, 0.36 mmol).

[0205] Step 6: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2-((1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0206]

[0207] To a solution of (1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol (60.0 mg, 0.36 mmol) in THF (5 mL) was added sodium hydride (26.84 mg, 0.66 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Then, tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (155 mg, 0.28 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaCl (15 mL×3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by preparative TLC (petroleum ether: EtOAc = 1:3) to obtain the title product (123.0 mg, 0.14 mmol). MS (ESI, m / e) [M+1] + 879.3.

[0208] Step 7: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0209] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2-((1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (123 mg, 0.14 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by HPLC to give the title product (80 mg). It was then further purified by chiral HPLC to give Isomer 1 (23.0 mg) and Isomer 2 (25.0 mg). Isomer 1: 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),6.12-5.90(m,1H),4.77-4.74(m, 2H),4.56-4.45(m,2H),3.87(s,2H),3.71-3.63(m,4H),2.06(s,2H),1.83-1.75(m,6H); MS(ESI,m / e)[M+1] + 679.4. Isomer 2: 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),6.12-5.90(m,1H),4.77 -4.74(m,2H),4.53-4.45(m,2H),3.87(s,2H),3.71-3.63(m,4H),2.06(s,2H),1.83-1.75(m,6H). MS(ESI,m / e)[M+1] + 679.4.

[0210] Example 2: 4-(2-((2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0211]

[0212] Step 1: tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0213]

[0214] A mixture of tert-butyl 3-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (244 mg, 0.5 mmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-2-yl)carbamate, DPEphosPdCl2 (72 mg, 0.1 mmol) and Cs2CO3 (490 mg, 1.5 mmol) in toluene (17.5 mL) was stirred under N2 atmosphere at 95°C for 4 hours. After completion, the reaction mixture was purified by combi-flash (petroleum ether / EtOAc=3:1) to give the title product (35 mg, 10% yield). MS (ESI, m / e) [M+1] + 701.6.

[0215] Step 2: tert-Butyl 3-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0216]

[0217] To a solution of (2-oxabicyclo[2.1.1]hexane-4-yl)methanol (28 mg, 0.25 mmol) in THF (5 mL) was added sodium hydride (8.0 mg, 0.334 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Then, 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-6-chloro-2,8-difluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (117 mg, 0.167 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaCl (15 mL×3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by preparative TLC (petroleum ether: EtOAc = 1: 1) to give the title product (100 mg, 75.8%). MS (ESI, m / e) [M+1] + 795.6.

[0218] Step 3: 4-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0219] To a solution of 3-(2-((2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-6-chloro-8-fluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.126 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC to give the title product (60 mg), which was separated by chiral HPLC (preparative HPLC equipment: Prep-HPLC-Gilson; chromatographic column: i-Cellulose-5, 21.2 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.2% 2M NH3 solution in MeOH); flow rate: 20 mL / min; temperature: 25°C; gradient: 40% B in 12 min; retention time-isomer 1: 7.5 min; retention time-isomer 2: 9.5 min) to give two isomers. Isomer 1 (20.47 mg, 27.3%): 1 HNMR(500MHz,CD3OD)δ7.86(s,1H),7.21-7.18(m,1H),7.04-7.01(m,1H),4.76-4.71(m,2H),4.56-4.42(m,3H ),3.73(s,2H),3.66-3.59(m,4H),1.96-1.95(m,2H),1.89-1.78(m,4H),1.64-1.61(m,2H); MS(ESI,m / e)[M+1] + 595.4. Isomer 2 (18.65 mg, 24.9%): 1 H NMR(500MHz,CD3OD)δ7.86(s,1H),7.21-7.18(m,1H),7.04-7.01(m,1H),4.76-4.71(m,2H),4.56-4.41(m,3H) ,3.73(s,2H),3.66-3.58(m,4H),1.96-1.95(m,2H),1.89-1.78(m,4H),1.64-1.61(m,2H); MS(ESI,m / e)[M+1] +595.4.

[0220] Example 3: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-methoxytetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0221]

[0222] Step 1: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((3-methoxytetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0223]

[0224] A solution of (3-methoxytetrahydrofuran-3-yl)methanol (120 mg, 0.91 mmol) in THF (20 mL) was cooled to 0°C. Then, NaH (36 mg, 0.91 mmol) was added in one portion and the mixture was stirred at 0°C for 30 min. Next, tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, 0.32 mmol) was added to the mixture. The resulting mixture was stirred at 0°C for 1 hour, then quenched with H2O (10 mL), extracted three times with EtOAc (20 mL), washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and purified by column chromatography to give the title product (144 mg, 52.17%). MS (ESI, m / e) [M+H] + 847.5.

[0225] Step 2: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-methoxytetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0226] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-((3-methoxytetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (140 mg, 0.16 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2-3 hours, and the resulting mixture was concentrated to dryness. The residue was then diluted with DCM / MeOH=10 / 1 (5 mL), followed by the addition of 5 drops of 7M NH3 solution in MeOH. The resulting solution was concentrated to dryness and purified by column chromatography to give the title product (85 mg, 77.3%). MS (ESI, m / e) [M+H] + 647.5. The product was separated twice by chiral HPLC (first time: preparative HPLC equipment: Prep-HPLC-Gilson; chromatographic column: Amylose-1, 21.2 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.2% 2M NH3 in MeOH); flow rate: 20 mL / min; temperature: 25°C; gradient: 60% B in 18 min; retention time-mixture 1: 5.5 min; retention time-mixture 2: 14.0 min; second time (separation of mixture 2 only): preparative HPLC equipment: Prep-HPLC-Gilson; chromatographic column: Cellulose-C, 20 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.2% 2M NH3 in MeOH); flow rate: 20 mL / min; temperature: 25°C; gradient: 20% in 40 min B; retention time-isomer 3: 28 min; retention time-isomer 4: 36 min) to obtain 3 isomers. Mixture 1 (a mixture of two stereoisomers): 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.22-7.19(m,1H),7.02-6.99(m,1H),4.75-4.70(m,1H),4.57-4.55(m,2H),4.46-4.44(m, 1H),3.98-3.83(m,4H),3.70-3.64(m,4H),3.36(s,3H),2.21-2.17(m,1H),2.07-2.02(m,1H),1.82(s,4H); MS(ESI,m / e)[M+H] + 647.5.Isomer 3: 1H NMR(500MHz,CD3OD)δ8.12(s,1H),7.22-7.19(m,1H),7.02–6.99(m,1H),4.75-4.45(m,4H),3.96 –3.64(m,8H),3.36(s,3H),2.21-2.17(m,1H),2.07-2.02(m,1H),1.83(s,4H); MS(ESI,m / e)[M+H] + 647.5. Isomer 4: 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.22-7.19(m,1H),7.02–6.99(m,1H),4.72-4.45(m,4H),3.97 –3.64(m,8H),3.36(s,3H),2.21-2.18(m,1H),2.08-2.02(m,1H),1.82(s,4H); MS(ESI,m / e)[M+H] + 647.5.

[0227] Example 4: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((4-methoxytetrahydro-2H-pyran-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0228]

[0229] Example 4 was prepared by a method similar to that described in Example 1 (Step 6 and Step 7) by replacing (1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexane-4-yl)methanol with (4-methoxytetrahydro-2H-pyran-4-yl)methanol to give the title compound. It was separated by chiral HPLC (preparative HPLC equipment: Prep-HPLC-Gilson; column: i-Cellulose-5, 21.2 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.2% 2M NH3 in MeOH); flow rate: 18 mL / min; temperature: 25° C.; gradient: 25% B in 15 μm; retention time-isomer 1: 10.5 min; retention time-isomer 2: 12.5 min) to give Isomer 1 (11.2 mg) and Isomer 2 (19.2 mg). Isomer 1: 1H NMR(500MHz,CD3OD)δ8.11(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),4.57-4. 45(m,4H),3.74-3.64(m,8H),3.33(s,3H),1.89-1.75(m,8H); MS(ESI,m / e)[M+H] + 661.5. Isomer 2: 1 HNMR(500MHz,CD3OD)δ8.11(s,1H),7.22-7.20(m,1H),7.02-7.01(m,1H),4.50-4 .45(m,4H),3.74-3.64(m,8H),3.33(s,3H),1.89-1.75(m,8H); MS(ESI,m / e)[M+H] + 661.4.

[0230] Example 5: 4-(2-((2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0231]

[0232] Example 5 was prepared by a procedure analogous to that described in Example 9 (step 1, step 2, and step 3) by replacing tert-butyl 8-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate with tert-butyl 8-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate to give the title product. It was separated by chiral HPLC (preparative HPLC equipment: Prep-HPLC-Gilson; chromatographic column: IE, 20 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (0.2% 2M NH3 in MeOH); flow rate: 18 mL / min; temperature: 25°C; gradient: 60% B in 13 min; retention time-isomer 1: 7.5 min; retention time-isomer 2: 10 min) to obtain isomer 1 (1.03 mg) and isomer 2 (1.31 mg). Isomer 1: 1H NMR(500MHz,CD3OD)δ7.89(s,1H),7.22-7.19(m,1H),7.05-7.01(m,1H),4.94-4.72(m,2H),4.75-4.71(m,2H),4.57-4.56(m,1H) ,3.73(s,2H),3.26-3.23(m,2H),2.93-2.90(m,2H),2.08-2.05(m,4H),1.95-1.94(m,2H),1.61-1.60(m,2H); MS(ESI,m / e)[M+H] + 595.4. Isomer 2: 1 H NMR(500MHz,CD3OD)δ7.89(s,1H),7.22-7.19(m,1H),7.05-7.01(m,1H),4.94-4.72(m,2H),4.75-4.71(m,2H),4.57-4.56(m,1H),3. 73(s,2H),3.25-3.23(m,2H),2.92-2.90(m,2H),2.07-2.05(m,4H),1.95-1.94(m,2H),1.61-1.60(m,2H); MS(ESI,m / e)[M+H]+595.3.

[0233] Example 6: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-hydroxytetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0234]

[0235] Step 1: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((3-hydroxytetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0236]

[0237] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.041 mmol) and 3-(hydroxymethyl)tetrahydrofuran-3-ol (10 mg, 0.082 mmol) in THF (10 mL) was added NaH (4 mg, 0.9 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under vacuum. The residue was purified by preparative TLC (eluted with DCM / MeOH=20 / 1) to give the title product (12 mg, 35.2% yield). MS (ESI, m / e) [M+1]+833.6.

[0238] Step 2: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-hydroxytetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0239] To a solution of 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-((3-hydroxytetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (12 mg, 0.014 mmol) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was concentrated and purified by preparative HPLC to give the title product (2 mg, 27% yield, formate). 1 H NMR(500MHz,CD3OD)δ8.48(s,0.5H),8.12(s,1H),7.23-7.20(m,1H),7.03-7.00(m,1H),4.6 6-4.55(m,1H),4.52-4.49(m,3H),4.02-3.75(m,8H),2.19-2.16(m,1H),2.14-2.01(m,5H). MS(ESI,m / e)[M+1] + 633.5.

[0240] Example 7: 4-(2-((2-oxabicyclo[2.2.1]heptane-4-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0241]

[0242] Example 7 was prepared by a procedure analogous to that described in Example 3 by replacing (3-methoxytetrahydrofuran-3-yl)methanol with (5-oxabicyclo[2.1.1]hexan-1-yl)methanol to give the title product (2.09 mg). 1 H NMR (500MHz, CD3OD) δ7.32(s,1H),6.42(s,1H),6.24-6.20(m,1H),3.88-3.59(m,5H),3.04-2.76(m,6H),1.07-0.85(m,9H),0.84-0.82(m,1H). MS(ESI,m / e)[M+H] + 643.4.

[0243] Example 8: 3-(((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-2-yl)oxy)methyl)-3-methylazetidine-1-carboxylic acid methyl ester

[0244]

[0245] Step 1: 3-(Hydroxymethyl)-3-methylazetidine-1-carboxylic acid methyl ester

[0246]

[0247] To a solution of (3-methylazetidin-3-yl)methanol hydrochloride (200 mg, 1.46 mmol) and DIPEA (565 mg, 4.38 mmol) in DCM (5 mL) was added methyl chloroformate (124 mg, 1.31 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. H2O (20 mL) was added to the solvent. The organic layer was concentrated to give the crude compound as a colorless oil (232 mg, 100% yield). MS (ESI, m / e) [M+1] + 160.1.

[0248] Example 8 was prepared by a procedure analogous to that described in Example 6 by replacing 3-(hydroxymethyl)tetrahydrofuran-3-ol with methyl 3-(hydroxymethyl)-3-methylazetidine-1-carboxylate to give the title product (4 mg, 12% yield as formate). 1H NMR(500MHz,CD3OD)δ8.48(s,0.5H),8.12(s,1H),7.23-7.20(m,1H),7.03-7.00(m,1H),4.65-4.60(m,1H), 4.56-4.53(m,1H),4.50-4.48(m,2H),4.10-3.80(m,4H),3.73-3.44(m,7H),2.02-1.96(m,4H),1.42(s,3H). MS(ESI,m / e)[M+1] + 674.5.

[0249] Example 9: 4-(2-((2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0250]

[0251] Step 1: tert-Butyl 8-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0252]

[0253] To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (10.0 g, 27.6 mmol) and DIPEA (7.10 g, 55.2 mmol) in DCM (200 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.86 g, 27.6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with water (100 mL), extracted with DCM (500 mL), and washed with saturated NaCl (100 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography using 0-40% MgSO4 in petroleum ether. Ethyl acetate Elution afforded the title product (10.0 g, 18.6 mmol).

[0254] Step 2: tert-Butyl 8-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0255]

[0256] To a solution of tert-butyl 8-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (10.0 g, 18.6 mmol) in DMSO (300 mL) was added KF (5.8 g, 100 mmol) at room temperature. The resulting mixture was stirred at 100 ° C for 16 hours. After completion, the reaction mixture was diluted with EtOAc (500 mL) and washed with saturated aqueous NaCl solution (100 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography with 0-80% Ethyl acetate Elution afforded the title product (6.5 g, 12.4 mmol).

