Linearly substituted oxazepin-5-one KRAS-g12d inhibitors

Abstract

Provided herein are linearly substituted oxazepin-5-one compounds useful in the treatment of cancers.

Description

LINEARLY SUBSTITUTED OXAZEPIN-5-ONE KRAS-G12D INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No.63 / 566,115, filed March 15, 2024 and U.S Provisional Application No.63 / 756,730, filed February 10, 2025. The disclosures of each of the foregoing applications are incorporated by reference herein in their entirety. BACKGROUND

[0002] Ras is a small GTP-binding protein that functions as a nucleotide-dependent switch forcentral 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, therebypromoting 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 andat 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 mediatedcancers. 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 some embodiments, the compound is a compound or a stereoisomer, atropisomer,tautomer, or pharmaceutically acceptable salt thereof as set forth in Table 1.

[0009] In another aspect provided herein is a pharmaceutical composition comprising acompound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable excipients.

[0010] In another aspect provided herein is a method of treating a cancer comprising a KRasmutation, the method comprising administering to a patient having such cancer, a compound, stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0011] In another aspect provided herein is a method for regulating the activity of a KRasmutant protein, the method comprising reacting the mutant protein with a compound, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0012] In another aspect provided herein is a method for inhibiting proliferation of a cellpopulation, the method comprising contacting the cell population with a compound, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein.

[0013] In another aspect provided herein is a method for inhibiting tumor metastasiscomprising 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.

[0014] In another aspect provided herein is method for preparing a labeled KRas G12D mutantprotein, 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

[0015] Disclosed herein are linearly substituted oxazepin-5-one compounds as describedherein, 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 ormodulators 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.

[0016] While the disclosure herein provides enumerated embodiments, it is understood thatthey 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.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the samemeaning 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.

[0018] The following definitions are provided to facilitate understanding of certain terms usedfrequently 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.

[0019] 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.

[0020] The term “alkyl” refers to a saturated linear or branched-chain monovalent hydrocarbonradical. 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.

[0021] The term “oxo” refers to =O, i.e., an oxygen atom double-bonded to a second atomother 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.

[0022] The term “alkoxy” refers to –O–alkyl.

[0023] The terms “cyano” or “nitrile” refers to –C≡N or –CN.

[0024] The term “haloalkoxy” refers to –O–haloalkyl.

[0025] The terms “hydroxy” and “hydroxyl” refer to –OH.

[0026] The term “alkenyl” refers to linear or branched-chain monovalent hydrocarbon radicalwith 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.

[0027] The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical withat 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 (–C≡CH), prop-1-ynyl (–C≡CCH3), prop-2- ynyl (propargyl, –CH2C≡CH), but-1-ynyl, but-2-ynyl, and but-3-ynyl.

[0028] The term “alkylene” refers to a saturated, branched, or straight chain hydrocarbongroup 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.

[0029] Cyclic (ring-containing) moieties comprise atoms bonded together in a ring, and haveone 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. Cyclic rings may be monocyclic (i.e., having one ring) or multicyclic (e.g., bicyclic (i.e., having two rings), tricyclic (i.e., having three rings).

[0030] Two ring atoms are adjacent to one another in that ring if they are bonded to oneanother 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 isnecessarily bonded to each other atom in the ring. Two adjacent ring atoms define one “edge” of the ring.

[0031] Two or more cyclic moieties may join to one another in one of several ways to formring systems that comprise more than one ring.

[0032] Two rings are fused to one another if two ring atoms are adjacent to one another in bothrings and are shared by both rings. Such rings are said to share an “edge.”

[0033] Spirocyclic ring systems comprise a pair of rings that share a single vertex. Suchsystems contain a ring junction at which the two rings share a single ring atom.

[0034] Bridged ring systems contain at least a pair of rings in which two or more non-adjacentring atoms are shared by two or more rings. The two non-adjacent ring atoms in question are referred to as “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.

[0035] Chained ring systems contain two or more rings that are joined to one another but donot 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, saturated or partially unsaturated. Biphenyl is an example of a chained ring system.

[0036] 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.

[0037] The term “carbocycle” as used herein refers to aromatic, saturated or unsaturated cyclicunivalent 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.

[0038] It is intended herein that the term carbocycle encompasses radicals having one or moreadjacent 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 of spirocycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.

[0039] “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.

[0040] Typical aryl groups include, but are not limited to, groups derived from fused ringsystems 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.

[0041] 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 thecyclic 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 may optionally be quaternized (e.g., [NR4]+Cl-, [NR4]+OH-). Examples of 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.

[0042] In particular embodiments, a heterocyclyl group or a heteroaryl group is attached at acarbon 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.

[0043] In certain embodiments, the heterocyclyl group or heteroaryl group is N-attached. Byway 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 a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β- carboline.

[0044] A heterocyclic ring may make fused, spiro, or bridged, connections or make anycombination of such connections to one or more other rings.

[0045] “Heteroaryl” or “heteroaromatic”, as used herein, refers to an aromatic cyclic grouphaving 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 carbonatoms and 1 to 6 annular heteroatoms independently selected from nitrogen, phosphorus, oxygen and sulfur.

[0046] 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, 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.

[0047] 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.

[0048] 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 that contain at least one aromatic ring and at least one partially saturated ring include fluorene, indane, and biphenylene.

[0049] A mixed ring system having more than one ring where at least one ring is aromatic andat 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.

[0050] A heteroaryl group having more than one ring where at least one ring is non-aromaticmay be connected to another structure at either an aromatic ring position or at a non-aromatic ring position.

[0051] Similarly, carbocyclic and heterocyclic groups may join to one another in one of severalways to form ring systems that comprise more than one ring.

[0052] “Heteroatom” refers to any atom other than carbon or hydrogen. Typical heteroatomsfound 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.

[0053] “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.

[0054] 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).

[0055] The term “haloalkyl” refers to an alkyl chain in which one or more hydrogen has beenreplaced by a halogen. The term “haloalkyl” is meant to include monohaloalkyl, polyhaloalkyl, and perhaloalkyl. 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.

[0056] As used herein a wavy line “ ” that intersects a bond in a chemical structureindicate 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.

[0057] In certain embodiments, divalent groups are described generically without specificbonding 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.

[0058] The term “pharmaceutically acceptable” refers to molecular entities and compositionsthat do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.

[0059] Compounds described herein may be in the form of a salt, such as a pharmaceuticallyacceptable 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.

[0060] The term “pharmaceutically acceptable base addition salts” include those derived frominorganic 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, such as 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.

[0061] 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).

[0062] A “sterile” formulation is aseptic or free from all living microorganisms and theirspores.

[0063] The term “stereoisomers” refer to compounds that have identical chemical constitutionbut differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, atropisomers, conformers and the like.

[0064] The term “chiral” refers to molecules that have the property of non-superimposabilityof the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

[0065] The term “diastereomer” refers to a stereoisomer with two or more centers of chiralityand 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.

[0066] The term “enantiomers” refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0067] The term “atropisomers” refers to two conformers resulting from hindered rotationabout a single bond where the steric strain barrier to rotation can be high enough to allow for the isolation of each conformer.

[0068] 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.

[0069] The term “tautomer” or “tautomeric form” refers to structural isomers of differentenergies 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.

[0070] Certain compounds described herein can exist in unsolvated forms as well as solvatedforms, 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 oramorphous forms. In general, all physical forms are contemplated herein. The term “hydrate” refers to the complex where the solvent molecule is water.

[0071] Compounds and pharmaceutically acceptable salts thereof described herein may containone 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.

[0072] In the structures shown herein, where the stereochemistry of any particular chiral atomis 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.

[0073] A “subject,” “individual,” or “patient” is a vertebrate and are used interchangeablyherein. 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.

[0074] The terms “inhibiting” and “reducing,” or any variation of these terms, includes anymeasurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease 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.

[0075] The term “treatment” refers to clinical intervention designed to alter the natural courseof 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 ofthose suffering from the disease, decreasing the dose of other medications required to treat the disease, and / or prolonging survival of patients.

[0076] 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.

[0077] 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.

[0078] An “effective amount” or “therapeutically effective amount” is at least the minimumamount 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 infiltration into 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.

[0079] The term “co-administration,” “administered in combination with,” and theirgrammatical 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.

[0080] The term “package insert” is used to refer to instructions customarily included incommercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0081] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to acompound 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.

[0082] The term “agonist” as used herein refers to a compound having the ability to initiate orenhance 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.

[0083] The terms “cancer” and “cancerous”, “neoplasm”, and “tumor” and related terms areused 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 cancer including 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).

[0084] A “chemotherapeutic agent” is an agent useful in the treatment of a given disorder, forexample, 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.

[0085] Unless otherwise stated, structures depicted herein are also meant to includecompounds 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.

[0086] It is specifically contemplated that any limitation discussed with respect to oneembodiment 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 or to utilize any compound and pharmaceutically acceptable salts thereof described herein or composition described herein.

[0087] Throughout this application, the term “about” is used to indicate that a value includesthe standard deviation of error for the device or method being employed to determine the value.

[0088] 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

[0089] In one aspect, provided herein is a compound have the structure of Formula (I),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 0, 1 or 2; q is 0 or 1; p is 0, 1, or 2; wherein n + m + q does not exceed 2, and p and q are not simultaneously 1;independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R2is hydrogen, -CN, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3A is hydrogen, halogen, C1-3alkyl, or C1-3haloalkyl, and R3B is hydrogen; or R3A and R3B are taken together to form oxo; each of R4Aand R4Bis independently hydrogen, C1-3alkyl, or C1-3haloalkyl;or R4Aand R4Bare taken together with the atom to which they are bound to form a 3- 6 membered monocyclic ring; R3Cis hydrogen, halogen, C1-3alkyl, or C1-3haloalkyl; R3Dis hydrogen; Z is hydrogen, C1-3alkyl, -L1–Cy, -L1–NR5R6, –OR6, or –SR6; wherein: L1is absent or –C(=O)–; R5 is hydrogen, C1-6alkyl, or –NH2; R6 is C1-6alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C1-6alkyl; L2is –(CR7AR7B)u–; u is 1, 2 or 3; each R7A and R7B is independently hydrogen or C1-3alkyl; Cy is a 3 – 11 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, wherein Cy optionally comprises one or more heteroatoms selected from N, O, and S and is optionally substituted with one or more R8; each R8is independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; – C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl; or R5and R6together with the nitrogen atom to which they are both bonded form a 3 – 6 membered monocyclic ring optionally substituted with one or more groups independently selected from: C1-6alkyl and hydroxyl; or Z and R2together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring; X is –NR11; and R11is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0090] In some embodiments, provided herein is a compound having the structure of formula(I):(I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 0, 1 or 2; q is 0 or 1; p is 0, 1, or 2; wherein n + m + q does not exceed 2, and p and q are not simultaneously 1; R1is , wherein each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R2 is hydrogen, cyano, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3A is hydrogen, halogen, C1-3alkyl, or C1-3haloalkyl, and R3B is hydrogen; or R3A and R3Bare taken together to form oxo; each of R4A and R4B is independently hydrogen, C1-3alkyl, or C1-3haloalkyl; or R4A and R4B are taken together with the atom to which they are bound to form a 3-6 membered monocyclic ring; R3C is hydrogen, halogen, C1-3alkyl, or C1-3haloalkyl; R3D is hydrogen; Z is hydrogen, C1-3alkyl, -L1–Cy, -L1–NR5R6, –OR6, or –SR6; wherein: L1 is absent or –C(=O)–; R5 is hydrogen, C1-6alkyl, or –NH2; R6is C1-6alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C1-6alkyl; L2 is –(CR7AR7B)u–;u is 1, 2 or 3; each R7A and R7B is independently hydrogen or C1-3alkyl; 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, wherein Cy optionally comprises one or more heteroatoms selected from N, O, and S and is optionally substituted with one or more R8; each R8is independently selected from: C1-6alkyl optionally substituted with hydroxyl; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3- 6cycloalkyl; and oxo; wherein each of R9 and R10 is independently hydrogen or C1-6alkyl; or R5and R6together with the nitrogen atom to which they are both bonded form a 3 – 6 membered monocyclic ring optionally substituted with one or more groups independently selected from: C1-6alkyl and hydroxyl; or Z and R2together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring; X is –NR11; and R11is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0091] In some embodiments, provided herein is a compound of Formula (I), or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0; n is 1; p is 1; q is 0; and R3Aand R3Bare both hydrogen.

[0092] In some embodiments, provided herein is a compound of Formula (I), or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0; n is 0; p is 0; and q is 1.

[0093] In some embodiments, X is -NR11 and R11 is hydrogen.

[0094] In some embodiments, no more than one of R01, R02, R03, R04, and R05 is hydrogen. Insome embodiments, no more than two of R01, R02, R03, R04, and R05is hydrogen. In some embodiments, at least one of R01, R02, R03, R04, and R05is halogen. In some embodiments, one of R01, R02, R03, R04, and R05 is halogen. In some embodiments, two of R01, R02, R03, R04, and R05 is halogen. In some embodiments, one of R01, R02, R03, R04, and R05 is fluoro. In some embodiments, two of R01, R02, R03, R04, and R05is fluoro. In some embodiments, one of R01, R02, R03, R04, and R05is C1-3haloalkyl. In some embodiments, one of R01, R02, R03, R04, and R05is –CH2CHF2. In some embodiments, one of R01, R02, R03, R04, and R05 is –CF3. In some embodiments, one of R01, R02, R03, R04, and R05is –NH2. In some embodiments, one of R01, R02, R03, R04, and R05is C1-6alkyl. In some embodiments, one of R01, R02, R03, R04, and R05is C1-3alkyl. In some embodiments, one of R01, R02, R03, R04, and R05 is methyl. In someembodiments, one of R01, R02, R03, R04, and R05is C3-6cycloalkyl. In some embodiments, each of R01, R02, R03, R04, and R05 is independently hydrogen, halogen, -NH2, C1-3alkyl, or C1-3haloalkyl. In some embodiments, each of R01, R02, R03, R04, and R05is independently hydrogen, fluoro, –NH2, methyl, or –CF3. In some embodiments, each of R01, R02, R03, R04, and R05is independently hydrogen, fluoro, –NH2, methyl, or –CH2CHF2.

[0095] In some embodiments, R1 is:, , , , , , , , , , , , , , , , , , , , , , , or .

[0096] In some embodiments, R1 is: , , ,, , or .

[0097] In some embodiments, R1 is: , or .

[0098] In some embodiments, R1 is: , , ,, or . In some embodiments, R1is . In some embodiments, R1is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is .

[0099] In some embodiments, R2 is halogen. In some embodiments, R2 is fluoro or chloro. Insome embodiments, R2is fluoro. In some embodiments, R2is chloro.

[0100] In some embodiments, R3A is hydrogen, halogen, C1-3 alkyl, or C1-3haloalkyl, and R3B ishydrogen. In some embodiments R3A is hydrogen. In some embodiments, R3A is halogen. In some embodiments, R3Ais C1-3alkyl. In some embodiments, R3Ais methyl. In some embodiments, R3A is C1-3haloalkyl. In some embodiments, R3A is –CF3. In some embodiments, R3A and R3B are taken together to form oxo.

[0101] In some embodiments, R3C is hydrogen. In some embodiments, R3C is halogen. Insome embodiments, R3C is C1-3 alkyl. In some embodiments, R3C is methyl. In some embodiments, R3Cis C1-3haloalkyl. In some embodiments, R3Cis –CF3.

[0102] In some embodiments, R3A and R3C are both hydrogen.

[0103] In some embodiments, each of R4A and R4B is independently hydrogen, C1-3alkyl, or C1-3haloalkyl.

[0104] In some embodiments, R4A is hydrogen. In some embodiments, R4A is C1-3alkyl. Insome embodiments, R4A is methyl. In some embodiments, R4A is ethyl. In some embodiments, R4A is C1-3haloalkyl. In some embodiments, R4A is –CHF2. In some embodiments, R4A is –CF3. In some embodiments, R4Ais –CD3.

[0105] In some embodiments, R4B is hydrogen. In some embodiments, R4B is C1-3alkyl. Insome embodiments, R4B is methyl. In some embodiments, R4B is ethyl. In some embodiments, R4Bis C1-3haloalkyl. In some embodiments, R4Bis –CHF2. In some embodiments, R4Bis -CF3. In some embodiments, R4Bis –CD3.

[0106] In some embodiments, R4A and R4B are both hydrogen. In some embodiments, R4A ishydrogen and R4Bis C1-3alkyl. In some embodiments, R4Ais C1-3alkyl and R4Bis hydrogen. In some embodiments, R4Ais hydrogen and R4Bis methyl. In some embodiments, R4Ais methyl and R4B is hydrogen. In some embodiments, R4A is hydrogen and R4B is ethyl. In some embodiments, R4A is ethyl and R4B is hydrogen. In some embodiments, R4A and R4B are both methyl. In some embodiments, R4Ais hydrogen and R4Bis C1-3haloalkyl. In some embodiments, R4Ais C1-3haloalkyl and R4Bis hydrogen. In some embodiments, R4Ais hydrogen and R4B is –CF3. In some embodiments, R4A is –CF3 and R4B is hydrogen. In some embodiments, R4Ais hydrogen and R4Bis –CHF2. In some embodiments, R4Ais –CHF2and R4Bis hydrogen. In some embodiments, R4Ais hydrogen and R4Bis –CD3. In some embodiments, R4A is –CD3 and R4B is hydrogen.

