Heterocyclic compounds, compositions thereof, and methods of treatment therewith

Abstract

Provided herein are compounds having the following structure (I), wherein the substituents are as defined herein, compositions comprising an effective amount of the compounds, and methods for modulating the activity of KRAS G12D and / or G12V. [Formula 1] TIFF2025510656000293.tif30164

Description

[Technical field]

[0001] Provided herein are heterocyclic compounds useful for the treatment of cancer, pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat cancer or a condition treatable or preventable by inhibition of KRAS G12V activity, comprising administering to a subject in need thereof an effective amount of the compounds. [Background technology]

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

[0003] KRas is one of the most frequently mutated genes in human cancer. Based on data from the Catalogue of Somatic Mutations (COSMIC) database, KRas mutations can be found in about 20% of human cancers, including pancreatic cancer, colorectal cancer, lung cancer, skin cancer, etc. (O'Bryan JP.Pharmacological targeting of RAS:Recent success with direct inhibitors.Pharmacol Res.2019;139:503-511). The most common KRas mutations are found at G12 and G13 positions, by blocking GTPase-activating proteins (GAPs) from stimulating the GTP hydrolysis activity of KRas (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). It leads to overactivation of the KRas protein, ultimately leading to uncontrolled cell proliferation and cancer.

[0004] Among various cancers, pancreatic cancer is considered the most KRas-dependent cancer type. KRas mutations are found in 94.1% of pancreatic ductal adenocarcinomas (PDAC). KRas G12D (41%) and G12V (34%) mutations are the two most prevalent cancers among 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 demonstrated 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 indicates that mutated KRas protein is a very attractive drug target for pancreatic cancer and other cancers with KRas mutations. WT KRas protein also plays a key role in normal tissue function, and WT KRas function has been demonstrated to be essential for adult hematopoiesis (Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459-465). It would be highly valuable if a potential drug molecule could selectively inhibit mutated KRas protein in cancer cells and spare its WT companion in normal cells.

[0005] Therefore, KRas G12D and G12V mutations are very attractive targets for pancreatic cancer and other cancers that harbor these mutations, and small molecule therapeutics that can selectively bind to and inhibit the function of KRas G12D and / or G12V are considered an attractive strategy for targeting cancers that harbor these mutations.

[0006] Citation or identification of any reference in this section should not be construed as an admission that the reference is prior art to the present application. Summary of the Invention [Means for solving the problem]

[0007] As used herein, compounds having the following formula (I): [ka] and pharma- ceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopically substituted derivatives, and prodrugs thereof, During the ceremony, Ring A is [ka] and X is N or CR 2 and Y is N or C-CN; Z is N or CR 3 and W is N or CR 5 and V is N or CR 7 and R 1 -NR 1a R 1b and R 2 is halogen, or unsubstituted or substituted alkyl; R 3 is halogen, or unsubstituted or substituted alkyl; R 4 is halogen, -NO2, or unsubstituted or substituted alkyl; R 5 is hydrogen, halogen, or -CN; R 7 is hydrogen, halogen, or -CN; R 8 , R9 , and R 10 each is independently hydrogen, halogen, unsubstituted or substituted alkyl, or -OH; R 1a and R 1b are each independently hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclylalkyl, with the proviso that R 1a and R 1b are not both hydrogen, or R 1a and R 1b together with the nitrogen atom to which they are attached form an unsubstituted or substituted heterocyclyl.

[0008] In one embodiment, the compound having formula (I) is a compound having ring A, [ka] In one embodiment, Y is N. In one embodiment, Y is C-CN. In one embodiment, X is CR 2 In one embodiment, R 2 is halogen or unsubstituted or halogen-substituted alkyl, preferably Cl or CF, more preferably CF. In one embodiment, R 1 -NHR 1a In one embodiment, R 1a is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; R 1a At least one ring in is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl.

[0009] In one embodiment, the compound having formula (I) is Ring A is [ka] In one embodiment, X is CR 2 In one embodiment, R 2 is halogen or unsubstituted or halogen-substituted alkyl, preferably Cl or CF, more preferably Cl. In one embodiment, R 8 is methyl, ethyl, Cl, -CN, or -CCH, preferably -CCH. In one embodiment, R 9 is hydrogen or F. In one embodiment, R 10 is -OH. In one embodiment, R 1 -NHR 1a In one embodiment, R 1a is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; R 1a At least one ring of R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl. 1a is cyclopropyl.

[0010] In one embodiment, the compound having formula (I) is Ring A is [ka] In one embodiment, X is CR 2 In one embodiment, R 2 is halogen, or unsubstituted or halogen-substituted alkyl, preferably Cl, or CF3, more preferably Cl.

[0011] In one embodiment, ring A is [ka] In one embodiment, R 1a and R 1b together with the nitrogen atom to which they are attached form an unsubstituted or substituted heterocyclyl.

[0012] In one embodiment, the compound having formula (I) is a compound having ring A, [ka] and R 1 but, [ka] In one embodiment, ring A is [ka] It is.

[0013] In one embodiment, the compound having formula (I) is a compound having ring A, [ka] and X is N. In one embodiment, ring A is [ka] In one embodiment, R 1 -NHR 1a In one embodiment, R 1a is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; R 1a At least one ring of is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl.

[0014] In one embodiment, ring A is [ka] It is.

[0015] In one embodiment, ring A is [ka] It is.

[0016] In one embodiment, R1a and R 1b together with the nitrogen atom to which they are attached form an unsubstituted or substituted monocyclic heterocyclyl or an unsubstituted or substituted spiroheterocyclyl containing zero or one or two additional heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur, preferably R 1 is unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidyl, unsubstituted or substituted piperidyl, unsubstituted or substituted morpholinyl, or unsubstituted or substituted [ka] is an unsubstituted or substituted heterocyclyl selected from:

[0017] In one embodiment, the compound having formula (I) is R 1a and R 1b together with the nitrogen atom to which they are attached form an unsubstituted or substituted heterocyclyl, which is an unsubstituted or substituted monocyclic heterocyclyl, an unsubstituted or substituted bicyclic heterocyclyl, an unsubstituted or substituted tricyclic heterocyclyl, an unsubstituted or substituted tetracyclic heterocyclyl, or an unsubstituted or substituted spirocyclic heterocyclyl.

[0018] In one embodiment, the compound is selected from Table 1, Table 2, and Table 3.

[0019] In one embodiment, provided herein is a method for inhibiting activity of a KRAS mutant protein in a cell, comprising contacting the cell with an effective amount of a compound provided herein, or a pharma- ceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof, optionally wherein the KRAS mutant protein is a KRAS G12V mutant protein.

[0020] 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 pharma- ceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof, and optionally, the cancer is mediated by a KRAS mutation, preferably a KRAS G12V mutation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition 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.

[0022] 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).

[0023] As used herein, "G12V mutation" refers to a mutation of the 12th amino acid residue located in the G domain of the KRAS protein from glycine to valine.

[0024] As used herein, "KRAS G12V" or "G12V" refers to a KRAS protein having a G12V mutation.

[0025] As used in this specification, and in this specification and the appended claims, the indefinite articles "a" and "an," as well as the definite article "the," include plural and singular referents unless the context clearly dictates otherwise.

[0026] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percentage of a component of a composition or dosage form, refer to a dose, amount, or weight percentage that is recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percentage. In certain embodiments, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percentage that is within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose, amount, or weight percentage.

[0027] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in reference to a numerical value or range of values ​​provided to characterize a particular solid form, such as a particular temperature or temperature range (such as those describing melting, dehydration, desolvation, or glass transition temperatures), mass change (such as mass change as a function of temperature or humidity), solvent or water content (e.g., in terms of mass or percentage), or peak position (such as, for example, analysis by IR or Raman spectroscopy or XRPD), indicate that the value or range of values ​​may deviate to an extent that would be considered reasonable by one of ordinary skill in the art while still describing the solid form. Techniques for characterizing crystalline forms and amorphous solids include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy, such as 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 numerical 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 values ​​of the XRPD peak positions can vary by up to ±0.2 degrees 2θ (or ±0.2 degrees 2θ) while still describing a particular XRPD peak.

[0028] An "alkyl" group is a saturated, partially saturated, or unsaturated straight or branched chain acyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbons, and in some embodiments from 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; saturated branched alkyls 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(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH) and -CHC≡C(CHCH), among others. The alkyl groups can be substituted or unsubstituted. When alkyl groups described herein are said to be "substituted," they may be substituted with any substituent or substituents as found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonato, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamine, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, B(OH)2, or O(alkyl)aminocarbonyl.

[0029] A "cycloalkyl" group is a saturated, partially saturated, or unsaturated cyclic alkyl group of 3 to 10 carbon atoms having a single cyclic ring or multiple fused or bridged rings, which may be optionally substituted with 1 to 3 alkyl groups. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyls containing more than one ring may be fused, spiro, or bridged, or combinations thereof. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple 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, and the like. Examples of unsaturated cycloalkyl groups include, among others, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl. The cycloalkyl groups may be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanol, and the like.

[0030] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, an aryl group contains 6 to 14 carbons, and in other embodiments, 6 to 12, or 6 to 10 carbon atoms in the ring portion of the group. Specific aryls include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, for example, fused aromatic aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0031] A "heterocyclyl" is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S, and N. In some embodiments, a heterocyclyl group contains 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. A heterocyclyl can also be attached to other groups at any ring atom (i.e., any carbon atom or heteroatom of the heterocycle). Heterocyclyl groups can be substituted or unsubstituted. Heterocyclyl groups can include multiple fused rings, including, but not limited to, bicyclic, tricyclic, and tetracyclic rings, as well as bridged or spirocyclic ring systems. Heterocyclyl groups include unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidine-2,4-dioneyl) groups. The phrase heterocyclyl includes fused ring species, including fused aromatic and non-aromatic groups, such as, for example, 1 and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing heteroatoms, including, for example, but not limited to, quinuclidyl. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzoisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, nyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithionyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decanyl, 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane, 1-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane , 3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane, 2-oxo-1-oxa-3,9-diazaspiro[5.5]undecane, homopiperazinyl, quinuclidyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoindolyl, isoindolinyl, azandolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzyl midazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzothioxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl , dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species that contain fused aromatic groups. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups are pyridyl or morpholinyl groups which may be mono- or polysubstituted, for example, 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents, such as, but not limited to, those described below.

[0032] A "heteroaryl" group is an aryl ring system having from 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, with the remaining atoms in the ring system being carbon atoms. In some embodiments, heteroaryl groups contain from 3 to 6 ring atoms, and in other embodiments, from 6 to 9, or from 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), iminophenyl, pyridazin ...idazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl Included are groups such as dazopyridyl (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, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0033] As used herein, "spirocyclic ring" refers to two or more rings in which adjacent rings are linked through a single atom. The individual rings in a spirocyclic ring may be the same or different. The individual rings in a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings in a set of spirocyclic rings.

[0034] A "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups can be substituted on 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.

[0035] An "aralkyl" group is a radical of the formula: -alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups can be substituted on the alkyl, aryl, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indanyl.

[0036] A "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. Substituted heterocyclylalkyl groups can be substituted on the alkyl, heterocyclyl, or both the 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.

[0037] A "halogen" is fluorine, chlorine, bromine, or iodine.

[0038] A "hydroxyalkyl" group is an alkyl group as described above that is substituted with one or more hydroxy groups.

[0039] An "alkoxy" or "alkoxyl" group is an --O-(alkyl), where alkyl is defined above.

[0040] An "alkoxyalkyl" group is an -(alkyl)-O-(alkyl), where alkyl is defined above.

[0041] An "amino" group is a radical of the formula: NH2.

[0042] An "alkylamino" group is a radical of the formula: -NH-alkyl or -N(alkyl)2, where each alkyl is independently as defined above.

[0043] A "carboxy" group is a radical of the formula: --C(O)OH.

[0044] An "aminocarbonyl" group has the formula: -C(O)N(R # )2, -C(O)NH(R # ) or -C(O)NH2, where each R # are independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclyl group, as defined herein.

[0045] An "acylamino" group has the formula: -NHC(O)(R # ) or -N(alkyl)C(O)(R # ), where each alkyl and R # are independently as defined above.

[0046] A "sulfonylamino" group has the formula: -NHSO(R # ) or -N(alkyl)SO2(R # ), where each alkyl and R # is defined above.

[0047] A "urea" group has 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 and R # are independently as defined above.

[0048] With the exception of alkyl groups, when groups described herein are said to be "substituted," they may be substituted with any suitable substituent or substituents. Illustrative examples of substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; monocyclic or fused. or heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl), aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0049] As used herein, the term "pharmaceutically acceptable salt(s)" 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 the compounds of formula (I) include, but are not limited to, those well known in the art. For example, see Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0050] As used herein, unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of that compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of that compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of that compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of that compound. The compounds may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

[0051] The use of stereoisomerically pure forms of such compounds, as well as mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of the enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving 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 Resolution sp. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0052] It should also be noted that the compounds may include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of E and Z isomers.

[0053] As used herein, unless otherwise indicated, "atropisomer" refers to a stereoisomer resulting from hindered rotation about a single bond axis, where the rotational barrier is high enough to permit isolation of individual rotamers.

[0054] "Tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of isomeric forms may vary depending on the environment in which the compound is found, for example, whether the compound is 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: [ka]

[0055] As will be readily appreciated by one of ordinary skill in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the invention.

[0056] It should also be noted that the compounds may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may contain unnatural proportions of atomic isotopes at one or more atoms, such as tritium ( 3 H), iodine-125( 125 I), Sulfur-35( 35 S), or carbon-14 ( 14 It may be radiolabeled with a radioisotope such as deuterium ( 2 H), Carbon-13( 13 C), or nitrogen-15 ( 15The isotopologue may be isotopically enriched, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 120, 132, 140, 141, 150, 161, 172, 183, 194, 195, 196, 197, 198, 199, 200, 210, 220, 230, 24

[0057] As used herein, "treating" refers to the total or partial alleviation of a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or the delay or halt of further progression or worsening of the symptoms, or the reduction or eradication of the cause(s) of the disorder, disease, or condition itself. In some embodiments, "treating" refers to the total or partial alleviation of a disorder, disease, or condition, or the delay or halt of further progression or worsening of the symptoms. In another embodiment, "treating" refers to the total or partial alleviation of a disorder, disease, or condition, or symptoms associated with a condition, which is treatable or preventable by the inhibition of KRAS G12V.

[0058] As used herein, "preventing" refers to a method of delaying and / or preventing, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition, a method of inhibiting a subject from acquiring a disorder, disease, or condition, or a method of reducing the risk of a subject acquiring a disorder, disease, or condition. In one embodiment, the condition is one that is treatable or preventable by inhibition of KRAS G12V.

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

[0060] The term "subject" includes animals, including, but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment includes mammals, and in another embodiment includes humans.

[0061] compound Aspect 1: Provided herein is a compound having the following formula (I): [ka] and pharma- ceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopically substituted derivatives, and prodrugs thereof, During the ceremony, Ring A is [ka] and X is N or CR 2 and Y is N or C-CN; Z is N or CR 3 and W is N or CR 5 and V is N or CR 7 and R 1 -NR 1a R 1b and R 2 is halogen, or unsubstituted or substituted alkyl; R 3 is halogen, or unsubstituted or substituted alkyl; R 4 is halogen, -NO2, or unsubstituted or substituted alkyl; R 5 is hydrogen, halogen, or -CN; R 7 is hydrogen, halogen, or -CN; R 8 , R 9 , and R 10 each is independently hydrogen, halogen, unsubstituted or substituted alkyl, or -OH; R 1a and R 1b are each independently hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heterocyclylalkyl, with the proviso that R 1a and R 1b are not both hydrogen, or R 1a and R 1b together with the nitrogen atom to which they are attached form an unsubstituted or substituted heterocyclyl.

[0062] Aspect 2: In one embodiment, the compound having formula (I) is one in which ring A is [ka] is a compound.

[0063] In one embodiment, Y is N.

[0064] In one embodiment, Y is C-CN.

[0065] In one embodiment, X is CR 2 In one embodiment, R 2 is halogen, or unsubstituted or halogen-substituted alkyl, preferably Cl, or CF3, more preferably CF3.

[0066] In one embodiment, R 1 -NHR 1a In one embodiment, R 1a is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; R 1a At least one ring in is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl. 1a is cycloalkyl, or heterocyclyl, and R 1a At least one ring of R is cyclopropyl. 1a is one or more,C 1-4 Alkyl, C 1-4 Optionally substituted with alkoxyl, halogen, -CN, -OH, or acetyl; C 1-4 Alkyl, and C 1-4 Each alkoxyl is independently optionally substituted with one or more halogen, -CN, -OH, or contains a carbon-carbon triple bond. 1a is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptan-2-yl, 2-oxaspiro[3.3]heptan-6-yl, bicyclo[1.1.1]pentan-1-yl, 3-oxabicyclo[3.1.0]hexan-6-yl, 1-(3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one-6-yl, or [ka] is preferably cyclopropyl, and R 1a is one or more C 1-4 Alkyl, halogen, -CN, -OH, or C 1-4Optionally substituted by alkoxyl, C 1-4 Alkyl and C 1-4 Each alkoxyl is independently optionally substituted with one or more halogen, -CN, -OH, or contains a carbon-carbon triple bond. 1a teeth, [ka] and preferably [ka] It is.

[0067] Aspect 3: In one embodiment, the compound having formula (I) is Ring A is [ka] is a compound.

[0068] In one embodiment, X is CR 2 In one embodiment, R 2 is halogen, or unsubstituted or halogen-substituted alkyl, preferably Cl, or CF3, more preferably Cl.

[0069] In one embodiment, R 8 is methyl, ethyl, Cl, -CN, or -CCH, preferably -CCH.

[0070] In one embodiment, R 9 is hydrogen or F.

[0071] In one embodiment, R 10 is -OH.

[0072] In one embodiment, R 1 -NHR 1a In one embodiment, R 1ais unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; R 1a At least one ring in is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl. 1a is cyclopropyl.

[0073] In one embodiment, R 1 -NR 1a R 1b and R 1a and R 1b together with the nitrogen atom to which they are attached form an unsubstituted or substituted monocyclic heterocyclyl or an unsubstituted or substituted spiroheterocyclyl. In some embodiments, the unsubstituted or substituted monocyclic heterocyclyl or the unsubstituted or substituted spiroheterocyclyl contains one or two additional heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur. In one embodiment, R 1a and R 1b together with the nitrogen atom to which they are attached, represent unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidyl, unsubstituted or substituted piperidyl, unsubstituted or substituted azepanyl, unsubstituted or substituted [ka] Unsubstituted or substituted [ka] Unsubstituted or substituted [ka] Unsubstituted or substituted [ka] or unsubstituted or substituted [ka] In one embodiment, the heterocyclyl is selected from one or more of: 1-4 Alkyl, halogen, -CN, -OH, C 1-4 Optionally substituted by alkoxyl, cycloalkylalkyl, or methylsulfonyl; C 1-4 Alkyl, and C 1-4 Each alkoxyl independently represents one or more of a halogen, -CN, -OH, or C 1-4 It is optionally substituted with alkoxyl.

[0074] In one embodiment, R 1 is azetidin-1-yl, [ka] 2-methyl-azetidin-1-yl, [ka] 3-methyl-azetidin-1-yl, [ka] 2,2-Dimethyl-azetidin-1-yl, [ka] 3-fluoro-azetidin-1-yl, [ka] 3,3-difluoro-azetidin-1-yl, [ka] 3-cyano-azetidin-1-yl, [ka] [ka] It is.

[0075] Aspect 4: In one embodiment, the compound having formula (I) is Ring A is [ka] is a compound.

[0076] In one embodiment, X is CR 2 It is.

[0077] In one embodiment, R 2 is halogen, or unsubstituted or halogen-substituted alkyl, preferably Cl, or CF3, more preferably Cl.

[0078] In one embodiment, ring A is [ka] It is.

