Heterocyclic compounds, compositions thereof, and methods of treatment therewith

Abstract

Provided herein are compounds having the structure: TIFF2025528128000404.tif74165, wherein the substituent is as defined herein, compounds, compositions comprising an effective amount of the compounds, and methods for modulating the activity of KRAS G12D and / or G12V.

Description

[Technical Field]

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

[0002] Ras is a family of proteins that are bound to the cell membrane via a C-terminal membrane-targeting domain and are known as molecular switches in intracellular signaling networks (Cox AD, Der CJ. Ras history: The saga continues. Small GTPases. 2010;1(1):2-27). Ras proteins bind either GTP or GDP, switching between an "on" state and an "off" state. When Ras proteins bind GDP, they are in an off (or inactive) state. When Ras is turned on by specific growth-promoting stimuli, such as growth factors, Ras proteins are induced to exchange their bound GDP for GTP and become on (or active) (Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459-465). By switching to an active state, Ras proteins can interact with different downstream proteins and activate related 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 comprises different subfamilies, including Ras, Ral, Rap, Rheb, Rad, Rit, and Miro (Wennerberg K, Rossman KL, Der CJ. The Ras superfamily at a glance. J Cell Sci. 2005;118(Pt5):843-846). HRas, NRas, and KRas are the most well-studied proteins in the Ras family, as these proteins are the most common oncogenes in human cancers (O'Bryan JP. Pharmacological targeting of RAS: Recent success with direct inhibitors. Pharmacol Res. 2019;139:503-511).

[0003] KRas is one of the most frequently mutated genes in human cancer. Based on data from the Catalogue of Somatic Mutations (COSMIC) database, KRas mutations can be 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 leads to excessive activation of the KRas protein, ultimately resulting in uncontrolled cell proliferation and cancer.

[0004] Among different cancers, pancreatic cancer is considered the most KRas-dependent cancer type. 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-mutant 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 demonstrate 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 makes mutant KRas proteins very attractive drug targets for pancreatic cancer and other cancers that harbor KRas mutations. Because wild-type KRas proteins also play important roles in normal tissue function and it has been demonstrated that wild-type KRas function is essential for adult hematopoiesis (Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459-465), it makes sense that potential drug molecules would selectively inhibit mutant Kras proteins in cancer cells while sparing their wild-type companions in normal cells.

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

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

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

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

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

[0010] In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, 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

[0011] 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.

[0012] 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).

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

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

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

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

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

[0018] As used herein, 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.

[0019] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or range of values ​​provided to characterize a particular solid form, such as a particular temperature or temperature range (e.g., 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 (e.g., such as 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.

[0020] 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; while saturated branched-chain 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 may be substituted with any substituent(s) as found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, 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, B(OH), or O(alkyl)aminocarbonyl.

[0021] 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.

[0022] 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 may be straight-chained, branched, or cyclic. Alkynyl includes, but is not limited to, radicals having 2 to 20 carbon atoms, i.e., C 2-20 Alkynyl; having 2 to 12 carbon atoms, i.e., C 2-12 Alkynyl; having 2 to 8 carbon atoms, i.e., C 2-8 Alkynyl, having 2 to 6 carbon atoms, i.e., C 2-6 Alkynyl and those having 2 to 4 carbon atoms, i.e., C 2-4 Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and butynyl.

[0023] 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.

[0024] A "bridged" bicyclic ring system includes 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 two tertiary carbon atoms, but not necessarily two) connected via 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, including, but not limited to, 6-dioxa-tricyclo[3.3.1.03,7]nonyl. 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 share a single ring atom (usually a quaternary carbon atom) between the two rings.

[0025] An "aryl" group is an aromatic carbocyclic group of 6 to 14 carbon atoms, having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, an aryl group contains 6 to 14 carbons, and in other embodiments, 6 to 12 or 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, for example, fused aromatic aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0026] 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 other groups 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-dioneyl) groups. The phrase 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 phrase 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 nyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithionyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decanyl, 2-oxo-1-oxa-3,8-diazaspiro[4.5]decane, 1-oxo-2,8-diazaspiro[4.5]decane, 3-oxo-2,8-diazaspiro[4.5]decane quinuclidyl, 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., indol-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), benzo[d][1,2,3]triazolyl), benzo[d][1,2,3]triazolyl, ... imidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (e.g., 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, thianaphthalenyl, dihydrobenzo Representative non-aromatic heterocyclyl groups include, but are not limited to, thiazinyl, 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 containing 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, piperidinyl, 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, pyridyl or morpholinyl groups that are 2-, 3-, 4-, 5-, or 6-substituted, or di-substituted with various substituents, including, but not limited to, those described below.

[0027] A "heteroaryl" group is an aryl ring system having 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, with the remainder of the atoms being carbon atoms. In some embodiments, heteroaryl groups have 3 to 6 ring atoms, and in other embodiments, 6 to 9 or 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazolyl, benzoindolyl ... Included are groups such as dazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0028] 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 within a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings within a set of spirocyclic rings.

[0029] 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.

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

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

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

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

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

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

[0036] An "amino" group is a radical of the formula: --NH.sub.2.

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

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

[0039] 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.

[0040] An “acylamino” group refers to 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.

[0041] A “sulfonylamino” group refers to a group of the formula: —NHSO(R # ) or -N(alkyl)SO2(R # ) radical, where each alkyl and R # is as defined above.

[0042] A "urea" group refers to 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.

[0043] With the exception of alkyl groups, when groups described herein are referred to as "substituted," they may be substituted with any suitable substituent(s). 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; cycloalkyl (which is a monocyclic or fused or non-fused polycyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclyl (which may be a monocyclic or fused or non-fused polycyclic ring) (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); a 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.

[0044] 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).

[0045] 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 is substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound contains 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.

[0046] 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 may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

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

[0048] As used herein, unless otherwise specified, "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.

[0049] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The concentration of isomers depends on the environment in which the compound is found and can vary, for example, depending on whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole can exhibit the following isomeric forms, which are called tautomers of each other: [ka]

[0050] 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.

[0051] 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 unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), sulfur-35( 35 S), or carbon-14 ( 14 It may be radiolabeled with a radioisotope such as 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,

[0052] As used herein, "treating" refers to the total or partial alleviation of a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or the slowing or halting of further progression or worsening of the symptoms, or the alleviation or eradication of the cause(s) of the disorder, disease, or condition itself. In some embodiments, "treating" refers to the total or partial alleviation of a disorder, disease, or condition, or the slowing or halting of further progression or worsening of the symptoms. In another embodiment, "treating" refers to the total or partial alleviation of a disorder, disease, or condition, or symptoms associated with a condition, which condition is treatable or preventable by inhibition of KRAS (preferably G12D and / or G12V).

[0053] 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; inhibiting a subject from acquiring a disorder, disease, or condition; or reducing the risk that a subject will acquire 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).

[0054] The term "effective amount" in reference to a compound means an amount that is capable of treating or preventing a disorder, disease, or condition disclosed herein, or a symptom thereof.

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

[0056] compound 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; The moiety B is an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocyclyl, or an unsubstituted or substituted C 2-5 is alkyl; X is N or CR 8 and W is O, NH, NR 9 , NC(=O)-R 10 , or O=S=O, R 0are each independently H, halogen, amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carboxy, nitro, thiol, or thioether; or any of the above 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 , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, halogen, amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered 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 R6a , and R 6b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 7a , and R 7b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 8a , and R 8b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 6a , and R 7a together with the atoms to which they are attached form an unsubstituted or substituted bridge, or R 6a , and R 8a together with the atoms to which they are attached form an unsubstituted or substituted bridge, or R 5 , and R 7a together with the atoms to which they are attached form an unsubstituted or substituted bridge, or R 5 , and R 8a together with the atoms to which they are attached form an unsubstituted or substituted bridge, 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; R 9 is a substituted or unsubstituted C 1-4Alkyl, 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; t is 0 or 1; and m and q are each independently an integer between 0 and the maximum number of substituents allowed on rings A and B, respectively.

[0057] Provided herein are compounds having the following formula (IA): [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; The moiety B is unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl; X is N or CR 8 and; W is O, NH, NR 9 , NC(=O)-R 10 , or O=S=O; R 0 are each independently H, halogen, amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4alkylamino, 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 , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are independently H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carbonyl, 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 6a , and R 6b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 7a , and R 7b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R8a , and R 8b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 6a , and R 7a together with the atoms to which they are attached form an unsubstituted or substituted bridge; or R 6a , and R 8a together with the atoms to which they are attached form an unsubstituted or substituted bridge; or R 5 , and R 7a together with the atoms to which they are attached form an unsubstituted or substituted bridge; or R 5 , and R 8a together with the atoms to which they are attached form an unsubstituted or substituted bridge; 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; R 9 is 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; t is 0 or 1; and m and q are each independently an integer between 0 and the maximum number of substituents allowed on rings A and B, respectively.

