Heterocyclic compounds, compositions thereof, and methods of treatment therewith

Abstract

As used herein, a compound having the structure: TIFF2025528147000555.tif53165, wherein the substituents are as defined herein, compositions comprising an effective amount of the compound, and methods of modulating the activity of KRAS G12D and / or G12V are provided.

Description

[Technical Field]

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

[0002] Ras is a family of proteins that associate with the plasma membrane via its 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, switching between an "on" and an "off" state. When Ras proteins are bound to GDP, they are in an off (or inactive) state. When Ras is switched on by specific growth-promoting stimuli, such as growth factors, the Ras protein is induced to exchange its bound GDP for GTP, thereby becoming in an 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 contains various subfamilies, including Ras, Ral, Rap, Rheb, Rad, Rit, and Miro (Wennerberg K, Rossman KL, Der CJ. The Ras superfamily at a glance. J Cell Sci. 2005;118(Pt 5):843-846). HRas, NRas, and KRas are the most common oncogenes in human cancers, and therefore these proteins are the most well-studied members of the Ras family (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 are found in approximately 20% of human cancers, including pancreatic, colorectal, lung, and skin cancers (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 the G12 and G13 positions, blocking the GTPase-activating protein (GAP)-stimulated 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). This results in overactivation of the KRas protein, ultimately leading to uncontrolled cell growth and cancer.

[0004] Among various cancers, pancreatic cancer is considered the most KRas-dependent. KRas mutations are found in 94.1% of pancreatic ductal adenocarcinoma (PDAC). KRas G12D (41%) and G12V (34%) mutations are the two most prevalent mutations in all KRas-mutated PDAC (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 revealed that the progression and maintenance of pancreatic cancer are highly dependent on constitutive activation of KRas downstream signaling (Siveke JT, Schmid RM. Chromosomal instability in mouse metastatic pancreatic cancer—it's KRas and Tp53 after all. Cancer Cell. 2005;7(5):405-407). This indicates that mutant KRas proteins are very attractive drug targets for pancreatic cancer and other cancers that harbor KRas mutations. Because wild-type KRas proteins also play critical roles in normal tissue function, and wild-type 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), drug molecules that can selectively inhibit mutant Kras proteins in cancer cells while sparing their wild-type counterparts in normal cells hold great promise.

[0005] Therefore, the KRas G12D and G12V mutations are very attractive targets for cancer and other cancers that harbor these mutations, and small molecule therapeutics that can selectively bind to and inhibit the function of Kras G12D or G12V should be highly useful.

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

[0007] As used herein, compounds having the following formula (I): [ka]

[0008] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof, wherein the substituents are as defined herein.

[0009] In one embodiment, the compound is selected from Tables 1-5.

[0010] In one embodiment, provided herein is a method for inhibiting KRAS mutant protein activity or KRAS amplification activity in a cell, comprising contacting the cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, wherein optionally, the KRAS mutant protein is a KRAS G12D and / or G12V mutant protein.

[0011] In one embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject in need of cancer treatment or prevention an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, wherein optionally the cancer is mediated by a KRAS mutation, preferably a KRAS G12D and / or G12V mutation. DETAILED DESCRIPTION OF THE INVENTION

[0012] 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.

[0013] 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).

[0014] As used herein, "G12D mutation" refers to a mutation of the 12th amino acid residue, located in the G domain of the KRAS protein, from glycine to aspartic acid.

[0015] As used herein, "KRAS G12D" or "G12D" refers to a KRAS protein having a G12D mutation.

[0016] 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.

[0017] As used herein, "KRAS G12V" or "G12V" refers to a KRAS protein having a G12V mutation.

[0018] As used herein, "KRAS amplification" or "KRAS gene amplification" refers to a genetic mutation that increases the copy number of the KRAS gene in some cancer cells. This can lead to high expression and activity of the KRAS protein, which is involved in cell proliferation and survival. KRAS amplification is found in several types of cancer, including lung cancer, breast cancer, esophageal cancer, ovarian cancer, and testicular cancer.

[0019] As used herein, and in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural referents as well as singular referents, unless the context clearly indicates otherwise.

[0020] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent 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 percent. In certain embodiments, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose, amount, or weight percent.

[0021] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or value provided to characterize a particular solid form, for example, a particular temperature or temperature range (such as those describing melting, dehydration, desolvation, or glass transition temperature), mass change (e.g., 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, in 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 and still describe 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 value of an XRPD peak position can vary by up to ±0.2 degrees 2θ (or ±0.2 degrees 2θ) and still describe a particular XRPD peak.

[0022] 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 carbon atoms, 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. Alkyl groups can be substituted or unsubstituted. When alkyl groups described herein are said to be "substituted," they can be substituted with any substituent or substituents such as 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, 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), or O(alkyl)aminocarbonyl.

[0023] An "alkenyl" group is a straight-chain or branched-chain acyclic hydrocarbon having 2 to 10 carbon atoms, typically 2 to 8 carbon atoms, and containing at least one carbon-carbon double bond. Representative straight-chain and branched (C2C8) alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, 2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl, 3-octenyl, and the like. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. An alkenyl group can be unsubstituted or substituted.

[0024] An "alkynyl" group refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynyl is optionally substituted and can be straight-chain, branched-chain, or cyclic. Alkynyl includes alkyl groups having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), and 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkynyl moieties include, but are not limited to, radicals having an alkynyl group (alkynyl). Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and butynyl.

[0025] 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, 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 can 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 ring 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, and hexadienyl. The cycloalkyl groups may be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and the like.

[0026] A "bridged" bicyclic ring system contains two rings that share three, four, or five adjacent ring atoms. As used herein, the term "bridge" refers to an atom or chain of atoms that connects two different parts of a molecule. The two atoms (usually, but not necessarily, two tertiary carbon atoms) connected by the bridge are called "bridgeheads." In addition to the bridge, the two bridgeheads are connected by at least two individual atoms or chains of atoms. Examples of bridged bicyclic ring systems include adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl (by way of example and not limitation). In one embodiment, the bridge is unsubstituted or substituted -(CH2). n -, where n is 1, 2, 3, 4, or 5. In one embodiment, the bridge is -CH2-. In one embodiment, the bridge is -(CH2)2-. In one embodiment, the bridge is -(CH2)3-. In one embodiment, the bridge is -CH2-O-CH2-. "Spiro" bicyclic ring systems are those which share a single ring atom (usually a quaternary carbon atom) between the two rings.

[0027] 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, aryl groups contain 6 to 14 carbons, and in other embodiments, 6 to 12 or even 6 to 10 carbon atoms in the ring portion of the group. Particular aryls include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing condensed rings, e.g., fused aromatic aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0028] A "heterocyclyl" is an aromatic (also called heteroaryl) or non-aromatic cycloalkyl in which 1 to 4 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 another group at any ring atom (i.e., any carbon atom or heteroatom of the heterocyclic ring). 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 encompass unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidine-2,4-dionyl) groups. The term heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as 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 term also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Representative examples of heterocyclyl groups include 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, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, Linyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, 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, azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]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, Representative non-aromatic heterocyclyl groups include, but are not limited to, 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 may be mono- or multiply substituted, for example, but are not limited to, pyridyl or morpholinyl groups that are di-, tri-, tetra-, pentad-, or hexad-substituted, or di-substituted with various substituents such as those described below.

[0029] A "heteroaryl" group is an aryl ring system having 1 to 4 heteroatoms as ring atoms in the aromatic heterocyclic ring system, with the remaining atoms in the ring system being carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in other embodiments, 6 to 9, or even 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include 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), imidazopyridyl (e.g., azaindolyl, benzo[d]imidazolyl), benzo[d]isoxazolyl, ... Examples of such groups include, but are not limited to, benzoimidazolyl 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.

[0030] As used herein, "spirocyclic ring" refers to two or more rings in which adjacent rings are connected via a single atom. The individual rings within 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 within a set of spirocyclic rings.

[0031] A "cycloalkylalkyl" group is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups can be substituted on the alkyl, the 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.

[0032] An "aralkyl" group is a radical of the formula: -alkyl-aryl, where alkyl and aryl are as 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.

[0033] A "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are as 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-ethylmorpholinyl, 4-propylmorpholinyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0034] "Halogen" is fluorine, chlorine, bromine, or iodine.

[0035] A "hydroxyalkyl" group is an alkyl group as defined above that is substituted with one or more hydroxy groups.

[0036] An "alkoxy" or "alkoxyl" group is an --O-(alkyl), where alkyl is as defined above.

[0037] An "alkoxyalkyl" group is an -(alkyl)-O-(alkyl), where alkyl is defined above.

[0038] An "amino" group is a radical of the formula: --NH.sub.2.

[0039] An "alkylamino" group is a radical of the formula: -NH-alkyl or -N(alkyl)2, where each alkyl is independently as defined above.

[0040] A "carboxy" group is a radical of the formula: --C(O)OH.

[0041] An “aminocarbonyl” group is a group of the formula: —C(O)N(R # )2, -C(O)NH(R # ), or a radical of —C(O)NH2, where each R # is independently a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclyl group as defined herein.

[0042] An "acylamino" group is a group of the formula: -NHC(O)(R # ) or -N(alkyl)C(O)(R # ) radical, where each alkyl and R # are independently as defined above.

[0043] A "sulfonylamino" group is a group of the formula: -NHSO(R # ) or -N(alkyl)SO2(R # ) radical, where each alkyl and R # is as defined above.

[0044] A "urea" group is a group of the formula: -N(alkyl)C(O)N(R # )2, -N(alkyl)C(O)NH(R # ), -N(alkyl)C(O)NH2, -NHC(O)N(R # )2, -NHC(O)NH(R # ), or -NH(CO)NHR # where each alkyl and R # are independently as defined above.

[0045] 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), O(alkyl)aminocarbonyl, monocyclic or fused or non-fused alkyl groups. 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.

[0046] 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 compounds of formula (I) include, but are not limited to, those well known in the art, and are described, for example, in 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).

[0047] As used herein, and 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 will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound will contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of that compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of that compound, greater 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 greater 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 contain 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.

[0048] The use of stereomerically 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 enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can 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, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0049] It should also be noted that the compounds can 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.

[0050] As used herein, and 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 allow isolation of individual rotamers.

[0051] "Tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of isomeric forms depends on the environment in which the compound is found, and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are called tautomers of each other: [ka]

[0052] As will be readily understood by one of ordinary skill in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the invention.

[0053] It should also be noted that the compounds may contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), sulfur-35( 35 S), or carbon-14 ( 14 It may be radiolabeled with a radioisotope such as C) or deuterium ( 2 H), carbon-13( 13 C), or nitrogen-15( 15The compound may be isotopically enriched, such as with 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, 113, 120, 121, 130, 131, 142, 143, 144, 150, 151, 162, 170, 171, 182, 190, 192, 193, 194, 195,

[0054] As used herein, "treating" means alleviating, in whole or in part, a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing or halting further progression or worsening of the symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In some embodiments, "treating" refers to alleviating, in whole or in part, a disorder, disease, or condition, or slowing or halting further progression or worsening of the symptoms. In another embodiment, "treating" refers to alleviating, in whole or in part, a symptom associated with a disorder, disease, or condition, or a condition that is treatable or preventable by inhibition of KRAS, preferably G12D and / or G12V.

[0055] As used herein, "preventing" means 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 barring a subject from acquiring a disorder, disease, or condition, or a method of reducing a subject's risk of acquiring a disorder, disease, or condition. In one embodiment, the condition is one that is treatable or preventable by inhibition of KRAS, preferably G12D and / or G12V.

[0056] 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.

[0057] The term "subject" includes animals, including 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, but is not limited to these.

[0058] compound

[0059] Aspect 1: Provided herein are compounds having the following formula (I): [ka] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof, During the ceremony, Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Ring B is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; X is N or CR 8 and R 0 each independently represents H, halogen, amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carboxy, nitro, thiol, or thioether, or R 0 one or more pairs of groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Optionally, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, halogen, unsubstituted or substituted amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carboxy, nitro, thiol, or thioether; or R 3a groups, and R 3b groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R 4a groups, and R 4b groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R 5a groups, and R 5b groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R 3a groups, and R 4agroups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R 3a groups, and R 5a groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R 4a groups, and R 5a groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R 6 is H, unsubstituted or substituted C 1-8 Alkyl, unsubstituted or substituted C 1-8 Alkoxy, unsubstituted or substituted C 3-8 cycloalkyl, or unsubstituted or substituted 3- to 8-membered heterocyclyl; R 8 is H, halogen, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Alkyl halides, unsubstituted or substituted C 3-5 Halogenated cycloalkyl, unsubstituted or substituted C 1-4 halogenated alkoxyl, CN, OH, or amino; t is 0 or 1, Each of m and q is independently an integer from 0 to the maximum number of substituents allowed on ring A and ring B, respectively.

[0060] Aspect 2A: Provided herein are compounds having the following formula (I): [ka] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof, During the ceremony, Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Ring B is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; X is N or CR 8 and R 0 each independently represents H, halogen, amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carboxy, nitro, thiol, or thioether, or R 0 one or more pairs of groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; R 3a groups, and R 4a The groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl, and R 3b , R 4b , R 5a , and R 5b each independently represents H, halogen, unsubstituted or substituted amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carboxy, nitro, thiol, or thioether, or R 5a groups, and R 5bgroups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R 3a groups, and R 5a The groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl, and R 3a , R 3b , R 4a , R 4b , and R 5b each independently represents H, halogen, unsubstituted or substituted amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carboxy, nitro, thiol, or thioether, or R 4a groups, and R 4b groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R 4a groups, and R 5a The groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted heterocyclyl, and R 3a , R 3b , R 4b , and R 5b each independently represents H, halogen, unsubstituted or substituted amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carboxy, nitro, thiol, or thioether, or R 3a groups, and R 3bgroups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; R 6 is H, unsubstituted or substituted C 1-8 Alkyl, unsubstituted or substituted C 1-8 Alkoxy, unsubstituted or substituted C 3-8 cycloalkyl, or unsubstituted or substituted 3- to 8-membered heterocyclyl; R 8 is H, halogen, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 1-4 Alkyl halides, unsubstituted or substituted C 3-5 Halogenated cycloalkyl, unsubstituted or substituted C 1-4 halogenated alkoxyl, CN, OH, or amino; t is 0 or 1, Each of m and q is independently an integer from 0 to the maximum number of substituents allowed on ring A and ring B, respectively.

[0061] In some embodiments, m is an integer from 0 to 5. In some embodiments, m is an integer from 1 to 4. In some embodiments, m is an integer from 2 to 3. In some embodiments, m is an integer of 2 or 3. In some embodiments, q is an integer from 0 to 5. In some embodiments, q is an integer from 1 to 4. In some embodiments, q is an integer from 1 to 3. In some embodiments, q is an integer of 1 or 2.

[0062] In one embodiment, X is N. In one embodiment, X is CR 8 In one embodiment, X is CH, CF, C—Cl, or C—CF. In one embodiment, X is C—Cl. In one embodiment, X is C—CF.

[0063] In one embodiment, R 6 is unsubstituted or substituted C 1-8 Alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted C 3-8 cycloalkyl, unsubstituted or substituted 3- to 8-membered heterocyclyl. In one embodiment, R 6 is methyl.

[0064] Aspect 3:

[0065] In one embodiment, ring A is an aryl group (eg, phenyl or naphthyl) optionally substituted with one or more substituents. In one embodiment, a substituent is F, Cl, Br, amino, -CN, OH, -CF, -CHF, -CHF, -CFCH, -CFCF, -OCHF, -OCF, vinyl (-CH=CH), -propylenyl (e.g., -C(CH)=CH), -CF=CH, aryl, heteroaryl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propylenyl, allyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, or hexoxy. In one embodiment, the substituents are F, Cl, Br, amino, -CN, OH, -CF3, -CHF2, -CH2F, -CF2CH3, -CF2CF3, -OCHF2, -OCF3, vinyl (-CH=CH), -propylenyl (such as -C(CH3)=CH), -CF=CH, aryl, heteroaryl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, methylcyclopropyl, fluorocyclopropyl, difluorocyclopropyl. , fluoromethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propylenyl, allyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, or hexoxy.

[0066] In one embodiment, Ring A is a 5- to 7-membered monocyclic heteroaryl group or an 8- to 12-membered bicyclic heteroaryl group, optionally substituted with one or more substituents. In some preferred embodiments, Ring A is pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyrazolopyridinyl, benzimidazolyl, quinazolinyl, or quinazolinyl. In one embodiment, the substituents are F, Cl, Br, C(CH3)=CH or -CH=CH, -CF=CH, -CN, OH, -NH2, -CF3, -CHF2, -CH2F, -CF2CH3, -CF2CF3, -OCHF2, -OCF3, aryl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propylenyl, allyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, or hexoxy. In one embodiment, the substituents are F, Cl, Br, C(CH3)=CH or -CH=CH, -CF=CH, -CN, OH, NH2, -CF3, -CHF2, -CH2F, -CF2CH3, -CF2CF3, -OCHF2, -OCF3, aryl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, methylcyclopropyl, fluorocyclopropyl, difluorocyclopropyl, fluoromethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, vinyl, propylenyl, allyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, or hexoxy. In some preferred embodiments, Ring A is pyridyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyrazolopyridinyl, benzimidazolyl, quinazolinyl, or quinazolinyl.

[0067] In one embodiment, ring A is [ka] is.

[0068] In one embodiment, ring A is [ka] is.

[0069] In one embodiment, ring A is [ka] is.

[0070] In one embodiment, ring A is [ka] is.

[0071] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] is.

[0072] Aspect 4:

[0073] In one embodiment, Ring B is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl. In one embodiment, the heterocyclyl contains at least one oxygen ring member. In one embodiment, the heterocyclyl contains at least one nitrogen ring member.

[0074] In one embodiment, Ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3-9 membered heterocycle containing 1, 2, or 3 nitrogen atoms as ring members. In one embodiment, Ring B is oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl, tetrahydropyridinyl, azetidinyl, pyrrolidinyl, octahydroindolizinyl, octahydroquinolidinyl, hexahydro-1H-pyrrolidinyl, tetrahydroisoquinolinyl, or tetrahydropyridyl, wherein Ring B is optionally substituted. In one embodiment, Ring B is oxetanyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dihydro-2H-pyranyl, oxabicyclo[2.1.1]hexyl, oxabicyclo[2.2.1]heptyl, oxaspiro[3.3]heptyl, oxabicyclo[3.2.1]octyl, oxabicyclo[2.2.2]octyl, oxaspiro[3.5]nonyl, or oxaspiro[3.4]octyl, and Ring B is optionally substituted. In one embodiment, Ring B is optionally substituted with halogen, cyano, hydroxy, alkoxy, or alkyl optionally substituted with halogen, cyano, hydroxy, alkoxy, heterocyclyl, cycloalkyl, or cycloalkyloxy.

[0075] In one embodiment, Ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3-9 membered heterocycle containing 1, 2, or 3 nitrogen atoms as ring members, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl, or tetrahydropyridinyl, optionally substituted with one or more substituents. In one embodiment, the substituents are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 1-8 Alkoxy-C 1-8 alkyl-, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazinyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, thiophenyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl or oxo, or two substituents together with the carbon atoms to which they are attached form a 3-8 membered unsaturated or saturated ring, said ring containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0076] In one embodiment, ring B is [ka] is.

[0077] In one embodiment, Ring B is azetidyl, pyridyl, isoxazolyl, oxazolyl, dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, pyrrolidinonyl, azaspiro[3.3]heptyl, azabicyclo[2.1.1]hexyl, pyrrolidyl, 1H-pyrazolyl, and Ring B is optionally substituted.

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

[0079] In one embodiment, ring B is [ka] is.

[0080] In one embodiment, Ring B is azetidyl, pyridyl, isoxazolyl, oxazolyl, dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, pyrrolidinonyl, azaspiro[3.3]heptyl, azabicyclo[2.1.1]hexyl, pyrrolidyl, 1H-pyrazolyl, and Ring B is optionally substituted.

[0081] In one embodiment, Ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or azetidyl, and Ring B is optionally substituted.

[0082] In one embodiment, ring B is [ka] is.

[0083] In one embodiment, ring B is [ka] is.

[0084] In one embodiment, ring B is [ka] is.

[0085] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] and where R a and R b each independently represents a substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 is cycloalkyl, or R a and R b together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S, R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 In one embodiment, Ring B is [ka] is.

[0086] Aspect 5:

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

[0088] In one embodiment, ring A is [ka] is.

[0089] In one embodiment, ring A is [ka] is.

[0090] In one embodiment, ring A is [ka] is.

[0091] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] is.

[0092] Aspect 6:

[0093] In one embodiment, Ring B is substituted or unsubstituted hexahydro-1H-pyrrolidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted aminomethylcyclopropyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted oxabicyclo[2.1.1]hexanyl, substituted or unsubstituted oxabicyclo[2.2.1]heptanyl.

[0094] In one embodiment, ring B is [ka] and where R a and R b each independently represents a substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 is cycloalkyl, or R a and R b together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S, R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 It is alkoxyl.

[0095] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] is.

[0096] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] and where R a and R b each independently represents a substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 is cycloalkyl, or R a and R b together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S, R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 In one embodiment, Ring B is [ka] is.

[0097] Aspect 7: In one embodiment, t is 0.

[0098] Group 2.1: In one embodiment, X is N.

[0099] In one embodiment, ring A is [ka] and ring B is [ka] is.

[0100] In one embodiment, R 1 is methyl, or Cl. In one embodiment, R 2 is —CF. In one embodiment, R 7 is -NH2.

[0101] Group 2.1.1: In one embodiment, ring A is [ka] is.

[0102] In one embodiment, ring B is [ka] is.

[0103] Group 2.1.1.1: In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] is.

[0104] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl.

[0105] In one embodiment, R 6 is methyl, ethyl, cyclopropyl, or cyclobutyl, optionally substituted with CN or OH. In one embodiment, R 6 is methyl. In one embodiment, R 6 is 2-hydroxyethyl. In one embodiment, R 6 is cyclopropyl.

[0106] In one embodiment, R 3a , R 3b , R 5a , and R 5b each independently represents H, OH, CN, amino, or unsubstituted or substituted C 1-4 In one embodiment, R3a , R 3b , R 5a , and R 5b each independently represents H, or an unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5a , and R 5b Each of R is independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. 3a , R 3b , R 5a , and R 5b Each of is independently H, methyl, or ethyl optionally substituted with OH, CN, amino, or methylamino.

[0107] In one embodiment, the compound is [ka] is.

[0108] In one embodiment, R 6 is methyl.

[0109] In one embodiment, R 5a and R 5b are unsubstituted or substituted C atoms, along with the atoms bonded to them. 3-5 In one embodiment, R 5a and R 5b together with the atom to which they are attached form an unsubstituted or substituted cyclopropyl, or an unsubstituted or substituted cyclobutyl.

[0110] In one embodiment, the compound is [ka] is.

[0111] In one embodiment, R 5a and R 5btogether with the atom to which they are attached form an unsubstituted or substituted heterocyclyl. In one embodiment, the heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl. In one embodiment, the heterocyclyl is oxetanyl or tetrahydrofuranyl. In one embodiment, the heterocyclyl is oxetanyl. In one embodiment, the heterocyclyl is tetrahydrofuranyl.

[0112] In one embodiment, the compound is [ka] is.

[0113] Group 2.1.2: In one embodiment, ring A is [ka] is.

[0114] In one embodiment, ring B is [ka] is.

[0115] Group 2.1.2.1: In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] is.

[0116] In one embodiment, the compound is [ka] is.

[0117] Aspect 8: In one embodiment, t is 1.

[0118] Group 3.1: In one embodiment, X is N.

[0119] Group 3.1.1: In one embodiment, ring A is [ka] is.

[0120] In one embodiment, ring B is [ka] is.

[0121] Group 3.1.1.1: In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] is.

[0122] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 It is alkyl.

[0123] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of is independently H, OH, CN, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl.

[0124] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl.

[0125] In one embodiment, R 6 is methyl, ethyl, cyclopropyl, or cyclobutyl, optionally substituted with CN or OH. In one embodiment, R 6 is methyl. In one embodiment, R 6 is cyclopropyl. In one embodiment, R 6 is cyclobutyl. In one embodiment, R 6 is 1-(methylamino)propan-2-yl.

[0126] In one embodiment, the compound is [ka] [ka] [ka] is.

[0127] In one embodiment, R 6 is methyl, 2-(methylamino)-ethyl, or 2-(dimethylamino)-ethyl.

[0128] In one embodiment, R 5a and R 5b are unsubstituted or substituted C atoms, along with the atoms bonded to them. 3-5 In one embodiment, C 3-5 In one embodiment, the cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment, the heterocyclyl is cyclopropyl or cyclobutyl. In one embodiment, the heterocyclyl is cyclopropyl. In one embodiment, the heterocyclyl is cyclobutyl.

[0129] In one embodiment, the compound is [ka] is.

[0130] In one embodiment, R 5a and R 5b together with the atom to which they are attached form an unsubstituted or substituted heterocyclyl. In one embodiment, the heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl. In one embodiment, the heterocyclyl is oxetanyl or tetrahydrofuranyl. In one embodiment, the heterocyclyl is oxetanyl. In one embodiment, the heterocyclyl is tetrahydrofuranyl.

[0131] In one embodiment, R 6 is methyl, 2-(methylamino)-ethyl, or 2-(dimethylamino)-ethyl.

[0132] In one embodiment, the compound is [ka] is.

[0133] In one embodiment, R 4a and R 4b together with the atom to which they are attached form an unsubstituted or substituted heterocyclyl. In one embodiment, the heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl. In one embodiment, the heterocyclyl is oxetanyl or tetrahydrofuranyl. In one embodiment, the heterocyclyl is tetrahydrofuranyl. In one embodiment, the heterocyclyl is oxetanyl.

[0134] In one embodiment, R 6 is methyl.

[0135] In one embodiment, the compound is [ka] is.

[0136] Group 3.1.1.3: In one embodiment, ring B is [ka] is.

[0137] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl.

[0138] In one embodiment, R 6 is methyl, ethyl, cyclopropyl, or cyclobutyl, optionally substituted with CN or OH. In one embodiment, R 6 is methyl.

[0139] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 It is alkyl.

[0140] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of R is independently H, OH, CN, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. 3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of is independently H or methyl.

[0141] In one embodiment, the compound is [ka] is.

[0142] In one embodiment, ring A is [ka] and ring B is [ka] and where R a and R b each independently represents a substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 is cycloalkyl, or R a and R b together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S, R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 It is alkoxyl.

[0143] Group 3.1.1.6: In one embodiment, ring B is [ka] is.

[0144] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 It is alkyl.

[0145] In one embodiment, R3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of R is independently H, OH, CN, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. 3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of is independently H or CN.

[0146] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl.

[0147] In one embodiment, R 6 is methyl, ethyl, cyclopropyl, or cyclobutyl, optionally substituted with CN or OH. In one embodiment, R 6 is 2-(dimethylamino)ethyl, or 1-(methylamino)propan-2-yl.

[0148] In one embodiment, the compound is [ka] is.

[0149] Group 3.1.2: In one embodiment, ring A is [ka] is.

[0150] In one embodiment, ring B is [ka] is.

[0151] Group 3.1.2.1: In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] is.

[0152] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl.

[0153] In one embodiment, R 6 is methyl, or pyrrolidinyl. In one embodiment, R 6 is methyl. In one embodiment, R 6 is pyrrolidinyl.

[0154] In one embodiment, the compound is [ka] is.

[0155] Group 3.1.4: In one embodiment, ring A is [ka] is.

[0156] In one embodiment, ring B is [ka] is.

[0157] Group 3.1.4.1: In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] is.

[0158] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl. In one embodiment, R 6 is methyl, cyclopropyl, or cyclobutyl. 6 is methyl. In one embodiment, R 6 is cyclopropyl. In one embodiment, R 6 is cyclobutyl.

[0159] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of is independently H or methyl.

[0160] In one embodiment, the compound is [ka] is.

[0161] Group 3.1.5: In one embodiment, ring A is [ka] is.

[0162] In one embodiment, ring B is [ka] is.

[0163] Group 3.1.5.1: In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] is.

[0164] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of is independently H or methyl.

[0165] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl. In one embodiment, R 6 is methyl, cyclopropyl, or cyclobutyl. 6 is methyl.

[0166] In one embodiment, the compound is [ka] is.

[0167] Group 3.2: In one embodiment, X is CH, CF, C—Cl, or C—CF 3 .

[0168] Group 3.2.4: In one embodiment, X is CH.

[0169] In one embodiment, ring A is [ka] is.

[0170] In one embodiment, ring B is [ka] is.

[0171] Group 3.2.4.1: In one embodiment, R 6 is methyl.

[0172] In one embodiment, ring B is [ka] is.

[0173] In one embodiment, the compound is [ka] is.

[0174] Group 3.2.6.1: In one embodiment, X is CH.

[0175] In one embodiment, ring A is [ka] is.

[0176] In one embodiment, ring B is [ka] is.

[0177] In one embodiment, ring B is [ka] In one embodiment, R 6 is methyl.

[0178] In one embodiment, the compound is [ka] is.

[0179] Group 3.3.4: In one embodiment, X is CF.

[0180] In one embodiment, ring A is [ka] is.

[0181] In one embodiment, ring B is [ka] is.