[0257] Step 3: 8-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-7-bromo-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[0258]

[0259] To a solution of (2-oxabicyclo [2.1.1] hexane-4-yl) methanol (114.1 mg, 1.0 mmol) in THF (5 mL) was added sodium hydride (80.0 mg, 2.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Then, 8-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester (552 mg, 1.0 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. After completion, the reaction mixture was quenched with water (10 mL), extracted with EtOAc (100 mL), and washed with saturated NaCl (15 mL × 3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography and eluted with 0-100% ethyl acetate in petroleum ether to give the title product (492.8 mg, 0.8 mmol). MS (ESI, m / e) [M+1] + 617.1.

[0260] Step 4: tert-butyl 8-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-chloro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0261]

[0262] To a solution of 8-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-7-bromo-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (308.5 mg, 0.5 mmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (418 mg, 1.0 mmol) and DPEpHosPdCl2 (71.6 mg, 0.1 mmol) in toluene (15 mL) was added Cs2CO3 (325.8 mg, 1.0 mmol) at room temperature. The resulting mixture was stirred at 100°C for 16 hours. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaCl (25 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by preparative TLC (pure EtOAc) to obtain the title product (162.6 mg, 0.20 mmol). MS (ESI, m / e) [M+1] + 829.4.

[0263] Step 5: 4-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0264] To a solution of 8-(2-((2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (162.6 mg, 0.20 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by HPLC to give the title product (80 mg), which was further purified by chiral HPLC (preparative HPLC equipment: Prep-HPLC-Gilson; chromatographic column: IE, 20 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.2% 2M NH3 in MeOH); flow rate: 18 mL / min; temperature: 25°C; gradient: 40% B in 16 min; retention time-isomer 1: 10 min; retention time-isomer 2: 14.5 min) to give Isomer 1 (40.5 mg) and Isomer 2 (19.0 mg). Isomer 1: 1 H NMR(500MHz,CD3OD)δ8.14(s,1H),7.23-7.20(m,1H),7.02-6.99(m,1H),4.97-4.75(m,2H),4.76-4.75(m,2H),4.57-4.56(m,1H) ,3.73(s,2H),3.25-3.23(m,2H),2.95-2.92(m,2H),2.09-2.08(m,4H),1.96-1.95(m,2H),1.61-1.60(m,2H); MS(ESI,m / e)[M+1] + 629.4. Isomer 2: 1 H NMR(500MHz,CD3OD)δ8.14(s,1H),7.23-7.20(m,1H),7.02-6.99(m,1H),4.97-4.75(m,2H),4.76-4.75(m,2H),4.57-4.56(m,1H) ,3.73(s,2H),3.25-3.23(m,2H),2.95-2.92(m,2H),2.09-2.08(m,4H),1.96-1.95(m,2H),1.61-1.60(m,2H); MS(ESI,m / e)[M+1] + 629.3.

[0265] Example 10: 3-(((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-2-yl)oxy)methyl)tetrahydrofuran-3-carbonitrile

[0266]

[0267] Example 10 was prepared by a procedure analogous to that described in Example 1 (step 6 and step 7) by replacing (1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol with 3-(hydroxymethyl)tetrahydrofuran-3-carbonitrile to provide the title compound. It was separated by chiral HPLC (preparative HPLC equipment: Prep-HPLC-Gilson; chromatographic column: IE, 20 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (0.2% 2M NH3 in MeOH); flow rate: 18 mL / min; temperature: 25°C; gradient: 40% B in 18 min; retention time-isomer 1: 9 min; retention time-isomer 2: 11 min; retention time-isomer 3: 13 min; retention time-isomer 4: 17 min) to obtain Isomer 1 (30.5 mg), Isomer 2 (27.2 mg), Isomer 3 (26.5 mg) and Isomer 4 (23.2 mg). Isomer 1: 1 H NMR(500MHz,CD3OD)δ8.14(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H)-,4.65-4.48(m,4H),4 .10-4.01(m,4H),3.72-3.66(m,4H),2.48-2.25(m,2H),1.95-1.69(m,4H); MS(ESI,m / e)[M+H] + 642.3. Isomer 2: 1 HNMR(500MHz,CD3OD)δ8.14(s,1H),7.22-7.20(m,1H),7.02-7.01(m,1H),4.67-4.48(m,4H),4.10-3.94 (m,4H),3.72-3.67(m,4H),2.53-2.43(m,1H),2.36-2.26(m,1H),1.93-1.74(m,4H); MS(ESI,m / e)[M+H] + 642.3. Isomer 3: 1H NMR(500MHz,CD3OD)δ8.14(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),4.67-4.49(m,4H),4.10-3.94 (m,4H),3.72-3.59(m,4H),2.51-2.43(m,1H),2.37-2.24(m,1H),1.93-1.74(m,4H); MS(ESI,m / e)[M+H] + 642.3. Isomer 4: 1 HNMR(500MHz,CD3OD)δ8.14(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),4.65-4.48(m,4H),4.10-4.01 (m,4H),3.72-3.55(m,4H),2.53-2.39(m,1H),2.39-2.24(m,1H),1.90-1.74(m,4H); MS(ESI,m / e)[M+H] + 642.3.

[0268] Example 11: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0269]

[0270] Step 1: (1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol

[0271]

[0272] To a solution of (1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane-4-yl)methanol (2.54 g, 10.0 mmol) in MeOH (20 mL) was added sodium methoxide (5.40 g, 100.0 mmol) at room temperature. The resulting mixture was stirred at 70 ° C for 16 hours. After completion, the reaction mixture was diluted with water (30 mL), extracted with EtOAc (100 mL) and washed with saturated NaCl (50 mLx3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a crude product (500 mg).

[0273] Example 11 was prepared by a method similar to that described in Example 1 (steps 6 and 7) by replacing (1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol with (1-methoxymethyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanol to give the title compound. It was separated by chiral HPLC (preparative HPLC equipment: Prep-HPLC-Gilson; column: IE, 20 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (0.2% 2M NH3 in MeOH); flow rate: 18 mL / min; temperature: 25°C; gradient: 40% B in 22 min; retention time-isomer 1: 9 min; retention time-isomer 2: 19 min) to give Isomer 1 (1.79 mg) and Isomer 2 (1.59 mg). Isomer 1: 1 H NMR(500MHz,CD3OD)δ8.11(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),4.75-4.72(m,2H),4.58-4.46(m, 2H),3.81(s,2H),3.71-3.63(m,6H),3.38(s,3H),1.89-1.83(m,6H),1.68-1.67(m,2H); MS(ESI,m / e)[M+H] + 673.4. Isomer 2: 1 H NMR(500MHz,CD3OD)δ8.11(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),4.75-4.72(m,2H),4.58-4.46(m, 2H),3.81(s,2H),3.71-3.63(m,6H),3.38(s,3H),1.89-1.83(m,6H),1.68-1.67(m,2H); MS(ESI,m / e)[M+H] + 673.4.

[0274] Example 12: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-ethyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0275]

[0276] Example 12 was prepared by a procedure analogous to that described in Example 1 (step 6 and step 7) by replacing (1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol with (1-ethyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanol to give the title compound (0.7 mg). 1 HNMR(500MHz,CD3OD)δ8.12(s,1H),7.21-7.20(m,1H),7.04-7.00(m,1H),4.80-4.49(m,4H),4.18-4.01(m,2H),3 .93-3.76(m,3H),3.70-3.64(m,1H),2.18-1.97(m,5H),1.96-1.87(m,1H),1.85-1.72(m,4H),1.61-1.55(m,3H). MS(ESI,m / e)[M+H] + 657.5.

[0277] Example 13: 4-(2-((1-acetyl-3-methylazetidin-3-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0278]

[0279] Step 1: 1-(3-(Hydroxymethyl)-3-methylazetidin-1-yl)ethan-1-one

[0280]

[0281] To a 25 mL round-bottom flask was added (3-methylazetidin-3-yl)methanol hydrochloride (530 mg, 4.0 mmol), DCM (20 mL), pyridine (530 mg, 6.7 mmol) and acetyl chloride (220 mg, 2.8 mmol). The reactants were stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum. The residue was purified by flash (MeOH: DCM = 15-20%) to give the title product (300 mg, 52.1% yield). MS (ESI, m / e) [M+H] + 144.3.

[0282] Step 2: tert-butyl 3-(2-((1-acetyl-3-methylazetidin-3-yl)methoxy)-7-(2-((tert-butyloxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0283]

[0284] To a 20 mL sealed tube was added 1-(3-(hydroxymethyl)-3-methylazetidin-1-yl)ethane-1-one (40 mg, 0.055 mmol), 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (40 mg, 0.278 mmol), THF (3 mL) and NaH (5 mg, 0.125 mmol, 60%). The mixture was stirred at room temperature for 16 hours. The reactant was quenched with saturated NH4Cl (10 mL) aqueous solution and extracted with EtOAc (20 mLx3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography (MeOH:DCM=5-10%) to give the title product (36 mg, 76.8% yield). MS (ESI, m / e) [M+H] + 858.3.

[0285] Step 3: 4-(2-((1-acetyl-3-methylazetidin-3-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0286] 3-(2-((1-acetyl-3-methylazetidine-3-yl)methoxy)-7-(2-((tert-butyloxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (36mg, 0.042mmol) and TFA (4mL) were added to a 25mL round-bottom flask. The reactant was stirred at room temperature for 16 hours. The reactant was concentrated under vacuum. The residue was dissolved in EtOAc (20mL) and saturated NaCO aqueous solution (10mL) was added. The solution was stirred at room temperature for 10min and extracted with EtOAc (20mLx2). The combined organic phase was washed with brine (20mL), dried over NaSO, and concentrated under vacuum. The residue was purified by preparative HPLC (column: XBridge Shield RP18 OBD column; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; gradient: 25% B to 65% B in 9 min) to give the title product (4.2 mg, 15.2% yield). 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.23-7.20(m,1H),7.03-7.00(m,1H),4.69-4.44(m,4H),4. 27-4.16(m,1H),4.10-3.75(m,6H),3.69-3.68(m,1H),2.03(s,4H),1.88(s,3H),1.45(s,3H). MS(ESI,m / e)[M+H] + 658.3.

[0287] Example 14: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(difluoromethyl)tetrahydrofuran-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0288]

[0289] Example 14 was prepared by replacing (3-methoxytetrahydrofuran-3-yl)methanol with (3-(difluoromethyl)tetrahydrofuran-3-yl)methanol in a manner similar to that described in Example 3 to give the title racemic product (84.39 mg), which was separated by chiral HPLC (preparative HPLC equipment: Prep-HPLC-Gilson; column: IE, 20 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (0.2% 2M NH3 in MeOH); flow rate: 18 mL / min; temperature: 25° C.; gradient: 30% B in 22 min; retention time - isomer 1: 7.5 min; retention time - isomer 2: 10 min; retention time - isomer 3: 17 min; retention time - isomer 4: 18 min) to give four isomers. Isomer 1: 1 H NMR(500MHz,CD3OD)δ8.13(s,1H),7.23-7.20(m,1H),7.03-6.99(m,1H),6.30-6.08(m,1H),4.59-4.67(m,4H),3 .95-3.85(m,4H),3.74-3.65(m,4H),2.37-2.09(m,1H),2.00-1.92(m,1H),1.89-1.73(m,4H); MS(ESI,m / e)[M+H] + 667.5. Isomer 2: 1 H NMR(500MHz,CD3OD)δ8.13(s,1H),7.23-7.20(m,1H),7.03-6.99(m,1H),6.30-6.08(m,1H),4.69-4.40(m,4H),4. 01-3.81(m,4H),3.74-3.65(m,4H),2.22–-2.17(m,1H),1.97-1.93(m,1H),1.91-1.73(m,4H); MS(ESI,m / e)[M+H] + 667.4. Isomer 3: 1 H NMR(500MHz,CD3OD)δ8.13(s,1H),7.23-7.20(m,1H),7.03-6.99(m,1H),6.30-6.08(m,1H),4.64-4.40(m,4H),4 .03-3.79(m,4H),3.72-3.64(m,4H),2.21-2.17(m,1H),2.05-1.93(m,1H),1.89-1.71(m,4H); MS(ESI,m / e)[M+H] + 667.4. Isomer 4: 1H NMR(500MHz,CD3OD)δ8.13(s,1H),7.23-7.20(m,1H),7.02-6.99(m,1H),6.30-6.08(m,1H),4.66-4.39(m,4H),4 .04-3.81(m,4H),3.69-3.63(m,4H),2.29-2.12(m,1H),2.04-1.93(m,1H),1.82-1.78(m,4H); MS(ESI,m / e)[M+H] + 667.4.

[0290] Example 15: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0291]

[0292] Step 1: tert-Butyl 3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0293]

[0294] To a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (6.0 g, 20 mmol) and DIEA (5.16 g, 40 mmol) in DCM (100 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.24 g, 20 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with DCM (200 mL) and washed with saturated water (150 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel (petroleum ether: EtOAc=3:1) to obtain the title product (6.5 g, 69.1%). MS (ESI, m / e) [M+1] + 471.4,473.4.