[0058] Provided herein are compounds having the following formula (II): [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; The moiety B is an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocyclyl, or an unsubstituted or substituted C 2-5 is alkyl; X is N or CR 8 and; W is O, NH, NR 9 , NC(=O)-R 10 or O=S=O; R 0 are each independently H, halogen, amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carboxy, nitro, thiol, or thioether; or said 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 , R 3b , R 4a , R 4b , R5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, halogen, amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered 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 6a , and R 6b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 7a , and R 7b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 8a , and R 8b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 6a , and R 7a together with the atoms to which they are attached form an unsubstituted or substituted bridge, or R 6a , and R8a together with the atoms to which they are attached form an unsubstituted or substituted bridge, or R 5 , and R 7a together with the atoms to which they are attached form an unsubstituted or substituted bridge, or R 5 , and R 8a together with the atoms to which they are attached form an unsubstituted or substituted bridge, 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 is halogenated alkoxyl, CN, OH, or amino; 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; t is 0 or 1; s and r are each independently 1 or 2; and m and q are each independently an integer between 0 and the maximum number of substituents allowed on rings A and B, respectively.

[0059] Provided herein are compounds having the following formula (IIA): [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; The moiety B is unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl; X is N or CR 8 and; W is O, NH, NR 9 , NC(=O)-R 10 , or O=S=O; R 0 are each independently H, halogen, amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkenyl, unsubstituted or substituted C 1-4 Alkynyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted 3- to 5-membered 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 , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, halogen, amino, —CN, —OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, unsubstituted or substituted C 3-5Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C 1-4 alkylamino, carbonyl, 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 6a , and R 6b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 7a , and R 7b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 8a , and R 8b together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R 6a , and R 7a together with the atoms to which they are attached form an unsubstituted or substituted bridge; or R 6a , and R 8a together with the atoms to which they are attached form an unsubstituted or substituted bridge; or R 5 , and R 7a together with the atoms to which they are attached form an unsubstituted or substituted bridge; or R 5 , and R 8a together with the atoms to which they are attached form an unsubstituted or substituted bridge; 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 is halogenated alkoxyl, CN, OH, or amino; R 9 is 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; t is either 0 or 1; s and r are each independently 1 or 2; and m and q are each independently an integer between 0 and the maximum number of substituents allowed on rings A and B, respectively.

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

[0061] In one embodiment, X is N. In one embodiment, X is CR 8In 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.

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

[0063] Aspect 2:

[0064] 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 (e.g., -C(CH3)=CH), -CF=CH, aryl, heteroaryl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, methylcyclopropyl, fluorocyclopropyl, difluorocyclopropyl. cyclopropyl, 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.

[0065] In one embodiment, Ring A is a 5- to 7-membered monocyclic heteroaryl 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.

[0066] In one embodiment, ring A is [ka] is.

[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]

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

[0071] Aspect 3:

[0072] In one embodiment, the moiety 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.

[0073] In one embodiment, the moiety 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, the moiety 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; and the moiety B is optionally substituted. In one embodiment, moiety 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 moiety B is optionally substituted. In one embodiment, moiety B is optionally substituted with halogen, cyano, hydroxy, alkoxy, or alkyl, optionally substituted with halogen, cyano, hydroxy, alkoxy, heterocyclyl, cycloalkyl, or cycloalkyloxy.

[0074] In one embodiment, the moiety B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3-9 membered heterocyclic ring 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 together with the carbon atom to which they are attached form a 3-8 membered unsaturated or saturated ring containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0075] In one embodiment, moiety B is [ka] [ka] is. In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0076] In one embodiment, moiety 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 moiety B is optionally substituted.

[0077] In one embodiment, moiety B is C 2-5 It is alkyl, substituted with hydroxy, further substituted with halogen, haloalkyl, or alkoxy.

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

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

[0080] In one embodiment, moiety B is [ka] is.

[0081] In one embodiment, moiety 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 moiety B is optionally substituted.

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

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

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

[0085] In one embodiment, moiety B is [ka] is.

[0086] Aspect 4:

[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] Aspect 5:

[0091] In some embodiments, moiety B is [ka] where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl; substituted or unsubstituted C 3-5 cycloalkyl; or R a and R b together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxyl, or C 1-4 It is alkoxyl-C(O)-.

[0092] In one embodiment, the moiety 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.

[0093] In one embodiment, moiety B is [ka] where R a and R b each independently being a substituted or unsubstituted C 1-4 Alkyl; substituted or unsubstituted C3-5 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; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 It is alkoxyl.

[0094] In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] In one embodiment, moiety B is [ka] In one embodiment, moiety B is [ka] In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] In one embodiment, moiety B is [ka] is.

[0095] Aspect 6:

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

[0097] In one embodiment, R 6a , and R 7a By or R 6a , and R 8a By or R 5 , and R 7a By or R 5 , and R 8a is —(CH)—. In one embodiment, the bridge is —(CH)—. In one embodiment, the bridge is —CH—O—CH—.

[0098] Aspect 7:

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

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

[0101] In one embodiment, ring A is [ka] and; and part B is [ka] is.

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

[0103] Group 1.1.1: In one embodiment, ring A is [ka] is.

[0104] In one embodiment, moiety B is [ka] is.

[0105] Group 1.1.1.1: In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

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

[0107] In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, OH, CN, amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H or unsubstituted or substituted C 1-4 In one embodiment, R3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, methyl, or ethyl, optionally substituted by OH, CN, amino, or methylamino. 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H or methyl.

[0108] In one embodiment, the compound is [ka] is.

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

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

[0111] In one embodiment, the compound is [ka] is.

[0112] Group 1.1.2: In one embodiment, ring A is [ka] is.

[0113] In one embodiment, moiety B is [ka] is.

[0114] Group 1.1.2.1: In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0115] Group 1.1.3: In one embodiment, ring A is [ka] is.

[0116] In one embodiment, moiety B is [ka] is.

[0117] Group 1.1.3.1: In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0118] In one embodiment, the compound is [ka] is.

[0119] In one embodiment, the compound is [ka] is.

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

[0121] In one embodiment, moiety B is [ka] is.

[0122] Group 1.1.4.1: In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0123] In one embodiment, the compound is [ka] is.

[0124] In one embodiment, the compound is [ka] is.

[0125] In one embodiment, the compound is [ka] is.

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

[0127] In one embodiment, the compound is [ka] is.

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

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

[0130] In one embodiment, the compound is [ka] is.

[0131] In one embodiment, the compound is [ka] is.

[0132] Group 1.1.4.2: In one embodiment, moiety B is [ka] is.

[0133] In one embodiment, moiety B is [ka] is.

[0134] In one embodiment, the compound is [ka] is.

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

[0136] Group 1.1.4.3: In one embodiment, moiety B is [ka] and In the formula, R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl; substituted or unsubstituted C 3-5cycloalkyl; or R a and R b together with the N to which they are attached form a substituted or unsubstituted N-, O-, or S-containing heterocycle.

[0137] In one embodiment, moiety B is [ka] is.

[0138] In one embodiment, the compound is [ka] is.

[0139] In one embodiment, the compound is [ka] is.

[0140] In one embodiment, the compound is [ka] is.

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

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

[0143] In one embodiment, the compound is [ka] is.

[0144] Group 1.1.5.1: In one embodiment, ring A is [ka] is.

[0145] In one embodiment, moiety B is [ka] is.

[0146] In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0147] In one embodiment, the compound is [ka] is.

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

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

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

[0151] In one embodiment, moiety B is [ka] In one embodiment, moiety B is [ka] is.

[0152] In one embodiment, the compound is [ka] is.

[0153] In one embodiment, the compound is [ka] is.

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

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

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

[0157] In one embodiment, moiety B is [ka] and In the formula, R a and R bare each independently substituted or unsubstituted C 1-4 Alkyl; substituted or unsubstituted C 3-5 cycloalkyl; or R a and R b together with the N to which they are attached form a substituted or unsubstituted N-, O-, or S-containing heterocycle.

[0158] In one embodiment, moiety B is [ka] is.

[0159] In one embodiment, the compound is [ka] is.

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

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

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

[0163] In one embodiment, the compound is [ka] is.

[0164] In one embodiment, the compound is [ka] is.

[0165] In one embodiment, the compound is [ka] is.

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

[0167] In one embodiment, ring A is [ka] is.

[0168] In one embodiment, moiety B is [ka] where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl; substituted or unsubstituted C 3-5 cycloalkyl; or R a and R b together with the N to which they are attached form a substituted or unsubstituted N-, O-, or S-containing heterocycle.

[0169] In one embodiment, moiety B is [ka] is.

[0170] In one embodiment, the compound is [ka] is.

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

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

[0173] In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0174] In one embodiment, the compound is [ka] is.

[0175] In one embodiment, the compound is [ka] is.

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

[0177] In one embodiment, ring A is [ka] is.

[0178] In one embodiment, moiety B is [ka] and In the formula, Ra and R b are each independently substituted or unsubstituted C 1-4 Alkyl; substituted or unsubstituted C 3-5 cycloalkyl; or R a and R b together with the N to which they are attached form a substituted or unsubstituted N-, O-, or S-containing heterocycle.

[0179] In one embodiment, moiety B is [ka] is.

[0180] In one embodiment, the compound is [ka] is.

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

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

[0183] In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0184] In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R7b , R 8a , and R 8b are each independently H, OH, CN, amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, methyl, or ethyl, optionally substituted by OH, CN, amino, or methylamino. 3a , R 3b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H or methyl.

[0185] In one embodiment, the compound is [ka] is.

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

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

[0188] In one embodiment, the compound is [ka] is.

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

[0190] In one embodiment, ring A is [ka] is.

[0191] In one embodiment, moiety B is [ka] and In the formula, R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl; substituted or unsubstituted C 3-5 cycloalkyl; or R a and R btogether with the N to which they are attached form a substituted or unsubstituted N-, O-, or S-containing heterocycle.

