WO2022266069A1

WO2022266069A1 - Tricyclic kras g12d inhibitors

Info

Publication number: WO2022266069A1
Application number: PCT/US2022/033391
Authority: WO
Inventors: Hengmiao Cheng; Jun Feng; Jean-Michel Vernier; Marcos GONZALEZ-LOPEZ; Benjamin Jones; Nicholas A. ISLEY; Ping Chen; Puhui LI; Peter C. Chua
Original assignee: Erasca, Inc.
Priority date: 2021-06-16
Filing date: 2022-06-14
Publication date: 2022-12-22

Abstract

The present embodiments provide compounds of Formula I, compositions of the compounds, and methods for treating diseases such as cancer.

Description

TRICYCLIC KRAS G12D INHIBITORS

BACKGROUND

[0001] Embodiments herein relate to compounds, compositions and methods for the treatment of RAS -mediated disease. In particular, embodiments herein relate to compounds and methods for treating diseases such as cancer via targeting oncogenic mutants of the K-RAS isoform.

[0002] Ras proteins are small guanine nucleotide-binding proteins that act as molecular switches by cycling between active GTP -bound and inactive GDP-bound conformations. Ras signaling is regulated through a balance between activation by guanine nucleotide exchange factors (GEFs), most commonly son of sevenless (SOS), and inactivation by GTPase-activating proteins (GAPs) such as neurofibromin or pl20GAP. The Ras proteins play an important role in the regulation of cell proliferation, differentiation, and survival. Dysregulation of the Ras signaling pathway is almost invariably associated with disease. Hyper-activating somatic mutations in Ras are among the most common lesions found in human cancer. Most of these mutations have been shown to decrease the sensitivity of Ras to GAP stimulation and decrease its intrinsic GTPase activity, leading to an increase in the active GTP -bound population. Although mutation of any one of the three Ras isoforms (K-Ras, N-Ras, or H-Ras) has been shown to lead to oncogenic transformation, K-Ras mutations are by far the most common in human cancer. For example, K- Ras mutations are known to be often associated with pancreatic, colorectal and non-small-cell lung carcinomas. Similarly, H-Ras mutations are common in cancers such as papillary thyroid cancer, lung cancers and skin cancers. Finally, N-Ras mutations occur frequently in hepatocellular carcinoma.

[0003] K-Ras is the most frequently mutated oncoprotein in human cancers, and the G12D mutation is among the most prevalent. Accordingly, there is a need to develop selective inhibitors of KRAS G12D. The present embodiments meet this and other needs. SUMMARY

[0004] In one aspect, the present embodiments provide compounds, or a pharmaceutically acceptable salt thereof, of Formula(I):

wherein m is 1 or 2; p is 1 or 2; j is an integer from 0 to 4; A is selected from:

wherein R³, R⁴, R⁵, and R⁶ are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino, C-amide (- CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), sulfonamide (- NHSO₂R or -SO₂NHR), and CF₃; wherein each R and R’ is independently hydrogen, alkyl, or cycloalkyl; or any two adjacent R³, R⁴, R⁵, or R⁶ form an optionally substituted fused 5- or 6-membered ring comprising 0 to 3 heteroatoms selected from N, O or S; provided that one of R³, R⁴, R⁵, or R⁶ is the bond representing the link between A and the tricyclic ring system; wherein G¹ and G² are independently selected from S, O, CH, -

CH=CH-, -CH=N-, N, NH, and NMe; wherein either G¹ or G² forms a double bond with carbon of the -CR¹⁰ moiety; wherein R⁷, R⁸, and R⁹, are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino; and R¹⁰ is hydroxyl, alkoxy, amino, N-alkylamino, C-amide (-CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), or sulfonamide (-NHSO₂R or -SO₂NHR)₃;

wherein G¹ and G² are independently selected from S, O, CH, - CH=CH-, -CH=N-, N, NH, and NMe; wherein either G¹ or G² forms a double bond with carbon of the -CR¹¹ moiety; R¹¹ is hydroxyl, alkoxy, amino, N-alkylamino, C-amide (- CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), or sulfonamide (- NHSO₂R or -SO₂NHR)₃;wherein X¹ is selected from CH, or N; and X² is selected from O, S, NH, and NMe; or

wherein Z¹, Z², Z³, and Z⁴ are independently selected from

N, NH, CH, C=O, or null; wherein null can only occur once, and at least one of Z¹, Z², Z³, and Z⁴ is NH and at least one of Z¹, Z², Z³, and Z⁴ adjacent to the NH is C=O; and wherein R¹¹, R¹², and R¹³, are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino;

wherein Z¹, Z², Z³, and Z⁴ are each independently selected from CH and -CE, wherein E is CN, -C≡CH, halogen, OH, OMe, alkyl- or aryl sulfonamide, alkyl- or aryl sulfone, acyl, formyl, amide, ester, carboxylic acid, or CF₃; and, R¹³, are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino; each V is independently selected from methyl, cyanomethyl, or any two V combine to form a bridge or spirocycle structure optionally comprising a heteroatom in the bridge or spirocycle selected from S, SO₂, O or N, and wherein the bridge or spirocycle structure is optionally substituted with oxo;

X is O or S;

R¹ is H, halo, CF₃, or C_1-3 alkyl; each R² is independently selected from the group consisting of alkyl, N- alkylamino, N, N-dialkylamino, N-alkylamidoalkyl (-alkylC=ONHalkyl), N- arylamidoalkyl (-alkylC=ONHaryl), -OCH₂CONRR’, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkyloxyalkyl, alkylcycloalkyl, hydroxyalkyl, halogen, haloalkyl, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclyl, mono- or bicyclic heterocyclylalkyl, mono- or bicyclic heterocyclyloxyalkyl, and heteroaryloxy any of which are optionally substituted; or when p is 2, two R² combine to form a spirocyclic 3-6-membered ring optionally containing 1 to 3 heteroatoms selected fromN, O, or S; wherein R and R’ are independently selected from hydrogen, alkyl, and cycloalkyl.

[0005] In another aspect, the present embodiments provide a pharmaceutical composition comprising a pharmaceutically effective amount of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0006] In another embodiment, the present embodiments provide a method of treating a subject having cancer, the cancer characterized by the presence of a KRAS G12D mutation, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as disclosed herein.

[0007] In another embodiment, the present embodiments provide a method for manufacturing a medicament for treating a subject having cancer, the cancer characterized by the presence of a KRAS G12D mutation, the medicament comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a a pharmaceutical composition as disclosed herein, is used.

[0008] In another embodiment, the present embodiments provide for the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a a pharmaceutical composition as disclosed herein, for the manufacture of a medicament for the treatment of cancer in a subject, the cancer characterized by the presence of a KRAS G12D mutation.

[0010] In another embodiment, the present embodiments provide the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or a a pharmaceutical composition as disclosed herein, for use in the treatment of cancer in a subject, the cancer characterized by a KRAS G12D mutation.

DETAILED DESCRIPTION

I. GENERAL

[0011] The present embodiments provide selective inhibitors of KRAS G12D exhibiting good selectivity over wild-type KRAS and are useful for treating a cancer characterized by a KRAS G12D mutation.

II. DEFINITIONS

[0012] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the embodiments belong. In addition, any method or material similar or equivalent to a method or material described herein can be used in the practice of the present embodiments. For purposes of the present embodiments, the following terms are defined.

[0013] “A,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so forth.

[0014] The following chemical functional group definitions are provided to give guidance in understanding their meaning and scope. Those skilled in the art will recognize that these functional groups are being used in a manner consistent with practice of the chemical arts. Any of the following chemical functional groups may be optionally substituted as defined below and each chemical functional group below may itself be an optional substitution.

[0015] The term “acyl,” as used herein, alone or in combination, refers to a carbonyl (C=O) attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or any other moiety were the atom attached to the carbonyl is carbon. An “acetyl” group, which is a type of acyl, refers to a (~C(=O)CH₃) group. An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, without limitation, methylcarbonyl and ethylcarbonyl. Similarly, an “arylcarbonyl” or “aroyl” group refers to an aryl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, without limitation, benzoyl and naphthoyl. Accordingly, generic examples of acyl groups include alkanoyl, aroyl, heteroaroyl, and so on. Specific examples of acyl groups include, without limitation, formyl, acetyl, acryloyl, benzoyl, trifluoroacetyl and the like.

[0016] The term “alkenyl,” as used herein, alone or in combination, refers to a straight- chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkenyl may comprise from 2 to 6 carbon atoms, or from 2 to 4 carbons, either of which may be referred to as “lower alkenyl.” The term “alkenylene” refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene (— CH=CH— ). Alkenyl can include any number of carbons, such as C₂, C_2-3, C_2-4, C_2-5, C_2-6, C_2-7, C_2-8, C_2-9, C_2-10, C₃, C_3-4,

C_3-5, C_3-6, C₄, C_4-5, C_4-6, C₅, C_5-6, and C₆, and so on up to 20 carbon atoms. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl,

2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl,

3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups.

[0017] The term “alkoxy,” as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Alkoxy groups may have the general formula: alkyl-O-. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C₁₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, secbutoxy, tertbutoxy, pentoxy, hexoxy, and the like. The alkoxy groups can be further optionally substituted as defined herein. [0018] The term “alkyl,” as used herein, alone or in combination, (sometimes abbreviated Alk) refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, the alkyl may comprise from 1 to 10 carbon atoms. In further embodiments, the alkyl may comprise from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. Alkyl can include any number of carbons, such as C_1-2, C_1-3, C_1-4, C_1-5, C_1-6, C_1-7, C_1-8, C_1-9, C_1-10, C_2-3, C_2-3, C_2-5, C_2-6, C_3-4, C_3-5, C_3-6, C_4-5, C_4-6 and C_5-6. For example, Ci-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH₂-). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. When the alkyl is methyl, it may be represented structurally as CH₃, Me, or just a single bond terminating with no end group substitution.

[0019] The term “alkylamino,” as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N- methylamino (— NHMe), N-ethylamino (— NHEt), N,N-dimethylamino (— NMe₂), N,N- ethylmethylamino (— NMeEt) and the like. The term “aminoalkyl” refers to reverse orientation in which the amino group appears distal to the parent molecular moiety and attachment to the parent molecular moiety is through the alkyl group. For example, NH₂(CH₂)_{n —} describes an aminoalkyl group with a terminal amine at the end of an alkyl group attached to the parent molecular moiety. The two terms alkylamino and aminoalkyl can be combined to describe an “alkylaminoalkyl” group in which an alkyl group resides on a nitrogen atom distal to the parent molecular moiety, such as MeNH(CH₂)_n— . In a similar manner, an aryl group, as defined herein, may combine in a similar fashion providing an arylaminoalkyl group ArNH(CH₂)_n— . For additional clarity nomenclature may be provided where the group that is attached to nitrogen is indicated so by use of "N-" in the name, such as N-arylaminoalkyl, which is understood to mean that the aryl group is a substituent on the nitrogen atom of the aminoalkyl group, the alkyl being attached the parent molecular moiety. [0020] The term “alkylidene,” as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[0021] The term “alkylthio,” as used herein, alone or in combination, refers to an alkyl thioether (AlkS-) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfmyl, and the like. Similarly, “arylthio” refers to arylthioether (ArS-) radical wherein the term aryl is as defined herein and wherein the sulfur may be singly or double oxidized.

[0022] The term “alkynyl,” as used herein, alone or in combination, refers to a straight- chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term “alkynylene” refers to a carbon-carbon triple bond attached at two positions such as ethynylene. Alkynyl can include any number of carbons, such as C₂, C_2-3, C_2-4, C_2-5, C_2-6, C_2-7, C_2-8, C_2-9, C_2-10, C₃, C_3-4, C_3-5, C_3-6, C₄, C_4-5, C_4-6, C₅, C_5-6, and C₆. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl,

1.4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl,

1.5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted. Unless otherwise specified, the term “alkynyl” may include “alkynylene” groups.

[0023] The terms “amido,” as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group. The term “C-amido” as used herein, alone or in combination, refers to a — C(=O)N(R)₂ group where is R as defined herein. The term “N-amido” as used herein, alone or in combination, refers to RC(=O)N(R’)- group, with R and R’ as defined herein. The term “acylamino” as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an “acylamino” group is acetylamino (CH₃C(O)NH— ). [0024] The term “amino,” as used herein, alone or in combination, refers to — N(R)(R’) or -N⁺(R)(R’)(R”), wherein R, R’ and R” are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted.

[0025] The term “amino acid,” as used herein, alone or in combination, means a substituent of the form — NRCH(R’)C(O)OH, wherein R is typically hydrogen, but may be cyclized with N (for example, as in the case of the amino acid proline), and R’ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, amido, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroaryl alkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, thiol, thioalkyl, alkylthioalkyl, and alkylthio, any of which may be optionally substituted. The term “amino acid” includes all naturally occurring amino acids as well as synthetic analogues.

[0026] The term “aryl,” as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, and biphenyl.

[0027] The term “arylalkenyl” or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group. [0028] The term “arylalkoxy” or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group. [0029] The term “arylalkyl” or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

[0030] The term “arylalkynyl” or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group. [0031] The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4- phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0032] The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy. [0033] The terms “benzo” and “benz,” as used herein, alone or in combination, refer to the divalent radical C₆H₄- derived from benzene. Examples include benzothiophene and benzimidazole.

[0034] The term “carbamate,” as used herein, alone or in combination, refers to an ester of carbamic acid (— NHCOO— ) which may be attached to the parent molecular moiety from either the nitrogen or acid (oxygen) end, and which may be optionally substituted as defined herein.

[0035] The term “O-carbamyl” as used herein, alone or in combination, refers to a — OC(O)NRR’, group, with R and R’ as defined herein.

[0036] The term “N-carbamyl” as used herein, alone or in combination, refers to a ROC(O)NR’~ group, with R and R’ as defined herein.

[0037] The term “carbonyl,” as used herein, when alone includes formyl [-C(=O)H] and in combination is a — C(=O)- group.

[0038] The term “carboxyl” or “carboxyl,” as used herein, refers to — C(=O)OH, O- carboxy, C-carboxy, or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt. An “O-carboxy” group refers to a RC(=O)O— group, where R is as defined herein. A “C-carboxy” group refers to a — C(=O)OR groups where R is as defined herein. [0039] The term “cyano,” as used herein, alone or in combination, refers to — CN.

[0040] The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In some embodiments, a cycloalkyl may comprise from from 3 to 7 carbon atoms, or from 5 to 7 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3- dihydro- lH-indenyl, adamantyl and the like. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclof 1.1.1] pentane, camphor, adamantane, and bicyclo [3.2.1] octane.