[0295] Step 2: tert-Butyl 3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0296]

[0297] A solution of (1R,5S)-3-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.73 g, 10 mmol) and KF (5.8 g, 100 mmol) in DMSO (40 mL) was stirred at 100°C for 15 hours. After completion, the reaction mixture was cooled to 0°C and poured into ice water, and filtered to give the title product (2.5 g, 55.1%). 1 H NMR(500MHz,DMSO)δ7.89-7.87(m,1H),7.65-7.62(m,1H),4.40-4.38(m,2H),4.26- 4.23(m,2H),3.62-3.60(m,2H),1.81-1.77(m,2H),1.65-1.63(m,2H),1.46(s,9H). MS(ESI,m / e)[M+1] + 455.3,457.3

[0298] Step 3: tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0299]

[0300] To a solution of tert-butyl 3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.87 mmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-2-yl)carbamate (365 mg, 0.87 mmol) and Pd(dtbpf)Cl2 (228 mg, 0.35 mmol) in 1,4-dioxane (15 mL) and H2O (3 mL) was added K3PO4 (556 mg, 2.62 mmol) at room temperature. The reaction mixture was then stirred at 90°C for about 4 hours. Upon completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product. The residue was purified by silica gel column chromatography and eluted with 0-40% DCM in ethyl acetate to give the title product (350 mg, 0.53 mmol). MS (ESI, m / e) [M+1] + 667.2.

[0301] Step 4: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0302]

[0303] To a solution of (1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methanol (19 mg, 0.15 mmol) in THF (2 mL) was added sodium hydride (6 mg, 0.15 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 0.5 hours. Then, 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoroquinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.075 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was quenched with water (10 mL), extracted with EtOAc (30 mL×3) and washed with saturated NaCl aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography and eluted with 0-3% MeOH in DCM to give the title product (45 mg, 0.058 mmol). MS (ESI, m / e) [M+1] + 775.3.

[0304] Step 5: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0305] To 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (45mg, 0.058mmol) in DCM (2mL) at room temperature, TFA (2mL) was added. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated to give a residue, which was dissolved in 3mL DCM and the pH was adjusted to about 10 using the 7M NH3 in MeOH. The residue was purified by preparative HPLC to give the title product (12mg, 0.021mmol, formate). 1 HNMR(500MHz,CD3OD)δ8.53(s,0.5H),7.81-7.80(m,1H),7.26-7.23(m,2H),7.04-7.00(m,1H),4.73-4.48(m,4H),3.92(s ,2H),3.80(s,2H),3.72-3.63(m,2H),2.11-1.91(m,4H),1.81(s,2H),1.64-1.62(m,2H),1.43(s,3H).δMS(ESI,m / e)[M+1] + 575.3.

[0306] Example 16: 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0307]

[0308] Step 1: tert-Butyl 9-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate

[0309]

[0310] A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (3.0 g, 8.2 mmol) and DIPEA (1.71 g, 13.14 mmol) in DCM (50 mL) was cooled to 0°C. Then, tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate was added. The mixture was stirred at 0°C for 2 hours, diluted with DCM (100 mL), washed with brine (20 mL), repeated three times and filtered. The filtrate was concentrated and purified by chromatography to give the title product (3.79 g, 83.1%). MS (ESI, m / e) [M+1] + 556.4.

[0311] Step 2: tert-Butyl 9-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate

[0312]

[0313] To a solution of tert-butyl 9-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (3.6 g, 6.5 mmol) in DMSO (50 mL) was added KF (2.28 g, 39.1 mmol). The mixture was stirred at 90 °C for 2-3 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc (50 mL), washed with brine (20 mL) and the operation was repeated three times. The organic phase was filtered and the filtrate was concentrated and purified by chromatography to give the title product (2.91 g, 83.1%). MS (ESI, m / e) [M+1] + 539.7.

[0314] Step 3: tert-Butyl 9-(7-bromo-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate

[0315]

[0316] A solution of (1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methanol (95 mg, 0.74 mmol) in THF (30 mL) was cooled to 0 ° C. NaH (29 mg, 0.74 mmol) was added to the solution at once, and the mixture was stirred at room temperature for 30 min. Then, 9-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (398 mg, 0.71 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 4-5 hours, then quenched with H2O (20 mL), extracted three times with EtOAc (30 mL), washed three times with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by column chromatography to give the title product (327 mg, 71.08%). MS (ESI, m / e) [M+H] + 647.9.

[0317] Step 4: tert-Butyl 9-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate

[0318]

[0319] A mixture of tert-butyl 9-(7-bromo-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (40 mg, 0.061 mmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (104 mg, 0.024 mmol), Cs2CO3 (60 mg, 0.18 mmol) and DPEphosPdCl2 (10 mg, 0.012) in toluene (10 mL) was degassed 3 times with N2 and stirred at 100°C for 16 h. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the title product (15 mg, 28.8%), MS (ESI, m / e) [M+H] + 859.2.

[0320] Step 5: 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0321] To a solution of tert-butyl 9-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (50 mg) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2-3 hours. The resulting mixture was concentrated to dryness and then diluted with DCM / MeOH=10 / 1 (5 mL) and 5 drops of 7M NH3 in MeOH were added. Next, the new solution was concentrated to dryness and purified by column chromatography to give the title product (21 mg, 55.2%). 1 H NMR(500MHz,CD3OD)δ7.96(s,1H),7.22-7.20(m,1H),7.03-6.99(m,1H),4.74-4 .72(m,2H),4.46(s,2H),4.31-4.10(m,4H),3.79(s,2H),3.53-3.37(m,4H),1.81 -1.80(m,2H),1.69-1.53(m,2H),1.42(s,3H). MS(ESI,m / e)[M+H] + 659.8.

[0322] Example 17: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3-(cyanomethyl)-3-methylazetidin-1-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0323]

[0324] Step 1: tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[b]thiophen-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0325]

[0326] At room temperature, tert-butyl 3-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 g, 0.097 mol), tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate (47.2 g, 0.11 mol), Pd(dtbpf)Cl2 (6.2 g, 0.096 mol), K3PO4 (36.5 g, 0.17 mol), dioxane (500 mL), and H2O (50 mL) were placed in a 1 L round-bottom flask. The resulting mixture was stirred at 90° C. under N2 atmosphere for 2 hours. The resulting mixture was extracted with EtOAc (2 L). The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether: EtOAc = 100: 0 to 70: 30, to obtain the title product (26 g, 38.2% yield). MS (ESI, m / e) [M+H] + =710.10.

[0327] Step 2: tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-7-fluoro-3-iodobenzo[b]thien-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0328]

[0329] Into a 1L round-bottom flask at room temperature, tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (39 g, 0.055 mol), CH3CN (400 mL), and NIS (16 g, 0.07 mol) were placed. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with petroleum ether:EtOAc=100:0~70:30 to give the title product (20 g, 43.5% yield). MS (ESI, m / e) [M+H] + =836.00.

[0330] Step 3: tert-Butyl 3-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0331]

[0332] 3-(7-(2-((tert-butyloxycarbonyl)amino)-7-fluoro-3-iodobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.12 mmol), Zn(CN)2 (70 mg, 0.6 mmol), Pd(PPh3)4 (83 mg, 0.07 mmol) and DMF (10 mL) were added to a 20 mL microwave tube at room temperature under N2 atmosphere. The resulting mixture was stirred with microwaves at 150°C for 10 min. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (3x30 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure. The residue was purified by TLC (petroleum ether: EtOAc = 1: 1) to give the title product (25 mg, 32.9% yield). MS (ESI, m / e) [M+H] = 635.05.

[0333] Step 4: tert-butyl 3-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2-(3-(cyanomethyl)-3-methylazetidin-1-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0334]

[0335] To a 10 mL vial was added tert-butyl 3-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.03 mmol), THF (1 mL), 2-(3-methylazetidin-3-yl)acetonitrile TFA salt (17 mg, 0.15 mmol) and DIEA (41 mg, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give the title crude product (40 mg, crude). MS (ESI, m / e) [M+H] + 725.15.

[0336] Step 5: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(3-(cyanomethyl)-3-methylazetidin-1-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0337] To a 10 mL vial was added tert-butyl 3-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2-(3-(cyanomethyl)-3-methylazetidin-1-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.03 mmol), DCM (1 mL) and TFA (0.2 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions (chromatographic column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B, 50% B in 9 min; wavelength: 254 nm) to give the title product (5.1 mg, 29.6% yield, TFA salt). 1 H NMR(300MHz,DMSO-d6)δ9.14-9.13(m,1H),8.94(s,1H),8.06(s,2H),7.90(s,1H),7.22-7 .08(m,2H),4.50-4.09(m,6H),3.99-3.89(m,4H),2.96(s,2H),1.94(s,4H),1.41(s,3H). F NMR: δ-57.00,-74.23,-116.68,-124.64. MS(ESI,m / e)[M+H] + 625.10.

[0338] Example 18: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-methyloxetane-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0339]

[0340] Example 18 was prepared by a procedure analogous to that described in Example 3 by replacing (3-methoxytetrahydrofuran-3-yl)methanol with (3-methyloxetan-3-yl)methanol to give the title product (12.75 mg). 1H NMR (500MHz, CD3OD) δ8.12(s,1H),7.33-7.13(m,1H),7.02-6.99(m,1H),4.68-4.46(m,8H),3.73-3.65(m,4H),1.85(s,4H),1.46(s,3H). MS(ESI,m / e)[M+H] + 617.5.

[0341] Example 19: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((4-hydroxytetrahydro-2H-pyran-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0342]

[0343] Example 19 was prepared by a procedure analogous to that described in Example 1 (steps 6 and 7) by replacing (1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol with 4-(hydroxymethyl)tetrahydro-2H-pyran-4-ol to give the title product (6.4 mg). 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.23-7.22(m,1H),7.04-6.99(m,1H),4.85-4.62(m,2H),4 .37-4.36(m,2H),4.24-4.22(m,2H),3.93-3.75(m,6H),2.18-2.13(m,4H),1.87-1.63(m,4H). MS(ESI,m / e)[M+H] + 647.5.

[0344] Example 20: 3-(((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-2-yl)oxy)methyl)-3-methylazetidine-1-carboxylic acid methyl ester

[0345]

[0346] Example 20 was prepared by a procedure analogous to that described in Example 8 by replacing (3-methylazetidin-3-yl)methanol hydrochloride with (3-methoxyazetidin-3-yl)methanol hydrochloride to give the title product (1 mg, 9% yield as formate salt). 1H NMR(500MHz,CD3OD)δ8.51(s,1H),8.17(s,1H),7.29-7.21(m,1H),7.03-7.00(m,1H),4.81-4.76(m,2H),4 .72-4.61(m,2H),4.12-4.00(m,5H),3.87-3.80(m,2H),3.75-3.68(m,3H),3.51-3.41(m,4H),2.05(s,4H). MS(ESI,m / e)[M+1] + 690.5.

[0347] Example 21: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0348]

[0349] Step 1: (4-(Hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-1-yl)methyl acetate

[0350]

[0351] Potassium acetate (980.0 mg, 10.0 mmol) was added to a solution of (1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane-4-yl)methanol (254 mg, 1.0 mmol) in DMSO (20 mL) at room temperature. The resulting mixture was stirred at 100 ° C for 16 hours. After completion, the reaction mixture was diluted with water (30 mL), extracted with EtOAc (100 mL) and washed with saturated NaCl (50 mLx3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a crude product (50 mg).

[0352] Example 21 was prepared by a procedure analogous to that described in Example 1 (Steps 6 and 7) by replacing (1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol with ((4-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-1-yl)methyl acetate to give the title product (0.8 mg, formate). 1H NMR (500MHz, CD3OD) δ8.50(s,1H),8.11(s,1H),7.24-7.16(m,1H),7.03-7.00(m,1H),4.80-4.46(m,4H),3.91-3.65(m,8H),2.16-1.78(m,8H). MS(ESI,m / e)[M+H] + 659.4

[0353] Example 22: 4-(((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile

[0354]

[0355] Example 22 was prepared by a method similar to that described in Example 1 (steps 6 and 7) by replacing (1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexane-4-yl)methanol with 4-(hydroxymethyl)tetrahydro-2H-pyran-4-carbonitrile to give the title compound. It was separated by chiral HPLC (preparative HPLC equipment: Prep-HPLC-Gilson; column: IE, 20 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (0.2% 2M NH3 in MeOH); flow rate: 18 mL / min; temperature: 25°C; gradient: 50% B in 14 min; retention time-isomer 1: 7 min; retention time-isomer 2: 11.5 min) to give Isomer 1 (21.2 mg) and Isomer 2 (20.2 mg). Isomer 1: 1 H NMR(500MHz,CD3OD)δ8.13(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),4.57-4.45(m,4H),4 .01-3.99(m,2H),3.74–3.64(m,6H),2.06-2.03(m,2H),1.87-1.82(m,6H); MS(ESI,m / e)[M+H] + 656.5. Isomer 2: 1H NMR(500MHz,CD3OD)δ8.13(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),4.57-4.45(m,4H),4 .01-3.99(m,2H),3.74-3.62(m,6H),2.06-2.03(m,2H),1.87-1.82(m,6H); MS(ESI,m / e)[M+H] + 656.5.

[0356] Example 23: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-2H-pyran-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0357]

[0358] Step 1: tert-Butyl 3-(7-bromo-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0359]

[0360] A mixture of tert-butyl 3-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (14.8 g, 28.3 mmol) and sodium thiomethoxide (1.96 g, 28.4 mmol) in THF (500 mL) was stirred at room temperature for 15 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaCl (15 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by combi-flash (petroleum ether: EtOAc = 10: 1) to obtain the title product (10.0 g, 64.1%). MS (ESI, m / e) [M + 1] + 551.4.

[0361] Step 2: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0362]

[0363] A mixture of tert-butyl 3-(7-bromo-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.5 g mg, 10 mmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (8.36 g, 20 mmol), Pd(dtbpf)Cl2 (3.26 g, 5 mmol) and K3PO4 (6.36 g, 30 mmol) in dioxane / water (550 mL / 55 mL) was stirred at 80° C. under N2 atmosphere for 0.5 h. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaCl (15 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by combi-flash (petroleum ether: EtOAc = 3: 1) to obtain the title product (2.9 g, 38.1%). MS (ESI, m / e) [M+1] + 763.5.