[0192] In one embodiment, moiety B is [ka] is.

[0193] In one embodiment, the compound is [ka] is.

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

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

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

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

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

[0199] In one embodiment, moiety B is [ka] where R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 It is alkoxyl.

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

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

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

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

[0204] In one embodiment, the compound is [ka] is.

[0205] Aspect 8:

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

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

[0208] In one embodiment, moiety B is [ka] where R a and R b each independently being 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; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 It is alkoxyl.

[0209] In one embodiment, ring A is [ka] and part B is [ka] is.

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

[0211] Group 2.1.1: In one embodiment, ring A is [ka] is.

[0212] In one embodiment, moiety B is [ka] is.

[0213] Group 2.1.1.1: In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

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

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

[0216] In one embodiment, the compound is [ka] is.

[0217] In one embodiment, the compound is [ka] is.

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

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

[0220] In one embodiment, the compound is [ka] is.

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

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

[0223] Group 2.1.4.1: In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0224] In one embodiment, the compound is [ka] is.

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

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

[0227] In one embodiment, the compound is [ka] is.

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

[0229] In one embodiment, ring A is [ka] is.

[0230] In one embodiment, moiety B is [ka] and In the formula, R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl; substituted or unsubstituted C 3-5cycloalkyl; or R a and R b together with the N to which they are attached form a substituted or unsubstituted N-, O-, or S-containing heterocycle.

[0231] In one embodiment, moiety B is [ka] is.

[0232] In one embodiment, the compound is [ka] is.

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

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

[0235] In one embodiment, the compound is [ka] is.

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

[0237] In one embodiment, ring A is [ka] is.

[0238] In one embodiment, moiety B is [ka] and In the formula, 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.

[0239] In one embodiment, moiety B is [ka] is.

[0240] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b is each independently H, or unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, methyl, or ethyl, optionally substituted by OH, CN, amino, or methylamino. 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H or methyl.

[0241] In one embodiment, the compound is [ka] is.

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

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

[0244] In one embodiment, the compound is [ka] is.

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

[0246] In one embodiment, ring A is [ka] is.

[0247] In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0248] In one embodiment, the compound is [ka] is.

[0249] In one embodiment, the compound is [ka] is.

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

[0251] In one embodiment, ring A is [ka] is.

[0252] In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0253] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R7a , R 7b , R 8a , and R 8b is each independently H, or unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H, methyl, or ethyl, optionally substituted by OH, CN, amino, or methylamino. 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently H or methyl.

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

[0255] Aspect 9: In some embodiments, compounds provided herein have the following formula: [ka] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof; During the ceremony: Ring C is unsubstituted or substituted C 3-6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocyclyl.

[0256] In some embodiments, the compounds provided herein have the following formula: [ka] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof; During the ceremony: Ring C is unsubstituted or substituted C 3-6 cycloalkyl, or unsubstituted or substituted 3- to 6-membered heterocyclyl.

[0257] In one embodiment, ring C comprises Y and R a where Y is CH2, O, NH, NR 9 , NC(=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; and R a is H, halogen, amino, -CN, -OH, unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 1-4 Alkoxy, or unsubstituted or substituted C 1-4 It is alkylamino.

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

[0259] In one embodiment, R 6a and R 7a together form a bridge, which is -CH2-CH2-.

[0260] In one embodiment, R 5 , and R 8a together form a bridge, which is -CH2-CH2-.

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

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

[0263] Aspect 10: In some embodiments, the compounds provided herein are compounds having the following formula: [ka] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof.

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

[0265] In one embodiment, ring A is [ka] is. In one embodiment, ring A is [ka] is.

[0266] In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0267] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b1 , R 8a2 , and R 8b2 are each independently H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 8a2 , and R 8b2 are each independently H or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a1 , R 8b1 , R 8a2 , and R 8b2 is each independently H, or unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a1 , R 8b1 , R 8a2 , and R8b2 are each independently H, methyl, or ethyl, optionally substituted by OH, CN, amino, or methylamino. 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a1 , and R 8b1 , R 8a2 , and R 8b2 are each independently H or methyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a1 , and R 8b1 , R 8a2 , and R 8b2 are each independently H.

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

[0269] Aspect 11: In some embodiments, the compounds provided herein are compounds having the following formula: [ka] and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, atropisomers, isotopic species, and prodrugs thereof.

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

[0271] In one embodiment, ring A is [ka] is. In one embodiment, ring A is [ka] is.

[0272] In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

[0273] In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b are each independently H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b are each independently H or unsubstituted or substituted C 1-4 In one embodiment, R 3a , R 3b , R4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b is each independently H, or unsubstituted or substituted methyl, or unsubstituted or substituted ethyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b are each independently H, methyl, or ethyl, optionally substituted by OH, CN, amino, or methylamino. 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , R 7b , R 8a , and R 8b are each independently H or methyl. In one embodiment, R 3a , R 3b , R 4a , R 4b , R 5 , R 6a1 , R 6b1 , R 6a2 , R 6b2 , R 7a , and R 7b , R 8a , and R 8b are each independently H.

[0274] In one embodiment, the compound is [ka] is.

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

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

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

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

[0279] In one embodiment, ring A is [ka] is.

[0280] In one embodiment, moiety B is an unsubstituted or substituted heterocyclyl, wherein the heterocyclyl does not contain a secondary or tertiary amine. In one embodiment, the heterocyclyl contains at least one oxygen as a ring member. In one embodiment, moiety B is [ka] where R a and R b are each independently substituted or unsubstituted C 1-4 Alkyl; substituted or unsubstituted C 3-5 cycloalkyl; or R a and R b together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R c is H, halogen, CN, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-5 Cycloalkyl, substituted or unsubstituted C 1-4 Alkoxyl, or C 1-4 In one embodiment, moiety B is: [ka] [ka] is. In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is optionally selected from halogen, cyano, hydroxy, C 1-3 Alkoxy, or C 1-3 alkyl substituted, optionally with halogen, cyano, hydroxy, or C 1-3In one embodiment, the moiety B is substituted with alkoxy. In one embodiment, the moiety B is substituted or unsubstituted oxabicyclo[2.1.1]hexanyl. In one embodiment, the moiety B is 2-oxabicyclo[2.1.1]hexan-4-yl, and is substituted with halogen, cyano, hydroxy, C 1-3 Alkoxy, or C 1-3 substituted with alkyl and optionally halogen, cyano, hydroxy, or C 1-3 In one embodiment, the moiety B is 2-oxabicyclo[2.1.1]hexan-4-yl.

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

[0282] In one embodiment, moiety B is [ka] is. In one embodiment, moiety B is [ka] is.

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

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

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

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

[0287] [Table 1]

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

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

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

[0291] Aspect 17: In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, 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, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein.

[0292] Aspect 18: Provided herein is a method of modulating the activity of KRAS G12D and / or G12V, 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.

[0293] Aspect 19: 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.

[0294] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments. Compound manufacturing method

[0295] The compounds can be made using conventional organic synthesis and commercially available starting materials. By way of example and not limitation, compounds of formula (I) can be prepared as outlined in Schemes 1-3 shown below, as well as in the Examples described herein. It should be noted that one of ordinary skill in the art would know how to modify the procedures described in the illustrative Schemes and Examples to arrive at the desired product. Common protecting groups 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.

[0296] Scheme 1 [ka]

[0297] 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); Compound 1-5 can further undergo a metal-catalyzed cross-coupling reaction, such as Suzuki, Negishi, or Stille coupling (e.g., for Suzuki coupling, Pd(dtbpf)Cl, KPO, 1,4-dioxane, water) to give compound 1-6 (where M can be a boronic acid, a boronic ester, a metal (e.g., Zn), tributyltin, etc.); and finally, the protecting group containing compound 1-6 can then be deprotected (e.g., if PG1 and PG2 contain Boc groups, deprotect the Boc groups with TFA and DCM, and if PG1 and PG2 contain TIPS groups, deprotect the TIPS groups with CsF and DMF) to give the compound defined as formula (I).

[0298] Scheme 2 [ka]

[0299] 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); compound 2-2 is then converted to compound 2-3 under substitution conditions (e.g., HATU, DIEA when X1 is OH; DIEA, DCM when X1 is Cl); compound 2-3 is then converted to compound 2-4 under oxidation conditions (e.g., m-CPBA oxidation when LG is methylsulfonyl or methylsulfinyl); compound 2-4 is then converted to compound 2-5, followed by a substitution or coupling reaction (e.g., NaH, THF); Compound 2-5 can further undergo a metal-catalyzed cross-coupling reaction, such as Suzuki, Negishi, or Stille coupling (e.g., for Suzuki coupling, Pd(dtbpf)Cl, KPO, 1,4-dioxane, water) to give compound 2-6 (where M can be a boronic acid, a boronic ester, a metal (e.g., Zn), tributyltin, etc.); finally, the protecting group containing compound 2-6 can then be deprotected (e.g., if PG1 and PG2 contain Boc groups, deprotect the Boc groups with TFA and DCM, and if PG1 and PG2 contain TIPS groups, deprotect the TIPS groups with CsF and DMF) to give the compound defined as formula (I).