[0107] In some embodiments, R4A and R4B are taken together with the atom to which they arebound to form a 3 – 6 membered monocyclic ring. In some embodiments, R4Aand R4Bare taken together with the atom to which they are bound to form a 3 – 6 membered monocyclic carbocyclic ring. In some embodiments, R4A and R4B, taken together with the atom to which they are both bound, form a 3 – 6 membered monocyclic ring optionally comprising one or more heteroatoms selected from N, O, and S. In some embodiments, R4Aand R4B, taken together with the atom to which they are both bound, form a 3 – 6 membered monocyclic ring comprising one or more heteroatoms selected from N and O. In some embodiments, R4Aand R4B, taken together with the atom to which they are both bound, form a 3 – 6 membered monocyclic ring comprisingone or more heteroatoms selected from N and S. In some embodiments, R4Aand R4B, taken together with the atom to which they are both bound, form a 3 – 6 membered monocyclic ring comprising one or more heteroatoms selected from S and O. In some embodiments, R4Aand R4B, taken together with the atom to which they are both bound, form a 3 – 6 membered monocyclic ring comprising one or more N. In some embodiments, R4A and R4B, taken together with the atom to which they are both bound, form a 3 – 6 membered monocyclic ring comprising one or more O. In some embodiments, R4Aand R4B, taken together with the atom to which they are both bound, form a 3 – 6 membered monocyclic ring optionally comprising one or more S.

[0108] In some embodiments, R4A and R4B, taken together with the atom to which they areboth bound, form an oxetane ring.

[0109] In some embodiments, Z is hydrogen. In some embodiments, Z is C1-3alkyl. In someembodiments, Z is methyl. In some embodiments, Z is -L1–Cy. In some embodiments, Z is - L1–NR5R6. In some embodiments, Z is –OR6. In some embodiments, Z is –SR6.

[0110] In some embodiments, L1 is absent. In some embodiments, L1 is –C(=O)–.

[0111] In some embodiments, R5 is hydrogen, C1-6alkyl, or –NH2; and R6 is C1-6alkyl,-L2–Cy, –C(=O)–Cy, or –C(=O)C1-6alkyl.

[0112] In some embodiments, R5 is hydrogen. In some embodiments, R5 is C1-6alkyl. In someembodiments, R5 is methyl. In some embodiments, R5 is –NH2.

[0113] In some embodiments, R6 is C1-6alkyl. In some embodiments, R6 is -L2–Cy. In someembodiments, R6is –C(=O)–Cy. In some embodiments, R6is –C(=O)C1-6alkyl.

[0114] In some embodiments, R5 is hydrogen and R6 is–C(=O)–Cy. In some embodiments, R5is hydrogen and R6 is–C(=O)–phenyl. In some embodiments, R5 is hydrogen and R6 is – C(=O)C1-6alkyl. In some embodiments, R5is hydrogen and R6is –C(=O)CH2CH3. In some embodiments, R5is –NH2and R6is C1-6alkyl. In some embodiments, R5is –NH2and R6is methyl. In some embodiments, R5 is hydrogen and R6 is C1-6alkyl. In some embodiments, R5 is hydrogen and R6is methyl.

[0115] In some embodiments, R5 and R6 together with the nitrogen atom to which they areboth bonded form a 3 – 6 membered monocyclic ring optionally substituted with one or more groups independently selected from: C1-6alkyl and hydroxyl. In some embodiments, R5 and R6 together with the nitrogen atom to which they are both bonded form a 3 – 6 membered monocyclic ring. In some embodiments, R5and R6are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring optionally comprising one or more heteroatoms selected from N, O, and S. In some embodiments, R5and R6are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclicring comprising one or more heteroatoms selected from N and O. In some embodiments, R5and R6 are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring comprising one or more heteroatoms selected from N and S. In some embodiments, R5and R6are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring optionally comprising one or more heteroatoms selected from S and O.

[0116] In some embodiments, R5 and R6 are taken together with the nitrogen atom to whichthey are bound to form an azetidine optionally substituted with one or more groups independently selected from: C1-6alkyl and hydroxyl. In some embodiments, R5 and R6 are taken together with the nitrogen atom to which they are bound to form an azetidine substituted with C1-6alkyl and hydroxyl. In some embodiments, R5and R6are taken together with the nitrogen atom to which they are bound to form an azetidine substituted with methyl and hydroxyl. In some embodiments, R5and R6are taken together with the nitrogen atom to which they are bound to form an azetidine.

[0117] In some embodiments, R5 and R6 are taken together with the nitrogen atom to whichthey are bound to form a 3 – 6 membered monocyclic ring comprising one or more N. In some embodiments, R5and R6are taken together with the nitrogen atom to which they are bound to form a pyrazole. In some embodiments, R5 and R6 are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring comprising one or more O. In some embodiments, R5and R6are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring comprising one or more S. In some embodiments, R5 and R6 are taken together with the atom to which they are bound to form a 3 – 6 membered monocyclic carbocyclic ring.

[0118] In some embodiments, each R7A is independently hydrogen. In some embodiments,each R7B is independently hydrogen. In some embodiments, each R7A and R7B are both hydrogen. In some embodiments, each R7Aand R7Bis independently C1-3alkyl. In some embodiments, each R7Ais independently C1-3alkyl. In some embodiments, each R7Ais independently methyl. In some embodiments, each R7B is independently C1-3alkyl. In some embodiments, each R7B is independently methyl. In some embodiments, each R7A is independently hydrogen and each R7Bis independently C1-3alkyl. In some embodiments, R7Ais hydrogen and R7Bis methyl.

[0119] In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is3.

[0120] In some embodiments, Cy is a 3 – 11 membered monocyclic ring optionally comprisingone or more heteroatoms selected from N, O, and S and optionally substituted with one or moreR8. In some embodiments, Cy is a 3 – 11 membered fused bicyclic ring optionally comprising one or more heteroatoms selected from N, O, and S and optionally substituted with one or moreR8. In some embodiments, Cy is a 3 – 11 bridged bicyclic ring optionally comprising one ormore heteroatoms selected from N, O, and S and optionally substituted with one or more R8. Insome embodiments, Cy is a 3 – 11 membered two or three chained rings optionally comprising one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8.

[0121] In some embodiments, Cy is a 3 – 11 membered monocyclic ring optionally comprisingone or more heteroatoms selected from N, O, and S. In some embodiments, Cy is a 3 – 11 membered fused bicyclic ring optionally comprising one or more heteroatoms selected from N,O, and S. In some embodiments, Cy is a 3 – 11 bridged bicyclic ring optionally comprising oneor more heteroatoms selected from N, O, and S. In some embodiments, Cy is a 3 – 11 membered two or three chained rings optionally comprising one or more heteroatoms selected from N, O, and S.

[0122] In some embodiments, Cy is a 3 – 10 membered monocyclic ring optionally comprisingone or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8. In some embodiments, Cy is a 3 – 10 membered fused bicyclic ring optionally comprising one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8. In some embodiments, Cy is a 3 – 10 bridged bicyclic ring optionally comprising one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8. In some embodiments, Cy is a 3 – 10 membered two or three chained rings optionally comprising one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8.

[0123] In some embodiments, Cy is a 3 – 10 membered monocyclic ring optionally comprisingone or more heteroatoms selected from N, O, and S. In some embodiments, Cy is a 3 – 10 membered fused bicyclic ring optionally comprising one or more heteroatoms selected from N, O, and S. In some embodiments, Cy is a 3 – 10 bridged bicyclic ring optionally comprising one or more heteroatoms selected from N, O, and S. In some embodiments, Cy is a 3 – 10 membered two or three chained rings optionally comprising one or more heteroatoms selected from N, O, and S.

[0124] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane,pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5- c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1- yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6- dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is optionally substituted with one or more R8.

[0125] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane,pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5- c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5- thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1- yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6- dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine.

[0126] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane,pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5- c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5- thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1- yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6- dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is substituted with one or more R8.

[0127] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane,pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5- c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1- yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6- dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted with one or more R8.

[0128] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane,pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5- c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5- thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1- yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6- dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0129] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane,pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5- c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5- thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1- yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6- dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is substituted with one or more R8.

[0130] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane,pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, or quinoline; wherein Cy is optionally substituted with one or more R8.

[0131] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane,pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, or quinoline.

[0132] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane,pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, or quinoline; wherein Cy is substituted with one or more R8.

[0133] In some embodiments, Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole,pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5- a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H- pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3- triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1- c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted with one or more R8.

[0134] In some embodiments, Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole,pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5- a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H- pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3- triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1- c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0135] In some embodiments, Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole,pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5- a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H- pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3- triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1- c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is substituted with one or more R8.

[0136] In some embodiments, Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is optionally substituted with one or more R8.

[0137] In some embodiments, Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine.

[0138] In some embodiments, Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is substituted with one or more R8.

[0139] In some embodiments, each R8 is independently selected from: C1-6alkyl optionallysubstituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; – C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9 and R10 are independently hydrogen or C1-6alkyl. In some embodiments, each R8is independently selected from: C1-6alkyl optionally substituted with hydroxyl; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl; and oxo; wherein each of R9 and R10 is independently hydrogen or C1-6alkyl. In some embodiments, each R8 is independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; cyano; oxo; –C(=O)OR10; and C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl. In some embodiments, each R8 is independently selected from: C1-6alkyl and halogen.

[0140] In some embodiment, Cy is substituted with 1-20 independently selected R8. In someembodiment, Cy is substituted with one R8. In some embodiment, Cy is substituted with twoindependently selected R8. In some embodiment, Cy is substituted with three independentlyselected R8. In some embodiment, Cy is substituted with four independently selected R8. Insome embodiment, Cy is substituted with five independently selected R8. In some embodiment,Cy is substituted with six independently selected R8. In some embodiment, Cy is substitutedwith seven R8. In some embodiment, Cy is substituted with eight R8. In some embodiment, Cyis substituted with nine R8. In some embodiment, Cy is substituted with ten R8.

[0141] In some embodiments R9 is hydrogen. In some embodiments R9 is C1-6alkyl. In someembodiments R9is methyl. In some embodiments R10is hydrogen. In some embodiments R10is C1-6alkyl. In some embodiments R10is methyl.

[0142] In some embodiments, each R8 is independently C1-6alkyl. In some embodiments, eachR8 is independently C1-6alkyl substituted with hydroxyl. In some embodiments, each R8 is independently C1-6alkyl substituted with C1-6alkoxy. In some embodiments, each R8is independently C1-3haloalkyl. In some embodiments, each R8is independently C3-6cycloalkyl substituted with hydroxy-C1-6alkyl.

[0143] In some embodiments, each R8 is independently –CH2OH, –CH2CH2OH, –CH2OCH3,methyl, ethyl, –CHF2, –CF3, chloro, fluoro, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxy, cyano, cyclopropyl substituted with –CH2OH, or cyclopropyl. In some embodiments,each R8is independently methyl, –CF3, –CHF2, fluoro, hydroxyl, cyano, –CH2OH, –C(=O)OH, –C(=O)OMe, or –C(=O)N(Me)2. In some embodiments, each R8 is independently –CH2OH, – CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chloro, fluoro, oxo,–C(=O)OH, cyano, cyclopropyl substituted with –CH2OH, or cyclopropyl. In some embodiments, each R8is independently methyl, ethyl, –CHF2, –CF3, chloro, or fluoro. In some embodiments, each R8 is independently methyl or fluoro.

[0144] In some embodiments, Z is -L1-Cy, L1 is absent and Cy is an optionally substitutedpyrazole or an optionally substituted pyrimidine. In some embodiments, Cy is a pyrazole. In some embodiments, Cy is a pyrimidine. In some embodiments, Cy is a substituted pyrazole. In some embodiments, Cy is a substituted pyrimidine. In some embodiments, Cy is a pyrazole substituted with methyl.

[0145] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen and R6 is -L2–Cy.

[0146] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine, wherein Cy is optionally substituted with one or more R8 independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0147] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine, wherein Cy is optionally substituted with one or more R8 independently selected from: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chloro, fluoro, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxy, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0148] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine, wherein Cy is substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1- 6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0149] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine, wherein Cy is substituted with one or more R8 independently selected from: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, – CHF2, –CF3, chloro, fluoro, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxy, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0150] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine.

[0151] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1- 3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0152] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine,imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is optionally substituted with one or more R8independently selected from: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chloro, fluoro, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxy, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0153] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0154] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is substituted with one or more R8 independentlyselected from: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chloro, fluoro, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxy, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0155] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0156] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridone, thiazole, or quinoline, wherein Cy is optionally substituted with one or more R8 independently selected from: C1-6alkyl optionally substituted with hydroxyl; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; – C(=O)OR10; C3-6cycloalkyl; and oxo; wherein each of R9and R10is independently hydrogen or C1-6alkyl. In some embodiments, Z is -L1–NR5R6, L1is absent, R5is hydrogen, R6is -L2–Cy, L2is –CH2– and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridone, thiazole, or quinoline, wherein Cy is substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl; and oxo; wherein each of R9and R10is independently hydrogen or C1-6alkyl. In some embodiments, Z is -L1–NR5R6, L1is absent, R5is hydrogen, R6is -L2–Cy, L2is –CH2– and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridone, thiazole, or quinoline, wherein Cy is optionally substituted with one or more R8independently selected from methyl, –CF3, –CHF2, fluoro, hydroxyl, cyano,–CH2OH, –C(=O)OH, –C(=O)OMe, and –C(=O)N(Me)2. In some embodiments, Z is - L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2– and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridone, thiazole, or quinoline, wherein Cy is substituted with one or more R8independently selected from methyl, –CF3, –CHF2, fluoro, hydroxyl, cyano,–CH2OH, –C(=O)OH, –C(=O)OMe, and –C(=O)N(Me)2. In some embodiments, Z is -L1–NR5R6, L1is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2– and Cy is phenyl, pyridine, imidazole, 2- oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridone, thiazole, or quinoline.

[0157] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; cyano; oxo; –C(=O)OR10; and C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl.

[0158] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; cyano; oxo; –C(=O)OR10; and C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl.

[0159] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole,1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is optionally substituted with one or more R8 independently selected from: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chloro, fluoro, oxo,–C(=O)OH, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0160] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is substituted with one or more R8independently selected from: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chloro, fluoro, oxo,–C(=O)OH, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0161] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0162] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl and halogen.

[0163] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is optionally substituted with one or more R8 independently selected from: methyl and fluoro.

[0164] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is substituted with one or more R8 independently selected from: C1-6alkyl and halogen.

[0165] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is substituted with one or more R8independently selected from: methyl and fluoro.

[0166] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH2– and Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine.

[0167] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is–CH(CH3)– and Cy is phenyl.

[0168] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen and R6 is methyl.

[0169] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen and R6 is –C(=O)–Cy. In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is –C(=O)–Cy, and Cy is phenyl.

[0170] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen and R6 is –C(=O)CH2CH3.

[0171] In some embodiments, Z is -L1–NR5R6, L1 is –C(=O)–, R5 is –NH2, and R6 is methyl.

[0172] In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 are taken togetherwith the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring optionally substituted with one or more groups independently selected from C1-6alkyl and hydroxyl.

[0173] In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 are taken togetherwith the nitrogen atom to which they are bound to form an azetidine optionally substituted with one and more groups independently selected from C1-6alkyl and hydroxyl. In some embodiments, Z is -L1–NR5R6, L1is absent, and R5and R6are taken together with the nitrogen atom to which they are bound to form an azetidine substituted with one or more groups independently selected from C1-6alkyl and hydroxyl. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5and R6are taken together with the nitrogen atom to which they are bound to form an azetidine substituted methyl and hydroxyl. In some embodiments, Z is -L1–NR5R6, L1is absent, and R5 and R6 are taken together with the nitrogen atom to which they are bound toform an azetidine. In some embodiments, Z is -L1–NR5R6, L1is absent, and R5and R6are taken together with the nitrogen atom to which they are bound to form a pyrazole.

[0174] In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 are taken togetherwith the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring optionally comprising one or more heteroatoms selected from N, O, and S. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring comprising one or more heteroatoms selected from N and O. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring comprising one or more heteroatoms selected from N and S. In some embodiments, Z is -L1–NR5R6, L1is absent, and R5and R6are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring optionally comprising one or more heteroatoms selected from S and O. In some embodiments, Z is -L1– NR5R6, L1is absent, and R5and R6are taken together with the nitrogen atom to which they are bound to form a 3-6 membered monocyclic ring comprising one or more N. In some embodiments, Z is -L1–NR5R6, L1is absent, and R5and R6are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring comprising one or more O. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 are taken together with the nitrogen atom to which they are bound to form a 3 – 6 membered monocyclic ring comprising one or more S. In some embodiments, Z is -L1–NR5R6, L1is absent, and R5and R6are taken together with the atom to which they are bound to form a 3 – 6 membered monocyclic carbocyclic ring.

[0175] In some embodiments, Z is –OR6, and R6 is -L2-Cy. In some embodiments, L2 is –CH2– and Cy is pyridine. In some embodiments, Z is –OR6, and R6is -L2-Cy, wherein L2is – CH2– and Cy is pyridine.

[0176] In some embodiments, Z is –SR6, and R6 is -L2-Cy. In some embodiments, L2 is –CH2–and Cy is pyridine. In some embodiments, Z is –SR6, and R6is -L2-Cy, wherein L2is –CH2– and Cy is pyridine.