[0182] In one embodiment, ring B is [ka] is.

[0183] In one embodiment, R 5a is methyl. In one embodiment, R 6 is methyl.

[0184] In one embodiment, the compound is [ka] is.

[0185] Group 3.4.2.1: In one embodiment, X is C-Cl. In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] is.

[0186] In one embodiment, ring B is [ka] is.

[0187] In one embodiment, ring B is [ka] is.

[0188] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of R is independently H or methyl. 5a is methyl. In one embodiment, R 5a is methylaminomethyl.

[0189] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl. In one embodiment, R6 is methyl, cyclopropyl, or cyclobutyl. 6 is methyl.

[0190] In one embodiment, the compound is [ka] is.

[0191] Group 3.4.4.1: In one embodiment, X is C—Cl.

[0192] In one embodiment, ring A is [ka] is.

[0193] In one embodiment, R 5a is methyl. In one embodiment, R 6 is methyl.

[0194] In one embodiment, the compound is [ka] is.

[0195] Group 3.4.4.3: In one embodiment, X is C-Cl. In one embodiment, ring A is [ka] In one embodiment, ring B is [ka] In one embodiment, R 5a is methyl. In one embodiment, R 6 is methyl.

[0196] In one embodiment, the compound is [ka] is.

[0197] Group 3.4.5.3: In one embodiment, X is C—Cl.

[0198] In one embodiment, ring A is [ka] is.

[0199] In one embodiment, ring B is [ka] is.

[0200] In one embodiment, ring B is [ka] is.

[0201] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of R is independently H or unsubstituted or substituted methyl. 5a is methylaminomethyl.

[0202] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl. In one embodiment, R6 is methyl, cyclopropyl, or cyclobutyl. 6 is methyl.

[0203] In one embodiment, the compound is [ka] is.

[0204] Group 3.4.6.1: In one embodiment, X is C—Cl.

[0205] In one embodiment, ring A is [ka] is.

[0206] In one embodiment, ring B is [ka] is.

[0207] In one embodiment, ring B is [ka] is.

[0208] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of R is independently H or methyl. 5a is methyl.

[0209] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl. In one embodiment, R 6 is methyl, cyclopropyl, or cyclobutyl. 6 is methyl.

[0210] In one embodiment, the compound is [ka] is.

[0211] Group 3.4.6.3: In one embodiment, X is C—Cl. In one embodiment, ring A is [ka] In one embodiment, ring B is [ka] In one embodiment, R 5a is methyl. In one embodiment, R 6 is methyl.

[0212] In one embodiment, the compound is [ka] is.

[0213] Group 3.4.6.6: In one embodiment, X is C—Cl.

[0214] In one embodiment, ring A is [ka] is.

[0215] In one embodiment, ring B is [ka] and where R a and R b each independently represents a substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 is cycloalkyl, or R a and R b together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S, R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 It is alkoxyl.

[0216] In one embodiment, ring B is [ka] is.

[0217] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b Each of R is independently H or unsubstituted or substituted methyl. 5a is methylaminomethyl.

[0218] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl. In one embodiment, R 6 is methyl, cyclopropyl, or cyclobutyl. 6 is methyl.

[0219] In one embodiment, the compound is [ka] is.

[0220] Group 3.4.7.1: In one embodiment, X is C—Cl.

[0221] In one embodiment, ring A is [ka] is.

[0222] In one embodiment, ring B is [ka] is.

[0223] In one embodiment, ring B is [ka] is.

[0224] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5a , and R 5bEach of R is independently H or unsubstituted or substituted methyl. 5a is methylaminomethyl.

[0225] In one embodiment, R 6 is unsubstituted or substituted C 1-5 Alkyl, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl. In one embodiment, R 6 is methyl, cyclopropyl, or cyclobutyl. 6 is methyl.

[0226] In one embodiment, the compound is [ka] is.

[0227] Aspect 9: In one embodiment, the compound is selected from Table 4 and Table 5.

[0228] Aspect 10: In some embodiments, compounds provided herein have the following formula: [ka]

[0229] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof;

[0230] During the ceremony,

[0231] Ring C is unsubstituted or substituted C 3-6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocyclyl.

[0232] In one embodiment, Ring C has one oxygen as the heteroatom.

[0233] In some embodiments, the compounds provided herein have the following formula: [ka]

[0234] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof;

[0235] During the ceremony,

[0236] Y is CH2, O, NH, NR 9 , NC(=O)-R 10 , or O=S=O,

[0237] R 9 is a substituted or unsubstituted C 1-4 Alkyl, or unsubstituted or substituted C 3-5 is cycloalkyl, R 10 is a substituted or unsubstituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl;

[0238] R a is H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, or unsubstituted or substituted C 1-4 It is alkylamino.

[0239] In one embodiment, Y is CH. In one embodiment, Y is O. In one embodiment, Y is NH.

[0240] Aspect 11: In some embodiments, compounds provided herein have the following formula: [ka]

[0241] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof,

[0242] During the ceremony,

[0243] Ring C is unsubstituted or substituted C 3-4 cycloalkyl, or unsubstituted or substituted 3- to 4-membered heterocyclyl.

[0244] In one embodiment, R 3a , R 3b , R 4a , and R 4b each independently represents H, OH, CN, halogen, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , and R 4b Each of R is independently H, F, or unsubstituted or substituted methyl. 3a , R 3b , R 4a , and R 4b Each of R is independently H, F, or unsubstituted methyl. 3a , R 3b , R 4a , and R 4b Each of R is independently H or F. In one embodiment, R 3a , R 3b , R 4a , and R 4b Each of is independently H.

[0245] In one embodiment, ring C is OH, CN, halogen, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4In one embodiment, ring C is a cyclopropyl ring, a cyclobutyl ring, or an oxetane ring optionally substituted with alkyl. In one embodiment, ring C is a cyclopropyl ring, a cyclobutyl ring, or an oxetane ring optionally substituted with OH. In one embodiment, ring C is a cyclopropyl ring, a cyclobutyl ring, or an oxetane ring, each of which is optionally substituted with one or more F. In one embodiment, ring C is a cyclopropyl ring optionally substituted with one or two F. In one embodiment, ring C is an unsubstituted cyclopropyl ring. In one embodiment, ring C is an unsubstituted cyclobutyl ring.

[0246] In one embodiment, R 6 is H, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 3-4 cycloalkyl, or unsubstituted or substituted 3- to 4-membered heterocyclyl. In one embodiment, R 6 is methyl, ethyl, 2-dimethylamino-ethyl, or cyclopropyl. 6 is methyl.

[0247] In one embodiment, X is N. In one embodiment, X is C—Cl.

[0248] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] is.

[0249] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] and where R a and R b each independently represents a substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 is cycloalkyl, or R a and R b together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S, R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 In one embodiment, Ring B is [ka] is.

[0250] In one embodiment, the compound is [ka] is.

[0251] In one embodiment, the compound is [ka] is.

[0252] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] is.

[0253] In one embodiment, the compound is [ka] is.

[0254] In one embodiment, the compound is [ka] is.

[0255] In one embodiment, the compound is [ka] is.

[0256] In one embodiment, the compound is [ka] is.

[0257] Aspect 12: In some embodiments, compounds provided herein have the following formula:

[0258] [ka]

[0259] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof,

[0260] During the ceremony,

[0261] Ring C is unsubstituted or substituted C 3-4 cycloalkyl, or unsubstituted or substituted 3- to 4-membered heterocyclyl.

[0262] In one embodiment, R 3a , and R 3b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C1-4 In one embodiment, R 3a , and R 3b Each of R is independently H or unsubstituted or substituted methyl. 3a , and R 3b Each of R is independently H or unsubstituted methyl. 3a , and R 3b Each of is independently H.

[0263] In one embodiment, ring C is OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, Ring C is a cyclopropyl ring, a cyclobutyl ring, or an oxetane ring, optionally substituted with alkyl. In one embodiment, Ring C is a cyclopropyl ring, a cyclobutyl ring, or an oxetane ring, optionally substituted with OH.

[0264] In one embodiment, R 6 is H, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 3-4 cycloalkyl, or unsubstituted or substituted 3- to 4-membered heterocyclyl. In one embodiment, R 6 is methyl, ethyl, 2-(dimethylamino)-ethyl, 2-(methylamino)-ethyl, 1-(methylamino)propan-2-yl, or cyclopropyl.

[0265] In one embodiment, X is N. In one embodiment, X is C—Cl.

[0266] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] is.

[0267] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] is.

[0268] In one embodiment, the compound is [ka] is.

[0269] Embodiment 13: Provided herein is a compound selected from the following table:

[0270] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0271] Aspect 14: In some embodiments, compounds provided herein have the following formula: [ka]

[0272] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof,

[0273] During the ceremony,

[0274] Ring D is an unsubstituted or substituted 3- to 6-membered cycloalkyl or an unsubstituted or substituted 3- to 6-membered heterocyclyl; or Ring D is unsubstituted or substituted 3- to 7-membered cycloalkyl or unsubstituted or substituted 3- to 7-membered heterocyclyl.

[0275] In one embodiment, Ring D has one oxygen as the heteroatom.

[0276] In some embodiments, ring D is an unsubstituted or substituted cyclopentyl ring, an unsubstituted or substituted cyclohexyl ring, an unsubstituted or substituted cycloheptyl ring, an unsubstituted or substituted tetrahydrofuranyl ring, an unsubstituted or substituted tetrahydropyranyl ring, or an unsubstituted or substituted oxepanyl ring.

[0277] In one embodiment, ring D is OH, CN, halogen, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, ring D is optionally substituted with OH, F, or CN.

[0278] In one embodiment, Ring D is optionally substituted with a 3- to 6-membered spirocycloalkyl or an unsubstituted or substituted 3- to 6-membered spiroheterocyclyl. In one embodiment, Ring D is optionally substituted with a spirocyclopropyl.

[0279] In one embodiment, R 3b , and R 5b each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3b , and R 5b Each of R is independently H or unsubstituted or substituted methyl. 3b , and R 5b Each of R is independently H or unsubstituted methyl. 3b , and R 5b Each of is independently H.

[0280] In one embodiment, R 6 is H, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 3-4 cycloalkyl, or unsubstituted or substituted 3- to 4-membered heterocyclyl. In one embodiment, R 6 is methyl, ethyl, 2-methylamino-ethyl, or cyclopropyl. 6 is methyl.

[0281] In one embodiment, X is N.

[0282] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] is.

[0283] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] and where R a and R b each independently represents a substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 is cycloalkyl, or R a and R btogether with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S, R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 In one embodiment, Ring B is [ka] is.

[0284] In one embodiment, the compound is [ka] is.

[0285] In one embodiment, the compound is [ka] is.

[0286] In one embodiment, the compound is [ka] is.

[0287] In one embodiment, the compound is [ka] is.

[0288] In one embodiment, the compound is [ka] is.

[0289] Aspect 15: In some embodiments, compounds provided herein have the following formula: [ka]

[0290] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof;

[0291] During the ceremony,

[0292] Z is CH, NH, or O;

[0293] R d is H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, or unsubstituted or substituted C 1-4 It is alkylamino.

[0294] In one embodiment, Z is CH. In one embodiment, Z is O. In one embodiment, Z is NH.

[0295] Embodiment 16: Provided herein is a compound selected from the following table:

[0296] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0297] Aspect 17: In some embodiments, compounds provided herein have the following formula: [ka]

[0298] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof,

[0299] During the ceremony,

[0300] Ring E is unsubstituted or substituted 4- to 6-membered cycloalkyl or unsubstituted or substituted 4- to 6-membered heterocyclyl.

[0301] In one embodiment, Ring E has one oxygen as the heteroatom.

[0302] In some embodiments, the compounds provided herein have the following formula: [ka]

[0303] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof,

[0304] During the ceremony,

[0305] Z is CH, NH, or O;

[0306] R e is H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4Alkoxy, or unsubstituted or substituted C 1-4 It is alkylamino.

[0307] In one embodiment, Z is CH. In one embodiment, Z is O. In one embodiment, Z is NH.

[0308] Aspect 18: In some embodiments, compounds provided herein have the following formula: [ka]

[0309] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof,

[0310] During the ceremony,

[0311] Ring E is an unsubstituted or substituted cyclopentyl ring, an unsubstituted or substituted cyclohexyl ring, an unsubstituted or substituted cycloheptyl ring, an unsubstituted or substituted tetrahydrofuranyl ring, an unsubstituted or substituted tetrahydropyranyl ring, or an unsubstituted or substituted oxepanyl ring.

[0312] In one embodiment, ring E is an unsubstituted or substituted cyclopentyl ring. In one embodiment, ring E is an unsubstituted or substituted tetrahydrofuranyl ring. In one embodiment, ring E is OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, ring E is optionally substituted with alkyl. In one embodiment, ring E is optionally substituted with OH. In one embodiment, ring E is an unsubstituted tetrahydrofuranyl ring. In one embodiment, ring E is an unsubstituted tetrahydropyranyl ring. In one embodiment, ring E is an unsubstituted oxepanyl ring.

[0313] In one embodiment, R 3a , R 3b , R 4b , and R 5beach independently represents H, OH, CN, halogen, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4b , and R 5b Each of R is independently H or unsubstituted or substituted methyl. 3a , R 3b , R 4b , and R 5b Each of R is independently H, OH, CN, halogen, or unsubstituted methyl. 3a , R 3b , R 4b , and R 5b Each of R is independently H, F, CN, or unsubstituted methyl. 3a , R 3b , R 4b , and R 5b Each of is independently H.

[0314] In one embodiment, R 6 is H, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 3-4 cycloalkyl, or unsubstituted or substituted 3- to 4-membered heterocyclyl. In one embodiment, R 6 is methyl, ethyl, 2-methylamino-ethyl, or cyclopropyl. 6 is methyl.

[0315] In one embodiment, X is N. In one embodiment, X is CCF. In one embodiment, X is CH.

[0316] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] In one embodiment, ring A is [ka] is.

[0317] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] In one embodiment, ring B is [ka] and where R a and R b each independently represents a substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 is cycloalkyl, or R a and R b together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S, R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 In one embodiment, Ring B is [ka] is.

[0318] In one embodiment, the compound is [ka] is.

[0319] In one embodiment, the compound is [ka] is.

[0320] In one embodiment, the compound is [ka] is.

[0321] Embodiment 19: Provided herein is a compound selected from the following table:

[0322] [Table 3-1] [Table 3-2] [Table 3-3]

[0323] Aspect 20: In one embodiment, provided herein is a pharmaceutical composition comprising an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0324] Aspect 21: In one embodiment, provided herein is a method of inhibiting KRAS mutant protein activity in a cell, comprising contacting the cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, wherein optionally, the KRAS mutant protein is a KRAS G12D and / or G12V mutant protein. In one embodiment, provided herein is a method of inhibiting KRAS amplification activity in a cell, comprising contacting the cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, wherein optionally, the KRAS mutant protein is a KRAS G12D and / or G12V mutant protein.

[0325] Aspect 22: In one embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject in need of cancer treatment or prevention an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, wherein optionally the cancer is mediated by a KRAS mutation, preferably a KRAS G12D and / or G12V mutation. Provided herein is a method for treating or preventing cancer, comprising administering to a subject in need of cancer treatment or prevention an effective amount of a compound provided herein.

[0326] Aspect 23: Provided herein is a method of modulating the activity of KRAS G12D and / or G12V, the method comprising contacting the cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof.

[0327] Aspect 24: Provided herein is a kit for treating cancer, the kit comprising: (a) a pharmaceutical composition comprising a compound provided herein; and (b) instructions for administering an effective amount of the pharmaceutical composition comprising a KRAS G12D and / or G12V inhibitor provided herein to treat cancer in an individual.

[0328] The present embodiments can be more fully understood by reference to the detailed description and examples, which are intended as non-limiting exemplifications of embodiments.

[0329] Compound manufacturing method

[0330] The compounds can be prepared using conventional organic synthesis methods 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 below, as well as in the Examples described herein. It should be noted that one skilled in the art would know how to modify the procedures shown in the illustrative Schemes and Examples to arrive at the desired products. Common protecting groups can be used to prevent particular functional groups from undergoing undesired reactions. Exemplary protecting groups are described in "Protective Groups in Organic Synthesis", 4 th Edition, PGM Wuts; TW Greene, John Wiley, 2007, and the references cited therein.

[0331] Scheme 1 [ka]

[0332] In some embodiments, provided herein are methods for preparing compounds defined as Formula (I), as shown in Scheme 1. Halogen-substituted compound 1-1 (X2 and X4 are halogen, X1 is OH or Cl, and X3 can be methylthiolyl) is converted to compound 1-2 under substitution conditions (e.g., HATU, DIEA when X1 is OH, DIEA, DCM when X1 is Cl), compound 1-2 is then converted to compound 1-3 under substitution conditions (e.g., NaH, THF), compound 1-3 is then converted to compound 1-4 under oxidation conditions (e.g., m-CPBA oxidation when LG is methylsulfonyl or methylsulfinyl), compound 1-4 is then converted to compound 1-5, followed by a substitution or coupling reaction (e.g., NaH, THF), and the resulting product is 1-6. Compound 1-5 may further undergo a metal-catalyzed cross-coupling reaction such as Suzuki, Negishi, or Stille coupling (e.g., Pd(dtbpf)Cl, KPO, 1,4-dioxane, water for Suzuki coupling) to give compound 1-6, where M can be a boronic acid, a boronic ester, a metal (e.g., Zn), tributyltin, etc., and then finally, compound 1-6 containing a protecting group is deprotected (e.g., TFA and DCM to deprotect the Boc group when PG1 and PG2 contain a Boc group, or CsF and DMF to deprotect the TIPS group when PG1 and PG2 contain a TIPS group) to give a compound defined as formula (I).

[0333] Scheme 2 [ka]

[0334] In some embodiments, provided herein are methods for preparing compounds defined as Formula (I), as shown in Scheme 2. Halogen-substituted compound 2-1 (X2 and X4 are halogen, X1 is OH or Cl, and X3 can be methylthiolyl) is converted to compound 2-2 under substitution conditions (e.g., NaH, THF), which is then converted to compound 2-3 under substitution conditions (e.g., HATU, DIEA when X1 is OH, DIEA, DCM when X1 is Cl), which is then converted to compound 2-4 under oxidation conditions (e.g., m-CPBA oxidation when LG is methylsulfonyl or methylsulfinyl), which is then converted to compound 2-5, followed by a substitution or coupling reaction (e.g., NaH, THF), which affords compound 2-5. Further metal-catalyzed cross-coupling reactions such as Suzuki, Negishi, or Stille coupling (e.g., Pd(dtbpf)Cl, KPO, 1,4-dioxane, water for Suzuki coupling) provide compounds 2-6, where M can be boronic acid, boronic ester, metal (e.g., Zn), tributyltin, etc., and then finally the protecting group-containing compounds 2-6 are deprotected (e.g., TFA and DCM to deprotect the Boc group when PG1 and PG2 contain Boc groups, or CsF and DMF to deprotect the TIPS group when PG1 and PG2 contain TIPS groups) to provide compounds defined as formula (I).

[0335] Scheme 3 [ka]

[0336] In some embodiments, provided herein are methods for preparing compounds defined as Formula (I), as shown in Scheme 3. Halogen-substituted compound 3-1 (X2 and X4 are halogen, X1 is OH or Cl, and X3 can be methylthiolyl) is converted to compound 3-2 under substitution conditions (e.g., NaH, THF), which is then converted to compound 3-3 under substitution conditions (e.g., HATU or BOPCl, DIEA when X1 is OH, DIEA, DCM when X1 is Cl), which is then converted to compound 3-3 under substitution conditions (e.g., R 6 is Me), then compound 3-4 is converted to compound 3-5 under oxidation conditions (m-CPBA oxidation when LG is methylsulfonyl or methylsulfinyl), then compound 3-5 is converted to compound 3-6, followed by a substitution or coupling reaction (e.g., NaH, THF), and compound 3-6 is further subjected to a metal-catalyzed cross-coupling reaction such as Suzuki, Negishi, or Stille coupling (e.g., P for Suzuki coupling). d(dtbpf)Cl, KPO, 1,4-dioxane, water) to give compound 3-7, where M can be a boronic acid, a boronic ester, a metal (such as Zn), tributyltin, etc., and then finally compound 3-7 containing the protecting group is deprotected (e.g., TFA and DCM to deprotect the Boc group when PG1 and PG2 contain a Boc group, or CsF and DMF to deprotect the TIPS group when PG1 and PG2 contain a TIPS group) to give the compound defined as formula (I).

[0337] The present embodiments can be more fully understood by reference to the detailed description and examples, which are intended as non-limiting exemplifications of embodiments. [Example]

[0338] The following examples are intended purely as illustrative and should not be construed as limiting in any way. Unless otherwise specified, experimental methods in the following examples are conventional. Unless otherwise specified, all reagents and materials are commercially available. 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. Unless otherwise specified, all elutions were with petroleum ether (60-90°C) / ethyl acetate (v / v) and visualized with a solution of iodine or molybdophosphate in ethanol. Unless otherwise specified, all extraction solvents were dried over anhydrous Na2SO4.

[0339] Unless otherwise indicated, the reactions described below were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents using drying tubes, reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe, and glassware was oven-dried and / or heat-dried.

[0340] Unless otherwise indicated, column chromatography purifications were performed on a Biotage system (manufacturer: Dyax Corporation) with a silica gel column or on silica SepPak cartridges (Waters), or on a Teledyne Isco Combiflash purification system using prepacked silica gel cartridges.

[0341] 1 1 H NMR spectra were recorded on a 400 MHz or 500 MHz Varian instrument using TMS (tetramethylsilane) as an internal standard. 1H-NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, with 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 ppm, (CD3)2CO: 2.05 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad line), dd (double doublet), and dt (double triplet). Coupling constants given are reported in Hertz (Hz).

[0342] 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) detecting at 214 nm and 254 nm and an ion trap (ESI source). All compound names, except for reagents, were generated by ChemDraw® 19.1.

[0343] In the examples below, the following abbreviations are used: [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0344] Compound synthesis

[0345] Example 1: 5-ethynyl-6-fluoro-4-(11-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazolin-10-yl)naphthalen-2-ol [ka]

[0346] Step 1: 7-Bromo-4-chloro-5,8-difluoro-2-(methylthio)quinazoline [ka]

[0347] To a suspension of 7-bromo-5,8-difluoro-2-(methylthio)quinazolin-4(3H)-one (10 g, 32.6 mmol) in POCl3 (30 mL) was added DIPEA (15 mL) dropwise. The mixture was stirred at 100 °C overnight. The mixture was then cooled to room temperature and concentrated in vacuo. The mixture was diluted with DCM, and the solid was filtered off to give the crude product, which was further purified by silica gel column chromatography (80 g, elution with PE / EtOAc = 100%:0% to 75%:25%) to give the title compound (6.9 g). MS (ESI, m / e) [M+H] + 324.4.

[0348] Step 2: 3-((7-bromo-5,8-difluoro-2-(methylthio)quinazolin-4-yl)(methyl)amino)propan-1-ol [ka]

[0349] To a solution of 7-bromo-4-chloro-5,8-difluoro-2-(methylthio)quinazoline (1.2 g, 3.7 mmol) and 3-(methylamino)propan-1-ol (0.4 g, 4.6 mmol) in DCM (20 mL) was added DIEA (1.43 g, 11.1 mol) at 0 °C. The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo, and the residue was purified by silica gel column chromatography (12 g, eluted with PE / EtOAc = 100%:0% to 0%:100%) to give the title compound (540 mg). MS (ESI, m / e) [M+H] + 378.0.

[0350] Step 3: 10-Bromo-11-fluoro-4-methyl-2-(methylthio)-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazoline [ka]

[0351] To a solution of 3-((7-bromo-5,8-difluoro-2-(methylthio)quinazolin-4-yl)(methyl)amino)propan-1-ol (540 mg, 1.4 mmol) in THF (20 mL) at 0° C., NaH (171 mg, 4.3 mmol, 60%) was added portionwise, and the mixture was stirred at 55° C. overnight. The mixture was cooled to room temperature, quenched with ice water (2.5 mL), and extracted with EtOAc (20 mL*3). The combined organic layer was concentrated in vacuo, and the residue was purified by silica gel column chromatography (12 g, elution with PE / EtOAc=100%:0% to 0%:100%) to give the title compound (190 mg). MS (ESI, m / e) [M+H] + 358.1.

[0352] Step 4: 10-Bromo-11-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazoline [ka]

[0353] To a mixture of 10-bromo-11-fluoro-4-methyl-2-(methylthio)-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazoline (190 mg, 0.5 mmol) in DCM (10 mL) was added m-CPBA (104 mg, 0.6 mmol) in portions at 0° C. The mixture was stirred at 0° C. for 2 hours. Meanwhile, to a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (253 mg, 1.59 mmol) in THF (5 mL) at 0° C., LiHMDS (1.06 mL, 1.06 mmol, 1 M in THF) was added dropwise. The mixture was stirred at room temperature for an additional 30 minutes, and the resulting THF mixture was added dropwise to the DCM solution. The mixture was stirred at room temperature for 2 hours, quenched with MeOH (5 mL), and concentrated in vacuo. The residue was purified by silica chromatography column (eluted with DCM / MeOH=90%:10%) to give the title compound (48 mg). MS (ESI, m / e) [M+H] + 469.3.

[0354] Step 5: 11-fluoro-10-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazoline [ka]

[0355] 10-Bromo-11-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazoline (48 mg, 0.1 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5 A mixture of 5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (105 mg, 0.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (8.5 mg, 0.01 mmol), and NaHCO (17.3 mg, 0.2 mmol) was stirred at 90 °C overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography column (4 g, eluted with DCM / MeOH = 90%:10%) to give the crude product, which was further purified by prep-TLC (DCM / MeOH = 17 / 1, twice) to give the title compound (10 mg). MS (ESI, m / e) [M+H] + 775.7.

[0356] Step 6: 10-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-11-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazoline [ka]

[0357] To a solution of 11-fluoro-10-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazoline (10 mg, 0.01 mmol) in DMF (5 mL) was added CsF (10 mg, 0.06 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was then filtered, and the filtrate was concentrated in vacuo to give the crude product, which was used in the next step without further purification (13 mg, crude). MS (ESI, m / e) [M+H] + 619.5.

[0358] Step 7: 5-ethynyl-6-fluoro-4-(11-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazolin-10-yl)naphthalen-2-ol [ka]

[0359] To a solution of 10-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-11-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazoline (13 mg, 0.021 mmol) in dioxane (4 mL) was added HCl (2 mL, 4 M in dioxane). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and purified by prep-HPLC to give the title product (4.2 mg). 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 7.99-7.90 (m, 1H), 7.50-7.39 (m, 1H), 7.37-7.29 (m, 1H), 7.07 (s, 1H), 6.70-6.62 (m, 1H), 5.36-5.20 (m, 1H), 4.32-4.17 (m, 2H), 4.12-4.06 (m, 1H), 4.00-3.92 (m, 2H), 3.64-3.50 (m, 2H), 3.27 (s, 3H), 3.14-3.06 (m, 2H), 3.02 (s, 1H), 2.85-2.83 (m, 1H), 2.17-2.07 (m, 1H), 2.05-1.93 (m, 4H), 1.89-1.71 (m, 3H). MS (ESI, m / e) [M+H] + 575.2.

[0360] Example 2: 2-amino-7-fluoro-4-(11-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-methyl-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazolin-10-yl)benzo[b]thiophene-3-carbonitrile [ka]

[0361] Example 2 was prepared by a similar procedure as described in Example 1 (steps 5 / 6 / 7) by substituting ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane with tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate to afford the title product (0.84 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.06-7.99 (s, 2H), 7.31-7.21 (m, 1H), 7.10-7.06 (m, 1H), 6.71-6.60 (m, 1H), 5.36-5.20 (m, 1H), 4.30 -4.00 (m, 4H), 3.59-3.54 (s, 2H), 3.20-3.00 (m, 2H), 2.89-2.82 (m, 2H), 2.25-1.76 (m, 7H). MS (ESI, m / e) [M+H] + 581.4.

[0362] Example 3: 3-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-methyl-4-(trifluoromethyl)aniline [ka]

[0363] Step 1: 2-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)ethan-1-ol [ka]

[0364] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (296 mg, 1 mmol) in DCM (15 mL) at 0° C., DIPEA (387 mg, 3 mmol) and 2-(methylamino)ethan-1-ol (68 mg, 0.9 mmol) were added. The resulting mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (PE:EA=2:1) ​​to give the title product (211 mg). MS (ESI, m / e) [M+H] + 337.1.

[0365] Step 2: 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene [ka]

[0366] To a solution of 2-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)ethan-1-ol (210 mg, 0.625 mmol) in THF (25 mL) at room temperature, NaH (50 mg, 1.25 mmol) was added and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was quenched with 2 drops of ice water and the solvent was evaporated. The residue was purified by silica chromatography column (PE:EA=1:1) to give the title product (40 mg). MS (ESI, m / e) [M+H] + 301.1.

