AZA-tetracyclic oxazepine inhibitors of KRAS-g12d

Abstract

Provided herein are aza-tetracyclic oxazepinyl compounds useful in the treatment of cancers.

Description

Attorney Dkt. No.: 000218-0078-WO1 AZA-TETRACYCLIC OXAZEPINE INHIBITORS OF KRAS-G12D CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of United States Provisional Application No.63 / 602,323 filed November 22, 2023, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch for central growth signaling pathways. In response to extracellular signals, Ras is converted from a GDP-bound (RasGDP) to a GTP-bound (RasGTP) state, as catalyzed by guanine nucleotide exchange factors (GEFs), notably the SOS1 protein. Active RasGTPmediates its diverse growth-stimulating functions through its direct interactions with effectors including Raf, PI3K, and Ral guanine nucleotide dissociation stimulator. The intrinsic GTPase activity of Ras then hydrolyzes GTP to GDP to terminate Ras signaling. The Ras GTPase activity can be further accelerated by its interactions with GTPase-activating proteins (GAPs), including the neurofibromin 1 tumor suppressor.

[0003] Mutant Ras has a reduced GTPase activity, which prolongs its activated state, thereby promoting Ras-dependent signaling and cancer cell survival or growth. Mutation in Ras that affects its ability to interact with GAP or to convert GTP back to GDP will result in a prolonged activation of the protein and consequently a prolonged signal to the cell telling it to continue to grow and divide. Because these signals result in cell growth and division, overactive RAS signaling may ultimately lead to cancer. Mutations in any one of the three main isoforms of RAS (HRas, NRas, or KRas) genes are common events in human tumorigenesis. Among the three Ras isoforms (K, N, and H), KRas is most frequently mutated.

[0004] The most common KRas mutations are found at residue G12 and G13 in the P-loop and at residue Q61. G12D is a frequent mutation of KRas gene (glycine-12 to aspartate). Mutations of Ras in cancer are associated with poor prognosis. Inactivation of oncogenic Ras in mice results in tumor shrinkage. Thus, Ras is widely considered an oncology target of exceptional importance.

[0005] Accordingly, there is a pressing need for therapies for G12D mutant KRas mediated cancers. BRIEF SUMMARY

[0006] Provided herein are solutions to the problems above and other problems in the art.

[0007] In a first aspect provided herein is a compound of formula (I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0008] In a second aspect provided herein is a compound of formula (II) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0009] In a third aspect provided herein is a compound of formula (III) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0010] In another aspect provided herein is a compound or pharmaceutically acceptable salt thereof as set forth in Table 1.

[0011] In another aspect provided herein is a pharmaceutical composition comprising a compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0012] In another aspect provided herein is a method of treating a cancer comprising a KRas mutation, the method comprising administering to a patient having such cancer, a compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0013] In another aspect provided herein is a method for regulating activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0014] In another aspect provided herein is a method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0015] In another aspect provided herein is a method for inhibiting tumor metastasis comprising administering to an individual in need thereof a therapeutically effective amount of the compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein or a pharmaceutical composition as described herein to a subject in need thereof.

[0016] In another aspect provided herein is method for preparing a labeled KRas G12D mutant protein, the method comprising reacting a KRas G12D mutant protein with a labeled compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, as described here to result in the labeled KRas G12D mutant protein. DETAILED DESCRIPTION Definitions

[0017] Disclosed herein are 6-aza tetracyclic oxazepine compounds as described herein or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof and pharmaceutical compositions thereof that, in certain embodiments, are inhibitors or modulators of mutant KRas. In certain instances, such compounds and compositions are inhibitors or modulators of mutant G12D KRas as provided herein. The compounds and compositions described herein are useful in treating diseases and disorders mediated by mutant KRas, including KRasG12Dmutations.

[0018] While the disclosure herein provides enumerated embodiments, it is understood that they are not intended to limit the compounds and methods described herein to those embodiments. On the contrary, the disclosure is intended to cover all alternatives, modifications, and equivalents that can be included within the scope of the present disclosure as defined by the claims.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The nomenclature used in this Application is based on IUPAC systematic nomenclature, unless indicated otherwise.

[0020] The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references referred to herein are incorporated by reference in their entirety.

[0021] The terms “halogen” and “halo” are used interchangeably and refer to F, Cl, Br or I. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl, polyhaloalkyl, and perhaloalkyl.

[0022] The term "alkyl" refers to a saturated linear or branched-chain monovalent hydrocarbon radical. In one example, the alkyl radical is one to eighteen carbon atoms (C1-18). In other examples, the alkyl radical is C1-12, C1-10, C1-8, C1-6, C1-5, C1-4, or C1-3. Examples of alkyl groups include methyl (Me, –CH3), ethyl (Et, –CH2CH3), 1-propyl (n-Pr, n-propyl, –CH2CH2CH3), 2-propyl (i-Pr, i-propyl, –CH(CH3)2), 1-butyl (n-Bu, n-butyl, –CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, – CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, –CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, – C(CH3)3), 1-pentyl (n-pentyl, –CH2CH2CH2CH2CH3), 2-pentyl (–CH(CH3)CH2CH2CH3), 3-pentyl (– CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (–CH(CH3)CH(CH3)2), 3- methyl-1-butyl (–CH2CH2CH(CH3)2), 2-methyl-1-butyl (–CH2CH(CH3)CH2CH3), 1-hexyl (– CH2CH2CH2CH2CH2CH3), 2-hexyl (–CH(CH3)CH2CH2CH2CH3), 3-hexyl (– CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (–C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (– CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (–CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (– C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (–CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (– C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (–CH(CH3)C(CH3)3, 1-heptyl and 1-octyl.

[0023] The term "alkoxy" refers to –O–alkyl.

[0024] The terms “cyano” or “nitrile” refers to –C≡N or –CN.

[0025] The term "haloalkoxy" refers to –O–haloalkyl.

[0026] The terms "hydroxy" and “hydroxyl” refer to –OH.

[0027] The term “alkylidene” refers to linear or branched-chain monovalent hydrocarbon radical having formula =CR’R”, where R’ and R" can be the same or different. In one example, an alkylidene radical is 1 to 6 carbons (C1-6). In another example, the alkylidene radical is C1-3, C1-2, or C1. Exemplary alkylidenes include, but are not limited to, methylidene (=CH2), ethylidene (=CHCH3), and propylidene (=CH-CH2-CH3).

[0028] The term "alkenyl" refers to linear or branched-chain monovalent hydrocarbon radical with at least one carbon-carbon double bond and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In one example, the alkenyl radical is two to eighteen carbon atoms (C2-18). In other examples, the alkenyl radical is C2-12, C2-10, C2-8, C2-6, or C2-3. Examples include, but are not limited to, ethenyl or vinyl (–CH=CH2), prop-1-enyl (–CH=CHCH3), prop-2-enyl (–CH2CH=CH2), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3- dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

[0029] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon, triple bond. In one example, the alkynyl radical is two to eighteen carbon atoms (C2-18). In other examples, the alkynyl radical is C2-12, C2-10, C2-8, C2-6, or C2-3. Examples include, but are not limited to, ethynyl (–CºCH), prop-1-ynyl (–CºCCH3), prop-2-ynyl (propargyl, –CH2CºCH), but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0030] The term "alkylene” refers to a saturated, branched, or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. In one example, the divalent alkylene group is one to eighteen carbon atoms (C1-18). In other examples, the divalent alkylene group is C1-12, C1-10, C1-8, C1-6, C1-5, C1-4, or C1-3. Example alkylene groups include methylene (–CH2–), 1,1-ethyl (–CH(CH3)–), (1,2-ethyl (–CH2CH2–), 1,1-propyl (–CH(CH2CH3)–), 2,2-propyl (–C(CH3)2–), 1,2- propyl (–CH(CH3)CH2–), 1,3-propyl (–CH2CH2CH2–), 1,1-dimethyleth-1,2-yl (–C(CH3)2CH2–), 1,4- butyl (–CH2CH2CH2CH2–), and the like.

[0031] Cyclic (ring-containing) moieties comprise atoms bonded together in a ring, and have one or more substituents other than hydrogen atoms bonded to one or more ring atoms. Each atom in the ring defines a vertex of a polygon.

[0032] Two ring atoms are adjacent to one another in that ring if they are bonded to one another in the ring. In rings having 4 or more ring atoms, adjacent atoms are bonded to one another but to no other atom in the same ring. In a three-membered ring, each atom is necessarily bonded to each other atom in the ring. Two adjacent ring atoms define one “edge” of the ring.

[0033] Two or more cyclic moieties may join to one another in one of several ways to form ring systems that comprise more than one ring.

[0034] Two rings are fused to one another if two ring atoms are adjacent to one another in both rings and are shared by both rings. Such rings are said to share an “edge.”

[0035] Spirocyclic ring systems comprise a pair of rings that share a single vertex. Such systems contain a ring junction at which the two rings share a single ring atom.

[0036] Bridged ring systems contain at least a pair of rings in which two or more non-adjacent ring atoms are shared by two or more rings. The two non-adjacent ring atoms in question are referred toas “bridgehead” atoms and the pair of bridgehead atoms are members of three different rings. Examples of carbocyclic radicals containing bridged bicyclic rings are norbornyl and adamantyl.

[0037] Chained ring systems contain two or more rings that are joined to one another but do not share any ring atom in common: one ring is a substituent of the other, and vice versa. Each ring in the chained ring system may independently be a carbocycle or a heterocycle and may be aromatic, partially unsaturated or saturated. Biphenyl is an example of a chained ring system.

[0038] Ring systems may contain pairs of rings that are fused or chained to one another, spiro- joined, or bridged, or in the case of three or more rings, joined in combinations of ways thereof.

[0039] The term “carbocycle” as used herein refers to aromatic, saturated or unsaturated cyclic univalent hydrocarbon groups having the number of annular (i.e., ring) carbon atoms designated (i.e., C3-10 means three to ten annular carbon atoms). Carbocyclic groups have a single ring (“monocycles”) or more than one ring (“bicycles”, “tricycles”, or polycycles, more generally). Two or more carbocyclic rings may be joined to one another by fused, spiro, bridged, or chained connections as further described elsewhere herein.

[0040] It is intended herein that the term carbocycle encompasses radicals having one or more adjacent pairs of ring atoms between which are double bonds, and that, where more than one such double bond is present, the double bonds may or may not form a conjugated system within the ring. Thus, carbocycles may be more specifically designated according to whether they are fully saturated (“cycloalkyl”), unsaturated at least in part (“cycloalkenyl”), or fully conjugated, (“aromatic” or “aryl”). Cycloalkyl groups are fully saturated radicals and are derived by the removal of one hydrogen atom from one carbon atom of a parent cycloalkane. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms (C3-12-cycloalkyl). A preferred cycloalkyl is a monocyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C3-8-cycloalkyl”), or having 3 to 6 carbon atoms (a “C3-6-cycloalkyl”). In other examples, cycloalkyl is C3-4, C3-5, C3-7, C3-8, C3-10, C3-10, or C5-10. In other examples, the cycloalkyl group, as a monocycle, is C3-4, C3-8, C3-6, or C5-6. In another example, the cycloalkyl group, as a spiro system, is C5-12. In another example, the cycloalkyl group, as a bicycle, is C7-C12. Single ring cycloalkyl radicals have formula CnH2n−1. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkenyl groups have one or more double bonds between adjacent ring carbon atoms. Examples of cycloalkenyl groups include 1-cyclohex-1-enyl, and 1-cyclohex-3- enyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples ofspirocycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.

[0041] “Aryl” as used herein refers to a carbocyclic group having an aromatic single ring (e.g., phenyl) or multiple aromatic rings fused to one another (e.g., naphthyl). Preferably, an aryl group comprises from 6 to 20 carbon atoms, more preferably between 6 to 12 carbon atoms. Particularly preferred aryl groups are those having from 6 to 14 annular carbon atoms (a “C6-14-aryl”). The term aromatic is used herein as it is typically used in organic chemistry, meaning, with a few understood exceptions, rings and ring systems in which the annular atoms contribute a total of (4n+2) pi electrons to a set of delocalized molecular orbitals, where n is a non-zero positive integer.

[0042] Typical aryl groups include, but are not limited to, groups derived from fused ring systems that comprise one or more aromatic rings, or conjugated ring systems, such as but not limited to aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, heptaphene, hexacene, hexaphene, as-indacene, s-indacene, indene, naphthalene (hexalene), octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, tetraphenylene, triphenylene, and trinaphthalene.

[0043] The terms “heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” are used interchangeably and refer to any mono-, bi-, tricyclic, chained, fused, spiro or bridged, saturated, partially saturated or unsaturated, non-aromatic ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-10 ring atoms (“members”) and includes monocycles, bicycles, tricycles, spiro, and bridged ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In other examples, heterocyclyl includes 4-10 or 5-10 ring atoms. In one example, heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclyl includes 1 to 3 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6 membered monocycles. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom mayoptionally be quaternized (e.g., [NR4]+Cl-, [NR4]+OH-). Example heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4- diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, 1,1-dioxoisothiazolyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7- tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, 3- azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3- azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2- azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8- azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl.

[0044] In particular embodiments, a heterocyclyl group or a heteroaryl group is attached at a carbon atom of the heterocyclyl group or the heteroaryl group. By way of example, carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.

[0045] In certain embodiments, the heterocyclyl group or heteroaryl group is N-attached. By way of example, nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline.

[0046] A heterocyclic ring may make fused, spiro, or bridged, connections or make any combination of such connections to one or more other rings.

[0047] “Heteroaryl” or “heteroaromatic”, as used herein, refers to an aromatic cyclic group having from 1 to 14 ring carbon atoms and at least one ring heteroatom, including but not limited to heteroatoms such as nitrogen, phosphorus, oxygen and sulfur. The term refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single ring atom of a parent heteroaromatic ring system. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple fused rings (e.g., indolizinyl, benzothienyl). Particular heteroaryl groups are 5- to 14- membered rings having 1 to 12 annular (i.e., ring) carbon atoms and 1 to 6 annular (i.e., ring) heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur; 5- to 10- membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur; and 5-, 6- or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur In one variation, heteroaryl include monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, heteroaryl includes polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur.

[0048] Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, p-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyridone, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. Preferred heteroaryl groups are thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine, and those derived therefrom.

[0049] Rings of different categories may be connected to one another, such as by fused, spiro, or bridged, connections, or by combinations thereof. Such a ring system can be referred to as a “mixed” ring system.

[0050] For example, at least one ring of a multiple ring system can be aromatic on its own, though one or more of the remaining fused rings may be not aromatic. Examples of fused ring systems thatcontain at least one aromatic ring and at least one partially saturated ring include fluorene, indane, and biphenylene.

[0051] A mixed ring system having more than one ring where at least one ring is aromatic and at least one ring is non-aromatic may be connected to another structure by bonding to either an aromatic ring atom or a non-aromatic ring atom.

[0052] A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to another structure at either an aromatic ring position or at a non-aromatic ring position.

[0053] Similarly, carbocyclic and heterocyclic groups may join to one another in one of several ways to form ring systems that comprise more than one ring.

[0054] “Heteroatom” refers to any atom other than carbon or hydrogen. Typical heteroatoms found in small organic molecules are selected from: nitrogen, oxygen, fluorine, phosphorous, sulfur, chlorine, and bromine. It is understood by those of skill in the art that where the term heteroatom used to denote a member of a ring (e.g., a heteroaromatic ring) then monovalent heteroatoms such as halogen are excluded.

[0055] “Fused” refers to any ring structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with an existing ring structure in the compounds described herein.

[0056] The term “acyl” refers to a carbonyl containing substituent represented by the formula – C(=O)-R in which R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl and heterocyclyl are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl (e.g., pyridinoyl).

[0057] The term “haloalkyl” refers to an alkyl chain in which one or more hydrogen has been replaced by a halogen. Examples of haloalkyls are trifluoromethyl, difluoromethyl, and fluoromethyl. A substituted haloalkyl refers to a haloalkyl having a moiety other than a halogen. An unsubstituted haloalkyl refers to a haloalkyl substituted with no moiety other than hydrogen or halogen as described herein.

[0058] “Carbenyl”, when used as a ring substituent, refers to the moiety =C, i.e., a carbon atom double-bonded to a carbon atom in a ring. It means that a single carbon atom replaces two hydrogen (or other monovalent) atoms that are bonded to a ring carbon atom and is therefore bonded to the ring carbon atom via a double bond. In general, a carbenyl may be represented as RcRdC=, where RcRc are independently either hydrogen or alkyl.

[0059] “Oxo” refers to the moiety =O, i.e., an oxygen atom double-bonded to a second atom other than oxygen. When used as a ring substituent it means that a ring atom such as a carbon atom is bonded via a double bond to an oxygen atom other than a ring atom.

[0060] “Sulfonyl” refers to the group -S(O)2R, where R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be optionallysubstituted, as defined herein. In some embodiments, R is -H, C1-C6alkyl, or C1-C6haloalkyl.

[0061] “Carboxyalkyl” refers to an alkyl group terminating with a carboxylic acid moiety. Examples of carboxyalkyl, include but are not limited to carboxymethyl, carboxyethyl, carboxypropyl and the like. For example, “carboxy-C1alkyl” refers to the moiety -C(O)2H.

[0062] As used herein a wavy line “ ” that intersects a bond in a chemical structureindicates the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule.

[0063] In certain embodiments, divalent groups are described generically without specific bonding configurations. It is understood that the generic description is meant to include both bonding configurations, unless specified otherwise. For example, in the group R1–R2–R3, if the group R2is described as –CH2C(O)–, then it is understood that this group can be bonded both as R1–CH2C(O)– R3, and as R1–C(O)CH2–R3, unless specified otherwise.

[0064] The term “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.

[0065] Compounds described herein may be in the form of a salt, such as a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” include both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0066] The term “pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particular base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, suchas isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particular organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0067] In some embodiments, a salt is selected from a hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5- dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulfonate), napsylate (2-naphthalenesulfonate), camsylate (camphor-10-sulfonate, for example (1S)-(+)-10-camphorsulfonic acid salt), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoic (2,2'- dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

[0068] A “sterile” formulation is aseptic or free from all living microorganisms and their spores.

[0069] The term “stereoisomers” refer to compounds that have identical chemical constitution but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, atropisomers, conformers and the like.

[0070] The term “chiral” refers to molecules that have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

[0071] The term “diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0072] The term “enantiomers” refers to two stereoisomers of a compound that are non- superimposable mirror images of one another.

[0073] The term “atropisomers” refers to two conformers resulting from hindered rotation about a single bond where the steric strain barrier to rotation can be high enough to allow for the isolation of each conformer.

[0074] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0075] The term “tautomer” or “tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0076] Certain compounds described herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. A “solvate” refers to an association or complex of one or more solvent molecules and a compound described herein. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. Certain compounds described herein can exist in multiple crystalline or amorphous forms. In general, all physical forms are contemplated herein. The term "hydrate" refers to the complex where the solvent molecule is water.

[0077] The compounds and pharmaceutically acceptable salts thereof described herein also embrace isotopically-labeled compounds that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated herein, and their uses. Exemplary isotopes that can beincorporated into compounds and pharmaceutically acceptable salts thereof described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I, and125I. Certain isotopically-labeled compounds or pharmaceutical acceptable salts thereof described herein (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as15O,13N,11C and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds or pharmaceutical acceptable salts thereof described herein can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.

[0078] Compounds and pharmaceutically acceptable salts thereof described herein may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Mixtures of particular diastereomeric compounds may be separated, or enriched in one or more particular diastereomers, by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated, or enantiomerically enriched, using the same techniques or others known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration and both of these configurations are contemplated herein.

[0079] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended.

[0080] A “subject,” “individual,” or “patient” is a vertebrate and are used interchangeably herein. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits and horses), primates, mice and rats. In certain embodiments, a mammal is a human. In embodiments comprising administration of a compound of to a patient, the patient is typically in need thereof.

[0081] The terms “inhibiting” and “reducing,” or any variation of these terms, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be adecrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of activity compared to normal.

[0082] The term “treatment” refers to clinical intervention designed to alter the natural course of the patient or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For example, a patient is successfully “treated” if one or more symptoms associated with a cancer described herein are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and / or prolonging survival of patients.

[0083] The term “delaying progression” of a disease refers to deferring, hindering, slowing, retarding, stabilizing, and / or postponing development of a cancer described herein. This delay can be of varying lengths of time, depending on the history of the cancer and / or patient being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the patient does not develop cancer or relapse.

[0084] A “mutant KRas mediated disease” and the like refer to a disease described herein (e.g., a cancer described herein) having symptoms or requiring treatment as set forth herein that is / are wholly or partly associated with, a result of, a function of, or otherwise correlated to mutant KRas activity as described herein. In one such embodiment, the mutant KRas is KRasG12D.

[0085] An “effective amount” or “therapeutically effective amount” is at least the minimum amount required to effect a measurable improvement or prevention of a cancer described herein. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the agent to elicit a desired response in the patient. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. Beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, delaying the onset of the disease (including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease), decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and / or prolonging survival. In some embodiments, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow or stop) cancer cell infiltrationinto peripheral organs; inhibit (i.e., slow or stop) tumor metastasis; inhibiting (i.e., slow or stop) tumor growth; and / or relieving one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations.

[0086] The term "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the subject at the same time. Co- administration includes simultaneous administration in separate compositions, administration at different times (i.e., sequential administration) in separate compositions, or administration in a composition in which both agents are present.

[0087] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0088] The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as a mutant form of KRas. Accordingly, the terms "antagonist" and "inhibitors" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor.

[0089] The term "agonist" as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0090] The terms “cancer” and “cancerous”, “neoplasm”, and “tumor” and related terms are used interchangeably herein and refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer) and lung cancerincluding small-cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung. Other cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral), lip, tongue, mouth, salivary gland, esophageal, larynx, hepatocellular, gastric, stomach, gastrointestinal, small intestine, large intestine, pancreatic, cervical, ovarian, liver, bladder, hepatoma, breast, colon, rectal, colorectal, genitourinary, biliary passage, thyroid, papillary, hepatic, endometrial, uterine, salivary gland, kidney or renal, prostate, testis, vulval, peritoneum, anal, penile, bone, multiple myeloma, B-cell lymphoma, diffuse large B-Cell lymphoma (DLBCL), central nervous system, brain, head and neck, Hodgkin’s, and associated metastases. Other examples of neoplastic disorders include myeloproliferative disorders, such as polycythemia vera, essential thrombocytosis, myelofibrosis, such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

[0091] A "chemotherapeutic agent" is an agent useful in the treatment of a given disorder, for example, cancer or inflammatory disorders. Examples of chemotherapeutic agents are well-known in the art. Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, as well as combinations of two or more of them.