[0364] Step 3: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(methylsulfonyl)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0365]

[0366] A mixture of 3-(7-(2-((tert-butyloxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-(methylthio)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.24 g, 1.63 mmol) and m-CPBA (561 mg, 3.26 mmol) in DCM (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 aqueous solution (15 mLx3). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was used directly in the next step without further purification. MS (ESI, m / e) [M+1] + 795.6.

[0367] Step 4: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thien-4-yl)-8-fluoro-2-((tetrahydro-2H-pyran-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0368]

[0369] LiHMDS (0.1 mL, 0.1 mmol) was added to a solution of (tetrahydro-2H-pyran-4-yl)methanol (12 mg, 0.1 mmol) in THF (2 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 0.5 hours. Then, 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-(methylsulfonyl)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (40 mg, 0.05 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with EtOAc (40 mL) and washed with saturated NaCl (15 mL×3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by preparative TLC (petroleum ether: EtOAc = 2: 1) to give the title product (35 mg, 85.4%). MS (ESI, m / e) [M+1] + 831.6.

[0370] Step 5: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((tetrahydro-2H-pyran-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0371] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-((tetrahydro-2H-pyran-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.042 mmol) in DCM (2 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 3 hours. Upon completion, the reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give the title product (9.79 mg, 36.9%). 1H NMR(500MHz,CD3OD)δ8.10(s,1H),7.28-7.15(m,1H),7.03-6.99(m,1H),4.66-4.52(m,2H),4.34-4.32(m,2H),4.00-3.91 (m,4H),3.82-3.72(m,2H),3.53-3.44(m,2H),2.14-2.11(m,1H),2.04-1.94(m,4H),1.79-1.77(m,2H),1.56-1.37(m,2H). MS(ESI,m / e)[M+1] + 631.5.

[0372] Example 24: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(1-methyl-1H-imidazol-2-yl)azetidin-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0373]

[0374] Step 1: (1-(1-methyl-1H-imidazol-2-yl)azetidin-3-yl)methanol

[0375]

[0376] A solution of azetidin-3-ylmethanol hydrochloride (500 mg, 4.06 mmol), 2-iodo-1-methyl-1H-imidazole (527 mg, 4.87 mmol), CuI (78 mg, 0.41 mmol), (R)-proline (94 mg, 10.82 mmol) and Cs2CO3 (2.65 g, 8.12 mmol) in DMF (30 mL) was stirred at 100°C for 3 hours. The solvent was concentrated and the residue was purified by silica gel column chromatography (DCM: MeOH = 15: 1) to give the title product (220 mg, 32%). MS (ESI, m / e) [M+1] + 168.4.

[0377] Example 24 was prepared by a procedure analogous to that described in Example 8 by replacing 3-(hydroxymethyl)-3-methylazetidine-1-carboxylic acid methyl ester with (1-(1-methyl-1H-imidazol-2-yl)azetidin-3-yl)methanol to give the title product (5 mg, 14% yield, formate). 1H NMR(500MHz,CD3OD)δ8.49(s,1H),8.12(s,1H),7.20-7.22(m,1H),7.06-7.00(m,1H),6.74(s,1H),6.69(s,1H),4.52-4.73(m, 4H),4.32-4.26(m,2H),4.12-4.05(m,2H),3.94-3.89(m,2H),3.81-3.72(m,2H),3.44(s,3H),3.30-3.15(m,1H),1.95(s,4H). MS(ESI,m / e)[M+1] + 682.5.

[0378] Example 25: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-fluorotetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0379]

[0380] Step 1: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((3-fluorotetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0381]

[0382] To a stirred mixture of (3-fluorotetrahydrofuran-3-yl)methanol (8.2 mg, 0.07 mmol) and NaH (3.3 mg, 0.14 mmol) in THF (1 ml) was added 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.07 mmol) in portions at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH4Cl aqueous solution. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc 1:1) to give the title product (30 mg, 69.47% yield). MS (ESI, m / e) [M+H]+ 835.35.

[0383] Step 2: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-fluorotetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0384] A solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((3-fluorotetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.04 mmol) and TFA (0.5 mL) in DCM (1.5 ml) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (chromatographic column: Xselect CSH C18 OBD column 30×150 mm 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 45% B, 45% B in 8 min; wavelength: 254 nm; RT1 (min): 7) to give the title product (8.1 mg, 35.52%, TFA salt / formate). 1 H NMR (300MHz, CD3OD) δ8.47(s,0.5H),8.13(s,1H),7.21(s,1H),7.02(s,1H),4.76-4.57(m,4H),4.26-3.68(m,8H),2.45-2.16(m,2H),2.05(s,4H). MS(ESI,m / e)[M+H] + 635.40.

[0385] Example 26: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)-2-((3-(trifluoromethyl)tetrahydrofuran-3-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0386]

[0387] Step 1: Diethyl 2-(2-(benzyloxy)ethyl)malonate

[0388]

[0389] To a solution of ((2-bromoethoxy)methyl)benzene (40 g, 185.97 mmol) in THF (500 mL) was added NaH (8.93 g, 223.16 mmol, 60%) in portions at 0°C. After stirring for 5 min, diethyl malonate (60 g, 371.94 mmol) was added. The resulting mixture was stirred at 0°C for 12 h. The resulting mixture was quenched with saturated aqueous NH4Cl at 0°C and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography and eluted with H2O:CH3CN (100:0–20:80) to give the title product (44 g, 80.38% yield). MS (ESI, m / e) [M+H] + 295.10.

[0390] Step 2: Diethyl 2-(2-(benzyloxy)ethyl)-2-(trifluoromethyl)malonate

[0391]

[0392] To a solution of diethyl 2-(2-(benzyloxy)ethyl)malonate (40 g, 135.89 mmol) in DMF (500 mL) was added NaH (6.52 g, 163.07 mmol, 60%) in portions at 0°C. After stirring at room temperature for 1 hour, 2,8-difluoro-5-(trifluoromethyl)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (87.24 g, 203.84 mmol) was added at -60°C. The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was quenched with saturated aqueous NH4Cl at 0°C and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether: EtOAc (100:0-80:20) to give the title product (10 g, 20.31% yield). MS (ESI, m / e) [M+H] + 363.10.

[0393] Step 3: 2-(2-(Benzyloxy)ethyl)-2-(trifluoromethyl)propane-1,3-diol

[0394]

[0395] To a solution of diethyl 2-(2-(benzyloxy)ethyl)-2-(trifluoromethyl)malonate (9.5 g, 26.22 mmol) in THF (100 mL) was added LiAlH4 (2.99 g, 78.65 mmol) in portions at 0°C. After stirring at room temperature for 1 hour, the resulting mixture was quenched with Na2SO4·10H2 at 0°C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether:EtOAc (100:0-60:40) to give the title product (2.1 g, 28.78% yield). MS (ESI, m / e) [M+H]+279.00.

[0396] Step 4: 4-(Benzyloxy)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(trifluoromethyl)butan-1-ol

[0397]

[0398] To a solution of 2-(2-(benzyloxy)ethyl)-2-(trifluoromethyl)propane-1,3-diol (2.1 g, 7.55 mmol) and 1H-imidazole (1.54 g, 22.64 mmol) in DCM (50 mL) was added TBDPSCl (2.28 g, 8.30 mmol) in portions at 0°C. After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether:EtOAc (100:0-70:30) to give the title product (2.5 g, 64.12% yield). MS (ESI, m / e) [M+Na] + 539.25.

[0399] Step 5: 2-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-(trifluoromethyl)butane-1,4-diol

[0400]

[0401] To a solution of 4-(benzyloxy)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(trifluoromethyl)butan-1-ol (1.2 g, 2.323 mmol) in EtOH (50 mL) was added Pd / C (1.2 g, 10%) at room temperature. After stirring at 80°C under H2(g) atmosphere for 12 h, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether:EtOAc (100:0-60:40) to give the title product (500 mg, 40.38% yield). MS (ESI, m / e) [M+H] + 427.15.

[0402] Step 6: tert-Butyldiphenyl((3-(trifluoromethyl)tetrahydrofuran-3-yl)methoxy)silane

[0403]

[0404] To a solution of 2-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(trifluoromethyl)butane-1,4-diol (480 mg, 1.13 mmol) and TsCl (300.3 mg, 1.58 mmol) in THF (50 mL) was added n-BuLi (0.54 mL, 1.35 mmol, 2.5 M in hexanes) at 0°C. After stirring at room temperature for 1.5 h, n-BuLi (0.54 mL, 1.35 mmol, 2.5 M in hexanes) was added at 0°C. The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was quenched with saturated NH4Cl aqueous solution at 0°C and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether:EtOAc (100:0-90:10) to give the title product (190 mg, 41.33% yield).

[0405] Step 7: (3-(Trifluoromethyl)tetrahydrofuran-3-yl)methanol

[0406]

[0407] To a solution of tert-butyldiphenyl((3-(trifluoromethyl)tetrahydrofuran-3-yl)methoxy)silane (90 mg, 0.22 mmol) in THF (50 mL) was added TBAF (0.55 mL, 0.55 mmol, 1 M in THF) at 0°C. After stirring at room temperature for 12 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether:EtOAc (100:0-60:40) to give the title product (15 mg, 40.02%).

[0408] Step 8: tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-6-((trifluoromethyl)-2-((3-trifluoromethyl)tetrahydrofuran-3-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0409]

[0410] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.03 mmol) and (3-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (9.26 mg, 0.06 mmol) in THF (2 mL) was added NaH (2.18 mg, 0.06 mmol, 60%) at 0°C. After stirring at room temperature for 2 hours, the mixture was quenched with saturated aqueous NH4Cl at 0°C and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC with petroleum ether: EtOAc (4:1) to give the title product (13 mg, 53.97% yield). MS (ESI, m / e) [M+H] + 885.25.

[0411] Step 9: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)-2-((3-(trifluoromethyl)tetrahydrofuran-3-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0412] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-6-(trifluoromethyl)-2-((3-(trifluoromethyl)tetrahydrofuran-3-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (13 mg, 0.015 mmol) in DCM (0.6 mL) was added TFA (0.2 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The crude product was purified by preparative HPLC (chromatographic column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 32% B to 62% B, 62% B in 9 min; wavelength: 220 nm; RT1 (min): 7) to give the title product (0.8 mg, 6.82% yield, TFA salt). 1H NMR (300MHz, CD3OD) δ8.13(s,1H),7.24-7.20(m,1H),7.09-6.98(m,1H),4.81-4.54(m,4H),4.23(s,2H),4.04-3.83(m,6H),2.39-2.05(m,6H). MS(ESI,m / e)[M+H] + 685.20.

[0413] Example 27: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((4-hydroxy-4-methyltetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0414]

[0415] Step 1: 4-Hydroxytetrahydrofuran-3-carboxylic acid methyl ester

[0416]

[0417] To a solution of methyl 4-oxoxolane-3-carboxylate (10 g, 69.38 mmol) in MeOH (1 L) was added NaBH4 (5.2 g, 83.26 mmol) in portions at 0°C. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The mixture was heated to 40°C with saturated NH4Cl The mixture was quenched with aqueous solution and extracted with DCM (5 x 500 mL). The resulting mixture was concentrated under vacuum. The crude product (5.7 g) was used directly in the next step without further purification.

[0418] Step 2: Methyl 4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-carboxylate

[0419]

[0420] A solution of 4-hydroxytetrahydrofuran-3-carboxylic acid methyl ester (5.7 g, 39.00 mmol), TBSCl (7.64 g, 50.00 mmol) and imidazole (5.31 g, 78.00 mmol) in DMF (57 mL) was stirred overnight at room temperature under a nitrogen atmosphere. At room temperature, the reaction was quenched with water (30 mL). The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether: EtOAc (5%-10%) to give the title product (9.5 g, 94% yield) as a colorless oil.

[0421] Step 3: 4-(Hydroxymethyl)tetrahydrofuran-3-ol

[0422]

[0423] LiAlH4 (2.4 g, 63.16 mmol) was suspended in THF (48 mL). A solution of methyl 4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-carboxylate (9.5 g, 36.48 mmol) in THF (57 mL) was slowly added dropwise at 0°C, and the mixture was stirred at 0°C for 1 hour. LiAlH4 (2.4 g, 63.16 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. The mixture was heated under reflux for 1 hour. The reaction solution was cooled to room temperature. Then, water (2.9 ml), 15% aqueous sodium hydroxide solution (2.9 ml) and water (5.8 ml) were added at 0°C to quench the reaction. The resulting mixture was stirred at room temperature for 15 min and dried over anhydrous MgSO4. The precipitated insoluble material was filtered off through diatomaceous earth. The filtrate was concentrated. The crude product (4.5 g) was used directly in the next step without further purification.

[0424] Step 4: 4-(((tert-Butyldimethylsilyl)oxy)methyl)tetrahydrofuran-3-ol

[0425]

[0426] A solution of 4-(hydroxymethyl)tetrahydrofuran-3-ol (2 g, 16.93 mmol), TBSCl (1.54 g, 10.20 mmol) and imidazole (2.31 g, 33.86 mmol) in DMF (100 mL) was stirred at room temperature overnight. The reaction was quenched with water (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether: EtOAc (5%-10%) to give the title product (1.7 g, 43% yield) as a colorless oil. MS (ESI, m / e) [M+H] + 233.15.

[0427] Step 5: 4-(((tert-Butyldimethylsilyl)oxy)methyl)dihydrofuran-3(2H)-one

[0428]

[0429] A solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-3-ol (1.7 g, 7.31 mmol) and DMP (6.21 g, 14.63 mmol) in DCM (16 mL) was stirred at 40 °C for 5 hours. The resulting mixture was filtered and the filter cake was washed with DCM (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether:EtOAc (5%-20%) to give the title product (1.3 g, 77% yield) as a colorless oil. MS (ESI, m / e) [M+H] + 231.15.