[0300] Scheme 3 [ka]

[0301] 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); compound 3-2 is then converted to compound 3-3 under substitution conditions (e.g., HATU, DIEA when X1 is OH; DIEA, DCM when X1 is Cl); compound 3-3 is then converted to compound 3-4 under oxidation conditions (e.g., m-CPBA oxidation when LG is methylsulfonyl or methylsulfinyl); compound 3-4 is then converted to compound 3-5, followed by a substitution or coupling reaction (e.g., NaH, THF); Compound 3-5 can then 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 3-6 (where M can be a boronic acid, a boronic ester, a metal (e.g., Zn), tributyltin, or the like); finally, the protecting group containing compound 3-6 can then be deprotected (e.g., with TFA and DCM if PG1 and PG2 contain Boc groups, and with CsF and DMF if PG1 and PG2 contain TIPS groups) to give a compound defined as formula (II). The present embodiments can be more fully understood by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. [Example]

[0302] The following examples are intended to be merely representative and should not be construed as limiting in any way. Unless otherwise indicated, experimental methods in the following examples are conventional. Unless otherwise indicated, 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 indicated, all elutions were performed with petroleum ether (60-90°C) / ethyl acetate (v / v) and visualized with iodine or molybdophosphate in ethanol. Unless otherwise indicated, all extraction solvents were dried over anhydrous Na2SO4.

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

[0304] Unless otherwise indicated, column chromatographic 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.

[0305] 1 1 H NMR spectra were recorded on a Varian instrument operating at 400 MHz or 500 MHz using TMS (tetramethylsilane) as the internal standard. 1H NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, using tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; DO: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)2CO: 2.05) as a 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), dd (double doublet), and dt (double triplet). Coupling constants given are reported in Hertz (Hz).

[0306] 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.

[0307] In the examples below, the following abbreviations are used: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0308] Compound synthesis

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

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

[0311] 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 filtered to obtain the crude product, which was further purified by silica gel column chromatography (80 g, eluted with PE / EtOAc = 100%:0% to 75%:25%) to obtain the title compound (6.9 g). MS (ESI, m / e) [M+H] + 324.4.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0331] To a stirred solution of (S)-2-chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (220 mg, 0.64 mmol) in DCM (15 mL) was added m-CPBA (156 mg, 0.77 mmol, 85%) at 0 °C, and the resulting mixture was stirred at 0 °C for 10 min. The reaction was quenched with 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] + 359.0.

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

[0333] To a stirred solution of (5aS)-2-chloro-1-fluoro-11-(methylsulfinyl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (0.64 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (206 mg, 1.3 mmol) in THF (15 mL) was added LiHMDS (1.3 mL, 1.3 mmol, 1 M in THF) dropwise at 0 °C, 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 column chromatography (DCM / MeOH=100:1 to 30:1) to give the title product (78 mg). MS (ESI, m / e) [M+H] + 454.2.

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

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

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

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

[0338] (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (30 mg, 0.07 mmol), ((2-fluoro-6-(methoxymethoxy) A mixture of )-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (72 mg, 0.14 mmol), Pd(dtbpf)Cl2 (9.0 mg, 0.014 mmol), NaHCO3 (18 mg, 0.21 mmol), dioxane (4.0 mL), and HO (0.8 mL) 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) to give the title product (37 mg). MS (ESI, m / e) [M+H] + 804.6.

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

[0340] To a stirred solution of (S)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (37 mg, 0.046 mmol) in DMF (3 mL) was added CsF (70 mg, 0.46 mmol), and the resulting mixture was stirred for 2 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] + 648.4.

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

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

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

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

[0345] (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (35 mg, 0.08 mmol), 2-(8-ethyl-7 A mixture of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (56 mg, 0.16 mmol), Pd(dtbpf)Cl (10 mg, 0.02 mmol), NaHCO (20 mg, 0.24 mmol), dioxane (4.0 mL), and HO (0.8 mL) 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) to give the title product (31 mg). MS (ESI, m / e) [M+H] + 652.1.

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

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

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

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

[0350] (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (35 mg, 0.08 mmol), 2-(3-chloro A mixture of (2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (54 mg, 0.16 mmol), Pd(dtbpf)Cl (10 mg, 0.02 mmol), NaHCO (20 mg, 0.24 mmol), dioxane (4.0 mL), and HO (0.8 mL) 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) to give the title product (42 mg). MS (ESI, m / e) [M+H] + 630.1.

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

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

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

[0354] To a stirred solution of (S)-2-chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (68 mg, 0.20 mmol) in DCM (3.0 mL) was added m-CPBA (48 mg, 0.24 mmol, 85%) at 0 °C, and the resulting mixture was stirred at 0 °C for 10 min. The reaction was quenched with 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.

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

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

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

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

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

[0360] To a stirred solution of (S)-1-fluoro-11-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (46 mg, 0.06 mmol) in DMF (3 mL) was added CsF (46 mg, 0.30 mmol) and the resulting mixture was stirred 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] + 622.4.

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

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

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

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

[0365] To a stirred solution of (S)-2-chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (200 mg, 0.58 mmol) in DCM (8.0 mL) was added m-CPBA (142 mg, 0.70 mmol, 85%) at 0 °C, and the resulting mixture was stirred at 0 °C for 10 min. The reaction was quenched with 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.

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

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

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

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

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

[0371] To a stirred solution of (S)-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-11-((1-morpholinomethyl)cyclopropyl)methoxy)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (90 mg, 0.11 mmol) in DMF (4.0 mL) was added CsF (167 mg, 1.1 mmol), and the resulting mixture was stirred for 2 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] + 660.4.

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

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

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

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

[0376] To a stirred solution of (S)-2-chloro-1-fluoro-11-(methylthio)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (68 mg, 0.20 mmol) in DCM (3.0 mL) was added m-CPBA (48 mg, 0.24 mmol, 85%) at 0 °C, and the resulting mixture was stirred at 0 °C for 10 min. The reaction was quenched with 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.

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

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

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

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

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

[0382] To a stirred solution of (S)-11-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5a,6,8,9-tetrahydro-5H-4,7-dioxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (60 mg, 0.08 mmol) in DMF (3.0 mL) was added CsF (60 mg, 0.40 mmol), and the resulting mixture was stirred for 2 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] + 603.4.

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

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

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

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

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

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

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

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

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

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

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

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

[0395] Step 1: tert-butyl 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate [ka]

[0396] tert-Butyl 2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate (60 mg, 0.10 mmol), ((2-fluoro-6-(methan) A mixture of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (153.7 mg, 0.30 mmol), NaHCO (25.2 mg, 0.30 mmol), Pd(dtbpf)Cl (32.6 mg, 0.05 mmol), dioxane (5 mL), and water (1 mL) was stirred at 100 °C for 4 h. After completion, the reaction mixture was diluted with DCM (20 mL) and washed with saturated NaCl (10 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title product (25 mg). MS (ESI, m / e) [M+H] + 929.5.

[0397] Step 2: tert-butyl 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene-14-carboxylate [ka]

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

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

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

[0401] Example 12: 3-chloro-5-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)-4-(trifluoromethyl)aniline [ka]

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

[0403] To a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (1.5 g, crude) and DIPEA (1.49 g, 11.57 mmol) in DCM (15 mL) was added (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (648.3 mg, 3.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaCl (15 mL × 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 column chromatography eluting with 0-60% ethyl acetate in petroleum ether to give the title product (500 mg). MS (ESI, m / e) [M+H] + 478.1.

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

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

[0406] Step 3: (S)-2-chloro-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylate tert-butyl ester [ka]

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

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

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

[0410] Step 5: 3-chloro-5-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)-4-(trifluoromethyl)aniline

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

[0412] Example 13: 3-chloro-5-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6,6a,7,8,9,10-hexahydro-5H-4-oxa-3,8,10a,11,13-pentaazabenzo[4,5]cycloocta[1,2,3-de]naphthalen-2-yl)-4-(trifluoromethyl)aniline [ka]

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

[0414] To a solution of tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (460.4 mg, 2.0 mmol) in THF (15 mL) was added NaH (200 mg, 5 mmol, 60%) 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(3H)-one (500 mg, 1.79 mmol) was added to the reaction mixture, and the mixture was stirred at 60° C. for 16 hours. After completion, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (40 mL × 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 column chromatography eluting with 0 to 100% ethyl acetate in petroleum ether to give the title product (350 mg). MS (ESI, m / e) [M+H] + 474.1.

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

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

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

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

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

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

[0421] Step 2: (S)-10-Bromo-11-chloro-9-fluoro-7-(methylthio)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepino[5,6,7-de]quinazoline [ka]

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

[0423] Step 3: (13aS)-10-Bromo-11-chloro-9-fluoro-7-(methylsulfinyl)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3',4':3,4][1,4]oxazepino[5,6,7-de]quinazoline [ka]

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

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

[0426] To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.33 g, 0.66 mmol) in THF (10 mL) was added LiHMDS (1.4 mL, 1.38 mmol), and a solution of (13aS)-10-bromo-11-chloro-9-fluoro-7-(methylsulfinyl)-3,4,13,13a-tetrahydro-1H-[1,4]oxazino[3'4':3,4][1,4]oxazepino[5,6,7-de]quinazoline (0.3 g, 0.69 mmol) in THF (10 mL) was added portionwise at 0° C. The mixture was stirred at room temperature for 30 minutes. Quenched with NH4Cl (saturated aqueous solution) and extracted with DCM (20 mL x 3), the combined organic layers were dried over Na2SO4, concentrated, and purified on a silica chromatography column (eluted with DCM / MeOH = 10 / 1) to give the title compound (200 mg). MS (ESI, m / e) [M+H] + 531.2.