[0177] In some embodiments, Z and R2 together with the carbon atoms to which they arebonded form a 5 – 6 membered monocyclic aromatic ring. In some embodiments, Z and R2together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic heteroaromatic ring. In some embodiments, Z and R2 together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring optionally comprising one or more heteroatoms selected from N, O, and S. In some embodiments, Z and R2together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ringcomprising one or more heteroatoms selected from N and O. In some embodiments, Z and R2together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring comprising one or more heteroatoms selected from N and S. In some embodiments, Z and R2together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring optionally one or more heteroatoms selected from O and S. In some embodiments, Z and R2 together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring optionally comprising one or more N. In some embodiments, Z and R2 together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring optionally comprising one or more O. In some embodiments, Z and R2together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring optionally comprising one or more S. In some embodiments, Z and R2 together with the carbon atoms to which they are bonded form a pyrazole. In some embodiments, Z and R2are taken together with the atom to which they are bound to form a C6aryl.

[0178] In some embodiments, the compound is any one of the compounds set forth in Table 1,or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0179] Table 1:

[0180] In some embodiments, the compound is selected from the group consisting ofcompounds 1-146 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 1-65 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 66-135 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 136-146 as set forth in Table 1, or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.Synthesis of Compounds

[0181] Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt 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;. 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 pharmaceutical acceptable 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.

[0182] Synthetic chemistry transformations and protecting group methodologies (protectionand 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.

[0183] Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt 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.

[0184] 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.

[0185] In preparing compounds or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable 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.

[0186] In the methods of preparing compounds or a stereoisomer, atropisomer, tautomer, orpharmaceutically 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.

[0187] Another class of separation methods involves treatment of a mixture with a reagentselected 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.

[0188] Diastereomeric mixtures can be separated into their individual diastereomers on thebasis 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.

[0189] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer can beobtained 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 salts thereof 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).

[0190] Under method (1), diastereomeric salts can be formed by reaction of enantiomericallypure 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.

[0191] Alternatively, by method (2), the substrate to be resolved is reacted with oneenantiomer 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.

[0192] The chemical reactions described herein may be readily adapted to prepare othercompounds 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 other than 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

[0193] Also provided herein are pharmaceutical compositions comprising compound or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable excipients.

[0194] Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt 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.

[0195] A typical formulation is prepared by mixing a compound or pharmaceuticallyacceptable 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).

[0196] The formulations can be prepared using conventional dissolution and mixingprocedures. 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 typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.

[0197] The pharmaceutical composition (or formulation) for application can be packaged in avariety 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.

[0198] 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.

[0199] The pharmaceutical composition ordinarily can be stored as a solid composition, alyophilized formulation or as an aqueous solution.

[0200] The pharmaceutical compositions described herein can be formulated, dosed andadministered 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.

[0201] As a general proposition, the initial pharmaceutically effective amount of the compoundor a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof administered parenterally 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.

[0202] Acceptable pharmaceutically acceptable excipients are nontoxic to recipients at thedosages and concentrations employed, and include buffers such as phosphate, citrate and otherorganic 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).

[0203] Sustained-release preparations of compounds or pharmaceutically acceptable saltsthereof 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.

[0204] 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.

[0205] Formulations of a compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically 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.

[0206] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulationsare 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 orpenetration 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.

[0207] 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.

[0208] 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 agents which 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 syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables.

[0209] The amount of active ingredient that can be combined with the carrier material toproduce 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.

[0210] Formulations suitable for parenteral administration include aqueous and non-aqueoussterile 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.

[0211] Formulations suitable for topical administration to the eye also include eye dropswherein 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.

[0212] Formulations suitable for topical administration in the mouth include lozengescomprising 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.

[0213] Formulations for rectal administration can be presented as a suppository with a suitablebase comprising for example cocoa butter or a salicylate.

[0214] Formulations suitable for intrapulmonary or nasal administration have a particle size forexample 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 the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can beprepared 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.

[0215] 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.

[0216] The formulations can be packaged in unit-dose or multi-dose containers, for examplesealed 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.

[0217] In one embodiment, the compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically 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

[0218] Compounds or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt 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 preferred route can vary with for example the condition of the recipient. Where the compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically 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.

[0219] Thus, in one aspect provided herein is a pharmaceutical composition comprising acompound 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.

[0220] 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.

[0221] A dose to treat human patients can range from about 10 mg to about 1000 mg of acompound 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

[0222] The compounds or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable 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.

[0223] Provided herein are methods of contacting a cell, such as an ex vivo cell, with acompound 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.

[0224] 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.

[0225] In one embodiment, the methods further comprise testing a sample (e.g., as set forthherein) 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.

[0226] The methods of treating a cancer described herein relate to the treatment of cancer suchas 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, fibrous histiocytoma 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.

[0227] In some embodiments, the cancer is a hematological cancer, pancreatic cancer, MYHassociated 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. In one embodiment, the cancer is lung 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.

[0228] The methods provided herein can also comprise testing a sample from the patientbefore 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, orpharmaceutically 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.

[0229] 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 such embodiment, the pancreatic cancer, lung cancer, or colorectal cancer comprises a KRasG12Dmutation.

[0230] 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.

[0231] Still further provided herein are methods of treating pancreatic cancer comprising aKRasG12Dmutation 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.

[0232] Still further provided herein are methods of treating colon cancer comprising aKRasG12Dmutation 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 thepatient. In one embodiment, the colon cancer is stage I or II. In another embodiment, the colon cancer is stage III or stage IV.

[0233] In one embodiment of the methods M1, M2, and M3 as described herein, the methodfurther comprises: (a) determining the absence or presence of a KRasG12Dmutation in a sample taken from a patient with a suspected diagnosed cancer; and (b) administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.

[0234] Further provided herein are methods of treating tissue agnostic cancer comprising aKRasG12Dmutation. In one embodiment of such methods, the method comprises: (a) determining the absence or presence of a KRasG12Dmutation in a sample taken from a patient with a suspected diagnosed cancer; and (b) administering to the patient an effective amount of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein.

[0235] In one embodiment of such methods, the patient is diagnosed with a cancer describedherein. 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).

[0236] Also provided herein is a compound or stereoisomer, atropisomer, tautomer, orpharmaceutically 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.

[0237] Further provided herein is a compound or stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of a cancer comprising a KRasG12Dmutation. In some embodiment, provided herein is a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof for use in treating a cancer as disclosed herein. In some embodiment, provided herein is a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof for use in preventing a cancer as disclosed herein. In some embodiment, provided herein is a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof for use ininhibiting tumor metastasis. 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. In some embodiment, provided herein is the use of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as disclosed herein for the manufacture of a medicament for treating a cancer as disclosed herein. In some embodiment, provided herein is the use of a compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof as disclosed herein for the manufacture of a medicament for preventing a cancer as disclosed herein. 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.

[0238] Further provided herein are methods for inhibiting tumor metastasis, the methodcomprising 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.

[0239] Further provided herein are methods for inhibiting proliferation of a cell population, themethod 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.

[0240] 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.

[0241] 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, theactivity 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.

[0242] 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.

[0243] Further provided herein are methods for preparing a labeled KRasG12D mutant 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 the labeled 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.

[0244] Still further provided herein are methods of inhibiting Ras-mediated cell signaling. Inone 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 todownstream signaling molecules including but not limited to Raf. Kits and commercially available assays can be utilized for determining one or more of the above.

[0245] KRas mutations, including G12D mutants, have also been identified in hematologicalmalignancies (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.

[0246] Determining whether a tumor or cancer comprises a KRasG12D mutation can beundertaken 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.

[0247] Methods for detecting a mutation in a KRas nucleotide sequence are known by those ofskill 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, mutant allele-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.

[0248] Methods for determining whether a tumor or cancer comprises a KRasG12D mutationcan use a variety of samples. In some embodiments, the sample is taken from a subject having atumor 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.

[0249] 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

[0250] The compounds or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable 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.

[0251] 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.

[0252] Combination therapies herein comprise the administration of a compound orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof described herein, and the use of at least one other treatment method. The amounts of the compound orstereoisomer, 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.

[0253] In various embodiments of the method, the additional therapeutic agent is an epidermalgrowth 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.

[0254] In some embodiments, the additional therapeutic agent is an epidermal growth factorreceptor (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).

[0255] In still other embodiments, the additional therapeutic agent is an insulin-like growthfactor 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).

[0256] 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.

[0257] In some other embodiments, the additional therapeutic agent is an anti-glypican 3antibody. In some embodiments, the anti-glypican 3 antibody is codrituzumab.

[0258] In some other embodiments, the additional therapeutic agent is an antibody drugconjugate (ADC). In some embodiments, the ADC is polatuzumab vedotin, RG7986, RG7882, RG6109, or RO7172369.

[0259] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist.In some embodiments, the MDM2 antagonist is idasanutlin.

[0260] In some other embodiments, the additional therapeutic agent is an agonistic antibodyagainst CD40. In some embodiments, the agonistic antibody against CD40 is selicrelumab (RG7876).

[0261] 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.

[0262] In some other embodiments, the additional therapeutic agent is a targetedimmunocytokine. In some embodiments, the targeted immunocytokine is RG7813 or RG7461.

[0263] In some other embodiments, the additional therapeutic agent is an antibody targetingcolony stimulating factor-1 receptor (CSF-1R). In some embodiments, the CSF-1R antibody is emactuzumab.

[0264] In some other embodiments, the additional therapeutic agent is a personalized cancervaccine. In some embodiments, the personalized cancer vaccine is RG6180.

[0265] 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.

[0266] In some other embodiments, the additional therapeutic agent is an antibody designed tobind to TIGIT. In some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0267] In some other embodiments, the additional therapeutic agent is a selective estrogenreceptor degrader (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545, giredestrant).

[0268] 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.

[0269] In more embodiments, the additional therapeutic agent is a SRC family non-receptortyrosine 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.

[0270] In yet other embodiments, the additional therapeutic agent is a mitogen-activatedprotein 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.

[0271] 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.

[0272] 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.

[0273] In addition to the above additional therapeutic agent, other chemotherapeutics arepresently 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.

[0274] Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptidesmall 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 methyl melamines 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). Where desired, 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.

[0275] The exact method for administering the compound and the additional therapeutic agentwill 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.

[0276] In some embodiments, the compound and the additional therapeutic agent areadministered 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

[0277] Also provided herein are articles of manufacture, or “kit”, containing materials usefulfor the treatment of a cancer provided herein. In one embodiment, the kit comprises a container comprising compound or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptablesalt 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.

[0278] In another embodiment, the kits are suitable for the delivery of solid oral forms of acompound 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

[0279] The disclosure also includes the following embodiments:

[0280] Embodiment 1. A compound of Formula (I),or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 0, 1 or 2; q is 0 or 1;p is 0, 1, or 2; wherein n + m + q does not exceed 2, and p and q are not simultaneously 1;, wherein each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R2is hydrogen, -CN, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3A is hydrogen, halogen, C1-3alkyl, or C1-3haloalkyl, and R3B is hydrogen; or R3A and R3Bare taken together to form oxo; each of R4Aand R4Bis independently hydrogen, C1-3alkyl, or C1-3haloalkyl; or R4A and R4B are taken together with the atom to which they are bound to form a 3- 6 membered monocyclic ring; R3Cis hydrogen, halogen, C1-3alkyl, or C1-3haloalkyl; R3Dis hydrogen; Z is hydrogen, C1-3alkyl, -L1–Cy, -L1–NR5R6, –OR6, or –SR6; wherein: L1is absent or –C(=O)–; R5 is hydrogen, C1-6alkyl, –NH2; R6is C1-6alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C1-6alkyl; L2is –(CR7AR7B)u–; u is 1, 2 or 3; each R7A and R7B is independently hydrogen or C1-3alkyl; 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, wherein Cy optionally comprises one or more heteroatoms selected from N, O, and S and is optionally substituted with one or more R8; each R8is independently selected from: C1-6alkyl optionally substituted with hydroxyl, C1-3haloalkyl, halogen, hydroxyl, cyano, –C(=O)NR9R10, –C(=O)OR10, C3- 6cycloalkyl, and oxo, wherein R9and R10are independently hydrogen or C1-6alkyl; or R5and R6together with the nitrogen atom to which they are both bonded form a 3 – 6 membered monocyclic ring optionally substituted with one or more groups independently selected from: C1-6alkyl and hydroxyl; orZ and R2together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring; X is –NR11; and R11is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0281] Embodiment 2. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to Embodiment 1, wherein: m is 0; n is 1; p is 1; q is 0; and R3Aand R3Bare both hydrogen.

[0282] Embodiment 3. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to Embodiment 1, wherein: m is 0; n is 0; p is 0; and q is 1.

[0283] Embodiment 4. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-3, wherein X is -NR11and R11is hydrogen.

[0284] Embodiment 5. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-4, wherein no more than one of R01, R02, R03, R04, and R05is hydrogen.

[0285] Embodiment 6. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-5, wherein one of R01, R02, R03, R04, and R05is halogen.

[0286] Embodiment 7. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 6, wherein one of R01, R02, R03, R04, and R05 is fluoro.

[0287] Embodiment 8. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-7, wherein one of R01, R02, R03, R04, and R05 is C1-3haloalkyl.

[0288] Embodiment 9. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-8, wherein one of R01, R02, R03, R04, and R05 is –NH2.

[0289] Embodiment 10. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-9, wherein R1.

[0290] Embodiment 11. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-10, wherein R2is halogen.

[0291] Embodiment 12. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 11, wherein R2 is fluoro or chloro.

[0292] Embodiment 13. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 1, wherein R3A and R3C are both H.

[0293] Embodiment 14. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-13, wherein R4Ais hydrogen and R4Bis methyl.

[0294] Embodiment 15. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-13, wherein R4A is hydrogen and R4B is ethyl.

[0295] Embodiment 16. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-13, wherein R4A and R4B are both methyl.

[0296] Embodiment 17. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-13, wherein R4A is hydrogen and R4B is -CF3.

[0297] Embodiment 18. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-13, wherein R4A and R4B, taken together with the atom to which they are both bound, form an oxetane ring.

[0298] Embodiment 19. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-18, wherein Z is hydrogen.

[0299] Embodiment 20. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-18, wherein Z is C1-3alkyl.

[0300] Embodiment 21. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 20, wherein Z is methyl.

[0301] Embodiment 22. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-18, wherein Z is -L1–Cy.

[0302] Embodiment 23. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 22, wherein L1is absent and Cy is a pyrazole or pyrimidine, wherein said pyrazole is optionally substituted with methyl.

[0303] Embodiment 24. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-18, wherein Z is -L1–NR5R6.

[0304] Embodiment 25. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 24, wherein L1is absent, R5is a hydrogen, and R6is -L2–Cy.

[0305] Embodiment 26. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 25, wherein L2is –CH2– and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridone, thiazole, or quinoline.

[0306] Embodiment 27. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 26, wherein Cy is optionally substituted with one or more R8independently selected from methyl, –CF3, –CHF2, fluoro, hydroxyl, cyano, –CH2OH, –C(=O)OH, –C(=O)OMe, and –C(=O)N(Me)2.

[0307] Embodiment 28. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 25, wherein L2is –CH(CH3)– and Cy is phenyl.

[0308] Embodiment 29. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 24, wherein L1is absent, R5is hydrogen, and R6 is methyl.

[0309] Embodiment 30. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 24, wherein L1is absent, R5is hydrogen, and R6is –C(=O)–Cy.

[0310] Embodiment 31. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 30, wherein Cy is phenyl.

[0311] Embodiment 32. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 29, wherein L1 is absent, R5 is hydrogen, and R6is –C(=O)CH2CH3.

[0312] Embodiment 33. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 24, wherein L1 is –C(=O)–, R5 is -NH2, and R6 is methyl.

[0313] Embodiment 34. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 24, wherein L1 is absent and R5 and R6 are taken together with the nitrogen atom to which they are bound to form an azetidine ring optionally substituted with hydroxyl and methyl.

[0314] Embodiment 35. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-18, wherein Z is –OR6.

[0315] Embodiment 36. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 35, wherein R6 is -L2–Cy, wherein L2is –CH2– and Cy is pyridine.

[0316] Embodiment 37. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-18, wherein Z is –SR6.

[0317] Embodiment 38. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment 37, wherein R6is -L2–Cy, wherein L2 is –CH2– and Cy is pyridine.

[0318] Embodiment 39. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments 1-18, wherein Z and R2 together with the carbon atoms to which they are bonded form a pyrazole.

[0319] Embodiment 40. A compound selected from any one of compounds 1-65 as setforth in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0320] Embodiment 41. A pharmaceutical composition comprising a compound or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-40, and one or more pharmaceutically acceptable excipients.

[0321] Embodiment 42. A method of treating cancer, the method comprising administeringan effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments 1-40, or a pharmaceutical composition of embodiment 41.

[0322] Embodiment 43. The method of embodiment 42, wherein the cancer ischaracterized as comprising a KRas mutation.

[0323] Embodiment 44. The method of embodiment 43, wherein the KRas mutationcorresponds to a KRasG12Dmutation.

[0324] Embodiment 45. The method of any one of embodiments 42-44, further comprisingtesting a sample from the patient before administration for the absence or presence of a KRasG12Dmutation.

[0325] Embodiment 46. The method of embodiment 45, 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.

[0326] Embodiment 47. The method of any one of embodiments 42-46, wherein the canceris tissue agnostic.