[0430] Step 6: 4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methyltetrahydrofuran-3-ol

[0431]

[0432] To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)dihydrofuran-3(2H)-one (1.2 g, 5.21 mmol) in THF (10 mL) was added MeMgBr (1.0 M solution, 0.87 mL) at -78 °C. The mixture was stirred at room temperature for 1 hour and quenched by saturated aqueous NH4Cl solution. After removing all volatiles under reduced pressure, the residue was diluted with DCM. The organic layer was washed twice with brine, dried over MgSO4 and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography and eluted with petroleum ether:EtOAc (5%-20%) to give the title product (1 g, 78% yield) as a colorless oil. MS (ESI, m / e) [M+H] + 247.15.

[0433] Step 7: 4-(Hydroxymethyl)-3-methyltetrahydrofuran-3-ol

[0434]

[0435] A solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyltetrahydrofuran-3-ol (500 mg, 2.03 mmol) and TBAF (6 mL, 6.09 mmol, 1 M in THF) in THF (10 mL) was stirred at room temperature under nitrogen for 2 hours. The resulting mixture was diluted with water (5 mL). The aqueous layer was extracted with EtOAc (5×5 mL). The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (0%-5%) to give the title product (10 mg, 3.73% yield) as a colorless oil.

[0436] Step 8: tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((4-hydroxy-4-methyltetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0437]

[0438] To a solution of 4-(hydroxymethyl)-3-methyltetrahydrofuran-3-ol (10 mg, 0.08 mmol) and tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37.1 mg, 0.051 mmol) in THF (0.5 mL) was added NaH (2.42 mg, 0.101 mmol) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was quenched with saturated aqueous NH4Cl solution (2 mL) at 0°C. The aqueous layer was extracted with EtOAc (3x10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: EtOAc = 1: 2) to give the title product (13 mg, 30% yield) as a white solid. MS (ESI, m / e) [M+H] + 847.30.

[0439] Step 9: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((4-hydroxy-4-methyltetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0440] A solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((4-hydroxy-4-methyltetrahydrofuran-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (12 mg, 0.014 mmol) and TFA (0.2 mL) in DCM (1 ml) was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (chromatographic column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 52% B in 9 min) to give the title product (1 mg, 11% yield, TFA salt). 1 H NMR(300MHz,CD3OD)δ8.11(s,1H),7.24-7.19(m,1H),7.05-6.99(m,1H),4.79-4.60(m,3H),4.54-4.42(m,1H),4.23(s,2H),4.14

[0441] -4.11(m,1H),3.98-3.80(m,3H),3.79-3.66(m,2H),2.64-2.48(m,1H),2.13(s,4H),1.44(s,3H). MS(ESI,m / e)[M+H] + 647.25.

[0442] Example 28: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-methoxyoxetane-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0443]

[0444] Example 28 was prepared by a procedure analogous to that described in Example 3 by substituting (3-methoxytetrahydrofuran-3-yl)methanol for (3-methoxyoxetan-3-yl)methanol to give the title product (2.65 mg). 1H NMR(500MHz,CD3OD)δ8.13(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),4.84-4.82(m,2H),4.74-4.72(m,2H),4.64-4. 62(m,2H),4.59-4.56(m,1H),4.47-4.45(m,1H),3.73-3.70(m,1H),3.66-3.64(m,3H),3.40(s,3H),1.87-1.77(m,4H). MS(ESI,m / e)[M+H] + 633.4.

[0445] Example 29: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)naphthalen-2-ol

[0446]

[0447] Step 1: tert-butyl 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0448]

[0449] To a mixture of tert-butyl 3-(7-bromo-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.08 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (49 mg, 0.16 mmol), DPEpHosPdCl2 (11 mg, 0.016 mmol) and Cs2CO3 (77 mg, 0.24 mmol) was added toluene (5 mL). The solution was degassed 3 times with N2. The mixture was stirred at 100°C for 3 hours. The cooled resulting mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title product (44 mg). MS (ESI, m / e) [M+H] + 739.5.

[0450] Step 2: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)naphthalen-2-ol

[0451] To a solution of tert-butyl 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-((1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (44 mg, 0.06 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2-3 hours. The resulting mixture was concentrated to dryness and then diluted with DCM / MeOH=10 / 1 (5 mL). Next, 5 drops of 7MNH3 / MeOH solution were added to the mixture. The solution was further concentrated to dryness and purified by chromatography to give the title product (2.64 mg). NMR(500MHz,CD3OD)δ8.21(s,1H),7.74-7.72(m,1H),7.41-7.37(m,1H),7.25-7.24(m,1H),7.17-7.16(m,2H),7.04-7.02(m, 1H),4.75-4.70(m,2H),4.57-4.53(m,2H),3.79(s,2H),3.72-3.69(m,4H),1.87-1.81(m,6H),1.62-1.61(m,2H),1.42(s,3H). MS(ESI,m / e)[M+H] + 595.5.

[0452] Example 30: 4-(((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-2-yl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane-1-carbonitrile

[0453]

[0454] Step 1: 1-(Iodomethyl)-4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane

[0455]

[0456] To a solution of (1-(iodomethyl)-2-oxabicyclo[2.1.1]hexane-4-yl)methanol (2.54 g, 10.0 mmol) in THF (20 mL) was added NaH (1.20 g, 30.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Then, 1-(chloromethyl)-4-methoxybenzene was added to the reaction mixture and stirred at room temperature for 1 hour. After completion, the reaction mixture was quenched with water (30 mL), extracted with EtOAc (100 mL) and washed with saturated NaCl (50 mLx3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography and eluted with 0-30% ethyl acetate in petroleum ether to obtain the title product (1.87 g, 5.0 mmol).

[0457] Step 2: (4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexan-1-yl)methanol

[0458]

[0459] To a solution of 1-(iodomethyl)-4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane (1.87 g, 5.0 mmol) in DMSO (30 mL) was added KOAc (2.45 g, 25 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 16 hours. Upon completion, the reaction mixture was diluted with EtOAc (200 mL) and washed with saturated aqueous NaCl (50 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. Sodium ethoxide (680 mg, 10 mmol) and EtOH (10 mL) were added to the residue. The reaction mixture was then stirred at room temperature for 1 hour. Upon completion, the reaction mixture was directly concentrated to obtain a residue. The residue was purified by silica gel column chromatography and eluted with 0-80% ethyl acetate in petroleum ether to obtain the title product (528.2 mg, 2.0 mmol).

[0460] Step 3: 4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane-1-carbaldehyde

[0461]

[0462] To a solution of (4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane-1-yl)methanol (528.2 mg, 2.0 mmol) in DCM (10 mL) was added DMP (848 mg, 2.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NaCl (50 mL×3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give the crude title product (1.0 g crude product).

[0463] Step 4: 4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane-1-carbonitrile

[0464]

[0465] To a solution of 4-(((4-methoxybenzyl)oxy)methyl)-2-oxabicyclo[2.1.1]hexane-1-carbaldehyde (100 mg crude) in pyridine (2 mL) was added hydroxylamine hydrochloride (87.0 mg, 1.26 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was directly concentrated to give a crude product (150 mg crude). Triethylamine (0.15 ml, 1.1 mmol), methanesulfonyl chloride (0.06, 0.41 mmol) and DCM (5 mL) were then added to the crude product. The resulting mixture was stirred at room temperature for 16 hours. After completion, the residue was purified by silica gel column chromatography and eluted with 0-60% ethyl acetate in petroleum ether to give the title product (60.0 mg, 0.23 mol).

[0466] Step 5: 4-(Hydroxymethyl)-2-oxabicyclo[2.1.1]hexane-1-carbonitrile

[0467]

[0468] DDQ (90.8 mg, 0.4 mmol) was added to a solution of 4-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexane-1-carbonitrile (60.0 mg, 0.23 mol) in DCM (5 mL) and water (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with water (10 mL), extracted with DCM (10 mL) and washed with saturated NaCl (10 mLx3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography and eluted with 0-60% ethyl acetate in petroleum ether to obtain the title product (20.0 mg, 0.14 mmol).

[0469] Example 30 was prepared by a procedure analogous to that described in Example 1 by substituting (1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol for 4-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexane-1-carbonitrile to give the title product (4.4 mg). 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.22-7.20(m,1H),7.02-6.99(m,1H),4.85-4.55(m,3 H),3.97(s,2H),3.85-3.75(m,5H),2.39(s,2H),2.02-1.99(m,6H).δMS(ESI,m / e)[M+1] + 654.5.

[0470] Example 31: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-(cyclopropanecarbonyl)-3-methylazetidin-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0471]

[0472] Example 31 was prepared by a procedure analogous to that described in Example 13 by replacing acetyl chloride with cyclopropanecarbonyl chloride to give the title product (4.4 mg). 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.23-7.20(m,1H),7.03-7.00(m,1H),4.68-4.47(m,4H),4.39-4.35(m, 1H),4.05-3.97(m,4H),3.83-3.69(m,3H),2.00(s,4H),1.61-1.56(m,3H),1.47(s,3H),0.86-0.79(m,4H). MS(ESI,m / e)[M+1] + 684.5.

[0473] Example 32: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-ethyloxetan-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0474]

[0475] Step 1: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2-((3-ethyloxetan-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0476]

[0477] To a solution of (3-ethyloxetane-3-yl)methanol (12 mg, 0.1 mmol) in THF (2 mL) was added LiHMDS (0.1 mL, 0.1 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 hours. Then, tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-(methylsulfonyl)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.05 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with EtOAc (40 mL) and washed with saturated NaCl (15 mL×3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain a residue. The residue was purified by preparative TLC (petroleum ether: EtOAc = 2: 1) to give the title product (35 mg, 84.4%). MS (ESI, m / e) [M+1] + 831.5.

[0478] Step 2: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-ethyloxetan-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0479] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2-((3-ethyloxetane-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.0842 mmol) in DCM (10 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 3 hours. Upon completion, the reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give the title product (7.5 mg, 14.2%). 1H NMR(500MHz,CD3OD)δ8.12(s,1H),7.23-7.20(m,1H),7.04-6.96(m,1H),4.64-4.60(m,4H),4 .60-4.54(m,1H),4.49-4.46(m,3H),3.69-3.59(m,4H),1.93-1.84(m,6H),1.01-0.98(m,3H). MS(ESI,m / e)[M+1] + 631.5.

[0480] Example 33: 4-(2-((2-oxaspiro[3.3]heptane-6-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0481]

[0482] Example 33 was prepared by a procedure analogous to that described in Example 32 by replacing (3-ethyloxetan-3-yl)methanol with (2-oxaspiro[3.3]heptan-6-yl)methanol to give the title product (11.5 mg, 21.7%). 1 H NMR(500MHz,CD3OD)δ8.10(s,1H),7.22-7.19(m,1H),7.02-6.98(m,1H),4.72(s,2H),4.66(s,2H),4.55-4.53(m,1H),4.45-4 .42(m,1H),4.37-4.36(m,2H),3.71-3.62(m,4H),2.64-2.58(m,1H),2.45-2.40(m,2H),2.19-2.15(m,2H),1.89-1.76(m,4H). MS(ESI,m / e)[M+1] + 643.4.

[0483] Example 34: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(1,1-difluoroethyl)oxetane-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0484]

[0485] Example 34 was prepared by a procedure analogous to that described in Example 32 by replacing (3-ethyloxetan-3-yl)methanol with (3-(1,1-difluoroethyl)oxetan-3-yl)methanol to give the title product (9.5 mg, 17.7%). 1 H NMR(500MHz,CD3OD)δ8.13(s,1H),7.23-7.20(m,1H),7.03-6.99(m,1H),4.80(s,2H),4.78-4.77(m, 2H),4.71-4.70(m,2H),4.59-4.56(m,1H),4.48-4.46(m,1H),3.73-3.65(m,4H),1.83-1.71(m,7H). MS(ESI,m / e)[M+1] + 667.4.

[0486] Example 35: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((4-(cyanomethyl)tetrahydro-2H-pyran-4-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0487]

[0488] Example 35 was prepared by a procedure analogous to that described in Example 37 by replacing tetrahydrofuran-3-carboxylic acid methyl ester with tetrahydro-2H-pyran-4-carboxylic acid ethyl ester to give the title product (4.5 mg, 19.56% yield). 1 H NMR(300MHz,CD3OD)δ8.13(s,1H),7.26-7.19(m,1H),7.06-6.97(m,1H),4.60-4.46(m,4H) ,3.87-3.73(m,4H),3.72-3.57(m,4H),2.84(s,2H),1.95-1.76(m,6H),1.75-1.66(m,2H). MS(ESI,m / e)[M+H] + 670.30.

[0489] Example 36: 4-(2-((1-acetyl-3-fluoroazetidin-3-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0490]

[0491] Step 1: (3-Fluoroazetidin-3-yl)methanol trifluoroacetate

[0492]

[0493] To a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (648 mg, 33 mmol) in DCM (10 ml) was added TFA (5 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated to dryness and used directly in the next step.

[0494] Example 36 was prepared by a procedure analogous to that described in Example 8 by substituting (3-methylazetidin-3-yl)methanol hydrochloride for (3-fluoroazetidin-3-yl)methanol trifluoroacetate to give the title product (10 mg, formate). 1 H NMR(500MHz,CD3OD)δ8.45(s,0.5H),8.13(s,1H),7.23-7.20(m,1H),7.04-7.00(m,1H),4.82-4.81(m,2H),4.71-4.69(m,1H),4.59-4.5 0(m,2H),4.42-4.38(m,1H),4.29-4.24(m,1H),4.17-4.10(m,1H),4.08-4.02(m,2H),3.87-3.75(m,2H),2.08-2.00(m,4H),1.92(s,3H). MS(ESI,m / e)[M+1] + 662.5.