[0092] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds and pharmaceutically acceptable salts thereof described herein, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I, and125I, respectively. Isotopically-labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds and pharmaceutically acceptable salts thereof described herein, one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0093] It is specifically contemplated that any limitation discussed with respect to one embodiment provided herein may apply to any other embodiment provided herein. Furthermore, any compound and pharmaceutically acceptable salts thereof described herein or composition described herein may be used in any method provided herein, and any method provided herein may be used to produce orto utilize any compound and pharmaceutically acceptable salts thereof described herein or composition described herein.

[0094] Throughout this application, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

[0095] Compounds described herein may have stereochemistry depicted as follows:It is understood that all three stereochemical depictions above are equivalent as set forth herein. Compounds

[0096] In one aspect, provided herein is a compound having the structure of formula (I):or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2;, wherein Y1 is N or CR01, Y2 is N or CR02, Y3 is N or CR03; and each of R01, R02, R03, R04, and R05 is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05is -NH2, and at least one of R01, R02, R03, R04, and R05is methyl;R2 is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z1is L1NR5R6, wherein: L1 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5 is L2NR8R9, C1-6alkyl, L2Cy, or -S(=O)2R8, wherein: L2 is selected from: -S(=O)2(CH2)q-, -C(=O)(CH2)q-, -(CH2)q-, -P(=O)3(CH2)q-, –(CH2)–CH=CH–, and –CH=CH–(CH2)–, wherein q = 1 – 3; R8and R9are each independently hydrogen, C1-6alkyl, or C1-3haloalkyl; and Cy is a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; R6 is H or C1-6alkyl; or R5and R6together with the nitrogen atom to which they are both bonded form a group Q; wherein Q is: a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; optionally substituted with one or more R10 groups independently selected from: sulfonyl, cyano, halo, -NH2, -NHR11, -N(R11)2, -R11-NH2, -R11-NH-R11, -R11-N(R11)2, hydroxyl, C1- 6alkoxy, C1-6alkyl, C1-6cycloalkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1-6alkyl, cyano-C1-6alkyl, C2-6alkenyl, hydroxy-C1-6alkyl, oxo, C1-6alkylcarbenyl, carboxy-C1-6alkyl, and C1-6haloalkyl; wherein each R11is independently selected from C1-6alkyl, C1-6haloalkyl, and hydroxyl-C1-6alkyl; wherein Q optionally comprises one or more heteroatoms selected from O, S(O)2, and N in addition to the nitrogen atom to which R5and R6are both bonded, wherein each additional instance of N is present in Q as N–H, N(R11), or as a tertiary N; and X is -O- or -NR12-, wherein R12is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0097] In some embodiments, provided herein is a compound having the structure of formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05 is -NH2, and at least one of R01, R02, R03, R04, and R05 is methyl; R2 is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z1 is L1NR5R6, wherein: L1 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5 is L2NR8R9, C1-6alkyl, L2Cy, or -S(=O)2R8, wherein: L2 is selected from: -S(=O)2(CH2)q-, -C(=O)(CH2)q-, -(CH2)q-, -P(=O)3(CH2)q-, –(CH2)–CH=CH–, and –CH=CH–(CH2)–, wherein q = 1 – 3; R8and R9are each independently hydrogen, C1-6alkyl, or C1-3haloalkyl; and Cy is a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; R6 is H or C1-6alkyl; or R5and R6together with the nitrogen atom to which they are both bonded form a group Q; wherein Q is: a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; optionally substituted with one or more R10 groups independently selected from: sulfonyl, cyano, halo, -NH2, -NHR11, -N(R11)2, -R11-NH2, -R11-NH-R11, -R11-amino-(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6cycloalkyl, C1-6alkoxy-C1-6alkyl, C2-6alkenyl, hydroxy-C1-6alkyl, oxo, C1-6alkylcarbenyl, carboxy-C1-6alkyl, and C1-6haloalkyl; wherein each R11is independently selected from C1-6alkyl, C1-6haloalkyl, and hydroxyl-C1-6alkyl; and wherein Q optionally comprises one or more heteroatoms selected from O and N in addition to the nitrogen atom to which R5 and R6 are both bonded, wherein each additional instance of N is present in Q as N–H, N(R11), or as a tertiary N; andX is -O- or -NR12-, wherein R12 is hydrogen, C1-6alkyl, or C1-6 haloalkyl.

[0098] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NR12-. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is NH. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O.

[0099] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 1, and p is 1.

[0100] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein no more than one of R01, R02, R03, R04, and R05 is hydrogen. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein no more than two of R01, R02, R03, R04, and R05is hydrogen. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R01, R02, R03, R04, and R05is halogen. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R01, R02, R03, R04, and R05 is C1-3haloalkyl. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R01, R02, R03, R04, and R05is amino. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R01, R02, R03, R04, and R05is C1-3alkyl. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each of R01, R02, R03, R04, and R05 is independently hydrogen, halogen, -NH2, C1-3alkyl, C1-3haloalkyl.

[0101] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1is:

[0102] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1is:

[0103] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is:.

[0104] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is fluoro.

[0105] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R3’ and R3” are both H.

[0106] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4’ is hydrogen and R4”is methyl. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4’ is hydrogen and R4” is -CF3. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4’ and R4” are both hydrogen. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4’ and R4” are both methyl. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4’ is hydrogen and R4” is -CH2OH.

[0107] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen, methyl, or C1-3haloalkyl. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is - NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is methyl. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is - NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is C1-3haloalkyl. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is -CHF2. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is - NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is -CF3.

[0108] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein, when present, at least one of R10 is selected from -NH2, -NHR11, -N(R11)2, -R11-NH2, -R11-NH-R11, -R11-N(R11)2.

[0109] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5and R6together with the nitrogen atom to which they are both bonded form Q; and Q is a 3-10 membered monocyclic ring optionally substituted with one or more R10 groups independently selected from sulfonyl, cyano,halo, -N(R11)2, -R11-NH-R11, -R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1-6alkyl, cyano-C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy-C1-6alkyl, and C1-6haloalkyl.

[0110] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5and R6together with the nitrogen atom to which they are both bonded form Q; and Q is a 3-10 membered monocyclic ring optionally substituted with one or more R10 groups independently selected from sulfonyl, cyano, halo, -N(R11)2, -R11-NH-R11, -R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy-C1-6alkyl, and C1-6haloalkyl.

[0111] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5and R6together with the nitrogen atom to which they are both bonded form an azetidine ring, a pyrrolidine ring, a piperazine ring, or a morpholine ring, optionally substituted with one or more R10 groups independently selected from sulfonyl, cyano, halo, -N(R11)2, -R11-NH-R11, -R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1-6alkyl, cyano-C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy-C1-6alkyl, and C1-6haloalkyl.

[0112] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the nitrogen atom to which they are both bonded form an azetidine ring, a pyrrolidine ring, a piperazine ring, or a morpholine ring, optionally substituted with one or more R10 groups independently selected from sulfonyl, cyano, halo, -N(R11)2, -R11-NH-R11, -R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy-C1-6alkyl, and C1-6haloalkyl.

[0113] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the nitrogen atom to which they are both bonded form an azetidine ring optionally substituted with one or more R10groups independently selected from sulfonyl, cyano, halo, -N(R11)2, -R11-NH-R11, - R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1-6alkyl, cyano- C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy-C1-6alkyl, and halo-C1-6alkyl.

[0114] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the nitrogen atom to which they are both bonded form an azetidine ring optionally substituted withone or more R10 groups independently selected from sulfonyl, cyano, halo, -N(R11)2, -R11-NH-R11, -R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy- C1-6alkyl, and halo-C1-6alkyl.

[0115] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5and R6together with the nitrogen atom to which they are both bonded form an azetidine ring.

[0116] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the nitrogen atom to which they are both bonded form a pyrrolidine ring optionally substituted with one or more groups selected from -N(R11)2, hydroxyl, C1-6alkyl, hydroxy-C1-6alkyl, oxo, and carboxy-C1-6alkyl.

[0117] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5and R6together with the nitrogen atom to which they are both bonded form a pyrrolidine ring.

[0118] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5 and R6together with the nitrogen atom to which they are both bonded form a piperazine ring optionally substituted with one or more oxo groups.

[0119] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the nitrogen atom to which they are both bonded form a morpholine ring optionally substituted with one or more groups selected from hydroxy-C1-6alkyl and oxo.

[0120] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5and R6together with the nitrogen atom to which they are both bonded form 3-10 membered two chained rings optionally substituted with one or more R10groups independently selected from halo, C1-6alkoxy, C1-6alkyl, and hydroxy-C1-6alkyl. In some embodiments, both rings of the two chained rings are saturated. In some embodiments, both rings of the two chained rings are heterocycles. In some embodiments, both rings of the two chained rings are saturated heterocycles, each independently comprising 1-3 ring heteroatoms independently selected from the group consisting of N, O, and S. In other embodiments, one ring of the two chained rings is saturated and the other is a heteroaryl. In some embodiments, one ring of the two chained rings is azetidine, and the second ring is a saturated heterocycle or heteroaryl, each comprising 1-3 ring heteroatoms independently selected from the group consisting of O and N. In some emboidments, the first ring is azetidine, and the second ring is azetidine, morpholine, triazole, or thietane dioxide. In some embodiments, the first ring is azetidine, and the second ring is azetidine or morpholine. In any such embodiments, the rings may be independently unsubstituted or substituted with one or more R10 groups independently selected from halo, C1-6alkoxy, C1-6alkyl, and hydroxy-C1-6alkyl; such as unsubstituted or substituted with 1-3 R10 groups.

[0121] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5and R6 together with the nitrogen atom to which they are both bonded form a 3-10 membered spirocyclic ring optionally substituted with one or more R10 groups independently selected from hydroxyl, C1-6alkyl, and oxo. In some embodiments, the spirocyclic ring is saturated. In some embodiments, the spirocylic ring comprises 1-3 annular heteroatoms independently selected from the group consisting of O, N, and S. In certain embodiments, the spirocyclic ring is a 3- 10 membered, saturated spirocyclic ring comprising 1-3 annular N atoms.

[0122] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R5 and R6 together with the nitrogen atom to which they are both bonded form a 3-10 membered fused bicyclic ring optionally substituted with one or more hydroxyl groups.

[0123] In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R10is dimethylamino. In some embodiments, provided herein is a compound of Formula (I), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R10 is methyl.

[0124] In one aspect, provided herein is a compound having the structure of formula (II),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;, wherein Y1 is N or CR01, Y2 is N or CR02, Y3 is N or CR03; and each of R01, R02, R03, R04, and R05 is independently hydrogen, halogen, CN, NH2, N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05is NH2, and at least one of R01, R02, R03, R04, and R05 is methyl; R2 is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3 alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z2is L0OR5, wherein: L0is a bond, –C(=O)–, or –C(H)R7–, wherein R7is H or C1-3alkyl; R5 is L1J1, or L2Q, wherein: L1 is selected from: –(CH2)q–, –(CH2)C(Ra)(Rb)–, –(CH2)C(H)(Ra)C(H)(Rb)–, –C(H)(Ra)C(H)(Rb)–, –(CH2)Cy– and a bond, wherein q = 1 – 3, Ra and Rb together with the carbon atoms to which each is attached form a ring, and Cy is an optionally substituted 1,2-linked cyclopropyl ring; J1is selected from: cyano, –C(=O)NR8R9, –C(=O)OR8, -OR8, and -R8; wherein R8and R9are independently selected from H, C1-6alkyl, C2-6alkenyl, and phenyl, with the proviso that R8 and R9 are not both H; and wherein Cy, Ra, Rb, R8 and R9 are each optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, alkylcarboxy, C1-6alkoxy, and oxo; and L2is selected from: –(CHR13)q–, -(CH2)q-C(=O)- and a bond; Qis a 3 – 11 membered ring selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, and a spirocyclic ring; wherein Q is optionally substituted with one or more groups independently selected from: halogen, sulfonyl, cyano, oxo, -NR13C(=O)R14, -C(=O)R14, hydroxyl, -OR14, and -R14; R13and R14are independently selected from: hydrogen, C1-6alkyl, and C2-6alkenyl; and wherein R13and R14are each optionally and independently substituted by one or more groups selected from: sulfonyl, -S(=O)2(R11), cyano, halogen, oxo, hydroxyl, C1-6alkoxy, and C1-6alkylcarboxy; R11 is selected from C1-6alkyl, C1-6haloalkyl, and hydroxyl-C1-6alkyl; andwherein Q optionally comprises one or more heteroatoms selected from O, S, S(O)2and N, wherein each instance of N is present in Q as an amide, amide lactam, or whereinQ is a heteroaromatic ring moiety; andX is -O- or -NR12-, wherein R12is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0125] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;wherein Y1 is N or CR01, Y2 is N or CR02, Y3 is N or CR03; and each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, CN, NH2, N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05is NH2, and at least one of R01, R02, R03, R04, and R05 is methyl; R2 is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3 alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z2is L0OR5, wherein: L0 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5 is L1J1, or L2Q, wherein: L1 is selected from: –(CH2)q–, –(CH2)C(Ra)(Rb)–, –(CH2)C(H)(Ra)C(H)(Rb)–, –C(H)(Ra)C(H)(Rb)–, –(CH2)Cy– and a bond, wherein q = 1 – 3, Raand Rbtogether with the carbon atoms to which each is attached form a ring, and Cy is an optionally substituted 1,2-linked cyclopropyl ring; J1 is selected from: cyano, –N(R8)C(=O)–, –C(=O)NR8R9, –C(=O)OR8, - OR8, and -R8; wherein R8 and R9 are independently selected from H, C1-6alkyl, C2-6alkenyl, and phenyl, with the proviso that R8and R9are not both H;and wherein Cy, Ra, Rb, R8 and R9 are each optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, alkylcarboxy, C1-6alkoxy, and oxo; and L2is selected from: –(CHR13)q–, -(CH2)q-C(=O)- and a bond; Qis a 3 – 11 membered ring selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, and a spirocyclic ring; wherein Q is optionally substituted with one or more groups independently selected from: halogen, sulfonyl, cyano, oxo, -NR13C(=O)R14, -C(=O)R14, hydroxyl, -OR14, and -R14; R13and R14are independently selected from: hydrogen, C1-6alkyl, and C2-6alkenyl; and wherein R13 and R14 are each optionally and independently substituted by one or more groups selected from: sulfonyl, - =S(=O)2(R11), cyano, halogen, oxo, hydroxyl, C1- 6alkoxy, and C1-6alkylcarboxy; and wherein Q optionally comprises one or more heteroatoms selected from O, S, S(O)2and N, wherein each instance of N is present in Q as an amide, amide lactam, or whereinQ is a heteroaromatic ring moiety; andX is -O- or -NR12-, wherein R12 is hydrogen, C1-6alkyl, or C1-6 haloalkyl.

[0126] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NR12-. In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is NH. In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O.

[0127] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m = 0; n = 1; and p = 1.

[0128] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein no more than one of R01, R02, R03, R04, and R05is hydrogen. In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein no more than two of R01, R02, R03, R04, and R05 is hydrogen. In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof, wherein one of R01, R02, R03, R04, and R05is halogen. Insome embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R01, R02, R03, R04, and R05is C1-3-haloalkyl. In some embodiments, provided herein is a compound of Formula (II), or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R01, R02, R03, R04, and R05is amino.

[0129] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1is: ,

[0130] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is:

[0131] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is.

[0132] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2is fluoro.

[0133] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R3' and R3'' are both H.

[0134] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R4' is hydrogen and R4'' is methyl.

[0135] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R4' is hydrogen and R4'' is -CF3.

[0136] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is - NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen, methyl, or C1-3haloalkyl. In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen. In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-; m = 0; n = 1; p = 1;R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is methyl. Insome embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' isC1-3haloalkyl. In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is - NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is -CHF2. In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is -CF3.

[0137] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L1is a bond.

[0138] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein J is R8.

[0139] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R8is C1-6alkyl optionally substituted with one or more groups selected from halogen, hydroxy, cyano, and oxo.

[0140] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L2 is a bond or –(CHR13)q–. In some embodiments, L2 is a bond. In some embodiments, L2 is – (CHR13)q–. In some embodiments, Z2 is –O-Q, –O-CH2-Q, –O-CH2CH2-Q, or –O-CH2CH2CH2- Q. In some embodiments, Z2is –O-CH2-Q. In some embodiments, Z2is –O-CH2CH2-Q. In some embodiments, Z2is –O-Q. In some embodiments, Z2is –O-CH2-Cy, or –O-CH2CH2-Cy. In some embodiments, Z2is –O-CH2-Cy. In some embodiments, Z2is –O-CH2CH2-Cy.

[0141] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Q is selected from: cyclopropane, cyclobutane, cyclohexane, benzene, pyrrolidine, piperidine, morpholine, pyridine, pyridone, pyridazine, pyrazine, pyrimidine, 1,4-dioxane, 1H-pyrazole, isoindoline-1,3-dione, 2-oxabicyclo[2.1.1]hexane, tetrahydrofuran, oxetane, tetrahydropyran, thietane, 2,3-dihydrobenzofuran, iso-oxazole, bicyclo[1.1.1]pentane, 6,7-dihydro-5H- pyrrolo[1,2-a]imidazole, imidazole, tetrahydro-2H-thiopyran, 1,2,4-triazole, 9-oxa-2- azaspiro[5.5]undecane, azetidine, 3-oxabicyclo[3.1.0]hexane, tetrahydrothiophene, and oxazolidine, wherein said Q is optionally substituted with one or more groups selected from halogen, sulfonyl, cyano, oxo, -NR13C(=O)R14, -C(=O)R14, hydroxyl, and -R14. In some embodiments, R14is C1-6alkyl optionally substituted by one or more groups selected from hydroxyl, halogen, and oxo. In some embodiments, R13 is hydrogen and R14 is C1-6alkyl.

[0142] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Q is selected from: cyclopropane, cyclobutane, cyclohexane, benzene, pyrollidine, piperidine, morpholine, pyridine, pyridone, pyridazine, pyrazine, pyrimidine, 1,4-dioxane, 1H-pyrazole, isoindoline-1,3-dione, 2-oxabicyclo[2.1.1]hexane, tetrahydrofuran, oxetane, tetrahydropyran, thietane, 2,3-dihydrobenzofuran, iso-oxazole, bicyclo[1.1.1]pentane, 6,7-dihydro-5H- pyrrolo[1,2-a]imidazole, imidazole, tetrahydro-2H-thiopyran, 1,2,4-triazole, 9-oxa-2- azaspiro[5.5]undecane, azetidine, 3-oxabicyclo[3.1.0]hexane, tetrahydrothiophene, and oxazolidine.

[0143] In some embodiments, provided herein is a compound of Formula (II), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Q is selected from: cyclopropane, cyclobutane, cyclohexane, benzene, pyrollidine, piperidine, morpholine, pyridine, pyridazine, pyrazine, pyrimidine, 1,4-dioxane, 1H-pyrazole, isoindoline-1,3-dione, 2- oxabicyclo[2.1.1]hexane, tetrahydrofuran, oxetane, tetrahydropyran, thietane, 2,3- dihydrobenzofuran, iso-oxazole, bicyclo[1.1.1]pentane, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, imidazole, tetrahydro-2H-thiopyran, 1,2,4-triazole, and 9-oxa-2-azaspiro[5.5]undecane.

[0144] In one aspect, provided herein is a compound having the structure of formula (III),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, CN, NH2, N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05 is NH2, and at least one of R01, R02, R03, R04, and R05 is methyl; R2 is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z3 is L1OR5, wherein: L1 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5 is L2J, or L2QJ, wherein: L2is selected from: –(CH2)q–, –(CH2)q–C(=O)–, and a bond, wherein q = 1 – 3; J is C1-6alkyl-NR8R9or -NR8R9; wherein R8 and R9 are independently selected from H, C1-6alkyl, and C2- 6alkenyl; wherein J is optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, and C1-6alkoxy; and, when not H, each of R8and R9is optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, C1-6alkylcarboxy, C1-6alkoxy, C1-6cycloalkyl, 5-6 membered heterocyclyl, and oxo; Q is a 3 – 8 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, and a spirocyclic ring; wherein Q is optionally substituted with one or more groups independently selected from: halogen, cyano, oxo, hydroxyl, C1-6alkoxy, and C1-6haloalkyl; wherein Q optionally comprises one or more heteroatoms selected from O, S, and N; wherein L2 and J both bond to the same ring atom of Q; and X is -O- or -NR12-, wherein R12is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0145] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NR12-. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is NH. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is O.

[0146] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-.

[0147] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m = 0; n = 1; and p = 1.

[0148] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein no more than one of R01, R02, R03, R04, and R05 is hydrogen. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein no more than two of R01, R02, R03, R04, and R05is hydrogen. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R01, R02, R03, R04, and R05 is halogen. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R01, R02, R03, R04, and R05 is C1-3-haloalkyl. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R01, R02, R03, R04, and R05is amino.

[0149] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is:

[0150] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is: ,

[0151] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein

[0152] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer,atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2is fluoro.

[0153] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R3' and R3'' are both H.

[0154] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R4' is hydrogen and R4'' is methyl.

[0155] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R4' is hydrogen and R4'' is -CF3.

[0156] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen, methyl, or C1-3haloalkyl. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is - NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is methyl. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is C1- 3haloalkyl. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is - NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is -CHF2. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is - NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is -CF3.

[0157] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L2is –(CH2)q–.

[0158] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein J is C1-6alkyl-NR8R9 optionally substituted with one or more groups independently selected from halogen and hydroxy. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein J is C1-6alkyl-NR8R9.

[0159] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein J is NR8R9.

[0160] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Q is cyclopropyl optionally substituted with one or more halogen. In some embodiments, Q is cyclopropyl.

[0161] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each of R8and R9is independently hydrogen or C1-6alkyl optionally substituted with oxo, halogen, C1-6alkoxy, and 5-6 membered heterocyclyl. In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each of R8 and R9 is independently hydrogen or C1-6alkyl.

[0162] In some embodiments, provided herein is a compound of Formula (III), or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein q = 1.