[0041] The term “electrophilic moiety,” as used herein, is used in accordance with its plain ordinary chemical meaning and refers to a chemical group that is electrophilic. Exemplary electrophilic moieties include, without limitation, unsaturated carbonyl containing compounds such as acrylamides, acrylates, unsaturated (i.e., vinyl) sulfones or phosphates, epoxides, and vinyl epoxides.

[0042] The term “ester,” as used herein, alone or in combination, refers to a carboxyl group bridging two moieties linked at carbon atoms (— CRR’C(=O)OCRR’- ), where each R and R’ are independent and defined herein.

[0043] The term “ether,” as used herein, alone or in combination, typically refers to an oxy group bridging two moieties linked at carbon atoms. “Ether” may also include poly ethers, such as, for example, — RO(CH₂)₂O(CH₂)₂O(CH₂)₂OR’, — RO(CH₂)₂O(CH₂)₂OR’, -RO(CH₂)₂OR’, and -RO(CH₂)₂OH.

[0044] The term “halo,” or “halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

[0045] The term “haloalkoxy,” as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0046] The term “haloalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl, trihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (— CFH— ), difluoromethylene (-CF₂-), chloromethylene (-CHCl-) and the like.

[0047] The term “heteroalkyl,” as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized (i.e. bond to 4 groups). The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, — CH₂NHOCH₃. The term heteroalkyl may include ethers.

[0048] The term “heteroaryl,” as used herein, alone or in combination, refers to 3 to 7 membered unsaturated heteromonocyclic rings, or fused polycyclic rings, each of which is 3 to 7 membered, in which at least one of the fused rings is unsaturated, wherein at least one atom is selected from the group consisting of O, S, and N. In some embodiments, a heteroaryl may comprise from 5 to 7 carbon atoms. The term also embraces fused polycyclic groups wherein heterocyclic radicals are fused with aryl radicals, wherein heteroaryl radicals are fused with other heteroaryl radicals, or wherein heteroaryl radicals are fused with cycloalkyl radicals. Non-limiting examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.

[0049] Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0050] The heteroaryl groups can be linked via any position on the ring. For example, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3- and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazole includes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5- and 6- pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5- and 6-triazine, 1,3,5-triazine includes 2- triazine, thiophene includes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazole includes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and 5-isothiazole, oxazole includes 2-, 4- and 5-oxazole, isoxazole includes 3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3- and 4- quinoline, isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2- and 4- quinoazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3- benzothiophene, and benzofuran includes 2- and 3-benzofuran.

[0051] Some heteroaryl groups include those having from 5 to 10 ring members and from 1 to 3 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having from 9 to 12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine. Still other heteroaryl groups include those having from 5 to 6 ring members and from 1 to 2 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0052] The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” or “heterocyclyl” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic radical containing at least one heteroatom as ring members, wherein each heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, a heterocycloalkyl may comprise from 1 to 4 heteroatoms as ring members. In further embodiments, a heterocycloalkyl may comprise from 1 to 2 heteroatoms ring members. In some embodiments, a heterocycloalkyl may comprise from 3 to 8 ring members in each ring. In further embodiments, a heterocycloalkyl may comprise from 3 to 7 ring members in each ring. In yet further embodiments, a heterocycloalkyl may comprise from 5 to 6 ring members in each ring.

“Heterocycloalkyl” and “heterocycle” are intended to include sugars, sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycloalkyl groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, epoxy, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycloalkyl groups may be optionally substituted unless specifically prohibited.

[0053] “Heterocycloalkyl” may refer to a saturated ring system having from 3 to 12 ring members and from 1 to 5 heteroatoms of N, O and S. The heteroatoms can also be oxidized, such as, but not limited to, S(O) and S(O)₂. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4 or 3 to 5. The heterocycloalkyl group can include any number of carbons, such as C_3-6, C_4-6, C_5-6, C_3-8, C_4-8, C_5-8, C_6-8, C_3-9, C_3-10, C_3-11, and C_3-12. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, diazepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline, diazabicycloheptane, diazabicyclooctane, diazaspirooctane or diazaspirononane. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with Cl 6 alkyl or oxo (=O), among many others. Heterocycloalkyl groups can also include a double bond or a triple bond, such as, but not limited to dihydropyridine or 1,2,3,6-tetrahydropyridine. [0054] The heterocycloalkyl groups can be linked via any position on the ring. For example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2- azetidine, pyrrolidine can be 1-, 2- or 3-pyrrolidine, piperidine can be 1-, 2-, 3- or 4-piperidine, pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3- or 4-imidazobdine, piperazine can be 1-, 2-, 3- or 4-piperazine, tetrahydrofuran can be 1- or 2-tetrahydrofuran, oxazolidine can be 2-, 3-, 4- or 5-oxazobdine, isoxazolidine can be 2-, 3-, 4- or 5- is oxazolidine, thiazolidine can be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine can be 2-, 3-, 4- or 5- isothiazolidine, and morpholine can be 2-, 3- or 4-morpholine.

[0055] When heterocycloalkyl includes 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxzoabdine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0056] The term “hydrazinyl” as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., — N-N-. In general, the hydrazinyl group has optional substitution on at least one NH hydrogen to confer stability. [0057] The term “hydroxamic acid” or its ester as used herein, refers to — C(O)0N(R)0(R’), wherein R and R’ are as defined herein, or the corresponding “hydroxamate” anion, including any corresponding hydroxamic acid salt.

[0058] The term “hydroxy,” as used herein, alone or in combination, refers to OH.

[0059] The term “hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group. “Hydroxyalkyl” or “alkylhydroxy” refers to an alkyl group, as defined above, where at least one of the hydrogen atoms is replaced with a hydroxy group. As for the alkyl group, hydroxyalkyl or alkylhydroxy groups can have any suitable number of carbon atoms, such as C_1-6. Exemplary C_1-4 hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxy ethyl (where the hydroxy is in the 1- or 2-position), hydroxypropyl (where the hydroxy is in the 1-, 2- or 3-position), hydroxybutyl (where the hydroxy is in the 1-, 2-, 3- or 4-position), 1,2-dihydroxy ethyl, and the like.

[0060] The term “imino,” as used herein, alone or in combination, refers to C=NR.

[0061] The term “iminohydroxy,” as used herein, alone or in combination, refers to C=N(OH) and it O-ether C=N— OR.

[0062] The term “isocyanato” refers to a — NCO group.

[0063] The term “isothiocyanato” refers to a — NCS group.

[0064] The phrase “linear chain of atoms” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

[0065] The term “linking group,” as used herein refers to any nitrogen containing organic fragment that serves to connect the pyrimidine or pyridone core of the compounds disclosed herein to the electrophilic moiety E, as defined herein. Exemplary linking groups include piperazines, aminoalkyls, alkyl- or aryl-based diamines, aminocycloalkyls, amine-containing spirocyclics, any of which may be optionally substituted as defined herein. In some embodiments, linking groups may comprise the substructure L-Q-L’-E wherein Q is a monocyclic 4 to 7 membered ring or a bicyclic, bridged, or fused, or spiro 6-11 membered ring, any of which optionally include one or more nitrogen atoms, E is the electrophilic group, L is bond, C_1-6 alkylene, — O — C_0-5 alkylene, — S — C_0-5 alkylene, or — NH — C_0-5 alkylene, and for C_2-6 alkylene, — O — C_2-5 alkylene, — S — C_2-5 alkylene, and NH — C_2-5 alkylene, one carbon atom of any of the alkylene groups can optionally be replaced with O, S, or NH; and L’ is bond when Q comprises a nitrogen to link to E, otherwise L’ is NR, where R is hydrogen or alkyl.

[0066] The term “lower,” as used herein, alone or in combination, means containing from 1 to and including 6 carbon atoms, or from 1 to 4 carbon atoms.

[0067] The term “mercaptyl” as used herein, alone or in combination, refers to an RS-- group, where R is as defined herein.

[0068] The term “nitro,” as used herein, alone or in combination, refers to — NO₂.

[0069] The terms “oxy” or “oxa,” as used herein, alone or in combination, refer to — O— . [0070] The term “oxo,” as used herein, alone or in combination, refers to =O.

[0071] The term “perhaloalkoxy” refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.

[0072] The term “perhaloalkyl” as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

[0073] The term “phosphoamide” as used herein, alone or in combination, refers to a phosphate group [(OH)₂P(=O)O—] in which one or more of the hydroxyl groups has been replaced by nitrogen, amino, or amido.

[0074] The term “phosphonate” as used herein, alone or in combination, refers to a group of the form ROP(OR’)(OR)O— wherein R and R’ are selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. “Phosphonate” includes “phosphate [(OH)₂P(O)O— ] and related phosphoric acid anions which may form salts. [0075] The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein, alone or in combination, refers to the -SO₃H group and its anion as the sulfonic acid is used in salt formation or sulfonate ester where OH is replaced by OR, where R is not hydrogen, but otherwise is as defined herein, and typically being alkyl or aryl.

[0076] The term “sulfanyl,” as used herein, alone or in combination, refers to — S— .

[0077] The term “sulfinyl,” as used herein, alone or in combination, refers to — S(O)— . [0078] The term “sulfonyl,” as used herein, alone or in combination, refers to — S(O)₂— . [0079] The term “N-sulfonamido” refers to a RS(=O)₂NR’— group with R and R’ as defined herein.

[0080] The term “S-sulfonamido” refers to a — S(=O)₂NRR’, group, with R and R’ as defined herein. [0081] The terms “thia” and “thio,” as used herein, alone or in combination, refer to a — S- - group or an ether wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfmyl and sulfonyl, are included in the definition of thia and thio.

[0082] The term “thiol,” as used herein, alone or in combination, refers to an — SH group. [0083] The term “thiocarbonyl,” as used herein, when alone includes thioformyl -C(=S)H and in combination is a — C(=S)- group.

[0084] The term “N-thiocarbamyl” refers to an ROC(=S)NR’- group, with R and R’ as defined herein.

[0085] The term “O-thiocarbamyl” refers to a — OC(=S)NRR’, group with R and R’ as defined herein.

[0086] The term “thiocyanato” refers to a — CNS group.

[0087] The term “trihalomethanesulfonamido” refers to a X₃CS(=O)₂NR— group with X is a halogen and R as defined herein.

[0088] The term “trihalomethanesulfonyl” refers to aX₃CS(=O)₂— group where X is a halogen.

[0089] The term “trihalomethoxy” refers to a X₃CO- group where X is a halogen.

[0090] The term “trisubstituted silyl,” as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amiNo. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.

[0091] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

[0092] When a group is defined to be “null,” what is meant is that said group is absent. A “null” group occurring between two other group may also be understood to be a collapsing of flanking groups. For example, if in — (CH₂)_xG¹G²G³, the element G² were null, said group would become — (CH₂)_xG¹G³. [0093] The term “optionally substituted” means the anteceding group or groups may be substituted or unsubstituted. Groups constituting optional substitution may themselves be optionally substituted. For example, where an alkyl group is embraced by an optional substitution, that alkyl group itself may also be optionally substituted. When substituted, the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: alkyl, alkenyl, alkynyl, alkanoyl, heteroalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, lower perhaloalkyl, perhaloalkoxy, cycloalkyl, phenyl, aryl, aryloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, alkylcarbonyl, carboxyester, carboxamido, cyano, hydrogen, halogen, hydroxy, amino, alkylamino, arylamino, amido, nitro, thiol, alkylthio, haloalkylthio, perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N₃, SH, SCH₃ C(O)CH₃, CO₂CH₃, CO₂H, pyridinyl, thiophene, furanyl, carbamate, and urea. Particular subsets of optional substitution include, without limitation: (1) alkyl, halo, and alkoxy; (2) alkyl and halo; (3) alkyl and alkoxy; (4) alkyl, aryl, and heteroaryl; (5) halo and alkoxy; and (6) hydroxyl, alkyl, halo, alkoxy, and cyaNo. Where an optional substitution comprises a heteroatom-hydrogen bond (-NH-, SH, OH), further optional substitution of the heteroatom hydrogen is contemplated and includes, without limitation optional substitution with alkyl, acyl, alkoxymethyl, alkoxyethyl, arylsulfonyl, alkyl sulfonyl, any of which are further optionally substituted. These subsets of optional substitutions are intended to be merely exemplary and any combination of 2 to 5, or 2 to 10, or 2 to 20 of the groups recited above up to all the group recited above and any subrange in between are contemplated. “Optionally substituted” may include any of the chemical functional groups defined hereinabove and throughout this disclosure. Two optional substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH₂CH₃), fully substituted (e.g., — CF₂CF₃), monosubstituted (e.g., -CH₂CH₂F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., — CH₂CF₃).

[0094] The various optional substitutions need not be the same and any combination of optional substituent groups may be combined. For example, a carbon chain may be substituted with an alkyl group, a halo group, and an alkoxy group. Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.”

[0095] The term R or the term R’, appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Each such R and R’ groups should be understood to be optionally substituted as defined herein. Each incidence of R and R’ should be understood to be independent. Whether an R group has a number designation or not, every R group, including R, R’ and Rⁿ where n = (1, 2, 3, . . . n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as — C(O)N(R)~ may be attached to the parent moiety at either the carbon or the nitrogen.

[0096] The groups defined above can optionally be substituted by any suitable number and type of subsituents. Representative substituents include, but are not limited to, halogen, haloalkyl, haloalkoxy, -OR’, =O, -OC(O)R’, -(O)R’, -O₂R’, -ONR’R ”, -OC(O)NR’R”, =NR’,

=N-OR’, -NR’R”, -NR”C(O)R’, -NR’-(O)NR”R”‘, -NR”C(O)OR’, -NH-(NH₂)=NH, -NR’ C(NH₂)=NH, -NH-(NH₂)=NR’, -SR’, -S(O)R’, -S(O)₂R’, -S(O)₂NR’R”, -NR’S(O)₂R”, -N 3 and -NO₂. R’, R” and R”‘ each independently refer to hydrogen, unsubstituted alkyl, such as unsubstituted C_1-6 alkyl. Alternatively, R’ and R”, or R” and R”‘, when attached to the same nitrogen, are combined with the nitrogen to which they are attached to form a heterocycloalkyl or heteroaryl ring, as defined above. [0097] “Salt” refers to acid or base salts of the compounds, which can be used in the methods disclosed herein. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0098] Pharmaceutically acceptable salts of the acidic compounds disclosed herein are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.

[0099] Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.

[0100] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present embodiments.

[0101] Certain compounds disclosed herein possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present embodiments. [0102] “Hydrate” refers to a compound that is complexed to at least one water molecule. The compounds disclosed herein can be complexed with from 1 to 10 water molecules. [0103] “Composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and deleterious to the recipient thereof.

[0104] “Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in the present embodiments include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present embodiments.

[0105] “Treat”, “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.