[0079] In one embodiment, R 1a and R 1b together with the nitrogen atom to which they are attached, represent unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidyl, unsubstituted or substituted piperidyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted [ka] In one embodiment, the heterocyclyl is selected from one or more C 1-4 Optionally substituted with alkyl, halogen, -CN, or -OH.

[0080] In one embodiment, R 1 teeth, [ka] It is.

[0081] Aspect 5: In one embodiment, the compound having formula (I) is one in which ring A is [ka] and R 1 but, [ka] is a compound.

[0082] In one embodiment, ring A is [ka] It is.

[0083] Aspect 6: In one embodiment, the compound having formula (I) is one in which ring A is [ka] and X is N.

[0084] In one embodiment, ring A is [ka] It is.

[0085] In one embodiment, R 1 -NHR 1a It is.

[0086] In one embodiment, R 1a is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; R 1a At least one ring in is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl.

[0087] In one embodiment, R 1a is cycloalkyl, or heterocyclyl, where R 1a At least one ring of R is cyclopropyl. 1a is one or more C 1-4 Optionally substituted with alkyl.

[0088] In one embodiment, R 1a is cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentan-1-yl, or 3-oxabicyclo[3.1.0]hexan-6-yl, preferably cyclopropyl; R 1a is one or more C 1-4 Optionally substituted with alkyl.

[0089] In one embodiment, R 1a teeth, [ka] and preferably [ka] It is.

[0090] In one embodiment, R 1a and R 1b together with the nitrogen atom to which they are attached form an unsubstituted or substituted heterocyclyl, in which at least one ring of the heterocyclyl is piperidyl, or morpholinyl.

[0091] In one embodiment, R 1 is one or more,C 1-4 Optionally substituted with alkyl, halogen, -CN, or -OH; C 1-4 Each alkyl is independently optionally substituted with one or more halogen, --CN, or --OH.

[0092] In one embodiment, R 1 teeth, [ka] and preferably [ka] It is.

[0093] In one embodiment, R 1 teeth, [ka] It is.

[0094] In one embodiment, ring A is [ka] It is.

[0095] Aspect 7: In one embodiment, the compound having formula (I) is R 1a and R 1b together with the nitrogen atom to which they are attached form an unsubstituted or substituted heterocyclyl, which is an unsubstituted or substituted monocyclic heterocyclyl, an unsubstituted or substituted bicyclic heterocyclyl, an unsubstituted or substituted tricyclic heterocyclyl, an unsubstituted or substituted tetracyclic heterocyclyl, or an unsubstituted or substituted spirocyclic heterocyclyl.

[0096] In one embodiment, R 1 is not unsubstituted or substituted piperazinyl.

[0097] In one embodiment, R 1 is unsubstituted or substituted [ka] Unsubstituted or substituted [ka] Unsubstituted or substituted [ka] Unsubstituted or substituted [ka] Unsubstituted or substituted [ka] Unsubstituted or substituted [ka] or unsubstituted or substituted [ka] isn't it.

[0098] In one embodiment, R 1 is unsubstituted or substituted 3,8-diazabicyclo[3.2.1]octan-3-yl, or unsubstituted or substituted [ka] isn't it.

[0099] Aspect 8: In one embodiment, the compound is selected from Table 1, Table 2, and Table 3.

[0100] Aspect 9: In one embodiment, provided herein is a pharmaceutical composition comprising an effective amount of a compound provided herein, or a pharma- ceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof, and a pharma- ceutically acceptable carrier, excipient, or vehicle.

[0101] Aspect 10: In one embodiment, provided herein is a method for inhibiting activity of a KRAS mutant protein in a cell, comprising contacting the cell with an effective amount of a compound provided herein, or a pharma- ceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof, optionally wherein the KRAS mutant protein is a KRAS G12D and / or G12V mutant protein.

[0102] Aspect 11: 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 pharma- ceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof, optionally wherein the cancer is mediated by a KRAS mutation, preferably a KRAS G12D and / or G12V mutation.

[0103] Aspect 12: Provided herein is a method of modulating KRAS G12D and / or G12V activity, comprising contacting the cell with an effective amount of a compound provided herein, or a pharma- ceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof.

[0104] Embodiment 13: 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.

[0105] Aspect 14: Provided herein is a kit for treating cancer, the kit comprising: (a) a pharmaceutical composition comprising a compound provided herein; and (b) instructions for administration of an effective amount of the pharmaceutical composition comprising a KRAS G12D and / or G12V inhibitor provided herein to treat cancer in an individual.

[0106] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments.

[0107] Methods for producing compounds The compounds can be prepared using conventional organic synthesis and commercially available starting materials. By way of example and not limitation, compounds of formula (I) can be prepared as outlined in Schemes 1-3 shown below, as well as in the Examples described herein. It should be noted that one of ordinary skill in the art would know how to modify the procedures described in the illustrative Schemes and Examples to arrive at the desired product. Common protecting groups may be used to prevent certain functional groups from undergoing undesired reactions. Exemplary protecting groups are described in “Protective Groups in Organic Synthesis”, 4 th , PGM Wuts; TW Greene, John Wiley, 2007, and references cited therein.

[0108] Scheme 1 [ka] In some embodiments, provided herein is a method for preparing a compound defined by formula (I), as shown in Scheme 1. A halogen-substituted compound 1-1 (X1, X2, X3 are halogens) is converted to compound 1-2 under basic conditions (e.g., NaH, THF); compound 1-2 is then converted to compound 1-3 under basic conditions (e.g., Cs2CO3, 1,4-dioxane) or Buchwald coupling conditions (e.g., RuPhos Pd catalyst, Cs2CO3, 1,4-dioxane); compound 1-3 further undergoes a metal-catalyzed cross-coupling reaction with A-M1, such as Suzuki or Stille coupling (e.g., Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water for Suzuki coupling), to obtain compound 1-4, where A may or may not contain a protecting group (PG2), and M1 is a boronic acid, a boronic ester, a metal (e.g., Zn), tributyltin, etc. Compound 1-5 can be prepared by deprotecting compound 1-4 (e.g., 10% Pd / C, H2, EtOAc to deprotect the benzyl when PG1 is Bn); compound 1-5 is converted to 1-6 under substitution or coupling reaction conditions (e.g., BOP or PyBOP, DIPEA, MeCN); compound 1-6 is then deprotected (e.g., TFA and DCM to deprotect the Boc group when PG1 is Boc) to obtain a compound defined as formula (I).

[0109] Scheme 2 [ka] As shown in Scheme 2, in some embodiments, methods for preparing compounds defined by formula (I) are provided herein. Halogen-substituted compound 2-1 (X1, X2, X3 are halogens) is converted to compound 2-2 under basic conditions (e.g., NaH, THF); compound 2-2 is then reacted with 2-1 under basic conditions (e.g., Cs2CO3, 1,4-dioxane) or Buchwald coupling conditions (e.g., RuPhos Compound 2-3 is further converted to compound 2-3 by a metal catalyzed cross-coupling reaction such as Suzuki or Stille coupling with A-M1 (e.g., for Suzuki coupling, Pd(dtbpf)Cl2, K3PO4, 1,4-dioxane, water) to give compound 2-4, where A may or may not contain a protecting group (PG2) and M1 may be a boronic acid, a boronic ester, a metal (such as Zn), tributyltin, etc.; Compound 2-5 is prepared by deprotecting compound 2-4 (e.g., TFA to deprotect benzyl and Boc when PG1 is Bn and PG2 is Boc); Compound 2-5 is converted to compound (I) defined as formula (I) under substitution or coupling reaction conditions (e.g., BOP or PyBOP, DIPEA, MeCN).

[0110] Scheme 3 [ka] As shown in Scheme 3, in some embodiments, a method for preparing a compound defined by formula (I) is provided herein. Halogen-substituted compound 3-1 (X1, X2, X3 are halogens) is converted to compound 3-2 under substitution or coupling reaction conditions (e.g., DIPEA, DCM); compound 3-2 is then converted to compound 3-3 under substitution conditions (e.g., KF, DMSO when X4 is F); compound 3-3 further undergoes a metal-catalyzed cross-coupling reaction with A-M1, such as Suzuki or Stille coupling (e.g., Pd(dppf)Cl2, K3PO4, THF, water for Suzuki coupling), to give compound 3-4, where A is M1 may or may not contain a protecting group (PG2), and may be a boronic acid, a boronic ester, a metal (such as Zn), tributyltin, or the like; compound 3-5 is prepared by modifying compound 3-4 (e.g., I2, Ag2SO4, and DMF for iodination, e.g., CuI, 2,2-difluoro-2-(fluorosulfonyl)methyl acetate, NMP for trifluoromethylation); compound 3-5 is converted to compound 3-6 under basic conditions (e.g., Cs2CO3, 1,4-dioxane) or Buchwald coupling conditions (e.g., RuPhos Pd catalyst, Cs2CO3, 1,4-dioxane); compound 3-6 is converted to a compound defined as formula (I) under deprotection conditions (e.g., TFA to deprotect the PMB group when PG2 is PMB).

[0111] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments. EXAMPLES

[0112] The following examples are intended to be merely illustrative and should not be considered as limiting in any way. Unless otherwise stated, the experimental methods in the examples described below are conventional methods. All reagents and materials are commercially available unless otherwise stated. All solvents and chemicals used are of analytical grade or chemical purity. All solvents are redistilled before use. All anhydrous solvents are prepared according to standard or reference methods. Silica gel (100-200 mesh) for column chromatography and silica gel (GF254) for thin layer chromatography (TLC) are commercially available from Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd., China, and were eluted with petroleum ether (60-90°C) / ethyl acetate (v / v) and visualized with iodine or molybdphosphoric acid in ethanol unless otherwise stated. All extraction solvents were dried over anhydrous Na2SO4 unless otherwise stated.

[0113] Unless otherwise indicated, reactions described below were carried out in anhydrous solvents, under a positive pressure of nitrogen or argon or using drying tubes, reaction flasks were fitted with rubber septa for introduction of substrates and reagents via syringe, and glassware was oven-dried and / or heat-dried.

[0114] Unless otherwise indicated, column chromatography purifications were performed on a Biotage system (Manufacturer: Dyax Corporation) with silica gel columns or silica SepPak cartridges (Waters) or on a Teledyne Isco Combiflash purification system using prepacked silica gel cartridges.

[0115] 1 1 H NMR spectra were recorded on Varian instruments operating at 400 MHz or 500 MHz with TMS (tetramethylsilane) as the internal standard. 1H-NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone, or (CD3)2CO as solvents and using tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm, CD3OD: 3.31 ppm, DO: 4.79 ppm, d6-DMSO: 2.50 ppm, d6-acetone: 2.05, (CD3)2CO: 2.05) as reference standards. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sexlet), m (multiplet), br (broadened), dd (double doublet), dt (double triplet). Coupling constants, when given, are reported in Hertz (Hz).

[0116] LC / MS data were recorded using an Agilent 1100, 1200 high performance liquid chromatography-ion trap mass spectrometer (LC-MSD trap) equipped with a diode array detector (DAD) detected at 214 nm and 254 nm, and an ion trap (ESI source). All compound names, other than those of the reagents, were generated by ChemDraw® version 19.1.

[0117] In the examples below, the following abbreviations are used: [Table 1-1] [Table 1-2] [Table 1-3]

[0118] Synthesis of compounds Example 1a (common intermediate): 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-ol [ka]

[0119] Step 1: 7-Bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline [ka] To a stirred solution of 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4-diol (20.0 g, 61.2 mmol) in 120 mL of POCl3, N,N-diisopropylethylamine (40.0 mL) was added and the resulting mixture was stirred at 100° C. for 2 h. The cooled reaction mixture was evaporated under vacuum. The residue was purified by flash chromatography column (PE / DCM=1 / 1) to give the title compound (16.5 g). MS (ESI, m / e) [M+H] + 364.7.

[0120] Step 2: 4-(benzyloxy)-7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazoline [ka] To a stirred solution of NaH (2.20 g, 54.4 mmol, 60%) in 50 mL of THF was added BnOH (5.15 g, 47.6 mmol) at 0° C. and stirred at 0° C. for 30 min. Then to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (16.5 g, 45.3 mmol) in 150 mL of THF was added the above mixture at −40° C. and the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water and extracted with EtOAc, the combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by flash chromatography column to give the title product (16.7 g). MS (ESI, m / e) [M+H] + 436.7.

[0121] Step 3: 4-(benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazoline [ka] To a stirred solution of 4-(benzyloxy)-7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazoline (12.5 g, 28.7 mmol) in 120 mL of dioxane, Cs2CO3 (23.4 g, 71.8 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (6.85 g, 43.1 mmol) were added and the resulting mixture was stirred at 80° C. overnight. The cooled reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=20 / 1) to give the title product (13.1 g). MS (ESI, m / e) [M+H] + 557.8.

[0122] Step 4: tert-Butyl (4-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate [ka] To a 250 mL round bottom flask was added 4-(benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazoline (10.0 g, 17.9 mmol), (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (11.2 g, 35.8 mmol), KPO (15.2 g, 71.6 mmol), Pd(dtbpf)Cl (1.17 g, 1.79 mmol), dioxane (120 mL), and HO (24 mL) and the reaction mixture was stirred at 100 °C for 3 h. The resulting cooled mixture was concentrated and purified by flash column chromatography (DCM / MeOH=20 / 1) to give the title product (8.67 g). MS (ESI, m / e) [M+H] + 745.9.

[0123] Step 5: 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-ol To a 250 mL round bottom flask was added tert-butyl (4-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate (10.0 g, 13.4 mmol) and TFA (100 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated under vacuum. The residue was purified by preparative HPLC to give the title compound (6.1 g). MS (ESI, m / e) [M+H] + 556.3.

[0124] Example 1b (Common Intermediate): tert-Butyl (7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxy-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate [ka]

[0125] Step 1: tert-Butyl (7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxy-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate To a stirred solution of tert-butyl (4-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate (8.67 g, 11.6 mmol) in 120 mL of EtOAc, 10% Pd / C (2.90 g) was added under N2, and the resulting mixture was degassed with H2 three times and stirred under H2 atmosphere at room temperature for 5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM / MeOH=10 / 1) to give the title product (6.54 g). MS (ESI, m / e) [M+1] + 656.3. 1 H NMR(500 MHz,DMSO-d6)δ 12.20(s,1H),8.18(s,1H),7.46-7.36(m,1H),7.25-7.35(m,1H),5.20-5.45(m,1H),2.80-3.23(m,4H),1.77-2.22(m,6H),1.47(s,9H).

[0126] Example 1: 4-(4-(cyclopropylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0127] Step 1: 4-(4-(cyclopropylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine To a solution of 7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-ol (25 mg, 0.04 mmol) in acetonitrile (5 mL) was added cyclopropanamine (5 mg, 0.09 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (36 mg, 0.08 mmol) and 0.2 mL of N,N-diisopropylethylamine at room temperature. After addition, the mixture was stirred at room temperature for 16 h. It was then diluted with dichloromethane and water. The organic layers were combined, dried over sodium sulfate and evaporated, and the residue was purified by preparative HPLC to give the title compound (6 mg). 1 H NMR(500 MHz,CD3OD)δ 8.44(s,1H),7.21-7.14(m,1H),6.99-6.92(m,1H),5.46-5.30(m,1H),4.51-4.35(m,2H),3.55-3.36(m,3H),3.19-3.06( m,2H),2.53-2.18(m,3H),2.16-2.05(m,2H),2.01-1.92(m,1H),1.00-0.89(m,2H),0.82-0.74(m,2H).MS(ESI,m / e)[M+H] +595.4.

[0128] Example 2: 7-Fluoro-4-(8-fluoro-4-(((1S,2R)-2-fluorocyclopropyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0129] Step 1: tert-Butyl (7-fluoro-4-(8-fluoro-4-(((1S,2R)-2-fluorocyclopropyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate [ka] To a solution of tert-butyl (7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxy-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate (50 mg, 0.08 mmol) in 10 mL of N,N-dimethylformamide was added (1S,2R)-2-fluorocyclopropan-1-amine hydrochloride (17 mg, 0.15 mmol), ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (80 mg, 0.15 mmol), and 0.3 mL of N,N-diisopropylethylamine. The reaction was stirred at room temperature for 16 hours after which it was diluted with ethyl acetate and water. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica to give the title compound (10 mg, 15%). MS (ESI, m / e) [M+H] +713.4.

[0130] Step 2: 7-Fluoro-4-(8-fluoro-4-(((1S,2R)-2-fluorocyclopropyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka] To a solution of tert-butyl (7-fluoro-4-(8-fluoro-4-(((1S,2R)-2-fluorocyclopropyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate (10 mg, 0.015 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at room temperature. After the addition, the mixture was stirred at room temperature for 4 h. The solution was then evaporated, the pH of the residue was adjusted to 11 with aqueous sodium carbonate solution, and the mixture was diluted with dichloromethane and water. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC to give the title compound (2 mg). 1 H NMR(500 MHz,CD3OD)δ 8.55(s,1H),7.22-7.16(m,1H),7.00-6.93(m,1H),5.50-5.33(m,1H),4.95-4.75(m,2H),4.60-4.47(m,2H),3. 73-3.45(m,3H),3.17-3.10(m,1H),2.58-2.22(m,3H),2.22-1.94(m,3H),1.42-1.28(m,2H).MS(ESI,m / e)[M+H] + 613.4.

[0131] Example 3: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((2-methylcyclopropyl)amino)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0132] Example 3 was prepared following a similar procedure as described in Example 1, substituting 2-methylcyclopropan-1-amine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.43(s,1H),7.22-7.15(m,1H),7.00-6.90(m,1H),5.50-5.30(m,1H),4.55-4.35(m,2H),3.65-3.35( m,3H),3.23-3.13(m,1H),2.78-2.70(m,1H),2.53-1.91(m,6H),1.26-0.70(m,6H).MS(ESI,m / e)[M+H] + 609.6.

[0133] Example 4: 4-(4-(((trans-2-ethylcyclopropyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0134] Example 4 was prepared following a similar procedure as described in Example 1, substituting trans-2-ethylcyclopropan-1-amine for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.44(s,1H),7.19-7.13(m,1H),6.98-6.91(m,1H),5.43-5.27(m,1H) ,4.47-4.32(m,2H),3.50-3.33(m,4H),3.13-3.05(m,1H),2.88-2.81( m,1H),2.45-1.89(m,6H),158-1.47(m,1H),1.45-1.35(m,1H),1.15-1.05(m,3H),0.97-0.89(m,1H),0.79-0.70(m,1H).MS(ESI,m / e)[M+H] + 623.3.

[0135] Example 5: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(((trans)-2-phenylcyclopropyl)amino)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0136] Example 5 was prepared following a similar procedure as described in Example 1, substituting trans-2-phenylcyclopropan-1-amine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.53-8.45(m,1H),7.41-7.06(m,6H),7.01-6.90(m,1H),5.45-5.25(m,1H),4.28-4.00(m,2H),3.62-3.3 7(m,3H),3.18-2.99(m,1H),2.39-1.68(m,7H),1.66-1.50(m,1H),1.48-1.34(m,1H).MS(ESI,m / e)[M+H] + 671.5.

[0137] Example 6: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((2-methoxycyclopropyl)amino)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0138] Example 6 was prepared following a similar procedure as described in Example 1, substituting 2-methoxycyclopropan-1-amine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.54(s,1H),7.23-7.14(m,1H),7.00-6.92(m,1H),5.48-5.29(m,1H),4.55-4.38(m,2H),3.64-3.40( m,4H),3.37-3.32(m,3H),3.24-3.15(m,2H),2.52-1.91(m,6H),1.19-1.08(m,2H).MS(ESI,m / e)[M+H] + 625.4.

[0139] Example 7: 4-(4-(((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0140] Example 7 was prepared following a similar procedure as described in Example 1, substituting (1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-amine for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.45(s,1H),7.20-7.15(m,1H),6.98-6.94(m,1H),5.50-5.39(m,1H) ,4.59-4.50(m,2H),4.10-4.08(m,2H),3.83-3.71(m,2H),3.74-3.61( m,3H),3.27-3.23(m,1H),2.87-2.85(m,1H),2.57-2.38(m,2H),2.33-2.25(m,1H),2.20-2.18(m,2H),2.11-1.98(m,3H).MS(ESI,m / e)[M+H] + 637.4.