[0163] In some embodiments the compound is a compound as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. Table 1:

[0164] In some embodiments, the compound is selected from the group consisting of compounds 1-262 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of compounds 1-182 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of compounds 183-262 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the compound is selected from the group consisting of compounds 1-7, 46-55, 75-79, 82-97, 194-214, 223-227, 229-230, 233-238, 243, 245, 248-249, 251-253, and 255-262 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of compounds 1-7, 46-55, 75-79, and 82-97 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of compounds 194-214, 223-227, 229-230, 233-238, 243, 245, 248-249, 251-253, and 255-262 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the compound is selected from the group consisting of compounds 8-31, 33-39, 66-67, 73-74, 98-177, 179-182, 183-192, 215-222, 228, 231-232, 239-242, 244, 246- 247, 250, and 254 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of compounds 8-31, 33-39, 66-67, 73-74, and 98-177, 179-182 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of compounds 183-192, 215-222, 228, 231-232, 239-242, 244, 246-247, 250, and 254 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the compound is selected from the group consisting of compounds 56-65, 68-72, 80-81, and 178 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the compound is selected from the group consisting of compounds 1-7, 83-89, and 97 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the compound is selected from the group consisting of compounds 40 and 41 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound is selected from the group consisting of compounds 42-45 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the compound is selected from the group consisting of compounds 46-48, 79, 90, and 93-94 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the compound is selected from the group consisting of compounds 49-55, 75-78, 82, 91-92, and 95-96 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the compound is selected from the group consisting of compounds 1, 26, 39, 56, 64, 65, 70, 71, 75, 76, and 97 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. Synthesis of Compounds

[0174] Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein of the present disclosure can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis; Wiley & Sons: New York, vol.1-21; R. C. LaRock, Comprehensive Organic Transformations, 2ndedition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol.1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.) Pergamon, Oxford 1984, vol.1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol.1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vol.1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds or pharmaceuticalacceptable salts thereof described herein can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained herein.

[0175] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing compounds described herein and necessary reagents and intermediates include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0176] Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein described herein can be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein of the formulae described herein can be prepared by a combinatorial split and mix approach or by multiple parallel syntheses using, for example, either solution phase or solid phase chemistry. Thus, according to a further aspect provided herein is a compound library comprising at least 2 compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0177] The Examples provide exemplary methods for preparing compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein described herein. Although specific starting materials and reagents are depicted and discussed in the Examples, other starting materials and reagents can be substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry.

[0178] In preparing compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein protection of remote functionality (e.g., primary or secondary amine) of intermediates can be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection can be readily determined. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0179] In the methods of preparing compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein, it can be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified to the desired degree of homogeneity by the techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.

[0180] Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid / liquid ion extraction reagents (LIX), or the like. Selection of appropriate methods of separation depends on the nature of the materials involved, such as, boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like.

[0181] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein described herein can be atropisomers (e.g., substituted biaryls). Enantiomers can also be separated by use of a chiral HPLC column.

[0182] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer can be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds or pharmaceutically acceptable saltsthereof described herein can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: “Drug Stereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

[0183] Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts can be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.

[0184] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., 1994, p.322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy- a-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem. (1982) 47:4165), of the racemic mixture, and analyzing the1H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96 / 15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (“Chiral Liquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375- 378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[0185] The chemical reactions described herein may be readily adapted to prepare other compounds and pharmaceutically acceptable salts thereof described herein. For example, the synthesis of non-exemplified compounds and pharmaceutically acceptable salts thereof described herein may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art otherthan those described, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds and pharmaceutically acceptable salts thereof described herein. Pharmaceutical Formulations

[0186] Also provided herein are pharmaceutical compositions comprising compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable excipients.

[0187] Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein as described herein can be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Thus, further provided herein is a pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein as described herein and one or more pharmaceutically acceptable excipients.

[0188] A typical formulation is prepared by mixing a compound or pharmaceutically acceptable salt thereof as described herein and an excipient. Suitable carriers, diluents and excipients include, but are not limited to, materials such as carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular excipient used will depend upon the means and purpose for which the compound or pharmaceutically acceptable salt thereof as described herein is being applied. Solvents are generally selected based on solvents recognized as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0189] The formulations can be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound or pharmaceutically acceptable salt thereof as described herein or stabilized form thereof (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein as described herein is typicallyformulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.

[0190] The pharmaceutical composition (or formulation) for application can be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container can also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label can also include appropriate warnings.

[0191] Pharmaceutical formulations of the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein can be prepared for various routes and types of administration. For example, a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof having the desired degree of purity can optionally be mixed with one or more pharmaceutically acceptable excipients (Remington’s Pharmaceutical Sciences (1980) 16thedition, Osol, A. Ed.), in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation can be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but can range from about 3 to about 8. For example, formulation in an acetate buffer at pH 5 can be a suitable embodiment.

[0192] The pharmaceutical composition ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.

[0193] The pharmaceutical compositions described herein can be formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The effective amount of the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, or treat the hyperproliferative disorder.

[0194] As a general proposition, the initial pharmaceutically effective amount of the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof administeredparenterally per dose will be in the range of about 0.01-100 mg / kg, namely about 0.1 to 20 mg / kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg / kg / day. In another embodiment, a pharmaceutical composition described herein comprises an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein in an amount of about: 1mg-10mg; 10mg-25mg; 20mg- 50mg; 50mg-75mg; 70mg-100mg;100mg-150mg; 100mg-200mg; 100mg-500mg; 200mg-500mg; 250mg-500mg; 500mg-1000mg; or 750mg-1000mg.

[0195] Acceptable pharmaceutically acceptable excipients are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN®, PLURONICS® or polyethylene glycol (PEG). The active pharmaceutical ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16thedition, Osol, A. Ed. (1980).

[0196] Sustained-release preparations of compounds or pharmaceutically acceptable salts thereof as described herein may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound or pharmaceutically acceptable salt thereof as described herein, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (US 3773919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(- )-3-hydroxybutyric acid.

[0197] The formulations include those suitable for the administration routes detailed herein. The formulations can conveniently be presented in unit dosage form and can be prepared by any methods. Techniques and formulations generally are found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0198] Formulations of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein suitable for oral administration can be prepared as discrete units such as pills, capsules, sachets or tablets each containing a predetermined amount of such compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs can be prepared for oral use. Formulations of compounds or pharmaceutically acceptable salts thereof as described herein intended for oral use can be prepared according to any method for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.

[0199] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of,for example, 0.075 to 20% W / W. When formulated in an ointment, the active ingredients can be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients can be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations can desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs. The oily phase of the emulsions of compositions provided herein can be constituted from known ingredients in a known manner. While the phase can comprise merely an emulsifier, it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of described herein include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

[0200] Aqueous suspensions comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein can contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

[0201] The pharmaceutical compositions of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated using suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables.

[0202] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans can contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95% of the total compositions (weight:weight(w / w)). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL / hr can occur.

[0203] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non- aqueous sterile suspensions which can include suspending agents and thickening agents.

[0204] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w / w, for example about 0.5 to 10% w / w, for example about 1.5%w / w.

[0205] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0206] Formulations for rectal administration can be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0207] Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach thealveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis disorders as described below.

[0208] Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers considered to be appropriate.

[0209] The formulations can be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0210] In one embodiment, the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof are formulated as a prodrug. The term prodrug as used herein refers to a derivative of a compound that can be hydrolyzed, oxidized, or cleaved under biological conditions to provide the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof. A prodrug as defined herein includes derivatives comprising one or more moieties that modulate or improve one or more physical, physiological or pharmaceutical property such as, but not limited to, solubility, permeability, uptake, biodistribution, metabolic stability, onset of action or some other druglike property, and is transformed to the bioactive or more biologically active substance as provided herein. In one embodiment, a prodrug herein has no biological activity until release of the compound or pharmaceutically acceptable salt thereof. Methods of Administration

[0211] Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous (IV), intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. In one embodiment, a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein is administered orally or by IV. For local immunosuppressive treatment, the compounds can be administered by intralesional administration, including perfusing or otherwise contacting the graft with the inhibitor before transplantation. It will be appreciated that the preferredroute can vary with for example the condition of the recipient. Where the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is administered orally, it can be formulated as a pill, capsule, tablet, etc. with a pharmaceutically acceptable carrier or excipient. Where the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is administered parenterally, it can be formulated with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below.

[0212] Thus, in one aspect provided herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable excipients. In one embodiment, compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are administered as pharmaceutical compositions capable of being administered to a subject orally or parenterally. The compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein can be formulated for topical or parenteral use where the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is dissolved or otherwise suspended in a solution suitable for injections, suspensions, syrups, creams, ointments, gels, sprays, solutions and emulsions.

[0213] Oral administration can promote patient compliance in taking the compound (e.g., formulated as a pharmaceutical composition), thereby increasing compliance and efficacy. Oral pharmaceutical compositions comprising a compound described herein include, but are not limited to, tablets (e.g., coated, non-coated and chewable) and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric coated capsules, and sustained release capsules). Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Oral pharmaceutical compositions comprising a compound described herein can be formulated for delayed or prolonged release.

[0214] A dose to treat human patients can range from about 10 mg to about 1000 mg of a compound described herein. A typical dose can be about 100 mg to about 300 mg of the compound. A dose can be administered once a day (QID), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. Administration as used herein refers to the frequency of dosing and not, for example, the number of individual units a patient described herein must take for a dose. Thus, in some embodiments, a patient may take two or more dosage units (e.g., two or more pills / tablets / capsules) QD. In addition, toxicity factors can influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet can be ingested daily or less frequently for a specified period of time. The regimen can be repeated for a number of cycles of therapy. Methods of Treating and Uses

[0215] The compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are useful as Ras inhibitors. In one aspect, the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are useful as KRas inhibitors. In another aspect, the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are useful as NRas inhibitors. In another aspect, the compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are useful as HRas inhibitors. In one embodiment, the compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein are useful as G12D Ras inhibitors, and as G12D KRas inhibitors.

[0216] Provided herein are methods of contacting a cell, such as an ex vivo cell, with a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein, to inhibit Ras activity (e.g., KRas activity) in the cell. In another embodiment, the activity is mutant G12D KRas activity.

[0217] Further provided herein are methods of treating a cancer comprising a KRas mutation, the method comprising administering to a patient having such cancer, an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof or a pharmaceutical composition as described herein. In one embodiment, the KRas mutation is a KRasG12Dmutation.

[0218] In one embodiment, the methods further comprise testing a sample (e.g., as set forth herein) from the patient before administration of a compound of pharmaceutically acceptable salt thereof described herein for the absence or presence of a KRasG12Dmutation. In one such embodiment, a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof or pharmaceutical composition described herein is administered to the patient after the patient sample is determined to be positive for (e.g., the presence of) a KRasG12Dmutation.

[0219] The methods of treating a cancer described herein relate to the treatment of cancer such as acute myeloid leukemia, cancer in adolescents, childhood adrenocortical carcinoma, AIDS-related cancers (e.g. lymphoma and Kaposi’s sarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibroushistiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancer.

[0220] In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendiceal cancer, or pancreatic cancer. In one embodiment, the cancer is pancreatic cancer, lung cancer, or colon cancer. The lung cancer can be adenocarcinoma, non- small cell lung cancer (NSCLC), or small cell lung cancer (SCLC). In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is lung adenocarcinoma.

[0221] The methods provided herein can also comprise testing a sample from the patient before administration of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein for the absence or presence of a KRasG12Dmutation. In one embodiment, a compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof or pharmaceutical composition is administered to the patient after the patient sample shows the presence of a KRasG12Dmutation. In one embodiment, a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein is not administered unless a patient sample comprises a KRasG12Dmutation.

[0222] In one embodiment, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In another embodiment, the cancer is tissue agnostic (comprises a KRasG12Dmutation). In one suchembodiment, the pancreatic cancer, lung cancer, or colorectal cancer comprises a KRasG12Dmutation.

[0223] Further provided herein are methods of treating lung cancer comprising a KRasG12Dmutation in a patient having such a lung cancer. In one such embodiment, is a method (M1) of treating lung cancer comprising a KRasG12Dmutation in a patient having such a lung cancer, the method comprising administering to the patient an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the same) described herein. In one embodiment, the lung cancer is non-small cell lung carcinoma (NSCLC). In one embodiment, lung cancer is adenocarcinoma, NSCLC, squamous-cell lung carcinoma (SCLC) or large-cell lung carcinoma. In one embodiment, lung cancer is adenocarcinoma, NSCLC, or SCLC. In another embodiment, the lung cancer is small cell lung carcinoma. In still another embodiment, the lung cancer is glandular tumors, carcinoid tumors or undifferentiated carcinomas. The lung cancer can be stage I or II lung cancer. In one embodiment, the lung cancer is stage III or IV lung cancer. The methods provided herein include administration of the compound as a 1L therapy.

[0224] Still further provided herein are methods of treating pancreatic cancer comprising a KRasG12Dmutation in a patient having such pancreatic cancer. In one such embodiment, is a method (M2) of pancreatic lung cancer comprising a KRasG12Dmutation in a patient having pancreatic cancer, the method comprising administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein. In one embodiment, the patient has been previously treated with radiation and one or more chemotherapy agents. In one embodiment, the pancreatic cancer is stage 0, I, or II. In another embodiment, the pancreatic cancer is stage III or stage IV.

[0225] Still further provided herein are methods of treating colon cancer comprising a KRasG12Dmutation in a patient having such colon cancer. In one such embodiment, is a method (M3) of treating colon cancer comprising a KRasG12Dmutation in a patient having, the method comprising administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein to the patient. In one embodiment, the colon cancer is stage I or II. In another embodiment, the colon cancer is stage III or stage IV.

[0226] In one embodiment of the methods M1, M2, and M3 as described herein, the method further comprises:

[0227] (a) determining the absence or presence of a KRasG12Dmutation in a sample taken from a patient with a suspected diagnosed cancer; and

[0228] (b) administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.

[0229] Further provided herein are methods of treating tissue agnostic cancer comprising a KRasG12Dmutation. In one embodiment of such methods, the method comprises:

[0230] (a) determining the absence or presence of a KRasG12Dmutation in a sample taken from a patient with a suspected diagnosed cancer; and

[0231] (b) administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.

[0232] In one embodiment of such methods, the patient is diagnosed with a cancer described herein. In another embodiment of such methods, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is taken before administration of any therapy. In another such embodiment, the sample is taken before administration of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein and after administration of another chemotherapeutic agent. In another embodiment of such methods, the compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein is administered as provided herein (e.g. orally or IV).

[0233] Also provided herein is a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof for use as a therapeutically active substance. In one such embodiment, the compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof can be for the therapeutic treatment of a cancer comprising a KrasG12Dmutation.

[0234] Further provided herein is a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of a cancer comprising a KRasG12Dmutation. In one embodiment, the compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof is used in the preparation of a medicament for the therapeutic treatment of a cancer comprising a KRasG12Dmutation. Still further provided herein are uses of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for inhibiting tumor metastasis.

[0235] Further provided herein are methods for inhibiting tumor metastasis, the method comprising administering to a patient having a tumor a therapeutically effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein. In one embodiment, the inhibition is of a tumor comprising a KRasG12Dmutation. In another embodiment, inhibiting tumor metastasis in a patient described herein results in reduction of tumor size. In another embodiment, inhibiting tumor metastasis in a patient described herein results in stabilizing (e.g. no further growth) of tumor size. In another embodiment, inhibiting tumor metastasis in a patient described herein results in remission of the cancer and / or its symptoms.

[0236] Further provided herein are methods for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein. In one embodiment, the cell population is in a human patient. In another embodiment, the cell population comprises a KRasG12Dmutation.

[0237] Further provided herein are methods of inhibiting KRas in a patient in need of therapy, comprising administering to the patient a therapeutically effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein. In one embodiment, the KRas inhibited is KRasG12D. In another embodiment, inhibiting KRas results in decreased tumor size. In another embodiment, inhibiting KRas results in remission of the cancer and / or its symptoms.

[0238] Further provided herein are methods for regulating activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein. In one embodiment, the mutant protein comprises a KRasG12Dmutation. In one embodiment, the activity of KRas is decreased after contacting with a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein. In another embodiment, the downregulation of activity of the KRas mutant protein treats a cancer described herein in a patient described herein. In another embodiment, the downregulation of activity of the KRas mutant protein results in decreased tumor size. In another embodiment, the downregulation of activity of the KRas mutant protein results in remission of a cancer described herein and / or its symptoms.

[0239] In some embodiments, the methods provided herein comprise inhibiting KrasG12Dactivity in a cell by contacting said cell with an amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRasG12Din said cell. In some embodiments, the methods provided herein comprise inhibiting KRasG12Dactivity in a tissue by contacting said tissue with an amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRasG12Din said tissue. In some embodiments, the methods provided herein comprise inhibiting KRasG12Dactivity in a patient described herein by contacting said patient with an amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein sufficient to inhibit the activity of KRasG12Din said patient.

[0240] Further provided herein are methods for preparing a labeled KRasG12Dmutant protein, the method comprising reacting a KRasG12Dmutant protein with a labeled compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein to result in thelabeled KRasG12Dmutant protein. In one embodiment, the label is an imaging agent. In one embodiment, the labeled KRasG12Dcan be used to detect the absence or presence of G12D mutant KRas in a patient sample, thereby detecting the presence or absence of a cancer mediated by mutant KRas.

[0241] Still further provided herein are methods of inhibiting Ras-mediated cell signaling. In one embodiment, the methods comprise contacting a cell with an effective amount of one or more compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof disclosed herein thereof. Inhibition of Ras-mediated signal transduction can be assessed and demonstrated by a wide variety of ways known in the art. Non-limiting examples include a showing of (a) a decrease in GTPase activity of Ras; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in K off of GTP or a decrease in K off of GDP; (d) a decrease in the levels of signaling transduction molecules downstream in the Ras pathway, such as a decrease in pMEK level; and / or (e) a decrease in binding of Ras complex to downstream signaling molecules including but not limited to Raf. Kits and commercially available assays can be utilized for determining one or more of the above.

[0242] KRas mutations, including G12D mutants, have also been identified in hematological malignancies (e.g., cancers that affect blood, bone marrow, and / or lymph nodes). Accordingly, certain embodiments are directed to administration of a disclosed compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof (e.g., in the form of a pharmaceutical composition) as described herein to a patient in need of treatment of a hematological malignancy. Such malignancies include but are not limited to leukemias and lymphomas. For example, the presently disclosed compounds can be used for treatment of diseases such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL) and / or other leukemias. In other embodiments, the compounds or a pharmaceutically acceptable salt thereof described herein are useful for treatment of lymphomas such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0243] Determining whether a tumor or cancer comprises a KRasG12Dmutation can be undertaken by assessing the nucleotide sequence encoding the KRas protein, by assessing the amino acid sequence of the KRas protein, or by assessing the characteristics of a putative KRas mutant protein. The sequence of wild-type human KRas (e.g., Accession No. NP203524) is known in the art.

[0244] Methods for detecting a mutation in a KRas nucleotide sequence are known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutantallele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some embodiments, samples are evaluated for G12d KRas mutations by real-time PCR. In real-time PCR, fluorescent probes specific for the KRas G12D mutation are used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRas G12D mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and / or exon 3) in the KRas gene. This technique will identify all possible mutations in the region sequenced.

[0245] Methods for determining whether a tumor or cancer comprises a KRasG12Dmutation can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA.

[0246] Further provided herein are uses of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein, in the manufacture of a medicament for treating cancer. In some embodiments, the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for injection (e.g. IV administration). In some embodiments, the cancer comprises a KRasG12Dmutation. In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, are uses of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein, in the manufacture of a medicament for inhibiting tumor metastasis. Combination Therapies

[0247] The compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein may be employed alone or in combination with other therapeutic agents for the treatment of a disease or disorder described herein. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound or a pharmaceutically acceptable salt thereof described herein such that they do not adversely affect each other. The combination therapy may provide "synergy" and prove "synergistic", i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.

[0248] The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.

[0249] Combination therapies herein comprise the administration of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein, and the use of at least one other treatment method. The amounts of the compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

[0250] In various embodiments of the method, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, phosphatidylinositol kinase (PI3K) inhibitor, insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, a SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular- signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor (such as irinotecan, or such as etoposide, or such as doxorubicin), a taxane (such as anti-microtubule agents including paclitaxel and docetaxel), an anti-metabolite agent (such as 5-FU or such as gemcitabine), or an alkylating agent (such as cisplatin or such as cyclophosphamide), or a taxane.

[0251] In some embodiments, the additional therapeutic agent is an epidermal growth factor receptor (EGFR) inhibitor, such as Erlotinib or such as Afatinib. In some embodiments the additional therapeutic agent is gefitinib, osimertinib, or dacomitinib. In some embodiments the additional therapeutic agent is a monoclonal antibody such as cetuximab (Erbitux) or panitumumab (Vectibix). In some embodiments the GFR inhibitor is a dual or pan- HER inhibitor. In other embodiments, the additional therapeutic agent is a phosphatidylinositol-3-kinase (PI3K) inhibitor, such as GDC-0077, GDC-0941, MLN1117, BYL719 (Alpelisib) or BKM120 (Buparlisib). GDC- 0941 refers to 2-(1H-indazol-4-yl)-6-(4- methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl- thieno[3,2-d]pyrimidine or a salt thereof (e.g., bismesylate salt).

[0252] In still other embodiments, the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor. For example, in some embodiments the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541. In other embodiments, the additional therapeutic agent is IGOSI-906 (Linsitinib), BMS-754807, or in other embodiments the additional therapeutic agent is a neutralizing monoclonal antibody specific to IGF1R such as AMG-479 (ganitumab), CP-751,871 (figitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (robatumumab).

[0253] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor. In some embodiments, the additional therapeutic agent is CYT387, GLPG0634, Baricitinib, Lestaurtinib, momelotinib, Pacritinib, Ruxolitinib, or TG101348.

[0254] In some other embodiments, the additional therapeutic agent is an anti-glypican 3 antibody. In some embodiments, the anti-glypican 3 antibody is codrituzumab.

[0255] In some other embodiments, the additional therapeutic agent is an antibody drug conjugate (ADC). In some embodiments, the ADC is polatuzumab vedotin, RG7986, RG7882, RG6109, or RO7172369.

[0256] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist. In some embodiments, the MDM2 antagonist is idasanutlin.