[0106] “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject.

[0107] “Therapeutically effective amount or dose” or “therapeutically sufficient amount or dose” or “effective or sufficient amount or dose” refer to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells. [0108] “Subject” refers to animals such as mammals, including, but not limited to, primates ( e.g humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.

III. COMPOUNDS [0109] The present embodiments provide compounds, and pharmaceutically acceptable salts thereof, of Formula(I):

wherein m is 1 or 2; p is 1 or 2; j is an integer from 0 to 4; A is selected from: wherein R³, R⁴, R⁵, and R⁶ are independently selected from

halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino, C-amide (- CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), sulfonamide (- NHSO₂R or -SO₂NHR), and CF₃; wherein each R and R’ is independently hydrogen, alkyl, or cycloalkyl; or any two adjacent R³, R⁴, R⁵, or R⁶ form an optionally substituted fused 5- or 6-membered ring comprising 0 to 3 heteroatoms selected fromN, O or S; provided that one of R³, R⁴, R⁵, or R⁶ is the bond representing the link between A and the tricyclic ring system;

wherein G¹ and G² are independently selected from S, O, CH, -

CH=CH-, -CH=N-, N, NH, and NMe; wherein either G¹ or G² forms a double bond with carbon of the -CR¹⁰ moiety; wherein R⁷, R⁸, and R⁹, are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino; and R¹⁰ is hydroxyl, alkoxy, amino, N-alkylamino, C-amide (-CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), or sulfonamide (-NHSO₂R or -SO₂NHR)₃; or (A2), wherein G¹ and G² are independently selected from S, O, CH, -CH=CH-, -CH=N-, N, NH, NMe or -CE, where E is CN, halogen, OH, OMe, alkyl- or aryl sulfonamide, alkyl- or aryl sulfone, acyl, formyl, amide, ester, carboxylic acid, or CF₃; wherein either G¹ or G² forms a double bond with carbon of the -CR¹⁰ moiety; wherein R⁷, R⁸, and R⁹, are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino; and R¹⁰ is hydrogen, hydroxyl, alkoxy, amino, N-alkylamino, C-amide (-CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), or sulfonamide (-NHSO₂R or -SO₂NHR)₃;

wherein G¹ and G² are independently selected from S, O, CH, - CH=CH-, -CH=N-, N, NH, and NMe; wherein either G¹ or G² forms a double bond with carbon of the -CR¹¹ moiety; R¹¹ is hydroxyl, alkoxy, amino, N-alkylamino, C-amide (- CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), or sulfonamide (- NHSO₂R or -SO₂NHR)₃;wherein X¹ is selected from CH, or N; and X² is selected from O, S, NH, and NMe; or (A3), wherein G¹ and G² are independently selected from S, O, CH, - CH=CH-, -CH=N-, N, NH, NMe or -CE, where E is CN, halogen, OH, OMe, alkyl- or aryl sulfonamide, alkyl- or aryl sulfone, acyl, formyl, amide, ester, carboxylic acid, or CF₃; wherein either G¹ or G² forms a double bond with carbon of the -CR¹¹ moiety; R¹¹ is hydroxyl, alkoxy, amino, N-alkylamino, C-amide (-CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), or sulfonamide (-NHSO₂R or -SO₂NHR)₃, wherein R and R’ are independently alkyl or hydrogen;wherein X¹ is selected from CH, or N; and X² is selected from O, S, NH, and NMe;or

wherein Z¹, Z², Z³, and Z⁴ are independently selected from

N, NH, CH, C=O, S or null; wherein null can only occur once, and at least one of Z¹, Z², Z³, and Z⁴ is NH and at least one of Z¹, Z², Z³, and Z⁴ adjacent to the NH is C=O; and wherein R¹¹, R¹², and R¹³, are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino;

X is O or S;

R¹ is H, halo, CF₃, or C_1-3 alkyl; each R² is independently selected from the group consisting of alkyl, N- alkylamino, N, N-dialkylamino, N-alkylamidoalkyl (-alkylC=ONHalkyl), N- arylamidoalkyl (-alkylC=ONHaryl), -OCH₂CONRR’, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkyloxyalkyl, alkylcycloalkyl, hydroxyalkyl, halogen, haloalkyl, aryl, aryloxy, aralkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocyclyl, mono- or bicyclic heterocyclylalkyl, mono- or bicyclic heterocyclyloxyalkyl, and heteroaryloxy any of which are optionally substituted; or when p is 2, two R² combine to form a spirocyclic 3-6-membered ring optionally containing 1 to 3 heteroatoms selected fromN, O, or S; wherein R and R’ are independently selected from hydrogen, alkyl, and cycloalkyl. [0110] In some embodiments, A in Formula (I) is:

wherein Q¹ and Q² are independently selected from N, -CH, C- halogen, with the proviso that at least one of Q¹ and Q² is N; R¹⁴ and R¹⁵ are selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, CF₃, haloalkyl, cycloalkyl, amino, N- alkylamino; and R¹⁶ is hydroxyl, alkoxy, amino, N-alkylamino, C-amide (-CONRR’), N- amide (-NHCOR), urea (-NHCONHR), ether (-OR), or sulfonamide (-NHSO₂R or -SO₂NHR)₃, wherein R and R’ are independently alkyl or hydrogen.

[0111] The compounds disclosed herein may exist as atropisomers. In embodiments, the atropisomeric mixture is not separated. In embodiments the compounds may exist as an atropisomeric mixture enriched in one atropisomers. In embodiments, the compound is a single atropisomer.

[0112] In embodiments, X is O. In embodiments, X is S. In embodiments, when X is S, sulfur may also be provided in a higher oxidation state, such as SO, or SO₂. [0113] In embodiments, (Al) is selected from:

wherein each W, U, Y, and Z are independently selected from C=O, NH, O, S, N, CH, C-Q, where Q is amino, alkylamino, OH, halogen, methyl, -O-alkyl, -O- cycloalkyl, trifluoromethyl, amide, and urea.

[0114] In embodiments, (A1) is selected from:

[0115] In embodiments, (A2) is selected from:

[0116] In embodiments, (A2) is:

[0117] In embodiments, (A3) is selected from:

[0118] In embodiments, (A4) is selected from:

[0119] In embodiments, (A5) is selected from:

[0120] In embodiments, R₁ is F. In embodiments, R₁ is methyl. In embodiments, R₁ is Cl. In embodiments, R₁ is H. In embodiments, R₁ is CF₃.

[0121] In embodiments, R² is selected from:

MeOCH₂-, EtOCH₂-, MeO(CH₂)₂NH-,

wherein R and R’ are independently selected from hydrogen, alkyl, and cycloalkyl; and wherein R¹⁵ and R¹⁶ is selected from hydrogen, hydroxyl, CN, Cl, F, CF₃, C_1-3 alkyl or C_1-3 alkoxy, methoxy, or amino. [0122] In embodiments, two V form a bridge: -CH₂-CH₂-. In embodiments, two V form a bridge: -CH₂-CH₂-CH₂-. In embodiments, two V form a bridge: -CH₂-. In embodiments, the piperazine moiety is selected from:

[0123] In embodiments, m is 1. Such compounds are provided as structure (la). In embodiments m is 2. Such compounds are provided as structure (lb).

[0124] In embodiments, the compound is:

[0125] In embodiments, the compound is selected from:

[0126] The compounds disclosed herein can exist as salts. The present embodiments include such salts, which can be pharmaceutically acceptable salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (eg (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in art. Also included are base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds disclosed herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0127] Other salts include acid or base salts of the compounds used in the methods of the present embodiments. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0128] Pharmaceutically acceptable salts includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds disclosed herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see. for example, Berge etal, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0129] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0130] Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present embodiments. Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present embodiments and are intended to be within the scope of the present embodiments.

[0131] Certain compounds disclosed herein possess asymmetric carbon atoms (optical centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present embodiments. The compounds disclosed herein do not include those which are known in art to be too unstable to synthesize and/or isolate. The present embodiments are meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The compounds disclosed herein can be provided as a mixture of atropisomers or can be pure atropisomers.

[0132] Isomers include compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0133] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the embodiments.

[0134] Unless otherwise stated, the compounds disclosed herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds disclosed herein may be labeled with radioactive or stable isotopes, such as for example deuterium (²H), tritium (³H), iodine- 125 (¹²⁵I), fluorine-18 (¹⁸F), nitrogen-15 (¹⁵N), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), carbon-13 (¹³C), or carbon-14 (¹⁴C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the scope of the present embodiments. [0135] In addition to salt forms, the present embodiments provide compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds disclosed herein. Additionally, prodrugs can be converted to the compounds disclosed herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds disclosed herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0136] Compounds disclosed herein 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, 2nd edition Wiley -VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vol. 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds disclosed 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.

[0137] For illustrative purposes, reaction Schemes below provide routes for synthesizing the compounds disclosed herein as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used. Although some specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be substituted to provide a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0138] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. [0139] Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, or, about 20 °C.

[0140] Some compounds in following schemes are depicted with generalized substituents; however, one skilled in the art will immediately appreciate that the nature of the substituents can varied to afford the various compounds contemplated in the present embodiments. Moreover, the reaction conditions are exemplary and alternative conditions are well known. The reaction sequences in the following examples are not meant to limit the scope of the embodiments as set forth in the claims. IV. PHARMACEUTICAL FORMULATIONS

[0141] In some embodiments, pharmaceutical compositions comprise a compound of any one of the compounds disclosed herein and a pharmaceutically acceptable excipient.

[0142] In some embodiments, there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any one of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0143] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.

[0144] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is an anti-microtubule agent, a platinum coordination complex, a alkylating agent, an antibiotic agent, a topoisomerase II inhibitor, a antimetabolite, a topoisomerase I inhibitor, a hormone or hormonal analogue, a signal transduction pathway inhibitor, a non-receptor tyrosine kinase angiogenesis inhibitor, a immunotherapeutic agent, a proapoptotic agent, an inhibitor of LDH-A, an inhibitor of fatty acid biosynthesis, a cell cycle signalling inhibitor, a HD AC inhibitor, a proteasome inhibitor, or an inhibitor of cancer metabolism. In some embodiments, the chemotherapeutic agent is cisplatin, carboplatin, doxorubicin, ionizing radiation, docetaxel or paclitaxel.

[0145] The compounds disclosed herein can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. The compounds disclosed herein can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds disclosed herein can be administered transdermally. The compounds disclosed herein can also be administered by in intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75: 107-111, 1995). Accordingly, the present embodiments also provide pharmaceutical compositions including one or more pharmaceutically acceptable carriers and/or excipients and either a compound of Formula I, or a pharmaceutically acceptable salt of a compound of Formula I.

[0146] For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.

A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington’s Pharmaceutical Sciences, Maack Publishing Co, Easton PA (“Remington’s”).

[0147] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties and additional excipients as required in suitable proportions and compacted in the shape and size desired.

[0148] The powders, capsules and tablets preferably contain from 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other exceipients, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. [0149] Suitable solid excipients are carbohydrate or protein fillers including, but not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from com, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0150] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). Pharmaceutical preparations can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the compounds disclosed herein mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the compounds disclosed herein may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.

[0151] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0152] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0153] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, 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., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). 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, aspartame or saccharin. Formulations can be adjusted for osmolarity.

[0154] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0155] Oil suspensions can be formulated by suspending the compounds disclosed herein in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.

281 :93-102, 1997. The pharmaceutical formulations can also be in the form of oil-inwater emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0156] The compounds disclosed herein can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0157] The compounds disclosed herein can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug -containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both trans dermal and intradermal routes afford constant delivery for weeks or months.

[0158] The pharmaceutical formulations of the compounds disclosed herein can be provided as a salt and can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms.

In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine,

0. l%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.

[0159] The pharmaceutical formulations of the compounds disclosed herein can be provided as a salt and can be formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl -ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.

[0160] In some embodiments, the formulations of the compounds disclosed herein can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the GR modulator into the target cells in vivo. (See, e.g., Al- Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698- 708, 1995; Ostro , Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0161] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0162] The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

[0163] The dosage regimen also takes into consideration pharmacokinetics parameters well known in the art, i.e., the rate of absorption, bioavailability, metabolism, clearance, and the like (see, e.g., Hidalgo- Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611- 617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; the latest Remington’s, supra). The state of the art allows the clinician to determine the dosage regimen for each individual patient, GR and /or MR modulator and disease or condition treated.

[0164] Single or multiple administrations of the compounds disclosed herein formulations can be administered depending on the dosage and frequency as required and tolerated by the patient. The formulations should provide a sufficient quantity of active agent to effectively treat the disease state. Thus, in one embodiment, the pharmaceutical formulations for oral administration of the compounds disclosed herein is in a daily amount of between about 0.5 to about 30 mg per kilogram of body weight per day. In an alternative embodiment, dosages are from about 1 mg to about 20 mg per kg of body weight per patient per day are used. Lower dosages can be used, particularly when the drug is administered to an anatomically secluded site, such as the cerebral spinal fluid (CSF) space, in contrast to administration orally, into the blood stream, into a body cavity or into a lumen of an organ. Substantially higher dosages can be used in topical administration. Actual methods for preparing formulations including the compounds disclosed herein for parenteral administration are known or apparent to those skilled in the art and are described in more detail in such publications as Remington’s, supra. See also Nieman, In “Receptor Mediated Antisteroid Action,” Agarwal, et al., eds., De Gruyter, New York (1987).

[0165] The compounds described herein can be used in combination with one another, with other active agents known to be useful in modulating a glucocorticoid receptor, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

[0166] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In some embodiments, the active agents can be formulated separately. In some embodiments, the active and/or adjunctive agents may be linked or conjugated to one another.

[0167] After a pharmaceutical composition including a compound disclosed herein has been formulated in one or more acceptable carriers, it can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of the compounds of Formula I, such labeling would include, e.g., instructions concerning the amount, frequency and method of administration.

[0168] In some embodiments, the compositions disclosed herein are useful for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. The formulations for administration will commonly comprise a solution of the compositions disclosed herein dissolved in one or more pharmaceutically acceptable carriers. Among the acceptable vehicles and solvents that can be employed are water and Ringer’s solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, tonicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient’s needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0169] In some embodiments, the formulations of the compositions disclosed herein can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions disclosed herein into the target cells in vivo. (See, e.g., Al-Muhammed , J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro ,Am. J. Hosp. Pharm. 46:1576-1587, 1989).

V. Methods

[0170] In some embodiments, there is provided a method of treating a disorder or condition in a subject, the method comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as disclosed herein.