[0141] Example 8: 4-(4-(bicyclo[3.1.0]hexan-6-ylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0142] Example 8 was prepared following a similar procedure to that described in Example 1, substituting bicyclo[3.1.0]hexan-6-amine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.48(s,1H),7.20-7.15(m,1H),6.99-6.93(m,1H),5.60-5.41(m,1H) ,4.72-4.55(m,2H),3.94-3.66(m,3H),3.42-3.34(m,1H),2.85-2.78( m,1H),2.66-2.44(m,2H),2.40-2.23(m,3H),2.22-1.95(m,3H),1.89-1.80(m,2H),1.74-1.58(m,3H),1.37-1.20(m,1H).MS(ESI,m / e)[M+H] + 635.4.

[0143] Example 9: 1-((1R,5S,6s)-6-((7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one [ka]

[0144] Example 9 was prepared following a similar procedure to that described in Example 1, substituting 1-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.44(s,1H),7.25-7.06(m,1H),7.00-6.88(m,1H),5.51-5.33(m,1H),4.60-4.45(m,2H),3.98-3.86(m,2H),3.85-3.74( m,1H),3.71-3.41(m,4H),3.28-3.22(m,2H),2.80-2.75(m,1H),2.59-2.23(m,3H),2.21-1.88(m,7H).MS(ESI,m / e)[M+H] + 678.4.

[0145] Example 10: 4-(4-(cyclobutylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0146] Example 10 was prepared following a similar procedure to that described in Example 1, substituting cyclobutanamine for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.54(s,1H),7.20-7.15(m,1H),6.99-6.92(m,1H),5.46-5.30(m,1H),4.41-4.36(m,2H),3. 55-3.37(m,3H),3.18-3.08(m,2H),2.53-2.18(m,7H),2.16-1.81(m,5H).MS(ESI,m / e)[M+H] + 609.3.

[0147] Example 11: cis-3-((7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)amino)cyclobutan-1-ol [ka]

[0148] Example 11 was prepared following a similar procedure as described in Example 1, substituting cis-3-aminocyclobutanol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.61-8.54(m,1H),7.22-7.13(m,1H),7.02-6.89(m,1H),5.49-5.34(m,1H),4.55-4.38(m,2H),4.33-4.09(m,2H),3.66-3.49(m,3H), 3.27-3.20(m,1H),2.94-2.83(m,2H),2.53-2.35(m,2H),2.31-2.23(m,1H),2.21-2.08(m,4H),2.05-1.94(m,1H).MS(ESI,m / e)[M+H] + 625.6.

[0149] Example 12: (trans)-3-((7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)amino)cyclobutan-1-ol [ka]

[0150] Example 12 was prepared following a similar procedure to that described in Example 1, substituting trans-3-aminocyclobutanol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.61(s,1 H),7.21-7.15(m,1H),7.00-6.93(m,1H),5.55-5.40(m,1 H),4.63-4.47(m,3 H),3.85-3.63(m,3 H),2.58-2.00(m,10 H).MS(ESI,m / e)[M+H] + 625.5.

[0151] Example 13: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(((cis)-3-methoxycyclobutyl)amino)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0152] Example 13 was prepared following a similar procedure to that described in Example 1, substituting cis-3-methoxycyclobutanamine for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.60(s,1H),7.28-7.10(m,1H),7.11-6.84(m,1H),5.59-5.42(m,1 H),4.70-4.55(m,2H),4.45-4.35(m,1H),3.96-3.70(m,5H),3.43-3.37(m,2H),2.94-2.84(m,2H),2.68-2 .64(m,1H),2.63-2.49(m,2H),2.42-2.36(m,1H),2.33-2.24(m,2H),2.20-2.06(m,3H).MS(ESI,m / e)[M+H] + 638.2.

[0153] Example 14: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(((trans)-3-methoxycyclobutyl)amino)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0154] Example 14 was prepared using a procedure similar to that described in Example 1, substituting trans-3-methoxycyclobutanamine for cyclopropanamine to give the title product. 1H NMR (500 MHz, CD3OD) δ 8.57 (s, 1 H), 7.21-7.14 (m, 1 H), 6.99-6.92 (m, 1 H), 5.58-5.31 (m, 1 H), 4.50-4.35 (m, 2 H), 4.20-4.10 (m, 1 H), 3.62-3.46 (m, 3 H), 2.20-3.12 (m, 1 H), 2.55-1.96 (m, 9 H). MS (ESI, m / e) [M+H] + 639.5.

[0155] Example 15: 7-Fluoro-4-(8-fluoro-4-(((cis)-3-fluorocyclobutyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0156] Example 15 was prepared following a similar procedure to that described in Example 1, substituting cis-3-fluorocyclobutanamine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.51(s,1H),7.17-7.05(m,1H),6.95-6.78(m,1H),5.47-5.35(m,1H),4.61-4.19(m,3H),3.90-3.69(m,3H),3. 36-3.29(m,2H),2.96-2.84(m,2H),2.53-2.28(m,5H),2.26-2.16(m,2H),2.06-1.96(m,1H).MS(ESI,m / e)[M+H] + 627.6.

[0157] Example 16: 7-Fluoro-4-(8-fluoro-4-(((trans)-3-fluorocyclobutyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0158] Example 16 was prepared following a similar procedure to that described in Example 1, substituting trans-3-fluorocyclobutanamine for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.55(s,1 H),7.21-7.14(m,1 H),7.00-6.92(m,1 H),5.48-5.24(m,2 H),5.01-4.92(m,1 H),4.51-4.36(m,2 H),3.63-3.46(m,3 H),3.28-3.16(m,1 H),2.80-1.96(m,10 H).MS(ESI,m / e)[M+H] + 627.4.

[0159] Example 17: 4-(4-((3,3-difluorocyclobutyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0160] Example 17 was prepared following a similar procedure as described in Example 1, substituting 3,3-difluorocyclobutan-1-amine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.57(s,1H),7.24-7.07(m,1H),7.02-6.91(m,1H),5.52-5.37(m,1H),4.65-4.30(m,3H),3.82-3.50(m,3H),3.20- 3.04(m,2H),2.96-2.78(m,2H),2.60-2.37(m,2H),2.37-2.26(m,1H),2.20(m,2H),2.03(m,1H).MS(ESI,m / e)[M+H] + 645.4.

[0161] Example 18: (cis)-3-((7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)amino)cyclobutane-1-carbonitrile [ka]

[0162] Example 18 was prepared following a similar procedure to that described in Example 1, substituting cis-3-aminocyclobutanecarbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.55(s,1H),7.26-7.10(m,1H),7.00-6.90(m,1H),5.54-5.37(m,1 H),4.60-4.46(m,2H),3.77-3.61(m,3H),3.48-3.40(m,1H),3.19-3.09(m,1H),3.00-2.91(m,2H),2.67-2 .58(m,2H),2.60-2.42(m,2H),2.36-2.29(m,1H),2.27-2.15(m,2H),2.08-2.00(m,1H).MS(ESI,m / e)[M+H] + 634.2.

[0163] Example 19: (trans)-3-((7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)amino)cyclobutane-1-carbonitrile [ka]

[0164] Example 19 was prepared following a similar procedure to that described in Example 1, substituting trans-3-aminocyclobutanecarbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.59(s,1 H),7.19-7.13(m,1 H),7.00-6.91(m,1 H),5.48-5.33(m,1 H),4.54-4.40(m,2 H),3.75-3.46(m,3 H),3.28-3.23(m,2 H),2.56-1.96(m,10 H).MS(ESI,m / e)[M+H] + 639.5.

[0165] Example 20: ((cis)-3-((7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)amino)cyclobutyl)methanol [ka]

[0166] Example 20 was prepared following a similar procedure as described in Example 1, substituting cis-3-amino-cyclobutanemethanol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.58(s,1H),7.26-7.12(m,1H),7.04-6.88(m,1H),5.58-5.40(m,1 H),4.76-4.50(m,3H),3.81-3.51(m,4H),2.64-1.95(m,11H).MS(ESI,m / e)[M+H] + 639.2.

[0167] Example 21: ((trans)-3-((7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)amino)cyclobutyl)methanol [ka]

[0168] Example 21 was prepared following a similar procedure as described in Example 1, substituting trans-3-amino-cyclobutanemethanol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.59(s,1 H),7.22-7.14(m,1 H),7.00-6.92(m,1 H),5.50-5.36(m,1 H),4.54-4.40(m,2 H),3.75-3.56(m,5 H),2.56-1.96(m,11 H).MS(ESI,m / e)[M+H] + 639.5.

[0169] Example 22: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(spiro[3.3]heptan-2-ylamino)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0170] Example 22 was prepared following a similar procedure as described in Example 1, substituting spiro[3.3]heptan-2-amine for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.54(s,1H),7.25-7.08(m,1H),7.00-6.90(m,1H),5.48-5.30(m,1H),4.70-4.55(m,1H),4.50-4.30(m,2H),3.69-3.39(m,3H),3. 25-3.12(m,1H),2.61-2.51(m,2H),2.51-2.31(m,2H),2.30-2.08(m,7H),2.07-1.95(m,3H),1.95-1.80(m,2H).MS(ESI,m / e)[M+H] + 649.4.

[0171] Example 23: 4-(4-((2-oxaspiro[3.3]heptan-6-yl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0172] Example 23 was prepared following a similar procedure as described in Example 1, substituting 2-oxaspiro[3.3]heptan-6-amine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.51(s,1H),7.25-7.07(m,1H),7.00-6.90(m,1H),5.49-5.33(m,1H),4.72-4.36(m,5H),3.72-3.42(m,3H),3.25-3.12( m,1H),2.93-2.76(m,2H),2.55-2.33(m,4H),2.32-2.21(m,1H),2.20-2.08(m,2H),2.06-1.90(m,1H).MS(ESI,m / e)[M+H] + 651.4.

[0173] Example 24: 4-(4-(bicyclo[1.1.1]pentan-1-ylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0174] Example 24 was prepared following a similar procedure as described in Example 1, substituting bicyclo[1.1.1]pentan-1-amine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.48(s,1H),7.21-7.13(m,1H),6.97-6.94(m,1H),5.49-5.38(m,1H),4.52-4.44(m ,2H),3.73-3.48(m,3H),3.29-3.21(m,1H),2.65-1.98(m,13H).MS(ESI,m / e)[M+H] + 621.5.

[0175] Example 25: 7-Fluoro-4-(8-fluoro-4-(((1S,3R)-3-fluorocyclopentyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0176] Example 25 was prepared following a similar procedure as described in Example 1, substituting (1S,3R)-3-fluorocyclopentan-1-amine for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.62(s,1H),7.23-7.13(m,1H),6.98-6.94(m,1H),5.47-5.15(m,2H),4.77-4.69(m,1H),4.56-4.40(m,2H),3. 72-3.48(m,3H),3.28-3.18(m,1H),2.66-2.35(m,3H),2.31-2.23(m,2H),2.22-1.82(m,7H).MS(ESI,m / e)[M+H] + 641.5.

[0177] Example 26: (1S,2R)-2-((7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)amino)cyclopentane-1-carbonitrile [ka]

[0178] Example 26 was prepared following a similar procedure as described in Example 1, substituting (1S,2R)-2-aminocyclopentane-1-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.71(s,1H),7.25-7.13(m,1H),7.01-6.92(m,1H),5.50-5.33(m,1H),4.58-4.35(m,2H),3.71-3.43(m,4H),3. 27-3.15(m,1H),2.56-2.34(m,2H),2.33-2.21(m,3H),2.20-1.96(m,6H),1.86-1.71(m,1H).MS(ESI,m / e)[M+H] + 648.4.

[0179] Example 27: 4-(4-(cyclohexylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0180] Example 27 was prepared following a similar procedure to that described in Example 1, substituting cyclohexamine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.57(s,1H),7.23-7.13(m,1H),7.01-6.92(m,1H),5.52-5.36(m,1H),4.60-4.44(m,2H),4.33-4.24(m ,1H),3.80-3.54(m,3H),2.56-1.70(m,11H),1.59-1.50(m,4H),1.34-1.22(m,1H).MS(ESI,m / e)[M+H] + 637.4.

[0181] Example 28a (common intermediate): tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxyquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate [ka]

[0182] Step 1: 4-(benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazoline [ka] To a solution of benzyl alcohol (3.27 g, 30.27 mmol) in THF (200 mL) was added NaH (1.33 g, 33.3 mmol) dropwise at 0° C. and the mixture was stirred at 0° C. for an additional 30 min. The mixture was cooled to −40° C. and 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (10 g, 30.27 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with water, filtered and the solid was collected to give the title product (11 g, 91%). MS (ESI, m / e) [M+H] + =400.

[0183] Step 2: 4-(benzyloxy)-7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline [ka] 4-(Benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazoline (11 g, 27.5 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (4.4 g, 27.5 mmol), RuPhos Pd G3 (2.3 g, 2.8 mmol), and Cs2CO3 (17.9 g, 55 mmol) were placed in dioxane (110 mL). The mixture was stirred for 16 h and then cooled to room temperature. The solvent was removed and the residue was purified by column chromatography (hexane / EtOAc=2 / 1) to give the title product (9 g). MS (ESI, m / e) [M+H] + =524.3.

[0184] Step 3: tert-Butyl (4-(4-(benzyloxy)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate [ka] 4-(benzyloxy)-7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (9 g, 17.2 mmol), (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (8.1 g, 25.8 mmol), Pd(dppf)Cl2 (1.2 g, 1.7 mmol), and NaHCO3 (2.9 g, 34.4 mmol) were placed in dioxane (90 mL). The mixture was stirred at 80° C. for 4 h and then cooled to room temperature. The solvent was removed and the residue was purified by column chromatography (hexane / EtOAc=1 / 2) to give the title product (8.8 g). MS (ESI, m / e) [M+H] + =712.4.

[0185] Step 4: tert-Butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-oxo-3,4-dihydroquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate tert-Butyl (4-(4-(benzyloxy)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate (8.8 g, 12.4 mmol) was taken in EtOAc (100 mL) and the mixture was stirred at 50° C. for 16 h. The solvent was removed and the residue was purified by column chromatography (DCM / MeOH=10 / 1) to give the title product (4.6 g, 60%). MS (ESI, m / e) [M+H] + =622.3.

[0186] Example 28: 4-(6-chloro-4-(cyclopropylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0187] Example 28 was prepared following a similar procedure as described in example 2, replacing tert-butyl (7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxy-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-yl)carbamate and (1S,2R)-2-fluorocyclopropan-1-amine with tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-oxo-3,4-dihydroquinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate and cyclopropanamine to give the title product. 1 H NMR(500 MHz,DMSO-d6)δ 10.87(s,1H),8.64(s,1H),8.34(s,1H),7.91(s,2H),7.27-7.16(m,1H ),7.10-7.01(m,1H),5.62-5.48(m,1H),4.62-4.56(m,2H),3.90-3.72 (m,3H),3.36-3.28(m,1H),3.18-3.10(m,1H),2.35-2.20(m,2H),2.23 -2.08(m,2H),2.08-1.98(m,1H),0.89-0.70(m,4H).MS(ESI,m / e)[M+H] + 561.5.

[0188] Example 29: 4-(4-(((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)amino)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0189] Example 29 was prepared following a similar procedure as described in Example 28, substituting (1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-amine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,DMSO-d6)δ 8.56(s,1H),8.27(s,1H),7.91(s,2H),7.28-7.16(m,1H),7.10-7.00(m,1H),5.49-5.28(m,1H),4.20-4.15(m,2H),4.00-3.88(m,2H) ,3.79-3.63(m,2H),3.25-3.05(m,2H),2.98-2.84(m,2H),2.30-2.10(m,2H),2.11-1.98(m,3H),1.95-1.75(m,3H).MS(ESI,m / e)[M+H] + 603.5.

[0190] Example 30: 1-((1R,5S,6s)-6-((7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one [ka]

[0191] Example 30 was prepared in a similar manner to that described in Example 28, substituting 1-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one for cyclopropanamine to give the title product. 1H NMR(500 MHz,DMSO-d6)δ 8.60(s,1H),8.26(s,1H),7.91(s,2H),7.31-7.17(m,1H),7.10-7.00(m,1H),5.47-5.23(m,1H),4.20-4.08(m,2H),3.80-3.64(m,3H),3. 47-3.36(m,1H),3.30-3.28(m,1H),3.23-3.00(m,2H),2.87(s,1H),2.76(s,1H),2.25-2.00(m,4H),2.00-1.66(m,7H).MS(ESI,m / e)[M+H] + 644.5.

[0192] Example 31: 4-(6-chloro-4-(cyclobutylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0193] Example 31 was prepared following a similar procedure as described in Example 28, substituting cyclobutanamine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,DMSO-d6)δ 10.85(s,1H),8.83-8.75(m,1H),8.44(s,1H),7.90(s,2H),7.24-7.21( m,1H),7.08-7.05(m,1H),5.65-5.45(m,1H),4.73-4.68(m,1H),4.62-4 .47(m,2H),3.90-3.74(m,3H),2.48-2.45(m,1H),2.36-2.31(m,3H),2. 19-2.17(m,4H),2.04-2.02(m,1H),1.84-1.72(m,2H).MS(ESI)m / e[M+1] + =575.4.

[0194] Example 32: 4-(4-(bicyclo[1.1.1]pentan-1-ylamino)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0195] Example 32 was prepared following a similar procedure to that described in Example 28, substituting bicyclo[1.1.1]pentan-1-amine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,DMSO-d6)δ 9.10(s,1H),8.33(s,1H),7.91(s,2H),7.28-7.21(m,1H),7.08-7.00(m,1H),5.56-5.28(m,1H),4.50- 4.00(m,2H),3.75-3.40(m,1H),3.20-2.85(m,3H),2.59(s,1H),2.32-1.80(m,12H).MS(ESI,m / e)[M+H] + 587.4.

[0196] Example 33: 4-(4-(azetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0197] Example 33 was prepared following a similar procedure as described in Example 2, substituting azetidine for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.07(s,1H),7.20-7.13(m,1H),6.98-6.91(m,1H),5.43-5.27(m,1H),4.79-4.52(m,2H),4.43-4.25( m,2H),3.54-3.34(m,5H),3.18-3.09(m,1H),2.67-2.56(m,2H),2.44-1.87(m,6H).MS(ESI,m / e)[M+H] + 595.4.

[0198] Example 34: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methylazetidin-1-yl)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0199] Example 34 was prepared following a similar procedure as described in Example 2, substituting 3-methylazetidine for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1 H NMR(500MHz,CD3OD)δ8.08(s,1H),7.20-7.12(m,1H),6.98-6.91(m,1H),5.47-5.25(m,1H),4 .40-4.25(m,2H),3.49-3.35(m,3H),3.18-2.98(m,3H),2.41-1.86(m,6H),1.43-1.38(m,3H). MS(ESI,m / e)[M+H] + 609.4.

[0200] Example 35: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-methylazetidin-1-yl)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0201] Example 35 was prepared following a similar procedure as described in Example 1, substituting 2-methylazetidine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.11(s,1H),7.25-7.15(m,1H),7.03-6.93(m,1H),5.61-5.47(m,1H),5.10-5.00(m,1H),4.77-4.53(m,3H),4. 03-3.79(m,3H),3.48-3.40(m,1H),2.88-2.76(m,1H),2.71-2.06(m,7H),1.74-1.66(m,3H).MS(ESI,m / e)[M+H] + 609.4.

[0202] Example 36: 4-(4-(2,2-dimethylazetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0203] Example 36 was prepared following a similar procedure to that described in Example 1, substituting 2,2-dimethylazetidine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.13(s,1H),7.19-7.14(m,1H),6.98-6.91(m,1H),5.42-5.26(m,1H),4.85-4.76(m,3H),4.37-4.21(m,2H), 3.51-3.34(m,3H),3.15-3.06(m,1H),2.45-2.38(m,2H),2.36-1.87(m,5H),1.82(s,6H).MS(ESI,m / e)[M+H] + 623.4.