[0257] In some other embodiments, the additional therapeutic agent is an agonistic antibody against CD40. In some embodiments, the agonistic antibody against CD40 is selicrelumab (RG7876).

[0258] In some other embodiments, the additional therapeutic agent is a bispecific antibody. In some embodiments, the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP- DR5), RG6160, RG6026, ERY974, or anti-HER2 / CD3.

[0259] In some other embodiments, the additional therapeutic agent is a targeted immunocytokine. In some embodiments, the targeted immunocytokine is RG7813 or RG7461.

[0260] In some other embodiments, the additional therapeutic agent is an antibody targeting colony stimulating factor-1 receptor (CSF-1R). In some embodiments, the CSF-1R antibody is emactuzumab.

[0261] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine. In some embodiments, the personalized cancer vaccine is RG6180.

[0262] In some other embodiments, the additional therapeutic agent is an inhibitor of BET (bromodomain and extraterminal family) proteins (BRD2 / 3 / 4 / T). In some embodiments, the BET inhibitor is RG6146.

[0263] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT. In some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0264] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor degrader (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545, giredestrant).

[0265] In some other embodiments the additional therapeutic agent is an MET kinase inhibitor, such as Crizotinib, tivantinib, AMG337, cabozantinib, or foretinib. In other embodiments the additional therapeutic agent is a neutralizing monoclonal antibody to MET such as onartuzumab.

[0266] In more embodiments, the additional therapeutic agent is a SRC family non-receptor tyrosine kinase inhibitor. For example, in some embodiments the additional therapeutic agent is an inhibitor of the subfamily of SRC family non-receptor tyrosine kinases. Exemplary inhibitors in this respect include Dasatinib. Other examples in this regard include Ponatinib, saracatinib, and bosutinib.

[0267] In yet other embodiments, the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is trametinib, selumetinib, COTELLIC® (cobimetinib), PD0325901, or RO5126766. In other embodiments the MEK inhibitor is GSK-1120212, also known as trametinib.

[0268] In yet other embodiments, the additional therapeutic agent is an extracellular-signal- regulated kinase (ERK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is SCH722984 or GDC-0994.

[0269] In other embodiments the protein kinase inhibitor is taselisib, ipatasertib, GDC-0575, GDC- 5573 (HM95573), RG6114 (GDC-0077), CKI27, Afatinib, Axitinib, Atezolizumab, Bevacizumab, Bostutinib, Cetuximab, Crizotinib, Dasatinib, Erlotinib, Fostamatinib, Gefitinib, Imatinib, Lapatinib, Lenvatinib, Ibrutinib, Nilotinib, Panitumumab, Pazopanib, Pegaptanib, Ranibizumab, Ruxolitinib, Sorafenib, Sunitinib, SU6656, Trastuzumab, Tofacitinib, Vandetanib, or Vemurafenib. In still more embodiments, the additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is Irinotecan. In some more embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include Taxol and Docetaxel.

[0270] In addition to the above additional therapeutic agent, other chemotherapeutics are presently known in the art and can be used in combination with the compounds and pharmaceutically acceptable salts thereof described herein. In some embodiments, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

[0271] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (Imatinib Mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and Adriamycin as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide and trimethylol melamine; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo- L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; polysaccharide K; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel (TAXOLTM, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERETM, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included as suitable chemotherapeutic cell conditioners are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, (Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda®; ibandronate; camptothecin- 11 (CPT-11); topoisomerase inhibitor RFS 2000; and difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical acceptable salts thereof or pharmaceutical composition as described herein can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, Venclexta™, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy), Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

[0272] The exact method for administering the compound and the additional therapeutic agent will be apparent to one of ordinary skill in the art. In some exemplary embodiments the compound and the additional therapeutic agent are co-administered. In other embodiments, the compound and the additional therapeutic agent are separately administered.

[0273] In some embodiments, the compound and the additional therapeutic agent are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound and any of the additional therapeutic agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound and any of the additional therapeutic agents described herein can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, the compound can be administered just followed by any of the additional therapeutic agents described herein, or vice versa. In some embodiments of the separate administration protocol, the compound and any of the additional therapeutic agents described herein are administered a few minutes apart, or a few hours apart, or a few days apart. Articles of Manufacture

[0274] Also provided herein are articles of manufacture, or "kit", containing materials useful for the treatment of a cancer provided herein. In one embodiment, the kit comprises a containercomprising compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein. The kit may further comprise a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound or a pharmaceutically acceptable salt thereof described herein or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound or a pharmaceutically acceptable salt thereof described herein. Alternatively, or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution or dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0275] In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound or a pharmaceutically acceptable salt thereof described herein, such as tablets or capsules. Such a kit can include a number of unit dosages. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. ENUMERATED EMBODIMENTS

[0276] The disclosure also includes the following embodiments:

[0277] Embodiment I-1. A compound of formula (I),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1;n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05 is independently hydrogen, halogen, CN, NH2, N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05 is NH2, and at least one of R01, R02, R03, R04, and R05is methyl; R2is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z1 is L1NR5R6, wherein: L1 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5is L2NR8R9, C1-6alkyl, L2Cy, or S(=O)2R8, wherein: L2is selected from: -S(=O)2(CH2)q-, -C(=O)(CH2)q-, -(CH2)q-, -P(=O)3(CH2)q-, –(CH2)–CH=CH–, and –CH=CH–(CH2)–, wherein q = 1 – 3; R8 and R9 are each independently hydrogen, C1-6alkyl, or C1-3haloalkyl; and Cy is a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; R6is H or C1-6alkyl; or R5and R6together with the nitrogen atom to which they are both bonded form a group Q; wherein Q is: a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; optionally substituted with one or more groups R10 independently selected from: sulfonyl, cyano, halo, -NH2, -NHR11, -N(R11)2, -R11-NH2, -R11-NH-R11, R11-amino- (R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6cycloalkyl, C1-6alkoxy-C1-6alkyl, C2-6alkenyl, hydroxy-C1-6alkyl, oxo, C1-6alkylcarbenyl, carboxy-C1-6alkyl, and halo-C1-6alkyl; wherein each R11 is independently selected from C1-6alkyl, C1-6haloalkyl, and hydroxyl-C1-6alkyl;wherein Q optionally comprises one or more heteroatoms selected from O and N in addition to the nitrogen atom to which R5and R6are both bonded, wherein each additional instance of N is present in Q as N–H, N(R11), or as a tertiary N; and X is -O- or -NR12-, wherein R12 is hydrogen, C1-6alkyl, or C1-6 haloalkyl.

[0278] Embodiment I-2. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein X is -NR12-.

[0279] Embodiment I-3. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-2, wherein X is -NH-.

[0280] Embodiment I-4. A compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein: m = 0; n = 1; and p = 1.

[0281] Embodiment I-5. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein no more than one of R01, R02, R03, R04, and R05 is hydrogen.

[0282] Embodiment I-6. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein no more than two of R01, R02, R03, R04, and R05 is hydrogen.

[0283] Embodiment I-7. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein one of R01, R02, R03, R04, and R05is halogen.

[0284] Embodiment I-8. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein one of R01, R02, R03, R04, and R05is C1-3-haloalkyl.

[0285] Embodiment I-9. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein one of R01, R02, R03, R04, and R05 is amino.

[0286] Embodiment I-10. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein R1 is:

[0287] Embodiment I-11. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein R1 is:

[0288] Embodiment I-12. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein

[0289] Embodiment I-13. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein R2is fluoro.

[0290] Embodiment I-14. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein R3' and R3'' are both H.

[0291] Embodiment I-15. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein each R4' is hydrogen and R4'' is methyl.

[0292] Embodiment I-16. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein each R4' is hydrogen and R4'' is CF3.

[0293] Embodiment I-17. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein, when present, at least one of R10is selected from -NH2, -NHR11, -N(R11)2, -R11-NH2, -R11-NH-R11, -R11-N-(R11)2.

[0294] Embodiment I-18. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein R5and R6together with the nitrogen atom to which they are both bonded form an azetidine ring.

[0295] Embodiment I-19. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-1, wherein R5 and R6 together with the nitrogen atom to which they are both bonded form a pyrrolidine ring.

[0296] Embodiment I-20. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-17, wherein one R10is dimethylamino.

[0297] Embodiment I-21. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-17, wherein one R10 is methyl.

[0298] Embodiment I-22. A compound of formula (II),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, CN, NH2, N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05 is NH2, and at least one of R01, R02, R03, R04, and R05 is methyl; R2 is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z2 is L0OR5, wherein: L0 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5 is L1J1, or L2Q, wherein:L1 is selected from: –(CH2)q–, –(CH2)C(Ra)(Rb)–, –(CH2)C(H)(Ra)C(H)(Rb)–, –C(H)(Ra)C(H)(Rb)–, –(CH2)Cy– and a bond, wherein q = 1 – 3, Raand Rbtogether with the carbon atoms to which each is attached form a ring, and Cy is an optionally substituted 1,2-linked cyclopropyl ring; J1 is selected from: cyano, –N(R8)C(=O)–, –C(=O)NR8R9, –C(=O)OR8, OR8, and R8; wherein R8 and R9 are independently selected from H, C1-6alkyl, C2-6alkenyl, and phenyl, with the proviso that R8and R9are not both H; and wherein Cy, Ra, Rb, R8and R9are each optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, alkylcarboxy, C1-6alkoxy, and oxo; and L2 is selected from: –(CHR13)q–, -(CH2)q-C(=O)- and a bond; Qis a 3 – 11 membered ring selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, and a spirocyclic ring; wherein Q is optionally substituted with one or more groups independently selected from: halogen, sulfonyl, cyano, oxo, NR13C(=O)R14, C(=O)R14, hydroxyl, OR14, and R14; R13 and R14 are independently selected from: hydrogen, C1-6alkyl, and C2- 6alkenyl; and wherein R13 and R14 are each optionally and independently substituted by one or more groups selected from: sulfonyl, - =S(=O)2(R11), cyano, halogen, oxo, hydroxyl, C1-6alkoxy, and C1-6alkylcarboxy; and wherein Q optionally comprises one or more heteroatoms selected from O, S, S(O)2 and N, wherein each instance of N is present in Q as an amide, amide lactam, or when Q is a heteroaromatic ring moiety; and X is -O- or -NR12-, wherein R12is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0299] Embodiment I-23. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein X is -NR12-.

[0300] Embodiment I-24. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-23, wherein X is -NH-.

[0301] Embodiment I-25. A compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein: m = 0;n = 1; and p = 1.

[0302] Embodiment I-26. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein no more than one of R01, R02, R03, R04, and R05 is hydrogen.

[0303] Embodiment I-27. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein no more than two of R01, R02, R03, R04, and R05is hydrogen.

[0304] Embodiment I-28. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein one of R01, R02, R03, R04, and R05 is halogen.

[0305] Embodiment I-29. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein one of R01, R02, R03, R04, and R05is C1-3-haloalkyl.

[0306] Embodiment I-30. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein one of R01, R02, R03, R04, and R05 is amino.

[0307] Embodiment I-31. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein R1 is:

[0308] Embodiment I-32. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein R1is:

[0309] Embodiment I-33. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein

[0310] Embodiment I-34. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein R2is fluoro.

[0311] Embodiment I-35. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein R3' and R3'' are both H.

[0312] Embodiment I-36. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein each R4' is hydrogen and R4'' is methyl.

[0313] Embodiment I-37. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein each R4' is hydrogen and R4'' is CF3.

[0314] Embodiment I-38. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein L1 is a bond.

[0315] Embodiment I-39. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-22, wherein Q is selected from: cyclopropane, cyclobutane, cyclohexane, benzene, pyrollidine, piperidine, morpholine, pyridine, pyridazine, pyrazine, pyrimidine, 1,4-dioxane, 1H-pyrazole, isoindoline-1,3-dione, 2- oxabicyclo[2.1.1]hexane, tetrahydrofuran, oxetane, tetrahydropyran, thietane, 2,3- dihydrobenzofuran, iso-oxazole, bicyclo[1.1.1]pentane, 6,7-dihydro-5H-pyrrolo[1,2- a]imidazole, imidazole, tetrahydro-2H-thiopyran, 1,2,4-triazole, and 9-oxa-2- azaspiro[5.5]undecane.

[0316] Embodiment I-40. A compound of formula (III),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;wherein Y1 is N or CR01, Y2 is N or CR02, Y3 is N or CR03; and each of R01, R02, R03, R04, and R05 is independently hydrogen, halogen, CN, NH2, N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, andwherein at least one of R01, R02, R03, R04, and R05 is NH2, and at least one of R01, R02, R03, R04, and R05is methyl; R2is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z3 is L1OR5, wherein: L1is a bond, –C(=O)–, or –C(H)R7–, wherein R7is H or C1-3alkyl; R5is L2J, or L2QJ, wherein: L2is selected from: –(CH2)q–, –(CH2)q–C(=O)–, and a bond, wherein q = 1 – 3; J is C1-6alkyl-NR8R9 or -NR8R9; wherein R8 and R9 are independently selected from H, C1-6alkyl, and C2- 6alkenyl; wherein J is optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, and C1-6alkoxy; and, when not H, each of R8 and R9 is optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, C1- 6alkylcarboxy, C1-6alkoxy, C1-6cycloalkyl, 5-6 membered heterocyclyl, and oxo; Q is a 3 – 8 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, and a spirocyclic ring; wherein Q is optionally substituted with one or more groups independently selected from: halogen, cyano, oxo, hydroxyl, C1-6alkoxy, and C1-6haloalkyl; wherein Q optionally comprises one or more heteroatoms selected from O, S, and N; wherein L2and J both bond to the same ring atom of Q; and X is -O- or -NR12-, wherein R12 is hydrogen, C1-6alkyl, or C1-6 haloalkyl.

[0317] Embodiment I-41. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein X is -NR12-.

[0318] Embodiment I-42. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-41, wherein X is -NH-.

[0319] Embodiment I-43. A compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein:m = 0; n = 1; and p = 1.

[0320] Embodiment I-44. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein no more than one of R01, R02, R03, R04, and R05 is hydrogen.

[0321] Embodiment I-45. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein no more than two of R01, R02, R03, R04, and R05is hydrogen.

[0322] Embodiment I-46. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein one of R01, R02, R03, R04, and R05 is halogen.

[0323] Embodiment I-47. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein one of R01, R02, R03, R04, and R05is C1-3-haloalkyl.

[0324] Embodiment I-48. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein one of R01, R02, R03, R04, and R05 is amino.

[0325] Embodiment I-49. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein R1 is:

[0326] Embodiment I-50. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein R1is:

[0327] Embodiment I-51. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein

[0328] Embodiment I-52. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein R2is fluoro.

[0329] Embodiment I-53. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein R3' and R3'' are both H.

[0330] Embodiment I-54. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein each R4' is hydrogen and R4'' is methyl.

[0331] Embodiment I-55. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment I-40, wherein each R4' is hydrogen and R4'' is CF3.

[0332] Embodiment I-56. The compound of Embodiment I-40, wherein Q is cyclopropyl.

[0333] Embodiment I-57. The compound of Embodiment I-40, wherein q = 1.

[0334] Embodiment I-58. A compound selected from any one of compounds I-182 as set forth in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0335] Embodiment I-59. A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments I-58, and one or more pharmaceutically acceptable excipients.

[0336] Embodiment I-60. A method of treating cancer, the method comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments I-1 to I-58, or a pharmaceutical composition of Embodiment I-59.

[0337] Embodiment I-61. The method of Embodiment I-60, wherein the cancer is characterized as comprising a KRas mutation.

[0338] Embodiment I-62. The method of Embodiment I-61, wherein the KRas mutation corresponds to a KRasG12Dmutation.

[0339] Embodiment I-63. The method of any one of Embodiments I-60 to I-61, further comprising testing a sample from the patient before administration for the absence or presence of a KRasG12Dmutation.

[0340] Embodiment I-64. The method of Embodiment I-63, wherein the compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof or pharmaceutical composition is administered to the patient after the patient sample shows the presence of a KRasG12Dmutation.

[0341] Embodiment I-65. The method of any one of Embodiments I-60 to I-64, wherein the cancer is tissue agnostic.

[0342] Embodiment I-66. The method of any one of Embodiments I-60 to I-64, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0343] Embodiment I-67. The method of Embodiment I-66, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

[0344] Embodiment I-68. The method of Embodiment I-66, wherein the cancer is pancreatic cancer.

[0345] Embodiment I-69. The method of Embodiment I-66, wherein the cancer is colorectal cancer.

[0346] Embodiment I-70. The method of any one of Embodiments I-60 to I-64, further comprising administering at least one additional therapeutic agent.

[0347] Embodiment I-71. The method of Embodiment I-70, wherein the additional therapeutic agent comprises an epidermal growth factor receptor (EGFR) inhibitor,phosphatidylinositol kinase (PI3K) inhibitor, insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, a SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular-signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an anti-metabolite agent, or an alkylating agent.

[0348] Embodiment I-72. A compound according to any one of Embodiments I-1 to I-58, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0349] Embodiment I-73. Use of a compound of any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

[0350] Embodiment I-74. Use of a compound according to any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0351] Embodiment I-75. Use of a compound of any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

[0352] Embodiment I-76. A compound according to any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, for the therapeutic and / or prophylactic treatment of a cancer comprising a KRasG12Dmutation.

[0353] Embodiment I-77. A method for regulating activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound of any one of Embodiments I- 1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0354] Embodiment I-78. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with the compound of any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0355] Embodiment I-79. A method of Embodiment I-78, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0356] Embodiment I-80. A method for inhibiting tumor metastasis comprising administering to an individual in need thereof a therapeutically effective amount of the compound of any one of Embodiments to I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof to a subject in need thereof.

[0357] Embodiment I-81. A compound of any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in regulating activity of a KRas mutant protein.

[0358] Embodiment I-82. A compound of any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting proliferation of a cell population.

[0359] Embodiment I-83. The compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt for use of Embodiment I-82, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0360] Embodiment I-84. A compound of any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting tumor metastasis.

[0361] Embodiment I-85. Use of a compound of any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for regulating activity of a KRas mutant protein.

[0362] Embodiment I-86. Use of a compound of any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting proliferation of a cell population.

[0363] Embodiment I-87. The use of Embodiment I-86, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0364] Embodiment I-88. Use of a compound of any one of Embodiments I-1 to I-58, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0365] Embodiment II-1. A compound of formula (I),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2;wherein n + m does not exceed 2;, wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05 is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1- 3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05is -NH2, and at least one of R01, R02, R03, R04, and R05is methyl; R2is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3 alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z1 is L1NR5R6, wherein: L1 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5is L2NR8R9, C1-6alkyl, L2Cy, or -S(=O)2R8, wherein: L2is selected from: -S(=O)2(CH2)q-, -C(=O)(CH2)q-, -(CH2)q-, -P(=O)3(CH2)q-, –(CH2)–CH=CH–, and –CH=CH–(CH2)–, wherein q = 1 – 3; R8 and R9 are each independently hydrogen, C1-6alkyl, or C1-3halo- alkyl; and Cy is a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; R6is H or C1-6alkyl; or R5 and R6 together with the nitrogen atom to which they are both bonded form a group Q; wherein Q is: a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; optionally substituted with one or more R10groups independently selected from: sulfonyl, cyano, halo, -NH2, -NHR11, -N(R11)2, -R11-NH2, -R11-NH-R11, -R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6cycloalkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1- 6alkyl, cyano-C1-6alkyl, C2-6alkenyl, hydroxy-C1-6alkyl, oxo, C1-6alkylcarbenyl, carboxy- C1-6alkyl, and C1-6 haloalkyl; wherein each R11is independently selected from C1-6alkyl, C1-6haloalkyl, and hydroxyl-C1-6alkyl;wherein Q optionally comprises one or more heteroatoms selected from O, S(O)2, and N in addition to the nitrogen atom to which R5and R6are both bonded, wherein each additional instance of N is present in Q as N–H, N(R11), or as a tertiary N; and X is -O- or -NR12-, wherein R12 is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0366] Embodiment II-2. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment II-1, wherein: wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;, wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05 is -NH2, and at least one of R01, R02, R03, R04, and R05 is methyl; R2 is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z1is L1NR5R6, wherein: L1 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5 is L2NR8R9, C1-6alkyl, L2Cy, or -S(=O)2R8, wherein: L2 is selected from: -S(=O)2(CH2)q-, -C(=O)(CH2)q-, -(CH2)q-, -P(=O)3(CH2)q-, –(CH2)–CH=CH–, and –CH=CH–(CH2)–, wherein q = 1 – 3; R8and R9are each independently hydrogen, C1-6alkyl, or C1-3halo- alkyl; and Cy is a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; R6is H or C1-6alkyl;or R5 and R6 together with the nitrogen atom to which they are both bonded form a group Q; wherein Q is: a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; optionally substituted with one or more R10 groups independently selected from: sulfonyl, cyano, halo, -NH2, -NHR11, -N(R11)2, -R11-NH2, -R11-NH-R11, -R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6cycloalkyl, C1-6alkoxy-C1-6alkyl, C2-6alkenyl, hydroxy-C1-6alkyl, oxo, C1-6alkylcarbenyl, carboxy-C1-6alkyl, and C1-6haloalkyl; wherein each R11is independently selected from C1-6alkyl, C1-6haloalkyl, and hydroxyl-C1-6alkyl; and wherein Q optionally comprises one or more heteroatoms selected from O and N in addition to the nitrogen atom to which R5 and R6 are both bonded, wherein each additional instance of N is present in Q as N–H, N(R11), or as a tertiary N; and X is -O- or -NR12-, wherein R12is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0367] Embodiment II-3. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment II-1 or II-2, wherein X is -NR12-.

[0368] Embodiment II-4. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-3, wherein X is - NH-.

[0369] Embodiment II-5. A compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-4, wherein: m = 0; n = 1; and p = 1.

[0370] Embodiment II-6. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-5, wherein no more than two of R01, R02, R03, R04, and R05is hydrogen.

[0371] Embodiment II-7. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-6, wherein no more than one of R01, R02, R03, R04, and R05 is hydrogen.

[0372] Embodiment II-8. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-7, wherein one of R01, R02, R03, R04, and R05is halogen.

[0373] Embodiment II-9. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-8, wherein one of R01, R02, R03, R04, and R05is C1-3-haloalkyl.

[0374] Embodiment II-10. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-9, wherein one of R01, R02, R03, R04, and R05 is amino.