[0327] Embodiment 48. The method of any one of embodiments 42-46, wherein the canceris pancreatic cancer, lung cancer, or colorectal cancer.

[0328] Embodiment 49. The method of embodiment 48, wherein the lung cancer is lungadenocarcinoma, NSCLC, or SCLC.

[0329] Embodiment 50. The method of embodiment 48, wherein the cancer is pancreaticcancer.

[0330] Embodiment 51. The method of embodiment 48, wherein the cancer is colorectalcancer.

[0331] Embodiment 52. The method of any one of embodiments 42-51, further comprisingadministering at least one additional therapeutic agent.

[0332] Embodiment 53. The method of embodiment 52, wherein the additional therapeuticagent 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.

[0333] Embodiment 54. A compound according to any one of embodiments 1-40, or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0334] Embodiment 55. Use of a compound of any one of embodiments 1-40, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

[0335] Embodiment 56. Use of a compound according to any one of embodiments 1-40, orstereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0336] Embodiment 57. Use of a compound of any one of embodiments 1-40, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

[0337] Embodiment 58. A compound according to any one of embodiments 1-40, orstereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, for the therapeutic and / or prophylactic treatment of a cancer comprising a KRasG12Dmutation.

[0338] Embodiment 59. A method for regulating activity of a KRas mutant protein, themethod comprising reacting the mutant protein with a compound of any one of embodiments 1- 40, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0339] Embodiment 60. A method for inhibiting proliferation of a cell population, themethod comprising contacting the cell population with the compound of any one of embodiments 1-40, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0340] Embodiment 61. A method of embodiment 60, wherein the inhibition ofproliferation is measured as a decrease in cell viability of the cell population.

[0341] Embodiment 62. A method for inhibiting tumor metastasis comprisingadministering to an individual in need thereof a therapeutically effective amount of the compound of any one of embodiments 1-40, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof to a subject in need thereof.

[0342] Embodiment 63. A compound of any one of embodiments 1-40, or stereoisomer,atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in regulating activity of a KRas mutant protein.

[0343] Embodiment 64. A compound of any one of embodiments 1-40, or stereoisomer,atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting proliferation of a cell population.

[0344] Embodiment 65. The compound, stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt for use of embodiment 64, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0345] Embodiment 66. A compound of any one of embodiments 1-40, or stereoisomer,atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting tumor metastasis.

[0346] Embodiment 67. Use of a compound of any one of embodiments 1-40, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for regulating activity of a KRas mutant protein.

[0347] Embodiment 68. Use of a compound of any one of embodiments 1-40, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting proliferation of a cell population.

[0348] Embodiment 69. The use of embodiment 68, wherein the inhibition ofproliferation is measured as a decrease in cell viability of the cell population.

[0349] Embodiment 70. Use of a compound of any one of embodiments 1-40, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0350] 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 0, 1 or 2; q is 0 or 1; p is 0, 1, or 2; wherein n + m + q does not exceed 2, and p and q are not simultaneously 1;, wherein each of R01, R02, R03, R04, and R05 is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl;R2is hydrogen, -CN, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3A is hydrogen, halogen, C1-3alkyl, or C1-3haloalkyl, and R3B is hydrogen; or R3A and R3Bare taken together to form oxo; each of R4Aand R4Bis independently hydrogen, C1-3alkyl, or C1-3haloalkyl; or R4A and R4B are taken together with the atom to which they are bound to form a 3- 6 membered monocyclic ring; R3Cis hydrogen, halogen, C1-3alkyl, or C1-3haloalkyl; R3D is hydrogen; Z is hydrogen, C1-3alkyl, -L1–Cy, -L1–NR5R6, –OR6, or –SR6; wherein: L1is absent or –C(=O)–; R5 is hydrogen, C1-6alkyl, or –NH2; R6is C1-6alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C1-6alkyl; L2is –(CR7AR7B)u–; u is 1, 2 or 3; each R7Aand R7Bis independently hydrogen or C1-3alkyl; Cy is a 3 – 11 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, wherein Cy optionally comprises one or more heteroatoms selected from N, O, and S and is optionally substituted with one or more R8; each R8is independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; – C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl; or R5 and R6 together with the nitrogen atom to which they are both bonded form a 3 – 6 membered monocyclic ring optionally substituted with one or more groups independently selected from: C1-6alkyl and hydroxyl; or Z and R2 together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring; X is –NR11; and R11is hydrogen, C1-6alkyl, or C1-6haloalkyl.

[0351] Embodiment I-2. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-1, wherein: 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 aspirocyclic ring, wherein Cy optionally comprises one or more heteroatoms selected from N, O, and S and is optionally substituted with one or more R8; each R8is independently selected from: C1-6alkyl optionally substituted with hydroxyl; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl; and oxo; wherein R9 and R10 are independently hydrogen or C1-6alkyl.

[0352] Embodiment I-3. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-1 or I-2, wherein: m is 0; n is 1; p is 1; q is 0; and R3A and R3B are both hydrogen.

[0353] Embodiment I-4. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-1 or I-2, wherein: m is 0; n is 0; p is 0; and q is 1.

[0354] Embodiment I-5. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-4, wherein R11is hydrogen.

[0355] Embodiment I-6. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-5, wherein each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, C1-3alkyl, C1-3haloalkyl, or -NH2.

[0356] Embodiment I-7. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-6, wherein no more than one of R01, R02, R03, R04, and R05 is hydrogen.

[0357] Embodiment I-8. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-7, wherein one of R01, R02, R03, R04, and R05is halogen.

[0358] Embodiment I-9. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-8, wherein one of R01, R02, R03, R04, and R05is fluoro.

[0359] Embodiment I-10. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-9, wherein one of R01, R02, R03, R04, and R05is C1-3haloalkyl.

[0360] Embodiment I-11. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-10, wherein one of R01, R02, R03, R04, and R05 is –NH2.

[0361] Embodiment I-12. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-11, wherein

[0362] Embodiment I-13. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-12, wherein.

[0363] Embodiment I-14. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-13, wherein R2 is halogen.

[0364] Embodiment I-15. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-14, wherein R2is fluoro or chloro.

[0365] Embodiment I-16. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-15, wherein R3Aand R3Care both hydrogen.

[0366] Embodiment I-17. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-16, wherein R4Aand R4Bare both hydrogen.

[0367] Embodiment I-18. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-16, wherein R4Ais hydrogen and R4Bis methyl, ethyl, -CHF2, or -CF3.

[0368] Embodiment I-19. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-16 or I-18, wherein R4Ais hydrogen and R4Bis methyl.

[0369] Embodiment I-20. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-16 or I-18, wherein R4A is hydrogen and R4B is ethyl.

[0370] Embodiment I-21. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-16, wherein R4A and R4B are both methyl.

[0371] Embodiment I-22. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-16 or I-18, wherein R4A is hydrogen and R4B is -CHF2.

[0372] Embodiment I-23. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-16 or I-18, wherein R4A is hydrogen and R4B is -CF3.

[0373] Embodiment I-24. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-16, wherein R4A and R4B, taken together with the atom to which they are both bound, form an oxetane ring.

[0374] Embodiment I-25. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-24, wherein Z is hydrogen.

[0375] Embodiment I-26. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-24, wherein Z is C1-3alkyl.

[0376] Embodiment I-27. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-26, wherein Z is methyl.

[0377] Embodiment I-28. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-24, wherein Z is -L1–Cy.

[0378] Embodiment I-29. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-28, wherein Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2- a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine,imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0379] Embodiment I-30. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-29, wherein Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2- a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0380] Embodiment I-31. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-30, wherein Cy is pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5- a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H- pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1- c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9 and R10 are independently hydrogen or C1-6alkyl.

[0381] Embodiment I-32. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-30, wherein Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, or quinoline; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0382] Embodiment I-33. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-30, wherein Cy is 1- azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro- 1H-pyrrolizine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0383] Embodiment I-34. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-28, wherein L1 is absent and Cy is a pyrazole or pyrimidine, wherein said pyrazole is optionally substituted with methyl.

[0384] Embodiment I-35. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-24, wherein Z is -L1–NR5R6.

[0385] Embodiment I-36. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-35, wherein L1 is absent, R5 is a hydrogen, and R6 is -L2–Cy.

[0386] Embodiment I-37. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-36, wherein L2is –CH2– and wherein Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0387] Embodiment I-38. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-36-I-37, wherein L2is – CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2- a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0388] Embodiment I-39. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-36-I-38, wherein Cy is pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5- a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H- pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1- c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9 and R10 are independently hydrogen or C1-6alkyl.

[0389] Embodiment I-40. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-36-I-37, wherein Cy is 1- azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro- 1H-pyrrolizine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

[0390] Embodiment I-41. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-37-I-40, wherein each R8is independently selected from: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chloro, fluoro, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxy, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0391] Embodiment I-42. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-36-I-37, wherein Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2- a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1- b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine.

[0392] Embodiment I-43. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-36, I-37-I-39, or I-42, wherein Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3- dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0393] Embodiment I-44. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-36-I-37, wherein L2is – CH2– and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridone, thiazole, or quinoline; wherein said Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; – C(=O)OR10; C3-6cycloalkyl; and oxo; wherein each of R9 and R10 is independently hydrogen or C1-6alkyl.

[0394] Embodiment I-45. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-44, wherein each R8 is independently selected from methyl, –CF3, –CHF2, fluoro, hydroxyl, cyano, –CH2OH, – C(=O)OH, –C(=O)OMe, and –C(=O)N(Me)2.

[0395] Embodiment I-46. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-44, wherein Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridone, thiazole, or quinoline.

[0396] Embodiment I-47. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-36-I-37, wherein Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4- thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2- a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2- a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1- yl)pyridine, wherein Cy is optionally substituted with one or more R8 independently selectedfrom: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; cyano; oxo; –C(=O)OR10; and C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl.

[0397] Embodiment I-48. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-47, wherein each R8is independently –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chloro, fluoro, oxo, –C(=O)OH, cyano, cyclopropyl substituted with –CH2OH, or cyclopropyl.

[0398] Embodiment I-49. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-47, wherein Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5- a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4- thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2- a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1- yl)pyridine.

[0399] Embodiment I-50. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-36 wherein L2 is – CH(CH3)– and Cy is phenyl.

[0400] Embodiment I-51. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-35, wherein L1 is absent, R5 is hydrogen, and R6is methyl.

[0401] Embodiment I-52. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-35, wherein L1 is absent, R5 is hydrogen, and R6is methyl, –C(=O)–phenyl or –C(=O)CH2CH3.

[0402] Embodiment I-53. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-35, wherein L1 is absent, R5 is hydrogen, and R6 is –C(=O)–Cy.

[0403] Embodiment I-54. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-53, wherein Cy is phenyl.

[0404] Embodiment I-55. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-35 or I-52, wherein L1is absent, R5is hydrogen, and R6is –C(=O)CH2CH3.

[0405] Embodiment I-56. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-35, wherein L1 is –C(=O)–, R5is -NH2, and R6is methyl.

[0406] Embodiment I-57. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-35, wherein L1 is absent and R5 and R6 are taken together with the nitrogen atom to which they are bound to form an azetidine ring optionally substituted with hydroxyl and methyl.

[0407] Embodiment I-58. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-24, wherein Z is –OR6or –SR6.

[0408] Embodiment I-59. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-24 or I-58, wherein Z is –OR6.

[0409] Embodiment I-60. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-59, wherein R6 is -L2–Cy, wherein L2is –CH2– and Cy is pyridine.

[0410] Embodiment I-61. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-24 or I-58, wherein Z is –SR6.

[0411] Embodiment I-62. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to embodiment I-61, wherein R6is -L2–Cy, wherein L2 is –CH2– and Cy is pyridine.

[0412] Embodiment I-63. The compound or a stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof according to any one of embodiments I-1-I-24, wherein Z and R2 together with the carbon atoms to which they are bonded form a pyrazole.

[0413] Embodiment I-64. A compound selected from any one of compounds 1-146 as setforth in Table 1 or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0414] Embodiment I-65. A pharmaceutical composition comprising a compound or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments I-1-I-64, and one or more pharmaceutically acceptable excipients.

[0415] Embodiment I-66. A method of treating cancer, the method comprising administeringan effective amount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of embodiments I-1-I-64, or a pharmaceutical composition of embodiment I-65.

[0416] Embodiment I-67. The method of embodiment I-66, wherein the cancer ischaracterized as comprising a KRas mutation.

[0417] Embodiment I-68. The method of embodiment I-67, wherein the KRas mutationcorresponds to a KRasG12Dmutation.

[0418] Embodiment I-69. The method of any one of embodiments I-66-I-68, furthercomprising testing a sample from the patient before administration for the absence or presence of a KRasG12Dmutation.

[0419] Embodiment I-70. The method of embodiment I-69, 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.

[0420] Embodiment I-71. The method of any one of embodiments I-66-I-70, wherein thecancer is tissue agnostic.

[0421] Embodiment I-72. The method of any one of embodiments I-66-I-70, wherein thecancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0422] Embodiment I-73. The method of embodiment I-72, wherein the lung cancer is lungadenocarcinoma, NSCLC, or SCLC.

[0423] Embodiment I-74. The method of embodiment I-72, wherein the cancer is pancreaticcancer.

[0424] Embodiment I-75. The method of embodiment I-72, wherein the cancer is colorectalcancer.

[0425] Embodiment I-76. The method of any one of embodiments I-66-I-75, furthercomprising administering at least one additional therapeutic agent.

[0426] Embodiment I-77. The method of embodiment I-76, wherein the additionaltherapeutic 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.

[0427] Embodiment I-78. A compound according to any one of embodiments I-1-I-64, or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0428] Embodiment I-79. A compound according to any one of embodiments I-1-I-64, or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use for use in treating cancer.

[0429] Embodiment I-80. The compound for use according to embodiment I-79, wherein thecancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0430] Embodiment I-81. Use of a compound according to any one of embodiments I-1-I-64,or stereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, in the manufacture of a medicament for treating cancer.

[0431] Embodiment I-82. The use according to embodiment I-81 wherein the cancer ispancreatic cancer, lung cancer, or colorectal cancer.

[0432] Embodiment I-83. Use of a compound of any one of embodiments I-1-I-64, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

[0433] Embodiment I-84. Use of a compound according to any one of embodiments I-1-I-64,or stereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0434] Embodiment I-85. Use of a compound of any one of embodiments I-1-I-64, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

[0435] Embodiment I-86. A compound according to any one of embodiments I-1-I-64, orstereoisomer, atropisomer, tautomer, or pharmaceutically salt thereof, for the therapeutic and / or prophylactic treatment of a cancer comprising a KRasG12Dmutation.

[0436] Embodiment I-87. A method for a) regulating activity of a KRas mutant protein, b)inhibiting proliferation of a cell population, or c) inhibiting tumor metastasis; wherein the method for regulating activity of a KRas mutant protein comprises reacting the mutant protein with a compound of any one of embodiments I-1-I-64, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof; wherein the method for inhibiting proliferation of a cell population, the method comprises contacting the cell population with the compound of any one of embodiments I-1-I-64, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof; and wherein the method for inhibiting tumor metastasis comprises administering to an individual in need thereof a therapeutically effective amount of the compound of any one of embodiments I-1-I-64, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof to a subject in need thereof.

[0437] Embodiment I-88. A method for regulating activity of a KRas mutant protein, themethod comprising reacting the mutant protein with a compound of any one of embodiments I- 1-I-64, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0438] Embodiment I-89. A method for inhibiting proliferation of a cell population, themethod comprising contacting the cell population with the compound of any one of embodiments I-1-I-64, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0439] Embodiment I-90. A method of embodiment I-87 or I-89, wherein the inhibition ofproliferation is measured as a decrease in cell viability of the cell population.

[0440] Embodiment I-91. A method for inhibiting tumor metastasis comprisingadministering to an individual in need thereof a therapeutically effective amount of the compound of any one of embodiments I-1-I-64, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof to a subject in need thereof.

[0441] Embodiment I-92. A compound of any one of embodiments I-1-I-64, or stereoisomer,atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in a) regulating activity of a KRas mutant protein, b) inhibiting proliferation of a cell population, or c) inhibiting tumor metastasis.

[0442] Embodiment I-93. A compound of any one of embodiments I-1-I-64, or stereoisomer,atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in regulating activity of a KRas mutant protein.

[0443] Embodiment I-94. A compound of any one of embodiments I-1-I-64, or stereoisomer,atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting proliferation of a cell population.

[0444] Embodiment I-95. The compound, stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt for use of embodiment I-92 or I-94, wherein the inhibition of proliferation is measured as a decrease in cell viability of the cell population.

[0445] Embodiment I-96. A compound of any one of embodiments I-1-I-64, or stereoisomer,atropisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in inhibiting tumor metastasis.

[0446] Embodiment I-97. Use of a compound of any one of embodiments I-1-I-64, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a) regulating activity of a KRas mutant protein, b) inhibiting proliferation of a cell population, or c) for inhibiting tumor metastasis.

[0447] Embodiment I-98. Use of a compound of any one of embodiments I-1-I-64, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for regulating activity of a KRas mutant protein.

[0448] Embodiment I-99. Use of a compound of any one of embodiments I-1-I-64, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting proliferation of a cell population.

[0449] Embodiment I-100. The use of embodiment I-97 or I-99, wherein the inhibition ofproliferation is measured as a decrease in cell viability of the cell population.

[0450] Embodiment I-101. Use of a compound of any one of embodiments I-1-I-64, orstereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis. Exemplary Embodiments

[0451] Provided below are exemplary embodiments of the invention.