[0204] Example 37: 7-Fluoro-4-(8-fluoro-4-(3-fluoroazetidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0205] Example 37 was prepared following a similar procedure as described in Example 2, substituting 3-fluoroazetidine for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.07(s,1H),7.23-7.14(m,1H),7.02-6.92(m,1H),5.69-5.43(m,2H),5.15-4.92(m,2H),4. 80-4.54(m,4H),3.98-3.78(m,3H),3.46-3.37(m,1H),2.64-2.03(m,6H).MS(ESI,m / e)[M+H] + 708.4.

[0206] Example 38: 4-(4-(3,3-difluoroazetidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0207] Example 38 was prepared following a similar procedure as described in Example 2, substituting 3,3-difluoroazetidine for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.03(s,1H),7.21-7.14(m,1H),6.99-6.93(m,1H),5.44-5.28(m,1H),5.11-4.99(m,4H),4. 45-4.32(m,2H),3.55-3.34(m,3H),3.17-3.09(m,1H),2.46-1.92(m,6H).MS(ESI,m / e)[M+H] + 631.4.

[0208] Example 39: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)azetidine-3-carbonitrile [ka]

[0209] Example 39 was prepared following a similar procedure as described in Example 2, substituting (1S,2R)-2-fluorocyclopropan-1-amine with azetidine-3-carbonitrile to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.03(s,1H),7.21-7.15(m,1H),7.00-6.93(m,1H),5.56-5.41(m,1H),5.03-4.90(m,2H),4.62-4.48( m,2H),4.06-3.97(m,1H),3.88-3.64(m,3H),3.40-3.32(m,3H),2.61-2.01(m,6H).MS(ESI,m / e)[M+H] + 620.3.

[0210] Example 40: 2-(1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)azetidin-3-yl)acetonitrile [ka]

[0211] Example 40 was prepared by a similar procedure described in Example 1, substituting 2-(azetidin-3-yl)acetonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.08(s,1H),7.20-7.14(m,1H),6.98-6.91(m,1H),5.47-5.32(m,1H),4.53-4.32(m,4H),3. 68-3.42(m,4H),3.24-3.13(m,3H),2.99-2.93(m,2H),2.50-1.92(m,6H).MS(ESI,m / e)[M+H] + 634.6.

[0212] Example 41: 3-(1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)azetidin-3-yl)propanenitrile [ka]

[0213] Example 41 was prepared by a similar procedure as described in Example 1 by substituting 3-(azetidin-3-yl)propanenitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.09(s,1H),7.21-7.14(m,1H),7.00-6.93(m,1H),5.49-5.32(m,1H),4.74-4.36(m,4H),3.71-3.45( m,3H),3.25-3.15(m,3H),3.11-3.01(m,1H),2.61-2.53(m,2H),2.52-1.91(m,8H).MS(ESI,m / e)[M+H] + 648.5.

[0214] Example 42: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-methylazetidine-3-carbonitrile [ka]

[0215] Example 42 was prepared following a similar procedure as described in Example 1, substituting 3-methylazetidine-3-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.03(s,1H),7.22-7.13(m,1H),7.02-6.92(m,1H),5.55-5.41(m,1H),4.62-4.5 3(m,4H),3.83-3.67(m,3H),2.61-1.97(m,9H),1.83(s,3H).MS(ESI,m / e)[M+H] + 634.2.

[0216] Example 43: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2-methylazetidine-3-carbonitrile [ka]

[0217] Example 43 was prepared following a procedure similar to that described in Example 1, substituting 2-methylazetidine-3-carbonitrile for cyclopropanamine to give the title product. 1H NMR (500 MHz, CD3OD) δ 8.01 (s, 1H), 7.22-7.13 (m, 1H), 7.02-6.93 (m, 1H), 5.60-5.40 (m, 1H), 5.26-5.03 (m, 2H), 4.68-4.51 (m, 2H), 4.20-4.11 (m, 1H), 3.92-3.70 (m, 3H), 3.43-3.35 (m, 1H), 2.66-2.02 (m, 6H), 1.87-1.78 (m, 3H). MS (ESI, m / e) [M+H] + 634.4.

[0218] Example 44: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(methylsulfonyl)azetidin-1-yl)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0219] Example 44 was prepared following a procedure similar to that described in Example 1, substituting 3-(methylsulfonyl)azetidine for cyclopropanamine to give the title product. 1H NMR (500 MHz, CD3OD) δ 8.07 (s, 1H), 7.24-7.14 (m, 1H), 7.01-6.92 (m, 1H), 5.59-5.42 (m, 1H), 4.66-4.48 (m, 3H), 3.93-3.54 (m, 3H), 3.47-3.35 (m, 3H), 3.10 (s, 1H), 2.90-2.85 (m, 1H), 2.70-2.10 (m, 6H). MS (ESI, m / e) [M+H] + 673.5.

[0220] Example 45: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-methoxyazetidin-1-yl)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0221] Example 45 was prepared following a similar procedure as described in Example 1, substituting 3-methoxyazetidine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.09(s,1H),7.22-7.12(m,1H),7.02-6.91(m,1H),5.51-5.32(m,1H),4.62-4.23(m,5H), 3.75-3.46(m,3H),3.41(s,3H),3.26-3.15(m,2H),2.56-1.90(m,6H).MS(ESI,m / e)[M+H] + 625.4.

[0222] Example 46: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-methylazetidin-3-ol [ka]

[0223] Example 46 was prepared following a similar procedure as described in Example 1, substituting 3-methylazetidin-3-ol for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.07(s,1H),7.22-7.12(m,1H),7.02-6.91(m,1H),5.45-5.27(m,1H),4.75-4.25(m,6H), 3.54-3.35(m,3H),3.20-3.05(m,1H),2.47-1.80(m,6H),1.61(s,3H).MS(ESI,m / e)[M+H] + 625.4.

[0224] Example 47: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2-methylazetidin-3-ol [ka]

[0225] Example 47 was prepared following a similar procedure as described in Example 1, substituting 2-methylazetidin-3-ol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.06(s,1H),7.25-7.09(m,1H),7.02-6.91(m,1H),5.45-5.28(m,1H),5.22-5.03(m,1H),4.63-4.24( m,3H),3.55-3.34(m,3H),3.20-3.06(m,1H),2.48-1.87(m,6H),1.70-1.54(m,3H).MS(ESI,m / e)[M+H] + 625.4.

[0226] Example 48: (1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)azetidin-3-yl)methanol [ka]

[0227] Example 48 was prepared following a similar procedure as described in Example 1, substituting azetidin-3-ylmethanol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.11(s,1H),7.30-7.12(m,1H),7.02-6.91(m,1H),5.48-5.28(m,1H),4.73-4.25(m,5H),3. 88-3.75(m,2H),3.67-3.37(m,4H),3.23-3.00(m,2H),2.48-1.89(m,6H).MS(ESI,m / e)[M+H] + 625.4.

[0228] Example 49: ((2R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)azetidin-2-yl)methanol [ka]

[0229] Example 49 was prepared following a similar procedure as described in Example 1, substituting (R)-azetidin-2-ylmethanol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.12(s,1H),7.22-7.12(m,1H),7.01-6.91(m,1H),5.49-5.34(m,1H),5.04-4.96(m,1H),4.83-4.76(m,1H),4.72-4.64(m,1H),4. 48-4.40(m,2H),4.24-4.17(m,1H),3.88-3.84(m,1H),3.69-3.43(m,3H),3.25-3.20(m,1H),2.70-1.94(m,8H).MS(ESI,m / e)[M+H] + 625.5.

[0230] Example 50: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(pyrrolidin-1-yl)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0231] Example 50 was prepared following a similar procedure as described in Example 2, substituting pyrrolidine for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.47(s,1H),7.22-7.14(m,1H),6.99-6.92(m,1H),5.47-5.30(m,1H),4.48-4.32(m,2H),4.0 9-3.98(m,4H),3.62-3.39(m,3H),3.22-3.12(m,1H),2.50-1.91(m,10H).MS(ESI,m / e)[M+H] + 609.4.

[0232] Example 51: 7-Fluoro-4-(8-fluoro-4-((R)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0233] Example 51 was prepared by a similar procedure as described in Example 2, replacing (1S,2R)-2-fluorocyclopropan-1-amine with (R)-3-fluoropyrrolidine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.44(s,1H),7.21-7.15(m,1H),7.00-6.91(m,1H),5.55-5.25(m,2H),4.41-4.01( m,6H),3.49-3.40(m,1H),3.10-3.02(m,1H),2.58-1.83(m,8H).MS(ESI,m / e)[M+H] + 627.4.

[0234] Example 52: 7-Fluoro-4-(8-fluoro-4-((S)-3-fluoropyrrolidin-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0235] Example 52 was prepared by a similar procedure as described in Example 2, replacing (1S,2R)-2-fluorocyclopropan-1-amine with (S)-3-fluoropyrrolidine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.48(s,1H),7.23-7.15(m,1H),7.02-6.94(m,1H),5.57-5.41(m,2H),4.68-4.53(m,2H),4. 36-4.19(m,4H),3.98-3.68(m,3H),3.43-3.35(m,1H),2.66-2.02(m,8H).MS(ESI,m / e)[M+H] + 627.4.

[0236] Example 53: 4-(4-(3,3-difluoropyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0237] Example 53 was prepared following a similar procedure as described in Example 2, substituting 3,3-difluoropyrrolidine for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.38(s,1H),7.22-7.15(m,1H),6.99-6.93(m,1H),5.47-5.31(m,1H),4.50-4.31(m,6H),3. 61-3.38(m,3H),3.21-3.12(m,1H),2.70-2.58(m,2H),2.50-1.93(m,6H).MS(ESI,m / e)[M+H] + 645.4.

[0238] Example 54: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-methylpyrrolidin-1-yl)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0239] Example 54 was prepared following a similar procedure as described in Example 1, substituting (R)-3-methylpyrrolidine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.44(s,1H),7.21-7.15(m,1H),6.98-6.91(m,1H),5.42-5.27(m,1H),4.42-4.25(m,2H),4.23-3.98(m ,3H),3.65-3.34(m,3H),3.14-3.03(m,1H),2.55-1.68(m,10H),1.24-1.18(m,3H).MS(ESI,m / e)[M+H] + 623.5.

[0240] Example 55: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-methylpyrrolidin-1-yl)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0241] Example 55 was prepared following a similar procedure as described in Example 1, substituting (R)-2-methylpyrrolidine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.46(s,1H),7.24-7.13(m,1H),7.02-6.91(m,1H),5.65-5.43(m,1H),4.87-4.57(m,3H),4.3 1-3.82(m,5H),3.49-3.42(m,1H),2.74-1.81(m,10H),1.52-1.45(m,3H).MS(ESI,m / e)[M+H] + 623.5.

[0242] Example 56: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-2-methylpyrrolidin-1-yl)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0243] Example 56 was prepared following a similar procedure as described in Example 1, substituting (S)-2-methylpyrrolidine for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.47(s,1H),7.28-7.14(m,1H),7.03-6.93(m,1H),5.60-5.43(m,1H),4.86-4.68(m,2H),4.3 0-3.85(m,5H),3.48-3.43(m,1H),2.72-1.85(m,10H),1.52-1.45(m,3H).MS(ESI,m / e)[M+H] + 623.5.

[0244] Example 57: 4-(4-(2,2-dimethylpyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0245] Example 57 was prepared following a similar procedure as described in Example 2, substituting 2,2-dimethylpyrrolidine for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.45(s,1H),7.21-7.15(m,1H),6.98-6.91(m,1H),5.41-5.25(m,1H),4.40-4.26(m,2H), 4.26-4.20(m,2H),3.23-3.01(m,4H),2.43-1.84(m,10H),1.79(s,6H).MS(ESI,m / e)[M+H] + 636.9.

[0246] Example 58: 4-(4-((R)-2-ethylpyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0247] Example 58 was prepared following a similar procedure as described in Example 1, substituting (R)-2-ethylpyrrolidine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.39(s,1H),7.25-7.12(m,1H),7.02-6.91(m,1H),5.55-5.35(m,1H),4.70-4.42(m,3H),4.24-4.05(m,2H),3.8 3-3.55(m,3H),2.63-2.41(m,2H),2.33-1.89(m,10H),1.72-1.58(m,1H),1.09-1.00(m,3H).MS(ESI,m / e)[M+H] + 637.5.

[0248] Example 59: 4-(4-((S)-2-ethylpyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0249] Example 59 was prepared following a similar procedure as described in Example 1, substituting (S)-2-ethylpyrrolidine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.41(s,1H),7.25-7.14(m,1H),7.02-6.93(m,1H),5.62-5.44(m,1H),4.70-4.60(m,3H),4.22-4.07(m,2H),4.04-3.81(m ,3H),3.47-3.43(m,1H),2.70-2.53(m,2H),2.42-1.92(m,10H),1.72-1.57(m,1H),1.09-1.00(m,3H).MS(ESI,m / e)[M+H] + 637.5.

[0250] Example 60: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)pyrrolidine-3-carbonitrile [ka]

[0251] Example 60 was prepared following a similar procedure as described in Example 2, substituting pyrrolidine-3-carbonitrile for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.40(s,1H),7.21-7.14(m,1H),6.99-6.92(m,1H),5.42-5.25(m,1H),4.44-4.15( m,6H),3.63-3.54(m,1H),3.15-3.04(m,1H),2.59-1.85(m,8H).MS(ESI,m / e)[M+H] + 634.4.

[0252] Example 61: 2-(1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)pyrrolidin-3-yl)acetonitrile [ka]

[0253] Example 61 was prepared following a similar procedure as described in Example 2, substituting 2-(pyrrolidin-3-yl)acetonitrile for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.43(s,1H),7.21-7.15(m,1H),6.98-6.91(m,1H),5.41-5.27(m,1H),4.43-4.07(m,5H),3.85-3.77( m,1H),3.47-3.36(m,3H),3.13-3.03(m,1H),2.85-2.72(m,3H),2.45-1.86(m,8H).MS(ESI,m / e)[M+H] + 647.8.

[0254] Example 62: 4-(4-(2-azabicyclo[2.1.1]hexan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0255] Example 62 was prepared following a similar procedure as described in Example 1, substituting 2-azabicyclo[2.1.1]hexane for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.41(s,1H),7.23-7.14(m,1H),7.01-6.91(m,1H),5.50-5.29(m,2H),4.42-4.27(m,2H),4.21-4.09( m,2H),3.56-3.39(m,3H),3.19-3.10(m,2H),2.47-1.93(m,8H),1.62-1.53(m,2H).MS(ESI,m / e)[M+H] + 621.4.

[0256] Example 63: (3R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)pyrrolidin-3-ol [ka]

[0257] Example 63 was prepared following a similar procedure as described in Example 1, substituting (R)-pyrrolidin-3-ol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.46(s,1H),7.25-7.13(m,1H),7.01-6.90(m,1H),5.50-5.32(m,1H),4.65-4.37(m,3H),4.32-4.03( m,3H),3.99-3.91(m,1H),3.75-3.40(m,3H),3.27-3.12(m,1H),2.60-1.88(m,8H).MS(ESI,m / e)[M+H] + 625.3.

[0258] Example 64: (3S)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)pyrrolidin-3-ol [ka]

[0259] Example 64 was prepared by a similar procedure as described in Example 1, substituting (S)-pyrrolidin-3-ol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.45(s,1H),7.25-7.11(m,1H),7.01-6.90(m,1H),5.48-5.32(m,1H),4.65-4.33(m,3H),4.31-4.02( m,3H),3.99-3.91(m,1H),3.62-3.37(m,3H),3.21-3.07(m,1H),2.54-1.89(m,8H).MS(ESI,m / e)[M+H] + 625.4.

[0260] Example 65: ((3R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)pyrrolidin-3-yl)methanol [ka]

[0261] Example 65 was prepared following a similar procedure as described in Example 1, substituting (R)-pyrrolidin-3-ylmethanol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.46(s,1H),7.23-7.13(m,1H),7.01-6.90(m,1H),5.47-5.30(m,1H),4.47-4.30(m,2H),4.27-3.80(m,4H),3. 76-3.60(m,2H),3.57-3.33(m,3H),3.18-3.10(m,1H),2.68-2.54(m,1H),2.48-1.87(m,8H).MS(ESI,m / e)[M+H] + 639.5.

[0262] Example 66: ((3S)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)pyrrolidin-3-yl)methanol [ka]

[0263] Example 66 was prepared following a similar procedure as described in Example 1, substituting (S)-pyrrolidin-3-ylmethanol for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.46(s,1H),7.25-7.09(m,1H),7.01-6.90(m,1H),5.47-5.30(m,1H),4.48-4.29(m,2H),4.24-3.80(m,4H),3. 76-3.60(m,2H),3.57-3.34(m,3H),3.20-3.06(m,1H),2.69-2.56(m,1H),2.49-1.85(m,8H).MS(ESI,m / e)[M+H] + 639.5.

[0264] Example 67: 7-Fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(piperidin-1-yl)-6-(trifluoromethyl)quinazolin-7-yl)benzo[d]thiazol-2-amine [ka]

[0265] Example 67 was prepared using a procedure similar to that described in Example 2, substituting piperidine for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1H NMR (500 MHz, CD3OD) δ 8.12 (s, 1H), 7.22-7.15 (m, 1H), 6.99-6.93 (m, 1H), 5.46-5.30 (m, 1H), 4.46-4.27 (m, 2H), 4.00-3.89 (m, 4H), 3.56-3.35 (m, 3H), 3.19-3.10 (m, 1H), 2.48-1.90 (m, 6H), 1.88-1.79 (m, 6H). MS (ESI, m / e) [M+H] + 623.4.

[0266] Example 68: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)piperidine-4-carbonitrile [ka]

[0267] Example 68 was prepared using a procedure similar to that described in Example 2, substituting piperidine-4-carbonitrile for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1H NMR (500 MHz, CD3OD) δ 8.10 (s, 1H), 7.21-7.14 (m, 1H), 7.00-6.93 (m, 1H), 5.37-5.21 (m, 1H), 4.35-4.14 (m, 4H), 3.85-3.75 (m, 2H), 3.26-3.14 (m, 4H), 3.04-2.96 (m, 1H), 2.35-1.85 (m, 10H). MS (ESI, m / e) [M+H] + 648.4.

[0268] Example 69: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-4-methylpiperidine-4-carbonitrile [ka]

[0269] Example 69 was prepared following a similar procedure as described in Example 1, substituting 4-methylpiperidine-4-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.12(s,1H),7.23-7.13(m,1H),7.00-6.92(m,1H),5.40-5.21(m,1H),4.56-4.47(m,2H),4.36-4.22(m,2H), 3.70-3.54(m,2H),3.28-3.15(m,3H),3.08-2.97(m,1H),2.39-1.79(m,10H),1.49(s,3H).MS(ESI,m / e)[M+H] + 662.6.

[0270] Example 70: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-4-fluoropiperidine-4-carbonitrile [ka]

[0271] Example 70 was prepared following a similar procedure as described in Example 1, substituting 4-fluoropiperidine-4-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.18(s,1H),7.25-7.13(m,1H),7.01-6.92(m,1H),5.51-5.31(m,1H),4.58-4.40(m,2H),4.2 5-3.96(m,4H),3.74-3.41(m,3H),3.27-3.15(m,1H),2.59-1.95(m,10H).MS(ESI,m / e)[M+H] + 666.5.

[0272] Example 71: 2-(1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)piperidin-4-yl)acetonitrile [ka]

[0273] Example 71 was prepared following a similar procedure as described in Example 1, substituting 2-(piperidin-4-yl)acetonitrile for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.12(s,1H),7.23-7.14(m,1H),7.01-6.92(m,1H),5.46-5.28(m,1H),4.66-4.52(m,2H),4.45-4.28(m,2H),3. 53-3.32(m,5H),3.19-3.05(m,1H),2.60-2.50(m,2H),2.47-1.89(m,9H),1.67-1.53(m,2H).MS(ESI,m / e)[M+H] + 662.4.