[0375] Embodiment II-11. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-10, wherein R1is:

[0376] Embodiment II-12. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-11, wherein R1

[0377] Embodiment II-13. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-12, wherein R1 is.

[0378] Embodiment II-14. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-13, wherein X is -NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen, methyl, or C1-3haloalkyl.

[0379] Embodiment II-15. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-14, wherein X is -NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen.

[0380] Embodiment II-16. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-14, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is methyl.

[0381] Embodiment II-17. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-14, wherein X is -NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is C1-3haloalkyl.

[0382] Embodiment II-18. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-14, wherein each R4' is hydrogen and R4'' is methyl.

[0383] Embodiment II-19. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-14, wherein each R4' is hydrogen and R4'' is -CF3.

[0384] Embodiment II-20. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-19, wherein R2is fluoro.

[0385] Embodiment II-21. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-20, wherein R3' and R3'' are both H.

[0386] Embodiment II-22. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-21, wherein R5and R6together with the nitrogen atom to which they are both bonded form a 3-10 membered monocyclic ring optionally substituted with one or more groups selected from sulfonyl, cyano, halo, -N(R11)2, R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1- 6haloalkoxy-C1-6alkyl, cyano-C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy-C1-6alkyl, and C1- 6haloalkyl.

[0387] Embodiment II-23. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-22, wherein R5and R6together with the nitrogen atom to which they are both bonded form a 3-10 membered monocyclic ring optionally substituted with one or more groups selected from sulfonyl, cyano, halo, -N(R11)2, R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1- 6alkyl, oxo, carboxy-C1-6alkyl, and C1-6haloalkyl.

[0388] Embodiment II-24. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-22, wherein R5and R6together with the nitrogen atom to which they are both bonded form an azetidine ring, a pyrrolidine ring, a piperazine ring, or a morpholine ring, optionally substituted with one or more R10groups independently selected from sulfonyl, cyano, halo, -N(R11)2, -R11-NH-R11, -R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1-6alkyl, cyano-C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy-C1-6alkyl, and C1-6haloalkyl.

[0389] Embodiment II-25. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiments II-1 to II-24, wherein R5and R6together with the nitrogen atom to which they are both bonded form an azetidine ring, a pyrrolidine ring, a piperazine ring, or a morpholine ring, optionally substituted with one or more R10 groups independently selected from sulfonyl, cyano, halo, -N(R11)2, -R11-NH-R11, -R11-N(R11)2, hydroxyl,C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy-C1-6alkyl, and C1-6haloalkyl.

[0390] Embodiment II-26. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-22 or II-24,wherein R5 and R6 together with the nitrogen atom to which they are both bonded form an azetidine ring optionally substituted with one or more groups selected from sulfonyl, cyano, halo, -N(R11)2, R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1-6alkyl, cyano-C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy-C1-6alkyl, and C1-6haloalkyl.

[0391] Embodiment II-27. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-26, wherein R5 and R6together with the nitrogen atom to which they are both bonded form an azetidine ring optionally substituted with one or more groups selected from sulfonyl, cyano, halo, -N(R11)2, R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, oxo, carboxy-C1-6alkyl, and C1-6haloalkyl.

[0392] Embodiment II-28. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-27, wherein R5 and R6together with the nitrogen atom to which they are both bonded form an azetidine ring.

[0393] Embodiment II-29. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-25, wherein R5and R6 together with the nitrogen atom to which they are both bonded form a pyrrolidine ring optionally substituted with one or more groups selected from -N(R11)2, hydroxyl, C1-6alkyl, hydroxy-C1-6alkyl, oxo, and carboxy-C1-6alkyl.

[0394] Embodiment II-30. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-25 or II-29, wherein R5and R6together with the nitrogen atom to which they are both bonded form a pyrrolidine ring.

[0395] Embodiment II-31. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-25, wherein R5 and R6together with the nitrogen atom to which they are both bonded form a piperazine ring optionally substituted with one or more oxo groups.

[0396] Embodiment II-32. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-25, wherein R5 and R6 together with the nitrogen atom to which they are both bonded form a morpholine ring optionally substituted with one or more groups selected from hydroxy-C1-6alkyl and oxo.

[0397] Embodiment II-33. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-21, wherein R5and R6together with the nitrogen atom to which they are both bonded form two chained ringscomprising 3-10 atoms optionally substituted with one or more groups selected from halo, C1-6alkoxy, C1-6alkyl, and hydroxy-C1-6alkyl.

[0398] Embodiment II-34. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment II-33, wherein both rings of the two chained rings are saturated heterocycles, each independently comprising 1-3 ring heteroatoms independently selected from the group consisting of N, O, and S.

[0399] Embodiment II-35. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment II-33, wherein one ring of the two chained rings is azetidine, and the second ring is a saturated heterocycle or heteroaryl, each comprising 1-3 ring heteroatoms independently selected from the group consisting of O and N.

[0400] Embodiment II-36. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-21, wherein R5 and R6 together with the nitrogen atom to which they are both bonded form a 3-10 membered spirocyclic ring optionally substituted with one or more groups selected from hydroxyl, C1-6alkyl, and oxo.

[0401] Embodiment II-37. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment II-36, wherein the spirocyclic ring is a 3-10 membered, saturated spirocyclic ring comprising 1-3 annular N atoms.

[0402] Embodiment II-38. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-21, wherein R5 and R6together with the nitrogen atom to which they are both bonded form a 3-10 membered fused bicyclic ring optionally substituted with one or more hydroxyl groups.

[0403] Embodiment II-39. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-21, wherein, when present, at least one of R10 is selected from -NH2, -NHR11, -N(R11)2, -R11-NH2, -R11-NH- R11, -R11-N(R11)2.

[0404] Embodiment II-40. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment II-39, wherein one R10is dimethylamino.

[0405] Embodiment II-41. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-21, wherein one R10is methyl.

[0406] Embodiment II-42. A compound of formula (II),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2;, wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, -CN, - NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05 is -NH2, and at least one of R01, R02, R03, R04, and R05 is methyl; R2 is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z2 is L0OR5, wherein: L0 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5 is L1J1, or L2Q, wherein: L1is selected from: –(CH2)q–, –(CH2)C(Ra)(Rb)–, –(CH2)C(H)(Ra)C(H)(Rb)–, –C(H)(Ra)C(H)(Rb)–, –(CH2)Cy– and a bond, wherein q = 1 – 3, Raand Rbtogether with the carbon atoms to which each is attached form a ring, and Cy is an optionally substituted 1,2-linked cyclopropyl ring;J1 is selected from: cyano, –C(=O)NR8R9, –C(=O)OR8, -OR8, and - R8; wherein R8and R9are independently selected from H, C1-6alkyl, C2-6alkenyl, and phenyl, with the proviso that R8and R9are not both H; and wherein Cy, Ra, Rb, R8 and R9 are each optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, alkylcarboxy, C1-6alkoxy, and oxo; and L2is selected from: –(CHR13)q–, -(CH2)q-C(=O)- and a bond; Q is a 3 – 11 membered ring selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, and a spirocyclic ring; wherein Q is optionally substituted with one or more groups independently selected from: halogen, sulfonyl, cyano, oxo, -NR13C(=O)R14, - C(=O)R14, hydroxyl, -OR14, and -R14; R13and R14are independently selected from: hydrogen, C1-6alkyl, and C2-6alkenyl; and wherein R13and R14are each optionally and independently substituted by one or more groups selected from: sulfonyl, -S(=O)2(R11), cyano, halogen, oxo, hydroxyl, C1-6alkoxy, and C1-6alkylcarboxy; R11 is selected from C1-6alkyl, C1-6haloalkyl, and hydroxyl-C1-6alkyl; and wherein Q optionally comprises one or more heteroatoms selected from O, S, S(O)2and N, wherein each instance of N is present in Q as an amide, amide lactam, or wherein Q is a heteroaromatic ring moiety; andX is -O- or -NR12-, wherein R12is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0407] Embodiment II-43. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment II-42, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, CN, NH2, N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05 is NH2, and at least one of R01, R02, R03, R04, and R05 is methyl; R2 is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z2 is L0OR5, wherein: L0 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5 is L1J1, or L2Q, wherein: L1is selected from: –(CH2)q–, –(CH2)C(Ra)(Rb)–, –(CH2)C(H)(Ra)C(H)(Rb)–, –C(H)(Ra)C(H)(Rb)–, –(CH2)Cy– and a bond, wherein q = 1 – 3, Raand Rbtogether with the carbon atoms to which each is attached form a ring, and Cy is an optionally substituted 1,2-linked cyclopropyl ring; J1 is selected from: cyano, –N(R8)C(=O)–, –C(=O)NR8R9, – C(=O)OR8, -OR8, and -R8; wherein R8and R9are independently selected from H, C1-6alkyl, C2-6alkenyl, and phenyl, with the proviso that R8and R9are not both H; and wherein Cy, Ra, Rb, R8and R9are each optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, alkylcarboxy, C1-6alkoxy, and oxo; and L2 is selected from: –(CHR13)q–, -(CH2)q-C(=O)- and a bond; Q is a 3 – 11 membered ring selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, and a spirocyclic ring; wherein Q is optionally substituted with one or more groups independently selected from: halogen, sulfonyl, cyano, oxo, -NR13C(=O)R14, - C(=O)R14, hydroxyl, -OR14, and -R14; R13 and R14 are independently selected from: hydrogen, C1-6alkyl, and C2-6alkenyl; and wherein R13and R14are each optionally and independently substitutedby one or more groups selected from: sulfonyl, - =S(=O)2(R11), cyano, halogen, oxo, hydroxyl, C1-6alkoxy, and C1-6alkylcarboxy; and wherein Q optionally comprises one or more heteroatoms selected from O, S, S(O)2and N, wherein each instance of N is present in Q as an amide, amide lactam, or whereinQ is a heteroaromatic ring moiety; andX is -O- or -NR12-, wherein R12 is hydrogen, C1-6alkyl, or C1-6 haloalkyl.

[0408] Embodiment II-44. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment II-42 or II-43, wherein X is -NR12-.

[0409] Embodiment II-45. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-44, wherein X is -NH-.

[0410] Embodiment II-46. A compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-45, wherein: m = 0; n = 1; and p = 1.

[0411] Embodiment II-47. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-46, wherein no more than two of R01, R02, R03, R04, and R05 is hydrogen.

[0412] Embodiment II-48. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-47, wherein no more than one of R01, R02, R03, R04, and R05is hydrogen.

[0413] Embodiment II-49. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-48, wherein one of R01, R02, R03, R04, and R05 is halogen.

[0414] Embodiment II-50. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-49, wherein one of R01, R02, R03, R04, and R05is C1-3-haloalkyl.

[0415] Embodiment II-51. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-50, wherein one of R01, R02, R03, R04, and R05 is amino.

[0416] Embodiment II-52. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-51, wherein R1is:

[0417] Embodiment II-53. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-52, wherein R1

[0418] Embodiment II-54. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-53, wherein R1

[0419] Embodiment II-55. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-54, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen, methyl, or C1-3haloalkyl.

[0420] Embodiment II-56. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-55, wherein X is -NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen.

[0421] Embodiment II-57. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-55, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is methyl.

[0422] Embodiment II-58. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-55, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is C1-3haloalkyl.

[0423] Embodiment II-59. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of any one of Embodiments II-42 to II-55, wherein each R4' is hydrogen and R4'' is methyl.

[0424] Embodiment II-60. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-55, wherein each R4' is hydrogen and R4'' is -CF3.

[0425] Embodiment II-61. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-60, wherein R2 is fluoro.

[0426] Embodiment II-62. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-61, wherein R3' and R3'' are both H.

[0427] Embodiment II-63. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62, wherein L1is a bond.

[0428] Embodiment II-64. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-63, wherein J1 is R8.

[0429] Embodiment II-65. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-64, wherein R8is C1-6alkyl optionally substituted with one or more groups selected from halogen, hydroxy, cyano, and oxo.

[0430] Embodiment II-66. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62, wherein L2 is a bond.

[0431] Embodiment II-67. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62, wherein L2is –(CHR13)q–. Embodiment II-68. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62 or II-66 to II-67, wherein Z2 is –O-Q, –O-CH2-Q, –O-CH2CH2-Q, or –O-CH2CH2CH2-Q.

[0432] Embodiment II-69. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62 or II-66 to II-68, wherein Z2is –O-Q.

[0433] Embodiment II-70. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62 or II-66 to II-68, wherein Z2 is –O-CH2-Q, –O-CH2CH2-Q, or –O-CH2CH2CH2-Q.

[0434] Embodiment II-71. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62, II-66 to 68, or II-70, wherein Z2is –O-CH2-Q.

[0435] Embodiment II-72. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62, II-66 to 68, or II-70, wherein Z2 is –O-CH2-CH2-Q.

[0436] Embodiment II-73. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62 or II-66 to II-72, wherein Q is selected from: cyclopropane, cyclobutane, cyclohexane, benzene, pyrrolidine, piperidine, morpholine, pyridine, pyridone, pyridazine, pyrazine, pyrimidine, 1,4-dioxane, 1H-pyrazole, isoindoline-1,3-dione, 2-oxabicyclo[2.1.1]hexane, tetrahydrofuran, oxetane, tetrahydropyran, thietane, 2,3-dihydrobenzofuran, iso-oxazole, bicyclo[1.1.1]pentane, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, imidazole, tetrahydro-2H-thiopyran, 1,2,4-triazole, 9- oxa-2-azaspiro[5.5]undecane, azetidine, 3-oxabicyclo[3.1.0]hexane, tetrahydrothiophene, and oxazolidine, optionally substituted with one or more groups selected from R14, sulfonyl, hydroxyl, halogen, cyano, oxo, C(=O)R14, and NR13C(=O)R14.

[0437] Embodiment II-74. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62 or II-66 to II-73, wherein R14is C1-6alkyl optionally substituted by one or more groups selected from hydroxyl, halogen, and oxo.

[0438] Embodiment II-75. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62 or II-66 to II-73, wherein R13 is hydrogen and R14 is C1-6alkyl.

[0439] Embodiment II-76. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62 or II-66 to II-73, wherein Q is selected from: cyclopropane, cyclobutane, cyclohexane, benzene, pyrollidine, piperidine, morpholine, pyridine, pyridone, pyridazine, pyrazine, pyrimidine, 1,4- dioxane, 1H-pyrazole, isoindoline-1,3-dione, 2-oxabicyclo[2.1.1]hexane, tetrahydrofuran, oxetane, tetrahydropyran, thietane, 2,3-dihydrobenzofuran, iso-oxazole, bicyclo[1.1.1]pentane, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, imidazole, tetrahydro-2H-thiopyran, 1,2,4-triazole, 9- oxa-2-azaspiro[5.5]undecane, azetidine, 3-oxabicyclo[3.1.0]hexane, tetrahydrothiophene, and oxazolidine.

[0440] Embodiment II-77. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-42 to II-62, II-66 to II- 73, or II-76, wherein Q is selected from: cyclopropane, cyclobutane, cyclohexane, benzene, pyrrolidine, piperidine, morpholine, pyridine, pyridazine, pyrazine, pyrimidine, 1,4-dioxane, 1H-pyrazole, isoindoline-1,3-dione, 2-oxabicyclo[2.1.1]hexane, tetrahydrofuran, oxetane, tetrahydropyran, thietane, 2,3-dihydrobenzofuran, iso-oxazole, bicyclo[1.1.1]pentane, 6,7- dihydro-5H-pyrrolo[1,2-a]imidazole, imidazole, tetrahydro-2H-thiopyran, 1,2,4-triazole, and 9- oxa-2-azaspiro[5.5]undecane.

[0441] Embodiment II-78. A compound of formula (III),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05 is independently hydrogen, halogen, -CN, - NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05is -NH2, and at least one of R01, R02, R03, R04, and R05is methyl; R2is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3 alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z3is L1OR5, wherein: L1is a bond, –C(=O)–, or –C(H)R7–, wherein R7is H or C1-3alkyl; R5is L2J, or L2QJ, wherein:L2 is selected from: –(CH2)q–, –(CH2)q–C(=O)–, and a bond, wherein q = 1 – 3; J is C1-6alkyl-NR8R9or -NR8R9; wherein R8and R9are independently selected from H, C1-6alkyl, and C2-6alkenyl; wherein J is optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, and C1-6alkoxy; and, when not H, each of R8and R9is optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, C1-6alkylcarboxy, C1-6alkoxy, C1-6cycloalkyl, 5-6 membered heterocyclyl, and oxo; Q is a 3 – 8 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, and a spirocyclic ring; wherein Q is optionally substituted with one or more groups independently selected from: halogen, cyano, oxo, hydroxyl, C1-6alkoxy, and C1-6haloalkyl; wherein Q optionally comprises one or more heteroatoms selected from O, S, and N; wherein L2 and J both bond to the same ring atom of Q; and X is -O- or -NR12-, wherein R12 is hydrogen, C1-6alkyl, or C1-6 haloalkyl.

[0442] Embodiment II-79. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment II-78, wherein X is -NR12-.

[0443] Embodiment II-80. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of Embodiment II-78 or II-79, wherein X is -NH-.

[0444] Embodiment II-81. A compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-80, wherein: m = 0; n = 1; and p = 1.

[0445] Embodiment II-82. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-81, wherein no more than two of R01, R02, R03, R04, and R05is hydrogen.

[0446] Embodiment II-83. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-82, wherein no more than one of R01, R02, R03, R04, and R05 is hydrogen.

[0447] Embodiment II-84. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-83, wherein one of R01, R02, R03, R04, and R05is halogen.

[0448] Embodiment II-85. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-84, wherein one of R01, R02, R03, R04, and R05 is C1-3-haloalkyl.

[0449] Embodiment II-86. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-85, wherein one of R01, R02, R03, R04, and R05is amino.

[0450] Embodiment II-87. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-86, wherein R1 is:

[0451] Embodiment II-88. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-87, wherein R1is:

[0452] Embodiment II-89. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-88, wherein R1

[0453] Embodiment II-90. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-89, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen, methyl, or C1-3haloalkyl.

[0454] Embodiment II-91. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-90, wherein X is -NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is hydrogen.

[0455] Embodiment II-92. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-90, wherein X is -NH-; m = 0; n = 1; p = 1; R2is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is methyl.

[0456] Embodiment II-93. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-90, wherein X is -NH-; m = 0; n = 1; p = 1; R2 is halogen; R3' and R3'' are independently hydrogen; R4' is hydrogen; and R4'' is C1-3haloalkyl.

[0457] Embodiment II-94. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of any one of Embodiments II-78 to II-90, wherein each R4' is hydrogen and R4'' is methyl.

[0458] Embodiment II-95. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-90, wherein each R4' is hydrogen and R4'' is -CF3.

[0459] Embodiment II-96. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-95, wherein R2 is fluoro.

[0460] Embodiment II-97. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-96, wherein R3' and R3'' are both H.

[0461] Embodiment II-98. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-97, wherein L2 is –(CH2)q–.

[0462] Embodiment II-99. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-98, wherein Q is cyclopropyl optionally substituted with one or more halogens.

[0463] Embodiment II-100. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-99, wherein Q is cyclopropyl.

[0464] Embodiment II-101. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-100, wherein J is C1-6alkyl-NR8R9optionally substituted with one or more groups independently selected from halogen and hydroxy.

[0465] Embodiment II-102. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-101, wherein J is C1-6alkyl-NR8R9.

[0466] Embodiment II-103. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-100, wherein J is NR8R9.

[0467] Embodiment II-104. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-103, wherein each of R8 and R9 are independently hydrogen or C1-6alkyl optionally substituted with oxo, halogen, C1-6alkoxy, and 5-6 membered heterocyclyl.

[0468] Embodiment II-105. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-78 to II-104, wherein each of R8 and R9 are independently hydrogen or C1-6alkyl.

[0469] Embodiment II-106. A compound selected from the group consisting of compounds 1-262 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0470] Embodiment II-107. A compound selected from the group consisting of compounds 1-182 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0471] Embodiment II-108. A compound selected from the group consisting of compounds 183- 262 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0472] Embodiment II-109. A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of Embodiments II-1 to II-108, and one or more pharmaceutically acceptable excipients.

[0473] Embodiment II-110. A method of treating cancer, the method comprising administering an effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of any one of Embodiments II-1 to II-108, or a pharmaceutical composition of Embodiment II-109.

[0474] Embodiment II-111. The method of Embodiment II-110, wherein the cancer is characterized as comprising a KRas mutation.

[0475] Embodiment II-112. The method of Embodiment II-111, wherein the KRas mutation corresponds to a KRasG12Dmutation.

[0476] Embodiment II-113. The method of Embodiment II-110 to II-112, further comprising testing a sample from the patient before administration for the absence or presence of a KRasG12Dmutation.

[0477] Embodiment II-114. The method of Embodiment II-113, wherein the compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof or pharmaceutical composition is administered to the patient after the patient sample shows the presence of a KRasG12Dmutation.

[0478] Embodiment II-115. The method of any one of Embodiments II-110 to II-114, wherein the cancer is tissue agnostic.

[0479] Embodiment II-116. The method of any one of Embodiments II-110 to II-114, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0480] Embodiment II-117. The method of Embodiment II-116, wherein the lung cancer is lung adenocarcinoma, NSCLC, or SCLC.

[0481] Embodiment II-118. The method of Embodiment II-116, wherein the cancer is pancreatic cancer.

[0482] Embodiment II-119. The method of Embodiment II-116, wherein the cancer is colorectal cancer.

[0483] Embodiment II-120. The method of any one of Embodiments II-110 to II-119, further comprising administering at least one additional therapeutic agent.

[0484] Embodiment II-121. The method of Embodiment II-120, wherein the additional therapeutic agent comprises an epidermal growth factor receptor (EGFR) inhibitor, phosphatidylinositol kinase (PI3K) inhibitor, insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, a SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular-signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an anti-metabolite agent, or an alkylating agent.

[0485] Embodiment II-122. A compound according to any one of Embodiments II-1 to II- 108, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0486] Embodiment II-123. Use of a compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

[0487] Embodiment II-124. Use of a compound according to any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0488] Embodiment II-125. Use of a compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

[0489] Embodiment II-126. A compound according to any one of Embodiments II-1 to II- 108, or stereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, for the therapeutic and / or prophylactic treatment of a cancer comprising a KRasG12Dmutation.