[0171] In some embodiments, there is provided a method for inhibiting KRAS G12D activity in a cell, comprising contacting the cell in which inhibition of KRAS G12D activity is desired with an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, there is provided a method for inhibiting KRAS G12D activity in a cell, comprising contacting the cell in which inhibition of KRAS G12D activity is desired with the pharmaceutical composition disclosed herein.

[0173] In some embodiments, there is provided a method for treating a KRAS G12D- associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, there is provided a method for treating a KRAS G12D- associated cancer comprising administering to a patient in need thereof the pharmaceutical composition disclosed herein. [0175] In some embodiments, there is provided a method of treating a subject having cancer, the cancer characterized by the presence of a KRAS G12D mutation, the method comprising administering to the human a therapeutically effective amount of a compound of any one of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a a pharmaceutical composition as disclosed herein.

[0176] In some embodiments, there is provided a method for manufacturing a medicament for treating a subject having cancer, the cancer characterized by the presence of a KRAS G12D mutation, the compound comprising Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0177] In some embodiments, there is provided a use of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a a pharmaceutical composition as disclosed herein, for the manufacture of a medicament for the treatment in a human having cancer, the cancer characterized by the presence of a KRAS G12D mutation.

[0178] In some embodiments, there are provided compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a a pharmaceutical composition as disclosed herein, for use in the treatment of a subject having cancer, the cancer characterized by the presence of a KRAS G12D mutation.

[0179] In some embodiments, there is provided a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., a KRAS G12D- associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound disclosed herein.

[0180] In some embodiments, there is provided a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12D mutation (e.g., a KRAS G12D- associated cancer); and (b) administering to the patient the pharmaceutical composition disclosed herein.

[0181] In some embodiments, the cancer is Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm’s tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial ‘carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin’s disease, non-Hodgkin’s lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; or Adrenal glands: neuroblastoma.

[0182] In some embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

[0183] In certain embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0184] The compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, can be inhibitors of KRAS G12D. For example, the inhibition constant (Ki) of the compounds disclosed herein can be less than about 50 μM, or less than about 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than about 1 μM. The inhibition constant (Ki) of the compounds disclosed herein can be less than about 1,000 nM, or less than about 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than about 1 nM. The inhibition constant (Ki) of the compounds disclosed herein can be less than about 1 nM, or less than about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or less than about 0.1 nM.

[0185] The compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, can be selective inhibitors of KRAS G12D. For example, KRAS G12D inhibition constant (IC50) of the compounds disclosed herein can be at least 2-fold less than the inhibition constant of one or more of KRAS wild-type, or NRAS, or HRAS, or at least 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100-fold less. The KRAS gl2D inhibition constant (Ki) of the compounds disclosed herein can also be at least 100-fold less than the inhibition constant of one or more of KRAS wild-type, or NRAS, or HRAS, or at least 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 10,000-fold less.

A. Cancer Combination Therapies

[0186] The compounds disclosed herein or salts thereof may be employed alone or in combination with other agents for treatment. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compounds disclosed herein such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer.

[0187] The term “co-administering” refers to either simultaneous administration, or any manner of separate sequential administration, of a compound disclosed herein or a salt thereof, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

[0188] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound disclosed herein, in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[0189] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with embodiments herein. For example, a compound disclosed herein may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present embodiments provide a single unit dosage form comprising a compound of Formula I, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0190] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, compositions disclosed herein are formulated such that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive can be administered.

[0191] Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Heilman (editors), 6^th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

[0192] In one embodiment, the treatment method includes the co-administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent. The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At²¹¹, 1¹³¹, 1¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.

[0193] Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signalling inhibitors; HD AC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.

[0194] “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA^®, Genentech/OSI Pharm.), bortezomib (VELCADE^®, Millennium Pharm.), disulfiram , epigallocatechin gallate , salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX^®, AstraZeneca), sunitib (SUTENT^®, Pfizer/Sugen), letrozole (FEMARA^®, Novartis), imatinib mesylate (GLEEVEC^®., Novartis), fmasunate (VATALANIB^®, Novartis), oxaliplatin (ELOXATIN^®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE^®, Wyeth), Lapatinib (TYKERB^®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR^®, Bayer Labs), gefitinib (IRESSA^®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN^® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gΐΐ and calicheamicin coll ( Angew Chem. Inti. Ed. Engl. 1994 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN^® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrobno-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs 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; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK^® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE^® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE^® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR^® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE^® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA^®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0195] Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX^®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene , 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON^® (toremifme citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE^® (megestrol acetate), AROMASIN^® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR^® (vorozole), FEMARA^® (letrozole; Novartis), and ARIMIDEX^® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME^®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN^®, LEUVECTIN^®, and VAXID^®; PROLEUKIN^®, rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN^®; ABARELIX^® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0196] Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds disclosed herein include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, peefusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin- 12 (ABT-874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgGi l antibody genetically modified to recognize interleukin- 12 p40 protein.

[0197] Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No. 4,943, 533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX^®) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (US Patent No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in US Patent No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/ Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as El.l, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6. 3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al, J. Biol. Chem. 279(29):30375- 30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in US Patent Nos:

5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459,

6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: W098/14451, W098/50038, W099/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA^® Genentech/OSI Pharmaceuticals); PD 183805 (Cl 1033, 2- propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6- quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro- 4’-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3- chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8- diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(l-phenylethyl)amino]-1H- pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1- phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3- bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4- fluorophenyl)amino] -3-cyano-7 -ethoxy-6-quinolinyl] -4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy] phenyl] -6 [5 [ [[2methy lsulfonyl)ethyl] amino] methyl] -2-furanyl] -4- quinazolinamine).

[0198] Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo- SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf- 1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimi dines; pyrrolopyrimi dines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Wamer-Lamber); antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affmitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-lCll (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: US Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

[0199] Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0200] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone- 17-buty rate, hydrocortisone- 17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone- 17-butyrate, cl obetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Mi prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa1/β2 blockers such as Anti- lymphotoxin alpha (LTa); radioactive isotopes (e.g., At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18- OCH₃, or famesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9- tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifamib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; famesyltransferase inhibitors such as lonafamib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin.

[0201] Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.

[0202] In certain embodiments, chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferons, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin, cisplatin, metronidazole, and imatinib mesylate, among others. In other embodiments, a compound disclosed herein is administered in combination with a biologic agent, such as bevacizumab or panitumumab.

[0203] In certain embodiments, compounds disclosed herein, or a pharmaceutically acceptable composition thereof, are administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, dromostanolone propionate, epirubicin, epoetin alfa, elotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserebn acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprobde acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6- TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, or zoledronic acid. [0204] Chemotherapeutic agents also include treatments for Alzheimer’s Disease such as donepezil hydrochloride and rivastigmine; treatments for Parkinson’s Disease such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex^® and Rebif^®), glatiramer acetate, and mitoxantrone; treatments for asthma such as albuterol and montelukast sodium; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

[0205] Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them.

VI. Examples [0206] Abbreviations:

ACN - acetonitrile AC₂O - acetyl acetate

BINAP - (+/-)-2,2’-bis(diphenylphosphino)-l,r-binaphthyl B_oc2O - di-tert-butyl dicarbonate

BOP - (benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate CO - carbon monoxide

DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE- 1,2-dichloroethane

DCM - dichloromethane

DIAD - diisopropyl azidodicarboxylate

DIEA or DIPEA - N,N-diisopropylethylamine

DMA - N,N-dimethylacetamide

DMAc -N,N-dimethylacetamide

DMAP - 4-dimethylaminopyridine

DMF - N,N-dimethylformamide

DMSO - dimethyl sulfoxide

EA - ethyl acetate

EtOAc - ethyl acetate

EtOH - ethanol h - hour

HATU -2-(7-azabenzotriazol-l -y 1 )-N,N,N ',N '-tetramethyluronium hexafluorophosphate

H₂O - water

HCl - hydrochloric acid

HFIP - hexafluoroisopropanol

HOAc - acetic acid

HPLC - high pressure/performance liquid chromatography iPrOAc - isopropyl acetate

KF - potassium fluoride

KOAc - potassium acetate

LDA - lithium diisopropylamide

LiHMDS - lithium bis(trimethylsilyl)amide mCPBA -3-chloroperoxybenzoic acid

MeCN - acetonitrile

Mel - iodomethane

MeOH - methanol

MeONa - sodium methoxide or sodium methanolate MTBE - methyl tert-butyl ether MS - mass spectroscopy

MW - molecular weight

NaBH(OAc)₃ - sodium triacetoxyborohydride

NaHCO₃ - sodium bicarbonate

Na₂SO₄ - sodium sulfate

NH₃ - ammonia

NH₄CI - ammonium chloride

NIS - N-iodosuccinimide

P(Cy)₃ or PCy₃ - tricyclohexylphosphine

P(t-Bu)₃HBF₄ - tri-tert-buty lphosphonium tetrafluoroborate

Pd/C - palladium on carbon

Pd₂(dba)₃ - tris(dibenzylideneacetone)dipalladium(0)

Pd₂(dba)₃CHCl₃ - tris(dibenzylidenacetone)dipalladium(0) chloroform Pd(dppf)Cl₂.CH₂Cl₂ - [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)or dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II), complexed with dichloromethane

Pd(PPh₃)₄ - tetrakis(triphenylphosphine)palladium(0)

Pd(PPh₃)₂Cl₂ - bis(triphenylphosphine)palladium(II) dichloride

PE - petroleum ether

PMBCl - 4-methoxybenzylchloride

POCl₃ - phorphorus oxychloride pTsA - p-toluenesulfbnic acid r.t. - room temperature

Sn₂(n-Bu)₆ - hexabutylditin

TBAF - tetrabutyl ammonium fluoride

TBSCl - tert-butyldimethylsilyl chloride or tert-butyldimethylchlorosilane [Rh(COD)Cl]₂ - chloro(1,5-cyclooctadiene)rhodium(I) dimer TEA - triethylamine

TFA- trifluoroacetic acid or 2,2,2-trifluoroacetic acid THF - tetrahydrofuran THP - tetrahydropyran TsOH - p-toluenesulfonic acid A. Synthetic Procedures General Procedure

[0207] The compounds of Formula I, la, and lb, may be prepared from commercially available reagents using the synthetic methods and reaction schemes herein, or using other reagents and conventional methods well known to those skilled in the art. For instance, compounds of the present invention may be prepared according to the general reaction Scheme I:

Reaction Scheme I.

[0208] Compounds of Formula (I) wherein all of the substituents are as defined for Formula I can be prepared according to Scheme I. In step A, compound (1) is reacted with compound (2), following Ullmann reaction conditions or Pd catalyzed coupling reaction conditions, to give compound (3). In step B, compound (3) is subjected to Mitsunobu reaction conditions to afford compound (4). The hydroxy group in compound (4) is first activated and then reacted with tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate to generate compound (5). Following Suzuki coupling conditions, compound (5) is reacted with compound (6) to afford compound (7). The Boc group in compound (7) is removed by treatment with an acid such as TFA to give compound of formula (I). If atropisomers exist for compound of formula (I), the diastereoisomers can be separated by chiral separation or regular chromatography separation. [0209] Example la and lb: (12S)-8-(2-amino-7-fluoro-3a,4,7,7a-tetrahydro-1,3- benzothiazol-4-yl)-7-chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-12-(methoxymethyl)- 10-thia-1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one (la), and (12S)-8-(2- amino-7-fluoro-5,6-dihydro-1,3-benzothiazol-4-yl)-7-chloro-4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-12-(methoxymethyl)-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one (lb)

[0210] Intermediate 1: (2R)-1-methoxy-3-sulfanyl-propan-2-ol

[0211] To a solution of (2S)-2-(methoxymethyl)oxirane (10 g, 113.5 mmol, 10 mL, 1 eq), trimethyl(trimethylsilylsulfanyl)silane (26.33 g, 147.55 mmol, 30.9 mL, 1.3 eq) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1 M, 56.7 mL, 0.5 eq) at 0 °C. Then the mixture was stirred at 25 °C for 1 hour. TLC showed the reaction was completed. The reaction mixture was concentrated in reduced pressure to give a residue which was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 1/0 to 10/1) to afford the desired product (8 g, 65.47 mmol, 57% yield) as a colorless oil. ¹H

NMR: (400 MHz, CHLOROFORM-d) δ: 3.90 - 3.75 (m, 1H), 3.54 - 3.42 (m, 2H), 3.41 - 3.37 (m, 3H), 2.86 - 2.54 (m, 3H), 1.49 (t, J= 8.6 Hz, 1H).

[0212] Step 1: 2-amino-4-bromo-5-chloro-3-iodo-benzoic acid

[0213] To a solution of 2-amino-4-bromo-5-chloro-benzoic acid (48 g, 191.63 mmol, 1 eq) in N,N-dimethylformamide (200 mL) was added N-iodosuccinimide (64.67 g, 287.45 mmol, 1.5 eq) and p-toluenesulfonic acid monohydrate (6.60 g, 38.33 mmol, 0.2 eq). The mixture was stirred at 70 °C for 1 h. LCMS showed the reaction was completed. The mixture was cooled to 25 °C, and the mixture was poured into water (5000 mL). The mixture was filtered and the filter cake was collected and dried by rotary evaporator to give the desired product (70 g, 185.99 mmol, 97% yield) as a brown solid. The product was used into the next step without further purification. LCMS: (ESI, m/z): 375.8 [M+1]⁺. 1H NMR: (400 MHz, DMSO-d₆) δ: 7.92 (s, 1H), 7.27 - 6.85 (m, 2H).