[0367] Step 3: 5-chloro-4-fluoro-10-methyl-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene [ka]

[0368] To a solution of 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (40 mg, 0.13 mmol) in DCM (10 mL) at room temperature, m-CPBA (27 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Upon completion, the mixture was diluted with water (10 mL). The aqueous layer was extracted with DCM (20 mL*3), and the combined organic layers were concentrated to give the residue (50 mg, crude) as the title compound. MS (ESI, m / e) [M+1] + 317.1

[0369] Step 4: 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene [ka]

[0370] At room temperature, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (75 mg, 0.474 mmol) in 10 mL of THF, LiHMDS (1N in THF, 0.3 mL, 0.3 mmol) was added, which was stirred at room temperature for 1 hour. Then, a solution of 5-chloro-4-fluoro-10-methyl-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (50 mg, 0.158 mmol) in THF (10 mL) was added to the reaction mixture, which was stirred at 0 ° C. for 1 hour and then to room temperature. After completion, the solvent was evaporated. The residue was purified by silica chromatography column (DCM:MeOH = 10:1) to give the title product (27 mg, crude). MS (ESI, m / e) [M+H] + 412.1.

[0371] Step 5: 3-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-methyl-4-(trifluoromethyl)aniline

[0372] A mixture of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (36 mg, 0.088 mmol), dioxane / HO (10 mL / 2 mL), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (106 mg, 0.352 mmol), NaHCO (22 mg, 0.26 mmol), and Pd(dtbpf)Cl (4 mg, 0.0088 mmol) was stirred at 95 °C for 3 h. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give a residue which was further purified by Prep-HPLC to give the title product (22.7 mg). 1 H NMR (500 MHz, CD3OD) δ 6.71 - 6.65 (m, 1H), 6.44 - 6.38 (m, 1H), 5.44 - 5.33 (m, 1H), 4.62 - 4.54 (m, 2H), 4.43 - 4.35 (m, 2H), 4.06 - 3.94 (m, 2H), 3.57 - 3.36 (m, 6H), 3.19 - 3.12 (m, 1H), 2.50 - 1.93 (m, 9H). MS (ESI, m / e) [M+H] + 571.2.

[0373] Example 4: 3-chloro-5-(11-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0374] Step 1: 3-(cyclopropylamino)propan-1-ol [ka]

[0375] At room temperature, cyclopropanamine (855 mg, 15 mmol) was mixed with 3-bromopropan-1-ol (417 mg, 3 mmol), and the mixture was stirred at 50° C. overnight. Upon completion, the mixture was concentrated to give a residue (658 mg, crude) as the title compound. MS (ESI, m / e) [M+H] + 116.1.

[0376] Step 2: 3-(cyclopropyl(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)amino)propan-1-ol [ka]

[0377] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (498 mg, 1.69 mmol) in DCM (25 mL) at 0° C., DIPEA (545 mg, 4.23 mmol) and 3-(cyclopropylamino)propan-1-ol (196 mg, 1.69 mmol) were added. The resulting mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (PE:EA=1:1) to give the title product (230 mg). MS (ESI, m / e) [M+H] + 377.1.

[0378] Step 3: 5-chloro-11-cyclopropyl-4-fluoro-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0379] To a solution of 3-(cyclopropyl(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)amino)propan-1-ol (230 mg, 0.61 mmol) in THF (25 mL) at room temperature was added NaH (50 mg, 1.22 mmol). The mixture was stirred at room temperature for 2 hours, then quenched with two drops of ice water, and the solvent was evaporated. The residue was purified by silica chromatography column (PE:EA=3:1) to give the title product (330 mg, crude). MS (ESI, m / e) [M+H] + 341.1.

[0380] Step 4: 5-chloro-11-cyclopropyl-4-fluoro-2-(methylsulfinyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0381] To a solution of 5-chloro-11-cyclopropyl-4-fluoro-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (330 mg, 0.62 mmol) in DCM (20 mL) at room temperature, m-CPBA (105 mg, 0.62 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Upon completion, the mixture was diluted with water (10 mL). The aqueous layer was extracted with DCM (20 mL*3), and the combined organic layers were concentrated to give the residue (339 mg, crude) as the title compound. MS (ESI, m / e) [M+1] + 357.1.

[0382] Step 5: 5-chloro-11-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0383] At room temperature, LiHMDS (1N in THF, 1.9 mL, 1.9 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (453 mg, 2.85 mmol) in 20 mL of THF, and the mixture was stirred at room temperature for 1 hour. Then, a solution of 5-chloro-11-cyclopropyl-4-fluoro-2-(methylsulfinyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (339 mg, 0.95 mmol) in THF (10 mL) was added to the reaction mixture, and the mixture was stirred at 0 ° C. for 1 hour up to room temperature. After completion, the solvent of the reaction mixture was evaporated. The residue was purified by silica chromatography column (DCM:MeOH = 10:1) to give the title product (44 mg, crude). MS (ESI, m / e) [M+H] + 452.1.

[0384] Step 6: 3-chloro-5-(11-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0385] To a solution of 5-chloro-11-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (22 mg, 0.049 mmol) in dioxane / HO (10 / 2 mL) at room temperature was added 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (63 mg, 0.196 mmol), NaHCO (12.3 mg, 0.147 mmol), and Pd(dtbpf)Cl (3.2 mg, 0.0049 mmol), and the mixture was stirred at 95 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated, and the residue was purified by column chromatography (DCM / MeOH=10 / 1) to give the crude product, which was further purified by Prep-HPLC to give the title product (2 mg). 1 H NMR (500 MHz, CD3OD) δ 6.89 - 6.85 (m, 1H), 6.55 - 6.45 (m, 1H), 5.48 - 5.30 (m, 1H), 4.49 - 4.39 (m, 4H), 3.75 - 3.65 (m, 2H), 3.44 - 3.41 (m, 2H), 3.24 - 3.13 (m, 3H), 2.48 - 1.93 (m, 8H), 1.09 - 0.96 (m, 4H). MS (ESI, m / e) [M+H] + 611.2.

[0386] Example 5: 4-(11-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka]

[0387] Step 1: 11-cyclopropyl-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0388] To a solution of 5-chloro-11-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (22 mg, 0.049 mmol) in dioxane / HO (10 / 2 mL) at room temperature was added ((2-fluoro To the mixture was added fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (100 mg, 0.196 mmol), NaHCO (12.3 mg, 0.147 mmol), and Pd(dtbpf)Cl (3.2 mg, 0.0049 mmol), and the mixture was stirred at 95 °C for 3 h. Upon completion, the mixture was evaporated and purified by silica chromatography column (DCM:MeOH = 20:1) to give the title product (23 mg, crude). MS (ESI, m / e) [M+H] + 802.4.

[0389] Step 2: 11-cyclopropyl-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0390] To a solution of 11-cyclopropyl-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (23 mg, 0.029 mmol) in DMF (1.5 mL) at room temperature was added CsF (22 mg, 0.145 mmol). Upon completion, the mixture was diluted with water (10 mL). The aqueous layer was extracted with DCM (20 mL*3) and the combined organic layers were concentrated to give the residue (12 mg, crude) as the title compound. MS (ESI, m / e) [M+H] + 646.3

[0391] Step 3: 4-(11-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0392] To a solution of 11-cyclopropyl-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (12 mg, 0.019 mmol) in EtOAc (5 mL) at room temperature was added HCl (4 N, 1 mL). The resulting mixture was concentrated at room temperature, the pH was adjusted to 7 with NaCO, and the organic layer was concentrated to give a residue, which was further purified by Prep-HPLC to give the title product (5.6 mg). 1H NMR (500 MHz, DMSO-d6) δ 10.50 - 9.70 (m, 1H), 7.97 - 7.94 (m, 1H), 7.47 - 7.43 (m, 1H), 7.39 - 7.33 (m, 1H), 7.23 -7.17 (m, 1H), 5.34 - 5.24 (m, 1H), 4.34 - 4.28 (m, 2H), 4.19 - 4.17 (m, 1H), 4.12 - 4.06 (m, 2H), 3.65 - 3.62 (m, 1H), 3.19 - 3.03 (m, 3H), 2.88 - 2.80 (m, 1H), 2.19 - 1.75 (m, 8H), 1.02 - 0.83 (m, 4H). MS (ESI, m / e) [M+H] + 602.3.

[0393] Example 6: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0394] Step 1: 3-(methylamino)butan-1-ol [ka]

[0395] To a solution of tert-butyl (4-hydroxybutan-2-yl)carbamate (1890 mg, 10 mmol) in THF (25 mL) at 0° C., LiAlH (650 mg, 17 mmol) was added, and the mixture was stirred at 70° C. overnight. Upon completion, the mixture was cooled to room temperature, sodium sulfate decahydrate was added, and stirred for 0.5 h. The resulting mixture was filtered, and the organic phase was concentrated to give a residue (707 mg, crude) as the title compound. MS (ESI, m / e) [M+H] + 104.1.

[0396] Step 2: 7-chloro-8-fluoro-5-(3-(methylamino)butoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol [ka]

[0397] To a solution of 3-(methylamino)butan-1-ol (153 mg, 1.5 mmol) in THF (10 mL) was added sodium hydride (80 mg, 2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Then, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (279 mg, 1 mmol) in THF (10 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (DCM:MeOH=10:1) to give the title product (134 mg). MS (ESI, m / e) [M+H] + 347.1.

[0398] Step 3: 5-chloro-4-fluoro-10,11-dimethyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0399] To a solution of 7-chloro-8-fluoro-5-(3-(methylamino)butoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (127 mg, 0.366 mmol) in 20 mL of DMF was added N,N-diisopropylethylamine (238 mg, 1.83 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (347 mg, 0.915 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. Then, another batch of N,N-diisopropylethylamine (708 mg, 5.49 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.47 g, 9.15 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by silica chromatography column (PE: EtOAc = 1:5) to give the title product (92 mg). MS (ESI, m / e) [M+H] + 329.1.

[0400] Step 4: 5-chloro-4-fluoro-10,11-dimethyl-2-(methylsulfinyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0401] To a solution of 5-chloro-4-fluoro-10,11-dimethyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (92 mg, 0.28 mmol) in DCM (10 mL) at room temperature, m-CPBA (53 mg, 0.31 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Upon completion, the mixture was diluted with water (10 mL). The aqueous layer was extracted with DCM (20 mL*3), and the combined organic layers were concentrated to give a residue (92 mg) as the title compound. MS (ESI, m / e) [M+H]+ 345.1.

[0402] Step 5: 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0403] At room temperature, LiHMDS (1N in THF, 0.5 mL, 0.5 mmol) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (127 mg, 0.8 mmol) in 10 mL of THF, and the mixture was stirred at room temperature for 1 hour. Then, 5-chloro-4-fluoro-10,11-dimethyl-2-(methylsulfinyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (92 mg, 0.267 mmol) in THF (10 mL) was added to the reaction mixture, and the mixture was stirred at 0 ° C. for 1 hour until it reached room temperature. After completion, the reaction mixture was evaporated. The residue was purified by silica chromatography column (DCM:MeOH = 10:1) to give the title product (27 mg). MS (ESI, m / e) [M+H] + 440.1.

[0404] Step 6: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline

[0405] To a solution of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (27 mg, 0.06 mmol) in dioxane / HO (10 / 2 mL) at room temperature, 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (77 mg, 0.24 mmol), NaHCO (15 mg, 0.18 mmol), and Pd(dtbpf)Cl (4 mg, 0.006 mmol) were added, and the mixture was stirred at 95 °C for 3 h. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give a residue which was further purified by Prep-HPLC to give the title product (4.2 mg). 1 H NMR (500 MHz, CD3OD) δ 6.88 - 6.87 (m, 1H), 6.62 - 6.34 (m, 1H), 5.44 - 5.27 (m, 1H), 4.49 - 4.30 (m, 4H), 4.10 - 3.98 (m, 1H), 3.52 - 3.33 (m, 3H), 3.29 (s, 3H), 3.15 - 3.07 (m, 1H), 2.46 - 1.90 (m, 8H), 1.49 - 1.39 (m, 3H). MS (ESI, m / e) [M+H] + 599.2.

[0406] Example 7: 2-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol [ka]

[0407] Step 1: 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine [ka]

[0408] To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.00 g, 3.57 mmol) in 15 mL of acetonitrile was added 0.5 mL of N,N-diisopropylethylamine and phosphoryl trichloride (760 mg, 5.00 mmol). The reaction was stirred at 80 °C for 16 hours, and then cooled to room temperature. The mixture was evaporated to give the title product (1.10 g, crude), which was used in the next step without purification.

[0409] Step 2: 2,2'-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)azanediyl)bis(ethan-1-ol) [ka]

[0410] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (crude 500 mg, 1.69 mmol) in 15 mL of dichloromethane at −40° C., 2,2′-azanediylbis(ethan-1-ol) (210 mg, 2.00 mmol) and 0.5 mL of N,N-diisopropylethylamine were added. The reaction was stirred at −40° C. for 4 hours, the mixture was diluted with dichloromethane and water, and the organic layers were combined, dried over sodium sulfate, and evaporated. The crude product (250 mg) was carried on to the next step without purification. MS (ESI, m / e) [M+H] + 367.4.

[0411] Step 3: 2-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol [ka]

[0412] To a solution of 2,2'-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)azanediyl)bis(ethan-1-ol) (250 mg, 0.68 mmol) in 10 mL of tetrahydrofuran at 0°C was added sodium hydride (60 mg, 1.50 mmol, 60% w / w). The reaction was stirred at room temperature for 16 hours, the mixture was diluted with dichloromethane and water, and the organic layers were combined, dried over sodium sulfate, and evaporated. The residue was purified by silica gel column to give the title compound (130 mg). MS (ESI, m / e) [M+H] + 331.2.

[0413] Step 4: 2-(5-chloro-4-fluoro-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10

[0414] -Tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol [ka]

[0415] To a solution of 2-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol (130 mg, 0.39 mmol) in 5 mL of dichloromethane at 0° C. was added 3-chloroperbenzoic acid (87 mg, 0.50 mmol). The reaction was stirred at 0° C. for 2 h, the mixture was diluted with dichloromethane and water, and the organic layers were combined, dried over sodium sulfate, and evaporated. The crude product (120 mg) was carried on to the next step without purification. MS (ESI, m / e) [M+H] + 347.0.

[0416] Step 5: 2-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)

[0417] (Methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol [ka]

[0418] 2-(5-chloro-4-fluoro-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa)

[0419] To a solution of 1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol (crude 120 mg, 0.35 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (160 mg, 1.00 mmol) was added. Then, lithium bis(trimethylsilyl)amide (1 mmol / L in tetrahydrofuran, 1.0 mL) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour, diluted with dichloromethane and water, and the organic layers were combined, dried over sodium sulfate, and evaporated. The residue was purified by silica gel column to give the title compound (20 mg). MS (ESI, m / e) [M+H] + 442.0.

[0420] Step 6: 2-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol

[0421] To a solution of 2-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol (20 mg, 0.05 mmol) in 2.5 mL of 1,4-dioxane and 0.5 mL of water was added 3-chloro-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-4-(trifluoromethyl)aniline (33 mg, 0.10 mmol), 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (6 mg, 0.01 mmol), and sodium bicarbonate (13 mg, 0.15 mmol). The reaction was stirred at 90°C for 6 hours, and then cooled to room temperature. It was then diluted with dichloromethane and water, and the organic layers were combined, dried over sodium sulfate, and evaporated. The residue was purified by prep-HPLC to give the title compound (0.6 mg). 1 H NMR (500 MHz, DMSO-d6) δ 6.86-6.85 (m, 1H), 6.45-6.44 (m, 1H), 6.30 (s, 2H), 5.37-5.18 (m, 1H), 4.56-4.50 (m, 2H), 4.13-3.82 (m, MS (ESI, m / e) [M+H] + 601.4.

[0422] Example 8: 3-chloro-5-(10-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0423] Step 1: 2-(cyclopropylamino)ethan-1-ol [ka]

[0424] To a solution of 2-bromoethan-1-ol (1.24 g, 10.0 mmol) in 30 mL of ethanol was added cyclopropanamine (1.72 g, 30.0 mmol). The reaction was stirred at 60° C. for 16 h, the mixture was cooled to room temperature, and it was evaporated to give the crude product (1.20 g), which was carried on to the next step without purification.

[0425] Step 2: 2-(cyclopropyl(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)amino)ethan-1-ol [ka]

[0426] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (crude 500 mg, 1.69 mmol) in 15 mL of dichloromethane at 0° C., 2-(cyclopropylamino)ethan-1-ol (crude 300 mg, 2.97 mmol) and 0.5 mL of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature for 4 hours, and the mixture was diluted with dichloromethane and water. The organic layers were combined, dried over sodium sulfate, and evaporated. The crude product was purified by silica gel column to give the title product (80 mg). MS (ESI, m / e) [M+H] + 363.4.

[0427] Step 3: 5-chloro-10-cyclopropyl-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene [ka]

[0428] To a solution of 2-(cyclopropyl(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)amino)ethan-1-ol (80 mg, 0.22 mmol) in 10 mL of tetrahydrofuran at 0° C. was added sodium hydride (24 mg, 0.60 mmol, 60% w / w). The reaction was stirred at room temperature for 16 hours, and the mixture was diluted with dichloromethane and water. The organic layers were combined, dried over sodium sulfate, and evaporated. The residue was purified by silica gel column to give the title compound (50 mg). MS (ESI, m / e) [M+H] + 327.3.

[0429] Step 4: 5-chloro-10-cyclopropyl-4-fluoro-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene [ka]

[0430] To a solution of 5-chloro-10-cyclopropyl-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (50 mg, 0.15 mmol) in 5 mL of dichloromethane at 0 °C, 3-chloroperbenzoic acid (31 mg, 0.20 mmol) was added. The reaction was stirred at 0 °C for 2 h, and the mixture was diluted with dichloromethane and water. The organic layers were combined, dried over sodium sulfate, and evaporated. The crude product (50 mg) was carried on to the next step without purification. MS (ESI, m / e) [M+H] + 349.2.

[0431] Step 5: 5-chloro-10-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene [ka]

[0432] To a solution of 5-chloro-10-cyclopropyl-4-fluoro-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (crude 50 mg, 0.14 mmol) in 5 mL of tetrahydrofuran, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (80 mg, 0.50 mmol) was added. Then, lithium bis(trimethylsilyl)amide (1 mmol / L in tetrahydrofuran, 0.5 mL) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour, and the mixture was diluted with dichloromethane and water. The organic layers were combined, dried over sodium sulfate, and evaporated. The residue was purified by silica gel column to give the title compound (22 mg). MS (ESI, m / e) [M+H] + 438.0.

[0433] Step 6: 3-chloro-5-(10-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline

[0434] 5-chloro-10-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H) in 2.5 mL of 1,4-dioxane and 0.5 mL of water

[0435] To a solution of 3-chloro-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-4-(trifluoromethyl)aniline (33 mg, 0.10 mmol), 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (6 mg, 0.01 mmol), and sodium bicarbonate (13 mg, 0.15 mmol) were added. The reaction was stirred at 90 °C for 6 hours, and the reaction was cooled to room temperature. It was then diluted with dichloromethane and water, and the organic layers were combined, dried over sodium sulfate, and evaporated. The residue was purified by prep-HPLC to give the title compound (0.7 mg). 1 H NMR (500 MHz, DMSO-d6) δ 6.86-6.84 (m, 1H), 6.47-6.44 (m, 1H), 6.29 (s, 2H), 5.37-5.20 (m, 1H), 4.55-4.47 (m, 2H), 4.20-4.07 (m, 2H), 3.96-3.91 (m, 2H), 3.15-3.00 (m, 4H), 2.88-2.79 (m, 1H), 2.17-1.97 (m, 3H), 1.88-1.75 (m, 3H), 0.95-0.90 (m, 2H), 0.80-0.74 (m, 2H). MS (ESI, m / e) [M+H] + 597.5.

[0436] Example 9: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0437] Step 1: 3-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)propan-1-ol [ka]

[0438] To a stirred solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.0 mmol) in DCM (10 mL) at 0 °C, DIEA (387 mg, 3.0 mmol) and 3-(methylamino)propan-1-ol (89 mg, 1.0 mmol) were added, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc = 4:1 to 1:2) to give the desired product (213 mg). MS (ESI, m / e) [M+H] + 351.1.

[0439] Step 2: 5-chloro-4-fluoro-11-methyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0440] To a stirred solution of 3-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)propan-1-ol (213 mg, 0.61 mmol) in THF (6 mL) at 0° C., NaH (48 mg, 1.2 mmol, 60%) was added, and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with HO and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash chromatography (PE / EtOAc=10:1 to 1:1) to give the product (186 mg). MS (ESI, m / e) [M+H] + 315.3.

[0441] Step 3: 5-chloro-4-fluoro-11-methyl-2-(methylsulfinyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0442] To a stirred solution of 5-chloro-4-fluoro-11-methyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (120 mg, 0.38 mmol) in DCM (6 mL) at 0 °C, m-CPBA (93 mg, 0.46 mmol, 85%) was added, and the resulting mixture was stirred at 0 °C for 10 min. The reaction was quenched with aq. NaSO and then extracted with DCM. The organic layer was washed with sat. aq. NaHCO and brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 331.1.

[0443] Step 4: 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0444] To a stirred solution of 5-chloro-4-fluoro-11-methyl-2-(methylsulfinyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (0.38 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (120 mg, 0.76 mmol) in THF (6 mL) at 0 °C, LiHMDS (0.76 mL, 0.76 mmol, 1 M in THF) was added dropwise, and the resulting mixture was stirred at 0 °C for 20 min. The reaction was quenched with aqueous NH Cl and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na SO , and concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the product (125 mg). MS (ESI, m / e) [M+H] + 426.2.

[0445] Step 5: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline

[0446] To a mixture of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (25 mg, 0.06 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (43 mg, 0.12 mmol, 89%), Pd(dtbpf)Cl (7.8 mg, 0.012 mmol), and NaHCO (15 mg, 0.18 mmol), dioxane (2.0 mL) and HO (0.4 mL) were added. The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 5:1) and then prep-HPLC to give the title product (6.2 mg). 1 H NMR (500 MHz, CD3OD) δ 6.87 (s, 1H), 6.50 (s, 1H), 5.42 - 5.24 (m, 1H), 4.52 - 4.21 (m, 4H), 3.73 - 3.62 (m, 2H), 3.40 (s, 3H), 3.11 - 3.02 (m, 1H), 2.43 - 1.85 (m, 8H). MS (ESI, m / e) [M+H] + 585.4.

[0447] Example 10: 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)naphthalen-2-ol [ka]

[0448] Step 1: 4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0449] To a mixture of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (50 mg, 0.12 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (123 mg, 0.24 mmol), Pd(dtbpf)Cl (15.6 mg, 0.024 mmol), and NaHCO (30 mg, 0.36 mmol), dioxane (5.0 mL) and HO (1.0 mL) were added. The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 10:1) to give the title product (75 mg). MS (ESI, m / e) [M+H] + 776.5.

[0450] Step 2: 5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0451] To a stirred solution of 4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (75 mg, 0.10 mmol) in DMF (3 mL) was added CsF (152 mg, 1.0 mmol), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and HO and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The crude material was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 620.3.

[0452] Step 3: 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)naphthalen-2-ol [ka]

[0453] To a stirred solution of 5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (0.10 mmol) in DCM (5.0 mL) at 0° C., 4 N HCl (in dioxane) (1.0 mL) was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and basified with DIEA. The residue was purified by flash chromatography (DCM / MeOH=100:1 to 10:1) and then by prep-HPLC to give the product (19.7 mg). 1 H NMR (500 MHz, CD3OD) δ 7.87 - 7.78 (m, 1H), 7.37 - 7.21 (m, 3H), 5.55 - 5.32 (m, 1H), 4.58 - 4.35 (m, 4H), 3.83 - 3.50 (m, 6H), 3.44 (s, 3H), 2.60 - 1.97 (m, 8H). MS (ESI, m / e) [M+H] + 576.8.

[0454] Example 11: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-10,11-dihydro-8H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-9,3′-oxetane]-1(11a),2,3a,3a1(6a),5-pentaen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0455] Step 1: (3-(((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)oxetan-3-yl)methanol [ka]

[0456] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (0.85 g, 2.9 mmol) in DCM (30 mL) at 0° C., DIPEA (1.1 g, 0.85 mmol) and (3-((methylamino)methyl)oxetan-3-yl)methanol (374 mg, 2.9 mmol) were added. The resulting mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (PE: EtOAc = 2:1) to give the title product (600 mg). MS (ESI, m / e) [M+H] + 393.3.

[0457] Step 2: 5-chloro-4-fluoro-11-methyl-2-(methylthio)-10,11-dihydro-8H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-9,3'-oxetane]-1(11a),2,3a,3a1(6a),5-pentaene [ka]

[0458] To a solution of (3-(((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)methyl)oxetan-3-yl)methanol (600 mg, 1.5 mmol) in THF (25 mL) at room temperature, LiHMDS (1N in THF) (1.5 mL, 1.5 mmol) was added and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was evaporated. The residue was purified by silica chromatography column (PE: EtOAc = 1:1) to give the title product (450 mg). MS (ESI, m / e) [M+H] + 357.1.

[0459] Step 3: 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-10,11-dihydro-8H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-9,3'-oxetane]-1(11a),2,3a,3a1(6a),5-pentaene [ka]

[0460] To a solution of 5-chloro-4-fluoro-11-methyl-2-(methylthio)-10,11-dihydro-8H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-9,3′-oxetane]-1(11a),2,3a,3a1(6a),5-pentaene (450 mg, 1.26 mmol) in DCM (20 mL) at room temperature, m-CPBA (231 mg, 1.51 mmol) was added, and the mixture was stirred at room temperature for 1 h as solution 1. Meanwhile, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (602 mg, 3.79 mmol) in 20 mL of THF at room temperature, LiHMDS (1N in THF, 2.5 mL, 2.5 mmol) was added, which was stirred at room temperature for 1 hour as solution 2. Then, solution 2 was added to solution 1 at room temperature, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was evaporated. The residue was purified by silica chromatography column (DCM:MeOH=10:1) to give the title product (180 mg). MS (ESI, m / e) [M+H] + 468.2.

[0461] Step 4: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-10,11-dihydro-8H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-9,3'-oxetane]-1(11a),2,3a,3a1(6a),5-pentaen-5-yl)-4-(trifluoromethyl)aniline

[0462] 5-Chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-10,11-dihydro-8H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-9,3'-oxetane]-1(11a),2,3a,3a1(6a),5- To a solution of pentaene (60 mg, 0.128 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (82 mg, 0.256 mmol), NaHCO (2.5 mg, 0.256 mmol), and Pd(dtbpf)Cl (16.6 mg, 0.0256 mmol) were added, and the mixture was stirred at 100° C. for 3 h. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give a residue that was further purified by Prep-HPLC to give the title product (4.43 mg). 1 H NMR (500 MHz, CD3OD) δ 6.96 - 6.81 (m, 1H), 6.55 - 6.40 (m, 1H), 5.48 - 5.26 (m, 1H), 4.74 - 4.56 (m, 5H), 4.40 - 4.26 (m, 2H), 4.01 - 3.92 (m, 2H), 3.45 - 3.32 (m, 3H), 3.13 - 3.05 (m, 1H), 2.41 - 1.88 (m, 8H). MS (ESI, m / e) [M+H] + 327.2.

[0463] Example 12: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0464] Step 1: 1-(methylamino)propan-2-ol [ka]

[0465] To a solution of tert-butyl (2-hydroxypropyl)(methyl)carbamate (440 mg, 2.33 mmol) in DCM (10 mL) at room temperature, TFA (5 mL) was added and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was evaporated to give the title product (300 mg, crude). MS (ESI, m / e) [M+H] + 90.1.

[0466] Step 2: 1-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)propan-2-ol [ka]

[0467] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (339 mg, 1.17 mmol) in DCM (30 mL) at 0° C., DIPEA (350 mg, 2.91 mmol) and 1-(methylamino)propan-2-ol (150 mg, 1.17 mmol) were added. The resulting mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (PE: EtOAc = 1:1) to give the title product (160 mg). MS (ESI, m / e) [M+H] + 351.1.

[0468] Step 3: 5-chloro-4-fluoro-8,10-dimethyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene [ka]

[0469] To a solution of 1-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)propan-2-ol (160 mg, 0.46 mmol) in THF (25 mL) at room temperature, NaH (37 mg, 0.92 mmol) was added and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was evaporated. The residue was purified by silica chromatography column (PE: EtOAc = 1:1) to give the title product (63 mg). MS (ESI, m / e) [M+H] + 315.1.

[0470] Step 4: 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene [ka]

[0471] To a solution of 5-chloro-4-fluoro-8,10-dimethyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (63 mg, 0.2 mmol) in DCM (20 mL) at room temperature, m-CPBA (34.5 mg, 0.2 mmol) was added, and the mixture, which became Solution 1, was stirred at room temperature for 1 hour. Meanwhile, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (95.4 mg, 0.6 mmol) in 20 mL of THF at room temperature, LiHMDS (1N in THF, 0.4 mL, 0.4 mmol) was added, which became Solution 2, and the mixture was stirred at room temperature for 1 hour. Then, Solution 2 was added to Solution 1 at room temperature, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was evaporated. The residue was purified by silica chromatography column (DCM:MeOH=10:1) to give the title product (80 mg, crude). MS (ESI, m / e) [M+H] + 426.1.