[0274] Example 72: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-fluoropiperidine-4-carbonitrile [ka]

[0275] Example 72 was prepared following a similar procedure as described in Example 1, substituting 3-fluoropiperidine-4-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.22(s,1H),7.23-7.14(m,1H),7.01-6.92(m,1H),5.59-5.39(m,1H),5.14-5.00( m,1H),4.67-4.52(m,4H),3.91-3.45(m,6H),2.62-2.06(m,8H).MS(ESI,m / e)[M+H] + 666.5.

[0276] Example 73: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-methylpiperidine-4-carbonitrile [ka]

[0277] Example 73 was prepared following a similar procedure as described in Example 1, substituting 3-methylpiperidine-4-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.16-8.09(m,1H),7.22-7.16(m,1H),7.00-6.93(m,1H),5.47-5.32(m,1H),4.58-4.25(m,3H),3.73-3.3 5(m,6H),3.24-3.06(m,2H),2.87-2.75(m,1H),2.54-1.90(m,8H),1.25-1.16(m,3H).MS(ESI,m / e)[M+H] + 662.6.

[0278] Example 74: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile [ka]

[0279] Example 74 was prepared following a similar procedure as described in Example 1, substituting trans-2-methylpiperidine-4-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.07(s,1H),7.22-7.16(m,1H),7.00-6.93(m,1H),5.48-5.32(m,1H),5.00-4.92(m,2H),4. 55-4.36(m,3H),3.68-3.46(m,4H),2.44-1.85(m,8H),1.59-1.51(m,3H).MS(ESI,m / e)[M+H] + 662.5.

[0280] Example 75: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-trans-3-hydroxypiperidine-4-carbonitrile [ka]

[0281] Example 75 was prepared following a similar procedure as described in Example 1, substituting trans-3-hydroxypiperidine-4-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.26(s,1H),7.25-7.13(m,1H),7.02-6.93(m,1H),5.49-5.32(m,1H),4.55-4.34(m,3H),4.26-4.95( m,2H),3.78-3.41(m,5H),3.26-3.14(m,1H),3.02-2.90(m,1H),2.56-1.92(m,8H).MS(ESI,m / e)[M+H] + 664.4.

[0282] Example 76: (3R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)piperidine-3-carbonitrile [ka]

[0283] Example 76 was prepared following a similar procedure as described in Example 1, substituting (R)-piperidine-3-carbonitrile for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.21(s,1H),7.27-7.15(m,1H),7.01-6.91(m,1H),5.52-5.32(m,1H),4.61-4.28(m,4H),4.18-4.10(m ,1H),4.05-3.95(m,1H),3.83-3.74(m,1H),3.69-3.50(m,3H),2.56-1.84(m,10H).MS(ESI,m / e)[M+H] + 648.4.

[0284] Example 77: (3S)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)piperidine-3-carbonitrile [ka]

[0285] Example 77 was prepared following a similar procedure as described in Example 1, substituting (3S)-piperidine-3-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.23(s,1H),7.27-7.13(m,1H),7.01-6.91(m,1H),5.63-5.47(m,1H),4.7 9-4.16(m,4H),4.05-3.78(m,5H),2.69-1.84(m,10H).MS(ESI,m / e)[M+H] + 648.4.

[0286] Example 78: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)piperidin-4-ol [ka]

[0287] Example 78 was prepared following a similar procedure as described in Example 2, substituting piperidin-4-ol for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.14(s,1H),7.21-7.15(m,1H),7.00-6.93(m,1H),5.47-5.29(m,1H),4.47-426(m,4H),4.06-3.97(m ,1H),3.75-3.64(m,2H),3.58-3.36(m,3H),3.22-3.12(m,1H),2.49-1.67(m,10H).MS(ESI,m / e)[M+H] + 639.4.

[0288] Example 79: (3S)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-methylpiperidin-3-ol [ka]

[0289] Example 79 was prepared following a similar procedure as described in Example 1, replacing cyclopropanamine with (S)-3-methylpiperidin-3-ol to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.44(s,1H),7.22-7.14(m,1H),7.00-6.92(m,1H),5.48-5.31(m,1H),4.50-4.30(m,3H),4.20-4.1 2(m,1H),3.56-3.34(m,5H),3.20-3.12(m,1H),2.53-1.73(m,10H),1.27(s,3H).MS(ESI,m / e)[M+H] + 653.5.

[0290] Example 80: (3R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-methylpiperidin-3-ol [ka]

[0291] Example 80 was prepared following a similar procedure as described in Example 1, replacing cyclopropanamine with (R)-3-methylpiperidin-3-ol to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.43(s,1H),7.22-7.14(m,1H),7.00-6.92(m,1H),5.46-5.28(m,1H),4.46-4.30(m,3H),4.19-4.0 8(m,1H),3.58-3.38(m,5H),3.22-3.14(m,1H),2.47-1.68(m,10H),1.28(s,3H).MS(ESI,m / e)[M+H] + 653.5.

[0292] Example 81: 4-(4-(azepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-amine [ka]

[0293] Example 81 was prepared following a similar procedure as described in Example 1, substituting azepane for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 8.32(s,1H),7.23-7.13(m,1H),7.00-6.92(m,1H),5.46-5.26(m,1H),4.45-4.28(m,2H),4.15-3.98(m ,4H),3.54-3.32(m,3H),3.17-3.08(m,1H),2.45-1.88(m,10H),1.80-1.62(m,4H).MS(ESI,m / e)[M+H] + 637.5.

[0294] Example 82: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)azepane-4-carbonitrile [ka]

[0295] Example 82 was prepared following a similar procedure as described in Example 1, substituting azepane-4-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.31(s,1H),7.27-7.11(m,1H),7.01-6.92(m,1H),5.46-5.29(m,1H),4.48-4.30(m,2H),4.2 5-3.96(m,4H),3.60-3.35(m,3H),3.23-3.08(m,2H),2.50-1.87(m,12H).MS(ESI,m / e)[M+H] + 662.5.

[0296] Example 83: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)azepane-3-carbonitrile [ka]

[0297] Example 83 was prepared following a similar procedure as described in Example 1, substituting azepane-3-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.34(s,1H),7.28-7.14(m,1H),7.02-6.92(m,1H),5.50-5.29(m,1H),4.67-4.39(m,3H),4.36-3.98(m ,3H),3.70-3.40(m,4H),3.24-3.10(m,1H),2.61-1.78(m,11H),1.65-1.45(m,1H).MS(ESI,m / e)[M+H] + 662.4.

[0298] Example 84: 1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)azepan-4-ol [ka]

[0299] Example 84 was prepared following a similar procedure as described in Example 1, substituting azepan-4-ol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.31(s,1H),7.24-7.13(m,1H),7.01-6.91(m,1H),5.48-5.29(m,1H),4.49-4.28(m,2H),4.2 1-3.86(m,5H),3.58-3.35(m,3H),3.20-3.08(m,1H),2.48-1.68(m,12H).MS(ESI,m / e)[M+H] + 653.5.

[0300] Example 85: (1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)azepan-4-yl)methanol [ka]

[0301] Example 85 was prepared following a similar procedure as described in Example 1, substituting azepan-4-ylmethanol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.32(s,1H),7.28-7.14(m,1H),7.01-6.91(m,1H),5.49-5.29(m,1H),4.51-4.20(m,4H),4.0 2-3.86(m,2H),3.64-3.39(m,6H),3.24-3.10(m,1H),2.53-1.62(m,12H).MS(ESI,m / e)[M+H] + 667.5.

[0302] Example 86: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka]

[0303] Example 86 was prepared following a procedure similar to that described in Example 2, substituting 1-oxa-3,8-diazaspiro[4.5]decan-2-one for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1H NMR (500 MHz, CD3OD) δ 8.17 (s, 1H), 7.24-7.15 (m, 1H), 7.01-6.91 (m, 1H), 5.52-5.32 (m, 1H), 4.55-4.40 (m, 2H), 4.38-4.28 (m, 2H), 3.93-3.79 (m, 2H), 3.71-3.43 (m, 5H), 3.28-3.19 (m, 1H), 2.55-1.95 (m, 10H). MS (ESI, m / e) [M+H] + 694.5.

[0304] Example 87: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka]

[0305] Example 87 was prepared following a procedure similar to that described in Example 1, substituting 3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one for cyclopropanamine to give the title product. 1H NMR (500 MHz, CD3OD) δ 8.15 (s, 1H), 7.24-7.14 (m, 1H), 7.01-6.92 (m, 1H), 5.42-5.25 (m, 1H), 4.46-4.26 (m, 4H), 3.86-3.78 (m, 2H), 3.54-3.36 (m, 5H), 3.18-3.04 (m, 1H), 2.86 (s, 3H), 2.43-1.89 (m, 10H). MS (ESI, m / e) [M+H] + 708.6.

[0306] Example 88: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-ethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka]

[0307] Example 88 was prepared following a similar procedure as described in Example 1, substituting 3-ethyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.15(s,1 H),7.24-7.14(m,1H),7.01-6.92(m,1H),5.45-5.28(m,1H),4.50-4.31(m,4H),3.96-3.78(m,2H) ,3.65-3.38(m,5H),3.19-3.10(m,1H),2.52-1.98(m,10H),1.23-1.14(m,3H).MS(ESI,m / e)[M+H] + 722.5.

[0308] Example 89: 2-(8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)acetonitrile [ka]

[0309] Example 89 was prepared following a similar procedure as described in Example 1, substituting 2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)acetonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.37(s,1H),7.47-7.30(m,1H),7.27-7.10(m,1H),5.66-5.50(m,1H),4.87-4.67(m,3H), 4.39(s,2H),4.15-3.85(m,5H),3.61-3.46(m,3H),2.78-2.09(m,10H).MS(ESI,m / e)[M+H] + 733.4.

[0310] Example 90: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-(2,2-difluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka]

[0311] Example 90 was prepared following a similar procedure as described in Example 1, substituting 3-(2,2-difluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.17(s,1H),7.23-7.15(m,1H),7.02-6.92(m,1H),6.20-5.90(m,1H),5.52-5.35(m,1H),4.5 6-4.32(m,4H),3.94-3.78(m,2H),3.74-3.51(m,8H),2.51-2.00(m,10H).MS(ESI,m / e)[M+H] + 758.5.

[0312] Example 91: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka]

[0313] Example 91 was prepared following a similar procedure as described in Example 1, substituting 3-(2,2,2-trifluoroethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.15(s,1H),7.24-7.14(m,1H),7.01-6.92(m,1H),5.43-5.26(m,1H),4.42-4.32(m,4H),4.08-3.9 6(m,2H),3.91-3.82(m,2H),3.63(s,2H),3.20-3.12(m,1H),2.46-1.98(m,10H).MS(ESI,m / e)[M+H] + 776.5.

[0314] Example 92: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-(cyclopropylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka]

[0315] Example 92 was prepared following a similar procedure as described in Example 1, substituting 3-(cyclopropylmethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.19(s,1H),7.24-7.15(m,1H),7.02-6.92(m,1H),5.59-5.42(m,1H),4.62-4.50(m,2H),4.43-4.32(m,2H),3.87-3.42(m ,8H),3.21-3.14(m,2H),2.65-1.87(m,10H),1.06-0.97(m,1H),0.72-0.53(m,2H),0.34-0.21(m,2H).MS(ESI,m / e)[M+H] + 748.4.

[0316] Example 93: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-(2-hydroxyethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka]

[0317] Example 93 was prepared following a similar procedure as described in Example 1, substituting 3-(2-hydroxyethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.17(s,1H),7.24-7.15(m,1H),7.02-6.92(m,1 H),5.51-5.34(m,1H),4.53-4.29(m,4H),3.92-3.83(m,2H),3.73-3.36(m,8H),3.21-3.10(m,2H),2.51-1.98(m,10H).MS(ESI,m / e)[M+H] + 738.5.

[0318] Example 94: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3-(2-methoxyethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka]

[0319] Example 94 was prepared following a similar procedure as described in Example 1, substituting 3-(2-methoxyethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.15(s,1H),7.23-7.15(m,1 H),7.01-6.92(m,1 H),5.45-5.28(m,1H),4.47-4.29(m,4H),3.91-3.79(m,2H),3.65-3.37(m,12H),3.20-3.13(m,1 H),2.47-1.90(m,10H).MS(ESI,m / e)[M+H] + 752.7.

[0320] Example 95: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,8-diazaspiro[4.5]decan-1-one [ka]

[0321] Example 95 was prepared following a similar procedure as described in Example 2, substituting 2,8-diazaspiro[4.5]decan-1-one for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.15(s,1H),7.24-7.15(m,1H),7.01-6.91(m,1H),5.45-5.28(m,1H),4.51-4.32(m,4H),3.7 4-3.65(m,2H),3.51-3.36(m,5H),3.15-3.08(m,1H),2.48-1.61(m,12H).MS(ESI,m / e)[M+H] + 692.5.

[0322] Example 96: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,8-diazaspiro[4.5]decan-3-one [ka]

[0323] Example 96 was prepared following a similar procedure as described in Example 2, substituting 2,8-diazaspiro[4.5]decan-3-one for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.18(s,1H),7.24-7.15(m,1H),7.02-6.92(m,1H),4.65-4.54(m,2H),4.16-4.05(m ,2H),4.01-3.79(m,5H),3.48-3.37(m,3H),2.64-1.83(m,12H).MS(ESI,m / e)[M+H] + 692.5.

[0324] Example 97: 8-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2-methyl-2,8-diazaspiro[4.5]decan-3-one [ka]

[0325] Example 97 was prepared following a similar procedure as described in example 2, substituting 2-methyl-2,8-diazaspiro[4.5]decan-3-one for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.14(s,1H),7.23-7.15(m,1H),7.02-6.92(m,1 H),5.47-5.30(m,1H),4.46-4.34(m,2H),4.09-3.95(m,4H),3.53-3.37(m, 5H),3.20-3.12(m,1H),2.87(s,3H),2.48-1.78(m,12H).MS(ESI,m / e)[M+H] + 706.5.

[0326] Example 98: 9-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ka]

[0327] Example 98 was prepared following a similar procedure as described in example 2, substituting 1-oxa-4,9-diazaspiro[5.5]undecan-3-one for (1S,2R)-2-fluorocyclopropan-1-amine to give the title product.1 H NMR(500 MHz,CD3OD)δ 8.18(s,1H),7.23-7.15(m,1H),7.02-6.92(m,1H),5.54-5.37(m,1H),4.56-4.4 1(m,4H),4.23(s,2H),3.78-3.54(m,5H),2.53-1.86(m,10H).MS(ESI,m / e)[M+H] + 708.4.

[0328] Example 99: 9-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one [ka]

[0329] Example 99 was prepared following a similar procedure as described in Example 1, substituting 1-oxa-3,9-diazaspiro[5.5]undecan-2-one for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.17(s,1H),7.24-7.15(m,1H),7.01-6.92(m,1H),5.49-5.32(m,1H),4.53-4.38(m,4H),3.9 5-3.78(m,2H),3.65-3.37(m,5H),2.20-2.12(m,1H),2.53-1.98(m,12H).MS(ESI,m / e)[M+H] + 708.5.

[0330] Example 100a (common intermediate): 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxy-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile [ka]

[0331] Step 1: tert-Butyl (4-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate [ka]

[0332] To a mixture of 4-(benzyloxy)-7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazoline (578 mg, 1.04 mmol) in toluene (38 mL), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (1739 mg, 4.160 mmol), DephosPdCl2 (149 mg, 0.208 mmol), and Cs2CO3 (1016 mg, 3.120 mmol) were added at room temperature. The mixture was stirred at 100 °C for 3 h. The resulting mixture was concentrated to give a residue which was further purified by flash to give the title product (123 mg).

[0333] Step 2: 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxy-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile

[0334] To a solution of tert-butyl (4-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (123 mg, 0.160 mmol) in DCM (5 mL) was added TFA (5 mL) at room temperature and the mixture was stirred at 45° C. for 2 h. The resulting mixture was concentrated to give a residue which was further purified by reverse phase to give the title product (54 mg).

[0335] Example 100: (2R,4S)-1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2-methylpiperidine-4-carbonitrile [ka]

[0336] To a mixture of 2-amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizidine-7a(5H)-yl)methoxy)-4-hydroxy-6-(trifluoromethyl)quinazolin-7-yl)benzo[b]thiophene-3-carbonitrile (50 mg, 0.086 mmol) in acetonitrile (5 mL) was added (2R,4S)-2-methylpiperidine-4-carbonitrile (42 mg, 0.26 mmol), BOP (114 mg, 0.258 mmol), and DIPEA (66 mg, 0.52 mmol). The mixture was stirred at 40° C. overnight. The resulting mixture was concentrated to give a residue which was further purified by preparative HPLC to give the title product (75 mg). 1H NMR(500 MHz,CD3OD)δ 8.10-8.00(m,1H),7.26-7.16(m,1H),7.03-6.99(m,1H),5.48-5.30(m,1H),4.99-4.91(m,1H),4.48-4.3 4(m,3H),3.63-3.33(m,5H),3.20-3.12(m,1H),2.50-1.95(m,10H),1.60-1.49(m,3H).MS(ESI,m / e)[M+H] + 686.7.

[0337] Example 101a (common intermediate): 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxyquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile [ka]

[0338] Step 1: tert-Butyl (4-(4-(benzyloxy)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate [ka] To a 100 mL round bottom flask was added 4-(benzyloxy)-7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (600 mg, 1.14 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 (1.43 g, 3.42 mmol), CsCO (1.11 g, 3.42 mmol), PdCl(DPEphos) (122 mg, 0.17 mmol), and toluene (40 mL) and the reaction mixture was stirred at 100 °C for 4 h. The resulting cooled mixture was concentrated and purified by flash column chromatography (DCM / MeOH=20 / 1) to give the title product (295 mg, 35%). MS (ESI, m / e) [M+H] + 736.3.

[0339] Step 2: 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxyquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile To a 50 mL round bottom flask was added tert-butyl (4-(4-(benzyloxy)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (295 mg, 0.40 mmol) and TFA (20 mL) and the resulting mixture was stirred at 40° C. for 6 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse flash (eluted with H2O (0.2% FA) / CH3CN) to give the title product (82 mg, 37%). MS (ESI, m / e) [M+H] + 546.1.

[0340] Example 101: (2R,4S)-1-(7-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-methylpiperidine-4-carbonitrile [ka]

[0341] Into a 50 mL round bottom flask were added 2-amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-hydroxyquinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (82 mg, 0.15 mmol), (2R,4S)-2-methylpiperidine-4-carbonitrile hydrochloride, BOP (99 mg, 0.22 mmol), DIEA (78 mg, 0.60 mmol), and CH3CN (8.0 mL), and the resulting mixture was stirred at 40° C. for 24 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash (eluted with H2O (0.2% FA) / CH3CN) to give the title product (45.1 mg, 46%). 1 H NMR(500 MHz,CD3OD)δ 7.76(s,1H),7.24-7.14(m,1H),7.10-6.96(m,1H),5.40-5.19(m,1H),4.37-4.13(m,3H),3.60-3.48(m ,1H),3.27-3.10(m,4H),3.06-2.94(m,1H),2.39-1.80(m,10H),1.54-1.43(m,3H).MS(ESI,m / e)[M+H] + 652.4.

[0342] Example 102: (3S)-1-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)pyrrolidin-3-ol [ka]

[0343] Step 1: Benzyl (S)-3-acetoxypyrrolidine-1-carboxylate [ka] To a solution of benzyl (S)-3-hydroxypyrrolidine-1-carboxylate (2.21 g, 10 mmol) in DCM (40 mL) was added acetyl chloride (1.02 g, 13 mmol) and DIPEA (3.58 g, 20 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (DCM / MeOH=7 / 3) to give the title compound (2.34 g, 88%). MS (ESI, m / e) [M+H] + 264.1.