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

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

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

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

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

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

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

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

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

[0436] Step 1: (R)-5-Methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate methyl [ka]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0458] A solution of K3PO4 (97 mg, 0.46 mmol) in dioxane / water (10 mL / 2 mL) was stirred at 80 °C for 10 min. (S)-10-Bromo-11-chloro-9-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1,3,4,13,14,14a-hexahydro-[1,4]oxazino[4',3':5,6][1,5]oxazocino[4,3,2-de]quinazoline (100 mg, 0.184 mmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzo[b]thiophen-2-yl)carboxylate (153 mg, 0.367 mol), and 1,1'-bis(di-t-butylphosphino)ferrocenepalladium dichloride (60 mg, 0.092 mmol) were added. The mixture was stirred at 80° C. for 1 hour, then the reaction was cooled to room temperature, concentrated in vacuo, and purified on a chromatography column on silica (12 g, eluted with DCM / MeOH=90%:10%) to give the crude product (70 mg, crude). MS (ESI, m / e) [M+H] + 757.4.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0474] From a synthetic standpoint, Example 23 differs from Example 17, which is an eight-membered ring. The synthesis of Example 23, which is an eight-membered ring, requires the key intermediate (1S,5R)-tert-butyl 2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. The synthesis of Example 23 requires specific synthetic procedures and extensive functional group transformations to avoid stereochemical epimerization.

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

[0476] Scheme 4: Synthetic Route to Intermediate 23-0 [ka]

[0477] As depicted in Scheme 4, three different synthetic routes could be used to generate intermediate 23-0 (tert-butyl (1S,5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) from commercially available starting materials. In Route 1, amine 23-1 undergoes protecting group manipulation and ester hydrolysis to generate carboxylic acid 23-3, which is further converted to diazoketone 23-5 via mixed anhydride 23-4, followed by Wolff rearrangement to generate ester 23-6. Ester reduction followed by deprotection affords the desired intermediate alcohol 23-0. Alternatively, in Route 2, alcohol 23-11 is converted to mesylate 23-13 after amine protection, which can be further converted to S N

[0047] Route 2 is further converted to the corresponding cyanide 23-14 via the ester 23-15 reaction. Cyanide 23-14 is hydrolyzed to the ester 23-15, which is further reduced to the alcohol 23-16, which after deprotection affords the desired intermediate alcohol 23-0. Alternatively, in Route 3, alcohol 23-21 is oxidized to the corresponding aldehyde 23-22 via common methods known in the art, which undergoes a Witch reaction to afford alkene 23-23. Alkene 23-23 undergoes a hydroboration reaction to produce alcohol 23-24, which after deprotection is further converted to the desired intermediate 23-0.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0514] Synthetic Route [ka]

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

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

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

[0518] [ka]

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

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

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

[0522] Step 4: (1S,2S,5R)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester [ka]

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

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

[0525] Synthetic Route [ka]

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

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

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

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

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

[0531] To a solution of (6aR,7S,10R)-2-chloro-1-fluoro-13-(methylthio)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate (378 mg, 0.8 mmol) in THF (28 mL) and water (7 mL) was added NaIO (505 mg, 2.4 mmol) and RuCl (16 mg, 0.08 mmol). The resulting mixture was stirred at 0 °C for 1 h. The mixture was diluted with water (20 mL) and extracted three times with EtOAc (20 mL). The organic phases were combined and concentrated in vacuo to give the crude title compound (335 mg), which was used directly in the next step. MS (ESI, m / e) [M+H] +514.2.

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

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

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

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

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

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

[0538] Examples 27-68: The following compounds were prepared in a similar manner as described in Example 26: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15]

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

[0540] Synthetic Route [ka]

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

[0542] (6aR,7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3- A mixture of tert-butyl [de]naphthalene-15-carboxylate (56 mg, 0.08 mmol), potassium vinyltrifluoroborate (54 mg, 0.4 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol), and NaHCO3 (20 mg, 0.24 mmol) in 1,4-dioxane (12.5 mL) and water (2.5 mL) was degassed by vacuum and filled with N2 three times. The resulting mixture was stirred at 95 °C for 2 h. The cooled mixture was concentrated in vacuo and dissolved in DCM (20 mL). After filtration, the filtrate was concentrated to give the title product, which was used in the next step without further purification. MS (ESI, m / e) [M+H] +700.1.

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

[0544] To a solution of tert-butyl (6aR,7S,10R)-13-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-2-(5-amino-2-(trifluoromethyl)-3-vinylphenyl)-1-fluoro-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta[4,5]cycloocta[1,2,3-de]naphthalene-15-carboxylate (crude, 0.08 mmol) in MeOH (30 mL) was added Pd / C (10% (w / w), 100 mg). The reaction mixture was heated at 200°C for 1 hour. 2 The mixture was stirred under a balloon at 25° C. for 1 hour. The resulting mixture was filtered and the filtrate was concentrated to give the title product, which was used in the next step without further purification. MS (ESI, m / e) [M+H] + 701.4.

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

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

[0547] Assay KRAS WT and KRAS G12V probe displacement assay

[0548] This assay was used to identify compounds that could bind to GDP-loaded KRAS protein and displace a biotinylated probe from 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 h. 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 h of incubation at 24 °C, MAb anti-GST-Tb Cryptate (Cisbio) and streptavidin-XL665 (Cisbio) were added and incubated for an additional 1 h at 24 °C. TR-FRET signals (excitation 337 nm, emission 665 nm / 620 nm) were read on a BMG PHERAstar FSX instrument. The percentage inhibition of KRAS protein binding to the biotinylated probe in the presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 665 nm to that at 620 nm. The IC of each compound was calculated based on the ratio of fluorescence at 665 nm to that at 620 nm. 50 Values ​​were calculated by fitting the data to a four-parameter logistic model using Dotmatics.

[0549] KRAS WT and KRAS G12D probe displacement assays

[0550] This assay was used to identify compounds that could bind to GDP-loaded KRAS protein and displace a biotinylated probe from 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 h. 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 h of incubation at 24 °C, MAb anti-GST-Tb Cryptate (Cisbio) and streptavidin-XL665 (Cisbio) were added and incubated for an additional 1 h at 24 °C. TR-FRET signals (excitation 337 nm, emission 665 nm / 620 nm) were read on a BMG PHERAstar FSX instrument. The percentage of inhibition of KRAS protein binding to the biotinylated probe in the presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 665 nm to that at 620 nm. The IC of each compound was calculated based on the ratio of fluorescence at 665 nm to that at 620 nm. 50 Values ​​were calculated by fitting the data to a four-parameter logistic model using Dotmatics.

[0551] KRAS G12V pERK assay

[0552] 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 restored from frozen stocks within 30 passages of the original purchased cells. 40,000 cells per well were seeded into 96-well plates and incubated overnight. Cells were treated with a 10-point dilution series. Final compound concentrations ranged from 0 to 10 μM. After 2 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. 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 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 induces fluorescence resonance energy transfer (FRET) toward the acceptor, which in turn fluoresces at 655 nm. FRET signals were measured using a PHERAstar FSX reader (BMG Labtech). IC50 determinations were performed by fitting curves of percent inhibition versus the logarithm of inhibitor concentration using Dotmatics.

[0553] KRAS G12D pERK assay

[0554] The AsPC-1 cell line was used in this study. 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 restored from frozen stocks within 30 passages of the original purchased cells. 30,000 cells per well were seeded into 96-well plates and incubated overnight. Cells were treated with a 10-point dilution series. Final compound concentrations ranged from 0 to 10 μM. After 2 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. 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 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 induces fluorescence resonance energy transfer (FRET) toward the acceptor, which in turn emits fluorescence at 655 nm. FRET signals were measured using a PHERAstar FSX reader (BMG Labtech). IC 50 Determination of was performed by curve fitting of percent inhibition against the logarithm of inhibitor concentration using Dotmatics.

[0555] Preparation and crystallization of KRAS G12D protein

[0556] KRAS G12D protein purification

[0557] KRAS G12D 1-169aa was cloned into the pET28a vector. The gene was placed in frame with an N-terminal 6Xhis tag and an Smo tag. This construct was transformed into BL21(DE3) cells. The cells reached an OD of 0.6. 600When the ATP concentration reached 100 kJ / ml, protein expression was induced by adding 1-thio-β-D-galactopyranoside (IPTG) to a final concentration of 200 μM, followed by overnight incubation at 16°C. 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 pints 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-smo tag was cleaved by overnight digestion with ULP1 protease, and the ULP1 His-smo tag was removed by reloading onto a His-trap HP column (Cytiva). The protein was further purified by gel filtration using Hi Load 16 / 600 Superdex 75 pg (Cytiva) equilibrated with 20 mM Tris pH 8.0, 100 mM NaCl, 5 mM MgCl. The protein solution was concentrated to 30–40 mg / ml for crystallization trials.

[0558] KRAS G12D crystallization

[0559] Co-crystals of KRAS G12D with small molecule inhibitors were grown at 20°C using sitting drop vapor diffusion by mixing 1 μL of protein (40 mg / ml) with an equal volume of crystallization buffer containing 1.0 M LiCl, 0.1 M citric acid pH 5.0, and 20% PEG6000. Crystals appeared dropwise. Diffraction data were collected at beamline BL10U2 at the Shanghai Synchrotron Radiation Facility.

[0560] Metabolic stability of liver microsomes in different species.