[0495] Example 37: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(cyanomethyl)tetrahydrofuran-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0496]

[0497] Step 1: Methyl 3-(cyanomethyl)tetrahydrofuran-3-carboxylate

[0498]

[0499] HMPA (5.9 g, 32.92 mmol) was added to a solution of LDA (4.23 ml, 8.46 mmol) in THF (8 mL) at -78 ° C, and the solution turned red. A solution of tetrahydrofuran-3-carboxylic acid methyl ester (1 g, 7.7 mmol) in THF (2 mL) was added to the solution at -78 ° C. The mixture was stirred at -78 ° C for 20 minutes. 2-bromoacetonitrile (1.85 g, 15.42 mmol) was then added and the reaction was warmed to room temperature. The solution was stirred for another 16 hours. The reactant was quenched with saturated NH4Cl (aqueous solution) (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / EtOAc (100:0-85:15) to give the title product (600 mg, 46% yield).

[0500] Step 2: 2-(3-(Hydroxymethyl)tetrahydrofuran-3-yl)acetonitrile

[0501]

[0502] LiBH4 (74 mg, 3.40 mmol) was added in batches to a stirred mixture of 3-(cyanomethyl)tetrahydrofuran-3-carboxylic acid methyl ester (250 mg, 1.48 mmol) in THF (3 mL) at 0 ° C. The resulting mixture was stirred at 80 ° C for 3 hours. The reaction was quenched with saturated NH4Cl aqueous solution at room temperature. The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether: EtOAc (100: 0-68: 32) to give the title product (89 mg, 43% yield).

[0503] Step 3: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-6-((trifluoromethyl)-2-((3-trifluoromethyl)tetrahydrofuran-3-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0504]

[0505] To a stirred solution of 2-(3-(hydroxymethyl)tetrahydrofuran-3-yl)acetonitrile (15 mg, 0.11 mmol) and tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (78.0 mg, 0.11 mmol) in THF (2 mL) was added NaH (5.1 mg, 0.21 mmol, 60%) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for another 1 hour. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: EtOAc = 1:2) to give the title product (70 mg, 77% yield). MS (ESI, m / e) [M+H] + 856.40.

[0506] Step 4: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(cyanomethyl)tetrahydrofuran-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0507] 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2-((3-(cyanomethyl)tetrahydrofuran-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (65 mg, 0.076 mmol), DCM (1.5 mL) and TFA (0.5 mL) were added to an 8 mL vial at room temperature. The resulting mixture was stirred at room temperature for another 2 hours. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 9 with saturated NaHCO3 aqueous solution. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (chromatographic column: Xselect CSH C18 OBD column 30*150 mm 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: CH 3 CN; flow rate: 60 mL / min; gradient: 15% B to 45% B in 8 min) to give the title product (10.2 mg, 20.48% yield formate salt). 1H NMR(300MHz,DMSO-d6)δ8.22(s,1H),8.10(s,3H),7.29-7.25(m,1H),7.17-7.11(m,1H),4.44-4.30(m,4H),3.87-3.82(m ,3H),3.78-3.72(m,1H),3.69-3.54(m,5H),2.94-2.82(m,2H),2.00-1.93(m,1H),1.93-1.81(m,1H),1.72-1.52(m,4H). MS(ESI,m / e)[M+H] + 656.10.

[0508] Example 38: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-methyl-1-(methylsulfonyl)azetidin-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0509]

[0510] Step 1: (3-methyl-1-(methylsulfonyl)azetidin-3-yl)methanol

[0511]

[0512] To a solution of (3-methylazetidine-3-yl)methanol hydrochloride (400 mg, 2.91 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.23 mL, 2.91 mmol), anhydrous pyridine (0.47 mL, 5.82 mmol) and DMAP (356 mg, 2.91 mmol) dropwise at 0 ° C. Then, the reaction mixture was stirred to RT and stirred for 16 hours. After completion, the reaction mixture was concentrated to give a crude product. The residue was purified by silica gel column chromatography and eluted with 50% ethyl acetate in petroleum ether to 2% methanol in DCM to give a crude title product (360 mg, 1.0 mmol, purity = 50%).

[0513] Example 38 was prepared by a procedure analogous to that described in Example 13 by replacing 1-(3-(hydroxymethyl)-3-methylazetidin-1-yl)ethan-1-one with (3-methyl-1-(methylsulfonyl)azetidin-3-yl)methanol to give the title product (34 mg). 1H NMR(500MHz,CD3OD)δ8.12(s,1H),7.23-7.20(m,1H),7.03-7.00(m,1H),4.66–4.46(m,4H),4. 00-3.98(m,4H),3.83-3.75(m,2H),3.68-3.67(m,2H),3.01(s,3H),2.00(s,4H),1.46(s,3H). MS(ESI,m / e)[M+1] + 694.5.

[0514] Example 39: 4-(2-((1-acetyl-3-methoxyazetidin-3-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0515]

[0516] Example 39 was prepared by a procedure analogous to that described in Example 3 by replacing (3-methoxytetrahydrofuran-3-yl)methanol with 1-(3-(hydroxymethyl)-3-methoxyazetidin-1-yl)ethan-1-one to give the title product (28.74 mg). 1 H NMR(500MHz,CD3OD)δ8.13(s,1H),7.22-7.20(m,1H),7.03-6.99(m,1H),4.78-4.71(m,2H),4.59-4.56(m,1H),4.49 -4.47(m,1H),4.31-4.22(m,2H),4.04-3.97(m,2H),3.73-3.65(m,4H),3.40(s,3H),1.90(s,3H),1.90-1.78(m,4H). MS(ESI,m / e)[M+H] + 674.4.

[0517] Example 40: 4-(2-((2-acetyl-2-azabicyclo[2.1.1]hexan-4-yl)methoxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0518]

[0519] Example 40 was prepared by a procedure analogous to that described in Example 3 by replacing (3-methoxytetrahydrofuran-3-yl)methanol with 1-(4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexan-2-yl)ethan-1-one to give the title product (19.66 mg). 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.22-7.20(m,1H),7.03-6.99(m,1H),4.76-4.68(m,3H),4.59-4.48(m, 2H),3.75-3.66(m,4H),3.59(s,1H),3.43(s,1H),2.13-2.04(m,5H),1.92-1.87(m,4H),1.64-1.57(m,2H). MS(ESI,m / e)[M+H] + 671.0.

[0520] Example 41: 4-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-8-fluoro-4-((1S,4R)-2-((2-methoxyethyl)amino)-7-azabicyclo[2.2.1]heptane-7-yl)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0521]

[0522] Step 1: (1S,4R)-tert-butyl 2-((2-methoxyethyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate

[0523]

[0524] A solution of (1S, 4R)-2-oxo-7-azabicyclo[2.2.1]heptane-7-carboxylic acid tert-butyl ester (2.11 g, 10 mmol) and 2-methoxyethane-1-amine (750 mg, 10 mmol) in methanol (40 mL) was stirred at 50 ° C for 15 hours. Then, NaBH4 (1520 mg, 40 mmol) was added at 0 ° C, and the reaction mixture was stirred at 25 ° C for 3 hours. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaCl (15 mL×3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel (petroleum ether: EtOAc=1:1) to obtain the title product (2.3 g, 85.2%). MS (ESI, m / e) [M+1] + 271.5.

[0525] Step 2: (1S,4R)-tert-butyl 2-(((benzyloxy)carbonyl)(2-methoxyethyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate

[0526]

[0527] A mixture of (1S, 4R)-2-((2-methoxyethyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylic acid tert-butyl ester (1.68 g, 6.0 mmol), CbzCl (1.02 g, 6.0 mmol) and DIPEA (1.55 g, 12.0 mmol) in DCM (20 mL) was stirred at 25 ° C for 3 hours. After completion, the reaction mixture was diluted with EtOAc (40 mL) and washed with saturated NaCl (15 mL×3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel (petroleum ether: EtOAc = 5: 1) to give the title product (1.6 g, 66.1%). MS (ESI, m / e) [M+1] + 405.5.

[0528] Step 3: Benzyl ((1S,4R)-7-azabicyclo[2.2.1]heptane-2-yl)(2-methoxyethyl)carbamate hydrochloride

[0529]

[0530] A solution of (1S,4R)-tert-butyl 2-(((benzyloxy)carbonyl)(2-methoxyethyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate (606 mg, 1.5 mmol) in HCl / dioxane (4N, 10 mL) was stirred at room temperature for 4 hours. Upon completion, the reaction mixture was concentrated. The residue was washed with ether and used directly in the next step without further purification. MS (ESI, m / e) [M+1] + 305.4.

[0531] Step 4: tert-Butyl ((1S,4R)-7-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-7-azabicyclo[2.2.1]heptane-2-yl)(2-methoxyethyl)carbamate

[0532]

[0533] A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (364 mg, 1.0 mmol), benzyl ((1S, 4R)-7-azabicyclo[2.2.1]heptane-2-yl)(2-methoxyethyl)carbamate hydrochloride (340 mg, 1.0 mmol) and DIPEA (516 mg, 4.0 mmol) in DCM (10 mL) was stirred at 25 °C under N2 atmosphere for 1 hour. After completion, the reaction mixture was diluted with DCM (50 mL) and washed with water (15 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel (petroleum ether: EtOAc = 3: 1) to give the title product (444 mg, 70.5%). MS (ESI, m / e) [M+1] + 631.4.

[0534] Step 5: Benzyl ((1S,4R)-7-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-7-bromo-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-7-azabicyclo[2.2.1]heptan-2-yl)(2-methoxyethyl)carbamate

[0535]

[0536] A solution of ((1S, 4R)-7-(7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-7-azabicyclo[2.2.1]heptane-2-yl)(2-methoxyethyl)carbamic acid benzyl ester (444 mg, 0.704 mmol), (2-oxabicyclo[2.1.1]hexane-4-yl)methanol (160 mg, 1.4 mmol) and KF (204 mg, 3.5 mmol) in DMSO (15 mL) was stirred at 100 ° C for 4 hours. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (15 mLx3). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel (petroleum ether: EtOAc = 3: 1) to obtain the title product (290 mg, 58.0%). MS (ESI, m / e) [M+1] + 709.5,711.5.

[0537] Step 6: Benzyl ((1S,4R)-7-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-7-azabicyclo[2.2.1]heptan-2-yl)(2-methoxyethyl)carbamate

[0538]

[0539] A mixture of benzyl ((1S,4R)-7-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-7-bromo-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-7-azabicyclo[2.2.1]heptan-2-yl)(2-methoxyethyl)carbamate (213 mg, 0.3 mmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (502 mg, 1.2 mmol), DPEphosPdCl2 (107 mg, 0.15 mmol) and Cs2CO3 (293 mg, 0.9 mmol) in toluene (50 mL) was stirred at 80°C for 4 hours. After completion, the reaction mixture was concentrated and purified by silica gel (petroleum ether: EtOAc = 3: 1) to give the title product (110 mg, 40%). MS (ESI, m / e) [M+1] + 921.5.

[0540] Step 7: tert-Butyl (4-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-8-fluoro-4-((1S,4R)-2-((2-methoxyethyl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)-6-(trifluoromethyl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate

[0541]

[0542] A mixture of benzyl ((1S,4R)-7-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-7-azabicyclo[2.2.1]heptan-2-yl)(2-methoxyethyl)carbamate (100 mg, 0.109 mmol) and 10% Pd / C (100 mg) in methanol (10 mL) was stirred at 20° C. under H2 atmosphere for 4 h. Upon completion, the reaction mixture was filtered and used directly in the next step without further purification. MS (ESI, m / e) [M+1] + 787.5.

[0543] Step 8: 4-(2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-8-fluoro-4-((1S,4R)-2-((2-methoxyethyl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0544] To a solution of tert-butyl (4-(2-((2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-8-fluoro-4-((1S,4R)-2-((2-methoxyethyl)amino)-7-azabicyclo[2.2.1]heptane-7-yl)-6-(trifluoromethyl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (70 mg, 0.089 mmol) in DCM (4 mL) was added TFA (4 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give the title product (2.0 mg, 3.3%). 1 HNMR(500MHz,CD3OD)δ8.28(s,1H),7.24-7.20(m,1H),7.04-7.00(m,1H),5.10-5.06(m,1H),5.03-4.96(m,1H),4.83 -4.79(m,2H),4.57(s,2H),3.73(s,3H),3.65-3.62(m,2H),3.44-3.40(m,4H),2.25-1.86(m,6H),1.70-1.53(m,4H). MS(ESI,m / e)[M+1] + 687.4.

[0545] Example 42: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol

[0546]

[0547] Step 1: tert-butyl 3-(7-bromo-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0548]

[0549] To a solution of (1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methanol (85 mg, 0.66 mmol) in THF (5 mL) was added sodium hydride (27 mg, 0.66 mmol) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. Then, tert-butyl 3-(7-bromo-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.44 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. After completion, the reaction mixture was quenched with water (10 mL), extracted with EtOAc (30 mL×3) and washed with saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give the crude title product (240 mg, 0.43 mmol). MS (ESI, m / e) [M+1] + 563.1.

[0550] Step 2: tert-butyl 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0551]

[0552] To a solution of tert-butyl 3-(7-bromo-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.18 mmol), 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (110 mg, 0.36 mmol) and PdCl2(dtbpf) (46 mg, 0.07 mmol) in 1,4-dioxane (3 mL) and H2O (0.6 mL) was added K3PO4 (115 mg, 0.54 mmol) at room temperature. The reaction mixture was then stirred at 90°C for 2 hours. After completion, the reaction mixture was quenched with water (30 mL), extracted with EtOAc (30 mL×3) and washed with saturated aqueous NaCl solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography and eluted with 0%-60% ethyl acetate in petroleum ether to obtain the title product (90 mg, 0.13 mmol). MS (ESI, m / e) [M+1] + 671.3.