[0344] Step 2: (S)-Pyrrolidin-3-yl acetate [ka] To a solution of benzyl (S)-3-acetoxypyrrolidine-1-carboxylate (2.21 g, 10 mmol) in THF (80 mL) was added Pd / C (10%, 468 mg) in one portion. The mixture was stirred at room temperature overnight. The solids were filtered off and the filtrate was concentrated in vacuo to give the title compound (1.18 g, crude), which was used in the next step without further purification. MS (ESI, m / e) [M+H] + 130.2.

[0345] Step 3: (S)-1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)pyrrolidin-3-yl acetate [ka] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (2.5 g, 7.62 mmol) in DCM (30 mL) was added (S)-pyrrolidin-3-yl acetate (1.18 g, 9.15 mmol) and DIPEA (2 g, 15.2 mmol) in one portion. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH=4 / 1) to give the title compound (2.96 g, 92%). MS (ESI, m / e) [M+H] + 422.0.

[0346] Step 4: (S)-1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)pyrrolidin-3-yl acetate [ka] A mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (2.96 g, 7.03 mmol) and KF (4.1 g, 70.3 mmol) in DMSO (30 mL) was stirred at 110° C. for 2 h. The mixture was cooled to room temperature and poured into ice water (300 mL). The precipitate was filtered from the suspension and dried in vacuum to give the title compound (2.29 g, 80%). MS (ESI, m / e) [M+H] + 406.1.

[0347] Step 5: (S)-1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)pyrrolidin-3-yl acetate [ka] A mixture of (S)-1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)pyrrolidin-3-yl acetate (581 mg, 1.43 mmol), (6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid (900 mg, 2.3 mmol), Pd(dppf)Cl2 (104.5 mg, 0.143 mmol) and K3PO4 (756 mg, 3.57 mmol) in THF / water (15 mL / 3 mL) was stirred at 65° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA=1 / 4) to give the title product (274 mg, 28%). MS (ESI, m / e) [M+H] + 674.5.

[0348] Step 6: (3S)-1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)pyrrolidin-3-yl acetate [ka] To a stirred solution of (S)-1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)pyrrolidin-3-yl acetate (274 mg, 0.4 mmol) in DMF / AcOH (6 mL / 3 mL) was added NIS (274 mg, 1.22 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 h. The mixture was extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (40 mL), NaHCO3 solution (40 mL) and dried over Na2SO4. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH=8 / 2) to give the title compound (116 mg, 35%). MS (ESI, m / e) [M+H] + 800.4.

[0349] Step 7: (3S)-1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)pyrrolidin-3-yl acetate [ka] A mixture of (3S)-1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)pyrrolidin-3-yl acetate (116 mg, 0.145 mmol), CuI (275 mg, 1.45 mmol), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (139 mg, 0.725 mmol) in DMA (10 ml) was stirred at 120° C. for 2 h. The reaction was cooled to room temperature, diluted with ice-cold water, and then extracted with EtOAc (30 mL×3). The combined organic layer was washed with brine (40 mL) and dried over Na2SO4. The residue was purified by silica gel column chromatography (PE / EA=1 / 4) to give the title product (80 mg, 48%). MS (ESI, m / e) [M+H] + 742.5.

[0350] Step 8: (3S)-1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)pyrrolidin-3-ol [ka] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (35 mg, 0.221 mmol) in THF (10 mL), NaH (16 mg, 0.333 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 30 min. Then, (3S)-1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)pyrrolidin-3-yl acetate (82 mg, 0.111 mmol) was added. The mixture was stirred from 0° C. to room temperature, then stirred at room temperature for another 2 h. The mixture was quenched with water (1 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The mixture was purified by silica gel column chromatography (DCM / MeOH=4 / 1) to give the title product (108 mg, crude). MS (ESI, m / e) [M+H] + 742.5.

[0351] Step 9: (3S)-1-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)pyrrolidin-3-ol A mixture of (3S)-1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)pyrrolidin-3-yl acetate (108 mg, 0.129 mmol) and TFA (5 mL). The mixture was stirred at 50° C. for 1 h. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to give the title product (1.28 mg, 1.6%). 1H NMR(500 MHz,DMSO-d6)δ 8.09(s,1H),6.86(s,2H),6.49(s,1H),5.49-5.28(m,1H),5.09(s,1H),4.43(s,1H),4. 35-3.67(m,6H),3.28-2.70(m,4H),2.37(s,3H),2.27-1.64(m,8H).MS(ESI,m / e)[M+H] + 599.4.

[0352] Example 103: 1-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile [ka]

[0353] Step 1: 1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (2.5 g, 7.62 mmol) in DCM (100 mL) was added piperidine-4-carbonitrile (0.924 g, 8.38 mmol) and DIPEA (3.24 g, 25.1 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE / EA=7 / 3) to give the title compound (390 mg, 13%). MS (ESI, m / e) [M+H] + 403.1.

[0354] Step 2: 1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] A mixture of 1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperidine-4-carbonitrile (385 mg, 0.958 mmol) and KF (278 mg, 4.79 mmol) in DMSO (10 mL) was stirred at 115° C. for 3 h. The mixture was cooled to room temperature and poured into ice water (150 mL). The solid was filtered as a crude product, which was purified by silica gel column chromatography (PE / EA=19 / 1) to give the title compound (269 mg, 72%). MS (ESI, m / e) [M+H] + 387.1.

[0355] Step 3: 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] A mixture of 1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (982 mg, 2.54 mmol), (6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid (1.75 g, 4.45 mmol), Pd(dppf)Cl2 (185 mg, 0.25 mmol), and K3PO4 (1.08 g, 5.08 mmol) in THF / water (30 mL / 6 mL) was stirred at 65° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=100%:0%-0%:100%) to give the title product (670 mg, 40%). MS (ESI, m / e) [M+H] + 655.5.

[0356] Step 4: 1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (570 mg, 0.871 mmol) in DMF / AcOH (20 mL / 10 mL) was added NIS (784 mg, 3.486 mmol). The mixture was stirred at room temperature for 1.5 h. The mixture was extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (80 mL), Na2S2O3 solution (40 mL) and dried over Na2SO4. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM / MeOH=10 / 1) to give the title compound (550 mg, 81%). MS (ESI, m / e) [M+H] + 781.5.

[0357] Step 5: 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] A mixture of 1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (550 mg, 1.964 mmol), CuI (2.02 g, 9.82 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (746 mg, 3.93 mmol) in DMA (20 mL) was stirred at 120° C. for 2 h. The cooled reaction mixture was extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to give the title product (455 mg, 89%). MS (ESI, m / e) [M+H] + 723.5.

[0358] Step 6: 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile [ka] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (150 mg, 0.943 mmol) in THF (10 mL) was added NaH (50 mg, 1.25 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. Then, 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (455 mg, 0.625 mmol) was added. The mixture was stirred from 0° C. to room temperature, then stirred at room temperature for another 3 h. The mixture was quenched with water (1 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA=1 / 4) to give the title product (390 mg, 72%). MS (ESI, m / e) [M+H] + 862.7.

[0359] Step 7: 1-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile A mixture of 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile (390 mg, 0.452 mmol) and TFA (5 mL). The mixture was stirred at 50° C. for 2.5 h. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to give the title product (245 mg, 87%). 1 H NMR(500 MHz,DMSO-d6)δ 7.82(s,1H),6.86(s,2H),6.50(s,1H),5.50-5.22(m,1H),4.40-3.90(m,4H),3.66-3.55(m,2 H),3.28-3.10(m,3H),3.02-2.90(m,1H),2.37(s,3H),2.25-1.73(m,10H).MS(ESI,m / e)[M+H] + 622.5.

[0360] Example 104: 1-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile [ka]

[0361] Step 1: 1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile [ka] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (759 mg, 2.3 mmol) in DCM (25 mL) was added trans-2-methylpiperidine-4-carbonitrile (370 mg, 2.3 mmol) and DIPEA (890 mg, 6.9 mmol) at room temperature, and the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated, and the residue was purified by chromatography column on silica (eluted with PE / EA=5 / 1) to give the title product (700 mg, 73%). MS (ESI, m / e) [M+H] + 417.0.

[0362] Step 2: 1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile [ka] To a solution of 1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile (700 mg, 1.68 mmol) in DMSO (30 mL) was added KF (292 mg, 5.04 mmol) at room temperature, and the mixture was stirred at 100° C. overnight. The resulting mixture was diluted with water (20 mL), extracted with DCM (30 mL×3), and the combined organic layers were concentrated to give a residue, which was purified by chromatography column on silica (eluted with PE / EA=10 / 1) to give the title product (370 mg, 53%). MS (ESI, m / e) [M+H] + 401.0.

[0363] Step 3: 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile [ka] To a solution of 1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile (304 mg, 0.758 mmol) in dioxane (30 mL), (6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid (743 mg, 1.895 mmol), Pd(dppf)Cl2 (124 mg, 0.15 mmol), K3PO4 (482 mg, 2.274 mmol) and water (6 mL) were added at room temperature, and the mixture was stirred at 100° C. for 2 hours. The resulting mixture was concentrated and the crude product was purified by chromatography column on silica (eluted with DCM / MeOH=20 / 1) to give the title product (344 mg, 38%). MS (ESI, m / e) [M+H] + 669.0.

[0364] Step 4: 1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile [ka] To a solution of 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile (324 mg, 0.485 mmol) in DMF (10 mL), I2 (859 mg, 3.395 mmol) and Ag2SO4 (45 mg, 0.1455 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (20 mL), extracted with DCM (30 mL x 3), and the combined organic layers were concentrated to give the crude product (304 mg). MS (ESI, m / e) [M+H] + 795.0.

[0365] Step 5: 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile [ka] To a solution of 1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile (304 mg, 0.382 mmol) in DMF (10 mL), 2,2-difluoro-2-(fluorosulfonyl)methyl acetate (735 mg, 3.83 mmol) and CuI (728 mg, 3.83 mmol) were added at room temperature, and the mixture was stirred at 90° C. for 4 h. The resulting mixture was concentrated, and the crude product was purified by chromatography column on silica (eluted with DCM / MeOH=20 / 1) to give the title product (107 mg, 38%). MS (ESI, m / e) [M+H] + 737.0.

[0366] Step 6: 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile [ka] To a solution of 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile (50 mg, 0.068 mmol) in THF (5 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (27 mg, 0.17 mmol) and NaH (7 mg, 0.17 mmol) at room temperature, and the mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with ice water, extracted with DCM (30 mL x 3), and the combined organic layer was concentrated to give the crude product (50 mg). MS (ESI, m / e) [M+H] + 842.0.

[0367] Step 6: 1-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile To a solution of 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-trans-2-methylpiperidine-4-carbonitrile (50 mg, 0.057 mmol) in DCM (1 mL) was added TFA (4 mL) at room temperature. The mixture was stirred at 50° C. for 1 h. The resulting mixture was concentrated at room temperature, the pH was adjusted to 7 with Na2CO3, and the organic layer was concentrated to give a residue which was further purified by preparative HPLC to give the title product (16.56 mg). 1H NMR(500 MHz,CD3OD)δ 7.76(s,1H),6.60(s,1H),5.50-5.32(m,1H),4.97-4.88(m,1H),4.50-4.35(m,2H),4.34-4.24(m,1H),3.65- 3.43(m,4H),3.39-3.32(m,1H),3.24-3.15(m,1H),2.55-1.95(m,13H),1.58-1.39(m,3H).MS(ESI,m / e)[M+H] + 636.6.

[0368] Example 105: 6-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-methylmorpholino)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0369] Step 1: (S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylmorpholine [ka] To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1.60 g, 4.85 mmol) in dichloromethane (15 mL) was added (S)-3-methylmorpholine (600 mg, 5.93 mmol) and 2 mL of N,N-diisopropylethylamine at 0° C. The reaction was stirred at room temperature for 0.5 h. The mixture was diluted with dichloromethane and water. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica to give the title compound (1.20 g, 63%). MS (ESI, m / e) [M+H] + 393.5.

[0370] Step 2: (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylmorpholine [ka] To a solution of (S)-4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylmorpholine (1.20 g, 3.03 mmol) in 30 mL of dimethylsulfoxide was added potassium fluoride (1.21 g, 20.86 mmol). The reaction was stirred at 95° C. for 16 h. The mixture was cooled to room temperature and diluted with dichloromethane and water. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica to give the title compound (950 mg, 82%). MS (ESI, m / e) [M+H] + 377.5.

[0371] Step 3: (S)-6-(6-chloro-2,8-difluoro-4-(3-methylmorpholino)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine [ka] To a solution of (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylmorpholine (368 mg, 0.98 mmol) in 10 mL of 1,4-dioxane was added N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)pyridin-2-amine (1.30 g, 2.04 mmol), copper(I) iodide (180 mg, 0.94 mmol), lithium chloride (180 mg, 4.29 mmol), and tetrakis(triphenylphosphine)palladium (350 mg, 0.30 mmol). The reaction was stirred under reflux for 8 hours and cooled to room temperature. The mixture was diluted with dichloromethane and water. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica to give the title compound (180 mg, 27%). MS (ESI, m / e) [M+H] + 646.3.

[0372] Step 4: 6-(6-chloro-2,8-difluoro-4-((S)-3-methylmorpholino)quinazolin-7-yl)-5-iodo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine [ka] To a solution of (S)-6-(6-chloro-2,8-difluoro-4-(3-methylmorpholino)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (120 mg, 0.19 mmol) in 20 mL of N,N-dimethylformamide was added iodine (110 mg, 0.43 mmol), silver sulfate (20 mg, 0.06 mmol). The reaction was stirred at room temperature for 16 h and the mixture was diluted with dichloromethane and water. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica to give the title compound (60 mg, 42%). MS (ESI, m / e) [M+H] + 772.5.

[0373] Step 5: 6-(6-chloro-2,8-difluoro-4-((S)-3-methylmorpholino)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] To a solution of 6-(6-chloro-2,8-difluoro-4-((S)-3-methylmorpholino)quinazolin-7-yl)-5-iodo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (60 mg, 0.08 mmol) in 5 mL of N-methyl-2-pyrrolidone, 2,2-difluoro-2-(fluorosulfonyl)methyl acetate (150 mg, 0.79 mmol) and copper(I) iodide (45 mg, 0.24 mmol) were added. The reaction was stirred at 90° C. for 2 h and then cooled to room temperature. The mixture was diluted with dichloromethane and water and the combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by preparative TLC to give the title compound (30 mg, 54%). MS (ESI, m / e) [M+H] + 714.3

[0374] Step 6: 6-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-methylmorpholino)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol hydrogen chloride (24 mg, 0.15 mmol) in 2 mL of tetrahydrofuran was added sodium hydride (60%, 6 mg, 0.15 mmol) at 0° C. and the mixture was stirred at room temperature for 0.5 h. A solution of 6-(6-chloro-2,8-difluoro-4-((S)-3-methylmorpholino)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (30 mg, 0.04 mmol) in 1 mL of tetrahydrofuran was added dropwise. After addition, the reaction was stirred at room temperature for 0.5 h and the mixture was diluted with dichloromethane and water. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by preparative TLC to give the title compound (18 mg, 50%). MS (ESI, m / e) [M+H]+ 853.3

[0375] Step 7: 6-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-methylmorpholino)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine A solution of 6-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-methylmorpholino)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (18 mg, 0.02 mmol) in trifluoroacetic acid (1 mL) was stirred at room temperature for 16 h and then at 40° C. for 8 h. The solvent was then evaporated and the pH was adjusted to 11 with aqueous sodium carbonate. The mixture was diluted with dichloromethane and water and the combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC to give the title compound (5 mg, 38%). 1 H NMR(500 MHz,CD3OD)δ 7.81(s,1H),6.60(s,1H),5.39-5.23(m,1H),4.72-4.62(m,1H),4.33-4.06(m,3H),3.99-3.92(m,1H),3. 88-3.69(m,4H),3.06-2.99(m,1H),2.47(s,3H),2.28-1.85(m,6H),1.55-1.48(m,3H).MS(ESI,m / e)[M+H] + 613.4.

[0376] Example 106: 8-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka]

[0377] Step 1: 8-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka] A mixture of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (1.27 g, 3.9 mmol), 3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one hydrochloride (800 mg, 3.9 mmol) in DCM (50 mL) and DIPEA (6 mL) was stirred at 0° C. to room temperature for 2 h. After completion, the solvent was evaporated and the crude product was purified by silica column (eluted with PE / EtOAc=1 / 4) to give the title product (1.4 g). MS (ESI, m / e) [M+H] + 463.3.

[0378] Step 2: 8-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka] To a mixture of 8-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (1.4 g, 3.0 mmol) in DMSO (40 mL) was added KF (2 g) and the mixture was stirred at 100° C. for 5 h. After completion, the resulting mixture was cooled, poured into water and extracted with EtOAc. The organic layers were combined and concentrated. The residue was then further purified by silica gel column (eluted with PE / EA=1 / 9) to give the title product (1 g). MS (ESI, m / e) [M+H] + 447.2

[0379] Step 3: 8-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka] A mixture of 4-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)pyridin-2-amine (1.4 g, 2.2 mmol), 8-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (500 mg, 1.1 mmol), Pd(PPh3)4 (387 mg, 0.3 mmol), CuI (225 mg), LiCl (170 mg) in dioxane (40 mL) was stirred at 110° C. for 14 hours. After completion, the resulting mixture was directly concentrated. The crude product was then further purified by silica column (eluted with PE / EtOAc=1 / 4) to give the title product (500 mg). MS (ESI, m / e) [M+H] + 715.4.

[0380] Step 4: 8-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka] A mixture of 8-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (500 mg, 0.7 mmol), Ag2SO4 (100 mg, 0.3 mmol), I2 (500 mg, 2 mmol) in DMF (50 mL) was stirred at room temperature for 1 h. After completion, the resulting mixture was poured directly into water and extracted with EtOAc. The crude product was then further purified by silica column to give the title product (300 mg). MS (ESI, m / e) [M+H] + 841.3.

[0381] Step 5: 8-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka] A mixture of 8-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (300 mg, 0.36 mmol), CuI (300 mg, 1.6 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.5 mL) in NMP (20 mL) was stirred at 90° C. for 1 h. After completion, the resulting mixture was poured directly into water and extracted with EtOAc. The crude product was then further purified by silica column to give the title product (150 mg). MS (ESI, m / e) [M+H] + 783.4.

[0382] Step 6: 8-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one [ka] To a solution of ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (150 mg, 0.94 mmol) in THF (20 mL), NaH (50 mg) was added and the mixture was stirred at room temperature for 30 min. Then, 8-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (150 mg, 0.19 mmol) was added. The reaction mixture was stirred at 50° C. for 4 h. After completion, the reaction was quenched with H2O. The solvent was evaporated and the crude product was purified by silica column (eluted with DCM / MeOH=4 / 1) to give the title product (120 mg). MS (ESI, m / e) [M+H] + 922.3.

[0383] Step 7: 8-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one A mixture of 8-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methyl-1-oxa-3,8-diazaspiro-[4.5]decan-2-one (120 mg, 0.13 mmol) in TFA (4 mL) was stirred at 50° C. for 3 h. After completion, the resulting mixture was directly concentrated and the pH of the residue was adjusted to 9 with DIPEA. The residue was then purified by C18 column (eluted with H2O / CH3CN=3 / 1) to give the title product (14 mg). 1 H NMR(500 MHz,CD3OD)δ 7.88(s,1H),6.60(s,1H),5.50-5.31(m,1H),4.49-4.35(m,2H),4.28-4.10(m,2H),3.87-3.75(m ,2H),3.65-3.38(m,5H),3.23-3.15(m,1H),2.89(s,3H),2.51-1.98(m,13H).MS(ESI,m / e)[M+H] + 682.6.