[0561] Liver microsomes were first mixed with NADPH to obtain final concentrations of 0.5 mg / mL and 1 mM microsomes and 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 solution was terminated by adding cold acetonitrile using an analytical IS. The samples were centrifuged at 4000 rpm for 5 minutes and then analyzed by LC-MS / MS.

[0562] The peak areas of samples 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 remaining percentage of parent drug versus incubation time curve. The in vitro half-life (in vitro t 1 / 2 ) was determined from the slope value:

number

number

[0563] A control compound (verapamil) was included in the assay to ensure data consistency. 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.

[0564] CYP (cytochrome P450) enzyme inhibition assay in human liver microsomes.

[0565] Incubations were performed in 96-well plates. 1 μL of test compound working solution or vehicle was added to 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). The incubation plate was preheated in a water bath at 37°C for 5 minutes, after which the reaction was initiated by adding 20 μL of 10 mM NADPH solution. The reaction was performed in a 37°C water bath.

[0566] At predetermined time points, the reaction was stopped by adding 300 μL of quenching solution (acetonitrile containing an 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 and then mixed with 100 μL of water for analysis by LC-MS / MS and data processing (i.e., determination of percent inhibition or IC50 at 10 μM).

[0567] Time-dependent cytochrome P450 (CYP) enzyme inhibition assay (TDI) in human liver microsomes

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

[0569] Bidirectional permeability assay in MDCKII-MDR1 cell monolayers

[0570] First, MDCKII-MDR1 cells were prepared in cell seeding medium. 50 μL of the cultured cell suspension was added to each well of a previously prepared transwell plate. The plate was incubated for 4–8 days. The medium was changed every other day. Prior to permeability measurements, the integrity of the cell monolayer was assessed using an electrical resistance method.

[0571] To determine the rate of drug transport from the apical to the basolateral direction, 125 μL of test compound working solution was added to the Transwell insert (apical compartment), and 50 μL of sample (D0 sample) was immediately transferred from the apical compartment to a new 96-well plate. To determine the rate of drug transport from the basolateral to the apical direction, 285 μL of compound working solution was added to the receiver plate well (basolateral compartment), and 50 μL of 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 transfer period, 50 μL was directly transferred from the apical and basolateral wells and 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. Vortexed for 5 minutes. The sample is centrifuged at 3,220 g for 20 minutes. An aliquot of 100 μL 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 can be calculated for the MDCKII-MDR1 drug transport assay using the following formula:

number

number

number

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

[0573] Intrinsic clearance in different hepatocyte types

[0574] Prepare 10 mM stock solutions of test compounds and positive controls in the appropriate solvent (DMSO). Place incubation medium (Williams E medium with GlutaMAX) in a 37°C water bath and allow to warm for at least 15 minutes before use. In separate conical tubes, dilute 10 mM test compounds and positive controls to 100 μM by mixing 198 μL of 50% acetonitrile / 50% water and 2 μL of 10 mM stock. Add 198 μL of cryopreserved hepatocytes (0.5 x 10 6100 μM test compound or positive control (viable cells / mL) is pipetted into each well of a 96-well uncoated plate. 2 μL of 100 μM test compound or positive control is pipetted into each well of the 96-well uncoated 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. 25 μL aliquots of the well contents are removed at 0, 15, 30, 60, 90, and 120 minutes. 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 is used for LC / MS / MS analysis. The supernatant may be diluted with ultrapure water according to the LC-MS signal response and peak shape. All incubations are performed in duplicate.

[0575] All calculations are performed using Microsoft Excel. Peak areas are determined from extracted ion chromatograms. Regression analysis of the percent disappearance of the parent compound versus time curve yields the in vitro half-life (t 1 / 2 ) is determined.

[0576] In vitro half-life 1 / 2 ) is determined from the slope value: In vitro 1 / 2 =0.693 / k In vitro 1 / 2 (min) to in vitro intrinsic clearance (in vitroCL Int , μL / min / 10 6 Conversion to HCl (in cells) is performed using the following formula: In vitro CL int =kV / N

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

[0578] PK studies in mice and rats

[0579] The pharmacokinetics of compounds were evaluated in male CD-1 mice or SD-JVC rats via intravenous and oral administration. For intravenous studies, test compounds were dissolved in DMA:30% Solutol HS 15 (w / v):saline (20:20:60, volume ratio) and injected via the tail vein at a dose of 1 mg / kg. For oral studies, test compounds were dissolved in 0.5% MC or PEG400 / Phosal 50PG / EtOH (30 / 60 / 10, volume ratio) and administered orally to mice at 10 mg / kg or 30 mg / kg by gavage. Animals were grouped and treated according to body weight. Blood samples were collected from the JVC at the following time points after administration: 5 minutes (IV only), 15 minutes, and 30 minutes, and 1, 2, 4, 8, and 24 hours after administration. Mice were anesthetized with isoflurane, and blood samples were collected via retro-orbital bleed. 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. The samples were stored at -80°C until ex vivo PK assay.

[0580] Plasma concentrations were determined via the following sample processing method and measurement conditions: 10 μL of sample aliquot was added with 200 μL of IS (terfenadine, 5 ng / mL) in ACN. The mixture was vortexed for 1 minute and centrifuged at 4000 rpm for 10 minutes at 4°C. 80 μL of supernatant aliquot was diluted with 80 μL of water, and the mixed sample was injected into a liquid chromatography-tandem mass spectrometry (LC-MS / MS, Triple Quad 5500) for analysis. Injected sample volume: 2 μL. Monitor: MRM; Column: Advanced Material Technology, HALO AQ-C18 2.7 μm 90 Å, 50 × 2.1 mm; Column temperature: 40 °C; Mobile phase A: HO-0.1% FA, Mobile phase B: ACN-0.1% FA, Gradient program: 15% B-15% B (0 min to 0.3 min), 15% B-90% B (0.3 min to 1.0 min), 90% B-90% B (1.0 min to 1.8 min), 90% B-30% B (1.8 min to 2.0 min), 30% B-30% B (2.0 min to 2.5 min).

[0581] SW1990 PD research:

[0582] Female NCG mice were inoculated with 5 x 10 cells per 200 µL of PBS / Matrigel into the right flank. 6 SW1990 cells were subcutaneously implanted. After inoculation, tumors grew to an average volume of approximately 350–450 mm. 3 Once the mice reached a size of 1000 mg / kg, they were randomized into treatment groups. Randomized mice were given a single dose of vehicle consisting of 0.5% MC or various doses of test compound (e.g., 30, 50, or 100 mg / kg) orally. Plasma was collected at 0.5, 2, 4, and 7 hours, and tumors were harvested 7 hours after administration to measure exposure levels. Tumor fragments were snap-frozen in homogenization tubes using liquid nitrogen 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.

[0583] SW1990 Efficacy Study:

[0584] Female NCG mice were inoculated with 5 x 10 cells per 200 µL of PBS / Matrigel into the right flank. 6 SW1990 cells were subcutaneously implanted. After inoculation, tumors grew to an average volume of approximately 150–250 mm. 3 Once the tumor reached a size of 0.5 mg / kg, the mice were randomized into treatment groups. Randomized mice were given a vehicle consisting of 0.5% MC or test compounds at various doses (e.g., 30, 50, or 100 mg / kg BID) orally. Animals were monitored daily, and tumor volumes were measured twice weekly in two dimensions using calipers and calculated using the formula: V = 0.5(a × b 2 ) to mm 3 where a and b are the long and short diameters of the tumor, respectively. Partial regression (PR) was defined as a tumor volume less than 50% of the initial tumor volume on the first day of treatment in three consecutive measurements, and complete regression (CR) was defined as a tumor volume less than 14 mm in three consecutive measurements. 3 Tumor growth inhibition (TGI) was calculated using the following formula:

number

[0585] Example 23, a monobasic G12D inhibitor, was found to exhibit improved KRas WT selectivity, enhanced oral exposure, reduced gastrointestinal accumulation, and reduced toxicity compared to dibasic G12D inhibitors (e.g., Example 17). Examples 26, 27, 29, 32, 35, 40, 41, and others were also found to exhibit improved oral pharmacodynamic efficacy.

[0586] SW620 PD research:

[0587] Female NOD / SCID mice were injected into the right flank with 5 x 10 cells per 200 µL of PBS / Matrigel. 6 SW620 cells were subcutaneously implanted. After inoculation, tumors grew to an average volume of approximately 350–450 mm. 3 Once the mice reached a tumor size of 1000 mg / kg, they were randomized into treatment groups. Randomized mice were given a single oral dose of a vehicle consisting of 0.5% MC or various doses of the test compound (e.g., 30, 50, or 100 mg / kg). Plasma was collected at 0.5, 2, 4, and 8 hours, and tumors were harvested 4 and 8 hours after administration to measure exposure levels. Tumor fragments were snap-frozen in homogenization tubes using liquid nitrogen 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.