[0214] Step 2: 7-bromo-6-chloro-8-iodo-1H-quinazoline-2,4-dione

[0215] A mixture of 2-amino-4-bromo-5-chloro-3-iodo-benzoic acid (70 g, 185.99 mmol, 1 eq) in urea (112 g, 1.86 mol, 100 mL, 10 eq) was stirred at 200 °C for 1 h under nitrogen. LCMS showed the reaction was completed. The mixture was cooled to 25 °C, and the mixture was poured into water (8000 mL). The mixture was filtered and the filter cake was collected and dried by rotary evaporator to give the desired product (26 g, 64.78 mmol, 35% yield) as a white solid. The product was used into the next step without further purification. LCMS: (ESI, m/z): 401.9 [M+1]⁺; Ή NMR: (400 MHz, DMSO-d₆) δ: 9.62 (s, 1H), 8.09 (s, 1H). [0216] Step 3: 7-bromo-6-chloro-8-[(2R)-2-hydroxy-3-methoxy-propyl]sulfanyl-1H- quinazoline-2,4-dione

[0217] To a solution of (2R)-1-methoxy-3-sulfanyl-propan-2-ol (2 g, 16.37 mmol, 1.4 eq), 7-bromo-6-chloro-8-iodo-1H-quinazoline-2,4-dione (4.69 g, 11.69 mmol, 1 eq) in dioxane (30 mL) was added tris(dibenzylideneacetone)dipalladium(0) (1.07 g, 1.17 mmol, 0.1 eq),

4,5-Bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (676 mg, 1.17 mmol, 0.1 eq) and potassium carbonate (3.23 g, 23.38 mmol, 2 eq). The mixture was stirred at 50 °C for 12 h. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated in reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18250*80mm*10 um;mobile phase: [water(0.1%TFA)-

ACN];B%:25%-50%,20min) to afford the desired product (2 g, 5.05 mmol, 43% yield) as a white solid. LCMS: (ESI, m/z): 396.9 [M+1]⁺; ¹H NMR: (400 MHz, CHLOROFORM- d) δ: 9.81 (s, 1H), 9.02 (br s, 1H), 8.20 (s, 1H), 3.84 (dt, J= 3.5, 6.1 Hz, 1H), 3.57 - 3.44 (m, 2H), 3.42 (s, 3H), 3.08 (dd, J= 3.3, 13.6 Hz, 1H), 2.92 - 2.80 (m, 1H) [0218] Step 4: (12S)-8-bromo-7-chloro-4-hydroxy-12-(methoxymethyl)-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one

[0219] To a solution of 7-bromo-6-chloro-8-[(2R)-2-hydroxy-3-methoxy-propyl]sulfanyl- 1H-quinazoline-2,4-dione (2 g, 5.05 mmol, 1 eq) in tetrahydrofuran (100 mL) was added triphenylphosphine (5.30 g, 20.22 mmol, 4 eq) and diisopropyl diazene-1,2-dicarboxylate (4.09 g, 20.22 mmol, 3.9 mL, 4 eq). The mixture was stirred at 25 °C for 1 hr. TLC showed the reaction was completed. The reaction mixture was concentrated in reduced pressure to give a residue which was purified by chiral SFC (column: Welch Ultimate XB- SiOH 250*50*10um; mobile phase: [Hexane-EtOH(0.1% FA)];B%: 1%-25%,15min) to give the desired product (1.9 g, 5.03 mmol, 99 % yield) as a colorless oil. ¹H NMR: (400 MHz, CHLOROFORM-d) δ : 9.03 (br s, 1H), 8.08 (s, 1H), 5.51 (tdd, J= 3.0, 5.8, 8.8 Hz, 1H), 3.68 (t, J= 9.0 Hz, 1H), 3.55 - 3.49 (m, 1H), 3.42 (s, 4H), 3.15 (dd, J= 2.9, 13.7 Hz, 1H). [0220] Step 5: tert-butyl 3-[(12S)-8-bromo-7-chloro-12-(methoxymethyl)-2-oxo-10-thia-

1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0221] To a solution of (12S)-8-bromo-7-chloro-4-hydroxy-12-(methoxymethyl)-10-thia-

1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one (300 mg, 0.79 mmol, 1 eq) in acetonitrile (10 mL) was addedp-tolylsulfonyl 4-methylbenzenesulfonate (518 mg, 1.59 mmol, 2 eq) and potassium carbonate (1.10 g, 7.94 mmol, 10 eq). The mixture was stirred at 25 °C for 1 h. After the reaction was completed, tert- butyl (1S,5R)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (505 mg, 2.38 mmol, 3 eq) was added and the mixture was stirred at 25 °C for 30 min. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated in reduced pressure to give a residue whiuch was purified by prep-TLC (Petroleum ether/Ethyl acetate = 1/1) to generate the desired product (130 mg, 0.22 mmol, 28% yield) as a white solid. ¹H NMR: (400 MHz, CHLOROFORM-d) δ : 7.48 (s, 1H), 5.59 - 5.37 (m, 1H), 4.91 - 4.54 (m, 1H), 4.47 - 4.22 (m, 2H), 4.01 - 3.86 (m, 1H), 3.84 - 3.56 (m, 3H), 3.49 (dd, J= 2.8, 13.2 Hz, 1H), 3.42 (s, 3H), 3.37 - 3.22 (m, 1H), 3.13 (dd, J= 2.4, 13.6 Hz, 1H), 2.05 - 1.79 (m, 3H), 1.51 (s, 10H). [0222] Step 6: tert- butyl 3-[(12S)-8-[2-( tert-butoxycarbonylamino)-7-fluoro-1,3- benzothiazol-4-yl]-7-chloro-12-(methoxymethyl)-2-oxo-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0223] To a solution of tert-butyl 3-[(12S)-8-bromo-7-chloro-12-(methoxymethyl)-2-oxo-

10-thia-1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 0.18 mmol, 1 eq) and [2-( tert- butoxycarbonylamino)-7-fluoro-1,3-benzothiazol-4-yl]boronic acid (68 mg, 0.22 mmol,

1.2 eq) in dioxane (3 mL) and water (0.6 mL) was added sodium carbonate (45 mg, 0.55 mmol, 3 eq) and ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (24 mg, 0.036 mmol, 0.2 eq). The mixture was stirred at 100 °C for 3 hr. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated in reduced pressure to give a residue which was purified by prep-TLC (Dichloromethane/Methanol= 10/1) to afford the desired product (105 mg, 0.14 mmol, 75% yield) as a yellow solid. LCMS: (ESI, m/z): 759.3 [M+1]⁺, ¹H NMR: (400 MHz, CHLOROFORM-d) δ: 7.54 (s, 1H), 7.17 - 7.08 (m, 2H), 4.73 - 4.62 (m, 1H), 4.46 - 4.19 (m, 4H), 4.15 - 4.02 (m, 2H), 3.73 - 3.57 (m, 5H), 3.39 (d, J= 1.6 Hz, 3H), 1.68 (br s, 4H), 1.55 (s, 18H). [0224] Step 7: (12S)-8-(2-amino-7-fluoro-3a,4,7,7a-tetrahydro-1,3-benzothiazol-4-yl)-7- chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-12-(methoxymethyl)-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one (la), and (12S)-8-(2-amino-7- fluoro-5,6-dihydro-1,3-benzothiazol-4-yl)-7-chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)- 12-(methoxymethyl)-10-thia-1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one (lb)

[0225] To a solution of tert-butyl 3-[(12S)-8-[2-(tert-butoxycarbonylamino)-7-fluoro-1,3- benzothiazol-4-yl]-7-chloro-12-(methoxymethyl)-2-oxo-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (100 mg, 0.13 mmol, 1 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL, 205 eq). The mixture was stirred at 25 °C for 3 h. LCMS showed the reaction was completed. The reaction mixture was concentrated in reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10um;mobile phase: [water(0.225%FA)- ACN];B%: 14%-41%,9min) and prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10um;mobile phase: [water(0.225%FA)-ACN];B%: 10%-40%,10min) to the desired product 1a (21 mg, 0.037 mmol, 28% yield) as a white solid, and 1b (15 mg, 0.27 mmol, 21% yield) as a white solid. Compound 1a: LCMS: (ESI, m/z): 559.2 [M+1]⁺, ¹H NMR: (400 MHz, DMSO-d₆) δ: 8.26 (s, 1H), 7.99 (s, 2H), 7.58 (s, 1H), 7.13 - 6.98 (m, 2H), 5.16 - 5.13 (m, 1H), 4.51 (d, J= 12.8 Hz, 1H), 3.40 - 3.34 (m, 1H), 3.68 - 3.64 (m, 2H), 3.55-3.40 (m, 3H), 3.27 (s, 3H), 3.24 - 3.15 (m, 3H), 3.10 - 3.05 (m, 1H), 1.81 - 1.45 (m, 4H). Compound 1b: LCMS: (ESI, m/z): 559.2 [M+1]⁺, ¹H NMR: EW29049-32-P2A (400 MHz, DMSO-d₆)δ: 8.28 (d, J= 2.4 Hz, 1H), 7.98 (s, 2H), 7.62 (s, 1H), 7.19 - 7.02 (m, 2H), 5.33 - 4.94 (m, 1H), 4.62 - 4.41 (m, 1H), 3.86 - 3.82 (m, 1H), 3.68 - 3.64 (m, 2H), 3.54 (d, J= 1.6 Hz, 2H), 3.36 - 3.30 (m, 3H), 3.25 - 3.18 (m, 4H), 3.04 - 2.98 (m, 1H), 1.85 - 1.42 (m, 4H).

[0226] Example 2a and 2b: (12S)-8-(2-amino-7-fluoro-1,3-benzothiazol-4-yl)-7-chloro- 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-12-[(4-ethylpiperazin-1-yl)methyl]-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one (2a) and (12S)-8-(2-amino-7- fluoro-1,3-benzothiazol-4-yl)-7-chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-12-[(4- ethylpiperazin-1-yl)methyl]-10-thia-1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8- tetraen-2-one (2b)

[0227] Step 1: tert- butyl 4-[(2R)-3-[(7-bromo-6-chloro-2,4-dioxo-1H-quinazolin-8- yl)sulfanyl]-2-hydroxy-propyl]piperazine-1-carboxylate

[0228] To a solution of 7-bromo-6-chloro-8-iodo-lH-quinazoline-2,4-dione (1.94 g, 4.82 mmol, 1 eq) and tert-butyl 4-[(2R)-2-hydroxy-3-sulfanyl-propyl]piperazine-1-carboxylate (2 g, 7.24 mmol, 1.5 eq) in dioxane (60 mL) was added tris(dibenzylideneacetone)dipalladium(0) (441 mg, 0.48 mmol, 0.1 eq), 4,5-

Bis(diphenylphosphino)-9,9-dimethylxanthene (279 mg, 0.48 mmol, 0.1 eq), and potassium carbonate (1.33 g, 9.65 mmol, 2 eq). The mixture was stirred at 90 °C for 12 h. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated in reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um); mobile phase: [water(0.1%TFA)- ACN];B%: 20%-45%,25min to give the desired product (1.4 g, 2.55 mmol, 52% yield) as a colorless white solid. LCMS: (ESI, m/z): 551.1 [M+1]⁺, ¹H NMR: (400 MHz, CHLOROFORM-d) δ: 10.58 - 8.91 (m, 1H), 8.16 (s, 1H), 3.98 - 3.88 (m, 1H), 3.73 (q, J = 6.8 Hz, 1H), 3.45 (br s, 4H), 3.07 (dd, J= 3.2, 13.6 Hz, 1H), 2.80 (dd, J= 7.6, 13.6 Hz, 1H), 2.59 (br d, J= 4.4 Hz, 2H), 2.52 - 2.34 (m, 4H), 1.45 (s, 9H).

[0229] Step 2: tert-butyl 4-[[(12S)-8-bromo-7-chloro-4-hydroxy-2-oxo-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-12-yl]methyl]piperazine-1-carboxylate

[0230] To a solution of tert-butyl 4-[(2R)-3-[(7-bromo-6-chloro-2,4-dioxo-1H-quinazolin- 8-yl)sulfanyl]-2-hydroxy-propyl]piperazine-1-carboxylate (1.4 g, 2.55 mmol, 1 eq) in tetrahydrofuran (40 mL) was added triphenylphosphine (2.67 g, 10.18 mmol, 4 eq) and diisopropyl azodicarboxylate (2.06 g, 10.18 mmol, 2.0 mL, 4 eq). The mixture was stirred at 25 °C for 1 hr. TLC showed the reaction was completed. The reaction mixture was concentrated in reduced pressure to give a residue which was purified by chiral-SFC (column: Welch Ultimate XB-SiOH 250*50* 10um;mobile phase: [Hexane-EtOH(0.1 % FA)];B%: l%-30%,15min) to afford the desired product (1.4 g, 2.37 mmol, 93% yield, 90% purity) as a colorless oil. LCMS: (ESI, m/z): 533.2 [M+1]⁺. [0231] Step 3: (12S)-8-bromo-7-chloro-4-hydroxy-12-(piperazin-1-ylmethyl)-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one

[0232] To a solution of tert- butyl 4-[[(12S)-8-bromo-7-chloro-4-hydroxy-2-oxo-10-thia-

1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-12-yl]methyl]piperazine-1- carboxylate (1.2 g, 2.26 mmol, 1 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (4.62 g, 40.52 mmol, 3 mL, 17.96 eq). The mixture was stirred at 25 °C for 0.5 h. LCMS showed the reaction was completed. The reaction mixture was concentrated in reduced pressure to give a yellow oil (1.2 g, 2.20 mmol, 97% yield, trifluoroacetate). The product was used into next step without purification. LCMS: (ESI, m/z): 433.0 [M+1]⁺. [0233] Step 4: (12S)-8-bromo-7-chloro-12-[(4-ethylpiperazin-1-yl)methyl]-4-hydroxy-10- thia-1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one

[0234] To a solution of (12S)-8-bromo-7-chloro-4-hydroxy-12-(piperazin-1-ylmethyl)-10- thia-1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one (1.2 g, 2.20 mmol, 1 eq, trifluoroacetate) and acetaldehyde (146 mg, 3.30 mmol, 0.2 mL, 1.5 eq) in ethanol (5 mL) was added triethylamine (222 mg, 2.20 mmol, 0.3 mL, 1 eq) and sodium triacetoxyborohydride (699 mg, 3.30 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed the reaction was completed. The reaction mixture was concentrated in reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um);mobile phase: [water(0.225%FA)-ACN];B%: 17%-47%,21min) to give the desired product (130 mg, 0.28 mmol, 12% yield) as a yellow solid. LCMS: (ESI, m/z): 461.0 [M+1]⁺.

[0235] Step 5: tert- butyl 3-[(12S)-8-bromo-7-chloro-12-[(4-ethylpiperazin-1-yl)methyl]-

2-oxo-10-thia-1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0236] To a solution of (12S)-8-bromo-7-chloro-12-[(4-ethylpiperazin-1-yl)methyl]-4- hydroxy-10-thia-1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one (130 mg, 0.28 mmol, 1 eq) in acetonitrile (5 mL) was added p-tolylsulfonyl 4- methylbenzenesulfonate (184 mg, 0.56 mmol, 2 eq) and potassium carbonate (390 mg, 2.83 mmol, 10 eq). The mixture was stirred at 25 °C for 1 h, then tert- butyl (lS,5R)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 0.84 mmol, 3 eq) was added to the reaction mixture. The mixture was stirred at 25 °C for 0.5 h. LCMS showed the reaction was completed. The reaction mixture was concentrated in reduced pressure to give a residue which was purified by prep-TLC (Petroleum ether/Ethyl acetate = 1/1) to generate the desired product (80 mg, 0.12 mmol, 43% yield) as a yellow solid. LCMS: (ESI, m/z): 655.2 [M+1]⁺.