[0490] Embodiment II-127. A method for regulating activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0491] Embodiment II-128. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with the compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0492] Embodiment II-129. The method of Embodiment II-128, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0493] Embodiment II-130. A method for inhibiting tumor metastasis comprising administering to an individual in need thereof a therapeutically effective amount of the compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof to a subject in need thereof.

[0494] Embodiment II-131. A compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in regulating activity of a KRas mutant protein.

[0495] Embodiment II-132. A compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting proliferation of a cell population.

[0496] Embodiment II-133. The compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt for use of Embodiment II-132, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0497] Embodiment II-134. A compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting tumor metastasis.

[0498] Embodiment II-135. Use of a compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for regulating activity of a KRas mutant protein.

[0499] Embodiment II-136. Use of a compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting proliferation of a cell population.

[0500] Embodiment II-137. The use of Embodiment II-136, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0501] Embodiment II-138. Use of a compound of any one of Embodiments II-1 to II-108, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0502] Embodiments

[0503] Provided below are exemplary embodiments of the invention. EXAMPLES

[0504] The following Examples are presented by way of illustration, not limitation. Intermediates

[0505] Intermediate 1: 5,7-Dichloro-8-fluoro-2-(methylthio) pyrido[4,3-d] pyrimidin-4(3H)-one

[0506] Step 1: 2,6-Dichloro-3-fluoropyridin-4-amine

[0507] Under nitrogen, a solution of 2,6-dichloropyridin-4-amine (9.01 g, 55.3 mmol) and SelectFlour (23.6 g, 66.6 mmol) in DMF (90 mL) and acetonitrile (90 mL) was stirred for 30 min at 80 °C. The mixture was concentrated under vacuum. The crude product was purified by reverse phase chromatography (gradient: 0–40 % acetonitrile in water (0.1% formic acid)) to afford the title compound (4.62 g, 46% yield) as a light brown solid. LC-MS: (ESI, m / z): [M+H]+= 181.1H NMR (300 MHz, DMSO-d6, ppm) δ 6.99 (s, 2H), 6.70 (d, J = 5.4 Hz, 1H).

[0508] Step 2: tert-Butyl N-tert-butoxycarbonyl-N-(2,6-dichloro-3-fluoro-4-pyridyl) carbamate

[0509] Under nitrogen, to a solution of 2,6-dichloro-3-fluoropyridin-4-amine (4.82 g, 26.6 mmol) in THF (100mL) was added NaHMDS (53.1 mL, 2M in THF) at 0°C. The resulting solution was stirred for 30 min at 0°C. Then Boc2O (29.0 g, 133 mmol) in THF (450 mL) was added at 0°C, and the mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl. Most of the THF was removed under vacuum and the resulting solution was extracted with EtOAc. The combined organic layers were concentrated under vacuum to afford the title compound (9.11 g, crude) as a white solid which was used without further purification. LC-MS: (ESI, m / z): [M+H]+= 381.1H NMR (300 MHz, DMSO-d6, ppm) δ 6.13 (s, 1H), 1.42 (s, 9H), 1.38 (d, J = 2.4 Hz, 9H).

[0510] tert-Butyl 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinate

[0511] Under nitrogen, to a solution of tert-butyl N-tert-butoxycarbonyl-N-(2,6-dichloro-3-fluoro- 4-pyridyl) carbamate (9.11 g, 23.9 mmol) in THF (180 mL) was added LDA (41.9 mL, 1M in THF) at –78 °C. The resulting solution was stirred for 0.5 h at –78 °C. The reaction was quenched with aq. NH4Cl and extracted with EtOAc (300 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-10%) to afford the title compound (4.18 g, 46 % yield) as a white solid. LC-MS: (ESI, m / z): [M+H]+=(300 MHz, DMSO-d6, ppm) δ 10.07 (s, 1H), 1.54 (s, 9H), 1.45 (s, 9H).

[0512] Step 4: 4-Amino-2,6-dichloro-5-fluoronicotinic acid

[0513] A solution of tert-butyl 4-((tert-butoxycarbonyl) amino)-2,6-dichloro-5-fluoronicotinate (4.18 g, 11.0 mmol) in TFA (15mL) and DCM (15mL) was stirred at 40 °C for 3 hours. The solvent was concentrated under vacuum to afford the title compound (2.86 g, crude) as a brown solid which was used without further purification. LC-MS: (ESI, m / z): [M+H]+= 225.

[0514] Step 5: 5,7-Dichloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d] pyrimidin-4(1H)-one

[0515] To a solution of 4-amino-2,6-dichloro-5-fluoronicotinic acid (2.01 g, 8.92 mmol) in MeCN (60 mL) / pyridine (20 mL) was added ethoxycarbonyl isothiocyanate (4.20 mL, 35.6 mmol). The resulting solution was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was purified by reverse phase chromatography (gradient: 0–40% acetonitrile in water (0.1% formic acid)) to afford the title compound 1.58 g (67% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 264.1H NMR (400 MHz, DMSO- d6, ppm) δ 13.30 (s, 1H), 12.86 (s, 1H).

[0516] Step 6: 5,7-Dichloro-8-fluoro-2-(methylthio) pyrido [4,3-d] pyrimidin-4(3H)-one

[0517] Under nitrogen, to a solution of 5,7-dichloro-8-fluoro-2-thioxo-2,3-dihydropyrido[4,3-d] pyrimidin-4(1H)-one (1.58 g, 5.93 mmol) in DMF (20 mL) was added CH3ONa (320 mg, 5.93 mmol) at 0oC. The resulting solution was stirred for 10 min at room temperature. Then CH3I (842 mg, 5.93 mmol) was added slowly at room temperature. The reaction mixture was stirred overnight at room temperature and subsequently added slowly with stirring to cold water. The solid wascollected by filtration and dried in an oven to afford the title compound 2.07 g (crude) as a yellow solid which was used for next step without further purification. LC-MS: (ESI, m / z): [M+H]+= 280.1H NMR (300 MHz, DMSO- d6, ppm) δ 13.35 (br, 1H), 2.61 (s, 3H).

[0518] Intermediate 2: tert-Butyl (5aS,6S,9R)-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

[0519] Step 1: tert-Butyl (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0520] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (50.0 g, 236 mmol) in DMF (800 mL) was added K2CO3(65.1 g, 472 mmol) and BnBr (60.1g, 353.53 mmol). The mixture was stirred at rt for 2 hours. Then the reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water (500 mL×3), dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0~10%) to afford the title compound (69 g, 96.9% yield) as ayellow oil. LC-MS: (ESI, m / z): [M+H]+ = 303.

[0521] Step 2: 3-(tert-Butyl) 2-methyl (1R,2S,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-2,3-dicarboxylate and 3-(tert-Butyl) 2-methyl (1R,2R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-2,3- dicarboxylate

[0522] Under N2, to a solution of tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (23.0 g, 76.06 mmol) and TMEDA (17.7 g, 152.59 mmol) in diethyl ether (500 mL) was added dropwise s-BuLi (117 mL, 1.3 M in hexane) at –78 °C and stirred at –78 °C for 1.5 hours. Then methyl chloroformate (17.9 g, 189 mmol) in 40 mL Et2O was added dropwise at –78 °C. The reaction was warmed to room temperature gradually and stirred additional 16 hours. The reaction was quenched with saturated NaHCO3 (aq), diluted with water and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0~10%) to afford 16 g of racemic mixtures (mixture of cis) as yellow oil. The mixture was separated by chiral-SFC (Column: Lux® 5µm Cellulose-2, 5×25cm, 5um; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NH3-MeOH); Flow rate:180 mL / min; Gradient:18% B; 220 nm; RT1:5.07; RT2: 5.57) to afford 5.9 g the faster peak and 5.6 g of the slower peak as yellow oil. LC-MS: (ESI, m / z): [M+H]+ = 361.

[0523] Step 3: tert-Butyl (1R,2S,5S)-8-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate

[0524] Under nitrogen, to a solution of 3-(tert-butyl) 2-methyl (1R,2S,5S)-8-benzyl-3,8- diazabicyclo[3.2.1]octane-2,3-dicarboxylate (20.0g, 55.5mmol, faster peak of previous operation) in THF (300 mL) was added LiAlH4 (4.20g, 111mmol) at 0°C. The resulting solution was stirred for 30 mins at 0°C and quenched with Na2SO4·10H2O. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0~20%) to afford the title compound (14.3 g, 77.5% yield) as a whitesolid. LC-MS: (ESI, m / z): [M+H]+ = 333.

[0525] Step 4: (6S,9R,9aS)-10-Benzylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one

[0526] Under nitrogen, to a solution of tert-Butyl (1R,2S,5S)-8-benzyl-2-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (5.1 g, 15.34 mmol) in THF (100 mL) was added NaH (1.35 g, 33.75 mmol, 60% in mineral oil) at 0°C. The resulting solution was stirred for 3 hours at room temperature, quenched with NH4Cl (aq) and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0~40%) toafford the title compound (3.5 g, 88.3% yield) as a white solid. LC-MS: (ESI, m / z): [M+H]+ = 259.

[0527] Step 5: (6S,9R,9aS)-Hexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one

[0528] A mixture of (6S,9R,9aS)-10-Benzylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3- one (10.0 g, 38.7 mmol) and Pd / C (3.0 g, 10% dry ) in methyl alcohol (200 mL) was stirred under an atmosphere of hydrogen at room temperature for 2 hours at room temperature. The catalyst was filtered off. The filtrate was concentrated under reduced pressure to afford 6g crude product whichwas used for next step without further purification. LC-MS: (ESI, m / z): [M+H]+ = 169.

[0529] Step 6: tert-Butyl (6S,9R,9aS)-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepine- 10-carboxylate

[0530] A solution of (6S,9R,9aS)-Hexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one (6.00 g, 35.7 mmol), (Boc)2O (12.6g, 57.8mmol) and DIPEA (10.0 g, 77.5 mmol) in dichloromethane (100 mL) was stirred at rt for 2 hours. The reaction mixture was washed with saturated sodium chloride solution. The organic phase was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0~40%) to afford the title compound 7.50 g (72% yield over two steps)as white solid. LC-MS: (ESI, m / z): [M+H]+ = 269.

[0531] Step 7: tert-Butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0532] A solution of tert-Butyl (6S,9R,9aS)-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4- a]azepine-10-carboxylate (7.50 g, 28.0 mmol) and NaOH (16.8 g, 420 mmol) in ethanol (200 mL) and water (70 mL) was stirred at 80°C for 16 hours. A majority of EtOH was stripped off under reduced pressure. The residual solution was adjusted to pH=8 with aqueous HCl (1M) and extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with DCM / MeOH (5 / 1) to afford the title compound (5 g, 73.8% yield) as an off white solid. LC-MS: (ESI, m / z):[M+H]+= 243.1H NMR (400 MHz, DMSO-d6, ppm) δ 4.72 - 4.57 (m, 1H), 4.02 - 3.90 (m, 2H), 3.25 - 3.15 (m, 2H), 2.82 - 2.68 (m, 2H), 2.64 - 2.53 (m, 1H), 1.85 - 1.61 (m, 3H), 1.61 - 1.47 (m, 1H), 1.41 (s, 9H).

[0533] Step 8: tert -Butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0534] Under nitrogen, to a solution of tert -butyl (1S,2S,5R)-2-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (289 mg, 1.19 mmol) in THF (20 mL) was added NaH (191 mg, 4.78 mmol, 60% in mineral oil) at 0oC. The resulting solution was stirred for 0.5 h at room temperature. Then 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (803 mg, 1.43 mmol, intermediate 1) was added at 0oC and stirred for 1 hour at room temperature. The reaction was quenched aqueous NH4Cl, diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (1.05 g crude) as a white solid which was used for next step without further purification. LC-MS: (ESI, m / z): [M+H]+= 486.

[0535] Step 9: tert -Butyl (5aS,6S,9R)-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

[0536] To a solution of tert -butyl (1S,2S,5R)-2-(((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.05 g, 2.15 mmol) in DCM (10 mL) was added DIPEA (4.16 g, 32.3 mmol) and BOPCl (2.20 g, 8.61 mmol). The resulting solution was stirred at room temperature for 2 hours, diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0%-40%) to afford the title compound (381 mg, 68% yield over two steps) as a light yellow solid. LC-MS: (ESI, m / z): [M+H]+= 469

[0537] Intermediate 3: tert-Butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0538] Step 1: tert-Butyl 8-benzyl-3,8-diazabicyclo [3.2.1] octane-3-carboxylateUnder nitrogen, to a solution of tert-butyl 3,8-diazabicyclo [3.2.1] octane-3-carboxylate (5.00 g, 23.5 mmol) in N, N-dimethylformamide (50 mL) were added K2CO3(6.51 g, 47.1 mmol) and (bromomethyl)benzene (6.01 g, 35.1 mmol) at 0 °C, and the mixture was warmed to room temperature. After 1 h, the reaction mixture was poured into ice water, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-30% EtOAc / petroleum ether) to yield 7 g (98% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 303.

[0539] Step 2: (1S,6S,9R,9aS)-10-Benzyl-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a] azepin-3-one

[0540] Under nitrogen, to a solution of tert-butyl 8-benzyl-3,8-diazabicyclo [3.2.1] octane-3- carboxylate (7.0 g, 23.1mmol) and TMEDA (5.38 g, 46.3mmol) in diethyl ether (70 mL) was added s-BuLi (35.6 mL, 46.3 mmol, 1.3 M in hexane) dropwise at –78 °C. After 1.5 h, acetaldehyde (2.55 g, 57.8 mmol) was added at –78 °C. The reaction was warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc inpetroleum ether) to yield 5.1 g mixture of 4 diastereoisomers. The mixture was separated by Prep- SFC (Column: CHIRALPAK IH, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: IPA(0.5% 2M NH3-MeOH); Flow rate: 70 mL / min; Gradient: isocratic 35% B; Column Temperature( ℃): 35; Back Pressure(bar): 100; Wavelength: 220 nm; RT1(min): 6.31; RT2(min): 8.33; Sample Solvent: MeOH-----Preparative; Injection Volume: 1.9 mL; Number Of Runs: 50) to yield compound a (1.39 g, 22% yield) (the first peak) and compound d (1.47 g, 23% yield) (the third peak) and mixture of compound b and c (the second peak). The mixture of compound b and c was re-separated by Prep- SFC (Column: CHIRALPAK IH, 5*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: IPA(0.5% 2M NH3-MeOH); Flow rate: 200 mL / min; Gradient: isocratic 50% B; Column Temperature( ℃): 35; Back Pressure(bar): 100; Wavelength: 220 nm; RT1(min): 5.73; RT2(min): 8.44; Sample Solvent: MeOH-----Preparative; Injection Volume: 10 mL; Number Of Runs: 6) to yield compound b (0.500 g, 8% yield) (the faster peak) and compound c (0.430 g, 7% yield) (the slower peak) as yellow solid. LC-MS: (ESI, m / z): [M+H]+= 273. Compound a is the desired isomer.

[0541] Step 3: (1S,6S,9R,9aS)-1-Methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one

[0542] A solution of (1S,6S,9R,9aS)-10-Benzyl-1-methylhexahydro-1H,3H-6,9- epiminooxazolo[3,4-a] azepin-3-one (1.00 g, 3.67 mmol) (compound A from the previous step) and Pd / C (500 mg, 10%) in methyl alcohol (15 mL) was stirred for 1 h at room temperature under an atmosphere of hydrogen gas. The catalyst was filtered and the filtrate was concentrated under vacuum to yield 658 mg (crude) of the title compound as a yellow oil which was used without further purification. LC-MS: (ESI, m / z): [M+H]+= 183.

[0543] Step 4: tert-Butyl (1S,6S,9R,9aS)-1-methyl-3-oxohexahydro-1H,3H-6,9- epiminooxazolo[3,4-a] azepine-10-carboxylate

[0544] A solution of (1S,6S,9R,9aS)-1-methylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a] azepin-3-one (658 mg, 3.61 mmol), (Boc)2O (1.18 g, 5.41 mmol) and DIPEA (1.4 g, 10.8 mmol) in dichloromethane (10 mL) was stirred for 30 min at room temperature. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by flashchromatography on silica gel (gradient: 0-100% EtOAc / petroleum ether) to yield the title compound (920 mg, 89% yield over two steps) as a white solid. LC-MS: (ESI, m / z): [M+H]+= 283.

[0545] Step 5: tert-Butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo [3.2.1] octane-8- carboxylate

[0546] A solution of tert-butyl (1S,6S,9R,9aS)-1-methyl-3-oxohexahydro-1H,3H-6,9- epiminooxazolo[3,4-a] azepine-10-carboxylate (0.90 g, 3.2 mmol) and NaOH (1.28 g, 32.0 mmol) in ethanol (12 mL) and water (4 mL) was heated at 80 °C. After 1 h, the reaction solution was cooled to room temperature, diluted with water, and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4and concentrated under vacuum to yield 815 mg (crude) of an oil that was used without further purification. LC-MS: (ESI, m / z): [M+H]+= 257.1H NMR (300 MHz, DMSO-d6) δ 4.54 (s, 1H), 3.94 (d, J = 5.1 Hz, 1H), 3.82 (s, 1H), 2.73 (d, J = 11.3 Hz, 1H), 2.60 (d, J = 11.5 Hz, 1H), 2.41 (d, J = 8.1 Hz, 1H), 2.15 (s, 1H), 179 – 1.67 (m, 3H), 1.56 (s, 1H), 1.40 (s, 9H), 1.04 (d, J = 6.3 Hz, 3H).

[0547] Intermediate 4: (5-(Bis(4-methoxybenzyl) amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl) boronic acid

[0548] Step 1: 5-Bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-3-methylaniline

[0549] Under nitrogen, to a solution of 5-bromo-2-fluoro-3-methylaniline (4.81 g, 23.5 mmol) in DMF (40 mL) was added NaH (2.82 g, 70.5 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred for 20 min at room temperature before the addition of PMBCl (7.42 g, 47.3 mmol). After 1 h, the reaction was quenched with saturated aqueous NH4Cl solution, diluted with H2O (20 mL), and extracted with EtOAc (2 ×80 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was slurried withethanol and filtered to yield 6.50 g (crude) of the title compound as an off-white solid which was used without further purification. LC-MS: (ESI, m / z): [M+H]+= 444

[0550] Step 2: 5-Bromo-2-fluoro-4-iodo-N, N-bis(4-methoxybenzyl)-3-methylaniline

[0551] Under nitrogen, to a solution of 5-bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-3- methylaniline (5.70 g, 12.8 mmol) in acetic acid (50 mL) was added NIS (3.20 g, 14.2 mmol) at room temperature. After 20 min, the reaction was quenched with saturated aqueous Na2S2O3 solution and diluted with EtOAc (150 mL). The collected organic layer was washed with water (4 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-30%) to yield 7.21 g (98.5% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 570.

[0552] Step 3: 5-Bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-3-methyl-4-(trifluoromethyl)aniline

[0553] Under nitrogen, to a solution of 5-bromo-2-fluoro-4-iodo-N, N-bis(4-methoxybenzyl)-3- methylaniline (7.08 g, 12.4 mmol) in DMF (80 mL) was added methyl 2,2-difluoro-2- (fluorosulfonyl) acetate (15.2 mL, 119 mmol) and CuI (23.4 g, 123 mmol) at room temperature. The reaction mixture was warmed to 75oC. After 6 h, the reaction mixture was cooled to room temperature diluted with H2O (40 mL), and extracted with EtOAc (2 × 70 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-50%) to yield 3.47 g (55% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 512.

[0554] Step 4: (5-(Bis(4-methoxybenzyl) amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl) boronic acid

[0555] Under nitrogen, to a solution of 5-bromo-2-fluoro-N, N-bis(4-methoxybenzyl)-3-methyl-4- (trifluoromethyl) aniline (2.40 g, 4.68 mmol) and triisopropyl borate (1.60 mL, 6.91mmol) in THF(35 mL) was added n-BuLi (2.2 mL, 2.5 M in THF) at –78 °C. The resulting solution was stirred for1h at –78 °C. The reaction was quenched with saturated aqueous NH4Cl solution, diluted with H2O(20 mL), and extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried overanhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc (0.1% TEA) / petroleum ether (10% DCM) (0-30%) to yield 1.22 g (55% yield) of the title compound as a yellow syrup. LC-MS: (ESI, m / z): [M+H]+= 478.

[0556] Intermediate 5: tert-butyl (5S,5aS,6S,9R)-2-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-5-methyl-12-(methylsulfonyl)-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

[0557] Step 1: tert-Butyl (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d] pyrimidin-5-yl) oxy) ethyl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate

[0558] Under nitrogen, to a solution of tert-butyl (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8- diazabicyclo [3.2.1] octane-8-carboxylate (769 mg, 3.00 mmol, intermediate 3) in THF (10 mL) was added NaH (480 mg, 12.0 mmol, 60% in mineral oil) at 0 °C. The resulting solution was stirred for 0.5 h at room temperature before recooling to 0 °C. 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d] pyrimidin-4(3H)-one (1.01 g, 3.60 mmol, intermediate 1) was added, and the reaction was warmed to room temperature. After 2 h, the reaction was quenched with saturated aqueous NH4Cl solution, diluted with water and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (1.61 g crude) as a white solid, which was used without further purification. LC-MS: (ESI, m / z): [M+H]+= 500.

[0559] Step 2: tert-Butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-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

[0560] To a solution of tert-butyl (1S,2S,5R)-2-((S)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo- 3,4-dihydropyrido[4,3-d] pyrimidin-5-yl) oxy) ethyl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (1.61g, 3.21mmol) in DCM (15 mL) were added DIPEA (6.22 g, 48.2 mmol) and BOPCl (3.28 g, 12.9 mmol) at room temperature. After 2 h, the reaction was concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0%-55%) to afford the title compound (1.21 g, 78% yield) as a light yellow solid. LC-MS: (ESI, m / z): [M+H]+= 482.

[0561] Step 3: tert-Butyl (5S,5aS,6S,9R)-2-(5-(bis(4-methoxybenzyl) amino)-4-fluoro-3-methyl-2- (trifluoromethyl) phenyl)-1-fluoro-5-methyl-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

[0562] Under nitrogen, to a solution of tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-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 (701 mg, 1.45 mmol) and (5-(bis(4-methoxybenzyl) amino)-4-fluoro- 3-methyl-2-(trifluoromethyl) phenyl) boronic acid (1.73 g, 3.63 mmol, intermediate 4) in THF (9 mL) were added cataCXium A Pd G3 (317 mg, 0.440 mmol) and K3PO4 (1.8 mL, 1.5 M in H2O) at room temperature. The resulting solution was stirred for 3 h at 60℃. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on pre-packed C18 column (gradient: 0-100% CH3CN in water (0.05% NH4HCO3)) to yield 941 mg (74% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 879.