[0588] SW620 Efficacy Study:

[0589] Female NOD / SCID mice were injected into the right flank with 5 x 10 cells per 200 µL of PBS / Matrigel. 6 SW620 cells were subcutaneously implanted. After inoculation, tumors grew to an average volume of approximately 150–250 mm. 3 Once the tumor reached a size of 0.5 mg / kg, the mice were randomized into treatment groups. Randomized mice were given a vehicle consisting of 0.5% MC or test compounds at various doses (e.g., 30, 50, or 100 mg / kg BID) orally. Animals were monitored daily, and tumor volumes were measured twice weekly in two dimensions using calipers and calculated using the formula: V = 0.5(a × b 2 ) to mm 3 where a and b are the long and short diameters of the tumor, respectively. Partial regression (PR) was defined as a tumor volume less than 50% of the initial tumor volume on the first day of treatment in three consecutive measurements, and complete regression (CR) was defined as a tumor volume less than 14 mm in three consecutive measurements. 3 Tumor growth inhibition (TGI) was calculated using the following formula:

number

[0590] RKN PD research:

[0591] Female NOD / SCID mice were injected into the right flank with 5 x 10 cells per 200 µL of PBS / Matrigel. 6 RKN cells were subcutaneously transplanted. After inoculation, tumors grew to an average volume of approximately 350–450 mm. 3 Once the mice reached a tumor size of 1000 mg / kg, they were randomized into treatment groups. Randomized mice were given a single oral dose of a vehicle consisting of 0.5% MC or various doses of the test compound (e.g., 30, 50, or 100 mg / kg). Plasma was collected at 0.5, 2, 4, and 8 hours, and tumors were harvested 4 and 8 hours after administration to measure exposure levels. Tumor fragments were snap-frozen in homogenization tubes using liquid nitrogen 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.

[0592] SW620 Efficacy Study:

[0593] Female NOD / SCID mice were injected into the right flank with 5 x 10 cells per 200 µL of PBS / Matrigel. 6 After inoculation, tumors grew to an average volume of approximately 150–250 mm. 3 Once the tumor reached a size of 0.5 mg / kg, the mice were randomized into treatment groups. Randomized mice were given a vehicle consisting of 0.5% MC or test compounds at various doses (e.g., 30, 50, or 100 mg / kg BID) orally. Animals were monitored daily, and tumor volumes were measured twice weekly in two dimensions using calipers and calculated using the formula: V = 0.5(a × b 2 ) to mm 3where a and b are the long and short diameters of the tumor, respectively. Partial regression (PR) was defined as a tumor volume less than 50% of the initial tumor volume on the first day of treatment in three consecutive measurements, and complete regression (CR) was defined as a tumor volume less than 14 mm in three consecutive measurements. 3 Tumor growth inhibition (TGI) was calculated using the following formula:

number

[0594] AsPC-1 PD research:

[0595] Female BALB / c nude mice were injected with 3 x 10 cells per 200 μL of PBS / Matrigel into the right flank. 6 AsPC-1 cells were subcutaneously implanted. After inoculation, tumors grew to an average volume of approximately 350–450 mm. 3 Once the mice reached a tumor size of 1000 mg / kg, they were randomized into treatment groups. Randomized mice were given a single oral dose of a vehicle consisting of 0.5% MC or various doses of the test compound (e.g., 30, 50, or 100 mg / kg). Plasma was collected at 0.5, 2, 4, and 8 hours, and tumors were harvested 4 and 8 hours after administration to measure exposure levels. Tumor fragments were snap-frozen in homogenization tubes using liquid nitrogen 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.

[0596] AsC-1 Efficacy Study:

[0597] Female BALB / c nude mice were injected with 3 x 10 cells per 200 μL of PBS / Matrigel into the right flank.6 AsPC-1 cells were subcutaneously implanted. After inoculation, tumors grew to an average volume of approximately 150–250 mm. 3 Once the tumor reached a size of 0.5 mg / kg, the mice were randomized into treatment groups. Randomized mice were given a vehicle consisting of 0.5% MC or test compounds at various doses (e.g., 30, 50, or 100 mg / kg BID) orally. Animals were monitored daily, and tumor volumes were measured twice weekly in two dimensions using calipers and calculated using the formula: V = 0.5(a × b 2 ) to mm 3 where a and b are the long and short diameters of the tumor, respectively. Partial regression (PR) was defined as a tumor volume less than 50% of the initial tumor volume on the first day of treatment in three consecutive measurements, and complete regression (CR) was defined as a tumor volume less than 14 mm in three consecutive measurements. 3 Tumor growth inhibition (TGI) was calculated using the following formula:

number

[0598] hERG assay

[0599] hERG (human ether-agogo-related gene) is a rapidly activating potassium channel (I) that contributes to repolarization of cardiac action potentials. Kr ) Blockade of the hERG channel can lead to electrocardiogram QT interval prolongation, known as long QT syndrome. Drug-induced delay in ventricular repolarization can potentially trigger a fatal arrhythmia—torsional apex ventricular tachycardia. Approximately 25–40% of major pharmaceutical compounds exhibit varying degrees of potential risk of hERG dependence, and many drugs have been withdrawn from the market due to the risk of QT interval prolongation.

[0600] Before testing hERG currents, the blank control is diluted with an appropriate amount of extracellular solution to make a control working solution. The positive control and test article stock solutions are removed from -20°C, thawed, and diluted with an appropriate amount of extracellular solution to make working solutions.

[0601] The working solution for the highest test substance concentration should be diluted from the stock solution with extracellular solution, or the stock solution should be diluted first with DMSO. For other test concentrations, serial dilutions should be made using DMSO, and then working solutions with extracellular solution should be prepared. The DMSO concentration in the final working solution is 0.3%. Specific preparation information should be recorded on the Compound Working Solution Preparation Form. Finally, sonicate all test article working solutions for 20 minutes before performing patch clamp experiments.

[0602] Blank control (DMSO) stock solution is kept at room temperature. Blank control working solution is prepared on the day of the test and kept at room temperature. Positive control stock solution and test article stock solution are kept at -20°C. Positive control and test article working solutions are prepared on the day of the test and kept at room temperature.

[0603] Test substance concentrations are automatically set to 30, 10, 3, 1, and 0.3 μM. The blank control is 0.3% DMSO, and the positive control (cisapride) concentrations are 1000, 100, 10, 1, and 0.1 nM.

[0604] For electrophysiological recording in this study, an automated patch clamp system, QPatch 48X (Sophion), was used.

[0605] The prepared cells are placed in the centrifuge of the Qpatch work surface, and the cells are washed by multiple centrifugations / suspensions, replacing the cell culture medium with extracellular solution. The MTP-96 plate is removed and placed in the MTP source position. The QPlate chip is removed and placed in the QPlate source position. The barcode reader scans the barcodes on the MTP-96 board and QPlate chip, and the gripper arm transports them to the measurement position. Intracellular and extracellular solutions from the saline reservoir are added to the intracellular saline well, cells, and compound wells of the QPlate chip. For measurements, all measurement points on the QPlate undergo initial quality control. The quality control process involves aspirating the cell suspension from the centrifuge cell container, placing the cells over the chip hole using the pressure controller, establishing a high-resistance seal, and establishing whole-cell recording mode. Once a stable baseline control current is obtained, test substances are applied to the cells by sequentially aspirating them from the MTP-96 plate in order of concentration. hERG currents were recorded using the whole-cell patch clamp technique at a holding potential of -80 mV, followed by a 0.5-second depolarization to -50 mV to test for leak currents. The voltage was then depolarized to 30 mV for 2.5 seconds. Peak tail currents were induced by a 4-second repolarization pulse to -50 mV. This protocol was repeated at 10-second intervals to observe the effects of the test substance on hERG tail currents. Data were collected by the QPatch screening station and stored in the QPatch database server.

[0606] In this experiment, each drug concentration is applied twice for at least a 5-minute recording period. Control and test solutions are applied to the cells sequentially, from low to high concentration. The current of each cell detected in compound-free extracellular solution serves as its own blank control.

[0607] I C 50 Calculate IC values ​​and fit the dose-response curve using the nonlinear regression equation above (where IC 50 (where IC is the half-maximal inhibitory concentration). GraphPad Prism software was used to calculate the IC50 Calculations and curve fitting are performed. Activity Table

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

[0609] [Table 4]

[0610] [Table 5-1] [Table 5-2]

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

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

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, having During the ceremony, Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; The moiety B is an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocyclyl, or an unsubstituted or substituted C ２－５ is alkyl; X is N or C-R ８ and W is O, NH, NR ９ , N-C(=O)-R １０ or O=S=O; R ０ are each independently H, halogen, amino, —CN, —OH, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkenyl, unsubstituted or substituted C １－４ Alkynyl, unsubstituted or substituted C １－４ Alkoxy, unsubstituted or substituted C ３－５ Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C １－４ alkylamino, carboxy, nitro, thiol, or thioether; or any of the above 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 , R ３ｂ , R ４ａ , R ４ｂ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ , and R ８ｂ are each independently H, halogen, amino, —CN, —OH, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkoxy, unsubstituted or substituted C ３－５ Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C １－４ alkylamino, carboxy, nitro, thiol, or thioether; 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 ６ａ , and R ６ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R ７ａ , and R ７ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R ８ａ , and R ８ｂ together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R ６ａ , and R ７ａ together with the atoms to which they are attached form an unsubstituted or substituted bridge, or R ６ａ , and R ８ａ together with the atoms to which they are attached form an unsubstituted or substituted bridge, or R ５ , and R ７ａ together with the atoms to which they are attached form an unsubstituted or substituted bridge, or R ５ , and R ８ａ together with the atoms to which they are attached form an unsubstituted or substituted bridge; 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; 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; t is 0 or 1; and The compound wherein m and q are each independently an integer between 0 and the maximum number of substituents allowed on rings A and B, respectively.

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

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

4. 4. The compound of claim 3, 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 moiety 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[2.2.2].