[0472] Step 5: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline

[0473] To a solution of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (42.5 mg, 0.1 mmol) in dioxane / HO (10 / 2 mL) at room temperature, 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (80 mg, 0.25 mmol), NaHCO (25.2 mg, 0.3 mmol), and Pd(dtbpf)Cl (6.5 mg, 0.01 mmol) were added, and the mixture was stirred at 95 °C for 3 h. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give a residue which was further purified by Prep-HPLC to give the title product (5.8 mg). 1 H NMR (500 MHz, CD3OD) δ 6.93 - 6.91 (m, 1H), 6.58 - 6.46 (m, 1H), 5.47 - 5.28 (m, 1H), 4.78 - 4.72 (m, 1H), 4.39 - 4.30 (m, 2H), 4.01 - 3.89 (m, 2H), 3.48 (s, 3H), 3.13 - 3.06 (m, 1H), 2.46 - 1.94 (m, 6H), 1.60 - 1.52 (m, 3H). MS (ESI, m / e) [M+H] + 585.2.

[0474] Example 13: 4-(11-cyclobutyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol [ka]

[0475] Step 1: 3-(cyclobutylamino)propan-1-ol [ka]

[0476] At room temperature, cyclobutanamine (710 mg, 10 mmol) was mixed with 3-bromopropan-1-ol (278 mg, 2 mmol), and the mixture was stirred at 50° C. overnight. Upon completion, the mixture was concentrated to give the residue (500 mg, crude) as the title compound. MS (ESI, m / e) [M+H] + 130.1.

[0477] Step 2: 3-(cyclobutyl(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)amino)propan-1-ol [ka]

[0478] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (330 mg, 1.11 mmol) in DCM (20 mL) at 0° C., DIPEA (358 mg, 2.78 mmol) and 3-(cyclobutylamino)propan-1-ol (258 mg, 1 mmol) were added. The resulting mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (PE: EtOAc = 1:1) to give the title product (230 mg). MS (ESI, m / e) [M+H] + 390.1.

[0479] Step 3: 5-chloro-11-cyclobutyl-4-fluoro-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0480] To a solution of 3-(cyclobutyl(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)amino)propan-1-ol (350 mg, 0.9 mmol) in THF (25 mL) at room temperature, NaH (72 mg, 1.8 mmol) was added and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was quenched with two drops of ice water and the mixture was evaporated. The residue was purified by silica chromatography column (PE: EtOAc = 3:1) to give the title product (280 mg, crude). MS (ESI, m / e) [M+H] + 355.1.

[0481] Step 4: 5-chloro-11-cyclobutyl-4-fluoro-2-(methylsulfinyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0482] To a solution of 5-chloro-11-cyclobutyl-4-fluoro-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (280 mg, 0.79 mmol) in DCM (20 mL) at room temperature, m-CPBA (163.5 mg, 0.95 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Upon completion, the mixture was diluted with water (10 mL). The aqueous layer was extracted with DCM (20 mL*3), and the combined organic layers were concentrated to give the residue (330 mg, crude) as the title compound. MS (ESI, m / e) [M+H] + 371.1

[0483] Step 5: 5-chloro-11-cyclobutyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0484] At room temperature, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (167 mg, 1.05 mmol) in 20 mL of THF, LiHMDS (1N in THF, 0.7 mL, 0.7 mmol) was added, which was stirred at room temperature for 1 hour. Then, a solution of 5-chloro-11-cyclobutyl-4-fluoro-2-(methylsulfinyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (130 mg, 0.35 mmol) in THF (10 mL) was added to the reaction mixture, and the mixture was stirred at 0 ° C. for 1 hour up to room temperature. After completion, the reaction mixture was evaporated. The residue was purified by silica chromatography column (DCM:MeOH = 10:1) to give the title product (78 mg, crude). MS (ESI, m / e) [M+H] + 466.1.

[0485] Step 6: 11-Cyclobutyl-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0486] To a solution of 5-chloro-11-cyclobutyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (48 mg, 0.1 mmol) in dioxane / HO (10 / 2 mL) at room temperature was added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (205 mg, 0.4 mmol), NaHCO (25 mg, 0.3 mmol), and Pd(dtbpf)Cl (6.5 mg, 0.01 mmol), and the mixture was stirred at 95 °C for 3 h. Upon completion, the mixture was evaporated and purified by silica chromatography column (DCM:MeOH=20:1) to give the title product (67 mg, crude). MS (ESI, m / e) [M+H] + 816.4.

[0487] Step 7: 11-cyclobutyl-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0488] To a solution of 11-cyclobutyl-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (67 mg, 0.082 mmol) in DMF (2 mL) at room temperature was added CsF (62 mg, 0.41 mmol). Upon completion, the mixture was diluted with water (10 mL). The aqueous layer was extracted with DCM (20 mL*3) and the combined organic layers were concentrated to give the residue (66 mg, crude) as the title compound. MS (ESI, m / e) [M+H] + 660.3.

[0489] Step 7: 4-(11-cyclobutyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0490] To a solution of 11-cyclobutyl-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (33 mg, 0.05 mmol) in EtOAc (5 mL) at room temperature was added HCl (4 N, 1 mL). The resulting mixture was concentrated at room temperature, the pH was adjusted to 7 with NaCO, and the organic layer was concentrated to give a residue, which was further purified by Prep-HPLC to give the title product (5.2 mg). 1H NMR (500 MHz, CD3OD) δ 7.89 - 7.82 (m, 1H), 7.40 - 7.25 (m, 3H), 5.63 - 5.42 (m, 1H), 5.22 - 5.14 (m, 1H), 4.71 - 4.44 (m, 4H), 4.02 - 3.40 (m, 7H), 2.73 - 1.83 (m, 14H). MS (ESI, m / e) [M+H] + 616.3.

[0491] Example 14: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0492] Step 1: 4-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)butan-2-ol [ka]

[0493] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (0.85 g, 2.9 mmol) in DCM (30 mL) at 0° C., DIPEA (1.1 g, 0.85 mmol) and 4-(methylamino)butan-2-ol (346 mg, 2.9 mmol) were added. The resulting mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (PE: EtOAc = 2:1) to give the title product (450 mg). MS (ESI, m / e) [M+H] + 365.2.

[0494] Step 2: 5-chloro-4-fluoro-8,11-dimethyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0495] To a solution of 4-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)butan-2-ol (450 mg, 1.23 mmol) in THF (25 mL) at room temperature, NaH (60% in oil, 49.5 mg, 1.23 mmol) was added and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was evaporated. The residue was purified by silica chromatography column (PE: EtOAc = 1:1) to give the title product (100 mg). MS (ESI, m / e) [M+H] + 329.1.

[0496] Step 3: 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene

[0497] [ka]

[0498] To a solution of 5-chloro-4-fluoro-8,11-dimethyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (100 mg, 0.3 mmol) in DCM (20 mL) at room temperature, m-CPBA (56 mg, 0.36 mmol) was added, and the mixture, which became Solution 1, was stirred at room temperature for 1 hour. Meanwhile, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (145 mg, 0.9 mmol) in 20 mL of THF at room temperature, LiHMDS (1N in THF, 0.6 mL, 0.6 mmol) was added, which became Solution 2, and the mixture was stirred at room temperature for 1 hour. Then, Solution 2 was added to Solution 1 at room temperature, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was evaporated. The residue was purified by silica chromatography column (DCM:MeOH=10:1) to give the title product (40 mg). MS (ESI, m / e) [M+H] + 440.2.

[0499] Step 4: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline

[0500] To a solution of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (40 mg, 0.09 mmol) in dioxane / HO (10 / 2 mL) at room temperature, 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (43.8 mg, 0.136 mmol), NaHCO (15.3 mg, 0.18 mmol), and Pd(dtbpf)Cl (5.9 mg, 0.009 mmol) were added, and the mixture was stirred at 100 °C for 3 h. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give a residue which was further purified by Prep-HPLC to give the title product (1.58 mg). 1 H NMR (500 MHz, CD3OD) δ 6.92 - 6.85 (m, 1H), 6.62 - 6.37 (m, 1H), 5.43 - 5.28 (m, 1H), 4.61 - 4.49 (m, 2H), 4.43 - 4.23 (m, 2H), 3.83 - 3.73 (m, 1H), 3.57 - 3.48 (m, 1H), 3.41 - 3.39 (m, 3H), 3.13 - 3.05 (m, 1H), 2.42 - 1.84 (m, 8H), 1.48 - 1.42 (m, 3H). MS (ESI, m / e) [M+H] + 599.2.

[0501] Example 15: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0502] Step 1: 3-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpropan-1-ol [ka]

[0503] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1000 mg, 3.3 mmol) in DCM (30 mL) at 0° C., DIPEA (1300 mg, 9.9 mmol) and 2-methyl-3-(methylamino)propan-1-ol (340 mg, 3.3 mmol) were added. The resulting mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (PE: EtOAc = 1:1) to give the title product (610 mg). MS (ESI, m / e) [M+H] + 365.1.

[0504] Step 2: 5-chloro-4-fluoro-9,11-dimethyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0505] To a solution of 3-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)-2-methylpropan-1-ol (585 mg, 1.6 mmol) in THF (25 mL) at room temperature, NaH (128 mg, 3.2 mmol) was added and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was evaporated. The residue was purified by silica chromatography column (PE: EtOAc = 1:2) to give the title product (486 mg). MS (ESI, m / e) [M+H] +329.1.

[0506] Step 3: 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0507] To a solution of 5-chloro-4-fluoro-9,11-dimethyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (486 mg, 1.48 mmol) in DCM (20 mL) at room temperature, m-CPBA (255 mg, 1.48 mmol) was added, and the mixture, which became solution 1, was stirred at room temperature for 1 hour. Meanwhile, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (706 mg, 4.44 mmol) in 20 mL of THF at room temperature, LiHMDS (1N in THF, 3 mL, 3 mmol) was added, which became solution 2, which was stirred at room temperature for 1 hour. Then, solution 2 was added to solution 1 at room temperature, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was evaporated. The residue was purified by silica chromatography column (DCM:MeOH=10:1) to give the title product (417 mg, crude). MS (ESI, m / e) [M+H] + 439.1.

[0508] Step 4: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline

[0509] To a solution of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (50 mg, 0.11 mmol) in dioxane / HO (10 / 2 mL) at room temperature, 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (85 mg, 0.275 mmol), NaHCO (28 mg, 0.33 mmol), and Pd(dtbpf)Cl (7 mg, 0.011 mmol) were added, and the mixture was stirred at 95 °C for 3 h. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give a residue which was further purified by Prep-HPLC to give the title product (1.66 mg). 1 H NMR (500 MHz, CD3OD) δ 6.89 - 6.85 (m, 1H), 6.54 - 6.44 (m, 1H), 5.43 - 5.26 (m, 1H), 4.43 - 4.21 (m, 4H), 3.58 - 3.32 (m, 8H), 3.12 - 3.05 (m, 1H), 2.43 - 1.91 (m, 7H), 1.25 - 1.17 (m, 3H). MS (ESI, m / e) [M+H] + 599.2.

[0510] Example 16: 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)naphthalen-2-ol [ka]

[0511] Step 1: 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0512] To a solution of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (48 mg, 0.11 mmol) in dioxane / HO (10 / 2 mL) at room temperature, 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79 mg, 0.22 mmol), NaHCO (28 mg, 0.33 mmol), and Pd(dtbpf)Cl (7 mg, 0.011 mmol) were added, and the mixture was stirred at 95 °C for 3 h. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give the title product (36 mg). MS (ESI, m / e) [M+H] + 638.2.

[0513] Step 2: 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)naphthalen-2-ol

[0514] To a solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (36 mg, 0.056 mmol) in EtOAc (4 mL) at room temperature, HCl (4N in dioxane, 1 mL) was added, and the mixture was stirred at room temperature for 2 hours. 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 Prep-HPLC to give the title product (8.8 mg). 1 H NMR (500 MHz, CD3OD) δ 7.66 - 7.63 (m, 1H), 7.30 - 6.96 (m, 3H), 5.47 - 5.28 (m, 1H), 4.58 - 4.00 (m, 5H), 3.61 - 3.35 (m, 3H), 3.32 - 3.28 (m, 3H), 3.16 - 3.12 (m, 1H), 2.61 - 1.96 (m, 8H), 1.48 - 1.42 (m, 3H), 0.91 - 0.85 (m, 3H). MS (ESI, m / e) [M+H] + 594.3.

[0515] Example 17: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-(2-(methylamino)ethyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline

[0516] [ka]

[0517] Step 1: tert-Butyl (2-((3-hydroxypropyl)amino)ethyl)(methyl)carbamate

[0518] [ka]

[0519] A solution of 3-bromopropan-1-ol (2.1 g, 10 mmol) in tert-butyl (2-aminoethyl)(methyl)carbamate (3 mL) was stirred at 40° C. for 15 hours. After completion, the reaction mixture was concentrated to give a residue. The residue (4.3 g, crude) was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 233.5.

[0520] Step 2: tert-butyl (2-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(3-hydroxypropyl)amino)ethyl)(methyl)carbamate [ka]

[0521] A mixture of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.1 g, 7.17 mmol), tert-butyl (2-((3-hydroxypropyl)amino)ethyl)(methyl)carbamate (3.9 g, 21.5 mmol), and DIPEA (4.6 g, 36 mmol) in DCM (20 mL) was stirred at 25 °C for 2 h. After completion, the reaction mixture was diluted with DCM (50 mL) and washed with water (15 mL x 3). The organic layer was dried over anhydrous NaSO, filtered, and the filtrate was concentrated to give a residue. The residue was purified by silica gel (PE: EtOAc = 1:4) to give the title product (800 mg). MS (ESI, m / e) [M+H] + 494.5.

[0522] Step 3: tert-butyl (2-(5-chloro-4-fluoro-2-(methylthio)-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate

[0523] [ka]

[0524] To a solution of tert-butyl (2-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(3-hydroxypropyl)amino)ethyl)(methyl)carbamate (494 mg, 1.0 mmol) in THF (5 mL) at 0° C. was added LiHMDS (2 mL, 2 mmol). The resulting mixture was stirred at room temperature for 4 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by Prep-TLC (PE: EtOAc = 1:1) to give the title product (380 mg). MS (ESI, m / e) [M+H] + 458.4.

[0525] Step 4: tert-butyl (2-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate

[0526] [ka]

[0527] A mixture of tert-butyl (2-(5-chloro-4-fluoro-2-(methylthio)-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate (535 mg, 1.17 mmol) and m-CPBA (404 mg, 2.34 mmol) in DCM (10 mL) was stirred at 25° C. for 1 hour to give mixture 1. Meanwhile, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (80 mg, 0.5 mmol) in THF (5 mL) at 0° C., LiHMDS (0.5 mL, 0.5 mmol) was added, and the resulting mixture was stirred at 0° C. for 0.5 hours to give mixture 2. Mixture 1 was then added to mixture 2, and the resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by Prep-TLC (PE: EtOAc = 1:10) to give the title product (98 mg). MS (ESI, m / e) [M+H] + 569.5.

[0528] Step 5: tert-butyl (2-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate [ka]

[0529] A mixture of tert-butyl (2-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate (85 mg, 0.15 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (145 mg, 0.45 mmol), Pd(dtbpf)Cl (10 mg, 0.015 mmol), and NaHCO (38 mg, 0.45 mmol) in dioxane (10 mL) and water (2 mL) was stirred at 80 °C for 2 h. After completion, the reaction mixture was concentrated and purified by prep-TLC (EtOAc:MeOH=10:1) to give the title product (90 mg). MS (ESI, m / e) [M+H] + 728.5.

[0530] Step 6: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-(2-(methylamino)ethyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline

[0531] To a solution of tert-butyl (2-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate (80 mg, 0.11 mmol) in DCM (4 mL) at room temperature was added TFA (4 mL). The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by prep-HPLC to give the title product (17.0 mg). 1H NMR (500 MHz, CD3OD) δ 6.89 (s, 1H), 6.50 (s, 1H), 5.48-5.30 (m, 1H), 4.55-4.23 (m, 5H), 4.08-3.95 (m, 1H), 3.72-3.65 (m, 2H), 3.59-3.44 (m, 3H), 3.38-3.35 (m, 2H), 3.25-3.16 (m, 1H), 2.77 (s, 3H), 2.45 - 1.93 (m, 8H). MS (ESI, m / e) [M+H] + 628.3.

[0532] Example 18: 2-amino-4-(8'-chloro-10'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4'-methyl-4'H,6'H-spiro[oxetane-3,5'-[1,4]oxazepino[5,6,7-de]quinazoline]-9'-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile [ka]

[0533] Example 18 was prepared by a similar procedure as described in Example 1 by replacing 7-bromo-4-chloro-5,8-difluoro-2-(methylthio)quinazoline and 3-(methylamino)propan-1-ol with 7-bromo-4,6-dichloro-5,8-difluoro-2-(methylthio)quinazoline and (3-(methylamino)oxetan-3-yl)methanol to give the title product (0.8 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 2H), 7.28-7.19 (m, 1H), 7.19-7.09 (m, 1H), 5.39-5.28 (m, 1H), 5.05-4.97 (m, 1H), 4.97-4.82 (m, 3H), 4.65-4.50 (m, 2H), 4.20-3.98 (m, 2H), 3.48 (s, 3H), 3.16-3.00 (m, 2H), 2.92-2.79 (m, 1H), 2.17-1.95 (m, 1H), 1.93-1.75 (m, 2H), 1.51-1.41 (m, 1H), 1.34-1.26 (m, 1H), 0.89-0.82 (m, 2H). MS (ESI, m / e) [M+H] + 643.3.

[0534] Example 19: 2-amino-4-((R)-9-chloro-11-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4,5-dimethyl-4,5,6,7-tetrahydro-[1,5]oxazocino[4,3,2-de]quinazolin-10-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile [ka]

[0535] Example 19 was prepared by a similar procedure as described in Example 1 by replacing 7-bromo-4-chloro-5,8-difluoro-2-(methylthio)quinazoline and 3-(methylamino)propan-1-ol with 7-bromo-4,6-dichloro-5,8-difluoro-2-(methylthio)quinazoline and (R)-3-(methylamino)butan-1-ol to give the title product (5.8 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 2H), 7.35-7.05 (m, 2H), 5.42-5.20 (m, 1H), 4.49-4.17 (m, 2H), 4.12-4.04 (m, 1H), 4.00-3.96 (m, 1H), 3.90-3.87 (m, 1H), 3.33-3.29 (m, 1H), 3.19-3.06 (m, 5H), 2.88-2.76 (m, 1H), 2.18-2.05 (m, 4H), 2.05-1.71 (m, 4H), 1.35-1.20 (m, 3H). MS (ESI, m / e) [M+H] + 629.4.

[0536] Example 20: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-11-(2-(methylamino)ethyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0537] Step 1: 4-((tert-butyldimethylsilyl)oxy)butan-2-one [ka]

[0538] To a solution of 4-hydroxybutan-2-one (5 g, 56.82 mmol), DIPEA (20 mL, 113.64 mmol), and DMAP (685 mg, 5.62 mmol) in dichloromethane (200 mL) at 0° C., TBSOTf (16.5 g, 62.49 mmol) was added. The mixture was stirred at room temperature for 2 hours. Then, it was diluted with dichloromethane and water. The organic layers were combined, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography column (petroleum ether: EtOAc = 5:1) to give the title compound (9.1 g). MS (ESI, m / e) [M+H] + 203.5.

[0539] Step 2: tert-Butyl (2-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)ethyl)(methyl)carbamate [ka]

[0540] To a solution of 4-((tert-butyldimethylsilyl)oxy)butan-2-one (1 g, 4.95 mmol) and tert-butyl (2-aminoethyl)(methyl)carbamate (861 mg, 4.95 mmol) in MeOH (100 mL) at room temperature, sodium triacetoxyborohydride (1.3 g, 5.94 mmol) was added. The mixture was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo. The residue was purified by silica gel chromatography column (DCM:MeOH=20:1) to give the title compound (320 mg). MS (ESI, m / e) [M+H] + 361.5.

[0541] Step 3: tert-Butyl (2-((4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate [ka]

[0542] To a solution of tert-butyl (2-((4-((tert-butyldimethylsilyl)oxy)butan-2-yl)amino)ethyl)(methyl)carbamate (300 mg, 0.83 mmol) in THF (20 mL) at room temperature, TBAF (0.92 mL, 0.92 mmol, 1 M THF solution) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was purified by silica gel chromatography column (DCM:MeOH=10:1) to give the crude product (containing 150 mg of TBAF). MS (ESI, m / e) [M+1] + 247.5.

[0543] Step 4: tert-butyl (2-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate [ka]

[0544] To a stirred solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.78 mmol) in DCM (10 mL) at 0 °C, DIEA (689 mg, 5.34 mmol) and tert-butyl (2-((4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate (440 mg, 1.78 mmol) were added. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and purified by flash chromatography (petroleum ether: EtOAc = 4:1 to 1:2) to give the desired product (262 mg). MS (ESI, m / e) [M+H] + 508.5.

[0545] Step 5: tert-butyl (2-(5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate [ka]

[0546] To a stirred solution of tert-butyl (2-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate (262 mg, 0.52 mmol) in THF (10 mL) at 0 °C, NaH (31 mg, 0.77 mmol, 60%) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with HO and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash chromatography (PE / EtOAc = 10:1 to 1:1) to give the product (162 mg). MS (ESI, m / e) [M+H] + 472.5.

[0547] Step 6: tert-butyl (2-(5-chloro-4-fluoro-10-methyl-2-(methylsulfinyl)-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate [ka]

[0548] To a solution of 5-chloro-4-fluoro-11-methyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (162 mg, 0.34 mmol) in DCM (6 mL) at 0 °C, m-CPBA (84 mg, 0.41 mmol, 85%) was added, and the resulting mixture was stirred at 0 °C for 10 min. The reaction was quenched with saturated aqueous NaSO and then extracted with DCM. The organic layer was washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was used directly in the next step without further purification. MS (ESI, m / e) [M+H] +488.5.

[0549] Step 7: tert-butyl (2-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate [ka]

[0550] To a solution of tert-butyl (2-(5-chloro-4-fluoro-10-methyl-2-(methylsulfinyl)-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate (0.34 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (108 mg, 0.68 mmol) in THF (6 mL) at 0 °C, LiHMDS (0.68 mL, 0.68 mmol, 1 M in THF) was added dropwise, and the resulting mixture was stirred at 0 °C for 20 min. The reaction was quenched with saturated aqueous NH4Cl and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the product (63 mg). MS (ESI, m / e) [M+H] + 583.5.

[0551] Step 8: tert-butyl (2-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate [ka]

[0552] To a mixture of tert-butyl (2-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate (60 mg, 0.10 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (64 mg, 0.2 mmol), Pd(dtbpf)Cl (7.8 mg, 0.012 mmol), and NaHCO (15 mg, 0.18 mmol), dioxane (2.0 mL) and HO (0.4 mL) were added. The reaction mixture was stirred for 2 hours at 90° C. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 5:1) and then prep-HPLC to give the title product (30 mg).

[0553] Step 9: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-11-(2-(methylamino)ethyl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline

[0554] To a mixture of tert-butyl (2-(5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-11(8H)-yl)ethyl)(methyl)carbamate (30 mg, 0.04 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by prep-HPLC to give the formate salt of the title product (4 mg). 1 H NMR (500 MHz, CD3OD) δ 8.48 (s, 1H), 6.89-6.88 (m, 1H), 6.59-6.35 (m, 1H), 5.42-5.31 (m, 1H), 4.52-4.11 (m, 6H), 3.85-3.74 (m, MS (ESI, m / e) [M+H] + 642.5.

[0555] Example 21: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,10,11-trimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0556] Step 1: 7-chloro-8-fluoro-5-((4-(methylamino)pentan-2-yl)oxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol [ka]

[0557] To a solution of 4-(methylamino)pentan-2-ol (234 mg, 2 mmol) in THF (10 mL) at room temperature, sodium hydride (80 mg, 2 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Then, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (560 mg, 2 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (DCM:MeOH=10:1) to give the title product (260 mg). MS (ESI, m / e) [M+H] + 361.1.

[0558] Step 2: 5-chloro-4-fluoro-8,10,11-trimethyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0559] To a solution of 7-chloro-8-fluoro-5-((4-(methylamino)pentan-2-yl)oxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (260 mg, 0.72 mmol) in 20 mL of N,N-dimethylformamide at room temperature, N,N-diisopropylethylamine (278.7 mg, 2.16 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (547.2 mg, 1.44 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Then, additional N,N-diisopropylethylamine (278.7 mg, 2.16 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (547.2 mg, 1.44 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water and extracted with EtOAc, and the organic layers were combined, dried over sodium sulfate, and evaporated. The residue was purified by silica chromatography column (PE: EtOAc = 1:5) to give the title product (70 mg). MS (ESI, m / e) [M+H] + 343.1.

[0560] Step 3: 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,10,11-trimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene [ka]

[0561] To a solution of 5-chloro-4-fluoro-8,10,11-trimethyl-2-(methylthio)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (70 mg, 0.205 mmol) in 10 mL of dichloromethane was added 3-chloroperbenzoic acid (42.4 mg, 0.246 mmol), which was stirred at room temperature for 2 hours as mixture 1. Meanwhile, LiHMDS (1N in THF, 0.4 mL) was added to ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (97.6 mg, 0.614 mmol) in THF (10 mL) at room temperature, which was stirred at room temperature for 2 hours as mixture 2. Then, mixture 2 was added to mixture 1 at room temperature, and the mixture was stirred at room temperature for 2 hours. Then, it was evaporated. The residue was purified by silica chromatography column (DCM:MeOH=10:1) to give the title product (87 mg). MS (ESI, m / e) [M+H] + 454.2.

[0562] Step 4: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,10,11-trimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0563] To a mixture of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,10,11-trimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalene (87 mg, 0.192 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (124 mg, 0.384 mmol), NaHCO (48.4 mg, 0.576 mmol), and Pd(dtbpf)Cl (25 mg, 0.0384 mmol), dioxane (10 mL) and water (2 mL) were added. The mixture was stirred at 95 °C for 3 hours. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give a residue which was further purified by Prep-HPLC to give the title product (1.6 mg). 1 H NMR (500 MHz, DMSO-d6) δ 6.95 - 6.80 (m, 1H), 6.63 - 6.39 (m, 1H), 6.36 - 6.27 (m, 2H), 5.39 - 5.21 (m, 1H), 4.57 - 4.40 (m, 1H), 4.15 - 4.06 (m, 1H), 4.03 - 3.96 (m, 1H), 3.61 - 3.47 (m, 1H), 3.13 - 3.06 (m, 5H), 3.02 - 3.01 (m, 1H), 2.85 - 2.79 (m, 1H), 2.12 - 1.96 (m, 4H), 1.86 - 1.69 (m, 4H), 1.43 - 1.37 (m, 3H), 1.26 - 1.20 (m, 3H). MS (ESI, m / e) [M+H] + 613.2.

[0564] Example 22: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0565] Example 22 was prepared by a similar procedure as described in Example 15 by substituting 2-(methylamino)propan-1-ol for 2-methyl-3-(methylamino)propan-1-ol to afford the title product (4 mg). 1 H NMR (500 MHz, DMSO-d6) δ 6.85 (s, 1 H), 6.54-6.40 (m, 1 H), 6.29 (s, 2 H), 5.36-5.20 (m, 1 H), 4.55-4.40 (m, 2 H), 4.13-3.99 (m, 3 H), 3.33-3.29 (m, 2 H), 3.14-3.01 (m, 3 H), 2.85-2.76 (m, 1 H), 2.14-1.96 (m, 3 H), 1.88-1.76 (m, 3 H), 1.32-1.22 (m, 4 H). MS (ESI, m / e) [M+H] + 585.4.

[0566] Example 23: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3′-oxetane]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0567] Step 1: 7-chloro-8-fluoro-5-((3-(methylamino)oxetan-3-yl)methoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol [ka]

[0568] To a solution of (3-(methylamino) oxetan-3-yl)methanol (412 mg, 4 mmol) in THF (20 mL) at room temperature, sodium hydride (100 mg, 5 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Then, 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (558 mg, 2 mmol) in THF (20 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (DCM:MeOH=10:1) to give the title product (826 mg, crude). MS (ESI, m / e) [M+H] + 361.1.

[0569] Step 2: 5-chloro-4-fluoro-10-methyl-2-(methylthio)-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-oxetane]-1(10a),2,3a,3a1(6a),5-pentaene [ka]

[0570] At room temperature, to a solution of 7-chloro-8-fluoro-5-((3-(methylamino)oxetan-3-yl)methoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (390 mg, 1.08 mmol) in 30 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (774 mg, 6 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1100 mg, 3 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Then, it was diluted with water and extracted with EtOAc, and the organic layers were combined, dried over sodium sulfate, and evaporated. The residue was purified by silica chromatography column (PE: EtOAc = 1:5) to give the title product (457 mg, crude). MS (ESI, m / e) [M+H] + 343.1.

[0571] Step 3: 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-oxetane]-1(10a),2,3a,3a1(6a),5-pentaene [ka]

[0572] To a solution of 5-chloro-4-fluoro-10-methyl-2-(methylthio)-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3′-oxetane]-1(10a),2,3a,3a1(6a),5-pentaene (200 mg, 0.58 mmol) in DCM (15 mL) at room temperature, m-CPBA (99.7 mg, 0.58 mmol) was added, and the mixture was stirred at room temperature for 1 h as mixture 1. Meanwhile, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (277 mg, 1.74 mmol) in 15 mL of THF at room temperature, LiHMDS (1N in THF, 1.16 mL, 1.16 mmol) was added, which became mixture 2, and stirred at room temperature for 1 hour. Then, mixture 2 was added to mixture 1 at room temperature, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was evaporated. The residue was purified by silica chromatography column (DCM:MeOH=10:1) to give the title product (145 mg). MS (ESI, m / e) [M+H] + 454.2.