[0563] Step 4: tert-butyl (5S,5aS,6S,9R)-2-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2- (trifluoromethyl)phenyl)-1-fluoro-5-methyl-12-(methylsulfonyl)-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

[0564] Under nitrogen, to a solution of tert-butyl (5S,5aS,6S,9R)-2-(5-(bis(4-methoxybenzyl) amino)-4-fluoro-3-methyl-2-(trifluoromethyl) phenyl)-1-fluoro-5-methyl-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 (910 mg, 1.04 mmol) in DCM (10 mL) was added m-CPBA (537 mg, 3.11 mmol) at 0 ℃. The resulting solution was warmed to room temperature for 2 h. The solution was diluted with saturated aqueous NaHCO3solution and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-51% EtOAc in petroleumether) to afford 378 mg (40% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z):[M+H]+= 911.

[0565] Intermediate 6: tert-Butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-(methylsulfonyl)-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

[0566] To a solution of tert-butyl (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-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 (1.21 g, 2.5 mmol, intermediate 5 / step 2) in EtOAc (20 mL) was added mCPBA (1.30 g, 7.52 mmol) at 0oC. The reaction mixture was stirred at room temperature for 1 hour, diluted with NaHCO3and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-60%) to afford the title compound (931 mg, 72% yield) as white solid. LC-MS: (ESI, m / z): [M+H]+= 514.1H NMR (300 MHz, DMSO-d6, ppm) δ 5.32 – 5.16 (m, 1H), 4.74 (t, J = 7.7 Hz, 1H), 4.35 (d, J = 5.2 Hz, 1H), 4.30 – 4.10 (m, 2H), 3.42 (s, 3H), 3.20 (d, J = 13.4 Hz, 1H), 1.93 – 1.70 (m, 4H), 1.53 (d, J = 6.3 Hz, 3H), 1.47 (s, 9H).

[0567] Intermediate 7: tert-butyl 2-chloro-1-fluoro-5,5-dimethyl-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

[0568] Step 1: tert-Butyl (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0569] Under nitrogen, to a solution of tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3- carboxylate (10.0 g, 47.1 mmol) and K2CO3 (13.1 g, 94.9 mmol) in N,N-dimethylformamide (70 mL) was added (bromomethyl)benzene (12.3 g, 71.9 mmol) at 0oC. The result solution was stirred at room temperature for 1.5 hours. The reaction was quenched with water, extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0-20% EtOAc / petroleum ether) to afford 12.8 g (89.8% yield) of the title compound as a light yellow oil. LC-MS: (ESI, m / z): [M+H]+= 303.

[0570] Step 2: 3-(tert-Butyl) 2-isopropyl (1R,5S)-8-benzyl-3,8-diazabicyclo [3.2.1]octane-2,3- dicarboxylate

[0571] Under nitrogen, to a solution of tert-butyl (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane- 3-carboxylate (10.0 g, 33.1 mmol) in diethyl ether (150 mL) was added N1,N1,N2,N2- tetramethylethane-1,2-diamine (7.69 g, 66.2 mmol) and s-BuLi (1.3 M in Cyclohexane) (51.2 mL, 66.6 mmol) at –78 °C. The solution was stirred at –78 °C for 1 hour. Then to the resulting solution was added isopropyl chloroformate (8.05 g, 65.7 mmol) at –78 °C. The resulting solution was then warmed to room temperature and stirred additional1.5 hours. The reaction was quenched with aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were dried overanhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0-15% EtOAc / petroleum ether) to afford 8.93 g (69.5% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H]+= 389.

[0572] Step 3: (6S,9R)-10-Benzyl-1,1-dimethylhexahydro-1H,3H-6,9-epiminooxazolo[3,4- a]azepin-3-one (two enantiomers)

[0573] Under nitrogen, to a solution of 3-(tert-butyl) 2-isopropyl (1R,5S)-8-benzyl-3,8- diazabicyclo[3.2.1]octane-2,3-dicarboxylate (8.93 g, 23.0 mmol) in tetrahydrofuran (150 mL) was added MeMgBr (1 M in THF) (80 mL, 80 mmol) at -20oC. The solution was stirred at room temperature for 16 hours. The reaction was quenched by aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0- 40% EtOAc / petroleum ether) to afford 7g mixture of enantiomer. The mixture was separated by Prep-Chiral-SFC with the conditions: (Column: (S, S)-Whelk-O 15μm Kromasil, 3*25 cm, 5 μm; Mobile Phase A: CO2; Mobile Phase B: IPA; Flow rate: 100 mL / min; Gradient: isocratic 30% B; Back Pressure(bar): 100; Wavelength: 220 nm; RT1(min): 6.2; RT2(min): 9; Sample Solvent: MeOH; Injection Volume: 3 mL) to afford 2.37 g (36% yield) of the faster peak) (enantiomer 1) and 2.33 g (35.4% yield) the slower peak (enantiomer 2) as a white solid. LC-MS: (ESI, m / z): [M+H]+= 287.

[0574] Step 4: (6S,9R)-1,1-Dimethylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a] azepin-3-one

[0575] Under hydrogen (2 atm), a solution of (6S,9R)-10-benzyl-1,1-dimethylhexahydro-1H,3H- 6,9-epiminooxazolo[3,4-a]azepin-3-one (2.31 g, 8.07 mmol) (step 3, the faster peak) and Pd / C (10%, 652 mg) in methyl alcohol (80 mL) was stirred at room temperature for 2 hours. Then the Pd / C was filtered out. And the filtrate was concentrated under vacuum to afford 1.52 g (crude) of the title compound as white solid. LC-MS: (ESI, m / z): [M+H]+= 197. The crude was used for next step without further purification.

[0576] Step 5: tert-Butyl (6S,9R)-1,1-dimethyl-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4- a]azepine-10-carboxylate

[0577] A solution of (6S,9R)-1,1-dimethylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3- one (1.51 g, 7.69 mmol), (Boc)2O (3.34 g, 15.3 mmol) and DIPEA (3.97 g, 30.8 mmol) in dichloromethane (40 mL) was stirred at room temperature for 2 hours. The solution was diluted with water, extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0-33% EtOAc / petroleum ether) to afford 2.04 g (89.5% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 297.

[0578] Step 6: tert-Butyl (1R,5S)-2-(2-hydroxypropan-2-yl)-3,8-diazabicyclo [3.2.1]octane-8- carboxylate

[0579] A solution of tert-butyl (6S,9R)-1,1-dimethyl-3-oxohexahydro-1H,3H-6,9-epiminooxazolo [3,4-a]azepine-10-carboxylate (1.01 g, 3.41 mmol) and NaOH (2.73 g, 68.3 mmol) in ethanol (12 mL) and water (6 mL) was stirred at 80oC for 6 hours. The solution was concentrated under vacuum. The residue was diluted with DCM. The solid was filtered out, and the filtrate was concentrated under vacuum to afford 892 mg (crude) of the title compound as yellow solid. LC- MS: (ESI, m / z): [M+H]+= 271. The crude was used for next step without further purification.

[0580] Step 7: tert-Butyl (1R,5S)-2-(2-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d] pyrimidin-5-yl)oxy)propan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (isomer 1)

[0581] Under nitrogen, to a solution of tert-butyl (1R,5S)-2-(2-hydroxypropan-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 1.11 mmol) in tetrahydrofuran (20 mL) was added NaH (60%) (305 mg) at 0oC. The solution was stirred at room temperature for 0.5 hour. Then 5,7- dichloro-8-fluoro-2-(methylthio) pyrido[4,3-d]pyrimidin-4(3H)-one (625 mg, 2.23 mmol, intermediate 1) was added at 0oC and stirred at 60℃ for 16 hours. The reaction was quenched withaqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0-5% MeOH / DCM) to afford 304 mg (53.3% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 514.

[0582] Step 8: tert-Butyl 2-chloro-1-fluoro-5,5-dimethyl-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 (isomer 1)

[0583] A solution of tert-butyl (1R,5S)-2-(2-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)propan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (isomer 1) (300 mg, 0.584 mmol), BOPCl (448 mg, 1.76 mmol) and DIPEA (603 mg, 4.67 mmol) in dichloromethane (12 mL) was stirred at room temperature for 24 hours. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0-20% EtOAc / petroleum ether) to afford 210 mg (72.5% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 496.

[0584] Intermediate 8: tert-Butyl (5aS,6S,9R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-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

[0585] Step 1: 3-Benzyl 8-(tert-butyl) (1R,2S,5S)-2-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0586] To a solution of tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo [3.2.1] octane-8- carboxylate (5.00 g, 20.6 mmol, intermediate 2 / step 7) and N-ethyl - N-isopropylpropan-2-amine (5.33 g, 41.3 mmol) in dichloromethane (50 mL) was added benzyl chloroformate (4.57 g, 26.9 mmol) at 0 °C. The resulting solution was stirred for 1 h at room temperature. The reaction was quenched with water and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-50% EtOAc / petroleum ether) to afford 7.70 g (99.1% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H]+= 377.

[0587] Step 2: 3-Benzyl 8-(tert-butyl) (1S,2S,5R)-2-formyl-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate (the faster peak) and 3-Benzyl 8-(tert-butyl) (1S,2R,5R)-2-formyl-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0588] Under nitrogen, to a solution of oxalyl dichloride (10.2 g, 80.9 mmol) in dichloromethane (130 mL) was added a solution of DMSO (12.6 g, 161 mmol) in dichloromethane (70 mL) dropwise slowly at –78 °C. After the solution was stirred at –78 °C for 15 min, a solution of 3-benzyl 8-(tert- butyl) (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (15.1 g, 40.1 mmol) in dichloromethane (70 mL) was added dropwise slowly at –78 °C. After the solution was stirred at –78 °C for 15 min, the Et3N (25.4 g, 251 mmol) was added. The resulting solution was then warmed to room temperature and stirred for 1 hour. The reaction was quenched with water, extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0-30% EtOAc / petroleum ether) to afford 8.65 g (57.6% yield) the faster peak and 4.18 g (27.8% yield) of the slower peak as light yellow oil. LC-MS: (ESI, m / z): [M+H]+= 375.

[0589] Step 3: 3-Benzyl 8-(tert-butyl) (1S,2S,5R)-2-(oxiran-2-yl)-3,8-diazabicyclo[3.2.1]octane- 3,8-dicarboxylate (two diastereomers)

[0590] To a solution of trimethylsulfoniumiodide (12.0 g, 58.9 mmol) in dimethyl sulfoxide (100 mL) and tetrahydrofuran (20 mL) was added NaH (60%) (2.17 g, 54.3 mmol) at room temperature. The solution was stirred for 1 hour. Then a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-formyl- 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (5.01 g, 13.4 mmol) (the faster peak of last step) in tetrahydrofuran (20 mL) was added and stirred for 2 hours at room temperature. The reaction was quenched with aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0-30% EtOAc / petroleum ether) to afford 0.83 g (16% yield) the faster peak (isomer 1) and 2.01 g (38.7% yield) of the slower peak (isomer 2) as light yellow oil. LC-MS: (ESI, m / z): [M+H]+= 389.

[0591] Step 4: 3-Benzyl 8-(tert-butyl) (1S,2S,5R)-2-(1,2-dihydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate Boc

[0592] To a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-(oxiran-2-yl)-3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylate (1.96 g, 5.05 mmol) (isomer 2 of last step) in tetrahydrofuran (18 mL) was added aqueous H2SO4 (10% in water, 2 mL). The solution was stirred at 50oC for 16 hours. Then the solution was adjusted to pH=9~10 with aqueous NaOH solution (10%). And then to the solution was added DIPEA (2.31 g, 17.9 mmol) and Boc2O (1.64 g, 7.59 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0-4% MeOH / DCM) to afford 1.52 g (74.4% yield) of the title compound as a light yellow oil. LC-MS: (ESI, m / z): [M+H]+= 407.

[0593] Step 5: 3-Benzyl 8-(tert-butyl) (1S,2S,5R)-2-(2-((tert-butyldiphenylsilyl)oxy)-1- hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (isomer 2)

[0594] To a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-(1,2-dihydroxyethyl)-3,8-diazabicyclo [3.2.1]octane-3,8-dicarboxylate (1.51 g, 3.71 mmol) (isomer 2), DMAP (0.91 g, 7.46 mmol) and DIPEA (2.45 g, 19.0 mmol) in N,N-dimethylformamide (20 mL) was added tert- butylchlorodiphenylsilane (2.24 g, 8.15 mmol). The solution was stirred at room temperature for 16 hours. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0-25% EtOAc / petroleum ether) to afford 2.22 g (92.7% yield) of the title compound as colorless oil. LC-MS: (ESI, m / z): [M+H]+= 645.

[0595] Step 6: tert-Butyl (1S,2S,5R)-2-(2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (isomer 2)

[0596] Under hydrogen (2 atm), a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-(2-((tert- butyldiphenylsilyl) oxy)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (2.22 g, 3.44 mmol) and Pd / C (10%, 517 mg, 0.490 mmol) in methyl alcohol (50 mL) was stirred at room temperature for 1.5 hours. Then the Pd / C was filtered out. The filtrate was concentrated under vacuum to afford 1.57 g (crude) of the title compound as crude white solid. LC-MS: (ESI, m / z): [M+H]+= 511. The crude was used for next step without further purification.

[0597] Step 7: tert-Butyl (1S,2S,5R)-2-(2-((tert-butyldiphenylsilyl)oxy)-1-((7-chloro-8-fluoro-2- (methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0598] Under nitrogen, to a solution of tert-butyl (1S,2S,5R)-2-(2-((tert-butyldiphenylsilyl)oxy)-1- hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.56 g, 3.05 mmol) in tetrahydrofuran (35 mL) was added NaH (60%) (1.03 g, 25.8 mmol) at 0oC. The solution was stirred at room temperature for 0.5 hour. Then 5,7-dichloro-8-fluoro-2-(methylthio) pyrido[4,3-d]pyrimidin-4(3H)- one (2.11 g, 7.53 mmol, intermediate 1) was added. The solution was stirred at room temperature for 16 hours. The reaction was quenched with aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-7% MeOH / DCM) to afford 1.44 g (62.6% yield) of the title compound as a brown solid. LC-MS: (ESI, m / z): [M+H]+= 754.

[0599] Step 8: tert-Butyl (5aS,6S,9R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-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 (isomer 2)

[0600] A solution of tert-butyl (1S,2S,5R)-2-(2-((tert-butyldiphenylsilyl) oxy)-1-((7-chloro-8- fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.44 g, 1.91 mmol) BOPCl (1.11 g, 4.35 mmol) and DIPEA (1.49 g, 11.6 mmol) in dichloromethane (40 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0-20% EtOAc / petroleum ether) to afford 1.14 g (81.1% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 736.

[0601] Intermediate 9: 2,2,2-Trifluoroacetaldehyde--(2-methylazetidin-2-yl)methanol

[0602] To a solution of tert-butyl 2-(hydroxymethyl)-2-methylazetidine-1-carboxylate (201 mg, 1.00 mmol) in HFIP (4 mL) was added 2,2,2-trifluoroacetic acid (0.2 mL, 2.70 mmol) at room temperature, and the mixture was stirred for 1 hour at room temperature. The solvent was concentrated under vacuum to afford the title compound (240 mg, crude) as a light yellow oil. LC- MS: (ESI, m / z): [M-TFA+H]+= 102. The crude was used for next step without further purification.

[0603] Intermediate 10: 2-(Azetidin-2-yl)-1-methyl-1H-imidazole

[0604] Step 1: Benzyl 2-(hydroxymethyl)azetidine-1-carboxylate

[0605] To a solution of azetidin-2-ylmethanol (1.00 g, 11.5 mmol) and DIPEA (2.97 g, 23.0 mmol) in dichloromethane (50 mL) was added a solution of CbzCl (2.94 g, 17.2 mmol) in dichloromethane (30 mL) dropwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under vacuum. The residue was purified by reverse phase flash chromatography on pre-packed C18 column (gradient: 0-100% CH3CN in water (0.05% NH4HCO3)) to afford the title compound (1.70 g, 67% yield) as a colorless solid. LC-MS: (ESI, m / z): [M+H]+= 222.

[0606] Step 2: Benzyl 2-formylazetidine-1-carboxylate

[0607] Under nitrogen, to a solution of benzyl 2-(hydroxymethyl)azetidine-1-carboxylate (1.00 g, 4.52 mmol) and DIPEA (1.75 g, 13.6 mmol) in dichloromethane (10 mL) was added a solution of py-SO3(2.16 g, 13.6 mmol) in DMSO (10 mL) dropwise at 0°C and stirred for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on pre-packed C18 column (gradient: 0-100% CH3CN in water (0.05% NH4HCO3)) to afford the title compound (660 mg, 67% yield) as a colorless oil. LC-MS: (ESI, m / z): [M+H]+= 220.

[0608] Step 3: Benzyl 2-(1H-imidazol-2-yl)azetidine-1-carboxylate

[0609] To a solution of benzyl 2-formylazetidine-1-carboxylate (660 mg, 3.01mmol) in methanol (15 mL) was added oxalaldehyde (40 wt% aqueous solution, 7 mL, 60.8 mmol) and ammonia (25 wt% aqueous solution, 8 mL, 107 mmol) at room temperature and stirred for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-60% ethyl acetate in petroleum ether) to afford the title compound (420 mg, 54% yield) as a colorless oil. LC-MS: (ESI, m / z): [M+H]+= 258.

[0610] Step 4: Benzyl 2-(1-methyl-1H-imidazol-2-yl)azetidine-1-carboxylate

[0611] To a solution of benzyl 2-(1H-imidazol-2-yl)azetidine-1-carboxylate (420 mg, 1.53 mmol) in tetrahydrofuran (10 mL) was added NaH (60% dispersion in mineral oil, 122 mg, 3.06 mmol) at 0 °C and stirred for 30 minutes. Then MeI (435 mg, 3.06 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl aqueous solution. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-10% methanol in dichloromethane) to afford the title compound (270 mg, 65% yield) as a brown oil. LC-MS: (ESI, m / z): [M+H]+= 272.

[0612] Step 5: 2-(Azetidin-2-yl)-1-methyl-1H-imidazole

[0613] Under hydrogen, a mixture of benzyl 2-(1-methyl-1H-imidazol-2-yl) azetidine-1- carboxylate (150 mg, 0.554 mmol) and 10%Pd / C (58.7 mg, 0.0554mmol) in ethyl acetate (20 mL) was stirred at room temperature 2 hours. The resulting mixture was filtered over celite, and the filter cake was washed with ethanol. The combined filtrate was concentrated under vacuum to afford the title compound (110 mg, crude) as a light yellow oil. LC-MS: (ESI, m / z): [M+H]+= 138.

[0614] Intermediate 11: 3-Fluoro-4-methoxy-1-(3-methylazetidin-3-yl) pyrrolidine dihydrochloride (two trans isomers)

[0615] Step 1: 1-(1-Benzhydryl-3-methylazetidin-3-yl)-3-fluoro-4-methoxypyrrolidine (two trans isomers)

[0616] A solution of 3-fluoro-4-methoxypyrrolidine (mixture of trans isomers, 0.500 g, 4.20 mmol) and 1-benzhydryl-3-methylazetidin-3-yl methanesulfonate (2.78 g, 8.40 mmol) in i-PrOH (50 ml) was stirred at 70 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography on pre-packed C18 column (gradient: 0-100% CH3CN in water (0.05% NH4HCO3)) to afford a mixture of trans isomers (1.10 g, 74.0% yield) as a yellow oil. Two trans isomers were separated by Chiral-Prep-HPLC with the following conditions: (Column: CHIRALPAK IF 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH): EtOH=85: 15; Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL / min; Gradient: isocratic;Wavelength: 220 / 254 nm; RT1(min) 4.56; RT2(min) 5) to afford 440 mg (29.5% yield, the fasterpeak) and 460 mg (30.9% yield, the slower peak) as yellow oils. LC-MS: (ESI, m / z): [M+H]+ =355.

[0617] Step 2: 3-Fluoro-4-methoxy-1-(3-methylazetidin-3-yl)pyrrolidine dihydrochloride (two trans isomers)

[0618] Under hydrogen, a mixture of 1-(1-benzhydryl-3-methylazetidin-3-yl)-3-fluoro-4- methoxypyrrolidine (200 mg, 0.563 mmol, the faster peak of last step), 20% Pd(OH)2 / C (78.8 mg, 0.0563 mmol, contain 50% water) and HCl (1M aqueous solution, 4 mL) in ethanol (20 mL) was stirred at room temperature overnight. The resulting mixture was filtered through Celite, and the filter cake was washed with ethanol. The combined filtrate was concentrated under vacuum to afford the title compound (200 mg, crude, trans isomer 1) as a light yellow oil. LC-MS: (ESI, m / z): [M-2HCl+H]+= 189. The crude was used without further purification.

[0619] Analogous to method described as above, trans isomer 2 (210 mg, crude) was preparedfrom the slower peak of last step (200 mg, 0.563 mmol) as a light yellow oil. LC-MS: (ESI, m / z):[M-2HCl+H]+= 189. The crude product was used without further purification.

[0620] Intermediate 12: tert-Butyl (1R,2S,5S)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0621] Step 1: 3-Benzyl 8-(tert-butyl) (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo [3.2.1]octane-3,8-dicarboxylate

[0622] To a solution of tert-butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo [3.2.1] octane-8- carboxylate (5.00 g, 20.6 mmol) and N-ethyl - N-isopropylpropan-2-amine (5.33 g, 41.3 mmol) in dichloromethane (50.0 mL) was added benzyl chloroformate (4.57 g, 26.9 mmol) at 0 °C. The resulting solution was stirred for 1 h at room temperature. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-50% EtOAc / petroleum ether) to afford 7.70 g (99.1% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H]+= 377.