[0237] Step 6: tert- butyl 3-[(12S)-8-[2-( tert-butoxycarbonylamino)-7-fluoro-1,3- benzothiazol-4-yl]-7-chloro-12-[(4-ethylpiperazin-1-yl)methyl]-2-oxo-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0238] To a solution of [2-(tert-butoxycarbonylamino)-7-fluoro-1,3-benzothiazol-4- yl]boronic acid (34 mg, 0.11 mmol, 1.2 eq) and tert- butyl 3-[(12S)-8-bromo-7-chloro-12- [(4-ethylpiperazin-1-yl)methyl]-2-oxo-10-thia-1,3-diazatricyclo[7.3.1.0^5,13]trideca- 3,5(13),6,8-tetraen-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.091 mmol, 1 eq) in dioxane (2 mL) and water (0.4 mL) was added sodium carbonate (22 mg, 0.27 mmol, 3 eq) and ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (12 mg, 0.018 mmol, 0.2 eq). The reaction mixture was stirred at 100 °C for 3 hr. LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated in reduced pressure to give a residue which was purified by prep-TLC

(Dichloromethane/Methanol = 10/1) to yield the desired product (65 mg, 0.77 mmol, 84% yield) as a yellow oil. LCMS: (ESI, m/z): 841.2 [M]⁺.

[0239] Step 7: (12S)-8-(2-amino-7-fluoro-1,3-benzothiazol-4-yl)-7-chloro-4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-12-[(4-ethylpiperazin-1-yl)methyl]-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-2-one (2a) and (12S)-8-(2-amino-7- fluoro-1,3-benzothiazol-4-yl)-7-chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-12-[(4- ethylpiperazin-1-yl)methyl]-10-thia-1,3-diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8- tetraen-2-one (2b)

[0240] To a solution of tert-butyl 3-[(12S)-8-[2-(tert-butoxycarbonylamino)-7-fluoro-1,3- benzothiazol-4-yl]-7-chloro-12-[(4-ethylpiperazin-1-yl)methyl]-2-oxo-10-thia-1,3- diazatricyclo[7.3.1.0^5,13]trideca-3,5(13),6,8-tetraen-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (65 mg, 0.077 mmol, 1 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (3.64 g, 31.92 mmol, 2.4 mL, 413.26 eq). The reaction mixture was stirred at 25 °C for 0.5 hr. LCMS showed the reaction was completed. The reaction mixture was concentrated in reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25mm* 10um;mobile phase: [water(0.225%FA)-ACN];B%:0%-29%,10min) to give two eluents which were assigned compound 2a and 2b.

[0241] Compound 2a (9 mg, 0.013 mmol, 17% yield, 95% purity) was obtained as a white solid. LCMS: (ESI, m/z): 641.2 [M]⁺. ¹H NMR: (400 MHz, DMSO-d₆) δ: 8.18 (s, 1H), 7.96 (s, 2H), 7.56 (s, 1H), 7.15 - 7.06 (m, 1H), 7.06 - 6.99 (m, 1H), 5.30 - 5.05 (m, 1H), 4.49 . 4.25 (m, 1H), 4.05 (br d, J = 11.7 Hz, 1H), 3.58 (br d, J= 2.0 Hz, 3H), 3.22 - 3.14

(m, 4H), 2.95 - 2.89 (m, 1H), 2.70 - 2.60 (m, 2H), 2.42 - 2.24 (m, 9H), 1.66 (br dd, J= 1.6, 11.6 Hz, 4H), 0.96 (t, J= 7.2 Hz, 3H).

[0242] Compound 2b (10 mg, 0.15 mmol, 19% yield, 94% purity) was obtained as a white solid. LCMS: (ESI, m/z): 641.2 [M]⁺. ¹H NMR: (400 MHz, DMSO-d₆) δ: 8.19 (s, 1H), 7.94 (s, 2H), 7.57 (s, 1H), 7.15 - 6.95 (m, 2H), 5.17 (br dd, J= 3.2, 5.2 Hz, 1H), 4.40 (br d,

J= 10.8 Hz, 1H), 4.01 (br d , J= 13.2 Hz, 1H), 3.59 - 3.53 (m, 4H), 3.23 - 3.18 (m, 3H), 3.05 - 2.99 (m, 1H), 2.65 - 2.57 (m, 2H), 2.38 - 2.20 (m, 9H), 1.73 - 1.56 (m, 4H), 0.96 (t, J= 7.2 Hz, 3H).

[0243] Example 3: (3ri)-10-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-7-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H- [1,4]thiazino[2,3,4-ij]quinazolin-5-one

[0244] Step 1: (R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-methoxypropyl)thio)-6- (trifluoromethyl)quinazolin-2(1H)-one

[0245] A mixture of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

(972 mg, 2.49 mmol, 1 eq), (R)- 1 -mercapto-3-methoxypropan-2-ol (761 mg, 6.228 mmol, 2.5 eq), tris(dibenzylideneacetone)dipalladium(0) (228 mg, 0.249 mmol, 0.1 eq), 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene (145 mg, 0.249 mmol, 0.1 eq) and potassium carbonate (1.03 g, 4.47 mmol, 3 eq) in dioxane (100 mL) under nitrogen atmosphere was stirred at 90 °C for 2 hours. After cooling down, the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluted by dichloromethane: methanol to give the product (880 mg, 2.29 mmol, 90% yield) as light-yellow solid. LCMS (ESI, m/z): 383.1 [M+1]⁺. [0246] Step 2: (S)- 10-chloro-7-hydroxy-3-(methoxymethyl)-9-(trifluoromethyl)-2,3- dihydro-5H-[1.4|thiazino[2.3.4-ij]quinazolin-5-one

[0247] To a solution of (R)-7-chloro-4-hydroxy-8-((2-hydroxy-3-methoxypropyl)thio)-6- (trifluoromethyl)quinazolin-2(1H )-one (880 mg, 2.28 mmol, 1 eq) and triphenylphosphine (1.79 g, 6.86 mmol, 3 eq) in THF (100 mL) at room temperature was added diisopropyl azodicarboxylate (1.38 g, 6.86 mmol, 3 eq). The resulting solution was stirred at room temperature for 30 minute before concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluted by dichloromethane: ethyl acetate to give the product (670 mg, 1.83 mmol, 80 % yield) as light-yellow solid. LCMS (ESI, m/z): 365.1 [M+1]⁺.

[0248] Step 3: tert-butyl (1R,5S)-3-((S)- 10-chloro-3-(methoxymethyl)-5-oxo-9- (trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0249] To a solution of (S)-10-chloro-7-hydroxy-3-(methoxymethyl)-9-(trifluoromethyl)- 2.3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-5-one (335 mg, 0.91 mmol, 1 eq ) in acetonitrile (30 mL) was added p-tolylsulfonyl 4-methylbenzenesulfonate (596 mg, 1.83 mmol, 2 eq) and potassium carbonate (1.51 g, 10.96 mmol, 12 eq). The mixture was stirred at room temperature for 1 hour before adding N,N-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (581 mg, 2.74 mmol, 3 eq). The resulting solution was stirred at room temperature for 1 hour before concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluted by dichloromethane: ethyl acetate to give the product (210 mg, 0.374 mmol, 40 % yield) as light-yellow solid. LCMS (ESI, m/z): 562.3 [M+1]⁺. ¹H NMR: (400MHz, CDCl₃) δ: 7.66 (s, 1H), 5.44 - 5.36 (m, 1H), 5.00 - 4.89 (m, 1H), 4.32 - 4.23 (m, 2H), 3.84 - 3.56 (m, 1H), 3.67 - 3.54 (m,3H), 3.50 (dd, 1H), 3.39 (s, 3H), 3.32 - 3.22 (m, 1H), 3.07 (dd, 1H), 1.96 - 1.82 (m, 3H), 1.48 (s, 10H). [0250] Step 4: tert- butyl (1R,5S)-3-((3S)- 10-(2-((tert-butoxycarbonyl)amino)-7- fluorobenzo[d]thiazol-4-yl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0251] A mixture of tert-butyl ( 1 R.5S)-3-((S)- 10-chloro-3-(methoxymethyl)-5-oxo-9- (trifluoromethyl)-2.3-dihydro-5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3.8- diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.0535 mmol, 1 eq), [2-(tert- butoxycarbonylamino)-7-fluoro-1,3-benzothiazol-4-yl]boronic acid (20 mg, 0.064 mmol, 1.2 eq), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) (12 mg, 0.016 mmol, 0.3 eq) and tripotassium phosphate (34 mg, 0.16 mmol, 3 eq) in dioxane: water (4:1, 5 mL) under nitrogen atmosphere was stieed at 90 °C for 30 minutes. After cooling down, the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluted by dichloromethane: ethyl acetate to give the product (15 mg, 0.018 mmol, 35 % yield) as light-yellow oil. LCMS (ESI, m/z): 793.3 [M+1]⁺.

[0252] Step 5: (3ri)-10-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-7-((1R,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-3-(methoxymethyl)-9-(trifluoromethyl)-2,3-dihydro-5H-

[1,4]thiazino[2,3,4-ij]quinazolin-5-one

[0253] To a solution of tert-butyl (1R,5S)-3-((3S)-10-(2-((tert-butoxycarbonyl)amino)-7- fluorobenzo[d]thiazol-4-yl)-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)-2,3-dihydro- 5H-[1,4]thiazino[2,3,4-ij]quinazolin-7-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15 mg, 0.018 mmol, 1 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for 2.5 hours. After concentrated under reduced pressure, the resulting residue was purified by prep-HPLC (acetonitrile/water/1 % formic acid) as white solid (3.0 mg, 27% yield). LCMS (ESI, m/z): 593.3 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD) δ: 7.78 (s, 1H), 7.04 - 6.83 (m, 2H), 5.26 - 5.15 (m, 1H), 4.29 - 3.79 (m, 4H), 3.69 - 3.39 (m, 4H), 3.26 (s, 3H), 3.07 - 2.86 (m, 2H), 2.20 - 2.09 (m, 1H), 2.03 - 1.75 (m, 3H).

[0254] Example 4: (12S)-8-(2-amino-7-fluoro-1,3-benzothiazol-4-yl)-7-chloro-4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-12-morpholino-10-thia-1,3- diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-2-one

[0255] Step 1: benzyl N-[(1S)-1-[(7-bromo-6-chloro-4-hydroxy-2-oxo-1H-quinazolin-8- yl)sulfanyImethyl] -2- [tert-butyl (diphenyl)silyl] oxy-ethyl] carbamate

[0256] A mixture of benzyl N-[(1S)-1-[[tert-butyl(diphenyl)silyl]oxymethyl]-2-sulfanyl- ethyl] carbamate (13 g, 27.10 mmol, 1 eq), 7-bromo-6-chloro-8-iodo-1H-quinazoline-2,4- dione (10.88 g, 27.10 mmol, 1 eq), cuprous iodide (2.06 g, 10.84 mmol, 0.4 eq) and potassium carbonate (11.24 g, 81.30 mmol, 3 eq) in ethylene glycol (70 mL) and isopropylalcohol (130 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 90 °C for 12 hours under nitrogen. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Welch Ultimate XB-SiOH 250*50* 10um;mobile phase: [Hexane-EtOH(0.1% FA)];B%: 1%-20%,15min) to afford the desired product (4.8 g, 6.37 mmol, 24% yield) as a yellow solid. LCMS: (ESI, m/z): 754.1 [M+1]⁺.

[0257] Step 2: benzyl N-[(1S)-1-[(7-bromo-6-chloro-4-hydroxy-2-oxo-1H-quinazolin-8- yl)sulfanyImethyl]-2-hydroxy-ethyl]carbamate

[0258] To a solution of benzyl N-[(1S)-1-[(7-bromo-6-chloro-4-hydroxy-2-oxo-1H- quinazolin-8-yl)sulfanylmethyl] -2- [tert- butyl(diphenyl)silyl ] oxy-ethyl] carbamate (4 g, 5.31 mmol, 1 eq) in tetrahydrofuran (50 mL) was added tetrabutylammonium fluoride (1 M, 26.5 mL, 5 eq). The mixture was stirred at 25 °C for 1 hour. TLC showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 10/1 to 0/1) to give the desired product (2.2 g, 4.27 mmol, 80% yield) as a yellow solid. LCMS: (ESI, m/z): 515.8 [M+1]⁺.

[0259] Step 3: benzyl N-[(12S)-8-bromo-7-chloro-4-hydroxy-2-oxo-10-thia-1,3- diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-12-yl]carbamate

[0260] To a solution of benzyl N-[(1S)-1-[(7-bromo-6-chloro-4-hydroxy-2-oxo-1H- quinazolin-8-yl)sulfanylmethyl] -2 -hydroxy-ethyl] carbamate (2.1 g, 4.08 mmol, 1 eq) in tetrahydrofuran (600 mL) was added triphenylphosphine (4.28 g, 16.32 mmol, 4 eq) and diethyl azodicarboxylate (2.84 g, 16.32 mmol, 2.9 mL, 4 eq). The mixture was stirred at 25 °C for 1 hour. LCMS showed the reaction was completed. The reaction mixture was concentrated in reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Luna C8 250*50mm*10um;mobile phase: [water(TFA)- ACN];B%: 35%-65%,20min). Compound benzyl N-[(12S)-8-bromo-7-chloro-4-hydroxy- 2-oxo-10-thia-1,3-diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-12-yl]carbamate (1.2 g, 2.42 mmol, 59% yield) was obtained as a white solid. LCMS: (ESI, m/z): 497.9 [M+1]⁺.

[0261] Step 4: (12S)-12-amino-8-bromo-7-chloro-4-hydroxy-10-thia-l,3 diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-2-one

[0262] To a solution of benzyl N-[(12S)-8-bromo-7-chloro-4-hydroxy-2-oxo-10-thia-1,3- diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-12-yl]carbamate (1 g, 2.01 mmol, 1 eq) in trifluoroacetic acid (1 mL) was added trifluoromethanesulfonicacid (170 mg, 1.13 mmol, 0.1 mL, 0.5 eq) and trifluoroacetic acid (3.08 g, 27.01 mmol, 2.0 mL, 13.42 eq). The mixture was stirred at 0 °C for 10 minutes. LCMS showed the reaction was completed. The reaction mixture was quenched by the addition of water (50 mL) at 0 °C. Triethylamine was added to adjust the pH = 9, then the mixture was extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C8250*50mm*10um;mobile phase: [water(FA)-ACN];B%: 5%-30%,20min) to give the desired product (700 mg, 1.71 mmol, 85% yield, formate) as a white solid. LCMS: (ESI, m/z): 364.1 [M+1]⁺. ¹H NMR: (400 MHz, DMSO-d6) δ: 8.18 (s, 1H), 7.91 (s, 1H), 5.30 (s, 2H), 3.22 (br s, 1H), 3.09 (br d, J= 2.4 Hz, 1H), 3.00 (br dd, J= 6.8, 13.2 Hz, 2H), 2.85 (br d, J= 6.8 Hz, 1H).