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

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

7. wherein the bridge is —(CH ２ ) ２ -, -(CH ２ ) ３ - or -CH ２ -O-CH ２ The compound according to claim 6, wherein

8. wherein t is 0, X is N, and ring A is 【Chemistry 4】 and part B is 【Chemistry 5】 and W is O or NH.

9. wherein t is 0; X is N; Ring A is 【Chemistry 6】 and Part B is 【Chemistry 7】 and and W is O or NH.

10. wherein t is 0; X is N; and ring A is 【Chemistry 8】 and part B is 【Chemistry 9】 and W is O or NH.

11. wherein t is 0; X is N; and ring A is 【Chemistry 10】 W is O or NH; or the moiety B is 【Chemistry 11】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ and the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S.

12. wherein t is 0; X is N; and ring A is 【Chemistry 12】 W is O or NH; and moiety B is 【Chemistry 13】 8. The compound of claim 7, wherein:

13. wherein t is 0; X is CH; Ring A is 【Chemistry 14】 and W is O or NH; and moiety B is 【Chemistry 15】 wherein R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ and the N to which they are attached form a substituted or unsubstituted N-, O-, or S-containing heterocycle.

14. wherein t is 0; X is CH; and ring A is 【Chemistry 16】 W is O or NH; and moiety B is 【Chemistry 17】 wherein R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ and the N to which they are attached form a substituted or unsubstituted N-, O-, or S-containing heterocycle.

15. wherein t is 0; X is C—Cl; Ring A is 【Chemistry 18】 and W is O or NH; and moiety B is 【Chemistry 19】 wherein R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ and the N to which they are attached form a substituted or unsubstituted N-, O-, or S-containing heterocycle.

16. wherein t is 0; X is C—Cl; Ring A is 【Chemistry 20】 and W is O or NH; and moiety B is 【Chemical 21】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ The compound of claim 7 which is an alkoxyl.

17. wherein t is 1; X is N; and ring A is 【Chemical 22】 W is O or NH; and moiety B is 【Chemical 23】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ The compound of claim 7 which is an alkoxyl.

18. wherein t is 1; X is N; Ring A is 【Chemistry 24】 and W is O or NH; and moiety B is 【Chemistry 25】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ The compound of claim 7 which is an alkoxyl.

19. wherein t is 0; X is C—H; Ring A is 【Chemical 26】 and W is O or NH; and moiety B is 【Chemical 27】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted １－４ The compound of claim 7 which is an alkoxyl.

20. wherein t is 1; X is C—Cl; Ring A is 【Chemical Formula 28】 and W is O or NH; and moiety B is 【Chemical 29】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ The compound of claim 7 which is an alkoxyl.

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

22. wherein t is 0; X is N; and ring A is 【Chemistry 30】 and moiety B is 【Chemical 31】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ 22. The compound of claim 21 which is alkoxyl.

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

24. wherein t is 0; X is N; and ring A is 【Chemical 32】 and moiety B is 【Chemical 33】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ 22. The compound of claim 21 which is alkoxyl.

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

26. wherein t is 0; X is C—Cl; and ring A is 【Chemical 34】 and moiety B is 【Chemical 35】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ 22. The compound of claim 21 which is alkoxyl.

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

28. wherein t is 1; X is N; and ring A is 【Chemical 36】 and moiety B is 【Chemical 37】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ 22. The compound of claim 21 which is alkoxyl.

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

30. wherein t is 1; X is N; and ring A is 【Chemical 38】 and moiety B is 【Chemical 39】 where R ａ and R ｂ are each independently substituted or unsubstituted C １－４ Alkyl; substituted or unsubstituted C ３－５ cycloalkyl; or R ａ and R ｂ together with the N to which they are attached form a substituted or unsubstituted heterocycle containing N, O, or S; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C ３－５ Cycloalkyl, substituted or unsubstituted C １－４ 22. The compound of claim 21 which is alkoxyl.

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

32. 4. The compound of claim 3, wherein the compound has the following formula: 【Chemistry 40】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopic species, or drug thereof; During the ceremony, Ring C is unsubstituted or substituted C ３－６ The compound is a cycloalkyl or an unsubstituted or substituted 3- to 6-membered heterocyclyl.

33. 33. The compound of claim 32, wherein ring C contains Y and R ａ wherein Y is substituted with 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; and R ａ is H, halogen, amino, —CN, —OH, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkoxy, or unsubstituted or substituted C １－４ The compound is alkylamino.

34. Y is CH ２ , O, or NH.

35. In the formula, R ６ａ and R ７ａ together form a bridge, and the bridge is -CH ２ -CH ２ The compound of claim 33, wherein

36. In the formula, R ５ and R ８ａ together form a bridge, and the bridge is -CH ２ -CH ２ The compound of claim 33, wherein

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

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

39. Compounds having formula (II): 【Chemistry 41】 or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer or prodrug thereof, During the ceremony, Ring A is unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; The moiety B is an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocyclyl, or an unsubstituted or substituted C ２－５ is alkyl; X is N or C-R ８ and W is O, NH, NR ９ , N-C(=O)-R １０ or O=S=O; 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 any of the above 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 , R ３ｂ , R ４ａ , R ４ｂ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ , and R ８ｂ are each independently H, halogen, amino, —CN, —OH, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １－４ Alkoxy, unsubstituted or substituted C ３－５ Cycloalkyl, unsubstituted or substituted 3- to 5-membered heterocyclyl, unsubstituted or substituted C １－４ alkylamino, carboxy, nitro, thiol, or thioether; Optionally, R ３ａ , and R ３ｂ taken 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 taken together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R ６ａ , and R ６ｂ taken together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R ７ａ , and R ７ｂ taken together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R ８ａ , and R ８ｂ taken together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, or an unsubstituted or substituted heterocyclyl; or R ６ａ , and R ７ａ together with the atoms to which they are attached form an unsubstituted or substituted bridge; or R ６ａ , and R ８ａ together with the atoms to which they are attached form an unsubstituted or substituted bridge; or R ５ , and R ７ａ together with the atoms to which they are attached form an unsubstituted or substituted bridge; or R ５ , and R ８ａ together with the atoms to which they are attached form an unsubstituted or substituted bridge, R ８ is H, halogen, unsubstituted or substituted C １－４ Alkyl, unsubstituted or substituted C １ー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 is halogenated alkoxyl, CN, OH, or amino; 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; t is 0 or 1; each of s and r is independently 1 or 2; and The compound wherein m and q are each independently an integer between 0 and the maximum number of substituents allowed on rings A and B, respectively.

40. 40. The compound of claim 39, having formula (IIf): 【Chemistry 42】 or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, having wherein X is N or CH; W is O or NH; Ring A is 【Chemistry 43】 and Part B is 【Chemical Formula 44】 and R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ１ , R ８ｂ１ , R ８ａ２ , and R ８ｂ２ each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C １－４ The compound is alkyl.

41. 40. The compound of claim 39, having formula (IIg): 【Chemistry 45】 or a pharmaceutically acceptable salt, tautomer, isotopic species, stereoisomer, enantiomer, atropisomer, or prodrug thereof, having wherein X is N or CH; W is O or NH; Ring A is 【Chemistry 46】 and part B is 【Chemistry 47】 and R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ , R ６ａ１ , R ６ｂ１ , R ６ａ２ , R ６ｂ２ , R ７ａ , R ７ｂ , R ８ａ , and R ８ｂ each independently represents H, OH, CN, unsubstituted or substituted amino, or unsubstituted or substituted C １－４ The compound is alkyl.

42. 40. The compound of claim 39, having formula (IIh): 【Chemistry 48】 or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, atropisomer, isotopic species, or prodrug thereof, having In the formula, R １１ is deuterium, or substituted or unsubstituted C １－３ is alkyl; and The compound wherein u is 0, 1, 2, 3, 4, or 5.

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

44. wherein ring A is 【Chemistry 49】 and R １２ is H, halogen, substituted or unsubstituted C １－３ alkyl or cyclopropyl, optionally substituted with F; and R １２ａ 43. The compound of claim 42, wherein is H, deuterium, F or Me.

45. wherein ring A is 【Chemistry 50】 43. The compound of claim 42, wherein:

46. 45. The compound of claim 44, wherein moiety B is an unsubstituted or substituted heterocyclyl, said heterocyclyl not containing a secondary or tertiary amine and including at least one oxygen as a ring member.

47. wherein moiety B is 【Chemistry 51】 wherein 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; and R ｃ is H, halogen, CN, substituted or unsubstituted C １－４ Alkyl, substituted or unsubstituted C １－４ Cycloalkyl, substituted or unsubstituted C １－４ Alkoxyl, or C １－４ 45. The compound of claim 44, which is alkoxyl-C(O)-.

48. 45. The compound of claim 44, wherein moiety B is 【Chemistry 52-1】 【Chemistry 52-2】 The compound,

49. wherein the moiety B is oxabicyclo[2.1.1]hexanyl, optionally containing halogen, cyano, hydroxy, C １－３ Alkoxy or C １－３ optionally substituted with alkyl, and optionally halogen, cyano, hydroxy, or C １－３ 45. The compound of claim 44, substituted with alkoxy.

50. wherein moiety B is 【Chemistry 53】 or 2-oxabicyclo[2.1.1]hexan-4-yl.

51. wherein moiety B is 【Chemical Formula 54】 45. The compound of claim 44, wherein:

52. 52. The compound of any one of claims 1 to 51, wherein the compound is selected from Tables 1 to 3.

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

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

55. 52. A method for the treatment or prevention of cancer, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 51, 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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