[0452] Abbreviations used herein are as follows: Ac = acetyl; HATU = hexafluorophosphateazabenzotriazole tetramethyl uronium; DIPEA = N,N-Diisopropylethylamine; EtOAc = ethyl acetate; DMSO = dimethyl sulfoxide; DCM = dichloromethane; ACN = acetonitrile; FA = formic acid; HEX = hexane; ETOH = ethanol; THF = tetrahydrofuran; TBAF = tetra-n- butylammonium fluoride; Bn = benzyl; DCE = 1,2-dichloroethane; TMEDA = tetramethylethylenediamine; LDA = lithium diisopropylamide; DMF = N,N-dimethylformamide; Ts = tosyl; TFA = trifluoroacetic acid; LiHMDS = lithium bis(trimethylsilyl)amide; DAST = diethylaminosulfur trifluoride; TTMSS = tris(trimethylsilyl)silane; dtbbpy = 4,4 ′-Di-tert-butyl- 2,2 ′-dipyridyl; TBS / TBDMS = tert-butyldimethylsilyl; DMAP = 4-dimethylaminopyridine; DPPA = diphenylphosphoryl azide; DBU = 1,8-diazabicyclo [5.4.0]undec-7-ene; PMB = para- methoxybenzyl; NIS = N-Iodosuccinimide; Pin = pinacolato; dppf = 1,1 ′- Bis(diphenylphosphino)ferrocene; DMA = dimethylacetamide; DME = 1,2-dimethoxyethane; Boc = tert-butyloxycarbonyl; BrOP = bromotris(dimethylamino)phosphonium hexafluorophosphate; BINAP = 2,2 ′-bis(diphenylphosphino)-1,1 ′-binaphthyl; dba = dibenzylideneacetone; DIAD = diisopropyl azodicarboxylate. Examples

[0453] The following Examples are presented by way of illustration, not limitation.

[0454] Example 1 – Preparation of Intermediates:

[0455] Intermediate 1: tert-Butyl (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0456] Intermediate 1 was prepared as described in WO2023 / 225302A1, the entire disclosureof which is incorporated by reference herein (see intermediate 4 in WO2023 / 225302A1).

[0457] Intermediate 2: (5-(Bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid

[0458] Intermediate 2 was prepared as described in WO2023 / 225302A1, the entire disclosureof which is incorporated by reference herein (see intermediate 20 in WO2023 / 225302A1).

[0459] Intermediate 3: tert-Butyl (8R,11S,11aS,12S)-4-bromo-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido[3,2- f][1,4]oxazepine-14-carboxylate

[0460] Step 1: 2-((S)-1-((1S,2S,5R)-8-(tert-Butoxycarbonyl)-3,8-diazabicyclo [3.2.1] octan-2-yl) ethoxy)-6-chloro-5-fluoronicotinic acid

[0461] Under nitrogen, to a solution of tert-butyl (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (610 mg, 2.38 mmol, intermediate 1) in tetrahydrofuran (5.00 mL) was added NaH (476 mg, 11.9 mmol, 60% in mineral oil) at 0 ℃. The resulting solution was stirred for 30 min at 0°C. Then 2,6-dichloro-5-fluoronicotinic acid (500 mg, 2.38 mmol) was added and the solution was stirred at room temperature overnight. The solution was quenched with water and concentrated under vacuum to afford 1.28 g (crude)of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 430. The crude was used for next step without further purification.

[0462] Step 2: tert-Butyl (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido[3,2-f][1,4]oxazepine-14- carboxylate

[0463] To a solution of 2-((S)-1-((1S,2S,5R)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo [3.2.1]octan-2-yl) ethoxy)-6-chloro-5-fluoronicotinic acid (1.28 g, 2.98 mmol) and DIPEA (1.15 g, 8.93 mmol) in N, N -dimethylacetamide (35.0 mL) was added HATU (1.36 g, 3.57 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 h. The reaction 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: 0-50% EtOAc in petroleum ether) to afford 429 mg (35% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 412.

[0464] Step 3: tert-Butyl (8R,11S,11aS,12S)-4-bromo-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11, 11a,12- hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido [3,2-f] [1,4] oxazepine- 14-carboxylate

[0465] Under nitrogen, to a solution of tert-butyl (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido [3,2-f] [1,4] oxazepine-14-carboxylate (900 mg, 2.19 mmol) in tetrahydrofuran (6.00 mL) was added MeLi (2.73 mL, 1.6 M in diethyl ether) at -78 ℃, and the mixture was stirred at -78 ℃ for 1 h. Then 1,2-dibromo-1,1,2,2-tetrachloroethane (1.07 g, 3.28 mmol) in tetrahydrofuran (7.50 mL) was added at -78 ℃ dropwise. The mixture was gradually warmed to room temperature and stirred at room temperature for an additional 1 hour. The reaction was quenched with aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The combined organic layers weredried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-40% EtOAc in petroleum ether) to afford 669 mg (62% yield) of the title compound as a pink solid. LC-MS: (ESI, m / z): [M+H]+= 490.

[0466] Intermediate 4: tert-Butyl (8R,11S,11aS,12S)-2-(5-(bis(4-methoxybenzyl) amino)-4-fluoro-3-methyl-2-(trifluoromethyl) phenyl)-4-bromo-3-fluoro-12-methyl-5-oxo- 8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido [3,2-f] [1,4] oxazepine - 14-carboxylate

[0467] Step1: tert-Butyl (8R,11S,11aS,12S)-2-(5-(bis(4-methoxybenzyl) amino)-4-fluoro-3-methyl-2-(trifluoromethyl) phenyl)-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro- 5H,7H-8,11-epiminoazepino[2,1-c]pyrido[3,2-f][1,4]oxazepine-14-carboxylate

[0468] Under nitrogen, a solution of tert-butyl (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido [3,2- f][1,4]oxazepine-14-carboxylate (409 mg, 0.990 mmol, intermediate 3, step 2), (5-(bis(4- methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (948 mg, 1.99 mmol, intermediate 2), CataCXium® A Pd G3(145 mg, 0.200 mmol) and K3PO4(1.66 mL, 1.5 M in water) in tetrahydrofuran (8.30 mL) was stirred at 60 ℃ for 1 h. The solution was dilutedwith 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: 0-55% EtOAc in petroleum ether) to afford 698 mg (87% yield) of the title compound as a pale yellow solid. LC-MS: (ESI, m / z): [M+H]+= 809.

[0469] Step 2: tert-Butyl (8R,11S,11aS,12S)-2-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-bromo-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12- hexahydro-5H,7H-8,11-epiminoazepino[2,1-c]pyrido[3,2-f][1,4]oxazepine-14-carboxylate (intermediate 4) & tert-butyl (8R,11S,11aS,12S)-2-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3- methyl-2-(trifluoromethyl)phenyl)-3-fluoro-4,12-dimethyl-5-oxo-8,9,10,11,11a,12-hexahydro- 5H,7H-8,11-epiminoazepino[2,1-c]pyrido[3,2-f][1,4]oxazepine-14-carboxylate (byproduct)

[0470] Under nitrogen, to a solution of tert-butyl (8R,11S,11aS,12S)-2-(5-(bis(4-methoxybenzyl) amino)-4-fluoro-3-methyl-2-(trifluoromethyl) phenyl)-3-fluoro-12-methyl-5- oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido[3,2-f] [1,4] oxazepine-14-carboxylate (500 mg, 0.620 mmol) in tetrahydrofuran (10.0 mL) was added MeLi (0.770 mL, 1.6 M in diethyl ether) at -78 ℃, and the solution was stirred at -78 ℃ for 1 h. Then 1,2-dibromo-1,1,2,2-tetrachloroethane in tetrahydrofuran (2.00 mL) was added dropwise at -78 ℃. The mixture was warmed to room temperature and stirred for an additional 1 hour. 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 (gradient: 0-50% EtOAc in petroleum ether) to afford 324 mg (59% yield) of the title compound as a yellow solid (contained 12% by- product) LC-MS: (ESI, m / z): [M+H]+= 887. The mixture was used for the synthesis of analogues without further purification.

[0471] Intermediate 5: tert-Butyl (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0472] Intermediate 5 was prepared as described in WO2023 / 225302A1, the entire disclosureof which is incorporated by reference herein (see intermediate 3 in WO2023 / 225302A1).

[0473] Intermediate 6: tert-Butyl (1R,2S,5S)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate

[0474] Intermediate 6 was prepared as described in WO2023 / 225302A1, the entire disclosureof which is incorporated by reference herein (see intermediate 163 in WO2023 / 225302A1).

[0475] Intermediate 7: tert-Butyl (8R,11S,11aS)-2-chloro-12-ethyl-3-fluoro-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido [3,2-f] [1,4] oxazepine- 14-carboxylate (single unknown stereoisomer)

[0476] Step 1: 3-Benzyl 8-(tert-butyl) (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate

[0477] Under nitrogen, to a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-formyl-3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylate (3.01 g, 8.04 mmol) (intermediate 6, step 2, the faster peak) in tetrahydrofuran (45 mL) was added EtMgBr (3 M in Et2O, 14 mL, 42 mmol) at -78oC. The solution was stirred at -78oC for 1.5 h. Then the reaction was quenched with aqueous NH4Cl solution at -78oC and the mixture was gradually warmed up to room temperature. The reaction solution was 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: 0-17% EtOAc / petroleum ether) to afford 2.02 g (62% yield) of the title compound (only a single isomer was obtained) as a colorless oil. LC-MS: (ESI, m / z): [M+H]+= 405.

[0478] Step 2: tert-Butyl (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0479] Under hydrogen (1 atm), a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-(1-hydroxypropyl) -3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (2.02 g, 4.99 mmol) and Pd / C (10%, 551 mg) in methanol (50 mL) was stirred at room temperature for 1.5 h. Then the Pd / C was removed by filtration. The filtrate was concentrated under vacuum to afford 1.12 g (crude) of the title compound as colorless oil. LC-MS: (ESI, m / z): [M+H]+= 271.

[0480] Step 3: 2-(1-((1S,2S,5R)-8-(tert-Butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-2-yl)propoxy)-6-chloro-5-fluoronicotinic acid

[0481] Under nitrogen, to a solution of tert-butyl (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 2.22 mmol) in tetrahydrofuran (20 mL) was added NaH (60% in mineral oil, 551 mg) at 0oC and the solution was stirred at room temperature for 0.5 hour. Then to the resulting solution was added 2,6-dichloro-5- fluoronicotinic acid (743 mg, 3.54 mmol) at 0oC. The solution was stirred at room temperature for 5 h. 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 C18 column (solvent gradient: 0-50%ACN in water (0.1% FA)) to afford 410 mg (42% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 444.

[0482] Step 4: tert-Butyl (8R,11S,11aS)-2-chloro-12-ethyl-3-fluoro-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido[3,2-f][1,4]oxazepine-14-carboxylate

[0483] A solution of 2-(1-((1S,2S,5R)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo [3.2.1] octan-2-yl) propoxy)-6-chloro-5-fluoronicotinic acid (360 mg, 0.811 mmol), HATU (617 mg, 1.62 mmol) and DIPEA (630 mg, 4.88 mmol) in N,N-dimethylacetamide (16 mL) was stirred at room temperature for 16 h. Then the reaction was diluted with brine 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: 0-18% EtOAc / petroleum ether) to afford 240 mg (70% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 426.

[0484] Intermediate 8: tert-Butyl (8R,11S,11aS)-2-chloro-12-ethyl-3-fluoro-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c]pyrido[3,2-f][1,4]oxazepine-14- carboxylate (intermediate 7, single unknown stereoisomer)

[0485] Step 1: 3-Benzyl 8-(tert-butyl) (1S,2S,5R)-2-propionyl-3,8-diazabicyclo [3.2.1]octane-3,8-dicarboxylate

[0486] Under nitrogen, to a solution of oxalyl dichloride (1.17 g, 9.2mmol) in dichloromethane (20 mL) was added a solution of DMSO (1.22 g, 15.6 mmol) in dichloromethane (20 mL) dropwise slowly at -78oC. After stirring at -78oC for 15 min, a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo [3.2.1] octane-3,8-dicarboxylate (1.51 g, 3.73 mmol, intermediate 7, step 1) in dichloromethane (15 mL) was added dropwise slowly at -78oC. After stirring at -78oC for 15 min, Et3N (2.42 g, 24.0 mmol) was added. The resulting solution was then warmed to room temperature and stirred for 1 h. 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: 0-20% EtOAc / petroleum ether) to afford 1.24 g (83% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H]+= 403.

[0487] Step 2: tert-Butyl (6R,9S,9aS)-1-ethyl-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4-a] azepine-10-carboxylate

[0488] To a solution of 3-benzyl 8-(tert-butyl) (1S,2S,5R)-2-propionyl-3,8-diazabicyclo [3.2.1]octane-3,8-dicarboxylate (1.24 g, 3.08 mmol) in methanol (13 mL) was added NaBH4(0.37 g, 9.74 mmol), and the mixture was stirred at room temperature for 0.5 h. Then the solution was stirred at 60oC for 2 h. The solution was concentrated under vacuum. The residue was diluted with brine, 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: 0-35% EtOAc / petroleum ether) to afford 820 mg (90% yield) of the title compound as colorless oil. LC-MS: (ESI, m / z): [M+H]+= 297.

[0489] Step 3: tert-Butyl (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0490] To a solution of tert-butyl (6R,9S,9aS)-1-ethyl-3-oxohexahydro-1H,3H-6,9-epiminooxazolo [3,4-a] azepine-10-carboxylate (820 mg, 2.77 mmol) in ethanol (10 mL) was added a solution of NaOH (2.41 g, 60.3 mmol) in water (4 mL). The solution was stirred at 80oC for 6 h. The solution was concentrated under vacuum. Then the residue was diluted with DCM. The solid was removed by filtration and the filtrate was concentrated under vacuum to afford 700 mg (crude) of the title compound as a brown oil. LC-MS: (ESI, m / z): [M+H]+= 271. The crude product was used for the next step without further purification.

[0491] Step 4: 2-(1-((1S,2S,5R)-8-(tert-Butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-2-yl)propoxy)-6-chloro-5-fluoronicotinic acid

[0492] Under nitrogen, to a solution of tert-butyl (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (320 mg, 1.18 mmol) in tetrahydrofuran (15 mL) was added NaH (60% in mineral oil, 291 mg) at 0oC, and the solution was stirred at room temperature for 0.5 h. Then 2,6-dichloro-5-fluoronicotinic acid (403 mg, 1.92 mmol) was added at 0oC. The solution was stirred at room temperature for 5 h. 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 reverse phase chromatography with C18 column (solvent gradient: 0-40% ACN in water (0.1% FA)) to afford 240 mg (46% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 444.

[0493] Step 5: tert-Butyl (8R,11S,11aS)-2-chloro-12-ethyl-3-fluoro-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido [3,2-f] [1,4] oxazepine-14-carboxylate

[0494] A solution of 2-(1-((1S,2S,5R)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo [3.2.1] octan-2-yl)propoxy)-6-chloro-5-fluoronicotinic acid (240 mg, 0.541 mmol), HATU (410 mg, 1.08 mmol) and DIPEA (437 mg, 3.39 mmol) in N,N-dimethylacetamide (6 mL) was stirred at roomtemperature for 6 h. Then to the reaction mixture was added brine, and the mixture was 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: 0-18% EtOAc / petroleum ether) to get the mixture of two diastereomers. The diastereomers were separated by prep-Chiral-HPLC (Column: CHIRALPAK® IF, 2*25 cm, 5 μm; Mobile Phase A: HEX(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 220 / 254 nm; RT1(min): 6.159; RT2(min): 7.505; Sample Solvent: EtOH; Injection Volume: 0.3 mL; Number Of Runs: 13) to afford 105 mg (the faster peak, intermediate 7) and 27 mg (the slower peak, intermediate 8) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 426.

[0495] Intermediate 9: tert-Butyl (1R,5S)-2-(2-hydroxypropan-2-yl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate

[0496] Step 1: tert-Butyl (1R,5S)-8-benzyl-3,8-diazabicyclo [3.2.1] octane-3-carboxylate

[0497] 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 solution was stirred at room temperature for 1.5 h. 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- 20% EtOAc / petroleum ether) to afford 12.8 g (90% yield) of the title compound as a light yellow oil. LC-MS: (ESI, m / z): [M+H]+= 303.

[0498] Step 2: 3-(tert-Butyl) 2-isopropyl (1R,5S)-8-benzyl-3,8-diazabicyclo [3.2.1] octane-2,3-dicarboxylate

[0499] 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) were added N1,N1,N2,N2-tetramethylethane-1,2-diamine (7.69 g, 66.2 mmol) and s-BuLi (51.2 mL, 66.6 mmol, 1.3 M in cyclohexane) at -78oC. The solution was stirred at -78oC for 1 h. Then to the resulting solution was added isopropyl carbonochloridate (8.05 g, 65.7 mmol) at -78oC. The resulting solution was then warmed to room temperature gradually and stirred for additional 1.5 h. 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 (gradient: 0-15% EtOAc / petroleum ether) to afford 8.93 g (70% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H]+= 389.