[0263] Step 5: (12S)-8-bromo-7-chloro-4-hydroxy-12-morpholino-10-thia-1,3- diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-2-one

[0264] To a solution of 2-(2-oxoethoxy)acetaldehyde (126.69 mg, 1.24 mmol, 1.5 eq) in acetonitrile (10 mL) and water (10 mL) was added (12S)-12-amino-8-bromo-7-chloro-4- hydroxy-10-thia-1,3-diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-2-one (300 mg, 0.83 mmol, 1 eq). The reaction mixture was stirred at 25°C for 5 minutes. Then sodium cyanoborohydride (260 mg, 4.14 mmol, 5 eq) was added. The mixture was stirred at 25 °C for 15 minutes. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (9% methanol in dichloromethane) to generate the desired product (290 mg, 0.67 mmol, 81% yield) as a white solid. LCMS: (ESI, m/z): 433.9 [M+1]⁺. [0265] Step 6: tert- butyl 3-[(12S)-8-bromo-7-chloro-12-morpholino-2-oxo-10-thia-1,3- diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-4-yl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate

[0266] To a solution of (12S)-8-bromo-7-chloro-4-hydroxy-12-morpholino-10-thia-1,3- diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-2-one (290 mg, 0.67 mmol, 1 eq) in dichloromethane (20 mL) was added trifluoromethanesulfonicanhydride (567 mg, 2.01 mmol, 3 eq) and potassium carbonate (926 mg, 6.70 mmol, 10 eq). The mixture was stirred at 25 °C for 10 minutes, then tert- butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (285 mg, 1.34 mmol, 2 eq) was added. The recti on mixture was stirred at 25 °C for 0.5 hour. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get the crude product which was purified by prep-HPLC (column: Phenomenex luna Cl 8 (250*70mm,10 um);mobile phase: [water(TFA)-ACN];B%: 20%-50%,20min) to afford the desired product (200 mg, 0.32 mmol, 48% yield) as a white solid. LCMS: (ESI, m/z): 628.1 [M+1]⁺. [0267] Step 7: tert-butyl 3-[(12S)-8-[2-( tert-butoxycarbonylamino)-7-fluoro-1,3- benzothiazol-4-yl] -7 -chloro- 12-morpholino-2-oxo- 10-thia- 1,3- diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-4-yl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate

[0268] A mixture of tert-butyl 3-[(12S)-8-bromo-7-chloro-12-morpholino-2-oxo-10-thia-

1,3-diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.08 mmol, 1 eq), [2 -(tert- butoxycarbonylamino)-7-fluoro-1,3-benzothiazol-4-yl]boronic acid (30 mg, 0.09 mmol, 1.2 eq), sodium carbonate (25 mg, 0.24 mmol, 3 eq), ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (5.20 mg, 0.008 mmol, 0.1 eq) in dioxane (3 mL) and water (0.6 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 1 hour in nitrogen. LCMS showed the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (9% methanol in dichloromethane) to give the desired product (60 mg, 0.07 mmol, 92% yield) as a yellow oil. LCMS: (ESI, m/z): 814.1[M+1]⁺. [0269] Step 8: (12S)-8-(2-amino-7-fluoro-1,3-benzothiazol-4-yl)-7-chloro-4-(3,8- diazabicyclo[3.2.1]octan-3-yl)-12-morpholino-10-thia-1,3- diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-2-one

[0270] To a solution of tert-butyl 3-[(12S)-8-[2-(tert-butoxycarbonylamino)-7-fluoro-1,3- benzothiazol-4-yl] -7 -chloro- 12-morpholino-2-oxo- 10-thia- 1,3- diazatricyclo[7.4.1.0^5,14]tetradeca-3,5(14),6,8-tetraen-4-yl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (60 mg, 0.07 mmol, 1 eq) in dichloromethane (0.5 mL) was added trifluoroacetic acid (924 mg, 8.10 mmol, 109.99 eq). The mixture was stirred at 25 °C for 5 minutes. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water(FA)-ACN];B%: 5%- 35%,7min) to give example 4 ( (24.48 mg, 0.04 mmol, 50% yield, 100% purity, formate) as a yellow solid. LCMS: (ESI, m/z): 614.1[M+1]⁺. ¹H NMR: (400 MHz, DMSO-d₆) δ : 8.18 (s, 1H), 7.93 (br d, J= 9.6 Hz, 2H), 7.59 (s, 1H), 7.15 - 6.90 (m, 2H), 5.21 (br d, J = 4.4 Hz, 1H), 4.51 - 4.31 (m, 1H), 4.03 (br d, J= 12.0 Hz, 1H), 3.79 - 3.66 (m, 5H), 3.62 (br d , J = 6.0 Hz, 1H), 3.08 - 2.91 (m, 1H), 2.71 - 2.62 (m, 1H), 2.60 - 2.50 (m, 4H), 2.44 -

2.31 (m, 4H), 1.85 - 1.68 (m, 4H), 1.24 (s, 1H).

[0271] Example 5a and 5b: (R)-11'-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8'- (piperazin-1-yl)-10'-(trifluoromethyl)-2'H,4'H,6'H-spiro[cyclobutane-1,3'- [1,4]thiazepino[2,3,4-ij]quinazolin]-6'-one (5a) and (S)-11'-(2-amino-7- fluorobenzo[d]thiazol-4-yl)-8'-(piperazin-1-yl)-10'-(trifluoromethyl)-2'H,4'H,6'H- spiro[cyclobutane-1,3'-[1,4]thiazepino[2,3,4-ij]quinazolin]-6'-one (5b)

[0272] Step 1: (l-(hydroxymethyl)cyclobutyl)methyl 4-methylbenzenesulfonate

[0273] To a mixture of cyclobutane- 1,1-diyldimethanol (5.37 g, 42.22 mmol) and triethyl amine (8.5 g, 84.44 mmol) in dichloromethane (60 mL) was added 4-methylbenzene-1- sulfonyl chloride (7.6 g, 40.1 mmol) at 0 °C. The mixture was stirred at room temperature for 16 hours. After completion, the mixture was concentrated to afford the crude product which was purified by silica gel column with petroleum ether/ethyl acetate = 10/1 to afford the desired product (7.3 g, yield: 64%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.06 (s, 2H), 3.62 (s, 2H), 2.45 (s, 3H), 1.92-1.75 (m, 6H).

[0274] Step 2: (1-(mercaptomethyl)cyclobutyl)methanol

[0275] To a solution of (1-(hydroxymethyl)cyclobutyl)methyl 4-methylbenzenesulfonate (3.7 g, 13.68 mmol) in ethanol (37 mL) was added sodium hydrosulfide (3.1 g, 54.72 mmol, 70% purity) at 0 °C. The mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. After completion, the mixture was filtered and the filtrate was concentrated to afford the crude product which was purified by silica gel column with dichloromethane/methanol = 100/1 to give the desired product (1.3 g, yield: 72%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.70 (s, 2H), 2.76 (d, J=8.4 Hz, 2H), 1.90- 1.75 (m, 6H), 1.25 (t, J= 2.8 Hz, 1H).

[0276] Step 3: 7-chloro-8-(((1-(hydroxymethyl)cyclobutyl)methyl)thio)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione

[0277] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2.5 g, 6.57 mmol) in dioxane (66 mL) were added potassium carbonate (2.7 g, 19.71 mmol), (1-(mercaptomethyl)cyclobutyl)methanol (1.3 g, 9.85 mmol), 4,5-bis(diphenyl- phosphino)-9,9-dimethylxanthene (570 mg, 0.98 mmol) and tris(dibenzylideneacetone) dipalladium (601 mg, 0.66 mmol). The mixture was stirred at 65 °C under nitrogen atmosphere for 16 hours. After completion, the mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were concentrated and the residue was purified by silica column (with 0.2%-1% methanol in dichloromethane) to afford the crude product (1.65 g, yield: 63%) as a yellow solid. MS (ESI) m/z 395.2 [M+H]⁺.

[0278] Step 4: 11-chloro-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4- ij]quinazohne-3,1'-cyclobutane]-6,8(4H,7H)-dione

[0279] To a mixture of 7-chloro-8-(((1-(hydroxymethyl)cyclobutyl)methyl)thio)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (1.65 g, 4.18 mmol) and triphenylphosphine (4.38 g, 16.72 mmol) in tetrahydrofuran (465 mL) was added diethyl azodicarboxylate (2.91 g, 16.72 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. After completion, the mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic phases were concentrated and the residue was purified by silica column (with 0.2%-1% methanol in dichloromethane) to give the desired product (1.5 g, yield: 95%) as a white solid. MS (ESI) m/z 375.1 [ [M+H]⁺.

[0280] Step 5: tert-butyl 4-(11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H- spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,1'-cyclobutan]-8-yl)piperazine-1-carboxylate

[0281] To a mixture of 11-chloro-10-(trifluoromethyl)-2H-spiro[[1,4]thiazepino[2,3,4- ij]quinazoline-3,1'-cyclobutane]-6,8(4H,7H)-dione (600 mg, 1.60 mmol) and potassium carbonate (2.2 g, 16.0 mmol) in acetonitrile (30 mL) and dichloromethane (15 mL) was added 4-methylbenzenesulfonic anhydride (2.1 g, 6.38 mmol) at 25 °C. The mixture was stirred at 25 °C for 6 hours, tert-butyl piperazine- 1-carboxylate (1.2 g, 6.38 mmol) was added into the reaction solution. The reaction mixture was stirred at 25 °C for 1 hour. After completion, the mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phases were concentrated and the residue was purified by flash silica column (with 0.2%-1% methanol in dichloromethane) to afford the desired product (350 mg, yield: 40%) as a pale-yellow solid. MS (ESI) m/z 545.2[M+H]⁺. [0282] Step 6: tert-butyl 4-(11-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol- 4-yl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H-spiro[[1,4]thiazepino[2,3,4- ij]quinazoline-3,1'-cyclobutan]-8-yl)piperazine-1-carboxylate

[0283] To a solution of tert-butyl 4-(11-chloro-6-oxo-10-(trifluoromethyl)-4,6-dihydro- 2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,1'-cyclobutan]-8-yl)piperazine-1- carboxylate (322 mg, 0.59 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added tripotassium phosphate (471 mg, 1.77 mmol), (2-((tert-butoxycarbonyl)amino)-7- fluorobenzo[d]thiazol-4-yl)boronic acid ( US20200115375A1) (240 mg, 0.77 mmol), and methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'- methylamino-1,1'-biphenyl-2-yl)palladium(II) (200 mg, 0.26 mmol). The mixture was stirred at 80 °C under nitrogen atmosphere for 15 min. After completion, the mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1) to afford the desired product (115 mg, yield: 25%) as a yellow solid. MS (ESI) m/z 777.2 [M+H]⁺.

[0284] Step 7: (R)-H'-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8'-(piperazin-1-yl)-10'- (trifluoromethyl)-2'H,4'H,6'H-spiro[cyclobutane-1,3'-[1,4]thiazepino[2,3,4-ij]quinazolin]- 6'-one (5a) and (S)-H'-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8'-(piperazin-1-yl)-10'- (trifluoromethyl)-2'H,4'H,6'H-spiro[cyclobutane-1,3'-[1,4]thiazepino[2,3,4-ij]quinazolin]- 6'-one (5b)

[0285] To a cooled mixture of tert-butyl 4-(11-(2-((tert-butoxycarbonyl)amino)-7- fluorobenzo[d]thiazol-4-yl)-6-oxo-10-(trifluoromethyl)-4,6-dihydro-2H- spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,1'-cyclobutan]-8-yl)piperazine-1-carboxylate (245 mg, 0.32 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL) at

0 °C. The reaction solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with saturated Na₂CO₃ aqueous solution. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 10/1) to afford 11-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-8-(piperazin-1-yl)-10-(trifluoromethyl)- 2H-spiro[[1,4]thiazepino[2,3,4-ij]quinazoline-3,1'-cyclobutan]-6(4H)-one (112 mg, yield: 61%) as a yellow solid. MS (ESI) m/z 577.2 [M+H]⁺.

[0286] The above racemate (112 mg) was dissolved in ethanol (4 mL) and separated by chiral supercritical fluid chromatography (separation condition: Column: IG 5 μm 20 x 250 mm; Mobile Phase: Hexane/ethanol/diethylamine = 75/25/0.2 at 25 mL/min; Temp:

25 °C; Wavelength: 254 nm) to afford the first atropisomer 5a (49 mg, yield: 44 %, 97.46% ee) and the second atropisomer 5b (49 mg, yield: 44%, 100% ee); Chiral HPLC Analytical: on IG was using 5 μm 4.6 × 250 mm column, Mobile Phase: Hexane/ethanol/diethylamine = 75/25/0.2 at 2.5 mL/min; temperature: 25 °C; Wavelength: 254 nm). [0287] 5a: ¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.09-7.06 (m, 1H), 6.96 (t, J= 8.8

Hz, 1H), 5.33 (s, 2H), 4.85-4.47 (m, 2H), 3.81 (s, 4H), 3.07-3.04 (m, 6H), 2.04-1.96 (m, 1H), 1.89-1.84 (m, 1H), 1.75-1.70 (m, 2H). MS (ESI) m/z 577.2 [M+H]⁺. Chiral HPLC fraction 1: e.e. = 97.46%, Rt = 7.235 min.

[0288] 5b: ¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.09-7.06 (m, 1H), 6.96 (t, J= 8.4 Hz, 1H), 5.35 (s, 2H), 4.90-4.54 (m, 2H), 3.82-3.80 (m, 4H), 3.13-3.02 (m, 6H), 2.04-1.97 (m, 1H), 1.89-1.83 (m, 1H), 1.81-1.72 (m, 2H).MS (ESI) m/z 577.2 [M+H]⁺. Chiral HPLC fraction 1: e.e. = 100%, Rt = 8.693 min.

[0289] Example 6: 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(8-fluoro-3- hydroxynaphthalen-1-yl)-2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-4-one (6)

[0290] Step 1: ethyl 4-amino-5-iodo-6-methoxynicotinate

[0291] To a dry dimethylformamide (65 mL) solution of ethyl 4-chloro-5-iodo-6- methoxynicotinate (6.50 g, 19.0 mmol) was added potassium carbonate (3.95 g, 28.5 mmol) and 2,4-dimethoxybenzylamine (3.50 mL, 22.8 mmol) and the mixture was stirred at 60 °C. After 17 hours, the mixture was cooled to room temperature, diluted with water and aqueous ammonium chloride (saturated), and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo after filtration, to give ethyl 4-((2,4-dimethoxybenzyl)amino)-5-iodo-6-methoxynicotinate intermediate as an orange oil. MS: 473.0 [M+H]+. To a dichloromethane (79 mL) solution of the oil was added trifluoroacetic acid (14.6 mL, 190 mmol) and the mixture was stirred at room temperature. After 30 minutes, the reaction mixture was quenched with aqueous sodium bicarbonate (saturated) and extracted with dichloromethane twice. The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated in vacuo after filtration. The residue was triturated with methyl tert- butyl ether to give ethyl 4-amino-5-iodo-6-methoxynicotinate as off-white solid. Yield: 5.9 g, 96%; MS: 322.9 [M+H]+.