[0384] Example 107: 1-(7-(2-amino-6-methyl-5-(trifluoromethyl)pyrimidin-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile [ka]

[0385] Step 1: 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methoxypyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] A mixture of 1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (400 mg, 1.036 mmol), 4-bromo-N,N-bis(4-methoxybenzyl)-6-methylpyrimidin-2-amine (884 mg, 2.072 mmol), Pd(PPh3)4 (120 mg, 0.104 mmol), Pd(PPh3)2Cl2 (72 mg, 0.104 mmol) and Bu6Sn2 (1.2 g, 2.07 mmol) was stirred at 100° C. overnight. The mixture was concentrated in vacuum and the residue was purified by silica gel column chromatography (PE / EA=4:1) to give the title compound (329 mg, crude). MS (ESI, m / e) [M+H] + 656.6.

[0386] Step 2: 1-(7-(2-(bis(4-methoxybenzyl)amino)-5-iodo-6-methylpyrimidin-4-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] In a 50 mL round bottom flask, 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (130 mg, 0.387 mmol) and NIS (261 mg, 1.161 mmol) were added and the mixture was cooled to 0° C. Then, HOAc (10 mL) was added. The mixture was stirred at 0° C. for 15-20 min. Then, the mixture was diluted with EtOAc, quenched with Na2S2O3 solution, and extracted with EtOAc. The combined organic layers were concentrated under vacuum and purified by silica column chromatography (PE / EA=4 / 1) to give the title product (40 mg, 33%). MS (ESI, m / e) [M+H] + 782.3.

[0387] Step 3: 1-(7-(2-(bis(4-methoxybenzyl)amino)-6-methyl-5-(trifluoromethyl)pyrimidin-4-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] A mixture of 1-(7-(2-(bis(4-methoxybenzyl)amino)-5-iodo-6-methylpyrimidin-4-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (40 mg, 0.055 mmol), CuI (21 mg, 0.11 mmol), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (53 mg, 0.276 mmol) in DMA (5 mL) was stirred at 120° C. for 2 h. The reaction mixture was cooled to room temperature and the solvent was extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (50 mL) and dried over Na2SO4. The mixture was concentrated in vacuo to give the title product, which was used directly without further purification (90 mg, crude). MS (ESI, m / e) [M+H] + 724.5.

[0388] Step 5: 1-(7-(2-(bis(4-methoxybenzyl)amino)-6-methyl-5-(trifluoromethyl)pyrimidin-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile [ka] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (20 mg, 0.124 mmol) in THF (10 mL) was added NaH (7.5 mg, 0.186 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. Then, 1-(7-(2-(bis(4-methoxybenzyl)amino)-6-methyl-5-(trifluoromethyl)pyrimidin-4-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (90 mg, 0.124 mmol) was added. The mixture was stirred from 0° C. to room temperature, then stirred at room temperature for another 3 h. The mixture was quenched with water (1 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA=1 / 4) to give the title product (35 mg, 32%). MS (ESI, m / e) [M+H] + 863.7.

[0389] Step 6: 1-(7-(6-amino-4-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile A mixture of 1-(7-(2-(bis(4-methoxybenzyl)amino)-6-methyl-5-(trifluoromethyl)pyrimidin-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile (35 mg, 0.040 mmol) and TFA (3 ml) was stirred at 50° C. for 2 h and then at 60° C. overnight. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to give the title product (3.63 mg). 1H NMR(500 MHz,DMSO-d6)δ 7.85(s,1H),7.80-7.58(m,2H),5.38-5.17(m,1H),4.14-3.90(m,4H),3.66-3.50(m,2H), 3.24(s,1H),3.12-2.97(m,3H),2.87-2.79(m,1H),2.16-1.68(m,10H).MS(ESI,m / e)[M+H] + 623.4.

[0390] Example 108: 1-(7-(6-amino-4-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile [ka]

[0391] Step 1: 6-Bromo-4-methoxy-N,N-bis(4-methoxybenzyl)pyridin-2-amine [ka] To a solution of 6-bromo-4-methoxypyridin-2-amine (1 g, 4.92 mmol) in DMF (20 mL) was added NaH (0.43 g, 10.8 mmol) dropwise at 0° C. and the mixture was stirred at 0° C. for an additional 30 min. Then, PMBCl (1.7 g, 10.8 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water, filtered and the solid was collected to give the title product (2 g, 92%). MS (ESI, m / e) [M+H] + 443.1.

[0392] Step 2: 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methoxypyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] A mixture of 1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (0.4 g, 0.76 mmol), 6-bromo-4-methoxy-N,N-bis(4-methoxybenzyl)pyridin-2-amine (0.5 g, 1.14 mmol), Pd(PPh3)4 (87.8 mg, 0.076 mmol), Pd(PPh3)2Cl2 (53 mg, 0.076 mmol) and Bu6Sn2 (0.66 g, 1.14 mmol) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, diluted with H2O (10 mL) and then extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (PE:EA=20:1 to 1:1) to give the title product (0.5 g, 72%). MS (ESI, m / e) [M+H] + 671.2.

[0393] Step 3: 1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methoxypyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] To a stirred solution of 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methoxypyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (0.47 g, 0.7 mmol) in DMF / AcOH=4:1 (5 mL) was added NIS (0.47 g, 2.1 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The solvent was removed by reduced pressure and the residue was diluted with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL×2) and dried over Na2SO4. The solid was filtered off and concentrated to give the crude product, which was purified by silica gel chromatography (PE:EA=20:1 to 1:1) to give the title product (0.45 g, 81%). MS (ESI, m / e) [M+H] +797.1.

[0394] Step 4: 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] A mixture of 1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methoxypyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (0.4 g, 0.5 mmol), CuI (0.8 g, 4.2 mmol), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.6 g, 8.3 mmol) in DMA (10 mL) was stirred at 120° C. for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give the crude product, which was purified by silica gel chromatography (DCM:MeOH=50:1 to 10:1) to give the title product (0.2 g, 48%). MS (ESI, m / e) [M+H] + 739.2.

[0395] Step 5: 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (100 mg, 0.135 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (21.6 mg, 0.135 mmol) in THF (10 mL) was added NaH (8 mg, 0.2 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. The mixture was diluted with ice water, filtered, and the solid was collected as a crude product and purified by silica gel chromatography (DCM:MeOH=50:1 to 10:1) to give the title product (100 mg, 90%). MS (ESI, m / e) [M+H] + 878.3.

[0396] Step 6: 1-(7-(6-amino-4-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile To a mixture of 1-(7-(6-(bis(4-methoxybenzyl)amino)-4-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile (50 mg, 0.057 mmol) in CHCl (5 mL) was added TFA (1 mL) dropwise. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to give the title product (10 mg, 36%). 1H NMR(500 MHz,DMSO-d6)δ 7.79(s,1H),6.85(s,2H),6.22(s,1H),5.37-5.17(m,1H),4.12-3.85(m,8H),3.65-3.55(m,2 H),3.28-3.18(m,1H),3.09-3.02(m,2H),2.90-2.75(m,1H),2.19-1.70(m,10H).MS(ESI)m / e [M+H] + =638.4.

[0397] Example 109: 7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N,N-dimethylquinazolin-4-amine [ka]

[0398] Step 1: 6-Bromo-3-methoxy-N,N-bis(4-methoxybenzyl)pyridin-2-amine [ka] To a solution of 6-bromo-3-methoxypyridin-2-amine (2.0 g, 15.2 mmol) in DMF (40 mL) was added NaH (1.0 g, 25 mmol) slowly at 0° C., the reaction mixture was stirred at 0° C. for 0.5 h, and then PMBCl (3.3 g, 21 mmol) was added. The reaction mixture was allowed to warm to room temperature over 16 h. EtOAc (200 mL) was added, and the organic layer was washed with water and brine, and dried over Na2SO4. The filtrate was concentrated and purified by column chromograph (hexane / EtOAc=4 / 1) to give the title product (3.7 g, 83%). MS (ESI, m / e) [M+H] + 443.2.

[0399] Step 2: 1-(7-(6-(bis(4-methoxybenzyl)amino)-5-methoxypyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] A mixture of 1-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (1.0 g, 2.6 mmol), 6-bromo-3-methoxy-N,N-bis(4-methoxybenzyl)pyridin-2-amine (1.5 g, 3.4 mmol), Pd(PPh3)2Cl2 (150 mg, 0.21 mmol), Pd(PPh3)4 and Bu6Sn2 (1.8 g, 3.1 mmol) in dioxane (25 mL) was stirred at room temperature for 1 h and then heated to 100° C. for 16 h. The mixture was concentrated and purified by column chromograph (hexane / EtOAc=1 / 1) to give the title product (530 mg, 30%). MS (ESI, m / e) [M+H] + 617.6.

[0400] Step 3: 1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-5-methoxypyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] To a solution of 1-(7-(6-(bis(4-methoxybenzyl)amino)-5-methoxypyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (500 mg, 0.75 mmol) in HOAc / DMF (2 mL / 10 mL), NIS (500 mg, 2.22 mmol) was added portionwise at room temperature, and the mixture was stirred at room temperature for 6 h. EtOAc (50 mL) was added, and the organic phase was washed with water (30 mL×2) and brine (30 mL×2), dried over Na2SO4, concentrated, and purified by column chromograph (hexane / EtOAc=1 / 2) to give the title product (160 mg, 27%). MS (ESI, m / e) [M+H]+ 797.4.

[0401] Step 4: 1-(7-(6-(bis(4-methoxybenzyl)amino)-5-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile [ka] A mixture of 1-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-5-methoxypyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (160 mg, 0.2 mmol), CuI (190 mg, 1.0 mmol), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (300 mg, 1.56 mmol) in DMA (6 mL) was heated to 140° C. for 2 h. The reaction was cooled to room temperature, diluted with EtOAc (50 mL), washed with water (30 mL×2) and brine (30 mL×2), and the resulting organic phase was dried over Na2SO4, concentrated, and purified by column chromograph (hexane / EtOAc=1 / 2) to give the title product (50 mg, 34%). MS (ESI, m / e) [M+H] + 739.4.

[0402] Step 5: 1-(7-(6-(bis(4-methoxybenzyl)amino)-5-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile [ka] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (50 mg, 0.31 mmol) in THF, NaH (10 mg, 0.25 mmol, 60%) was added in portions at 0° C. and the mixture was stirred at 0° C. for 30 min. 1-(7-(6-(bis(4-methoxybenzyl)amino)-5-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)piperidine-4-carbonitrile (50 mg, 0.068 mmol) was added in portions to the mixture at 0° C. The mixture was stirred at room temperature for another 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted three times with EtOAc. The combined organic phase was dried over Na2SO4, concentrated and purified by column chromography (DCM / MeOH=10 / 1) to give the title product (35 mg, 57%). MS (ESI, m / e) [M+H] + 878.5.

[0403] Step 6: 1-(7-(6-amino-5-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile A mixture of 1-(7-(6-(bis(4-methoxybenzyl)amino)-5-methoxy-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)piperidine-4-carbonitrile (35 mg, 0.039 mmol) and TFA (3 mL) was stirred at 50° C. for 16 h. Concentration and purification by preparative HPLC gave the title product (7 mg, 28%). 1H NMR(500 MHz,DMSO-d6)δ 7.82(s,1H),7.31(s,1H),6.80(s,2H),5.43-5.23(m,1H),4.20-4.10(m,2H),4.05-3.95(m,5H), 3.64-3.60(m,2H),3.30-3.10(m,4H),2.94-2.90(m,1H),2.22-1.82(m,10H).MS(ESI,m / e)[M+H] + 638.7.

[0404] Example 110a (common intermediate): 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol [ka]

[0405] Step 1: 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine [ka] To a solution of 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (10 g, 39.8 mmol) in 200 mL of POCl3, DIPEA (10.0 mL) was added and the mixture was stirred at 100° C. for 4 h. The mixture was then cooled and concentrated to give a brown oil. The oil was dissolved in DCM and the solution was washed twice with ice water. The organic layer was concentrated and purified by silica gel column with PE:EtOAc=3:1 to give the title compound (7 g, 60%). MS (ESI, m / e) [M+H] + 252.

[0406] Step 2: 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine [ka] To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (7 g, 28 mmol) in 100 mL of 1,4-dioxane was added benzyl alcohol (6 g, 56 mmol), DIPEA (10.8 g, 84 mmol), and molecular sieves (4 Å, 10 g). The mixture was stirred at 60° C. for 16 h. It was then diluted with water and the combined organic layers were dried over sodium sulfate. The solvent was evaporated and the residue was purified by chromatography column on silica to give the title compound (4 g, 78%). MS (ESI, m / e) [M+H] + 324.

[0407] Step 3: 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine [ka] To a solution of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (4 g, 12.38 mmol) in 100 mL of 1,4-dioxane was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (3.9 g, 24.76 mmol), DIPEA (4.8 g, 37.14 mmol), and molecular sieves (4 Å, 10 g). The mixture was stirred at 80° C. for 16 h. The mixture was diluted with water and the combined organic layers were dried over sodium sulfate. The solvent was evaporated and the residue was purified by chromatography column on silica to give the title product (3.4 g, 62%). MS (ESI, m / e) [M+H] + 447.

[0408] Step 4: 3-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline [ka] In a 250 mL round bottom flask, add 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (3.4 g, 7.6 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (2.9 g, 9.1 mmol), K3PO4 (3.2 g, 15.2 mmol), methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct, min. 95% [cataCXium(R)A Palladacycle]. Gen.3] (0.55 g, 0.76 mmol), THF (120 mL), and H2O (24 mL) were added. The mixture was stirred at 70°C for 3 h. The resulting cooled mixture was concentrated and purified by flash column chromatography (DCM / MeOH = 30 / 1) to give the title product (2.8 g, 61%). MS (ESI, m / e) [M+H] + 606.

[0409] Step 5: 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol To a 250 mL round bottom flask was added 3-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-(trifluoromethyl)aniline (2.8 g, 4.6 mmol) and TFA (50 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and diluted with DCM. The pH of the solution was adjusted to 7 with DIPEA. The mixture was purified by reverse phase flash to give the title compound (1.3 g, 55%). MS (ESI, m / e) [M+H] + 516.2.

[0410] Example 110: 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine [ka]

[0411] Step 1: 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine To a mixture of 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (25 mg, 0.0485 mmol) in acetonitrile (5 mL) was added cyclopropanamine (7.2 mg, 0.126 mmol), BOP (43 mg, 0.097 mmol) and DIPEA (37.5 mg, 0.291 mmol) stepwise. The mixture was stirred at 40° C. overnight. The resulting mixture was concentrated to give a residue which was further purified by preparative HPLC to give the title product (5.67 mg). 1 H NMR(500 MHz,MeOD)δ 9.08(s,1H),6.90(s,1H),6.48(s,1H),5.50-5.35(m,1H),4.58-4.44(m,2H),3.67-3.43(m,3H) ,3.25-3.12(m,2H),2.57-1.96(m,6H),0.97-0.92(m,2H),0.81-0.75(m,2H).MS(ESI,m / e)[M+H] + 555.3.

[0412] Example 111: 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-cyclobutyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine [ka]

[0413] Example 111 was prepared following a similar procedure as described in Example 110, substituting cyclobutanamine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.17(s,1H),6.91(s,1H),6.49(s,1H),5.48-5.34(m,1H),4.50-4.39(m,2H),3.64-3. 42(m,3H),3.24-3.14(m,1H),2.51-2.25(m,7H),2.17-1.82(m,5H).MS(ESI,m / e)[M+H] + 569.4.

[0414] Example 112: 7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-N-(bicyclo[1.1.1]pentan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine [ka]

[0415] Example 112 was prepared following a similar procedure as described in Example 110, substituting bicyclo[1.1.1]pentan-1-amine for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 9.10(s,1H),6.90(s,1H),6.49(s,1H),5.47-5.36(m,1H),4.50-4.37(m,2H),3.67-3. 42(m,3H),3.24-3.15(m,1H),2.62-2.31(m,9H),2.28-1.96(m,4H).MS(ESI,m / e)[M+H] + 581.4.

[0416] Example 113: 3-chloro-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline [ka]

[0417] Example 113 was prepared following a similar procedure as described in Example 110, substituting morpholine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.05(s,1H),6.94-6.88(m,1H),6.53-6.46(m,1H),5.48-5.34(m,1H),4.50-4.34(m,2H),4.14-4.08( m,4H),3.87-3.85(m,4H),3.60-3.42(m,3H),3.23-3.14(m,1H),2.52-1.94(m,6H).MS(ESI,m / e)[M+H] + 585.3.

[0418] Example 114: 3-chloro-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-3-methylmorpholino)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline [ka]

[0419] Example 114 was prepared following a similar procedure as described in Example 110, substituting (S)-3-methylmorpholine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.02(s,1H),6.98-6.84(m,1H),6.54-6.47(m,1H),5.52-5.32(m,1H),4.95-4.92(m,1H),4.55-4.38( m,3H),4.05-3.53(m,8H),3.29-3.24(m,1H),2.59-1.99(m,6H),1.65-1.55(m,3H).MS(ESI,m / e)[M+H] + 599.2.

[0420] Example 115: 3-chloro-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-3-methylmorpholino)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline [ka]

[0421] Example 115 was prepared following a similar procedure as described in Example 110, substituting (R)-3-methylmorpholine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.00(s,1H),6.95-6.84(m,1H),6.55-6.47(m,1H),5.42-5.32(m,1H),4.50-4.35(m,3H),4.05-3.58( m,5H),3.46-3.36(m,3H),3.20-3.10(m,1H),2.48-1.89(m,6H),1.65-1.55(m,3H).MS(ESI,m / e)[M+H] + 599.4.

[0422] Example 116: 3-chloro-5-(4-((S)-3-ethylmorpholino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline [ka]

[0423] Example 116 was prepared following a similar procedure as described in Example 110, substituting (S)-3-ethylmorpholine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.02(s,1H),6.95-6.86(m,1H),6.60-6.41(m,1H),5.50-5.32(m,1H),4.47-4.26(m,3H),4.01-3.92( m,3H),3.82-3.49(m,6H),3.24-3.17(m,1H),2.50-2.01(m,8H),1.05-0.94(m,3H).MS(ESI,m / e)[M+H] + 613.2.

[0424] Example 117: 3-chloro-5-(4-((R)-3-ethylmorpholino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline [ka]

[0425] Example 117 was prepared following a similar procedure as described in Example 110, substituting (R)-3-ethylmorpholine for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 9.04(s,1H),6.93-6.89(m,1H),6.53-6.48(m,1H),5.57-5.41(m,1H),4.60-4.27(m,3H),4.01-3.95( m,3H),3.82-3.62(m,6H),2.57-2.43(m,2H),2.36-2.05(m,6H),1.02-0.96(m,3H).MS(ESI,m / e)[M+H] + 613.2.

[0426] Example 118: 3-chloro-5-(4-((3S,5S)-3,5-dimethylmorpholino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline [ka]

[0427] Example 118 was prepared following a similar procedure as described in Example 110, substituting (3S,5S)-3,5-dimethylmorpholine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.12(s,1H),6.95-6.89(m,1H),6.54-6.47(m,1H),5.54-5.40(m,1H),4.60-4.50(m,2H),4.26-4.18( m,2H),4.12-4.04(m,2H),3.73-3.53(m,5H),2.63-2.00(m,6H),1.27-1.18(m,6H).MS(ESI,m / e)[M+1] + 613.5.

[0428] Example 119: 3-chloro-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-methylmorpholino)pyrido[4,3-d]pyrimidin-7-yl)-4-(trifluoromethyl)aniline [ka]

[0429] Example 119 was prepared following a similar procedure as described in Example 110, substituting 2-methylmorpholine for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.13-8.96(m,1H),7.05-6.84(m,1H),6.59-6.42(m,1H),5.53-5.36(m,1H),4.60-4.49(m,3H),4.48-4.41(m,1H),4.07-3.9 8(m,1H),3.81-3.73(m,2H),3.63-3.56(m,3H),3.29-3.22(m,3H),2.56-1.99(m,6H),1.29-1.21(m,3H).MS(ESI,m / e)[M+H] + 599.2.