[0573] Step 4: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-oxetane]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)-4-(trifluoromethyl)aniline

[0574] 5-Chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-oxetane]-1(10a),2,3a,3a1(6a),5- To a solution of pentaene (55 mg, 0.12 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (77 mg, 0.24 mmol), NaHCO (30 mg, 0.35 mmol), and Pd(dtbpf)Cl (7.8 mg, 0.012 mmol) were added, and the mixture was stirred at 95° C. for 3 h. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give a residue that was further purified by Prep-HPLC to give the title product (5.29 mg). 1 H NMR (500 MHz, CD3OD) δ 6.92 - 6.84 (m, 1H), 6.52 - 6.42 (m, 1H), 5.44 - 5.26 (m, 1H), 5.13 - 5.11 (m, 2H), 4.93 - 4.90 (m, 2H), 4.74 - 4.69 (m, 2H), 4.42 - 4.33 (m, 2H), 3.66 (s, 3H), 3.45 - 3.35 (m, 3H), 3.13 - 3.08 (m, 1H), 2.44 - 1.89 (m, 6H). MS (ESI, m / e) [M+H] + 613.2.

[0575] Example 24: 3-chloro-5-(4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaen-5'-yl)-4-(trifluoromethyl)aniline [ka]

[0576] Step 1: (1-(methylamino)cyclobutyl)methanol [ka]

[0577] To a solution of 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (1.5 g, 6.98 mmol) in THF (25 mL) at 0 °C, LiAlH (663 mg, 17.48 mmol) was added and the mixture was stirred at 70 °C overnight. Upon completion, the mixture was cooled to room temperature, sodium sulfate decahydrate was added, and stirred for 0.5 h. The resulting mixture was filtered and the organic phase was concentrated to give a residue (721 mg, crude) as the title compound. MS (ESI, m / e) [M+H] + 130.1.

[0578] Step 2: (1-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclobutyl)methanol [ka]

[0579] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1540 mg, 2.6 mmol) in DCM (25 mL) at 0° C., DIPEA (671 mg, 5.2 mmol) and (1-(methylamino)cyclobutyl)methanol (300 mg, 2.6 mmol) were added. The resulting mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature. After completion, the reaction mixture was concentrated to give a residue. The residue was purified by flash silica column (PE: EtOAc = 1:1) to give the title product (498 mg). MS (ESI, m / e) [M+H] + 377.1.

[0580] Step 3: 5'-chloro-4'-fluoro-10'-methyl-2'-(methylthio)-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaene [ka]

[0581] To a solution of (1-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)cyclobutyl)methanol (498 mg, 1.32 mmol) in THF (25 mL) at room temperature, LiHMDS (1.7 mL, 1.7 mmol) was added and the mixture was stirred at room temperature for 2 hours. Upon completion, the mixture was evaporated. The residue was purified by silica chromatography column (PE: EtOAc = 1:2) to give the title product (97 mg). MS (ESI, m / e) [M+H] + 341.1.

[0582] Step 4: 5'-chloro-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaene [ka]

[0583] To a solution of 5'-chloro-4'-fluoro-10'-methyl-2'-(methylthio)-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaene (97 mg, 0.285 mmol) in DCM (10 mL) at room temperature, m-CPBA (49 mg, 0.285 mmol) was added, and the mixture was stirred at room temperature for 1 h as mixture 1. Meanwhile, to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (136 mg, 0.855 mmol) in 10 mL of THF at room temperature, LiHMDS (1N in THF, 0.6 mL, 0.6 mmol) was added, which became mixture 2, and stirred at room temperature for 1 hour. Then, mixture 2 was added to mixture 1 at room temperature, and the mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was evaporated. The residue was purified by silica chromatography column (DCM:MeOH=10:1) to give the title product (75 mg). MS (ESI, m / e) [M+H] + 452.2.

[0584] Step 5: 3-chloro-5-(4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaen-5'-yl)-4-(trifluoromethyl)aniline

[0585] 5'-chloro-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a in dioxane / HO (10 / 2 mL) at room temperature To a solution of 1'(6a'),5'-pentaene (45 mg, 0.1 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (80 mg, 0.25 mmol), NaHCO (25 mg, 0.3 mmol), and Pd(dtbpf)Cl (13 mg, 0.02 mmol) were added, and the mixture was stirred at 95 °C for 3 h. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH = 10 / 1) to give a residue that was further purified by prep-HPLC to give the title product (9 mg). 1 H NMR (500 MHz, CD3OD) δ 6.92 - 6.84 (m, 1H), 6.49 (s, 1H), 5.49 - 5.30 (m, 1H), 4.71 - 4.59 (m, 2H), 4.44 - 4.36 (m, 2H), 3.59 - 3.39 (m, 6H), 3.20 - 3.15 (m, 1H), 2.76 -2.65 (m, 2H), 2.50 - 1.93 (m, 10H). MS (ESI, m / e) [M+H] + 611.2.

[0586] Example 25: 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)naphthalen-2-ol [ka]

[0587] Step 1: 4'-Fluoro-5'-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaene [ka]

[0588] 5'-Chloro-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-penta[de]naphthalene] in dioxane / H2O (10 / 2 mL) at room temperature. To a solution of tetraethene (30 mg, 0.067 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (86 mg, 0.17 mmol), NaHCO (17 mg, 0.2 mmol), and Pd(dtbpf)Cl (5 mg, 0.007 mmol) were added, and the mixture was stirred at 95 °C for 3 h. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH = 10 / 1) to give the title product (25 mg). MS (ESI, m / e) [M+H] + 802.4.

[0589] Step 2: 5'-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaene [ka]

[0590] To a solution of 4'-fluoro-5'-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaene (25 mg, 0.03 mmol) in DMF (4 mL) at room temperature was added CsF (23 mg, 0.15 mmol). Upon completion, the mixture was diluted with water (10 mL). The aqueous layer was extracted with DCM (20 mL*3), and the combined organic layers were concentrated to give the residue (30 mg, crude) as the title compound. MS (ESI, m / e) [M+H] + 646.3.

[0591] Step 3: 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)naphthalen-2-ol

[0592] To a solution of 5'-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaene (30 mg, 0.046 mmol) in DCM (2 mL) at room temperature, HCl (4 N in dioxane, 1 mL) was added, and the mixture was stirred at room temperature for 2 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 Prep-HPLC to give the title product (7.9 mg). 1 H NMR (500 MHz, CD3OD) δ 7.85 - 7.82 (m, 1H), 7.35 - 7.18 (m, 3H), 5.49 - 5.30 (m, 1H), 4.72 - 4.64 (m, 2H), 4.48 - 4.37 (m, 2H), 3.59 - 3.40 (m, 7H), 3.20 - 3.15 (m, 1H), 2.85 - 2.78 (m, 1H), 2.72 - 2.62 (m, 1H), 2.49 - 1.96 (m, 10H). MS (ESI, m / e) [M+H] + 602.3.

[0593] Example 26: 3-chloro-5-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10,11-dimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0594] Example 26 was prepared by a similar procedure as described in Example 6 by substituting (R)-3-(methylamino)butan-1-ol for 3-(methylamino)butan-1-ol to afford the title product (6.4 mg). 1 H NMR (500 MHz, CD3OD) δ 6.89 - 6.87 (m, 1H), 6.68 - 6.30 (m, 1H), 5.45 - 5.27 (m, 1H), 4.53 - 4.22 (m, 4H), 4.10 - 3.98 (m, 1H), 3.50 - 3.33 (m, 3H), 3.29 (s, 3H), 3.15 - 3.07 (m, 1H), 2.46 - 1.90 (m, 8H), 1.49 - 1.39 (m, 3H). MS (ESI, m / e) [M+H] + 599.2.

[0595] Example 27: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,10,11,11a,12-hexahydro-8H-7-oxa-1,3,6,10,12-pentaazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0596] Step 1: tert-butyl 3-(((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-4-(methylamino)pyrrolidine-1-carboxylate [ka]

[0597] To a mixture of tert-butyl 3-(hydroxymethyl)-4-(methylamino)pyrrolidine-1-carboxylate (253 mg, 1.1 mmol) in THF (50 mL) was added NaH (48 mg, 2 mmol) and 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (279 mg, 1 mmol). The mixture was stirred at 40° C. for 3 hours. The cooled mixture was then concentrated. The residue was purified by column chromatography (DCM / MeOH=10 / 1) to give the product (420 mg). MS (ESI, m / e) [M+H] + 474.4.

[0598] Step 2: tert-butyl 5-chloro-4-fluoro-12-methyl-2-(methylthio)-8a,9,11a,12-tetrahydro-8H-7-oxa-1,3,6,10,12-pentaazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene-10(11H)-carboxylate [ka]

[0599] To a solution of tert-butyl 3-(((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-4-(methylamino)pyrrolidine-1-carboxylate (420 mg, 0.888 mmol) in DCM (40 mL) was added HATU (675 mg, 1.776 mmol) and DIPEA (0.76 mL, 4.44 mmol) and stirred at room temperature for 12 h. The resulting cooled solution was concentrated and purified by pre-TLC (petroleum ether: EtOAc = 1:1) to give the title product (80 mg). MS (ESI, m / e) [M+H] + 456.4.

[0600] Step 3: tert-butyl 5-chloro-4-fluoro-12-methyl-2-(methylsulfinyl)-8a,9,11a,12-tetrahydro-8H-7-oxa-1,3,6,10,12-pentaazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene-10(11H)-carboxylate [ka]

[0601] A mixture of tert-butyl 5-chloro-4-fluoro-12-methyl-2-(methylthio)-8a,9,11a,12-tetrahydro-8H-7-oxa-1,3,6,10,12-pentaazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene-10(11H)-carboxylate (91 mg, 0.2 mmol) and m-CPBA (42 mg, 0.24 mmol) in DCM (4 mL) was stirred at 0 °C for 60 min. The resulting cooled mixture was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 472.5.

[0602] Step 4: tert-butyl 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,11a,12-tetrahydro-8H-7-oxa-1,3,6,10,12-pentaazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene-10(11H)-carboxylate [ka]

[0603] To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (64 mg, 0.4 mmol) in THF (2 mL) was added LiHMDS (1 M, 0.4 mL, 0.4 mmol) at 0° C. for 10 min. The solution obtained in step 3 was then decanted into this reaction mixture, stirred for 30 min, and concentrated. The residue was purified by pre-TLC (DCM / MeOH=10 / 1) to give the title product (80 mg). MS (ESI, m / e) [M+H] + 567.4.

[0604] Step 5: tert-butyl 5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,11a,12-tetrahydro-8H-7-oxa-1,3,6,10,12-pentaazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene-10(11H)-carboxylate [ka]

[0605] tert-Butyl 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,11a,12-tetrahydro-8H-7-oxa-1,3,6,10,12-pentaazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene-10(11H)-carboxylate (80 mg, 0.142 mmol) To a mixture of 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (136 mg, 0.426 mmol), 1,4-dioxane (5 mL) and water (1 mL) were added, and the mixture was stirred at 90 °C for 2 h. The resulting cooled mixture was concentrated and purified by pre-TLC (DCM / MeOH = 10 / 1) to give the title product (79 mg). MS (ESI, m / e) [M+H] + 726.6.

[0606] Step 6: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,10,11,11a,12-hexahydro-8H-7-oxa-1,3,6,10,12-pentaazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0607] To a solution of tert-butyl 5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,11a,12-tetrahydro-8H-7-oxa-1,3,6,10,12-pentaazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene-10(11H)-carboxylate (22 mg, 0.03 mmol) in 4 mL of dichloromethane was added 4 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours. Then, it was evaporated below 35° C. The residue was purified by prep-HPLC to give the title product (3.0 mg). 1 H NMR (500 MHz, CD3OD) δ 6.93 - 6.88 (m, 1H), 6.58 - 6.40 (m, 1H), 5.65 - 5.45 (m, 1H), 4.75 - 4.51 (m, 5H), 4.08 - 3.49 (m, 10H), 3.10 - 3.03 (m, 1H), 2.61 - 2.11 (m, 6H). MS (ESI, m / e) [M+H] + 626.5.

[0608] Example 28: 2-amino-4-(9'-chloro-11'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4'-methyl-6',7'-dihydro-4'H-spiro[oxetane-3,5'-[1,5]oxazocino[4,3,2-de]quinazoline]-10'-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile [ka]

[0609] Example 28 was prepared by a similar procedure as described in Example 19 by replacing (R)-3-(methylamino)butan-1-ol with 2-(3-(methylamino)oxetan-3-yl)ethan-1-ol to afford the title product (25 mg).1 H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 2H), 7.29 - 7.05 (m, 2H), 5.60 - 5.40 (m, 1H), 4.80 - 4.13 (m, 8H), 3.18 (s, 3H), 2.64 - 2.53 (m, 3H), 2.47 - 1.90 (m, 6H). [M+H] + 657.5.

[0610] Example 29: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10-methyl-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,1′-cyclopropane]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0611] Example 29 was prepared by a similar procedure as described in Example 23 by substituting (1-(methylamino)cyclopropyl)methanol for (3-(methylamino)oxetan-3-yl)methanol to afford the title product (12 mg). 1 H NMR (500 MHz, CD3OD) δ 6.92 - 6.84 (m, 1H), 6.56 - 6.45 (m, 1H), 5.45 - 5.24 (m, 1H), 4.57 - 4.52 (m, 2H), 4.41 - 4.27 (m, 2H), 3.47 - 3.32 (m, 6H), 3.13 - 3.08 (m, 1H), 2.42 - 1.92 (m, 6H), 1.29 - 1.20 (m, 4H). MS (ESI, m / e) [M+H] + 597.2.

[0612] Example 30: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3′-oxetane]-1(11a),2,3a,3a 1 (6a), 5-pentaen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0613] Step 1: 7-chloro-8-fluoro-5-(2-(3-(methylamino)oxetan-3-yl)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol [ka]

[0614] To a stirred solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (560 mg, 1.0 mmol) and 2-(3-(methylamino)oxetan-3-yl)ethan-1-ol (260 mg, 1.0 mmol) in THF (10 mL) at 0 °C, NaH (560 mg, 7.0 mmol, 60%) was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with HO, and then the pH was adjusted to 6 with 1 N aq. HCl. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash chromatography (CHCl / MeOH = 100:1 to 5:1) to give the product (660 mg). MS (ESI, m / e) [M+H] + 375.3.

[0615] Step 2: 5-chloro-4-fluoro-11-methyl-2-(methylthio)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3'-oxetane]-1(11a),2,3a,3a 1 (6a), 5-pentaene [ka]

[0616] To a stirred solution of 7-chloro-8-fluoro-5-(2-(3-(methylamino)oxetan-3-yl)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (375 mg, 1.0 mmol) in ACN (50 mL) at room temperature, DIPEA (323 mg, 2.5 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BopCl) (760 mg, 3 mmol) were added, and the resulting mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated and purified by flash chromatography (CHCl / EtOAc = 4:1 to 1:3) to give the desired product (240 mg). MS (ESI, m / e) [M+H] + 357.3.

[0617] Step 3: 5-chloro-4-fluoro-11-methyl-2-(methylsulfinyl)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3'-oxetane]-1(11a),2,3a,3a 1 (6a), 5-pentaene [ka]

[0618] 5-Chloro-4-fluoro-11-methyl-2-(methylthio)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3′-oxetane]-1(11a),2,3a,3a in CHCl (2.5 mL) at 0 °C 1To a stirred solution of (6a),5-pentaene (260 mg, 0.72 mmol), m-CPBA (200 mg, 1 mmol, 85%) was added, and the resulting mixture was stirred for 10 min at 0° C. The reaction mixture was used in the next step without further purification.

[0619] Step 4: 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3'-oxetane]-1(11a),2,3a,3a 1 (6a), 5-pentaene [ka]

[0620] 5-chloro-4-fluoro-11-methyl-2-(methylsulfinyl)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3′-oxetane]-1(11a),2,3a,3a at 0°C. 1 To a stirred solution of (6a),5-pentaene (0.72 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (240 mg, 1.5 mmol) and LiHMDS (2 mL, 2 mmol, 1 M in THF) in THF (2.5 mL) were added dropwise, and the resulting mixture was stirred at 0 °C for 20 min. The reaction was quenched with HO and concentrated in vacuo. The residue was purified by flash chromatography (CHCl / MeOH = 100:1 to 30:1) to give the product (190 mg). MS (ESI, m / e) [M+H] + 468.5.

[0621] Step 5: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3'-oxetane]-1(11a),2,3a,3a 1 (6a), 5-pentaen-5-yl)-4-(trifluoromethyl)aniline

[0622] 5-Chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3'-oxetane]-1(11a),2,3a,3a 1 To a mixture of (6a), 5-pentaene (100 mg), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (160 mg, 0.5 mmol), Pd(dtbpf)Cl (35 mg, 0.05 mmol), and NaHCO (84 mg, 1 mmol), dioxane (10.0 mL) and HO (2 mL) were added, and the reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100:1 to 10:1), followed by further purification by prep-HPLC to give the title product (6.3 mg). 1 H NMR (500 MHz, CD3OD) δ 6.91 - 6.83 (m, 1H), 6.65 - 6.37 (m, 1H), 5.53 - 5.30 (m, 1H), 4.72 - 4.35 (m, 7H), 3.67 - 3.42 (m, 3H), 3.26 (s, 3H), 3.25 - 3.18 (m, 1H), 2.55 - 1.93 (m, 8H). [M+H] + 627.3.

[0623] Example 31: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,1′-cyclopropane]-1(11a),2,3a,4,6-pentaen-5-yl)-4(trifluoromethyl)aniline [ka]

[0624] Example 31 was prepared by a similar procedure as described in Example 30 by substituting 2-(1-(methylamino)cyclopropyl)ethan-1-ol for 2-(3-(methylamino)oxetan-3-yl)ethan-1-ol to provide the title product (7.8 mg). 1 H NMR (500 MHz, CD3OD) δ 6.92 - 6.79 (m, 1H), 6.69 - 6.45 (m, 1H), 5.42 - 5.24 (m, 1H), 4.62 - 4.41 (m, 2H), 4.38 - 4.16 (m, 2H), 3.38 - 3.35 (m, 3H), 3.09 - 3.02 (m, 1H), 2.66 - 1.54 (m, 8H), 1.37 - 1.27 (m, 3H), 1.02 - 0.83 (m, 4H). MS (ESI, m / e) [M+H] + 611.2.

[0625] Example 32: 3-chloro-5-(4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11'-methyl-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'-pentaen-5'-yl)-4-(trifluoromethyl)aniline [ka]

[0626] Example 32 was prepared by a similar procedure as described in Example 30 by substituting 2-(1-(methylamino)cyclobutyl)ethan-1-ol for 2-(3-(methylamino)oxetan-3-yl)ethan-1-ol to provide the title product (12.6 mg). 1 H NMR (500 MHz, CD3OD) δ 6.90 - 6.84 (m, 1H), 6.65 - 6.25 (m, 1H), 5.49 - 5.30 (m, 1H), 4.56 - 4.33 (m, 4H), 3.59 - 3.38 (m, 3H), 3.24 (s, 3H), 3.19 - 3.14 (m, 1H), 2.68 - 1.61 (m, 14H). MS (ESI, m / e) [M+H] + 625.2.

[0627] Example 33: 5'-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11'-methyl-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'-pentaen-3-ol [ka]

[0628] Step 1: Ethyl 2-(3-(benzyloxy)cyclobutylidene)acetate [ka]

[0629] A mixture of 3-(benzyloxy)cyclobutan-1-one (5 g, 28.37 mmol) and ethyl 2-(triphenyl-15-phosphanylidene)acetate (11.86 g, 34.05 mmol) in DCM (100 mL) was stirred at 40° C. for 16 hours. The reaction mixture was quenched with water (5 mL), then diluted with water (100 mL), and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EtOAc = 100:1 to 10:1) to give the title product (4.5 g). MS (ESI, m / e) [M+H] + 247.

[0630] Step 2: Ethyl 2-(3-(benzyloxy)-1-(methylamino)cyclobutyl)acetate [ka]

[0631] In a 20 mL sealed tube, ethyl 2-(3-(benzyloxy)cyclobutylidene)acetate (3.5 g, 14.22 mmol), EtOH (3.5 mL), and CHNH (30% in EtOH) (1.71 g, 30%, 16.50 mmol) were added. After stirring at 50 °C for 12 h, the mixture was concentrated. The crude product (3.6 g) was used directly in the next step without further purification. (ESI, m / e) [M+H] 278.

[0632] Step 3: Ethyl 2-(3-hydroxy-1-(methylamino)cyclobutyl)acetate [ka]

[0633] To a solution of ethyl 2-(3-(benzyloxy)-1-(methylamino)cyclobutyl)acetate (3.6 g, 12.95 mmol) in EtOH (30 mL) at room temperature was added Pd / C (10%, 3.6 g). After stirring at 60 °C under an atmosphere of H2(g) for 6 h, the mixture was filtered through a Celite pad and concentrated under reduced pressure. The crude product (2.3 g) was used directly in the next step without further purification. (ESI, m / e) [M+H] + 188.

[0634] Step 4: Ethyl 2-(3-((tert-butyldimethylsilyl)oxy)-1-(methylamino)cyclobutyl)acetate [ka]

[0635] To a solution of ethyl 2-(3-hydroxy-1-(methylamino)cyclobutyl)acetate (2.3 g, 12.23 mmol) in DCM (20 mL) at 0 °C, imidazole (2.5 g, 36.70 mmol) and TBSCl (2.2 g, 14.68 mmol) were added. After stirring at room temperature for 3 h, the mixture was quenched with NH4Cl(aq) at 0 °C and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (PE: EtOAc = 100:0 to 50:50) to give the title product (3.5 g). (ESI, m / e) [M+H] + 302.

[0636] Step 5: 2-(3-((tert-butyldimethylsilyl)oxy)-1-(methylamino)cyclobutyl)ethan-1-ol [ka]

[0637] To a solution of ethyl 2-(3-((tert-butyldimethylsilyl)oxy)-1-(methylamino)cyclobutyl)acetate (3.2 g, 10.63 mmol) in THF (50 mL) at 0 °C was added LiAlH (0.81 g, 21.26 mmol). After stirring overnight at room temperature, the mixture was diluted with NaSO at 0 °C. . The mixture was quenched with 10H2O. The resulting mixture was filtered, and the filter cake was washed with DCM / MeOH (3:1). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM:MeOH = 100:0 to 0:100) to give the title product. MS (ESI, m / e) [M+H] + 260.2.

[0638] Step 6: 5-(2-(3-((tert-butyldimethylsilyl)oxy)-1-(methylamino)cyclobutyl)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol [ka]

[0639] To a stirred solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (280 mg, 1.0 mmol) and 2-(3-((tert-butyldimethylsilyl)oxy)-1-(methylamino)cyclobutyl)ethan-1-ol (260 mg, 1.0 mmol) in THF (10 mL) at 0° C., NaH (160 mg, 4.0 mmol, 60%) was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with HO, and then the pH was adjusted to 6 with 1 N aq. HCl. The mixture was filtered, and the filter cake was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 503.4.

[0640] Step 7: 3-((tert-butyldimethylsilyl)oxy)-5'-chloro-4'-fluoro-11'-methyl-2'-(methylthio)-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'-pentaene [ka]

[0641] To a stirred solution of 5-(2-(3-((tert-butyldimethylsilyl)oxy)-1-(methylamino)cyclobutyl)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.0 mmol) in MeCN (50 mL) at room temperature, DIEA (387 mg, 3.0 mmol) and BOPCl (508 mg, 2.0 mmol) were added, and the resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc = 20:1 to 5:1) to give the desired product (180 mg). MS (ESI, m / e) [M+H]+ 485.4.

[0642] Step 8: 3-((tert-butyldimethylsilyl)oxy)-5'-chloro-4'-fluoro-11'-methyl-2'-(methylsulfinyl)-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'-pentaene [ka]

[0643] To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)-5'-chloro-4'-fluoro-11'-methyl-2'-(methylthio)-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'-pentaene (180 mg, 0.37 mmol) in DCM (5 mL) at 0 °C, m-CPBA (76 mg, 0.37 mmol, 85%) was added, and the resulting mixture was stirred at 0 °C for 15 min. The reaction was quenched with aq. NaSO and then extracted with DCM. The organic layer was washed with sat. aq. NaHCO and brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0644] Step 9: 3-((tert-butyldimethylsilyl)oxy)-5'-chloro-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11'-methyl-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'-pentaene [ka]

[0645] To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)-5'-chloro-4'-fluoro-11'-methyl-2'-(methylsulfinyl)-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'-pentaene (0.37 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (118 mg, 0.74 mmol) in THF (8 mL) at 0°C, LiHMDS (0.74 mL, 0.74 mmol, 1 M in THF) was added dropwise, and the resulting mixture was stirred at 0°C for 20 min. The reaction was quenched with aqueous NH4Cl and then extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH = 100:1 to 30:1) to give the product (115 mg). MS (ESI, m / e) [M+H]+ 596.1.

[0646] Step 10: 3-(3-((tert-butyldimethylsilyl)oxy)-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11'-methyl-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'-pentaen-5'-yl)-5-chloro-4-(trifluoromethyl)aniline [ka]

[0647] 3-((tert-Butyldimethylsilyl)oxy)-5'-chloro-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11'-methyl-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'- To a mixture of pentaene (115 mg, 0.19 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (73 mg, 0.23 mmol), Pd(dtbpf)Cl2 (24 mg, 0.04 mmol), and NaHCO3 (32 mg, 0.38 mmol), dioxane (5.0 mL) and HO (1.0 mL) were added, and the resulting mixture was stirred at 90 °C for 1 h. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100:1 to 5:1) to give the product (78 mg). MS (ESI, m / e) [M+H]+ 755.6.

[0648] Step 11: 5'-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11'-methyl-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'-pentaen-3-ol [ka]

[0649] To a mixture of 3-(3-((tert-butyldimethylsilyl)oxy)-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11'-methyl-8',9'-dihydro-11'H-7'-oxa-1',3',6',11'-tetraazaspiro[cyclobutane-1,10'-cycloocta[de]naphthalene]-1'(11a'),2',3a',3a1'(6a'),5'-pentaen-5'-yl)-5-chloro-4-(trifluoromethyl)aniline (78 mg, 0.10 mmol) in DCM (4.0 mL) was added 4 N HCl (in dioxane) (4.0 mL). The resulting mixture was stirred for 20 min. The reaction mixture was concentrated and basified with DIEA, followed by prep-HPLC to give the title product (34.5 mg). 1 H NMR (500 MHz, CD3OD) δ 6.90 - 6.81 (m, 1H), 6.73 - 6.19 (m, 1H), 5.42 - 5.18 (m, 1H), 4.70 - 4.38 (m, 2H), 4.36 - 4.15 (m, 2H), 4.13 - 3.97 (m, 1H), 3.29 (s, 3H), 3.28 - 3.12 (m, 3H), 3.09 - 2.84 (m, 2H), 2.83 - 2.55 (m, 1H), 2.50 - 1.80 (m, 10H). MS (ESI, m / e) [M+H] + 641.5.

[0650] Example 34: 3-chloro-5-((8S,10R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,10,11-trimethyl-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0651] Step 1: (4S,6S)-4,6-dimethyl-1,3,2-dioxathiane 2-oxide [ka]

[0652] To a solution of (2S,4S)-pentane-2,4-diol (90 g, 0.87 mol) and TEA (262 g, 2.61 mol) in CHCl (4.5 L) at 0 °C, SOCl (113 g, 0.95 mol) was slowly added. The mixture was warmed to room temperature and stirred for an additional 60 min. The reaction was then quenched by adding ice water (1.8 L). The two layers were separated, and the aqueous phase was extracted three times with EtO (900 mL). The combined organic layers were washed with 6% NaHCO solution, brine, and H2O, respectively. The organic layer was then dried over Na2SO4, filtered, and the solvent removed. The crude product (120 g) was used directly in the next step without further purification.

[0653] Step 2: (4S,6S)-4,6-dimethyl-1,3,2-dioxathiane 2,2-dioxide [ka]

[0654] To a previously prepared cooled solution (0 °C) of (4S,6S)-4,6-dimethyl-1,3,2-dioxathiane 2-oxide (120 g, crude) in a mixture of CH2Cl2 (900 mL) and MeCN (900 mL) was added RuCl3 .H2O (2 g) was added, followed by a solution of NaIO4 (311 g, 1.44 mol) in water (1.35 L). The resulting two-phase mixture was stirred at 0 °C for 15 min, warmed to room temperature, and stirred for an additional 45 min. During this time, the reaction mixture changed color from dark brown to orange. Et2O (6 L) was then added, the two phases were separated, and the aqueous layer was extracted with Et2O. The organic layers were combined and subsequently washed with saturated NaHCO3 solution, brine, and water. The organic layer was dried over Na2SO4, filtered, and the solvent removed in vacuo. The crude product was recrystallized from Et2O / pentane to give the title product (85 g, crude).