[0623] Step 2: 3-Benzyl 8-(tert-butyl) (1R,2S,5S)-2-formyl-3,8-diazabicyclo [3.2.1] octane-3,8- dicarboxylate and 3-benzyl 8-(tert-butyl) (1R,2R,5S)-2-formyl-3,8-diazabicyclo[3.2.1]octane-3,8- dicarboxylate

[0624] Under nitrogen, to a solution of oxalyl dichloride (18.4 mL, 2 M in DCM) in dichloromethane (10.0 mL) was added dimethylsulfoxide (5.73 g, 73.5 mmol) in dichloromethane (10.0 mL) at –78 °C. The resulting solution was stirred for 30 min at –78 °C. Then 3-benzyl 8-(tert- butyl) (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylate (6.90 g, 18.3 mmol) in dichloromethane (70.0 mL) was added at –78 °C, and the mixture was stirred for 1 h. Then triethylamine (11.1 g, 110 mmol) was added at –78 °C. The reaction mixture was warmed to room temperature and stirred additional 1 h. The reaction was diluted with water and extracted withDCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-30% EtOAc / petroleum ether) to afford 1.46 g (21% yield) of the faster peak and 2.9 g (42% yield) of the slower peak as colorless oil. LC-MS: (ESI, m / z): [M+H]+= 375. Note: 3-Benzyl 8-(tert-butyl) (1R,2S,5S)-2-formyl-3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylate epimerizes on silica gel.

[0625] Faster peak: 1H NMR (300 MHz, DMSO-d6) δ 9.43 (d, J = 3.8 Hz, 1H), 7.38 - 736 (s,5H), 5.12 (s, 2H), 4.23 (s, 1H), 4.08 (s, 1H), 3.78 (s, 1H), 3.57 (d, J = 12.1 Hz, 1H), 3.16 – 3.20 (m, 1H), 2.00 – 1.86 (m, 2H), 1.79 – 1.73 (m, 2H), 1.42 (s, 9H).

[0626] Slower peak: 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 7.45 – 7.23 (m, 5H), 5.15 –5.00 (m, 2H), 4.76 (t, J = 8.1 Hz, 1H), 4.60 -4.64 (m, 1H), 4.22 – 3.98 (m, 1H), 3.75 – 3.58 (m, 1H), 3.18 – 3.06 (m, 1H), 2.09 – 1.80 (m, 2H), 1.82 – 1.52 (m, 2H), 1.36 (s, 9H).

[0627] Step 3: 3-Benzyl 8-(tert-butyl) (1R,2S,5S)-2-(2,2,2-trifluoro-1-((trimethylsilyl) oxy) ethyl)- 3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylate and 3-benzyl 8-(tert-butyl) (1R,2R,5S)-2-(2,2,2- trifluoro-1-((trimethylsilyl) oxy) ethyl)-3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylate

[0628] A solution of 3-benzyl 8-(tert-butyl) (1R,2S,5S)-2-formyl-3,8-diazabicyclo [3.2.1] octane- 3,8-dicarboxylate (faster peak of step 2) (1.46 g, 3.90 mmol), trimethyl(trifluoromethyl)silane (1.11 g, 7.82 mmol) and LiOAc (258 mg, 3.90 mmol) in N, N-dimethylformamide (15.0 mL) was stirred for 1 h at room temperature. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 2.00 g (crude) of compound A as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 517.

[0629] Analogous to method described as above, 3.80 g crude compound B was prepared from 2.80g slower peak of step 2.

[0630] Step 4: 3-Benzyl 8-(tert-butyl) (1R,2S,5S)-2-((S)-2,2,2-trifluoro-1-((trimethylsilyl) oxy) ethyl)-3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylate and 3-benzyl 8-(tert-butyl) (1R,2S,5S)-2- ((R)-2,2,2-trifluoro-1-((trimethylsilyl) oxy) ethyl)-3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylate

[0631] The mixture of diastereomers of 3-Benzyl 8-(tert-butyl) (1R,2S,5S)-2-(2,2,2-trifluoro-1- ((trimethylsilyl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (6.50 g crude, compound A of last step) was separated by flash chromatography on silica gel (gradient: 0-15% EtOAc in petroleum ether) to afford 3.20 g compound A1 (the faster peak) and 810 mg compound A2 (the slower peak, desired isomer) as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 517.

[0632] Compound A1:1H NMR (300 MHz, DMSO-d6) δ 7.46 – 7.11 (m, 5H), 5.07 (s, 2H), 4.87 (m, 1H), 4.38 (d, J = 46.1 Hz, 1H), 4.24 – 3.93 (m, 3H), 3.17 – 2.83 (m, 1H), 2.43 (m, 1H), 1.86 (s, 2H), 1.56 (s, 1H), 1.33 (s, 9H), 0.09 (s, 9H).

[0633] Compound A2:1H NMR (300 MHz, DMSO-d6) δ 7.49 – 7.19 (m, 5H), 4.99 (d, J = 8.0 Hz, 2H), 4.70 (d, J = 29.2 Hz, 2H), 4.28 (d, J = 16.8 Hz, 1H), 4.11 (s, 2H), 2.69 (d, J = 16.1 Hz, 1H), 2.02 (d, J = 13.2 Hz, 1H), 1.88 (d, J = 27.8 Hz, 2H), 1.54 (d, J = 10.9 Hz, 1H), 1.31 (d, J = 9.6 Hz, 9H), 0.07 (s, 9H).

[0634] Step 5: tert-Butyl (1R,6S,9R,9aS)-3-oxo-1-(trifluoromethyl) hexahydro-1H,3H-6,9- epiminooxazolo[3,4-a] azepine-10-carboxylate

[0635] A solution of 3-benzyl 8-(tert-butyl) (1R,2S,5S)-2-((R)-2,2,2-trifluoro-1-((trimethylsilyl) oxy) ethyl)-3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylate (compound A2 of last step) (800 mg, 1.55 mmol) and TBAF (1.60 mL, 1 M in THF) in tetrahydrofuran (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and washed with water. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a C18 column (solvent gradient: 0-100% MeOH in water (0.05% NH4HCO3)) to afford 480 mg (92% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 337.

[0636] Step 6: tert-Butyl (1R,2S,5S)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0637] To a solution of tert-butyl (1R,6S,9R,9aS)-3-oxo-1-(trifluoromethyl) hexahydro-1H,3H-6,9- epiminooxazolo[3,4-a] azepine-10-carboxylate (480 mg, 1.43 mmol) in ethanol (5.00 mL) was added NaOH (571 mg, 14.3 mmol) in water (1.0 mL). The resulting solution was stirred for 1 h at 80 °C. The solvent was evaporated under vacuum. The residue was dissolved in DCM and solidswere removed by filtration. The solvent was evaporated under vacuum to afford 460 mg (crude) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 311.1H NMR (300 MHz, DMSO-d6) δ 3.95 (br, 2H), 3.67 (br, 1H), 2.90-2.80 (br, 1H), 2.80-2.70 (m, 1H), 2.68-2.60 (m, 1H), 2.25 (br, 1H), 1.95-1.85 (m, 1H), 1.82-1.52 (m, 3H), 1.40 (s, 9H).

[0638] Intermediate 13: tert-Butyl (5R,5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5- (trifluoromethyl)-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

[0639] Step 1: tert-Butyl (1S,2S,5R)-2-((R)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d] pyrimidin-5-yl) oxy)-2,2,2-trifluoroethyl)-3,8-diazabicyclo [3.2.1] octane-8- carboxylate

[0640] Under nitrogen, to a solution of tert-butyl (1R,2S,5S)-2-((R)-2,2,2-trifluoro-1- hydroxyethyl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (460 mg, 1.48 mmol, intermediate 12) in tetrahydrofuran (10.0 mL) was added NaH (356 mg, 8.90 mmol, 60% in mineral oil) at 0 °C.

[0641] The resulting solution was stirred for 30 min at room temperature and then recooled to 0 °C. 5,7-Dichloro-8-fluoro-2-(methylthio) pyrido[4,3-d] pyrimidin-4(3H)-one (621 mg, 2.22 mmol, intermediate 1) was then added at 0 °C, and the reaction was stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1.10 g (crude) of the title compound as a yellow solid. LC- MS: (ESI, m / z): [M+H]+= 554.

[0642] Step 2: tert-Butyl (5R,5aS,6S,9R)-2-chloro-1-fluoro-12-(methylthio)-5-(trifluoromethyl)- 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

[0643] A solution of tert-butyl (1S,2S,5R)-2-((R)-1-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4- dihydropyrido[4,3-d] pyrimidin-5-yl) oxy)-2,2,2-trifluoroethyl)-3,8-diazabicyclo [3.2.1] octane-8- carboxylate (700 mg, 1.26 mmol), BOPCl (1.2 g, 5.1 mmol) and DIPEA (2.46 g, 19.0 mmol) in dichloromethane (15.0 mL) was stirred overnight at room temperature. The solvent was then concentrated under vacuum, and the resulting residue was purified by flash chromatography on silica gel (gradient: 0-25% EtOAc in petroleum ether) to afford 548 mg (81% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 536.1H NMR (300 MHz, DMSO-d6) δ 5.74 – 5.69 (m, 1H), 5.24 (d, J = 13.3 Hz, 1H), 4.44 (d, J = 10.0 Hz, 1H), 4.31 (d, J = 18.1 Hz, 2H), 3.20 (d, J = 13.3 Hz, 1H), 2.58 (s, 3H), 1.89 (s, 4H), 1.46 (s, 9H).

[0644] Intermediate 14: tert-Butyl (5R,5aS,6S,9R)-2-chloro-1-fluoro-12-(methylsulfonyl)-5- (trifluoromethyl) -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

[0645] Under nitrogen, to a solution of tert-butyl (5R,5aS,6S,9R)-2-chloro-1-fluoro-12- (methylthio)-5-(trifluoromethyl)-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 (80.0 mg, 0.150 mmol, intermediate 13) in ethyl acetate (2.00 mL) was added 3-chlorobenzoperoxoic acid (77.2 mg, 0.450 mmol) at 0 °C. The resulting solution was stirred for 1 h at room temperature. The solution was quenched with Na2S2O3 aqueous and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-50% EtOAc / petroleum ether) to afford 51.0 mg (60.2% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 568.

[0646] Intermediate 15: 3-Fluoro-N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

[0647] Step 1: 4-Bromo-3-fluoro-6-methylpyridin-2-amine

[0648] To a solution of 4-bromo-6-methylpyridin-2-amine (1.00g, 5.35mmol) in CHCl3(6mL) and water (6mL) was added selectfluor (946mg, 2.67mmol) at room temperature. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. EtOAc was added and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-100% EtOAc in petroleum ether) to afford faster peak (112mg, 10.2% yield) and slower peak (215mg, 19.1% yield) as yellow solids.

[0649] Faster peak: LC-MS: (ESI, m / z): [M+H]+= 205.1H NMR (300 MHz, DMSO-d6) δ 6.64 (d, J = 3.7 Hz, 1H), 6.40 (s, 2H), 2.21 (d, J = 1.2 Hz, 3H).

[0650] Slower peak: LC-MS: (ESI, m / z): [M+H]+= 205.1H NMR (300 MHz, DMSO-d6) δ 6.54 (d, J = 3.8 Hz, 1H), 5.99 (s, 2H), 2.25 (d, J = 3.2 Hz, 3H).

[0651] Step 2: 4-Bromo-3-fluoro-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine

[0652] To a solution of 4-bromo-3-fluoro-6-methylpyridin-2-amine (110mg, 0.540mmol, the faster peak of last step) in DMF (1 mL) was added 60% NaH (53.6mg, 1.34mmol) at 0 °C. The mixture was stirred for 20 min at 0oC. PMBCl (185mg, 1.18mmol) was added and the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified byflash chromatography on silica gel (gradient: 0-40% EtOAc in petroleum ether) to afford the title compound (175mg, 72.3% yield) as a white solid. LC-MS: (ESI, m / z): [M+H]+= 445.

[0653] Step 3: 3-Fluoro-N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2-amine

[0654] Under nitrogen, a solution of 4-bromo-3-fluoro-N,N-bis(4-methoxybenzyl)-6- methylpyridin-2-amine (150mg, 0.340mmol), B2Pin2(128mg, 0.510mmol), Pd(dppf)Cl2(49.3mg, 0.0700mmol) and KOAc (66.0mg, 0.670mmol) in 1,4-dioxane (3mL) was stirred at 80 °C for 4 hours. The solution was cooled to room...

Claims

CLAIMS What is claimed is:

1. A compound of formula (I),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;, wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05 is -NH2, and at least one of R01, R02, R03, R04, and R05 is methyl; R2is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z1 is L1NR5R6, wherein: L1 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5 is L2NR8R9, C1-6alkyl, L2Cy, or S(=O)2R8, wherein: L2is selected from: -S(=O)2(CH2)q-, -C(=O)(CH2)q-, -(CH2)q-, -P(=O)3(CH2)q-, –(CH2)–CH=CH–, and –CH=CH–(CH2)–, wherein q = 1 – 3;R8 and R9 are each independently hydrogen, C1-6alkyl, or C1-3haloalkyl; and Cy is a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; R6is H or C1-6alkyl; or R5 and R6 together with the nitrogen atom to which they are both bonded form a group Q; wherein Q is: a 3 – 10 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, two or three chained rings, and a spirocyclic ring; optionally substituted with one or more R10groups independently selected from: sulfonyl, cyano, halo, -NH2, -NHR11, -N(R11)2, -R11-NH2, -R11-NH-R11, -R11-N(R11)2, hydroxyl, C1-6alkoxy, C1-6alkyl, C1-6cycloalkyl, C1-6alkoxy-C1-6alkyl, C1-6haloalkoxy-C1- 6alkyl , cyano-C1-6alkyl C2-6alkenyl, hydroxy-C1-6alkyl, oxo, C1-6alkylcarbenyl, carboxy- C1-6alkyl, and C1-6haloalkyl; wherein each R11is independently selected from C1-6alkyl, C1-6haloalkyl, and hydroxyl-C1-6alkyl; wherein Q optionally comprises one or more heteroatoms selected from O, S(O)2, and N in addition to the nitrogen atom to which R5 and R6 are both bonded, wherein each additional instance of N is present in Q as N–H, N(R11), or as a tertiary N; and X is -O- or -NR12-, wherein R12 is hydrogen, C1-6alkyl, or C1-6haloalkyl.

2. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of claim 1, wherein X is -NR12-.

3. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of claim 1 or 2, wherein X is -NH-.

4. A compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-3, wherein: m = 0; n = 1; and p = 1.

5. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-4, wherein one of R01, R02, R03, R04, and R05 is amino.

6. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-5, wherein R1is:

7. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-6, wherein R1is:

8. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-7, wherein9. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-8, wherein R2is fluoro.

10. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-9, wherein R3' and R3'' are both H.

11. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-10, wherein each R4' is hydrogen and R4'' is methyl.

12. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-11, wherein, when present, at least one of R10is selected from -NH2, -NHR11, -N(R11)2, -R11-NH2, -R11-NH-R11, -R11-N(R11)2.

13. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-12, wherein R5 and R6 together with the nitrogen atom to which they are both bonded form an azetidine ring.

14. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 1-12, wherein R5and R6together with the nitrogen atom to which they are both bonded form a pyrrolidine ring.

15. A compound of formula (II),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2; p is 0, 1, or 2;, wherein Y1is N or CR01, Y2is N or CR02, Y3is N or CR03; and each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05 is -NH2, and at least one of R01, R02, R03, R04, and R05 is methyl; R2is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl; Z2 is L0OR5, wherein: L0 is a bond, –C(=O)–, or –C(H)R7–, wherein R7 is H or C1-3alkyl; R5is L1J1, or L2Q, wherein: L1is selected from: –(CH2)q–, –(CH2)C(Ra)(Rb)–, –(CH2)C(H)(Ra)C(H)(Rb)–, –C(H)(Ra)C(H)(Rb)–, –(CH2)Cy– and a bond, wherein q = 1 – 3, Ra and Rb together with the carbon atoms to which each is attached form a ring, and Cy is an optionally substituted 1,2-linked cyclopropyl ring; J1 is selected from: cyano, –C(=O)NR8R9, –C(=O)OR8, -OR8, and - R8; wherein R8and R9are independently selected from H, C1-6alkyl, C2-6alkenyl, and phenyl, with the proviso that R8and R9are not both H; and wherein Cy, Ra, Rb, R8 and R9 are each optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, alkylcarboxy, C1-6alkoxy, and oxo; and L2is selected from: –(CHR13)q–, -(CH2)q-C(=O)- and a bond; Q is a 3 – 11 membered ring selected from a monocyclic ring, a fused bicyclic ring, a bridged bicyclic ring, and a spirocyclic ring; wherein Q is optionally substituted with one or more groups independently selected from: halogen, sulfonyl, cyano, oxo, -NR13C(=O)R14, -C(=O)R14, hydroxyl, -OR14, and -R14; R13and R14are independently selected from: hydrogen, C1-6alkyl, and C2-6alkenyl; and wherein R13and R14are each optionally and independentlysubstituted by one or more groups selected from: sulfonyl, -S(=O)2(R11), cyano, halogen, oxo, hydroxyl, C1-6alkoxy, and C1-6alkylcarboxy; R11is selected from C1-6alkyl, C1-6haloalkyl, and hydroxyl-C1-6alkyl; and wherein Q optionally comprises one or more heteroatoms selected from O, S, S(O)2 and N, wherein each instance of N is present in Q as an amide, amide lactam, or when Q is aheteroaromatic ring moiety; andX is -O- or -NR12-, wherein R12is hydrogen, C1-6alkyl, or C1-6haloalkyl.

16. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of claim 15, wherein X is -NR12-.

17. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of claim 15 or 16, wherein X is -NH-.

18. A compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 15-17, wherein: m = 0; n = 1; and19. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 15-18, wherein one of R01, R02, R03, R04, and R05 is amino.

20. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 15-19, wherein R1is:

21. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 15-20, wherein R1 is:

22. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 15-21, wherein23. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 15-22, wherein R2is fluoro.

24. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 15-23, wherein R3' and R3'' are both H.

25. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 15-24, wherein each R4' is hydrogen and R4'' is methyl.

26. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 15-25, wherein L1is a bond.

27. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 15-26, wherein Q is selected from: cyclopropane, cyclobutane, cyclohexane, benzene, pyrollidine, piperidine, morpholine, pyridine, pyridazine, pyrazine, pyrimidine, 1,4-dioxane, 1H-pyrazole, isoindoline-1,3-dione, 2-oxabicyclo[2.1.1]hexane, tetrahydrofuran, oxetane, tetrahydropyran, thietane, 2,3-dihydrobenzofuran, iso-oxazole, bicyclo[1.1.1]pentane, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, imidazole, tetrahydro-2H- thiopyran, 1,2,4-triazole, and 9-oxa-2-azaspiro[5.5]undecane.

28. A compound of formula (III),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 1 or 2; wherein n + m does not exceed 2;and each of R01, R02, R03, R04, and R05 is independently hydrogen, halogen, -CN, -NH2, - N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl, and wherein at least one of R01, R02, R03, R04, and R05 is -NH2, and at least one of R01, R02, R03, R04, and R05is methyl; R2is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3' and R3'' are independently hydrogen, halogen, oxo, C1-3alkyl, or C1-3haloalkyl; R4' and R4'' are independently hydrogen, methyl, or C1-3haloalkyl;Z3 is L1OR5, wherein: L1is a bond, –C(=O)–, or –C(H)R7–, wherein R7is H or C1-3alkyl; R5is L2J, or L2QJ, wherein: L2is selected from: –(CH2)q–, –(CH2)q–C(=O)–, and a bond, wherein q = 1 – 3; J is C1-6alkyl-NR8R9 or -NR8R9; wherein R8 and R9 are independently selected from H, C1-6alkyl, and C2- 6alkenyl; wherein J is optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, and C1-6alkoxy; and, when not H, each of R8 and R9 is optionally and independently substituted with one or more groups selected from: halogen, cyano, hydroxyl, C1- 6alkylcarboxy, C1-6alkoxy, C1-6cycloalkyl, 5-6 membered heterocyclyl, and oxo; Q is a 3 – 8 membered ring moiety selected from a monocyclic ring, a fused bicyclic ring, and a spirocyclic ring; wherein Q is optionally substituted with one or more groups independently selected from: halogen, cyano, oxo, hydroxyl, C1-6alkoxy, and C1- 6haloalkyl; wherein Q optionally comprises one or more heteroatoms selected from O, S, and N; wherein L2and J both bond to the same ring atom of Q; and X is -O- or -NR12-, wherein R12is hydrogen, C1-6alkyl, or C1-6haloalkyl.

29. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of claim 28, wherein X is -NR12-.

30. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of claim 28 or 29, wherein X is -NH-.

31. A compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 28-30, wherein: m = 0; n = 1; and p = 1.

32. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 28-31, wherein one of R01, R02, R03, R04, and R05is amino.

33. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 28-32, wherein R1 is:

34. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 28-33, wherein R1is:

35. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 28-34, wherein36. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 28-35, wherein R2is fluoro.

37. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 28-36, wherein R3' and R3'' are both H.

38. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt thereof of any one of claims 28-37, wherein each R4' is hydrogen and R4'' is methyl.

39. The compound of any one of claims 28-38, wherein Q is cyclopropyl.

40. The compound of any one of claims 28-39, wherein q = 1.

41. A compound selected from any one of compounds 1-262 as set forth in Table 1 or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising a compound or a stereoisomer, atropisomer,tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-41, and one or more pharmaceutically acceptable excipients.

43. A method of treating cancer, the method comprising administering an effective amountof a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-41, or a pharmaceutical composition of claim 42.

44. The method of claim 43, wherein the cancer is characterized as comprising a KRasmutation.

45. The method of claim 44, wherein the KRas mutation corresponds to a KRasG12Dmutation.

46. The method of any one of claims 43-45, wherein the cancer is tissue agnostic.

47. The method of any one of claims 43-45, wherein the cancer is pancreatic cancer, lungcancer, or colorectal cancer.

48. The method of claim 47, wherein the lung cancer is lung adenocarcinoma, NSCLC, orSCLC.

49. A compound according to any one of claims 1-41, or a stereoisomer, atropisomer,tautomer, or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

50. Use of a compound of any one of claims 1-41, or stereoisomer, atropisomer, tautomer,or pharmaceutically acceptable salt thereof, for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

51. Use of a compound of any one of claims 1-41, or stereoisomer, atropisomer, tautomer,or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

52. A compound according to any one of claims 1-41, or stereoisomer, atropisomer,tautomer, or pharmaceutically salt thereof, for the therapeutic and / or prophylactic treatment of a cancer comprising a KRasG12Dmutation.

53. Use of a compound of any one of claims 1-41, or stereoisomer, atropisomer, tautomer,or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting proliferation of a cell population.

54. Use of a compound of any one of claims 1-41, or stereoisomer, atropisomer, tautomer,or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

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