[0553] Step 3: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol

[0554] To a solution of 3-(8-fluoro-7-(3-(methoxymethoxy)naphthalene-1-yl)-2-((1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70 mg, 0.10 mmol) in DCM (24 mL) was added TFA (4.5 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated to obtain a residue. It was dissolved in 3 mL DCM and adjusted to pH = ~ 10 using 7N NH3 in MeOH. After concentration, the residue was purified by preparative HPLC to obtain the title product (3 mg, formate). 1 H NMR(500MHz,CD3OD)δ8.50(s,0.5H),7.87-7.73(m,2H),7.46-7.38(m,2H),7.36-7.28(m,1H),7.26-7.17(m,2H),7.09(s,1H),4.74(s,2H ),4.63-4.55(m,2H),3.96(s,2H),3.80(s,2H),3.70-3.67(m,2H),2.06-2.04(m,4H),1.82-1.80(m,2H),1.65-1.62(m,2H),1.43(s,3H). MS(ESI,m / e)[M+1]+527.4.

[0555] Example 43: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((4-(difluoromethyl)tetrahydro-2H-pyran-4-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0556]

[0557] Example 43 was prepared by a procedure analogous to that described in Example 6 by replacing 3-(hydroxymethyl)tetrahydrofuran-3-ol with (4-(difluoromethyl)tetrahydro-2H-pyran-4-yl)methanol to give the title product (12 mg, 26.7% yield). 1H NMR(500MHz,CD3OD)δ8.12(s,1H),7.25-7.21(m,1H),7.04-7.01(m,1H),6.08-5.86(m,1H),4.85-4.62 (m,4H),4.20-4.12(m,2H),3.90-3.69(m,6H),2.14-2.03(m,4H),1.90-1.85(m,2H),1.72-1.69(m,2H). MS(ESI,m / e)[M+1] + 681.6.

[0558] Example 44: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-fluorooxetane-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0559]

[0560] Step 1: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((3-fluorooxetan-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0561]

[0562] To a 20 mL sealed tube was added (3-fluorooxetane-3-yl)methanol (70 mg, 0.660 mmol), tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.068 mmol), THF (6 mL) and NaH (8 mg, 0.2 mmol, 60%). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc (40 mLx3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude title product (40 mg, 89.6% yield). MS (ESI, m / e) [M+H] + 821.5.

[0563] Step 2: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-fluorooxetan-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0564] 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-((3-fluorooxetanes-3-yl)methoxy)-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (40mg, 0.049mmol) / TFA(4mL) and DCM(2mL) were added into a 25mL round-bottom flask. The reactant was stirred at room temperature for 16 hours. The reactant was concentrated under vacuum. The residue was dissolved in EtOAc(40mL) and saturated NaCOaqueous solution (20mL) was added. The solution was stirred at room temperature for 10min and extracted with EtOAc(40mLx2). The combined organic phase was washed with brine (20mL), dried over anhydrous NaSO, and then concentrated under vacuum. The residue was purified by preparative HPLC (chromatographic column: XBridge Shield RP18 OBD column; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: CH3CN; gradient: 20% B to 75% B in 9 min) to give the title product (7 mg, 23.0% yield). 1 H NMR (500MHz, CD3OD) δ8.13(s,1H),7.25-7.19(m,1H),7.03-7.00(m,1H),4.78-4.58(m,7H),3.99(s,2H),3.86-3.77(m,3H),2.00(s,4H). MS(ESI,m / e)[M+H] + 621.3.

[0565] Example 45: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-methoxycyclopropyl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0566]

[0567] Example 45 was prepared by a procedure analogous to that described in Example 44 by replacing (3-fluorooxetan-3-yl)methanol with (1-methoxycyclopropyl)methanol to give the title product (11.8 mg, 39.0% yield). 1H NMR(500MHz,CD3OD)δ8.11(s,1H),7.23-7.22(m,1H),7.04-7.00(m,1H),4.68-4.59(m,4H) ,4.23(s,2H),3.92-3.83(m,2H),3.41(s,3H),2.14-2.13(m,4H),0.92(s,2H),0.80(s,2H). MS(ESI,m / e)[M+H] + 617.4.

[0568] Example 46: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-methyl-1-(oxazol-2-yl)azetidin-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0569]

[0570] Example 46 was prepared by a procedure analogous to that described in Example 24 by replacing azetidin-3-ylmethanol hydrochloride and 2-iodo-1-methyl-1H-imidazole with (3-methylazetidin-3-yl)methanol hydrochloride and 2-iodooxazole to give the title product (12 mg, 26.7% yield). 1 H NMR(500MHz,CD3OD)δ8.13(s,1H),7.53(s,1H),7.22-7.19(m,1H),7.11-7.08(m,1H),7.04-7.01(m,1H),4.77-4.74(m,1H),4 .67-4.64(m,1H),4.59-4.54(m,2H),4.30-4.24(m,4H),4.01-3.99(m,2H),3.91-3.80(m,2H),2.20-2.07(m,4H),1.51(s,3H). MS(ESI,m / e)[M+1] + 683.6.

[0571] Example 47: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((1-(cyclopropyloxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0572]

[0573] Example 47 was prepared by a procedure analogous to that described in Example 11 by replacing sodium methoxide with sodium cyclopropionate to give the title product (1 mg, 16.1% yield). 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.28-7.13(m,1H),7.02-6.99(m,1H),4. 81-4.69(m,2H),4.63-4.54(m,2H),3.94-3.88(m,2H),3.82-3.80(m,2H),3 .79-3.76(m,1H),3.75-3.73(m,2H),3.44-3.39(m,2H),2.03-1.92(m,4H), 1.91-1.84(m,2H),1.72-1.60(m,2H),0.60-0.50(m,2H),0.50-0.41(m,2H). MS (ESI, m / e) [M+1] + 699.6.

[0574] Example 48: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(difluoromethyl)oxetane-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0575]

[0576] Example 48 was prepared by a method similar to that described in Example 32 by replacing (3-ethyloxetane-3-yl)methanol with (3-(difluoromethyl)oxetane-3-yl)methanol to give the title product (101 mg), which was further separated by chiral HPLC (preparative HPLC equipment: Prep-HPLC-Gilson; column: IE, 20 mm×250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: EtOH (0.2% 2M NH3 in MeOH); flow rate: 18 mL / min; temperature: 25° C.; gradient: 40% B in 14 min; retention time - isomer 1: 6.5 min; retention time - isomer 2: 11.5 min) to give several atropisomers. Isomer 1 (42.0 mg, 30.4%): 1H NMR(500MHz,CD3OD)δ8.13(s,1H),7.23-7.20(m,1H),7.03-6.99(m,1H),6.37-6.15(m,1H),4.81(s,2H),4.78-4.77(m, 2H),4.70-4.65(m,2H),4.59-4.57(m,1H),4.50-4.47(m,1H),3.74-3.66(m,4H),1.90-1.81(m,4H); MS(ESI,m / e)[M+1] + 653.7. Isomer 2 (40.0 mg, 29.0%): 1 H NMR(500MHz,CD3OD)δ8.13(s,1H),7.23-7.20(m,1H),7.03-6.99(m,1H),6.38-6.15(m,1H),4.80(s,2H),4.78-4.77(m, 2H),4.70-4.65(m,2H),4.58-4.56(m,1H),4.49-4.47(m,1H),3.73-3.65(m,4H),1.90-1.81(m,4H); MS(ESI,m / e)[M+1] + 653.6.

[0577] Example 49: 3-(((7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-6-(trifluoromethyl)quinazolin-2-yl)oxy)methyl)oxetane-3-carbonitrile

[0578]

[0579] Example 49 was prepared by a procedure analogous to that described in Example 3 by replacing (3-methoxytetrahydrofuran-3-yl)methanol with 3-(hydroxymethyl)oxetane-3-carbonitrile to give the title product (24.91 mg). 1H NMR (500 MHz, CD3OD) δ 8.14 (s, 1H), 7.23-7.20 (m, 1H), 7.03-6.99 (m, 1H), 4.97-4.95 (m, 4H), 4.78-4.77 (m, 2H), 4.61-4.58 (m, 1H), 4.51-4.48 (m, 1H), 3.74-3.66 (m, 4H), 1.89-1.78 (m, 4H). MS (ESI, m / e) [M+H] + 628.4.

[0580] Example 50: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0581]

[0582] Step 1: tert-Butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0583]

[0584] To a solution of (tetrahydro-2H-pyran-4,4-diyl)dimethanol (44 mg, 0.3 mmol) in THF (10 mL) was added sodium hydride (15 mg, 0.60 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Then, tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (73.4 mg, 0.10 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaCl (15 mL×3) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. The residue was purified by preparative TLC (petroleum ether: EtOAc = 1: 1) to give the title product (40 mg, 46.5%). MS (ESI, m / e) [M+1] + 860.5.

[0585] Step 2: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0586] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.0465 mmol) in DCM (2 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 3 hours. Upon completion, the reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give the title product (15.0 mg, 48.9%). 1 H NMR(500MHz,CD3OD)δ8.11(s,1H),7.24-7.19(m,1H),7.04-7.00(m,1H),4.71-4.68(m,1H),4.60-4.58(m,1H) ,4.51-4.45(m,2H),4.06-4.02(m,2H),3.90-3.70(m,6H),3.64(s,2H),2.09-2.01(m,4H),1.69-1.58(m,4H). MS(ESI,m / e)[M+1] + 661.5.

[0587] Example 51: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((3-(cyanomethyl)oxetan-3-yl)methoxy)-8-fluoro-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0588]

[0589] Example 51 was prepared by a procedure analogous to that described in Example 6 by replacing 3-(hydroxymethyl)tetrahydrofuran-3-ol with 2-(3-(hydroxymethyl)oxetan-3-yl)acetonitrile to give the title product (25 mg, 40.2% yield as formate). 1 H NMR(500MHz,CD3OD)δ8.47(s,1H),8.13(s,1H),7.23-7.20(m,1H),7.04-7.00(m,1H),4.79-4.75(m,2H),4 .70-4.68(m,3H),4.63-4.61(m,3H),4.01-3.95(m,2H),3.85-3.77(m,2H),3.06(s,2H),2.04-1.95(m,4H). MS(ESI,m / e)[M+1] + 642.5.

[0590] Example 52: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethyl-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0591]

[0592] Step 1: tert-Butyl 3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0593]

[0594] A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (0.2 g, 0.47 mmol) and DIPEA (0.12 g, 0.94 mmol) in DCM (10 mL) was cooled to 0°C, tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate was added, the mixture was stirred at 0°C for 2 hours, diluted with DCM (10 mL), the operation was repeated three times, washed with brine (10 mL), filtered, the filtrate was concentrated, and purified by silica gel chromatography to give the title product (0.23 g, 82.1%). MS (ESI, m / e) [M+1] + 598.4.

[0595] Step 2: tert-Butyl 3-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0596]

[0597] To a solution of tert-butyl 3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.1 g, 0.16 mmol) in DMSO (5 mL) was added KF (0.039 g, 0.64 mmol) and stirred at 90 ° C for 5-6 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc (10 mL), repeated three times, washed with brine (10 mL), and filtered. The filtrate was concentrated and purified by silica gel chromatography to give the title product (0.08 g, 82.4%). MS (ESI, m / e) [M+1] + 581.3.

[0598] Step 3: tert-Butyl 3-(7-bromo-2,8-difluoro-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0599]

[0600] Pd(dppf)Cl2DCM (173 mg, 0.21 mmol) was added to a mixture of tert-butyl 3-(7-bromo-2,8-difluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (620 mg, 1.06 mmol), potassium trifluoro(vinyl)-14-borane (428 mg, 3.2 mmol), NaHCO3 (268 mg, 3.2 mmol), dioxane (20 mL) and H2O (2 mL), degassed with N2 three times, stirred at 70°C for 2 hours, the resulting mixture was filtered, the filtrate was concentrated and purified by column chromatography to give the title product (450 mg, 87.8%). MS (ESI, m / e) [M+H] + 481.1.

[0601] Step 4: tert-Butyl 3-(7-bromo-6-ethyl-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0602]

[0603] To a solution of tert-butyl 3-(7-bromo-2,8-difluoro-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (250 mg, 0.51 mmol) in EtOAc (15 mL) was added Pt / C (10%) (25 mg), the mixture was stirred at room temperature for 48 hours, the resulting mixture was filtered, the filtrate was concentrated and purified by column chromatography to give the title product (160 mg, 64.2%). MS (ESI, m / e) [M+H] + 483.1.

[0604] Step 5: tert-butyl 3-(7-bromo-6-ethyl-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0605]

[0606] A solution of (1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methanol (100 mg, 0.78 mmol) in THF (30 mL) was cooled to 0°C, NaH (29 mg, 0.74 mmol) was added in one portion, stirred at 0°C for 30 min, and then added to tert-butyl 3-(7-bromo-6-ethyl-2,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.33 mmol). The resulting mixture was stirred at room temperature for 4-5 hours, then quenched with H2O (20 mL), extracted three times with EtOAc (30 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated and purified by column chromatography to give the title product (150 mg, 76.9%). MS (ESI, m / e) [M+H] + 591.3.

[0607] Step 6: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-ethyl-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0608]

[0609] To the mixture were tert-butyl 3-(7-bromo-6-ethyl-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.084 mmol), (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)amino Toluene (10 mL) was added to a mixture of tert-butyl ester (140 mg, 0.034 mmol), Cs2CO3 (82 mg, 0.25 mmol) and DPEphosPdCl2 (12 mg, 0.017), degassed with N2 three times, and reacted at 100 ° C for 5 hours. The resulting mixture was filtered, the filtrate was concentrated and purified by column chromatography to give the title product (25 mg, 36.7%), MS (ESI, m / e) [M+H] + 803.6.

[0610] Step 7: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethyl-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0611] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-6-ethyl-8-fluoro-2-((1-methyl-2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.1 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give the title product (3.0 mg, 5.0%, formate), 1 HNMR(500MHz,CD3OD)δ8.49(s,0.5H),7.61(s,1H),7.18-7.15(m,1H),7.05 -7.02(m,1H),4.74-4.68(m,2H),4.58-4.56(m,1H),4.52-4.49(m,1H),4.0 0(s,2H),3.79(s,2H),3.73-3.66(m,2H),2.62-2.42(m,2H),2.08-2.04(m, 4H),1.81-1.80(m,2H),1.62-1.61(m,2H),1.42(s,3H),1.10-1.07(m,3H). MS(ESI,m / e)[M+1] + 603.4.