[0655] Step 3: (2S,4R)-4-((4-Methoxybenzyl)(methyl)amino)pentan-2-yl hydrogen sulfate [ka]

[0656] A mixture of [(4-methoxyphenyl)methyl](methyl)amine (155 g, 1.02 mol) and (4S,6S)-4,6-dimethyl-1,3,2-dioxathiane 2,2-dioxide (85 g, 0.51 mol) was stirred for 1 hour at 45° C. The crude product (240 g) was used directly in the next step without further purification.

[0657] Step 4: (2S,4R)-4-((4-methoxybenzyl)(methyl)amino)pentan-2-ol [ka]

[0658] (2S,4R)-4-((4-methoxybenzyl)(methyl)amino)pentan-2-yl hydrogen sulfate (240 g, crude) and 2M H2SO4 in THF (3.4 L) / HO (0.34 L) were stirred at 0 °C for 15 min. The resulting mixture was stirred at 50 °C for an additional 2 h. The mixture was basified with NaHCO3 (aq) to pH > 7 and extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl2 / MeOH (100:0 to 90:10) to give the title product (75 g). MS (ESI, m / e) [M+H] + 238.25.

[0659] Step 5: (2S,4R)-4-(methylamino)pentan-2-ol hydrochloride [ka]

[0660] A solution of (2S,4R)-4-((4-methoxybenzyl)(methyl)amino)pentan-2-ol (20 g, 84 mmol) and Pd / C (20 g) in MeOH (200 mL) was stirred at 50° C. for 16 h. The resulting mixture was filtered. A mixture of the filtrate and 4 M HCl in dioxane (100 mL) was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in HO (200 mL) and extracted with EtOAc (3*300 mL). The aqueous phase was concentrated. This gave the title product (11 g, 85%). MS (ESI, m / e) [M+H] + 118.1.

[0661] Example 34 was prepared by a similar procedure as described in Example 30 by substituting (2S,4R)-4-(methylamino)pentan-2-ol hydrochloride for 2-(3-(methylamino)oxetan-3-yl)ethan-1-ol to afford the title product (23 mg). 1H NMR (500 MHz, CD3OD) δ 6.94 - 6.79 (m, 1H), 6.70 - 6.38 (m, 1H), 5.46 - 5.23 (m, 1H), 4.63 - 4.50 (m, 1H), 4.44 - 4.24 (m, 2H), 3.76 - 3.57 (m, 1H), 3.44 - 3.33 (m, 3H), 3.27 - 3.21 (m, 3H), 3.13 - 3.05 (m, 1H), 2.41 - 1.77 (m, 8H), 1.53 - 1.47 (m, 3H), 1.35 - 1.29 (m, 3H). MS (ESI, m / e) [M+H] + 613.2.

[0662] Example 35: 3-chloro-5-(11-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3′-oxetane]-1(11a),2,3a,3a1(6a),5-pentaen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0663] Example 35 was prepared by a similar procedure as described in Example 30 by substituting 2-(3-(ethylamino)oxetan-3-yl)ethan-1-ol for 2-(3-(methylamino)oxetan-3-yl)ethan-1-ol to afford the title product (32 mg). 1H NMR (500 MHz, CD3OD) δ 6.90 - 6.83 (m, 1H), 6.58 - 6.46 (m, 1H), 5.42 - 5.23 (m, 1H), 4.71 - 4.46 (m, 5H), 4.42 - 4.17 (m, 3H), 3.76 - 3.60 (m, 2H), 3.10 - 3.01 (m, 1H), 2.43 - 1.87 (m, 7H), 1.54 - 1.46 (m, 3H). MS (ESI, m / e) [M+H] + 641.2.

[0664] Example 36: 3-chloro-5-(4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-(2-(methylamino)ethyl)-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaen-5'-yl)-4-(trifluoromethyl)aniline [ka]

[0665] Example 36 was prepared by a similar procedure as described in example 20 by substituting tert-butyl (2-((4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate with tert-butyl (2-((1-(hydroxymethyl)cyclobutyl)amino)ethyl)(methyl)carbamate to provide the title product (2.0 mg). 1H NMR (500 MHz, CD3OD) δ 6.89 (s, 1H), 6.48 (s, 1H), 5.42-5.22 (m, 1H), 4.75-4.60 (m, 2H), 4.37-4.21 (m, 4H), 3.34-3.31 (m, 4H), 3.11-3.07 (m, 1H), 2.77 (s, 3H), 2.62-2.58 (m, 2H), 2.33-2.18 (m, 5H), 2.04-1.91 (m, 5H). MS (ESI, m / e) [M+H] + 654.5.

[0666] Example 37: 3-chloro-5-(10'-(2-(dimethylamino)ethyl)-4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaen-5'-yl)-4-(trifluoromethyl)aniline [ka]

[0667] Example 37 was prepared by a similar procedure as described in example 36 by substituting (1-((2-(dimethylamino)ethyl)amino)cyclobutyl)methanol for tert-butyl (2-((1-(hydroxymethyl)cyclobutyl)amino)ethyl)(methyl)carbamate to afford the title product (0.5 mg). 6.88 (s, 1H), 6.48 (s, 1H), 5.45-5.25 (m, 1H), 4.66-4.65 (m, 2H), 4.34-4.32 (m, 2H), 4.17-4.15 (m, 2H), 2.85-2.83 (m, 2H), 2.62-2.58 (m, 2H), 2.50 (s, 6H), 2.33-2.01 (m, 10H). MS (ESI, m / e) [M+H] + 668.5.

[0668] Example 38: 3-chloro-5-(4'-fluoro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-10'-(1-(methylamino)propan-2-yl)-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalene]-1'(10a'),2',3a',3a1'(6a'),5'-pentaen-5'-yl)-4-(trifluoromethyl)aniline [ka]

[0669] Step 1: tert-Butyl (2-((1-(hydroxymethyl)cyclobutyl)amino)propyl)carbamate [ka]

[0670] To a mixture of 1-aminocyclobutyl)methanol hydrochloride (1.37 mg, 10 mmol) and tert-butyl (2-oxopropyl)carbamate (1.73 g, 10 mmol) in THF (20 mL) and HOAc (2 mL) was added NaBH(OAc)3 (4.24 g, 20 mmol). The mixture was stirred at 20 °C for 15 h. The cooled mixture was concentrated. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to give the product (2.2 g). MS (ESI, m / e) [M+H]+ 259.4.

[0671] Example 38 was prepared by a similar procedure as described in example 20 by substituting tert-butyl (2-((4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate with tert-butyl (2-((1-(hydroxymethyl)cyclobutyl)amino)propyl)carbamate to provide the title product (5.2 mg). 1H NMR (500 MHz, CD3OD) δ 6.89 (s, 1H), 6.47 (s, 1H), 5.41-5.21 (m, 1H), 4.58-4.44 (m, 3H), 4.39-4.23 (m, 3H), 3.76-3.69 (m, 1H), 3.49-3.30 (m, 4H), 2.75 (s, 3H), 2.51 - 1.91 (m, 12H), 1.65-1.64 (m, 3H). MS (ESI, m / e) [M+H]+ 668.5.

[0672] Example 39: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-(1-(methylamino)propan-2-yl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0673] Example 39 was prepared by a similar procedure as described in example 20 by substituting tert-butyl (2-((4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate with tert-butyl (2-((3-hydroxypropyl)amino)propyl)(methyl)carbamate to afford the title product (2.5 mg). 1H NMR (500 MHz, DMSO-d6) δ 6.85 (s, 1H), 6.47 (s, 1H), 6.30 (s, 2H), 5.38-5.17 (m, 1H), 4.45-4.32 (m, 2H), 4.12-3.99 (m, 2H), 3.58-3.47 (m, 2H), 3.19-2.99 (m, 5H), 2.85-2.82 (m, 2H), 2.39 (s, 3H), 2.12-1.77 (m, 8H), 1.34-1.33 (m, 3H). MS (ESI, m / e) [M+H]+ 642.6.

[0674] Example 40: 3-chloro-5-(11-(1-(dimethylamino)propan-2-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0675] Example 40 was prepared by a similar procedure as described in example 39 by substituting tert-butyl (2-((3-hydroxypropyl)amino)propyl)(methyl)carbamate with 3-((1-(dimethylamino)propan-2-yl)amino)propan-1-ol to afford the title product (0.9 mg). 1H NMR (500 MHz, CD3OD) δ 6.99-6.88 (m, 1H), 6.62-6.50 (m, 1H), 5.45-5.24 (m, 1H), 4.52-4.23 (m, 4H), 3.67-3.60 (m, 2H), 3.34-3.31 (m, 3H), 3.09-2.92 (m, 2H), 2.18-1.91 (m, 6H), 1.31-1.29 (m, 3H). MS (ESI, m / e) [M+H] + 656.4.

[0676] Example 41: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-((R)-pyrrolidin-3-yl)-8,9,10,11-tetrahydro-7-oxa-1,3,6,11-tetraazacycloocta[de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0677] Example 41 was prepared by a procedure similar to that described in Example 20, substituting tert-butyl (2-((4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate with tert-butyl (R)-3-((3-hydroxypropyl)amino)pyrrolidine-1-carboxylate to afford the title product (8.1 mg). MS (ESI, m / e) [M+H] + 641.0.

[0678] Example 42: 3-chloro-5-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-(2-(methylamino)ethyl)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,1′-cyclopropane]-1(11a),2,3a,4,6-pentaen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0679] Example 42 was prepared by a similar procedure as described in example 20 by substituting tert-butyl (2-((4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate with tert-butyl (2-((1-(2-hydroxyethyl)cyclopropyl)amino)ethyl)(methyl)carbamate to provide the title product (20 mg). 1 H NMR (500 MHz, CD3OD) δ 6.89 (s, 1H), 6.64-6.38 (m, 1H), 5.50-5.30 (m, 1H), 4.58-4.47 (m, 4H), 4.12 (s, 2H), 3.52-3.41 (m, 5H), 3.22- 3.16 (m, 1H), 2.79 (s, 3H), 2.65-1.95 (m, 7H), 1.68-1.58 (m, 1H), 1.11-0.61 (m, 4H). MS (ESI, m / e) [M+H] + 654.3.

[0680] Example 43: 3-chloro-5-(11-(2-(dimethylamino)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,1′-cyclopropane]-1(11a),2,3a,4,6-pentaen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0681] Example 43 was prepared by a similar procedure as described in example 42 by substituting 2-(1-((2-(dimethylamino)ethyl)amino)cyclopropyl)ethan-1-ol for tert-butyl (2-((1-(2-hydroxyethyl)cyclopropyl)amino)ethyl)(methyl)carbamate to afford the title product (20 mg). 1 H NMR (500 MHz, CD3OD) δ 7.02-6.89 (m, 1H), 6.64-6.38 (m, 1H), 5.54-5.33 (m, 1H), 4.57-4.44 (m, 4H), 4.14-3.96 (m, 2H), 3.69-3.53 (m, 3H), 3.16-3.06 (m, 2H), 2.64-2.62 (m, 6H), 2.50-2.37 (m, 2H), 2.30-2.15 (m, 3H), 2.07-1.98 (m, 1H), 1.67-1.58 (s, 1H), 1.12-1.57 (m, 4H). MS (ESI, m / e) [M+H] + 668.3.

[0682] Example 44: 3-chloro-5-(11-(2-(dimethylamino)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3′-oxetane]-1(11a),2,3a,4,6-pentaen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0683] Example 44 was prepared by a similar procedure as described in example 20 by substituting 2-(3-((2-(dimethylamino)ethyl)amino)oxetan-3-yl)ethan-1-ol for tert-butyl (2-((4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate to afford the title product (2 mg).1 H NMR (500 MHz, CD3OD) δ 7.03-6.89 (m, 1H), 6.63-6.51 (m, 1H), 5.62-5.43 (m, 1H), 4.70-4.55 (m, 7H), 3.91-3.77 (m, 5H), 3.49-3.40 (m, 4H), 2.89-2.80 (m, 6H), 2.65-2.10 (m, 7H). MS (ESI, m / e) [M+H] + 684.3.

[0684] Example 45: 3-chloro-5-((7a,10a-trans)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-7a,8,9,10,10a,11-hexahydro-7-oxa-1,3,6,11-tetraazanaphtho[1,8-fg]azulen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0685] Step 1: 1,2-trans-2-(methylamino)cyclopentan-1-ol [ka]

[0686] To a solution of tert-butyl (trans-2-hydroxycyclopentyl)carbamate (1 g, 4.97 mmol) in THF (100 mL) was added LiAlH (400 mg, 9.3 mmol), and the mixture was stirred at 60 °C overnight. After completion, the mixture was quenched with NaSO.10H0. It was then filtered, and the filtrate was concentrated to give the title product (500 mg). MS (ESI, m / e) [M+H] + 116.2.

[0687] Example 45 was prepared by a similar procedure as described in Example 24 by substituting 1,2-trans-2-(methylamino)cyclopentan-1-ol for (1-(methylamino)cyclobutyl)methanol to afford the title product (18 mg). 1 H NMR (500 MHz, DMSO-d6) δ 6.85 (s, 1H), 6.54-6.30 (m, 3H), 5.41-5.21 (m, 1H), 4.78-4.72 (m, 1H), 4.25-4.00 (m, 3H), 3.26-3.07 (m, 6H), 2.93-2.84 (m, 1H), 2.40-2.24 (m, 2H), 2.30-1.67 (m, 10H). MS (ESI, m / e) [M+H] + 611.4.

[0688] Example 46: 3-chloro-5-((7aS,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapleyaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0689] Step 1: (1S,2S)-2-(methylamino)cyclohexan-1-ol [ka]

[0690] To a solution of tert-butyl ((1S,2S)-2-hydroxycyclohexyl)carbamate (1 g, 4.65 mmol) in THF (25 mL) at 0° C., LiAlH (530 mg, 13.95 mmol) was added and the mixture was stirred at 70° C. overnight. Upon completion, the mixture was cooled to room temperature, sodium sulfate decahydrate was added, and stirred for 0.5 h. The resulting mixture was filtered and the organic phase was concentrated to give a residue (630 mg, crude) as the title compound. MS (ESI, m / e) [M+H] + 130.1.

[0691] Example 46 was prepared by a similar procedure as described in Example 24 by substituting (1S,2S)-2-(methylamino)cyclohexan-1-ol for (1-(methylamino)cyclobutyl)methanol to afford the title product (6.1 mg). 1 H NMR (500 MHz, CD3OD) δ 6.90 - 6.86 (m, 1H), 6.58 - 6.37 (m, 1H), 5.46 - 6.25 (m, 1H), 4.39 - 4.26 (m, 3H), 3.90 - 3.70 (m, 1H), 3.49 - 3.31 (m, 3H), 3.14 - 3.06 (m, 1H), 2.58 - 2.56 (m, 1H), 2.44 - 1.68 (m, 10H), 1.46 - 1.26 (m, 3H). MS (ESI, m / e) [M+H] + 625.2.

[0692] Example 47: (7aR*,11S*,11aR*)-5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapleiaden-11-ol [ka]

[0693] Step 1: 5-(((1R,2R,3S)-2-amino-3-hydroxycyclohexyl)oxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol [ka]

[0694] To a stirred solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (560 mg, 2.0 mmol) and (1R*,2r*,3S*)-2-aminocyclohexane-1,3-diol (CAS#38332-12-6, batch #22102304 from Shanghai Topbiochem Technology, relative stereochemistry, 265 mg, 2.0 mmol) in THF (20 mL) at 0 °C, NaH (320 mg, 8.0 mmol, 60%) was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with HO, and then the pH was adjusted to 6 with 1 N aq. HCl. The mixture was filtered, and the filter cake was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 375.2.

[0695] Step 2: (7aR*,11S*,11aR*)-5-chloro-4-fluoro-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapleiaden-11-ol [ka]

[0696] To a stirred solution of 5-(((1R,2R,3S)-2-amino-3-hydroxycyclohexyl)oxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (2.0 mmol) in MeCN (100 mL) at room temperature, DIEA (774 mg, 6.0 mmol) and BOPCl (1.0 g, 4.0 mmol) were added, and the resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated and purified by flash chromatography (DCM / EtOAc = 5:1 to 3:1) to give the desired product (250 mg). MS (ESI, m / e) [M+H] + 357.1.

[0697] Step 3: (7aR*,11S*,11aS*)-11-((tert-butyldimethylsilyl)oxy)-5-chloro-4-fluoro-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapleiaden [ka]

[0698] To a stirred solution of (7aR*,11S*,11aR*)-5-chloro-4-fluoro-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapleiaden-11-ol (250 mg, 0.7 mmol) in DCM (10 mL) at 0 °C, DIEA (290 mg, 1.1 mmol) and TBSOTf (180 mg, 1.4 mmol) were added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc = 5:1 to 1:1) to give the desired product (138 mg). MS (ESI, m / e) [M+H] + 471.2.

[0699] Step 4: (7aR*,11S*,11aS*)-11-((tert-butyldimethylsilyl)oxy)-5-chloro-4-fluoro-12-methyl-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapleiaden [ka]

[0700] To a stirred solution of (7aR*,11S*,11aS*)-11-((tert-butyldimethylsilyl)oxy)-5-chloro-4-fluoro-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapuleiadene (138 mg, 0.3 mmol) in THF (6 mL) at 0 °C, NaH (36 mg, 0.9 mmol, 60%) was added, and the resulting mixture was stirred at 0 °C for 15 min. Then, CHCl (128 mg, 0.9 mmol) was added to the above mixture, and the reaction mixture was stirred at 50 °C for 3 h. The reaction was quenched with water, and the crude was purified by flash chromatography (PE / EtOAc = 5:1 to 1:1) to give the desired product (132 mg). MS (ESI, m / e) [M+H] + 485.3.

[0701] Step 5: (7aR*,11S*,11aS*)-11-((tert-butyldimethylsilyl)oxy)-5-chloro-4-fluoro-12-methyl-2-(methylsulfinyl)-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapleiaden [ka]

[0702] To a stirred solution of (7aR*,11S*,11aS*)-11-((tert-butyldimethylsilyl)oxy)-5-chloro-4-fluoro-12-methyl-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapuleiadene (132 mg, 0.27 mmol) in DCM (4 mL) at 0 °C, m-CPBA (55 mg, 0.27 mmol, 85%) was added, and the resulting mixture was stirred at 0 °C for 15 min. The reaction was quenched with aq. NaSO and then extracted with DCM. The organic layer was washed with sat. aq. NaHCO and brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0703] Step 6: (7aR*,11S*,11aS*)-11-((tert-butyldimethylsilyl)oxy)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapleiaden [ka]

[0704] To a stirred solution of (7aR*,11S*,11aS*)-11-((tert-butyldimethylsilyl)oxy)-5-chloro-4-fluoro-12-methyl-2-(methylsulfinyl)-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapuleiadene (0.27 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (86 mg, 0.54 mmol) in THF (6 mL) at 0 °C, LiHMDS (0.54 mL, 0.54 mmol, 1 M in THF) was added dropwise, and the resulting mixture was stirred at 0 °C for 20 min. The reaction was quenched with aqueous NH4Cl and then extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH = 100:1 to 30:1) to give the product (75 mg). MS (ESI, m / e) [M+H] + 596.4.

[0705] Step 7: 3-((7aR*,11S*,11aS*)-11-((tert-butyldimethylsilyl)oxy)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapuleiaden-5-yl)-5-chloro-4-(trifluoromethyl)aniline [ka]

[0706] (7aR*,11S*,11aS*)-11-((tert-butyldimethylsilyl)oxy)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapleiaden (75 mg, 0.12 mmol) To a mixture of 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (58 mg, 0.18 mmol), Pd(dtbpf)Cl (15 mg, 0.02 mmol), and NaHCO (30 mg, 0.36 mmol), dioxane (4.0 mL) and HO (0.8 mL) were added, and the resulting mixture was stirred at 90 °C for 1 h. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100:1 to 5:1) to give the product (68 mg). MS (ESI, m / e) [M+H] + 755.5.

[0707] Step 8: (7aR*,11S*,11aR*)-5-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapleiaden-11-ol [ka]

[0708] To a mixture of 3-((7aR*,11S*,11aS*)-11-((tert-butyldimethylsilyl)oxy)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapuleiaden-5-yl)-5-chloro-4-(trifluoromethyl)aniline (68 mg, 0.09 mmol) in DCM (3.0 mL) was added 4 N HCl in dioxane (3.0 mL). The resulting mixture was stirred for 20 minutes. The reaction mixture was concentrated and basified with DIEA, followed by prep-HPLC to give the title product (19.5 mg). 1 H NMR (500 MHz, CD3OD) δ 6.92 - 6.77 (m, 1H), 6.60 - 6.37 (m, 1H), 5.44 - 5.19 (m, 1H), 4.80 - 4.51 (m, 2H), 4.45 - 4.12 (m, 2H), 4.09 - 3.85 (m, 1H), 3.53 (s, 3H), 3.46 - 3.35 (m, 1H), 3.27 - 3.12 (m, 2H), 3.11 - 2.90 (m, 1H), 2.50 - 1.20 (m, 12H). MS (ESI, m / e) [M+H] + 641.3.

[0709] Example 48: 3-chloro-5-((7aS,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-(2-(methylamino)ethyl)-7a,8,10,11,11a,12-hexahydro-9H-7-oxa-1,3,6,12-tetraazapuleiaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0710] Example 48 was prepared by a similar procedure as described in Example 20 by substituting tert-butyl (2-((4-hydroxybutan-2-yl)amino)ethyl)(methyl)carbamate with tert-butyl ((1S,2S)-2-hydroxycyclohexyl)carbamate to afford the title product (2.2 mg). 1 H NMR (500 MHz, CD3OD) δ 6.89 (s, 1H), 6.54 -6.38 (m,1H), 5.44-5.25 (m, 1H), 4.38-4.32 (m, 3H), 4.25-4.16 (m, 1H), 3.94-3.86 (m, 2H), 3.42-3.33 (m, 5H), 3.12-3.08 (m, 1H), 2.76 (s, 3H), 2.34-2.18 (m, 5H), 2.07-2.03 (m, 2H), 1.95-1.73 (m, 4H), 1.42-1.39 (m, 3H). MS (ESI, m / e) [M+H] + 668.5.

[0711] Example 49: 3-chloro-5-((7aR,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0712] Step 1: 5-(((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)oxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol [ka]

[0713] To a stirred solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (280 mg, 1.0 mmol) and (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (154 mg, 1.0 mmol) in THF (10 mL) at 0 °C, NaH (160 mg, 4.0 mmol, 60%) was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with HO, and then the pH was adjusted to 6 with 1 N aq. HCl. The mixture was filtered, and the filter cake was used directly in the next step without further purification. MS (ESI, m / e) [M+H] + 361.1.

[0714] Step 2: (7aR,11aS)-5-chloro-4-fluoro-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden [ka]

[0715] To a stirred solution of 5-(((3R,4S)-4-aminotetrahydro-2H-pyran-3-yl)oxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.0 mmol) in ACN (50 mL) at room temperature, DIEA (387 mg, 3.0 mmol) and BOPCl (508 mg, 2.0 mmol) were added, and the resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was concentrated and purified by flash chromatography (DCM / EtOAc = 5:1 to 3:1) to give the desired product (75 mg). MS (ESI, m / e) [M+H] + 343.1.

[0716] Step 3: (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden [ka]

[0717] To a stirred solution of (7aR,11aS)-5-chloro-4-fluoro-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiadene (75 mg, 0.2 mmol) in THF (3 mL) at 0 °C, NaH (24 mg, 0.6 mmol, 60%) was added, and the resulting mixture was stirred at 0 °C for 15 min. Then, CHCl (85 mg, 0.6 mmol) was added to the above mixture, and the reaction mixture was stirred at 50 °C for 3 h. The reaction was quenched with water, and the crude was purified by flash chromatography (PE / EtOAc = 5:1 to 1:1) to give the desired product (74 mg). MS (ESI, m / e) [M+H] + 357.1.

[0718] Step 4: (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-(methylsulfinyl)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden [ka]

[0719] To a stirred solution of (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiadene (74 mg, 0.21 mmol) in DCM (3 mL) at 0 °C, m-CPBA (43 mg, 0.21 mmol, 85%) was added, and the resulting mixture was stirred at 0 °C for 15 min. The reaction was quenched with aqueous NaSO and then extracted with DCM. The organic layer was washed with aqueous NaHCO and brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0720] Step 5: (7aR,11aS)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiadene [ka]

[0721] To a stirred solution of (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-(methylsulfinyl)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiadene (0.21 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (222 mg, 0.42 mmol) in THF (8 mL) at 0 °C, LiHMDS (0.4 mL, 0.42 mmol, 1 M in THF) was added dropwise, and the resulting mixture was stirred at 0 °C for 20 min. The reaction was quenched with aqueous NH4Cl and then extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the product (53 mg). MS (ESI, m / e) [M+H] + 468.3.

[0722] Step 6: 3-chloro-5-((7aR,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0723] (7aR,11aS)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden (27 mg, 0.06 mmol), 3-chloro-5-(4,4,5, To a mixture of 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (38 mg, 0.12 mmol), Pd(dtbpf)Cl (8 mg, 0.01 mmol), and NaHCO (15 mg, 0.18 mmol), dioxane (3.0 mL) and HO (0.6 mL) were added, and the resulting mixture was stirred at 90 °C for 1 h. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100:1 to 5:1) followed by prep-HPLC to give the product (7.9 mg). 1 H NMR (500 MHz, CD3OD) δ 6.92 - 6.83 (m, 1H), 6.62 - 6.30 (m, 1H), 5.42 - 5.20 (m, 1H), 4.46 - 4.17 (m, 4H), 4.11 - 3.95 (m, 2H), 3.54 - 3.43 (m, 2H), 3.40 - 3.32 (m, 3H), 3.29 - 3.14 (m, 2H), 3.11 - 2.97 (m, 1H), 2.53 - 1.63 (m, 8H). MS (ESI, m / e) [M+H] + 627.3.

[0724] Example 50: 3-chloro-5-((7aS,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,11a,12-tetrahydro-9H,11H-7,10-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0725] Example 50 was prepared by a procedure similar to that described in Example 49, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride with (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol to afford the title product (6.1 mg). 1 H NMR (500 MHz, CD3OD) δ 6.92 - 6.83 (m, 1H), 6.56 - 6.39 (m, 1H), 5.43 - 5.23 (m, 1H), 4.59 - 4.44 (m, 3H), 4.38 - 4.26 (m, 3H), 4.08 - 3.88 (m, 3H), 3.48 - 3.36 (m, 2H), 3.10 - 3.03 (m, 2H), 2.32 - 1.89 (m, 10H). MS (ESI, m / e) [M+H] + 627.2.

[0726] Example 51: 3-chloro-5-((7aR,11aR)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,11a,12-tetrahydro-9H,11H-7,10-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0727] Example 51 was prepared by a procedure similar to that described in Example 49, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride with (3R,4R)-3-aminotetrahydro-2H-pyran-4-ol hydrochloride to provide the title product (15 mg). 1H NMR (500 MHz, CD3OD) δ 6.92 - 6.83 (m, 1H), 6.60 - 6.32 (m, 1H), 5.49 - 5.23 (m, 1H), 4.62 - 4.26 (m, 4H), 4.10 - 3.86 (m, 2H), 3.55 - 3.34 (m, 4H), 3.27 - 3.19 (m, 1H), 3.16 - 3.05 (m, 1H), 2.47 - 1.84 (m, 8H). MS (ESI, m / e) [M+H] + 627.3.

[0728] Example 52: 3-chloro-5-((8aS,11aR)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,10,11,11a,12-hexahydro-8H-7-oxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0729] Step 1: ((1S,2R)-2-(methylamino)cyclopentyl)methanol [ka]

[0730] A solution of (1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (1 g, 4.4 mmol) in THF (20 mL) at ambient temperature was treated with lithium aluminum hydride (1N in THF, 5.3 mL) followed by reflux for 16 h. The mixture was cooled to 0-5°C and carefully quenched with excess sodium sulfate decahydrate. Additional THF and diethyl ether were added to facilitate stirring. The mixture was filtered through Celite® and the filtrate was evaporated to give the product (0.44 g). MS (ESI, m / e) [M+H]+ 130.

[0731] Example 52 was prepared by a similar procedure as described in Example 11 by substituting ((1S,2R)-2-(methylamino)cyclopentyl)methanol for (3-((methylamino)methyl)oxetan-3-yl)methanol to afford the title product (5.9 mg). 1 H NMR (500 MHz, CD3OD) δ 6.92 - 6.86 (m, 1H), 6.64 - 6.40 (m, 1H), 5.44 - 5.23 (m, 1H), 4.43 - 4.23 (m, 3H), 3.79 - 3.37 (m, 4H), 3.17 - 3.04 (m, 1H), 2.60 - 1.46 (m, 16H). MS (ESI, m / e) [M+H] + 625.2.