[0430] Example 120: ((2S)-4-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-((2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)methanol [ka]

[0431] Example 120 was prepared using a procedure similar to that described in Example 110, substituting (S)-morpholin-2-ylmethanol for cyclopropanamine to give the title product. 1H NMR (500 MHz, CD3OD) δ 9.07(s,1H), 6.91(s,1H), 6.50(s,1H), 5.50-5.34(m,1H), 4.68-4.32(m,4H), 4.08-4.05(m,1H), 3.84-3.44(m,9H), 3.28-3.34(m,1H), 2.51-1.92(m,6H). MS (ESI,m / e) [M+H] + 615.5.

[0432] Example 121: 1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile [ka]

[0433] Example 121 was prepared using a procedure similar to that described in Example 110, substituting piperidine-4-carbonitrile for cyclopropanamine to give the title product. 1H NMR (500 MHz, CD3OD) δ 9.02 (s, 1H), 6.91 (s, 1H), 6.50 (s, 1H), 5.52-5.34 (m, 1H), 4.54-4.25 (m, 4H), 3.97-3.86 (m, 2H), 3.62-3.47 (m, 3H), 3.26-3.18 (m, 2H), 2.57-1.98 (m, 10H). MS (ESI, m / e) [M+H] + 608.2.

[0434] Example 122: 1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-fluoropiperidine-4-carbonitrile [ka]

[0435] Example 122 was prepared following a similar procedure as described in Example 110, substituting 3-fluoropiperidine-4-carbonitrile for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 9.07(s,1H),6.92(s,1H),6.51(s,1H),5.53-5.36(m,1H),5.20-5.02(m,1H),4.79-4. 46(m,4H),4.00-3.85(m,1H),3.65-3.50(m,5H),2.54-2.01(m,8H).MS(ESI,m / e)[M+H] + 626.2.

[0436] Example 123: 1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-4-carbonitrile [ka]

[0437] Example 123 was prepared following a similar procedure as described in Example 110, substituting 3-methylpiperidine-4-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.04(s,1H),6.91(s,1H),6.50(s,1H),5.58-5.40(m,1H),4.71-4.55(m,3H), 3.75-3.60(m,6H),2.88-2.05(m,10H),1.30-1.18(m,3H).MS(ESI,m / e)[M+H] + 622.2.

[0438] Example 124: 1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperidine-4-carbonitrile [ka]

[0439] Example 124 was prepared following a similar procedure as described in Example 110, substituting 2-methylpiperidine-4-carbonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 8.97(s,1H),6.98-6.86(m,1H),6.64-6.45(m,1H),5.58-5.41(m,1H),5.20-5.06(m,1H),4.65-4.48(m ,3H),3.89-3.60(m,4H),3.39-3.33(m,2H),2.68-1.99(m,10H),1.56-1.50(m,3H).MS(ESI,m / e)[M+H] + 622.2.

[0440] Example 125: 2-(1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)acetonitrile [ka]

[0441] Example 125 was prepared following a similar procedure as described in Example 110, substituting 2-(piperidin-4-yl)acetonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.01(s,1 H),6.91(s,1H),6.50(s,1H),5.53-5.37(m,1H),4.85-4.70(m,2H),4.56-4.40(m,2H),3.8 0-3.38(m,6H),2.56-2.28(m,4H),2.26-1.95(m,7H),1.62-1.56(m,2H).MS(ESI,m / e)[M+H] + 622.5.

[0442] Example 126: 2-(1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile [ka]

[0443] Example 126 was prepared following a similar procedure as described in Example 110, substituting 2-(piperidin-3-yl)acetonitrile for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.05(s,1H),6.91(s,1H),6.50(s,1H),5.54-5.37(m,1H),4.82-4.70(m,2H), 4.60-4.45(m,3H),3.77-3.55(m,4H),2.64-1.50(m,14H).MS(ESI,m / e)[M+H] + 622.2.

[0444] Example 127: 1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-ol [ka]

[0445] Example 127 was prepared following a similar procedure as described in Example 110, substituting piperidin-4-ol for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 9.03(s,1H),6.92(s,1H),6.48(s,1H),5.59-5.42(m,1H),4.65-4.50(m,3H),4.46-4.33(m,2H) ,4.10-4.00(m,1H),3.90-3.67(m,5H),2.65-2.02(m,8H),1.80-1.69(m,2H).MS(ESI,m / e)[M+H] + 599.2.

[0446] Example 128: (R)-1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [ka]

[0447] Example 128 was prepared following a similar procedure as described in Example 110, substituting (3R)-3-methylpiperidin-3-ol for cyclopropanamine to give the title product. 1 H NMR(500 MHz, CD3OD)δ 9.21(s,1H),6.92(s,1H),6.50(s,1H),5.65-5.48(m,1H),4.74-4.68(m,1H ),4.66-4.58(m,2H),4.36-4.24(m,1H),4.06-3.84(m,3H),3.65-3.56(m,1 H),3.51-3.37(m,2H),2.78-2.54(m,2H),2.48-2.40(m,1H),2.38-2.31(m, 2H),2.22-2.08(m,2H),1.89-1.75(m,3H),1.29(s,3H).MS(ESI,m / e)[M+H] + 613.2.

[0448] Example 129: (S)-1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [ka]

[0449] Example 129 was prepared following a similar procedure as described in Example 110, substituting (S)-3-methylpiperidin-3-ol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.18(s,1H),6.91(s,1H),6.50(s,1H),5.57-5.38(m,1H),4.61-4.50( m,2H),4.48-4.40(m,1H),4.33-4.22(m,1H),3.75-3.53(m,4H),3.46- 3.38(m,1H),3.29-3.22(m,1H),2.59-2.38(m,2H),2.34-2.26(m,1H), 2.24-1.99(m,4H),1.89-1.73(m,3H),1.28(s,3H).MS(ESI,m / e)[M+H] + 613.2.

[0450] Example 130: 1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-ethylpiperidin-3-ol [ka]

[0451] Example 130 was prepared following a similar procedure as described in Example 110, substituting 3-ethylpiperidin-3-ol for cyclopropanamine to give the title product. 1H NMR(500 MHz,CD3OD)δ 9.20(s,1H),6.91(s,1H),6.50(s,1H),5.51-5.34(m,1H),4.64-4.28(m,4H),3.69-3.3 9(m,5H),3.26-3.18(m,1H),2.53-1.50(m,12H),1.02-0.94(m,3H).MS(ESI,m / e)[M+H] + 627.4.

[0452] Example 131: 3-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[4.1.0]heptan-1-ol [ka]

[0453] Example 131 was prepared following a similar procedure as described in Example 110, substituting 3-azabicyclo[4.1.0]heptan-1-ol for cyclopropanamine to give the title product. 1 H NMR(500 MHz,CD3OD)δ 9.06(s,1H),6.91(s,1H),6.50(s,1H),5.53-5.36(m,1H),4.54-4.43(m,3H),4.20-4.17(m,1H),4.06-3.97(m,1H),3.73-3. 52(m,4H),3.29-3.21(m,1H),2.57-1.82(m,8H),1.47-1.38(m,1H),1.03-0.97(m,1H),0.64-0.58(m,1H).MS(ESI,m / e)[M+H] + 611.5.

[0454] Assay Biochemical assays KRAS WT and KRAS G12V probe displacement assay This assay was used to identify compounds that can bind to GDP-loaded KRAS protein and displace a biotinylated probe that occupies the KRAS binding site. GST-tagged GDP-loaded WT KRAS (amino acids 1-169) and GST-tagged GDP-loaded KRAS G12V (amino acids 1-169) were expressed in E. coli and purified in-house. All proteins and reaction solutions were prepared in assay buffer containing 50 mM HEPES pH 7.5, 50 mM NaCl, 1 mM MgCl2, 1 mM TCEP, 0.01% BSA, and 0.008% Brij-35. Purified WT KRAS (3 nM final concentration) or KRAS G12V protein (2 nM final concentration) were incubated with 3-fold serially diluted compounds in assay plates (384-well microplates, black, Corning). Plates are incubated at 24 °C for 1 h. After incubation, biotinylated probe 1 (60 nM final assay concentration) for WT KRAS and biotinylated probe 2 (2.5 nM final assay concentration) for KRAS G12V were added to the assay plate, respectively. After 1 h incubation at 24 °C, Mab anti-GST-Tb cryptate (Cisbio) and streptavidin-XL665 (Cisbio) were added and further incubated for 1 h at 24 °C. TR-FRET signals (excitation 337 nm, emission 665 nm / 620 nm) were read on a BMG PHERAstar FSX instrument. The percentage inhibition of KRAS protein binding with the biotinylated probe in the presence of increasing compound concentrations was calculated based on the ratio of fluorescence at 665 nm to fluorescence at 620 nm. IC of each compound 50 Values ​​were derived by fitting the data to a four-parameter logistic model using Dotmatics.

[0455] KRAS WT and KRAS G12D probe displacement assay This assay was used to identify compounds that can bind to GDP-loaded KRAS protein and displace a biotinylated probe that occupies the KRAS binding site. GST-tagged GDP-loaded WT KRAS (amino acids 1-188) and GST-tagged GDP-loaded KRAS G12D (amino acids 1-188) were expressed in E. coli and purified in-house. All proteins and reaction solutions were prepared in assay buffer containing 50 mM HEPES pH 7.5, 50 mM NaCl, 1 mM MgCl2, 1 mM TCEP, 0.01% BSA, and 0.008% Brij-35. Purified WT KRAS (3 nM final concentration) or KRAS G12D protein (0.5 nM final concentration) were incubated with 3-fold serially diluted compounds in assay plates (384-well microplates, black, Corning). Plates are incubated at 24 °C for 1 h. After incubation, biotinylated probe 1 (60 nM final assay concentration) for WT KRAS and biotinylated probe 2 (4 nM final assay concentration) for KRAS G12D were added to the assay plate, respectively. After 1 h incubation at 24 °C, Mab anti-GST-Tb cryptate (Cisbio) and streptavidin-XL665 (Cisbio) were added and further incubated for 1 h at 24 °C. TR-FRET signals (excitation 337 nm, emission 665 nm / 620 nm) were read on a BMG PHERAstar FSX instrument. The percentage inhibition of KRAS protein binding with the biotinylated probe in the presence of increasing compound concentrations was calculated based on the ratio of fluorescence at 665 nm to fluorescence at 620 nm. IC of each compound 50 Values ​​were derived by fitting the data to a four-parameter logistic model using Dotmatics.

[0456] KRAS G12V pERK assay In this study, SW620 cell line was used. Cells were maintained in RPMI1640 supplemented with 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin and streptomycin (Thermo Fisher) and kept at 37 °C in a humidified atmosphere of 5% CO2 in air. Cells were restored from frozen stocks within 30 passages from the original cells purchased. 40000 cells per well were seeded in 96-well plates and incubated overnight. Cells were treated with a 10-point dilution series. Final compound concentrations ranged from 0 to 10 μM. After 2 h of compound treatment, cells were lysed and pERK1 / 2 (THR202 / TYR204) levels in cell lysates were detected by HTRF kit (Cisbio). Briefly, a total of 16 μL of cell lysate from each well of the 96-well plate was transferred to a 384-well white assay plate. Lysates from each well were 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) in the dark overnight at room temperature. When the donor and acceptor are in close proximity, excitation of the donor by a laser causes fluorescence resonance energy transfer (FRET) to the acceptor, which then fluoresces at a wavelength of 655 nm. FRET signals were measured using a PHERAstar FSX reader (BMG Labtech). IC50 determinations were performed by fitting curves of percent inhibition versus the logarithm of inhibitor concentration using Dotmatics.

[0457] KRAS G12D pERK assay In this study, the AsPC-1 cell line was used. Cells were maintained in RPMI-1640 supplemented with 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin and streptomycin (Thermo Fisher) and kept at 37 °C in a humidified atmosphere of 5% CO2 in air. Cells were restored from frozen stocks within 30 passages from the original cells purchased. 30,000 cells per well were seeded in a 96-well plate and incubated overnight. Cells were treated with a 10-point dilution series. Final compound concentrations ranged from 0 to 10 μM. After 2 h of compound treatment, cells were lysed and pERK1 / 2 (THR202 / TYR204) levels in the cell lysates were detected by HTRF kit (Cisbio). Briefly, a total of 16 μL of cell lysate from each well of the 96-well plate was transferred to a 384-well white assay plate. Lysates from each well were 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) in the dark overnight at room temperature. When the donor and acceptor are in close proximity, excitation of the donor by a laser causes fluorescence resonance energy transfer (FRET) to the acceptor, which then fluoresces at a wavelength of 655 nm. The FRET signal was measured using a PHERAstar FSX reader (BMG Labtech). IC 50 Determination of was performed by curve fitting of percent inhibition versus the logarithm of inhibitor concentration using Dotmatics.

[0458] Activity Table Each of the compounds in Tables 1, 2 and 3 has been tested in, and found to have activity in, one or more of the biochemical assays provided herein. Table 1. [Table 2] Table 2. [Table 3-1] [Table 3-2] Table 3. [Table 4]

[0459] As demonstrated by the data in Tables 1-3, the inventors have surprisingly and unexpectedly discovered that the exemplary compounds in Tables 1-3 modulate or inhibit the activity of KRAS G12V.

[0460] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or enantiomer thereof, During the ceremony, Ring A is, 【Chemistry 2】 And, X is N, or C-R 2 And, Y is N, or C-CN. Z is N, or C-R 3 And, W is N, or C-R 5 And, V is N, or C-R 7 And, R 1 -NR 1a R 1b And, R 2 is a halogen, or an unsubstituted or substituted alkyl group. R 3 is a halogen, or an unsubstituted or substituted alkyl, R 4 Halogen, -NO 2 , or unsubstituted or substituted alkyl groups, R 5 is hydrogen, halogen, or -CN, R 7 is hydrogen, halogen, or -CN, R 8 , R 9 , and R 10 Each of them is independently hydrogen, halogen, unsubstituted or substituted alkyl, or -OH. R 1a and R 1b Each of these is independently hydrogen, an unsubstituted or substituted alkyl, an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted cycloalkylalkyl, an unsubstituted or substituted heterocyclyl, or an unsubstituted or substituted heterocyclylalkyl, provided that R 1a and R 1b Neither of them is hydrogen, or R 1a and R 1b The compounds of formula (I), or pharmaceutically acceptable salts, tautomers, stereoisomers, or enantiomers thereof, which, together with the nitrogen atoms to which they are bonded, form unsubstituted or substituted heterocyclines.

2. Ring A is 【Transformation 3】 The compound according to claim 1.

3. The compound according to claim 2, wherein Y is N.

4. The compound according to claim 2, wherein Y is C-CN.

5. X is CR 2 The compound according to claim 2.

6. R 2 However, it is a halogen, or an unsubstituted or halogen-substituted alkyl, preferably Cl or CF 3 And moreover, CF 3 The compound according to claim 2.

7. R 1 However, -NHR 1a The compound according to claim 2.

8. R 1a However, R is an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocycline. 1a The compound according to claim 7, wherein at least one ring is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl.

9. Ring A is 【Chemistry 4】 The compound according to claim 1.

10. X is CR 2 The compound according to claim 9.

11. R 1a and R 1b However, together with the nitrogen atoms to which they are bonded, they form an unsubstituted or substituted monocyclic heterocycline or an unsubstituted or substituted spiroheterocycline, wherein the unsubstituted or substituted monocyclic heterocycline or the unsubstituted or substituted spiroheterocycline contains zero, one or two additional heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur, preferably R 1 However, unsubstituted or substituted azetidinil, unsubstituted or substituted pyrrolidil, unsubstituted or substituted piperidil, unsubstituted or substituted azepanil, unsubstituted or substituted 【Transformation 5】 Non-substitution or substitution 【Transformation 6】 Non-substitution or substitution 【Transformation 7】 Non-substitution or substitution 【Transformation 8】 or non-substitution or substitution 【Chemistry 9】 The compound according to claim 2, which is an unsubstituted or substituted heterocyclyl selected from the above.

12. Ring A is 【Chemistry 10】 The compound according to claim 1.

13. X is CR 2 The compound according to claim 12.

14. R 2 However, it is a halogen, or an unsubstituted or halogen-substituted alkyl, preferably Cl or CF 3 The compound according to claim 13, wherein the compound is, more preferably, Cl.

15. Ring A is 【Chemistry 11】 The compound according to claim 14.

16. R 1a and R 1b However, together with the nitrogen atoms to which they are bonded, they form an unsubstituted or substituted monocyclic heterocycline or an unsubstituted or substituted spiroheterocycline, wherein the unsubstituted or substituted monocyclic heterocycline or the unsubstituted or substituted spiroheterocycline contains zero, one or two additional heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur, preferably R 1 However, unsubstituted or substituted azetidinil, unsubstituted or substituted pyrrolidil, unsubstituted or substituted piperidil, unsubstituted or substituted morpholinil, or unsubstituted or substituted 【Chemistry 12】 The compound according to claim 12, which is an unsubstituted or substituted heterocyclyl selected from the above.

17. R 1 but, 【Chemistry 13】 The compound according to claim 12.

18. Ring A is 【Chemistry 14】 The compound according to claim 17.

19. The compound according to claim 12, wherein X is N.

20. Ring A is 【Chemistry 15】 The compound according to claim 19.

21. R 1 However, -NHR 1a The compound according to claim 19.

22. R 1a However, R is an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocycline. 1a The compound according to claim 21, wherein at least one ring is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl.

23. R 1a and R 1b However, together with the nitrogen atom to which they are bonded, they form an unsubstituted or substituted monocyclic heterocycline or an unsubstituted or substituted spiroheterocycline, wherein the unsubstituted or substituted monocyclic heterocycline or the unsubstituted or substituted spiroheterocycline contains zero, one or two additional heteroatoms selected from oxygen, nitrogen, or optionally oxidized sulfur, preferably R 1 The compound according to claim 19, wherein at least one ring is piperidyl or morpholinyl.

24. R 1 However, one or more C 1-4 The C is optionally substituted with alkyl, halogen, -CN, or -OH. 1-4 The compound according to claim 23, wherein each alkyl group is independently and optionally substituted with one or more halogens, -CN, or -OH groups.

25. R 1 but, 【Chemistry 16】 The compound according to claim 19.

26. Ring A is 【Chemistry 17】 The compound according to claim 25.

27. R 1a and R 1b The compound according to claim 1, wherein they combine with the nitrogen atoms to which they are bonded to form an unsubstituted or substituted monocyclic heterocycline, an unsubstituted or substituted bicyclic heterocycline, an unsubstituted or substituted tricyclic heterocycline, or an unsubstituted or substituted spirocyclic heterocycline.

28. R 1 The compound according to claim 1, but which is not an unsubstituted or substituted piperazinyl.

29. R 1 However, non-substitution or substitution [Chemistry 18] Non-substitution or substitution 【Chemistry 19】 Non-substitution or substitution 【Chemistry 20】 Non-substitution or substitution 【Chemistry 21】 Non-substitution or substitution 【Chemistry 22】 Non-substitution or substitution 【Chemistry 23】 or non-substitution or substitution 【Chemistry 24】 The compound described in claim 1, not the compound described in claim 1.

30. R 1 However, unsubstituted or substituted 3,8-diazabicyclo[3.2.1]octan-3-yl, or unsubstituted or substituted 【Chemistry 25】 The compound described in claim 1, not the compound described in claim 1.

31. The compound according to claim 1, wherein the compound is selected from Table 1, Table 2, and Table 3.

32. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, tautomer, isotope-substituted compound, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

33. A pharmaceutical composition according to claim 32 for inhibiting the activity of a KRAS mutant protein in a cell, wherein the KRAS mutant protein is optionally a KRAS G12D and / or G12V mutant protein.

34. A pharmaceutical composition according to claim 32 for the treatment or prevention of cancer, wherein the cancer is optionally mediated by a KRAS mutation, preferably a KRAS G12D and / or G12V mutation.

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