[0500] Step 3: (6S,9R)-10-Benzyl-1,1-dimethylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one (two isomers)

[0501] 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) at -20oC. The solution was gradually warmed to room temperature and stirred 16 more hours. 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: 0-40% EtOAc / petroleum ether) to get the mixture of two diastereomers. The mixture was separated by Prep-Chiral-SFC (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; Wave Length: 220 nm; RT1(min): 6.2; RT2(min): 9; Sample Solvent: MeOH; Injection Volume: 3 mL) to afford 2.37 g (the faster peak) and 2.33 g (the slower peak) as a white solid. LC-MS: (ESI, m / z): [M+H]+= 287.

[0502] Step 4: (6S,9R)-1,1-Dimethylhexahydro-1H,3H-6,9-epiminooxazolo[3,4-a]azepin-3-one

[0503] Under hydrogen (1 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) (the faster peak of last step) and Pd / C (10%, 652 mg) in methanol (80 mL) was stirred at room temperature for 2 h. Then the Pd / C was removed by filtration. The filtrate was concentrated under vacuum to afford 1.52 g (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 197.

[0504] Step 5: tert-Butyl (6S,9R)-1,1-dimethyl-3-oxohexahydro-1H,3H-6,9-epiminooxazolo[3,4-a] azepine-10-carboxylate

[0505] 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), Boc2O (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 h. The solution was diluted with brine, 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 (90% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 297.

[0506] Step 6: tert-Butyl (1R,5S)-2-(2-hydroxypropan-2-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0507] 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 h. The solution was concentrated under vacuum. The residue was diluted with DCM. The solid was removed by filtration, and the filtrate was concentrated under vacuum to afford 892 mg (crude) of the titlecompound as yellow solid. LC-MS: (ESI, m / z): [M+H]+= 271. The crude was used for next step without further purification.

[0508] Intermediate 10: tert-Butyl (1R,5S)-2-(2-hydroxypropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (the enantiomer of intermediate 9)

[0509] Analogous to method described as intermediate 9, 920 mg of the title compound wasobtained from 2.33 g the slower peak of intermediate 9-step 3.

[0510] Intermediate 11: tert-Butyl (1S,4S)-6-(2,2,2-trifluoro-1-hydroxyethyl)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

[0511] Step 1: tert-Butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl) pyrrolidine-1-carboxylate

[0512] Under nitrogen, to a solution of 1-(tert-butyl) 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (30.1 g, 123 mmol) in THF (500 mL) was added LiAlH4 (58.9 mL, 2.5M in THF) at 0oC. The resulting solution was stirred for 2 h at room temperature. The reaction was quenched with Na2SO4∙10H2O. After filtration, the filtrate was concentrated under reducedpressure to afford 15.6 g (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 218. The crude was used for next step without further purification.

[0513] Step 2: tert-Butyl (2S,4R)-2-(((tert-butyldimethylsilyl) oxy) methyl)-4-hydroxypyrrolidine-1-carboxylate

[0514] Under nitrogen, a solution of tert-butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (40.5 g, 186 mmol) in DCM (300 mL) was added 2,6-lutidine (20.1 g, 187 mmol) at room temperature. The reaction system was cooled to -78oC and TBDMSOTf (39.4 g, 149 mmol) was added. The reaction was stirred at -78oC for 1 h. The reaction was diluted with water 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: 0-40% EtOAc in petroleum ether) to afford 18.9 g (31% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H]+= 332.

[0515] Step 3: tert-Butyl (2S,4R)-2-(((tert-butyldimethylsilyl) oxy) methyl)-4-(tosyloxy)pyrrolidine-1-carboxylate

[0516] A solution of tert-butyl (2S,4R)-2-(((tert-butyldimethylsilyl) oxy) methyl)-4-hydroxypyrrolidine-1-carboxylate (32.6 g, 98.3 mmol) in pyridine (400 mL) was added TsCl (56.1 g, 295 mmol) at room temperature, and the mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-50% EtOAc in petroleum ether) to afford 36.2 g (76% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 486.

[0517] Step 4: tert-Butyl (2S,4R)-2-(hydroxymethyl)-4-(tosyloxy) pyrrolidine-1-carboxylate

[0518] A solution of tert-butyl (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(tosyloxy)pyrrolidine-1-carboxylate (36.2 g, 74.5 mmol) in THF (300 mL) was added TBAF(212 mL, 1M in THF), and the mixture was stirred at room temperature for 3 h. The resulting reaction was diluted with EtOAc, washed with water. The 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%-80% EtOAc in petroleum ether) to afford 15.1 g (55% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 372.

[0519] Step 5: tert-Butyl (2S,4R)-2-formyl-4-(tosyloxy)pyrrolidine-1-carboxylate

[0520] Under nitrogen, to a solution of DMSO (16.9 g, 216 mmol) in DCM (500 mL) wasadded (COCl)2(13.8 g, 108 mmol) at -70oC. The resulting solution was stirred for 0.5 h at -70oC. Then tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(tosyloxy) pyrrolidine-1-carboxylate (20.2 g, 54.3 mmol) was added, and the mixture was stirred at -70oC for 1 h. Then Et3N (33.1 g, 328 mmol) was added. The reaction system was gradually warmed to room temperature, and the mixture was stirred an additional 1 hour. The solution was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 18.2 g (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 370.

[0521] Step 6: tert-Butyl (2S,4R)-2-((S)-(benzylamino) (cyano)methyl)-4-(tosyloxy)pyrrolidine-1-carboxylate

[0522] To a solution of tert-butyl (2S,4R)-2-formyl-4-(tosyloxy) pyrrolidine-1-carboxylate(27.6 g, 74.7 mmol) in THF (300 mL) was added diethyl phosphorocyanidate (14.6 g, 89.5 mmol) and BnNH2(19.9 g, 186 mmol). The resulting solution was stirred at room temperature for 16 h. The solution was 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 (gradient: 0%-50% EtOAc in petroleum ether) to afford 22.5 g (62% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 486.

[0523] Step 7: tert-Butyl (1S,4S)-5-benzyl-6-cyano-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate

[0524] A solution of tert-butyl (2S,4R)-2-((S)-(benzylamino) (cyano)methyl)-4-(tosyloxy)pyrrolidine -1-carboxylate (22.3 g, 45.9 mmol) and DIPEA (29.5 g, 228 mmol) in DCE (300 mL) was stirred at 85 °C for 18 h. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting (gradient: 0%-40% EtOAc in petroleum ether) to afford 3.71 g (26% yield) of the faster peak and 6.21 g (43% yield) of the slower peak as yellow oil. LC-MS: (ESI, m / z): [M+H]+= 314.

[0525] faster peak: 1H NMR (500 MHz, DMSO- d6, ppm) δ 7.44 – 7.21 (m, 5H), 4.40 (d, J =16.3 Hz, 1H), 3.88 (d, J = 13.5 Hz, 1H), 3.74 (dd, J = 13.5, 4.4 Hz, 1H), 3.67 – 3.58 (m, 2H), 3.48 (d, J = 9.5 Hz, 1H), 3.10 (dd, J = 16.1, 10.5 Hz, 1H), 1.97 (d, J = 10.1 Hz, 1H), 1.89 (dd, J = 15.9, 10.4 Hz, 1H), 1.44 (s, 9H).

[0526] slower peak: 1H NMR (500 MHz, DMSO- d6, ppm) δ 7.44 – 7.23 (m, 5H), 4.52 (d, J =42.4 Hz, 1H), 3.88 – 3.79 (m, 2H), 3.69 (d, J = 13.5 Hz, 1H), 3.51 (s, 1H), 3.30 – 3.13 (m, 2H), 1.88 (d, J = 10.4 Hz, 1H), 1.85 – 1.70 (m, 1H), 1.41 (s, 9H).

[0527] Step 8: 2-(tert-Butyl) 6-methyl (1S,4S)-5-benzyl-2,5-diazabicyclo [2.2.1] heptane-2,6-dicarboxylate

[0528] A solution of tert-butyl (1S,4S)-5-benzyl-6-cyano-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (6.21 g, 19.8 mmol) (the slower peak of last step) in MeOH (100 mL) was added MeONa (5.66 g, 104 mmol) and the solution was stirred at 60 °C for 6 h. Then HCl (62 mL, 3 N) was added at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction was quenched with aqueous NaHCO3. The solution 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 eluting (gradient: 0%-50% EtOAc in petroleum ether) to afford 3.32 g (48% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+ = 347.

[0529] Step 9: tert-Butyl (1S,4S)-5-benzyl-6-(hydroxymethyl)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate

[0530] Under nitrogen, to a solution of 2-(tert-butyl) 6-methyl (1S,4S)-5-benzyl-2,5-diazabicyclo [2.2.1] heptane-2,6-dicarboxylate (3.31 g, 9.55 mmol) in THF (100 mL) was added LiAlH4 (5.2 mL, 2.5M in THF) at 0oC. The resulting solution was stirred for 1 h at 0oC. The reaction was quenched with Na2SO4∙10H2O. After filtration, the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-90% EtOAc in petroleum ether) to afford 2.89 g (crude) of the title compound as a colorless oil. LC- MS: (ESI, m / z): [M+H]+= 319. The crude was used for next step without further purification.

[0531] Step 10: tert-Butyl (1S,4S)-5-benzyl-6-formyl-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

[0532] Under nitrogen, to a solution of DMSO (2.83 g, 36.2 mmol) in DCM (100 mL) wasadded (COCl)2 (2.31 g, 18.2mmol) at -70oC. The resulting solution was stirred for 0.5 h at -70oC. Then tert-butyl (1S,4S)-5-benzyl-6-(hydroxymethyl)-2,5-diazabicyclo [2.2.1] heptane-2- carboxylate (2.89 g, 9.08 mmol) was added, and the mixture was stirred at -70oC for 1 h. Then Et3N (5.49 g, 54.3 mmol) was added, and the mixture was stirred at room temperature for 1h. The solution was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 2.81 g (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 317. The crude was used for next step without further purification.

[0533] Step 11: tert-Butyl (1S,4S)-5-benzyl-6-(2,2,2-trifluoro-1-((trimethylsilyl) oxy) ethyl)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

[0534] Under nitrogen, to a solution of tert-butyl (1S,4S)-5-benzyl-6-formyl-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (2.81 g, 8.88 mmol) in DMF (80 mL) was added LiOAc (588 mg, 8.91 mmol) and trimethyl(trifluoromethyl)silane (2.52 g, 17.7 mmol). The solution was stirred at room temperature for 1.5 h. The reaction system was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum to afford 3.81 g (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 459. The crude was used for next step without further purification.

[0535] Step 12: tert-Butyl (1S,4S)-5-benzyl-6-(2,2,2-trifluoro-1-hydroxyethyl)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate

[0536] To a solution of tert-butyl (1S,4S)-5-benzyl-6-(2,2,2-trifluoro-1-((trimethylsilyl) oxy)ethyl)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (3.81 g, 8.31 mmol) in THF (100 mL) was added TBAF (5.7 mL, 1 M in THF), and the mixture was stirred at room temperature for 1 h. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (gradient: 0-50 % EtOAc in petroleum ether) to afford 1.31 g (41% yield) the faster peak and 1.25 g (39% yield) the slower peak as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 387.

[0537] The faster peak: 1H NMR (500 MHz, DMSO- d6, ppm) δ 7.32 (m, 4H), 7.23 (t, J = 6.6Hz, 1H), 6.10 (dd, J = 29.5, 6.3 Hz, 1H), 4.53 (s, 1H), 3.57 (t, J = 12.3 Hz, 3H), 3.15 (d, J = 25.3 Hz, 2H), 3.02 – 2.70 (m, 2H), 1.88 (t, J = 11.8 Hz, 1H), 1.55 – 1.49 (m, 1H), 1.41 (s, 9H).

[0538] The slower peak: 1H NMR (500 MHz, DMSO- d6, ppm) 7.46 – 7.21 (m, 5H), 6.33 –5.80 (m, 1H), 4.32 (d, J = 25.4 Hz, 1H), 3.85- 3.80 (m, 2H), 3.58 (dd, J = 19.1, 13.2 Hz, 1H), 3.28 – 3.04 (m, 2H), 2.93 (dd, J = 35.7, 9.0 Hz, 2H), 1.95 (d, J = 10.1 Hz, 1H), 1.56 (d, J = 10.2 Hz, 1H), 1.39 (s, 9H).

[0539] Step 13: tert-Butyl (1S,4S)-6-(2,2,2-trifluoro-1-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0540] Under H2 (4 atm), to a solution of tert-butyl (1S,4S)-5-benzyl-6-(2,2,2-trifluoro-1-hydroxyethyl)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (1.25 g, 3.23 mmol) (the faster peak of last step) in MeOH (10 mL) was added Pd(OH)2 / C (1.25 g) and the solution was stirred for 6 h at room temperature. After filtration, the filtrate was concentrated under reduced pressure to afford 921 mg (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 297. The crude was used for next step without further purification.

[0541] Intermediate 12: tert-Butyl (1S,4S)-6-(2,2,2-trifluoro-1-hydroxyethyl)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylate (The other isomer of intermediate 11)

[0542] Analogous to method described as above, this isomer was synthesized from the slowerpeak of intermediate 11, step 12.

[0543] Intermediate 13: tert-Butyl 2-(3-hydroxyoxetan-3-yl)-3,8-diazabicyclo [3.2.1] octane-

[0544] Step 1: 10’-Benzylhexahydro-3’H-spiro[oxetane-3,1’-[6,9]epiminooxazolo[3,4-a]azepin]-3’-one

[0545] Under nitrogen, to a solution of tert-butyl 8-benzyl-3,8-diazabicyclo [3.2.1] octane-3-carboxylate (5.00 g, 16.5 mmol), TMEDA (3.84 g, 33.1 mmol) in diethyl ether (70 mL) was added s-BuLi (13.3 mL, 2.5 M in hexane) at -78 °C, and the mixture was stirred at -78 °C for 1 h. Then oxetan-3-one (2.38 g, 33.1 mmol) was added at -78 °C, and the mixture was stirred at - 78 °C for 10 min. The solution was warmed to room temperature and stirred overnight. 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 (gradient: 0-20% EtOAc in petroleum ether) to afford 1.41 g of mixture product as a yellow oil. The mixture was separated by Chiral- Prep-HPLC with the following conditions (Column: CHIRALPAK® ID, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MEOH; Flow rate: 100 mL / min; Gradient: isocratic 30% B; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 4.3; RT2(min): 6.5; Sample Solvent: MeOH) to yield 625 mg (13% yield) the faster peak and 637 mg (13% yield) the slower peak as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 301.

[0546] The faster peak: 1H NMR (300 MHz, DMSO-d6, ppm): δ 7.52 – 7.17 (m, 5H), 4.85 –4.55 (m, 4H), 4.22 – 4.09 (m, 1H), 3.63 – 3.48 (m, 3H), 3.36 (d, 1H), 3.16 – 3.06 (m, 1H), 3.01 (d, J = 12.4, 2.3 Hz, 1H), 2.12 – 1.78 (m, 2H), 1.49 – 1.28 (m, 1H), 1.11 – 0.93 (m, 1H).

[0547] The slower peak: 1H NMR (300 MHz, DMSO-d6, ppm): δ 7.52 – 7.18 (m, 5H), 4.85 –4.57 (m, 4H), 4.22 – 4.11 (m, 1H), 3.63 – 3.47 (m, 3H), 3.43 – 3.37 (m, 1H), 3.18 – 3.07 (m, 1H), 3.06 – 2.97 (m, 1H), 2.11 – 1.82 (m, 2H), 1.48 – 1.31 (m, 1H), 1.11 – 0.92 (m, 1H).

[0548] Step 2: tert-Butyl 3’-oxohexahydro-3’H-spiro[oxetane-3,1’- [6,9] epiminooxazolo [3,4-a] azepine] -10’-carboxylate

[0549] Under hydrogen (4 atm), to a solution of 10’-benzylhexahydro-3’H-spiro[oxetane-3,1’-[6,9]epiminooxazolo[3,4-a]azepin]-3’-one (575 mg, 1.91 mmol) (the faster peak of last step) in MeOH (10 mL) was added Pd / C (288 mg). The solution was stirred at room temperature for 2 h. Then Boc2O (581 mg, 2.67 mmol) was added, and the mixture was stirred at room temperature for 2 more hours. After filtration, the solution was concentrated under vacuum to afford 698 mg (crude) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 311. The crude was used for next step without further purification.

[0550] Step 3: tert-Butyl 2-(3-hydroxyoxetan-3-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate

[0551] To a solution of tert-butyl 3’-oxohexahydro-3’H-spiro[oxetane-3,1’- [6,9]epiminooxazolo [3,4-a]azepine]-10’-carboxylate (688 mg, 2.22 mmol) in EtOH (7.5 mL) and water (2.5 mL) was added NaOH (355 mg, 8.88 mmol). The solution was stirred at 80 °C for 2 h. The solution was cooled to room temperature and concentrated under vacuum. The solid was washed with DCM and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 702 mg (crude) of the title compound as a white solid. LC- MS: (ESI, m / z): [M+H]+= 285.1H NMR (400 MHz, DMSO-d6, ppm): δ 5.89 (s, 1H), 4.70 – 4.54 (m, 1H), 4.51 – 4.24 (m, 3H), 4.08 – 3.84 (m, 2H), 2.92 (s, 1H), 2.80 (d, J = 12.6 Hz, 1H), 2.63 (d, J = 12.6 Hz, 1H), 2.28 (s, 1H), 2.02 (s, 1H), 1.74 (s, 2H), 1.61 (s, 1H), 1.42 (s, 9H). The crude was used for next step without further purification.