[0732] Example 53: 3-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-11-methyl-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,1'-cyclopropane]-1(11a),2,3a,3a1(6a),5-pentaen-5-yl)-5-methyl-4-(trifluoromethyl)aniline [ka]

[0733] Example 53 was prepared by a procedure similar to that described in Example 31 by replacing 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline with 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline in the final step to provide the title product (13.7 mg). 1H NMR (500 MHz, CD3OD) δ 6.78 - 6.60 (m, 1H), 6.60 - 6.34 (m, 1H), 5.41 - 5.21 (m, 1H), 4.58 - 4.48 (m, 2H), 4.36 - 4.18 (m, 2H), 3.36 (s, 3H), 3.27 - 3.23 (m, 2H), 3.09 - 3.00 (m, 1H), 2.68 - 1.48 (m, 11H), 1.10 - 0.42 (m, 4H). MS (ESI, m / e) [M+H] + 591.2.

[0734] Example 54: 3-(11-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,1'-cyclopropane]-1(11a),2,3a,3a1(6a),5-pentaen-5-yl)-5-methyl-4-(trifluoromethyl)aniline [ka]

[0735] Example 54 was prepared by a similar procedure as described in example 31 / 53 by substituting 2-(1-(methylamino)cyclopropyl)ethan-1-ol and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline for 2-(1-(ethylamino)cyclopropyl)ethan-1-ol and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline to afford the title product (11 mg). 1H NMR (500 MHz, CD3OD) δ 6.72-6.64 (m, 1H), 6.60-6.30 (m, 1H), 5.43-5.25 (m, 1H), 4.60-4.54 (m, 2H), 4.43-4.30 (m, 2H), 4.10-4.04 (m, 1H), 3.92-3.77 (m, 1H), 3.40-3.32 (m, 2H), 3.14-3.04 (m, 1H), 2.69-1.90 (m, 10H), 1.70-1.53 ​​(m, 1H), 1.50-1.40 (m, 3H), 1.20-0.80 (m, 3H), 0.70-0.43 (m, 1H). MS (ESI, m / e) [M+H] + 605.4.

[0736] Example 55: 3-chloro-5-(11-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,1′-cyclopropane]-1(11a),2,3a,3a1(6a),5-pentaen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0737] Example 55 was prepared by a similar procedure as described in Example 54 by substituting 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline for 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline to provide the title product (16 mg). 1H NMR (500 MHz, DMSO-d6) δ 6.90-6.80 (m, 1H), 6.65-6.28 (m, 3H), 5.38-5.20 (m, 1H), 4.62-4.50 (m, 2H), 4.13-3.58 (m, 4H), 3.36-3.30 (m, 2H), 3.10-2.89 (m, 3H), 2.85-2.78 (m, 1H), 2.16-1.87 (m, 3H), 1.84-1.72 (m, 3H), 1.57-1.46 (m, 1H), 1.34-1.28 (m, 3H), 1.07-0.98 (m, 1H), 0.87-0.74 (m, 2H). MS (ESI, m / e) [M+H] + 625.4.

[0738] Example 56: 3-(11-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8,9-dihydro-11H-7-oxa-1,3,6,11-tetraazaspiro[cycloocta[de]naphthalene-10,3'-oxetane]-1(11a),2,3a,3a1(6a),5-pentaen-5-yl)-5-methyl-4-(trifluoromethyl)aniline [ka]

[0739] Example 56 was prepared by a similar procedure as described in example 35 by substituting 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline for 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline to provide the title product (18.5 mg). 1H NMR (500 MHz, CD3OD) δ 6.67 (s, 1H), 6.51-6.39 (m, 1H), 5.48-5.27 (m, 1H), 4.69-4.48 (m, 4H), 4.46-4.29 (m, 2H), 3.80-3.58 (m, MS (ESI, m / e) [M+H] + 621.4.

[0740] Example 57: 3-((7aR,11aS)-12-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-5-methyl-4-(trifluoromethyl)aniline [ka]

[0741] Step 1: (7aR,11aS)-5-chloro-12-ethyl-4-fluoro-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden [ka]

[0742] To a stirred solution of (7aR,11aS)-5-chloro-4-fluoro-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiadene (482 mg, 1.4 mmol) in DMF (15 mL) at 0 °C, NaH (168 mg, 4.2 mmol, 60%) was added, and the resulting mixture was stirred at 0 °C for 15 min. Then, CHCl (655 mg, 4.2 mmol) was added to the above mixture, and the reaction mixture was stirred at 50 °C for 6 h. The reaction was quenched with water, and the crude was purified by flash chromatography (PE / EtOAc = 5:1 to 1:1) to give the desired product (466 mg). MS (ESI, m / e) [M+H] + 371.2.

[0743] Step 2: (7aR,11aS)-5-chloro-12-ethyl-4-fluoro-2-(methylsulfinyl)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden [ka]

[0744] To a stirred solution of (7aR,11aS)-5-chloro-12-ethyl-4-fluoro-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiadene (466 mg, 1.26 mmol) in DCM (10 mL) at 0 °C, m-CPBA (256 mg, 1.26 mmol, 85%) was added, and the resulting mixture was stirred at 0 °C for 15 min. The reaction was quenched with aqueous NaSO and then extracted with DCM. The organic layer was washed with aqueous NaHCO and brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was used directly in the next step without further purification.

[0745] Step 3: (7aR,11aS)-5-chloro-12-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden [ka]

[0746] To a stirred solution of (7aR,11aS)-5-chloro-12-ethyl-4-fluoro-2-(methylsulfinyl)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiadene (1.26 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (400 mg, 2.52 mmol) in THF (15 mL) at 0 °C, LiHMDS (2.5 mL, 2.52 mmol, 1 M in THF) was added dropwise, and the resulting mixture was stirred at 0 °C for 20 min. The reaction was quenched with aqueous NH4Cl and then extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH=100:1 to 30:1) to give the product (270 mg). MS (ESI, m / e) [M+H] + 482.4.

[0747] Step 4: 3-((7aR,11aS)-12-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-5-methyl-4-(trifluoromethyl)aniline

[0748] (7aR,11aS)-5-chloro-12-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden (80 mg, 0.17 mmol), 3-methyl-5-(4,4,5 To a mixture of 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (75 mg, 0.25 mmol), Pd(dtbpf)Cl (22 mg, 0.03 mmol), and NaHCO (29 mg, 0.34 mmol), dioxane (5.0 mL) and HO (1.0 mL) were added, and the reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100:1 to 5:1) followed by prep-HPLC to give the product (36.2 mg). 1 H NMR (500 MHz, CD3OD) δ 6.68 (s, 1H), 6.55 - 6.21 (m, 1H), 5.48 - 5.17 (m, 1H), 4.49 - 4.17 (m, 4H), 4.13 - 3.81 (m, 4H), 3.59 - 3.41 (m, 2H), 3.11 - 2.97 (m, 1H), 2.62 - 1.68 (m, 11H), 1.61 - 1.34 (m, 3H). MS (ESI, m / e) [M+H] + 621.4.

[0749] Example 58: 3-chloro-5-((7aR,11aS)-12-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0750] (7aR,11aS)-5-chloro-12-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden (126 mg, 0.26 mmol), 3-chloro-5-(4,4,5, To a mixture of 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (100 mg, 0.31 mmol), Pd(dtbpf)Cl (33 mg, 0.05 mmol), and NaHCO (44 mg, 0.52 mmol), dioxane (10 mL) and HO (2.0 mL) were added, and the resulting mixture was stirred at 90 °C for 1 h. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100:1 to 5:1) followed by prep-HPLC to give the product (48.5 mg). 1 H NMR (500 MHz, CD3OD) δ 6.88 (s, 1H), 6.62 - 6.29 (m, 1H), 5.47 - 5.22 (m, 1H), 4.45 - 4.20 (m, 4H), 4.11 - 3.96 (m, 3H), 3.95 - 3.82 (m, 1H), 3.55 - 3.32 (m, 5H), 3.15 - 3.03 (m, 1H), 2.59 - 1.73 (m, 8H), 1.51 - 1.34 (m, 3H). MS (ESI, m / e) [M+H] + 641.4.

[0751] Example 59: 3-((7aR,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-5-methyl-4-(trifluoromethyl)aniline [ka]

[0752] Step 1: 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine [ka]

[0753] To a solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.12 g, 4.0 mmol) in MeCN (30 mL) was added DIEA (774 mg, 6.0 mmol) and POCl (797 mg, 5.2 mmol), and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification.

[0754] Step 2: (3R,4S)-4-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)tetrahydro-2H-pyran-3-ol [ka]

[0755] To a stirred solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (4.0 mmol, crude) in DCM (30 mL) at 0 °C, DIEA (1.3 g, 10 mmol) and (3R,4S)-4-(methylamino)tetrahydro-2H-pyran-3-ol hydrochloride (704 mg, 4.2 mmol) were added, and the resulting mixture was stirred at 0 °C for 30 min. The reaction mixture was concentrated and purified by flash chromatography (PE / EtOAc = 4:1 to 1:2) to give the desired product. MS (ESI, m / e) [M+H] + 393.2.

[0756] Step 3: (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden [ka]

[0757] To a stirred solution of (3R,4S)-4-((5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)(methyl)amino)tetrahydro-2H-pyran-3-ol (1.55 g, 3.9 mmol) in THF (30 mL) at 0 °C, NaH (236 mg, 5.9 mmol, 60%) was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with HO and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash chromatography (PE / EtOAc = 2:1 to 1:2) to give the desired product. MS (ESI, m / e) [M+H] + 357.2.

[0758] Step 4: (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-(methylsulfonyl)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden [ka]

[0759] To a stirred solution of (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-(methylthio)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiadene (545 mg, 1.5 mmol) in THF (16 mL) and HO (4.0 mL) was added RuCl (31 mg, 0.15 mmol). NaIO (963 mg, 4.5 mmol) was then added to the mixture in several portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / EtOAc (1:1) to give the title product. MS (ESI, m / e) (M+H) + 389.1.

[0760] Step 5: (7aR,11aS)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiadene [ka]

[0761] To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (95 mg, 0.6 mmol) in THF (1.5 mL) at 0° C., LiHMDS (0.6 mL, 1.0 M in THF) was added, and the resulting mixture was stirred at this temperature for 10 min. The above mixture was then added to a mixture of (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-(methylsulfonyl)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiadene (122 mg, 0.3 mmol) and 4A MS (150 mg, 4A MS was previously baked in a muffle furnace at 400 °C for 4 h) in THF (3.0 mL) at 0 °C, and the resulting mixture was stirred for an additional 5 min at 0 °C. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (30:1) to give the title product. MS (ESI, m / e) (M+H) + 468.3.

[0762] Step 6: 3-((7aR,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-5-methyl-4-(trifluoromethyl)aniline

[0763] To a mixture of (7aR,11aS)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiadene (469 mg, 1.25 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (566 mg, 1.88 mmol), Pd(dtbpf)Cl (163 mg, 0.25 mmol), and NaHCO (315 mg, 3.75 mmol), dioxane (15 mL) and HO (3.0 mL) were added. The reaction mixture was stirred for 1 hour at 90° C. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 10:1) and then prep-HPLC to give the product. 1 H NMR (500 MHz, CD3OD) δ 6.68 (s, 1H), 6.57 - 6.25 (m, 1H), 5.50 - 5.26 (m, 1H), 4.50 - 4.32 (m, 3H), 4.31 - 4.18 (m, 1H), 4.13 - 3.92 (m, 2H), 3.61 - 3.09 (m, 9H), 2.60 - 2.49 (m, 1H), 2.48 - 2.26 (m, 5H), 2.26 - 2.17 (m, 1H), 2.16 - 2.04 (m, 2H), 2.03 - 1.90 (m, 1H), 1.80 - 1.62 (m, 1H).MS (ESI, m / e) [M+H] + 607.4.

[0764] Example 60: 3-chloro-5-((7aR,11aS)-4-fluoro-12-methyl-2-((7-methyloctahydropyrido[2,1-c][1,4]oxazin-7-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0765] Step 1: (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-((7-methyloctahydropyrido[2,1-c][1,4]oxazin-7-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden [ka]

[0766] To a stirred mixture of (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-(methylsulfonyl)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiadene (200 mg, 0.5 mmol), (7-methyloctahydropyrido[2,1-c][1,4]oxazin-7-yl)methanol (185 mg, 1.0 mmol), and MS 4A (500 mg, previously baked in a muffle furnace at 400 °C for 4 h) in THF (4.0 mL) at 0 °C, LiHMDS (1.0 mL, 1.0 M in THF) was added, and the resulting mixture was stirred at 0 °C for 10 min. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (30:1) to give the title product. MS (ESI, m / e) (M+H) + 494.4.

[0767] Step 2: 3-chloro-5-((7aR,11aS)-4-fluoro-12-methyl-2-((7-methyloctahydropyrido[2,1-c][1,4]oxazin-7-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleiaden-5-yl)-4-(trifluoromethyl)aniline

[0768] To a mixture of (7aR,11aS)-5-chloro-4-fluoro-12-methyl-2-((7-methyloctahydropyrido[2,1-c][1,4]oxazin-7-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiadene (100 mg, 0.20 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (77 mg, 0.24 mmol), Pd(dtbpf)Cl (26 mg, 0.04 mmol), and NaHCO (34 mg, 0.40 mmol), dioxane (7.5 mL) and HO (1.5 mL) were added. The reaction mixture was stirred for 1 hour at 90° C. The reaction mixture was concentrated and purified by flash chromatography (DCM / MeOH=100:1 to 10:1) and then prep-HPLC to give the product. 1 H NMR (500 MHz, CD3OD) δ 6.88 (s, 1H), 6.65 - 6.29 (m, 1H), 4.67 - 4.46 (m, 2H), 4.44 - 4.32 (m, 1H), 4.32 - 4.20 (m, 1H), 4.15 - 3.96 (m, 2H), 3.88 - 3.75 (m, 1H), 3.74 - 3.59 (m, 2H), 3.56 - 3.43 (m, 2H), 3.40 - 3.33 (m, 3H), 3.30 - 3.20 (m, 1H), 2.98 - 2.83 (m, 1H), 2.70 - 2.49 (m, 1H), 2.42 - 2.24 (m, 1H), 2.16 - 2.04 (m, 1H), 2.04 - 1.97 (m, 1H), 1.96 - 1.85 (m, 1H), 1.82 - 1.64 (m, 1H), 1.49 - 1.28 (m, 3H), 1.05 (s, 3H). MS (ESI, m / e) (M+H) + 653.4.

[0769] Example 61: 3-((7aR,11aR)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,11a,12-tetrahydro-9H,11H-7,10-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-5-methyl-4-(trifluoromethyl)aniline [ka]

[0770] Example 61 was prepared by a similar procedure as described in Example 51 by substituting 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline for 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline to provide the title product (33 mg). 1 H NMR (500 MHz, CD3OD) δ 6.75 - 6.60 (m, 1H), 6.52 - 6.30 (m, 1H), 5.47 - 5.25 (m, 1H), 4.62 - 4.26 (m, 4H), 4.10 - 3.86 (m, 2H), 3.55 - 3.34 (m, 4H), 3.27 - 3.19 (m, 1H), 3.16 - 3.05 (m, 1H), 2.47 - 1.84 (m, 11H). MS (ESI, m / e) [M+H] + 607.4.

[0771] Example 62: 3-chloro-5-((7aR,11aS)-4-fluoro-12-methyl-2-(((S)-2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0772] Example 62 was prepared by a similar procedure as described in Example 49 by substituting (S)-(2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol for ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol to afford the title product (25 mg). 1 H NMR (500 MHz, CD3OD) δ 6.88 (s, 1H), 6.62 - 6.32 (m, 1H), 5.09 (s, 2H), 4.53 - 4.32 (m, 3H), 4.31 - 4.19 (m, 1H), 4.13 - 3.90 (m, 3H), 3.60 - 3.42 (m, 3H), 3.38 - 3.33 (m, 4H), 2.97 - 2.79 (m, 2H), 2.66 - 2.46 (m, 2H), 2.30 - 2.17 (m, 1H), 2.13 - 1.88 (m, 3H), 1.78 - 1.58 (m, 1H). MS (ESI, m / e) [M+H] + 621.4.

[0773] Example 63: 3-chloro-5-((7aR,11aS)-2-((2,4-dimethylmorpholin-2-yl)methoxy)-4-fluoro-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0774] Example 63 was prepared by a procedure similar to that described in Example 49 by substituting (2,4-dimethylmorpholin-2-yl)methanol for ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol to afford the title product (7 mg). 1H NMR (500 MHz, DMSO-d6) δ 6.86 (s, 1H), 6.59 - 6.25 (m, 3H), 4.72 - 4.54 (m, 1H), 4.44 (s, 1H), 4.30 - 4.20 (m, 1H), 4.15 - 3.86 (m, 3H), 3.77 - 3.59 (m, 2H), 3.49 - 3.34 (m, 2H), 3.32 (s, 3H), 2.47 - 2.43 (m, 2H), 2.33 (s, 1H), 2.25 - 2.08 (m, 5H), 1.60 (s, 1H), 1.25 (s, 3H). MS (ESI, m / e) [M+H] + 613.4.

[0775] Example 64: 3-chloro-5-((7aR,11aS)-4-fluoro-12-methyl-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0776] Example 64 was prepared by a procedure similar to that described in Example 49 by substituting ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol with ((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methanol to afford the title product (45 mg). 1H NMR (500 MHz, CD3OD) δ 6.88 (s, 1H), 6.61 - 6.37 (m, 1H), 4.53 - 4.33 (m, 3H), 4.32 - 4.20 (m, 1H), 4.12 - 3.94 (m, 2H), 3.55 - 3.45 (m, 2H), 3.36 (s, 3H), 3.21 - 3.04 (m, 1H), 2.83 (s, 1H), 2.69 - 2.57 (m, 1H), 2.57 - 2.38 (m, 4H), 2.05 - 1.84 (m, 3H), 1.83 - 1.69 (m, 7H), 1.66 - 1.57 (m, 1H). MS (ESI, m / e) [M+H] + 637.4.

[0777] Example 65: 3-((7aR,11aS)-4-fluoro-12-methyl-2-(((4aS,7aR)-1-methyloctahydro-4aH-cyclopenta[b]pyridin-4a-yl)methoxy)-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapuleiaden-5-yl)-5-methyl-4-(trifluoromethyl)aniline [ka]

[0778] Example 65 was prepared by a similar procedure as described in Example 64 by substituting 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline for 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline to provide the title product (43 mg). 1H NMR (500 MHz, CD3OD) δ 6.69 (s, 1H), 6.53 - 6.28 (m, 1H), 4.56 - 4.48 (m, 1H), 4.46 - 4.32 (m, 2H), 4.27 (s, 1H), 4.12 - 3.95 (m, 2H), 3.69 (s, 1H), 3.51 - 3.44 (m, 2H), 3.36 (s, 3H), 3.28 - 3.20 (m, 1H), 3.19 - 3.09 (m, 1H), 2.83 (s, 3H), 2.59 - 2.49 (m, 1H), 2.41 (s, 3H), 2.25 - 2.11 (m, 2H), 2.05 - 1.94 (m, 2H), 1.91 - 1.67 (m, 7H). MS (ESI, m / e) [M+H] + 617.4.

[0779] Example 66: 3-chloro-2-fluoro-5-((7aR,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-4-(trifluoromethyl)aniline [ka]

[0780] Example 66 was prepared by a similar procedure as described in Example 59 by substituting 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline for 3-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline to provide the title product (72 mg). 1H NMR (500 MHz, CD3OD) δ 6.85 - 6.52 (m, 1H), 5.49 - 5.28 (m, 1H), 4.51 - 4.22 (m, 4H), 4.17 - 3.92 (m, 2H), 3.53 - 3.41 (m, 5H), 3.34 (s, 3H), 3.21 - 3.12 (m, 1H), 2.59 - 2.18 (m, 4H), 2.16 - 1.91 (m, 3H), 1.72 (s, 1H). MS (ESI, m / e) [M+H] + 645.4.

[0781] Example 67: 2-fluoro-5-((7aR,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-7a,8,10,11,11a,12-hexahydro-7,9-dioxa-1,3,6,12-tetraazapleyaden-5-yl)-3-methyl-4-(trifluoromethyl)aniline [ka]

[0782] Example 67 was prepared by a similar procedure as described in example 59 by substituting 2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline for 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline to provide the title product (35 mg). 1H NMR (500 MHz, CD3OD) δ 6.68 - 6.45 (m, 1H), 5.49 - 5.28 (m, 1H), 4.45 - 4.21 (m, 4H), 4.11 - 3.94 (m, 2H), 3.58 - 3.38 (m, 5H), 3.36 (s, 3H), 3.21 - 3.06 (m, 1H), 2.56 - 1.88 (m, 10H), 1.78 - 1.66 (m, 1H). MS (ESI, m / e) [M+H] + 625.4.

[0783] Example 68 Isomer 1 and Isomer 2: 3-chloro-5-((8aR,11aR)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,11a,12-tetrahydro-8H,11H-7,10-dioxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalen-5-yl)-4-(trifluoromethyl)- ... methyl)aniline, and 3-chloro-5-((8aS,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,11a,12-tetrahydro-8H,11H-7,10-dioxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalen-5-yl)-4-(trifluoromethyl)aniline [ka]

[0784] Step 1: 7-chloro-8-fluoro-5-((trans-4-(methylamino)tetrahydrofuran-3-yl)methoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol [ka]

[0785] To a solution of trans-(4-(methylamino)tetrahydrofuran-3-yl)methanol (2 g, 15.2 mmol) and 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (4.2 g, 15.2 mmol) in THF (250 mL) at room temperature, sodium hydride (3.05 g, 76.3 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was quenched with ice water and concentrated to give a residue. The residue was purified by flash silica column (DCM:MeOH=10:1) to give the title product (1.5 g). MS (ESI, m / e) [M+H] + 375.

[0786] Step 2: (8a,11a-trans)-5-chloro-4-fluoro-12-methyl-2-(methylthio)-8a,9,11a,12-tetrahydro-8H,11H-7,10-dioxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene [ka]

[0787] To a solution of 7-chloro-8-fluoro-5-((trans-4-(methylamino)tetrahydrofuran-3-yl)methoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (1.5 g, 4 mmol) in 300 mL of ACN at room temperature, N,N-diisopropylethylamine (1.5 g, 12 mmol) and Bop-Cl (2.03 g, 8 mmol) were added, which was stirred at 70° C. for 16 hours. After completion, the reaction mixture was quenched with ice water and concentrated to give a residue. The residue was purified by flash silica column (DCM:MeOH=20:1) to give the title product. MS (ESI, m / e) [M+H] + 357.

[0788] Step 3: (8a,11a-trans)-5-chloro-4-fluoro-12-methyl-2-(methylsulfonyl)-8a,9,11a,12-tetrahydro-8H,11H-7,10-dioxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene [ka]

[0789] To a stirred solution of (8a,11a-trans)-5-chloro-4-fluoro-12-methyl-2-(methylthio)-8a,9,11a,12-tetrahydro-8H,11H-7,10-dioxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene (270 mg, 0.76 mmol) in THF (16 mL) and HO (4.0 mL) was added RuCl (23.5 mg, 0.11 mmol). NaIO (492 mg, 2.28 mmol) was then added in portions to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / EtOAc (1:1) to give the title product. MS (ESI, m / e) [M+H] + 389.1.

[0790] Step 4: (8a,11a-trans)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,11a,12-tetrahydro-8H,11H-7,10-dioxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene [ka]

[0791] To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (106 mg, 0.67 mmol) in THF (15 mL) at 0° C., LiHMDS (1 mL, 1.0 M in THF) was added, and the resulting mixture was stirred at this temperature for 10 min. The mixture was then added to a mixture of (8a,11a-trans)-5-chloro-4-fluoro-12-methyl-2-(methylsulfonyl)-8a,9,11a,12-tetrahydro-8H,11H-7,10-dioxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalene (130 mg, 0.33 mmol) and MS 4A (150 mg, previously baked in a muffle furnace at 400 °C for 4 h) in THF (3.0 mL) at 0 °C, and the resulting mixture was stirred for an additional 5 min at 0 °C. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (30:1) to give the title product. MS (ESI, m / e) [M+H] + 468.3.

[0792] Step 5: 3-chloro-5-((8aR,11aR)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,11a,12-tetrahydro-8H,11H-7,10-dioxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalen-5-yl)-4-(trifluoromethyl)anilini Phosphorus and 3-chloro-5-((8aS,11aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,11a,12-tetrahydro-8H,11H-7,10-dioxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2,3-de]naphthalen-5-yl)-4-(trifluoromethyl)aniline

[0793] (8a,11a-trans)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-12-methyl-8a,9,11a,12-tetrahydro-8H,11H-7,10-dioxa-1,3,6,12-tetraazacyclopenta[5,6]cycloocta[1,2, To a solution of [3-de]naphthalene (130 mg, 0.28 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (134 mg, 0.42 mmol), NaHCO (70 mg, 0.84 mmol), and Pd(dppf)Cl (41 mg, 0.05 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The resulting cooled mixture was concentrated and purified by column chromatography (DCM / MeOH=10 / 1) to give a residue that was further purified by prep-HPLC to give a mixture of Isomer 1 and Isomer 2 of Example 68. Each of the isomers in the mixture (88 mg) was further separated using preparative chiral HPLC (Prep-HPLC-Gilson GX-281, column: I-Cellulose-5 4.6*250 mm 5 μm, diluent: ethanol (5.5 mL), injection volume: 1 mL or 1.5 mL each time, mobile phase A: hexane, mobile phase B: ethanol containing 0.2% 2M NH3 in methanol, gradient: mobile phase A:mobile phase B (50%:50%, v / v), flow rate: 18 mL / min, temperature: 25 °C, wavelength: UV 220 nm and 240 nm, retention time: isomer 1: 6.5 min, and retention time: isomer 2: 8.5 min). Analytical chiral HPLC method: the equipment is HPLC-Agilent 1260 Infinity II, the column is ChiralPak IC 4.6*150mm 5uM, the diluent is ethanol, the injection volume is 2uL, the mobile phase A is hexane, the mobile phase B is ethanol containing 0.1% 2M NH3 in methanol, the gradient is mobile phase A:mobile phase B (60%:40%, v / v), the flow rate is 1.0mL / min, the temperature is 25℃, and the wavelength is UV 214nm and 254nm.

[0794] Isomer 1: Retention time by analytical chiral HPLC is 4.1 minutes. 1 H NMR (500 MHz, CD3OD) δ 6.89 (s, 1H), 6.69 - 6.36 (m, 1H), 5.45 - 5.18 (m, 1H), 4.28 - 3.65 (m, 5H), 3.53 - 3.38 (m, 1H), 3.32 - 3.13 (m, 9H), 3.08 - 2.86 (m, 2H), 2.42 - 2.08 (m, 3H), 2.06 - 1.81 (m, 3H). MS (ESI, m / e) [M+H] + 627.4.

[0795] Isomer 2: Retention time by analytical chiral HPLC is 6.5 min. 1 H NMR (500 MHz, CD3OD) δ 6.89 (s, 1H), 6.69 - 6.36 (m, 1H), 5.45 - 5.18 (m, 1H), 4.40 - 4.28 (m, 1H), 4.26 - 4.18 (m, 1H), 4.17 - 4.03 (m, 2H), 4.00 - 3.74 (m, 1H), 3.54 - 3.38 (m, 1H), 3.33 - 3.15 (m, 9H), 3.08 - 2.87 (m, 2H), 2.39 - 2.07 (m, 3H), 2.05 - 1.81 (m, 3H). [M+H] + 627.4.

[0796] Assay KRAS WT and KRAS G12V probe displacement assay

[0797] This assay was used to identify compounds capable of binding to GDP-loaded KRAS protein and displacing a biotinylated probe occupying 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 (final concentration 3 nM) or KRAS G12V protein (final concentration 2 nM) was incubated with 3-fold serial dilutions of compounds in an assay plate (384-well black microplate, Corning). The plate was incubated at 24°C for 1 hour. After incubation, biotinylated probe 1 for WT KRAS (final assay concentration 60 nM) and biotinylated probe 2 for KRAS G12V (final assay concentration 2.5 nM) were added to the assay plate, respectively. After 1 hour of incubation at 24°C, MAb Anti-GST-Tb Cryptate (Cisbio) and Streptavidin-XL665 (Cisbio) were added and incubated for another hour at 24°C. TR-FRET signals (excitation 337 nm, emission 665 nm / 620 nm) were read on a BMG PHERAstar FSX instrument. With increasing concentrations of compounds, the percentage inhibition of KRAS protein binding to the biotinylated probe was calculated based on the ratio of fluorescence at 665 nm to fluorescence at 620 nm. The IC of each compound was calculated. 50 Values ​​were calculated by fitting data to a four-parameter logistic model in Dotmatics.

[0798] KRAS WT and KRAS G12D probe displacement assay

[0799] This assay was used to identify compounds capable of binding to GDP-loaded KRAS protein and displacing a biotinylated probe occupying the KRAS binding site. GST-tagged, GDP-loaded WT KRAS (amino acids 1-188) and GST-tagged, GDP-loaded KRAS G12D (amino acids 1-188) were expressed in E. coli and purified in-house. All proteins and reaction solutions were prepared in assay buffer containing 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 (final concentration 3 nM) or KRAS G12D protein (final concentration 0.5 nM) was incubated with 3-fold serial dilutions of compounds in an assay plate (384-well black microplate, Corning). The plate was incubated at 24°C for 1 hour. After incubation, biotinylated probe 1 for WT KRAS (final assay concentration 60 nM) and biotinylated probe 2 for KRAS G12D (final assay concentration 4 nM) were added to the assay plate, respectively. After 1 hour of incubation at 24°C, MAb Anti-GST-Tb Cryptate (Cisbio) and Streptavidin-XL665 (Cisbio) were added and incubated for another hour at 24°C. TR-FRET signals (excitation 337 nm, emission 665 nm / 620 nm) were read on a BMG PHERAstar FSX instrument. With increasing concentrations of compounds, the percentage inhibition of KRAS protein binding to the biotinylated probe was calculated based on the ratio of fluorescence at 665 nm to fluorescence at 620 nm. The IC of each compound was calculated. 50 Values ​​were calculated by fitting data to a four-parameter logistic model in Dotmatics.