[0612] Example 53: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(fluoromethyl)oxetane-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0613]

[0614] Example 53 was prepared by a procedure analogous to that described in Example 6 by replacing 3-(hydroxymethyl)tetrahydrofuran-3-ol with (3-(fluoromethyl)oxetan-3-yl)methanol to give the title product (17 mg, 36.2% yield). 1HNMR(500MHz,CD3OD)δ8.13(s,1H),7.23-7.20(m,1H),7.04-6.99(m,1H),4.83-4.81(m,1H),4.75-4.71 (m,3H),4.69-4.66(m,2H),4.63-4.60(m,3H),4.54-4.51(m,1H),3.81-3.70(m,4H),1.97-1.83(m,4H). MS(ESI,m / e)[M+1] + 635.5.

[0615] Example 54: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-methyl-1-(1-methyl-1H-imidazol-2-yl)azetidin-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0616]

[0617] Example 54 was prepared by a procedure analogous to that described in Example 46 by replacing azetidin-3-ylmethanol hydrochloride with (3-methylazetidin-3-yl)methanol hydrochloride to give the title product (4 mg, 16.7% yield %). 1 H NMR(500MHz,CD3OD)δ8.12(s,1H),7.22-7.20(m,1H),7.03-7.00(m,1H),6.77-6.73(m,2H),4.67-4.55(m, 4H),4.22-4.19(m,2H),3.97-3.89(m,4H),3.83-3.75(m,2H),3.50(s,3H),2.00-1.92(m,4H),1.51(s,3H). MS(ESI,m / e)[M+1] + 696.5.

[0618] Example 55: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((6-methyl-2-oxaspiro[3.3]heptane-6-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0619]

[0620] Example 55 was prepared by a procedure analogous to that described in Example 1 (Step 6 and Step 7) by replacing (1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)methanol with (6-methyl-2-oxaspiro[3.3]heptan-6-yl)methanol to give the title product (15 mg, 48.3%). 1 HNMR(500MHz,CD3OD)δ8.10(s,1H),7.21-7.20(m,1H),7.03-6.99(m,1H),4.74-4.71(m,4H),4.59-4.57(m,1H),4 .49-4.46(m,1H),4.22(s,2H),3.79-3.67(m,4H),2.40-2.37(m,2H),2.07-2.05(m,2H),1.89(s,4H),1.19(s,3H). MS(ESI,m / e)[M+H] + 657.5

[0621] Example 56: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(methoxymethyl)-3,3-dimethyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0622]

[0623] Step 1: 1-(2-Hydroxypropan-2-yl)-3-methylenecyclobutane-1-carboxylic acid methyl ester

[0624]

[0625] To a mixture of diisopropylamine (1.11 g, 0.011 mol) in THF (50 mL) was added n-BuLi (4.4 mL, 2.5 N, 0.011 mol) dropwise at -78 °C. Then, it was heated to 0 °C and kept for 30 minutes. After recooling to -78 °C, 3-methylenecyclobutane-1-carboxylic acid methyl ester (1.27 g, 0.01 mol) was added to the reaction mixture and stirred at -78 °C for 1 hour. Then, acetone (1.17 g, 0.02 mol) was added dropwise to the reaction mixture, heated to room temperature and kept for 2 hours. After completion, the reaction mixture was quenched with 50 mL of H2O and extracted with EtOAc (50 mL×3). The combined organic layers were washed with saturated aqueous NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give the crude title product (1.15 g, 6.25 mmol). 1H NMR (500MHz, CDCl3) δ4.84(s,2H),3.77(s,3H),3.11(s,1H),3.07-3.04(m,2H),2.93-2.90(m,2H),1.24(s,6H).

[0626] Step 2: 1-(Iodomethyl)-3,3-dimethyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid methyl ester

[0627]

[0628] At room temperature to 1- (2-hydroxypropyl-2-yl) -3-methylenecyclobutane-1-methyl formate (650mg, 3.53mmol) in tert-butyl methyl ether (20mL) and H2O (10mL) in the mixture of add I2 (1.79g, 7.06mmol) and NaHCO3 (594mg, 7.06mmol). Then, it was stirred at room temperature for 4 hours. After completion, the reaction mixture was diluted with tert-butyl methyl ether (100mL), and quenched with saturated Na2S2O3 aqueous solution (100mL). The combined organic layer was washed with saturated NaCl aqueous solution (100mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a crude title product (720mg, 2.32mmol). 1 H NMR (500MHz, CDCl3) δ3.72(s,3H),3.38(s,2H),2.23-2.22(m,2H),2.05-2.04(m,2H),1.43(s,6H).

[0629] Step 3: 1-(Methoxymethyl)-3,3-dimethyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid

[0630]

[0631] To a mixture of 1-(iodomethyl)-3,3-dimethyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid methyl ester (600 mg, 1.94 mmol) in HPLC grade MeOH (30 mL) at 0°C was added sodium methoxide (3.14 g, 58.2 mmol). It was then heated to reflux and maintained for 24 hours. Upon completion, the reaction mixture was concentrated. The residue was diluted with H2O (100 mL). The aqueous layer was extracted with tert-butyl methyl ether (50 mL×2). The aqueous layer was then adjusted to PH=1-2 using 1N HCl aqueous solution and extracted with DCM (70 mL×3). The combined organic layers were washed with saturated NaCl aqueous solution (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate concentrated to give the crude title product as a brown solid (243 mg, 1.22 mmol, purity %=75%). 1 HNMR (500MHz, CDCl3) δ3.58(s,2H),3.40(s,3H),2.25-2.24(m,2H),2.11-2.05(m,2H),1.46(s,6H).

[0632] Step 4: (1-(Methoxymethyl)-3,3-dimethyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanol

[0633]

[0634] To a mixture of 1-(methoxymethyl)-3,3-dimethyl-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid (190 mg, 0.95 mmol) in THF (5 mL) was added dropwise BH3·THF (1.9 mL, 1 N, 1.90 mmol) at 0°C. Then, it was stirred at room temperature for 3 hours. After completion, the reaction mixture was quenched with MeOH (10 mL) at 0°C and concentrated to give a crude product. It was purified by silica gel column chromatography and eluted with 0-1.2% MeOH in DCM to give the title product as a colorless oil (60 mg, 0.32 mmol). 1H NMR (500MHz, CDCl3) δ3.79(s,2H),3.58(s,2H),3.40(s,3H),1.89-1.88(m,2H),1.71-1.70(m,2H),1.32(s,6H).

[0635] Step 5: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((1-(methoxymethyl)-3,3-dimethyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0636]

[0637] To a mixture of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70.0 mg, 0.095 mmol) in THF (5 mL) at 0°C was added (1-(methoxymethyl)-3,3-dimethyl-2-oxabicyclo[2.1.1]hexane-4-yl)methanol (35 mg, 0.19 mmol) and sodium hydride (11.4 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with saturated aqueous NaCl solution (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude title product. It was purified by silica gel column chromatography and eluted with 0-20% EtOAc in petroleum ether to give the title product as a yellow solid (45 mg, 0.05 mmol). MS (ESI, m / e) [M+1] + 901.7.

[0638] Step 6: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(methoxymethyl)-3,3-dimethyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0639] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-((1-(methoxymethyl)-3,3-dimethyl-2-oxabicyclo[2.1.1]hexane-4-yl)methoxy)-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.05 mmol) in DCM (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give the title product as a yellow solid (25 mg, 71% yield). 1 H NMR(500MHz,CD3OD)δ8.11(s,1H),7.23-7.20(m,1H),7.03-7.00(m,1H),4.72-4.54(m,4H),4.02(s,2H),3.84-3. 81(m,1H),3.78-3.76(m,1H),3.55(s,2H),3.36(s,3H),2.02(s,4H),1.97-1.96(m,2H),1.84(s,2H),1.36(s,6H). MS(ESI,m / e)[M+1] + 701.4.

[0640] Example 57: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(hydroxymethyl)oxetane-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0641]

[0642] Step 1: tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0643]

[0644] To a solution of tert-butyl 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-2,8-difluoro-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.20 mmol) and oxetane-3,3-diyldimethanol (110 mg, 0.93 mmol) in THF (3 mL) was added NaH (10 mg, 0.25 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaCl (15 mL) aqueous solution. The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to obtain a residue. It was purified by silica gel column chromatography and eluted with 0-100% EtOAc in petroleum ether to give the title product (100 mg, 0.12 mmol). MS (ESI, m / e) [M+1] + 833.5.

[0645] Step 2: 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile

[0646] To 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4-yl)-8-fluoro-2-((3-(hydroxymethyl)oxetanes-3-yl)methoxy)-6-(trifluoromethyl)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50mg, 0.06mmol) in DCM (4mL) at room temperature, TFA (2mL) was added. The reaction mixture was stirred at room temperature for 4 hours. The solvent was concentrated. The residue was dissolved in EtOAc (20mL) and saturated NaCO aqueous solution (20mL) was added. The solution was stirred at room temperature for 10min and extracted with EtOAc (40mLx2). The organic phase merged was washed with brine (20mL), dried over NaSO, and then concentrated under vacuum. This was purified by preparative HPLC to give the title product (20 mg, 53% yield). 1H NMR(500MHz,CD3OD)δ8.49(s,0.5H),8.12(s,1H),7.23-7.20(m,1H),7.03-7.00(m,1H),4.73-4 .68(m,3H),4.64-4.63(m,2H),4.56-4.55(m,3H),3.91(s,4H),3.83-3.74(m,2H),1.97(s,4H). MS(ESI,m / e)[M+1] + 633.4.

[0647] Determination

[0648] KRAS probe displacement assay

[0649] 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 (60nM final assay concentration) and biotinylated probe 2 for KRAS G12D (4nM 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.

[0650] pERK assay

[0651] 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 cryopreserved 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 (THR 202 / 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 FS X reader (BMG Labtech). IC was performed by fitting a curve of percent inhibition versus the logarithm of the inhibitor concentration using Dotmatics 50 Determination.

[0652] Active Table

[0653] Each compound in Table 2 was tested in one or more of the biochemical assays provided herein and found to be active therein.

[0654] Table 2

[0655]

[0656]

[0657]

[0658] As shown in the data in Table 2, the present inventors surprisingly and unexpectedly discovered that the exemplary compounds in Table 2 can modulate or inhibit the activity of KRAS G12D.

[0659] 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 or prodrug thereof, in R 5 is H, -Cl, -CF3 or unsubstituted C 1-4 alkyl; R 8 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted aryl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroaralkyl, unsubstituted or substituted spiro, or unsubstituted or substituted -alkyl-spiro; R 11 is 3,8-diazabicyclo[3.2.1]oct-3-yl, 3,8-diazabicyclo[3.2.1]oct-8-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl or and L 1 It is -O- or bond.

2. The compound of claim 1, wherein L 1 Yes -O-.

3. The compound as claimed in claim 2, wherein R 5 Yes - CF3; R 11 yes R 8 is unsubstituted or substituted heterocyclylalkyl.

4. The compound of claim 3, wherein the heterocyclylalkyl group comprises at least one oxygen.

5. The compound as claimed in claim 4, wherein R 8 Yes-L 8a -R 8a ; L 8a Yes – (CH2) n – n is an integer 1, 2 or 3; R 8a 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; R 8a is optionally substituted.

6. The compound as claimed in claim 5, wherein R 8 yes 7. The compound of claim 3, wherein the heterocyclylalkyl group comprises at least one nitrogen.

8. The compound of claim 7, wherein R 8 Yes-L 8a -R 8a ; L 8a Yes – (CH2) n – n is an integer 1, 2 or 3; R 8a 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 R 8a is optionally substituted.

9. The compound of claim 8, wherein R 8 yes 10. The compound of claim 1, wherein L 1 is the key; R 5 Yes - CF3; R 11 yes R 8 is unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclylalkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted cycloalkylalkyl.

11. The compound of claim 10, wherein R 8 Yes-L 8a -R 8a ; L 8a Yes – (CH2) n – n is an integer 0, 1, 2 or 3; R 8a is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or azetidinyl; and R 8a is optionally substituted.

12. The compound of claim 11, wherein R 8 yes 13. The compound of claim 1, wherein R 5 Yes - CF3; L 1 is-O-; R 11 is 3,8-diazabicyclo[3.2.1]oct-8-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl or R 8 yes and R 8 is optionally substituted.

14. The compound of claim 13, wherein the compound is 15. The compound of claim 1, wherein R 5 is -Cl; L 1 is-O-; R 8 yes and R 8 is optionally substituted.

16. The compound of claim 15, wherein the compound is 17. The compound of claim 1, wherein R 5 is unsubstituted C 1-4 alkyl; R 11 yes L 1 is-O-; R 8 yes and R 8 is optionally substituted.

18. The compound of claim 17, wherein the compound is 19. The compound of claim 1, wherein R 5 Yes - CF3; R 11 is 3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl; L 1 is-O-; R 8 yes and R 8 is optionally substituted.

20. The compound of claim 19, wherein the compound is 21. The compound of any one of claims 1-20, wherein the compound is selected from Table 2.

22. A pharmaceutical composition comprising an effective amount of a compound as described in any one of claims 1 to 21, or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

23. A method for inhibiting the activity of a KRAS mutant protein in a cell, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt, tautomer, isotopologue, stereoisomer or prodrug thereof, optionally wherein the KRAS mutant protein is a KRAS G12D mutant protein.

24. 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 21 or a pharmaceutically acceptable salt, tautomer, isotopomer, stereoisomer or prodrug thereof, optionally wherein the cancer is mediated by a KRAS mutation; preferably a KRAS G12D mutation.

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