[0552] Intermediate 14: tert-Butyl 2-(3-hydroxyoxetan-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (the other isomer of intermediate 13)

[0553] Analogous to method described as above, this isomer was synthesized from the slowerpeak of intermediate 13, step 1.

[0554] Intermediate 15: 5-(Aminomethyl)-N, N-dimethylpicolinamide

[0555] Step 1: 5-(((tert-Butoxycarbonyl) amino) methyl) picolinic acid

[0556] To a solution of 5-(aminomethyl) pyridine-2-carboxylic acid (680 mg, 4.47 mmol) andDIPEA (2.89 g, 22.4 mmol) in dichloromethane (15 mL) was added di-tert-butyl dicarbonate (1.95 g, 8.94 mmol). The resulting mixture was stirred at 25oC for 1 h. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column (solvent gradient: 0–60 % acetonitrile in water (1% formic acid)) to afford 350 mg (31% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 253.

[0557] Step 2: tert-Butyl N-[[6-(dimethylcarbamoyl)-3-pyridyl] methyl] carbamate

[0558] To a solution of 5-[(tert-butoxycarbonylamino) methyl] pyridine-2-carboxylic acid(490mg, 1.94mmol) and DIPEA (1.26 g, 9.71 mmol) in N, N-Dimethylformamide (6 mL) was added HATU (1.48 mg, 3.88 mmol) and N,N-dimethylamine hydrochloride (317 mg, 3.88 mmol). The resulting mixture was stirred at 25oC for 1 h. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column(solvent gradient: 0-80% ACN in water (0.05% NH4HCO3)) to afford 170 mg (31% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 280.

[0559] Step 3: 5-(Aminomethyl)-N, N-dimethylpicolinamide TFA salt

[0560] A solution of tert-Butyl N-[[6-(dimethylcarbamoyl)-3-pyridyl] methyl] carbamate (200mg, 0.720 mmol) in 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 20 mins. The resulting mixture was diluted with CH2Cl2(4 mL) and concentrated under reduced pressure to afford the title compound 110 mg (crude) as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 180. The crude was used for next step without further purification.

[0561] Intermediate 16: (1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl) methanamine

[0562] Step 1: 1-Methyl-4-(trifluoromethyl)-1H-pyrazole-3-carboxamide

[0563] To a solution of 1-methyl-4-(trifluoromethyl) pyrazole-3-carboxylic acid (240 mg, 1.24mmol) and DIPEA (799 mg, 6.18 mmol) in N, N-dimethylformamide (5mL) was added HATU (940 mg, 2.47 mmol) and NH4Cl (265 mg, 4.95 mmol). The resulting mixture was stirred at 25oC for 1 h. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column (solvent gradient: 0-80% ACN in water (0.05% NH4HCO3)) to afford 220 mg (92% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+=194.

[0564] Step 2: (1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl) methanamine

[0565] To a solution of 1-methyl-4-(trifluoromethyl) pyrazole-3-carboxamide (270 mg, 1.40mmol) in tetrahydrofuran (3 mL) was added LiAlH4 (2.8 mL, 1M in THF) dropwise at 0oC, and the mixture was stirred at 60oC for 2 h. The reaction was quenched with Na2SO4.10H2O and filtered over celite. The filtrate was concentrated under vacuum to afford 210 mg (crude) of the title compound as a white solid LC-MS: (ESI, m / z): [M+H]+=180. The crude was used for next step without further purification.

[0566] Intermediate 17: (1-(Difluoromethyl)-1H-pyrazol-3-yl) methanamine

[0567] Step 1: 1-(Difluoromethyl)-1H-pyrazole-3-carboxamide

[0568] To a solution of 1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (500 mg, 3.08mmol) and DIPEA (1.99 g, 15.4 mmol) in N, N-dimethylformamide (13 mL) was added HATU (2.34 g, 6.17 mmol) and NH4Cl (660 mg, 12.3 mmol). The resulting mixture was stirred at 25oC for 1 h. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column (solvent gradient: 0-80% ACN in water (0.05% NH4HCO3)) to afford 450 mg (91% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+=162.

[0569] Step 2: (1-(Difluoromethyl)-1H-pyrazol-3-yl) methanamine

[0570] To a solution of 1-(difluoromethyl) pyrazole-3-carboxamide (300 mg, 1.86 mmol) intetrahydrofuran (3 mL) was added LiAlH4 (3.7 mL, 1M in THF) dropwise at 0oC, and the mixture was stirred at 60oC for 2 h. The reaction was quenched with Na2SO4.10H2O and filtered over celite. The filtrate was concentrated under vacuum to afford 180 mg (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+=148. The crude was used for next step without further purification.

[0571] Intermediate 18: (4-Fluoro-1-methyl-1H-pyrazol-3-yl) methanamine

[0572] Step 1: 4-Fluoro-1-methyl-1H-pyrazole-3-carboxamide

[0573] To a solution of 4-fluoro-1-methyl-pyrazole-3-carboxylic acid (200 mg, 1.39mmol) and DIPEA (897 mg, 6.94 mmol) in N, N-dimethylformamide (5mL) was added HATU (1.05 g, 2.78 mmol) and NH4Cl (297 mg, 5.55 mmol). The resulting mixture was stirred at 25oC for 2 h. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column (solvent gradient: 0-80% ACN in water (0.05% NH4HCO3)) to afford 180 mg (91% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+=144.

[0574] Step 2: (4-Fluoro-1-methyl-1H-pyrazol-3-yl) methanamine

[0575] To a solution of 4-fluoro-1-methyl-pyrazole-3-carboxamide (390 mg, 2.72mmol) in tetrahydrofuran (6 mL) was added LiAlH4 (5.4 mL, 1M in THF) dropwise at 0oC, and the mixture was stirred at 60oC for 2 h. The reaction was quenched with Na2SO4.10H2O and filtered over celite. The filtrate was concentrated under vacuum to afford 210 mg (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+=130. The crude was used for next step without further purification.

[0576] Intermediate 19: (1-Cyclopropyl-1H-pyrazol-3-yl) methanamine

[0577] Step 1: 1-Cyclopropyl-1H-pyrazole-3-carboxamide

[0578] To a solution of 1-cyclopropyl-1H-pyrazole-3-carboxylic acid (100 mg, 0.66 mmol),DIPEA (129 mg, 3.29 mmol) in N, N-dimethylformamide (10 mL) was added HATU (502 mg, 1.32 mmol) and NH4Cl (106 mg, 1.98 mmol). The resulting mixture was stirred for 2 h at room temperature. The solution 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 to afford 90.0 mg (crude) of the title compound as a brown solid LC-MS: (ESI, m / z): [M+H]+= 152.

[0579] Step 2: (1-Cyclopropyl-1H-pyrazol-3-yl) methanamine

[0580] To a solution of 1-cyclopropyl-1H-pyrazole-3-carboxamide (90.0 mg, 0.60 mmol) intetrahydrofuran (5 mL) was added LiAlH4(1.20 mL, 1M in THF) at 0oC, and the mixture was stirred at 60oC for 2 h. The reaction was quenched with Na2SO4.10H2O. After filtration, the filtrate was collected and concentrated under vacuum to afford 68.0 mg (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 138. The crude was used for next step without further purification.

[0581] Intermediate 20: tert-Butyl (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino)-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11- epiminoazepino [2,1-c] pyrido[3,2-f] [1,4] oxazepine-14-carboxylate

[0582] Step 1: tert-Butyl (8R,11S,11aS,12S)-4-bromo-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11, 11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c]pyrido[3,2-f][1,4]oxazepine-14- carboxylate

[0583] Under nitrogen, to a solution of tert-butyl (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c]pyrido[3,2-f][1,4] oxazepine -14-carboxylate (3.62 g, 8.79 mmol, intermediate 3, step 2) in tetrahydrofuran (70 mL) was added LDA (10.1 mL, 21.8 mmol) at -78 ℃. The resulting solution was stirred at - 78℃ for 1 h. Then, 1,2-dibromo-1,1,2,2-tetrachloroethane (4.29 g, 13.2 mmol) in tetrahydrofuran (7 ml) was added at -78℃, and the mixture stirred at room temperature for 1 h. The reaction was quenched with aq. 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 (gradient: 0%-30% EtOAc / petroleum ether) to afford 1.73 g (40.1% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 490.

[0584] Step 2: tert-Butyl (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-4-(((1-methyl-1H-pyrazol-3-yl) methyl) amino)-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11- epiminoazepino[2,1-c]pyrido [3,2-f][1,4]oxazepine-14-carboxylate

[0585] To a solution of tert-butyl (8R,11S,11aS,12S)-4-bromo-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-epiminoazepino[2,1-c] pyrido[3,2- f][1,4]oxazepine-14-carboxylate (1.13 g, 2.30 mmol) and DIPEA (742 mg, 5.76 mmol) in 1,4- dioxane (10 mL) was added (1-methyl-1H-pyrazol-3-yl)methanamine (768 mg, 6.91 mmol) at room temperature. and the mixture was stirred at rt for 1 h, and the resulting solution was partitioned between water and 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%-100% EtOAc / petroleum ether) to afford 1.08 g (90% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 521.

[0586] Intermediate 21: Pyrazolo[1,5-a]pyrazin-2-ylmethanamine

[0587] Step 1: 3-Bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide

[0588] A solution of 3-bromo-1H-pyrazole-5-carboxylic acid (3.00 g, 15.7 mmol), 2,2-dimethoxyethan-1-amine (1.20 g, 18.8 mmol), HATU (8.96 g, 23.6 mmol) and DIPEA (6.09 g, 47.1 mmol) in DMF (35 mL) was stirred at 25 °C for 1 hour. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column (solvent gradient: 0-17% ACN in water (0.05% NH4HCO3)) to afford 1.80 g (41.2% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 278.

[0589] Step 2: 2-Bromo-7-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0590] A solution of 3-bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide (1.80 g,6.47 mmol), TsOH (1.67 g, 9.71 mmol) in acetone (30 mL) and water (3 mL) was stirred at 70oC for 2 hours. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column (solvent gradient: 0-20% ACN in water (0.05% NH4HCO3)) to afford 650 mg (43.3% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 232.

[0591] Step 3: 2-Bromopyrazolo[1,5-a] pyrazin-4(5H)-one

[0592] A solution of 2-bromo-7-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (650mg, 2.80 mmol) in TFA (7 mL) was stirred at 80 °C for 2 hours. The resulting mixture was concentrated under reduced pressure to afford 580 mg (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+=214. The crude product was used in the next step without further purification.

[0593] Step 4: tert-Butyl ((4-hydroxypyrazolo[1,5-a]pyrazin-2-yl)methyl)carbamate

[0594] Under nitrogen, a solution of 2-bromopyrazolo[1,5-a]pyrazin-4(5H)-one (580 mg, 2.71mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (1.42 g, 5.96 mmol), cataCXium® A Pd G3 (395 mg, 0.542 mmol) and Cs2CO3 (5.30 g, 16.3 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was stirred at 100oC overnight. The resulting solution was partitioned between water and 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%-90% EtOAc / petroleum ether) to afford 490 mg (68.2% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 265.

[0595] Step 5: (4-Chloropyrazolo[1,5-a]pyrazin-2-yl)methanamine

[0596] A solution of tert-butyl ((4-hydroxypyrazolo[1,5-a]pyrazin-2-yl)methyl)carbamate (490mg, 1.85 mmol) in DCE (4 mL) and POCl3 (2 mL) was stirred at 80oC for 3 hours. The resulting mixture was concentrated under reduced pressure to afford 200 mg (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 183. The crude product was used in the next step without further purification.

[0597] Step 6: tert-Butyl ((4-chloropyrazolo[1,5-a]pyrazin-2-yl)methyl)carbamate

[0598] To a solution of (4-chloropyrazolo[1,5-a]pyrazin-2-yl)methanamine (150 mg, 0.820mmol) and DIPEA (1.06 g, 8.22 mmol) in DCM (4 mL) was added (Boc)2O (358 mg, 1.64 mmol) at 0oC. The solution was stirred at room temperature for 1.5 hours. The resulting solution was partitioned between water and 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%-25% EtOAc / petroleum ether) to afford 50.0 mg (21.5% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 283.

[0599] Step 7: tert-Butyl (pyrazolo[1,5-a]pyrazin-2-ylmethyl)carbamate

[0600] Under nitrogen, a solution of tert-butyl ((4-chloropyrazolo[1,5-a] pyrazin-2-yl)methyl)carbamate (50.0 mg, 0.177 mmol), sodium formate (18.0 mg, 0.265 mmol), and Pd(PPh3)4 (10.2 mg, 0.009 mmol) in DMF (3 mL) was stirred at 120oC for 2 hours. The resulting solution was partitioned between water and 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%-40% EtOAc / petroleum ether) to afford 25.0 mg (56.7% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 249.

[0601] Step 8: Pyrazolo[1,5-a]pyrazin-2-ylmethanamine

[0602] A solution of tert-butyl (pyrazolo[1,5-a]pyrazin-2-ylmethyl)carbamate (25.0 mg, 0.10mmol) in DCM (1 mL) and TFA (0.3 mL) was stirred at 25oC for 1 hour. The resulting mixture was concentrated under reduced pressure to afford 14.0 mg (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 149. The crude product was used in the next step without further purification.

[0603] Intermediate 22: 4-(Aminomethyl)-1-methyl-1H-pyrazole-5-carbonitrile

[0604] Step 1: tert-Butyl ((5-cyano-1-methyl-1H-pyrazol-4-yl)methyl)carbamate

[0605] A solution of 4-bromo-1-methyl-1H-pyrazole-5-carbonitrile (400 mg, 2.15 mmol),potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (1.53 g, 6.45 mmol),cataCXium® A Pd G3 (313 mg, 0.430 mmol), and Cs2CO3 (2.10 g, 6.45 mmol) in 1,4-dioxane(24 mL) and H2O (4 mL) was stirred at 100 ℃ for 1 hour. 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, eluting (gradient: 0-50% EtOAc / petroleum ether) to afford 290 mg (56.9% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 237.

[0606] Step 2: 4-(Aminomethyl)-1-methyl-1H-pyrazole-5-carbonitrile

[0607] A solution of tert-butyl ((5-cyano-1-methyl-1H-pyrazol-4-yl)methyl)carbamate (290mg, 1.22 mmol) in HCl (5 mL, 4 M in 1,4-dioxane) was stirred at room temperature for 1 hour. The solution was concentrated under vacuum to afford 200 mg (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 137. The crude product was used in the next step without further purification.

[0608] Intermediate 23: Pyrazolo[1,5-c]pyrimidin-2-ylmethanamine

[0609] Step 1: tert-Butyl (2-oxo-3-(pyrimidin-4-yl)propyl)carbamate

[0610] Under nitrogen, to a solution of ethyl (tert-butoxycarbonyl)glycinate (1.00 g, 4.90mmol) and 4-methylpyrimidine (466 mg, 4.90 mmol) in tetrahydrofuran (20 mL) was added LiHMDS (9.8 mL, 1 M in THF) at 0 °C. The resulting solution was stirred at 0 °C for 0.5 hour and then at room temperature for 3 hours. The resulting solution was partitioned between water and 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%-15% MeOH / DCM) to afford 1.10 g (89.1% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 252.

[0611] Step 2: tert-Butyl (Z)-(2-(hydroxyimino)-3-(pyrimidin-4-yl)propyl)carbamate

[0612] A solution of tert-butyl (2-oxo-3-(pyrimidin-4-yl)propyl)carbamate (1.10 g, 4.37mmol), hydroxylamine hydrochloride (1.30 g, 18.8 mmol) and sodium hydroxide (3.5 mL, 2.8 M in water) in methanol (20 mL) was stirred at 80oC for 3 hours. The resulting mixture was concentrated under reduced pressure. The resulting solution was partitioned between water and 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%-10% MeOH / DCM) to afford 550 mg (47.1% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 267.

[0613] Step 3: tert-Butyl (pyrazolo[1,5-c]pyrimidin-2-ylmethyl)carbamate

[0614] Under nitrogen, to a solution of tert-butyl (Z)-(2-(hydroxyimino)-3-(pyrimidin-4-yl)propyl)carbamate (550 mg, 2.06 mmol) in 1,2-dimethoxyethane (10 mL) were added 2,2,2- trifluoroacetic anhydride (433 mg, 2.06 mmol) and Et3N (418 mg, 4.13 mmol) at 0 °C. The resulting solution was stirred at 25 °C for 2 hours. Then, FeCl2(55.0 mg, 0.434 mmol) was added, and the resulting solution was stirred additional 2 hours at 80 °C. The resulting solution was partitioned between water and 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%-19% MeOH / DCM) to afford 80 mg (15.6% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 249.

[0615] Step 4: Pyrazolo[1,5-c]pyrimidin-2-ylmethanamine

[0616] A solution of tert-butyl (pyrazolo[1,5-c]pyrimidin-2-ylmethyl)carbamate (80.0 mg,0.321 mmol) in dichloromethane (3 mL) and TFA (1 mL) was stirred at 25oC for 1 hour. The resulting mixture was concentrated under reduced pressure to afford 45.0 mg (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 149. The crude product was used in the next step without further purification.

[0617] Intermediate 24: Pyrazolo[1,5-a]pyrimidin-2-ylmethanamine

[0618] Step 1: tert-Butyl (pyrazolo[1,5-a]pyrimidin-2-ylmethyl)carbamate

[0619] Under nitrogen, a solution of potassium (((tert-butoxycarbonyl) amino) methyl)trifluoroborate (793 mg, 3.33 mmol), 2-bromopyrazolo[1,5-a]pyrimidine (300 mg, 1.51 mmol), CataCXium® A Pd G3(221 mg, 0.300 mmol), and Cs2CO3(2.96 g, 9.09 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred for 1 hour at 100oC. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column (solvent gradient: 0-100% ACN in water (0.05% NH4HCO3)) to afford 250 mg (79.8% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 249.