[0800] KRAS G12V pERK assay

[0801] This study used the SW620 cell line. Cells were maintained in RPMI 1640 supplemented with 10% fetal bovine serum (Thermo Fisher) and 50 units / mL penicillin and streptomycin (Thermo Fisher) at 37°C in a humidified atmosphere of 5% CO2 in air. Cells were reconstituted from frozen stocks established within 30 passages of the original purchased cells. 40,000 cells per well were seeded in a 96-well plate and incubated overnight. Cells were treated with a 10-fold dilution series. Final compound concentrations ranged from 0 to 10 μM. After 2 hours of compound treatment, cells were lysed, and pERK1 / 2 (THR202 / TYR204) levels in the cell lysates were detected using an 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 overnight at room temperature in the dark with 2 μL of Eu3+-cryptate (donor)-labeled anti-phospho-ERK1 / 2 antibody and 2 μL of D2 (acceptor)-labeled anti-phospho-ERK1 / 2 antibody (Cisbio). When the donor and acceptor are in close proximity, laser excitation of the donor leads to fluorescence resonance energy transfer (FRET) toward the acceptor, which then emits fluorescence at 655 nm. FRET signals were measured using a PHERAstar FSX reader (BMG Labtech). IC50 values ​​were determined by fitting the curve of percent inhibition versus the logarithm of inhibitor concentration using Dotmatics.

[0802] KRAS G12D pERK assay

[0803] This study used the AsPC-1 cell line. Cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (Thermo Fisher) and 50 units / mL penicillin and streptomycin (Thermo Fisher) at 37°C in a humidified atmosphere of 5% CO2 in air. Cells were reconstituted from frozen stocks established within 30 passages of the original purchased cells. 30,000 cells per well were seeded in a 96-well plate and incubated overnight. Cells were treated with a 10-fold dilution series. Final compound concentrations ranged from 0 to 10 μM. After 2 hours of compound treatment, cells were lysed, and pERK1 / 2 (THR202 / TYR204) levels in the cell lysates were detected using an 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. The lysate from each well was incubated overnight in the dark at room temperature with 2 μL of Eu3+-cryptate (donor)-labeled anti-phospho-ERK1 / 2 antibody and 2 μL of D2 (acceptor)-labeled anti-phospho-ERK1 / 2 antibody (Cisbio). When the donor and acceptor are in close proximity, fluorescence resonance energy transfer (FRET) occurs toward the acceptor upon laser excitation of the donor, which then emits fluorescence at 655 nm. FRET signals were measured using a PHERAstar FSX reader (BMG Labtech). IC 50 was determined by fitting a curve of percent inhibition versus the logarithm of inhibitor concentration using Dotmatics.

[0804] Preparation and crystallization of KRAS G12D protein

[0805] Purification of KRAS G12D protein

[0806] KRAS G12D 1-169aa was cloned into the pET28a vector. The gene was placed in frame with an N-terminal 6Xhis tag and a Sumo tag. The construct was transformed into BL21(DE3) cells. The OD of the cells was increased by adding 1-thio-β-D-galactopyranoside (IPTG) to a final concentration of 200 μM, followed by overnight incubation at 16°C. 600 Protein expression was induced when the RI reached 0.6. Bacteria were harvested by centrifugation (4000 rpm, 20 min, 4°C), and 1 liter of cell paste was resuspended in 30 ml of 50 mM Tris (pH 8.0), 300 mM NaCl, 20 mM imidazole, and 5 mM MgCl2 supplemented with two packets of EDTA-free protease inhibitor cocktail (Roche Diagnostics). Protein was purified on a His-trap HP column (Cytiva) according to standard protocols. The N-terminal His-sumo tag was cleaved by overnight digestion with ULP1 protease, and the ULP1 His-sumo tag was removed by reloading onto a His-trap HP column (Cytiva). The protein was further purified by gel filtration using a HiLoad 16 / 600 Superdex 75 pg (Cytiva) column equilibrated with 20 mM Tris (pH 8.0), 100 mM NaCl, and 5 mM MgCl. The protein solution was concentrated to 30–40 mg / ml for crystallization studies.

[0807] KRAS G12D crystallization

[0808] Cocrystals of KRAS G12D with small molecule inhibitors were grown at 20 °C by mixing 1 μl of protein (40 mg / ml) with an equal volume of crystallization buffer and using the sitting-drop vapor diffusion method. Crystals appeared in droplets containing 1.0 M LiCl, 0.1 M citric acid (pH 5.0), and 20% PEG 6000. Diffraction data were collected at beamline BL10U2 of the Shanghai Synchrotron Radiation Facility.

[0809] Metabolic stability in liver microsomes from different species

[0810] First, liver microsomes were mixed with NADPH to a final concentration of 0.5 mg / mL and 1 mM NADPH, respectively. Test compounds were added to the incubation system at a final concentration of 1 μM and incubated at 37°C. The incubation was initiated by adding NADPH to the system. 20 μL aliquots were taken from the incubation system at 0, 15, 30, 45, and 60 minutes after the start of incubation. The reaction of the solution was stopped by adding cold acetonitrile containing analytical IS. The samples were centrifuged at 4000 rpm for 5 minutes and then analyzed by LC-MS / MS.

[0811] The sample peak areas at various time points were determined from the extracted ion chromatograms and then plotted to calculate metabolic stability. The slope value k was determined by linear regression of the natural logarithm of the parent drug remaining versus incubation time curve. The in vitro half-life (in vitro t 1 / 2 ) was determined from the slope value:

number

number

[0812] A control compound (verapamil) was included in the assay to ensure data integrity, and a negative control (identical experimental setup but without NADPH in the incubation system) was used to exclude misleading factors due to the instability of the chemical itself.

[0813] CYP (cytochrome P450) enzyme inhibition assay in human liver microsomes.

[0814] Incubations were performed in a 96-well plate. 179 μL of human liver microsomes enriched with substrates for CYP1A2 (40 μM phenacetin), 2C9 (6 μM diclofenac), 2C19 (50 μM (S)-mephenytoin), 2D6 (10 μM dextromethorphan), and 3A4 (1 μM midazolam or 50 μM testosterone) were added with 1 μL of a standard solution of the test compound or vehicle. The incubation plate was preheated to 37°C in a water bath for 5 minutes, and the reaction was initiated by adding 20 μL of 10 mM NADPH solution. The reaction was performed in a 37°C water bath.

[0815] At predetermined time points, the reaction was stopped by adding 300 μL of quenching solution (acetonitrile containing internal standard) to each well. The sample plate was vortexed for 1 minute and centrifuged at 3000 g for 10 minutes. 100 μL of the supernatant was transferred to a new 96-well plate, then mixed with 100 μL of water and analyzed by LC-MS / MS, followed by data processing (i.e., determination of the percent inhibition or IC50 at 10 μM).

[0816] Time-dependent cytochrome P450 (CYP) enzyme inhibition assay (TDI) in human liver microsomes

[0817] The TDI assay involves pre-incubating 0.1 mg mL-1 human liver microsomes with 10 uM test compound and a positive control in the presence or absence of 1 mM NADPH for 30 min at 37°C ("inactivation incubation"). After the preincubation period, residual CYP activity was determined by adding substrate (40 μM phenacetin for 1A2, 50 μM bupropion for CYP2B6, 5 μM paclitaxel for CYP2C8, 6 μM diclofenac for CYP2C9, 50 μM (S)-mephenytoin for CYP2C19, 10 μM dextromethorphan for CYP2D6, and 1 μM midazolam or 50 μM testosterone for CYP3A) and NADPH to the preincubation mixture, and the "activity incubation" was continued for an additional 20 min for CYP1A2, 2B6, 2C19, and 2D6, an additional 10 min for CYP2C8 and CYP3A (testosterone), an additional 6 min for CYP2C9, and an additional 5 min for 3A (midazolam). All reactions are terminated by the addition of ice-cold acetonitrile containing an internal standard and then centrifuged for LC-MS / MS analysis.

[0818] Bidirectional permeability assay in MDCKII-MDR1 cell monolayers

[0819] First, MDCKII-MDR1 cells were prepared in cell seeding medium. 50 μL of the cultured cell suspension was added to each well of a pre-prepared Transwell plate. The plate was incubated for 4 to 8 days, with the medium replaced every other day. Prior to permeability measurements, the integrity of the cell monolayer was assessed by electrical resistance.

[0820] To measure the drug transport rate from the apical to the basolateral direction, 125 μL of a standard solution of the test compound was added to the Transwell insert (apical compartment), and 50 μL of a sample (D0 sample) was immediately transferred from the apical compartment to a new 96-well plate. To measure the drug transport rate from the basolateral to the apical direction, 285 μL of a standard solution of the compound was added to the receiver plate well (basolateral compartment), and 50 μL of a sample (D0 sample) was immediately transferred from the basolateral compartment to a new 96-well plate. The plate was incubated at 37°C for 2 hours. At the end of the transport period, 50 μL of the apical and basolateral wells were directly transferred to a new plate. 200 μL of cold acetonitrile containing internal standards (IS: 2 μM ketoprofen, 200 nM labetalol, 200 nM caffeine, and 100 nM alprazolam) was then added to the plate. The plate was vortexed for 5 minutes. Samples are centrifuged at 3,220 g for 20 minutes. A 100 μL aliquot of the supernatant is diluted with 100 μL of ultrapure HO, and the mixture is used for LC / MS / MS analysis. All incubations are performed in duplicate. The apparent permeability (Papp) in centimeters per second for the MDCKII-MDR1 drug transport assay can be calculated using the following formula:

number

number

number

[0821] In the formula, V A is the volume in the acceptor well (mL) (0.235 mL for apical to basal flux and 0.075 mL for basal to apical), and V D is the volume (mL) in the donor well (0.075 mL for apical to basal flux and 0.235 mL for basolateral to apical).

[0822] Intrinsic clearance in hepatocytes from different species

[0823] 10 mM stock solutions of test compounds and positive controls are prepared in the appropriate solvent (DMSO). Place incubation medium (William's E Medium supplemented with GlutaMAX) in a 37°C water bath and warm for at least 15 minutes before use. 10 mM test compounds and positive controls are diluted to 100 μM by combining 198 μL of 50% acetonitrile / 50% water with 2 μL of the 10 mM stock solution in separate conical tubes. Cryopreserved hepatocytes (0.5 x 10 6198 μL of 100 μM test compound or positive control (viable cells / mL) is pipetted into each well of a 96-well non-coated plate. 2 μL of 100 μM test compound or positive control is pipetted into each well of the 96-well non-coated plate to initiate the reaction. The final concentration of test compound or control compound is 1 μM. The plate is returned to the incubator and placed on an orbital shaker. At 0, 15, 30, 60, 90, and 120 minutes, the contents of the wells are removed in 25 μL aliquots. The aliquots are then mixed with 6 volumes (150 μL) of cold acetonitrile containing IS (2 μM ketoprofen, 200 nM labetalol, 200 nM caffeine, and 100 nM alprazolam) to terminate the reaction. Centrifuge at 3,220 g for 30 minutes. A 100 μL aliquot of the supernatant will be used for LC / MS / MS analysis. The supernatant may be diluted with ultrapure water depending on the LC-MS signal response and peak shape. All incubations are performed in duplicate.

[0824] All calculations are performed using Microsoft Excel. Peak areas are determined from extracted ion chromatograms. The in vitro half-life (t 1 / 2 ) is determined by regression analysis of the disappearance rate versus time curve of the parent compound.

[0825] In vitro half-life (in vitro t 1 / 2 ) is determined from the slope value: in vitro t 1 / 2 =0.693 / k in vitro t 1 / 2 In vitro intrinsic clearance (in vitro CL) int ,μL / min / 10 6 Conversion to HCl (cells) is performed using the following formula: In vitro CL int =kV / N

[0826] V = incubation volume (0.2 mL), N = number of hepatocytes per well (0.1 × 10 6 cell).

[0827] PK studies in mice and rats

[0828] The pharmacokinetics of compounds were evaluated in male CD-1 mice or SD-JVC rats by intravenous and oral administration. For intravenous administration, test compounds were dissolved in DMA:30% Solutol HS 15 (w / v):saline (20:20:60 by volume) and injected via the tail vein at a dose of 1 mg / kg. For oral administration, test compounds were dissolved in 0.5% MC or PEG400 / Phosal 50 PG / EtOH (30 / 60 / 10 by volume) and administered to mice by gavage at 10 mg / kg or 30 mg / kg. Animals were grouped and treated according to body weight. At post-administration time points (5 minutes (IV only), 15 minutes, and 30 minutes, and 1, 2, 4, 8, and 24 hours after administration), blood samples were collected from the JVC of rats, and mice were anesthetized with isoflurane and blood samples were collected by orbital bleeding. Blood samples were collected in 1.5 mL EDTA.K2-coated EP tubes. Approximately 50 μL of blood (mice) and 150 μL of blood (rats) were collected at each time point, placed on ice, and then centrifuged at 5600 rpm for 7 minutes at 4°C to obtain plasma. The plasma was transferred to a new tube and temporarily stored at -20°C or on dry ice. Samples were stored at -80°C until ex vivo PK assay.

[0829] Plasma concentrations were measured using the following sample processing method and measurement conditions: 200 μL of IS (terfenadine, 5 ng / mL) in ACN was added to a 10 μL aliquot of the sample. The mixture was vortexed for 1 minute and centrifuged at 4000 rpm for 10 minutes at 4°C. An 80 μL aliquot of the supernatant was diluted with 80 μL of water, and the mixed sample was injected into a liquid chromatography-tandem mass spectrometer (LC-MS / MS, Triple Quad 5500) for analysis. The volume of the injected sample was 2 μL. Monitor: MRM, Column: Advanced Materials Technology, HALO AQ-C18 2.7 μm 90 Å, 50*2.1 mm, Column temperature: 40 °C, Mobile phase A: H2O-0.1% FA, Mobile phase B: ACN-0.1% FA, Gradient program: 15% B - 15% B (0 min - 0.3 min), 15% B - 90% B (0.3 min - 1.0 min), 90% B - 90% B (1.0 min - 1.8 min), 90% B - 30% B (1.8 min - 2.0 min), 30% B - 30% B (2.0 min - 2.5 min).

[0830] SW1990 PD Test:

[0831] Female NCG mice were treated with 5 x 10 cells per 200 µL PBS / Matrigel on the right flank. 6 SW1990 cells were subcutaneously transplanted. After seeding, the tumor size was approximately 350–450 mm in average volume. 3 Upon reaching 100 mg / kg, mice were randomly assigned to treatment groups. Randomized mice received a single oral dose of vehicle or test compound (e.g., 30 or 100 mg / kg) in 0.5% MC. Plasma was collected 0.5, 2, 4, and 7 hours after administration, and tumors were harvested 7 hours after administration to determine exposure levels. Tumor pieces were snap-frozen in liquid nitrogen in homogenization tubes and homogenized in T-PER Tissue Protein Extraction Buffer supplemented with protease and phosphatase inhibitors before use. Tumor lysates were then analyzed for ERK1 / 2 phosphorylation.

[0832] SW1990 Efficacy Test:

[0833] Female NCG mice were treated with 5 x 10 cells per 200 µL PBS / Matrigel on the right flank. 6 SW1990 cells were subcutaneously transplanted. After seeding, the tumor size was approximately 150–250 mm in average volume. 3 Upon reaching a tumor mass of 1000 mg / kg, mice were randomly assigned to treatment groups. Randomized mice were orally administered a vehicle consisting of 0.5% MC or test compound at various doses (e.g., 30 or 100 mg / kg BID). Animals were monitored daily, and tumor volume was measured twice weekly in two dimensions using calipers and calculated using the formula: V = 0.5(a × b 2 ) (where a and b are the long and short diameters of the tumor, respectively) 3 A partial response (PR) was defined as a tumor volume that was less than 50% of the initial tumor volume on the first day of treatment in three consecutive measurements, and a complete response (CR) was defined as a tumor volume that was 14 mm or less in three consecutive measurements. 3 Tumor growth inhibition (TGI) was calculated using the following formula:

number

[0834] SW620 PD Test:

[0835] Female NOD / SCID mice were injected with 5 x 10 cells per 200 μL PBS / Matrigel into the right fla...

Claims

1. Compounds having formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof (In the formula, Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; Ring B is unsubstituted or substituted cycloalkyl or unsubstituted or substituted heterocyclyl; X is N or C-R ８ and R ０ each independently represents H, halogen, amino, —CN, —OH, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkenyl, unsubstituted or substituted C １－４ Alkynyl, unsubstituted or substituted C １－４ Alkoxy, unsubstituted or substituted C ３－５ Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C １－４ alkylamino, carboxy, nitro, thiol, or thioether, or ０ one or more pairs of groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ａ , and R ５ｂ each independently represents H, halogen, unsubstituted or substituted amino, —CN, —OH, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkoxy, unsubstituted or substituted C ３－５ Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C １－４ alkylamino, carboxy, nitro, thiol, or thioether; or Optionally, R ３ａ , and R ３ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R ４ａ , and R ４ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R ５ａ , and R ５ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or The R ３ａ group, and the R ４ａ groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or The R ３ａ group, and the R ５ａ groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or The R ４ａ group, and the R ５ａ groups, together with the atoms to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R ６ is H, unsubstituted or substituted C １－８ Alkyl, unsubstituted or substituted C １－８ Alkoxy, unsubstituted or substituted C ３－８ cycloalkyl, or unsubstituted or substituted 3- to 8-membered heterocyclyl; R ８ is H, halogen, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkenyl, unsubstituted or substituted C ３－５ Cycloalkyl, unsubstituted or substituted C １－４ Alkoxyl, unsubstituted or substituted C １－４ Alkyl halides, unsubstituted or substituted C ３－５ Halogenated cycloalkyl, unsubstituted or substituted C １－４ halogenated alkoxyl, CN, OH, or amino; t is 0 or 1; Each of m and q is independently an integer from 0 to the maximum number of said substituents permitted on ring A and ring B, respectively.

2. X is N, C—H, C—Cl, or C—CF ３ 2. The compound of claim 1, wherein:

3. The compound of claim 2, wherein ring A is substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzo[b]thiophenyl, or substituted or unsubstituted benzo[d]thiazolyl, and ring B is substituted or unsubstituted hexahydro-1H-pyrrolidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted aminomethylcyclopropyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted oxabicyclo[2.1.1]hexanyl, or substituted or unsubstituted oxabicyclo[2.2.1]heptanyl.

4. Ring A is 【Chemistry 2】 3. The compound of claim 2, wherein:

5. Ring B is 【Chemistry 3】 and Here, R ａ and R ｂ each independently represents a substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ cycloalkyl, or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S; R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ The compound of claim 4 which is an alkoxyl.

6. R ６ is unsubstituted or substituted C １－５ Alkyl, unsubstituted or substituted C ３－５ The compound of claim 5, which is cycloalkyl or unsubstituted or substituted 3- to 5-membered heterocyclyl.

7. R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ａ , and R ５ｂ each independently represents H, OH, CN, halogen, unsubstituted or substituted amino, or unsubstituted or substituted C １－４ is alkyl, Optionally, R ３ａ , and R ３ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R ４ａ , and R ４ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R ５ａ , and R ５ｂ The compound of claim 6 , wherein: together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl.

8. t is 0, X is N, and ring A is 【Chemistry 4】 and ring B is 【Chemistry 5】 8. The compound of claim 7, wherein:

9. The compound is 【Chemistry 6】 9. The compound of claim 8, wherein:

10. t is 0, X is N, and ring A is 【Chemistry 7】 and ring B is 【Chemistry 8】 8. The compound of claim 7, wherein:

11. The compound is 【Chemistry 9】 11. The compound of claim 10, wherein:

12. t is 1, X is N, and ring A is 【Chemistry 10】 and ring B is 【Chemistry 11】 8. The compound of claim 7, wherein:

13. The compound is 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 13. The compound of claim 12, wherein:

14. t is 1, X is N, and ring A is 【Chemistry 13】 and ring B is 【Chemistry 14】 8. The compound of claim 7, wherein:

15. The compound is 【Chemistry 15】 15. The compound of claim 14, wherein:

16. t is 1, X is N, and ring A is 【Chemistry 16】 and ring B is 【Chemistry 17】 and Here, R ａ and R ｂ each independently represents a substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ cycloalkyl, or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S; R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ The compound of claim 7 which is an alkoxyl.

17. The compound is 【Chemistry 18】 17. The compound of claim 16, wherein:

18. t is 1, X is N, and ring A is 【Chemistry 19】 and ring B is 【Chemistry 20】 8. The compound of claim 7, wherein:

19. The compound is 【Chemical 21】 19. The compound of claim 18, wherein:

20. t is 1, X is N, and ring A is [Chemical 22] and ring B is 【Chemical 23】 8. The compound of claim 7, wherein:

21. The compound is 【Chemistry 24】 21. The compound of claim 20, wherein:

22. t is 1, X is N, and ring A is 【Chemistry 25】 and ring B is 【Chemical 26】 8. The compound of claim 7, wherein:

23. The compound is 【Chemical 27】 23. The compound of claim 22, wherein:

24. t is 1, X is C—H, and ring A is 【Chemical Formula 28】 and ring B is 【Chemical 29】 8. The compound of claim 7, wherein:

25. The compound is 【Chemistry 30】 25. The compound of claim 24, wherein:

26. t is 1, X is C—H, and ring A is 【Chemical 31】 and ring B is 【Chemical 32】 8. The compound of claim 7, wherein:

27. The compound is 【Chemical 33】 27. The compound of claim 26, wherein:

28. t is 1, X is C—F, and ring A is 【Chemical 34】 and ring B is 【Chemistry 35】 8. The compound of claim 7, wherein:

29. The compound is 【Chemical 36】 29. The compound of claim 28, wherein:

30. t is 1, X is C—Cl, and ring A is 【Chemical 37】 and ring B is 【Chemical 38】 8. The compound of claim 7, wherein:

31. The compound is 【Chemical 39】 31. The compound of claim 30, wherein:

32. t is 1, X is C—Cl, and ring A is 【Chemistry 40】 and ring B is 【Chemistry 41】 8. The compound of claim 7, wherein:

33. The compound is 【Chemistry 42】 33. The compound of claim 32, wherein:

34. t is 1, X is C—Cl, and ring A is 【Chemistry 43】 and ring B is 【Chemical 44】 8. The compound of claim 7, wherein:

35. The compound is 【Chemistry 45】 35. The compound of claim 34, wherein:

36. t is 1, X is C—Cl, and ring A is 【Chemistry 46】 and ring B is 【Chemistry 47】 8. The compound of claim 7, wherein:

37. The compound is 【Chemistry 48】 37. The compound of claim 36, wherein:

38. t is 1, X is C—Cl, and ring A is 【Chemistry 49】 and ring B is 【Chemistry 50】 8. The compound of claim 7, wherein:

39. The compound is 【Chemistry 51】 39. The compound of claim 38, wherein:

40. t is 1, X is C—Cl, and ring A is 【Chemistry 52】 and ring B is 【Chemistry 53】 8. The compound of claim 7, wherein:

41. The compound is 【Chemical 54】 41. The compound of claim 40, wherein:

42. t is 1, X is C—Cl, and ring A is 【Chemistry 55】 and ring B is 【Chemical 56】 and Here, R ａ and R ｂ each independently represents a substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ cycloalkyl, or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O or S; R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ The compound of claim 7 which is an alkoxyl.

43. The compound is 【Chemical 57】 43. The compound of claim 42, wherein:

44. t is 1, X is C—Cl, and ring A is 【Chemistry 58】 and ring B is 【Chemical Formula 59】 8. The compound of claim 7, wherein:

45. The compound is 【Chemistry 60】 45. The compound of claim 44, wherein:

46. R ３ａ , and R ３ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R ４ａ , and R ４ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl, or R ５ａ , and R ５ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ａ , and R ５ｂ each independently represents H, OH, halogen, CN, unsubstituted or substituted amino, or unsubstituted or substituted C １－４ The compound of claim 6, wherein the compound is alkyl.

47. t is 0, X is N, and ring A is 【Hua 61】 and ring B is 【Hua 62】 47. The compound of claim 46, wherein:

48. R ５ａ and R ５ｂ are unsubstituted or substituted C together with the atoms bonded to them. ３－５ 48. The compound of claim 47, which forms a cycloalkyl, or an unsubstituted or substituted heterocyclyl.

49. The compound is 【Chemistry 63】 49. The compound of claim 48, wherein:

50. t is 1, X is N, and ring A is 【Hua 64】 and ring B is 【Chemistry 65】 47. The compound of claim 46, wherein:

51. R ５ａ and R ５ｂ are unsubstituted or substituted C together with the atoms bonded to them. ３－５ 51. The compound of claim 50, which forms a cycloalkyl.

52. The compound is 【Hua 66-1】 【Hua 66-2】 52. The compound of claim 51, wherein:

53. R ５ａ and R ５ｂ 51. The compound of claim 50, wherein together with the atom to which they are attached form an unsubstituted or substituted heterocyclyl.

54. The compound is 【Hua 67】 54. The compound of claim 53, wherein:

55. R ４ａ and R ４ｂ 51. The compound of claim 50, wherein together with the atom to which they are attached form an unsubstituted or substituted heterocyclyl.

56. The compound is 【Chemistry 68】 56. The compound of claim 55, wherein:

57. The compound has the following formula: 【Chemical Formula 69】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopic species, or prodrug thereof; During the ceremony, Ring C is unsubstituted or substituted C ３－６ The compound of claim 2, which is cycloalkyl or unsubstituted or substituted 3- to 6-membered heterocyclyl.

58. The compound has the following formula: 【Chemistry 70】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopic species, or prodrug thereof; During the ceremony, Y is CH ２ , O, N.H., N-R ９ , N-C(=O)-R １０ or O=S=O, R ９ is a substituted or unsubstituted C １－４ Alkyl, or unsubstituted or substituted C ３－５ is cycloalkyl, R １０ is a substituted or unsubstituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkoxy, unsubstituted or substituted C ３－５ cycloalkyl, or unsubstituted or substituted 3- to 5-membered heterocyclyl; R ａ is H, halogen, amino, —CN, —OH, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkoxy, or unsubstituted or substituted C １－４ The compound of claim 2 which is alkylamino.

59. The compound has the following formula: 【Chemical 71】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopic species, or prodrug thereof; During the ceremony, The compound of claim 2, wherein Ring D is an unsubstituted or substituted 3- to 7-membered cycloalkyl or an unsubstituted or substituted 3- to 7-membered heterocyclyl.

60. t is 1, X is N, and ring A is 【Chemical 72】 and ring B is 【Chemical 73】 60. The compound of claim 59, wherein:

61. The compound is 【Hua 74-1】 【Chemistry 74-2】 61. The compound of claim 60, wherein:

62. The compound has the following formula: 【Chemistry 75】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopic species, or prodrug thereof; During the ceremony, Z is CH ２ , NH, or O, and R ｄ is H, halogen, amino, —CN, —OH, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkoxy, or unsubstituted or substituted C １－４ The compound of claim 2 which is alkylamino.

63. The compound has the following formula: 【Chemical 76】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopic species, or prodrug thereof; During the ceremony, The compound of claim 2, wherein Ring E is an unsubstituted or substituted 4- to 6-membered cycloalkyl or an unsubstituted or substituted 4- to 6-membered heterocyclyl.

64. The compound has the following formula: [Chemical 77] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopic species, or prodrug thereof; During the ceremony, Z is CH ２ , NH, or O, and R ｅ is H, halogen, amino, —CN, —OH, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkoxy, or unsubstituted or substituted C １－４ The compound of claim 2 which is alkylamino.

65. The compound has the following formula: 【Chemical 78】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopic species, or prodrug thereof; During the ceremony, The compound of claim 2, wherein ring E is an unsubstituted or substituted cyclopentyl ring, an unsubstituted or substituted cyclohexyl ring, an unsubstituted or substituted cycloheptyl ring, an unsubstituted or substituted tetrahydrofuranyl ring, an unsubstituted or substituted tetrahydropyranyl ring, or an unsubstituted or substituted oxepanyl ring.

66. The compound is 【Chemical Formula 79】 66. The compound of claim 65, wherein:

67. The compound is 【Chemical 80-1】 【Hua 80-2】 【Chemical 80-3】 【Chemical 80-4】 2. The compound of claim 1, wherein:

68. 68. The compound of any one of claims 1 to 67, wherein the compound is selected from Tables 1 to 5 or a compound provided in the claims.

69. 69. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

70. A method for inhibiting KRAS mutant protein activity or KRAS amplification activity in a cell, comprising contacting the cell with an effective amount of a compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, wherein optionally the KRAS mutant protein is a KRAS G12D and / or G12V mutant protein.

71. 100. A method for treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, wherein optionally the cancer is mediated by a KRAS mutation, preferably a KRAS G12D and / or G12V mutation.

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