[0620] Step 2: Pyrazolo[1,5-a]pyrimidin-2-ylmethanamine

[0621] A solution of tert-butyl (pyrazolo[1,5-a]pyrimidin-2-ylmethyl)carbamate (250 mg, 1.01mmol) in 2,2,2-trifluoroacetic acid (2.5 mL) and dichloromethane (5 mL) was stirred for 1 hour at room temperature. The reaction was concentrated under vacuum to afford 150 mg (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 149. The crude product was used in the next step without further purification.

[0622] Intermediate 25: Imidazo[2,1-b]oxazol-6-ylmethanamine

[0623] Step 1: 2-(3-(2-Iminooxazol-3(2H)-yl)-2-oxopropyl)isoindoline-1,3-dione

[0624] A solution of oxazol-2-amine (100 mg, 1.19 mmol) and 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (335 mg, 1.19 mmol) in THF (2 mL) and ACN (3 mL) was stirred at roomtemperature for 26 hours. After filtration, the solids were collected and dried under vacuum to afford 270 mg (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 286. The crude product was used in the next step without further purification.

[0625] Step 2: 2-(Imidazo[2,1-b]oxazol-6-ylmethyl)isoindoline-1,3-dione

[0626] Under nitrogen, to a solution of 2-(3-(2-iminooxazol-3(2H)-yl)-2-oxopropyl)isoindoline-1,3-dione (270 mg, crude) in toluene (3 mL) was added TiCl4 (358 mg, 1.89 mmol) at 0 ℃. The resulting solution was stirred for 10 h at 100 ℃. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were concentrated under vacuum to afford 130 mg (crude) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 268. The crude product was used in the next step without further purification.

[0627] Step 3: Imidazo[2,1-b]oxazol-6-ylmethanamine

[0628] To a solution of 2-(imidazo[2,1-b]oxazol-6-ylmethyl)isoindoline-1,3-dione (120 mg,crude) in EtOH (5 mL) was added N2H4•H2O (140 mg, 80%) at room temperature. The resulting solution was stirred for 1 h at 120 ℃ in a microwave reactor. The reaction mixture was cooled to room temperature. After filtration, the filtrate was concentrated under vacuum to afford 82.3 mg (crude) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 138. The crude product was used in the next step without further purification.

[0629] Intermediate 26: (5-(Difluoromethyl)-1-methyl-1H-pyrazol-3-yl)methanamine

[0630] Step 1: 3-Bromo-5-(difluoromethyl)-1-methyl-1H-pyrazole

[0631] Under nitrogen, to a solution of 3-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (500mg, 2.64 mmol) in dichloromethane (15 mL) was added diethylaminosulfur trifluoride(DAST)(1.28 g, 7.95 mmol) at -10℃. The solution was stirred at room temperature for 2 hours. The reaction was quenched with aq. NaHCO3 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 500 mg (89.7% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H]+= 211.

[0632] Step 2: tert-Butyl ((5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)methyl)carbamate

[0633] Under nitrogen, a solution of 3-bromo-5-(difluoromethyl)-1-methyl-1H-pyrazole (500mg, 2.37 mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (1.69 g, 7.13mmol), cataCXium® A Pd G3 (345 mg, 0.474 mmol), and Cs2CO3 (2.33 g, 7.17 mmol) in 1,4-dioxane (24 mL) and H2O (4 mL) was stirred at 100 ℃ for 1 hour. The reaction 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: 0-50% EtOAc / petroleum ether) to afford 370 mg (59.5% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 262.

[0634] Step 3: (5-(Difluoromethyl)-1-methyl-1H-pyrazol-3-yl)methanamine

[0635] A solution of tert-butyl ((5-(difluoromethyl)-1-methyl-1H-pyrazol-3-yl)methyl)carbamate (370 mg, 1.41 mmol) in HCl (5 mL, 4 M in 1,4-dioxane) was stirred at room temperature for 1 hour. The solution was concentrated under vacuum to afford 120 mg (crude) of the title compound as a brown solid. LC-MS: (ESI, m / z): [M+H]+= 162. The crude product was used in the next step without further purification.

[0636] Intermediate 27: 3-(Aminomethyl)-1-methyl-1H-pyrazole-5-carbonitrile

[0637] Step 1: tert-Butyl ((5-cyano-1-methyl-1H-pyrazol-3-yl)methyl)carbamate

[0638] Under nitrogen, a solution of 3-bromo-1-methyl-1H-pyrazole-5-carbonitrile (400 mg,2.15 mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (1.53 g, 6.45mmol), cataCXium® A Pd G3 (315 mg, 0.432 mmol), and Cs2CO3 (2.10 g, 6.45 mmol) in 1,4-dioxane (24 mL) and H2O (4 mL) was stirred at 100 ℃ for 1 hour. The reaction was diluted with water and extracted with ethyl acetate. 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 140 mg (27.4% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 237.

[0639] Step 2: 3-(Aminomethyl)-1-methyl-1H-pyrazole-5-carbonitrilee

[0640] A solution of tert-butyl ((5-cyano-1-methyl-1H-pyrazol-3-yl)methyl)carbamate (140mg, 0.590 mmol) in HCl (4 mL, 4 M in 1,4-dioxane) was stirred at room temperature for 1 hour. The solution was concentrated under vacuum to afford 100 mg (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 137. The crude product was used in the next step without further purification.

[0641] Intermediate 28: (5-Fluoro-1-methyl-1H-pyrazol-3-yl)methanamine

[0642] Step 1: tert-Butyl ((5-fluoro-1-methyl-1H-pyrazol-3-yl)methyl)carbamate

[0643] Under nitrogen, a solution of 5-fluoro-3-iodo-1-methyl-1H-pyrazole (400 mg, 1.77mmol), Cs2CO3 (2.31 g, 7.08 mmol), potassium (((tert- butoxycarbonyl)amino)methyl)trifluoroborate (1.26 g, 5.31 mmol), and cataCXium® A Pd G3(258 mg, 0.354 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 80 ℃ for 4 h. The resulting solution was partitioned between water and 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%-40% EtOAc / petroleum ether) to afford 198 mg (48.6% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 230.

[0644] Step 2: (5-Fluoro-1-methyl-1H-pyrazol-3-yl)methanamine

[0645] A solution of tert-butyl ((5-fluoro-1-methyl-1H-pyrazol-3-yl)methyl)carbamate (198mg, 0.861 mmol) in HCl (5 mL, 4 M in 1,4-dioxane) was stirred at room temperature for 1 hour. The solvent was concentrated under vacuum to afford 142 mg (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H]+= 130. The crude product was used in the next step without further purification.

[0646] Intermediate 29: (6-(Methoxymethyl)pyridin-3-yl)methanamine

[0647] Step 1: tert-Butyl ((6-(methoxymethyl)pyridin-3-yl)methyl)carbamate

[0648] Under nitrogen, a solution of 5-bromo-2-(methoxymethyl)pyridine (216 mg, 1.07mmol), potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (813 mg, 3.43 mmol), cataCXium® A Pd G3 (156 mg, 0.214 mmol), and Cs2CO3(1.39 g, 4.28 mmol) in 1,4-dioxane (12 mL) and water (2 mL) was stirred at 100 ℃ for 1 hour. The reaction was diluted with water and extracted with ethyl acetate. 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%-10% MeOH / DCM) to afford 258 mg (95.3% y...

Claims

Attorney Dkt. No.: 000218-0084-WO1 CLAIMS What is claimed is:

1. A compound of Formula (I),(I) or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 0, 1 or 2; q is 0 or 1; p is 0, 1, or 2; wherein n + m + q does not exceed 2, and p and q are not simultaneously 1; R1is , wherein each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R2is hydrogen, -CN, halogen, C1-3alkyl, C1-3haloalkyl, or cyclopropyl; R3A is hydrogen, halogen, C1-3alkyl, or C1-3haloalkyl, and R3B is hydrogen; or R3A and R3B are taken together to form oxo; each of R4Aand R4Bis independently hydrogen, C1-3alkyl, or C1-3haloalkyl; or R4Aand R4Bare taken together with the atom to which they are bound to form a 3- 6 membered monocyclic ring; R3Cis hydrogen, halogen, C1-3alkyl, or C1-3haloalkyl; R3Dis hydrogen;Z is hydrogen, C1-3alkyl, -L1–Cy, -L1–NR5R6, –OR6, or –SR6; wherein: L1is absent or –C(=O)–; R5is hydrogen, C1-6alkyl, or –NH2; R6 is C1-6alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C1-6alkyl; L2 is –(CR7AR7B)u–; u is 1, 2 or 3; each R7A and R7B is independently hydrogen or C1-3alkyl; Cy is a 3 – 11 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, wherein Cy optionally comprises one or more heteroatoms selected from N, O, and S and is optionally substituted with one or more R8 ; each R8is independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; – C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl; or R5and R6together with the nitrogen atom to which they are both bonded form a 3 – 6 membered monocyclic ring optionally substituted with one or more groups independently selected from: C1-6alkyl and hydroxyl; or Z and R2together with the carbon atoms to which they are bonded form a 5 – 6 membered monocyclic aromatic ring; X is –NR11; and R11is hydrogen, C1-6alkyl, or C1-6haloalkyl.

2. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 1, wherein: 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, wherein Cy optionally comprises one or more heteroatoms selected from N, O, and S and is optionally substituted with one or more R8; each R8is independently selected from: C1-6alkyl optionally substituted with hydroxyl; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl; and oxo; wherein R9 and R10 are independently hydrogen or C1-6alkyl.

3. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 1 or 2, wherein R11is hydrogen.

4. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-3, wherein each of R01, R02, R03, R04, and R05is independently hydrogen, halogen, C1-3alkyl, C1-3haloalkyl, or -NH2.

5. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-4, wherein no more than one of R01, R02, R03, R04, and R05 is hydrogen.

6. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-5, wherein R2 is halogen.

7. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-6, wherein R3Aand R3Care both H.

8. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-7, wherein R4A and R4B are both hydrogen.

9. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-7, wherein R4A is hydrogen and R4B is methyl, ethyl, -CHF2, or -CF3.

10. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-9, wherein Z is hydrogen.

11. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-9, wherein Z is C1-3alkyl.

12. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-9, wherein Z is -L1–Cy.

13. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 12, wherein Cy is imidazole, phenyl, pyridine, 2- oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3- thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3- triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy- C1-6alkyl; and oxo; wherein R9 and R10 are independently hydrogen or C1-6alkyl.

14. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 13, wherein Cy is pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2- a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3- triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted with one or more R8independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; – C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

15. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 13, wherein Cy is imidazole, phenyl, pyridine, 2- oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, or quinoline; wherein Cy is optionally substituted with one or more R8 independently selected from: C1-6alkyl optionally substituted with hydroxyl; C1- 3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl; and oxo; wherein R9and R10are independently hydrogen or C1-6alkyl.

16. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 12, wherein L1 is absent and Cy is a pyrazole or pyrimidine, wherein said pyrazole is optionally substituted with methyl.

17. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-9, wherein Z is -L1–NR5R6.

18. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 17, wherein L1is absent, R5is a hydrogen, and R6is -L2–Cy.

19. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 18, wherein L2is –CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4- thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2- a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3- triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrrolizine; wherein Cy is optionally substituted with one or more R8 independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy- C1-6alkyl; and oxo; wherein R9 and R10 are independently hydrogen or C1-6alkyl.

20. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 18 or 19, wherein L2is –CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2- a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2- b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro- 5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4- b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3- triazole, 2,3-dihydroindolizin-5(1H)-one, pyridazin-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted with one or more R8 independently selected from: C1-6alkyl optionally substituted with hydroxyl or C1-6alkoxy; C1-3haloalkyl; halogen; hydroxyl; cyano; – C(=O)NR9R10; –C(=O)OR10; C3-6cycloalkyl optionally substituted with hydroxy-C1-6alkyl; and oxo; wherein R9 and R10 are independently hydrogen or C1-6alkyl.

21. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 19 or 20, wherein each R8is independently selected from: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chloro, fluoro, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxy, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

22. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 18 or 19, wherein L2 is –CH2– and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridone, thiazole, or quinoline; wherein said Cy is optionally substituted with one or more R8 independently selected from: C1-6alkyl optionally substituted with hydroxyl; C1-3haloalkyl; halogen; hydroxyl; cyano; –C(=O)NR9R10; – C(=O)OR10; C3-6cycloalkyl; and oxo; wherein each of R9and R10is independently hydrogen or C1-6alkyl.

23. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 22, wherein each R8is independently selected from methyl, –CF3, –CHF2, fluoro, hydroxyl, cyano, –CH2OH, –C(=O)OH, –C(=O)OMe, and –C(=O)N(Me)2.

24. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 22, wherein Cy is phenyl, pyridine, imidazole, 2- oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridone, thiazole, or quinoline.

25. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 18, wherein L2 is –CH(CH3)– and Cy is phenyl.

26. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 17, wherein L1is absent, R5is hydrogen, and R6is methyl, –C(=O)–phenyl or –C(=O)CH2CH3.

27. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 17, wherein L1 is –C(=O)–, R5 is -NH2, and R6 is methyl.

28. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 17, wherein L1 is absent and R5 and R6 are taken together with the nitrogen atom to which they are bound to form an azetidine ring optionally substituted with hydroxyl and methyl.

29. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-9, wherein Z is –OR6 or –SR6.

30. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to claim 29, wherein R6is -L2–Cy, wherein L2is –CH2– and Cy is pyridine.

31. The compound or a stereoisomer, atropisomer, tautomer, or pharmaceuticallyacceptable salt thereof according to any one of claims 1-9, wherein Z and R2together with the carbon atoms to which they are bonded form a pyrazole.

32. A compound selected from any one of compounds 1-146 as set forth in Table 1 or astereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising a compound or a stereoisomer,atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1- 32, and one or more pharmaceutically acceptable excipients.

34. A method of treating cancer, the method comprising administering an effectiveamount of a compound or a stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof of any one of claims 1-32, or a pharmaceutical composition of claim 33.

35. The method of claim 34, wherein the cancer is characterized as comprising a KRasmutation.

36. The method of claim 35, wherein the KRas mutation corresponds to a KRasG12Dmutation.

37. The method of any one of claims 34-36, further comprising testing a sample from thepatient before administration for the absence or presence of a KRasG12Dmutation.

38. The method of claim 37, 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.

39. The method of any one of claims 34-38, wherein the cancer is pancreatic cancer,lung cancer, or colorectal cancer.

40. The method of any one of claims 34-39, further comprising administering at leastone additional therapeutic agent.

41. The method of claim 40, wherein the additional therapeutic agent comprises anepidermal 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.

42. A compound according to any one of claims 1-32, or a stereoisomer, atropisomer,tautomer, or pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

43. A compound according to any one of claims 1-32, or a stereoisomer, atropisomer,tautomer, or pharmaceutically acceptable salt thereof, for use for use in treating cancer.

44. The compound for use according to claim 43, wherein the cancer is pancreaticcancer, lung cancer, or colorectal cancer.

45. Use of a compound according to any one of claims 1-32, or stereoisomer,atropisomer, tautomer, or pharmaceutically salt thereof, in the manufacture of a medicament for treating cancer.

46. The use according to claim 45, wherein the cancer is pancreatic cancer, lung cancer,or colorectal cancer.

47. Use of a compound of any one of claims 1-32, or stereoisomer, atropisomer,tautomer, or pharmaceutically acceptable salt thereof, for the therapeutic treatment of a cancer comprising a KRasG12Dmutation.

48. Use of a compound according to any one of claims 1-32, or stereoisomer,atropisomer, tautomer, or pharmaceutically salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

49. Use of a compound of any one of claims 1-32, 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.

50. A compound according to any one of claims 1-32, or stereoisomer, atropisomer,tautomer, or pharmaceutically salt thereof, for the therapeutic and / or prophylactic treatment of a cancer comprising a KRasG12Dmutation.

51. A method for a) regulating activity of a KRas mutant protein, b) inhibitingproliferation of a cell population, or c) inhibiting tumor metastasis; wherein the method for regulating activity of a KRas mutant protein comprises reacting the mutant protein with a compound of any one of claims 1-32, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof; wherein the method for inhibiting proliferation of a cell population, the method comprises contacting the cell population with the compound of any one of claims 1-32, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof; and wherein the method for inhibiting tumor metastasis comprises administering to an individual in need thereof a therapeutically effective amount of the compound of any one of claims 1-32, or stereoisomer, atropisomer, tautomer, or pharmaceutically acceptable salt thereof to a subject in need thereof.

52. The method of claim 51, wherein the inhibition of proliferation is measured as adecrease in cell viability of the cell population.

53. A compound of any one of claims 1-32, or stereoisomer, atropisomer, tautomer, orpharmaceutically acceptable salt thereof, for use in a) regulating activity of a KRas mutant protein, b) inhibiting proliferation of a cell population, or c) inhibiting tumor metastasis.

54. Use of a compound of any one of claims 1-32, or stereoisomer, atropisomer,tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a) regulating activity of a KRas mutant protein, b) inhibiting proliferation of a cell population, or c) for inhibiting tumor metastasis.

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