[0292] Step 2: 8-iodo-7-methoxypyrido[4,3-d]pyrimidine-2,4-diol

[0293] To a dry tetrahydrofuran (12 mL) solution of ethyl 4-amino-5-iodo-6- methoxynicotinate (5.90 g, 18.3 mmol) under argon was added trichloroacetyl isocyanate (2.67 mL, 22.0 mmol). The mixture was stirred at room temperature for 30 minutes then concentrated in vacuo. The residue was triturated with methyl terbt-utyl ether. To a dry methanol (87.2 mL) solution of the obtained material was added ammonia solution (7M in methanol, 10.5 mL, 73.3 mmol). The mixture was stirred at room temperature for 1 hour, concentrated in vacuo and the residue was triturated with methyl terbtu-tyl ether to give 8- iodo-7-methoxypyrido[4,3-d]pyrimidine-2,4-diol as white solid. Yield: 5.73 g, 98%; MS: 319.9 [M+H]+.

[0294] Step 3: Synthesis of 2-ethylhexyl 3-((2,4-dihydroxy-7-methoxypyrido[4,3- ri] pyrimi din-8 yl)thio)propanoate

[0295] To a dry dioxane (163 mL) solution of 8-iodo-7-methoxypyrido[4,3-d ]pyrimidine- 2,4-diol (5.20 g, 16.3 mmo) under argon was added 2-ethylhexyl 3-mercaptopropionate (3.91 g, 17.9 mmol) and N,N-diisopropylethylamine (7.10 mL, 40.7 mmol). The mixture was purged with argon and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) DCM (1.40 g, 1.63 mmol) was added. The mixture was purged with argon again and stirred at 100 °C for 17 hours. The mixture was then cooled to room temperature, and HCl (1M) was added. The aqueous layer was extracted with ethyl acetate and the extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo after filtration. Purification of the residue by silica gel chromatography (0-70% ethyl acetate in hexanes) gave 2-ethylhexyl 3-((2.4-dihydroxy-7-methoxypyrido[4,3-d]pyrimidin-8 yl)thio)propanoate as orange solid. Yield: 3.5 g, 55%; MS: 410.1 [M+H]+. [0296] Step 4: Synthesis of 8-((2-hydroxyethyl)thio)-7-methoxypyrido[4,3-d]pyrimidine-

2, 4-diol

[0297] To a dry tetrahydrofuran (72 mL) solution of 2-ethylhexyl 3-((2,4-dihydroxy-7- methoxy py rido[4,3-d]pyri midin-8 yl)thio)propanoate (2.96 g, 7.23 mmol) under argon was added sodium t-butoxide solution (14.5 mL, 28.9 mmol, 2M in THF) at room temperature. The reaction mixture was cooled to 0 °C and 2-chloroethanol (1.45 mL, 21.7 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred for 17 hours at ambient temperature, the solvent was concentrated in vacuo and water (20 mL) was added. The mixture was acidified with HCl (2M) to pH of 3-4 to form a precipitate which was collected, rinsed with ether and triturated with methyl terbtu-tyl ether to give 8-((2- hydroxyethyl)thio)-7-methoxypyrido[4,3-d]pyrimidine-2,4-diol as an orange solid. Yield: 2.6 g, 134%; MS: 270.0 [M+H]+. The material was used in the next step without further purification.

[0298] Step 5: Synthesis of 9-methoxy-2,3-dihydro-4H-1-thia-3a,5,8-triazaphenalene- 4,6(5H)-dione

[0299] To a dry dichloromethane (45 mL) solution of 8-((2 -hydroxyethyl)thio)-7- methoxypyrido[4,3-d]pyrimidine-2,4-diol (1.10 g, 4.09 mmol) under argon was added triethylamine (2.86 mL, 20.4 mmol). The reaction mixture was cooled at 0 °C and methanesulfonic anhydride (0.712 mg, 4.09 mmol) was added. The reaction mixture was heated to 50 °C for 17 hours. Then another portion of methanesulfonic anhydride (0.712 mg, 4.09 mmol) was added and the reaction mixture was stirred at room temperature for an additional 1 hour, concentrated in vacuo and diluted with water. The precipitate was collected by filtration and rinsed with ether to give 9-methoxy-2.3-dihydro-4H-1-thia- 3a,5,8-triazaphenalene-4,6(5H)-dione as yellow solid. Yield: 1.02 g, 99%; MS: 251.9 [M+H]+.

[0300] Step 6: Synthesis of 6-chloro-9-methoxy-2,3-dihydro-4H-1-thia-3a,5,8- triazaphenalen-4-one

[0301] A mixture of 9-methoxy-2,3-dihydro-4H-1-thia-3a,5,8-triazaphenalene-4,6(5H)- dione (0.30 g, 1.19 mmol) and N,N- diisopropylethylamine (1.05 mL, 5.97 mmol) in phosphorus (V) oxychloride (2.25 mL, 23.9 mmol) was stirred at 100 °C. After 1 hour, the mixture was cooled to room temperature and concentrated in vacuo to give 6-chloro-9- methoxy-2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-4-one as brown oil. Yield: 322 mg, quantitative; MS: 269.9 [M+H]+.

[0302] Step 7: Synthesis of tert-butyl -3-(9-methoxy-4-oxo-2,3-dihydro-4H-1-thia-3a,5,8- triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0303] To a dry dimethylacetamide (13 mL) solution of 6-chloro-9-methoxy-2,3-dihydro- 4H-1-thia-3a.5.8-triazaphenalen-4-one (1.03 g, 3.83 mmol) under argon was added tert- butyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.02 g, 4.60 mmol) and N.N- diisopropylethylamine (2.0 mL, 11.5 mmol). The mixture was stirred at 60 °C for 17 hours, cooled to room temperature, diluted with water and extracted with ethyl acetate (3X). The combined extracts were dried over anhydrous sodium sulfate and concentrated in vacuo after filtration. Purification of the residue by silica gel chromatography (0-10% methanol in dichloromethane) gave tert-butyl-3-(9-methoxy-4-oxo-2,3-dihydro-4H-1-thia- 3a,5,8-triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as orange solid. Yield: 1.03 g, 60%; MS: 446.1 [M+H]+. [0304] Step 8: Synthesis of tert-butyl (lR,5S)-3-(9-hydroxy-4-oxo-2,3-dihydro-4H-1- thia-3a,5,8-triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0305] To a dry dimethylformamide (11.4 mL) solution of tert-butyl -3-(9-methoxy-4-oxo- 2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6-yl)-3.8-diazabicyclo[3.2.1]octane-8- carboxylate (1.01 g, 2.27 mmol) under argon was added sodium thiomethoxide (0.33 mg, 4.55 mmol). The mixture was stirred at 140 °C for 17 hours, cooled to room temperature and concentrated in vacuo. Purification of the residue by silica gel chromatography (0- 10% methanol in dichloromethane) gave tert-butyl -3-(9-hydroxy-4-oxo-2.3-dihydro-4H-1- thia-3a,5,8-triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as yellow solid. Yield: 0.63 g, 64%; MS: 432.1 [M+H]+.

[0306] Step 9: Synthesis of tert-butyl -3-(4-oxo-9-(((trifluoromethyl)sulfonyl)oxy)-2,3- dihydro-4H-1-thia-3a,5,8-triazaphenalen-6-yl)-3.8-diazabicyclo[3.2.1]octane-8- carboxylate

[0307] To a dry acetonitrile (2.0 mL) solution of tert-butyl -3-(9-hydroxy-4-oxo-2,3- dihydro-4H-1-thia-3a,5,8-triazaphenalen-6-yl)-3.8-diazabicyclo[3.2.1]octane-8- carboxylate (9, 0.30 g, 0.695 mmol) under argon was added pyridine (0.064 mL, 0.800 mmol). The mixture was cooled to 0 °C and trifluoromethanesulfonic anhydride (0.129 mL, 0.765 mmol) was added dropwise. The mixture was stirred for 30 minutes then concentrated in vacuo. Purification of the residue by silica gel chromatography (0-15% methanol in dichloromethane) gave tert-butyl-3-(4-oxo-9- (((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate as yellow solid. Yield: 0.144 g, 37%; MS: 564.0 [M+H]+.

[0308] Step 10: Synthesis of tert-butyl-3-(9-(8-fluoro-3-(methoxymethoxy)naphthalen-1- yl)-4-oxo-2,3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (6)

[0309] To a dioxane (0.587 mL) and water (0.196 mL) solution of tebrut-tyl-3-(4-oxo-9- (((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6-yl)-3.8- diazabicyclo[3.2.1]octane-8-carboxylate (39.7 mg, 0.070 mmol) under argon was added 2- (8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30.4 mg, 0.092 mmol) and cesium carbonate (68.9 mg, 0.211 mmol). The mixture was purged with argon and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) DCM (7.27 mg, 0.008 mmol) was added. The mixture was purged again with argon and stirred at 100 °C for 17 hours. The mixture was then cooled at room temperature and the solvent was removed in vacuo. Purification of the residue by silica gel chromatography (0-10% methanol in dichloromethane) gave tert-butyl-3-(9-(8-fluoro-3-

(methoxymethoxy)naphthalen- 1 -yl)-4-oxo-2,3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as brown solid. Yield: 0.037 g, 85%; MS: 620.1 [M+H]+. [0310] Step 11: Synthesis of 6-(-3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(8-fluoro-3- hydroxynaphthalen-1-yl)-2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-4-one (6)

[0311] To a dichloromethane (0.20 mL) solution of tert-butyl -3-(9-(8-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4-oxo-2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37.0 mg, 0.059 mmol) was added hydrogen chloride (0.448 mL, 1.79 mmol, 4M in dioxane) and the mixture was stirred at room temperature for 1 hour. Aqueous sodium bicarbonate solution (saturated) was added to pH of 8 and the solvent was removed in vacuo. Purification of the residue by reverse- phase chromatography (C18 column, 5-30% acetonitrile in water + 0.1% formic acid) gave 6-(-3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(8-fluoro-3-hydroxynaphthalen-1-yl)-2,3- dihydro-4H-1-thia-3a,5,8-triazaphenalen-4-one (6) as white solid. Yield: 6.9 mg, 24%; MS: 476.0 [M+H]+; ¹H NMR (CD₃OD, 400 MHz): δ 1.98 (4H, m), 3.21-3.11 (2H, m), 3.64 (1H, d, J= 13.6 Hz), 3.82 (1H, d, J= 13.6 Hz), 3.94 (2H, bs), 4.20-4.15 (1H, m), 4.52-4.43 (2H, m), 4.72 (1H, bd, J= 14.1 Hz), 6.87 (1H, m), 7.02 (1H, d, J= 2.4 Hz), 7.29 (1H, t, J= 2.2 Hz), 7.37 (1H, m), 7.56 (1H, m), 8.68 (1H, s). [0312] Example 7: 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-2,3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-4-one (7)

[0313] Step 1: tert-butyl -3-(9-chloro-4-oxo-2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen- 6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0314] A mixture of tert-butyl-3-(9-hydroxy-4-oxo-2.3-di hydro-4H-1-thia-3a,5,8- triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (from the synthesis of example 6, 100 mg, 0.232 mmol) and N,N- diisopropylethylamine (0.203 mL, 1.16 mmol) in phosphorus (V) oxychloride (0.829 mL, 8.81 mmol) was stirred at 100 °C. After 2 hours, the mixture was cooled at room temperature and concentrated in vacuo. The residue was dissolved in dimethylformamide and purified by reverse-phase column chromatography (C18 column, 10-70% acetonitrile in water + 0.1% formic acid) to give tert-butyl-3-(9-chloro-4-oxo-2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6-yl)-3.8- diazabicyclo[3.2.1]octane-8-carboxylate as brown solid. Yield: 34.6 mg, 32%; MS: 450.0 [M+H]⁺.

[0315] Step 2: tert-butyl -3-(9-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-oxo-2,3-dihydro-4H-1-thia-3a,5,8- triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0316] To a dioxane (0.556 mL) and water (0.185 mL) solution of tert- butyl-3-(9-chloro- 4-oxo-2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6-yl)-3.8-diazabicyclo[3.2.1]octane-8- carboxylate (30 mg, 0.067 mmol) under argon was added ((2-fluoro-6-(methoxymethoxy)- 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (44.4 mg, 0.087 umol) and cesium carbonate (65.2 mg, 0.200 mmol). The mixture was purged with argon and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) DCM (6.88 mg, 0.008 mmol) was added. The mixture was purged again with argon and stirred at 100 °C for 17 hours. The mixture was then cooled to room temperature and concentrated in vacuo. Purification of the residue by silica gel chromatography (20-100% ethyl acetate in hexanes) gave tert-butyl -3-(9-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-oxo-2,3-dihydro-4H-1-thia-3a,5,8- triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3) as yellow solid. Yield: 20.3 mg, 38%; MS: 800.1 [M+H]⁺.

[0317] Step 3: Synthesis of tert-butyl -3-(9-(8-ethynyl-7-fluoro-3-

(methoxymethoxy)naphthalen-1-yl)-4-oxo-2,3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0318] To a dry tetrahydrofuran (0.120 mL) solution of tert-butyl-3-(9-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-oxo-2.3-dihydro-4H- 1-thia-3a,5,8-triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3, 19.2 mg, 0.024 mmol) was added tetrabutylammonium fluoride solution (0.024 mL, 0.024 mmol, 1M in THF). The mixture was stirred at rt for 1 hour and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-15% methanol in dichloromethane) gave tert- butyl (3-(9-(8-ethynyl-7-fluoro-3-

(methoxymethoxy)naphthalen-1-yl)-4-oxo-2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4) as yellow solid. Yield: 15.4 mg,

100%; MS: 644.1 [M+H]⁺.

[0319] Step 4: Synthesis of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(8-ethynyl-7-fluoro-3- hydroxynaphthalen- 1 -yl)-2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-4-one (7)

[0320] To a dichloromethane (0.08 mL) solution of tert-butyl -3-(9-(8-ethynyl-7-fluoro-3-

(methoxymethoxy)naphthalen-1-yl)-4-oxo-2.3-dihydro-4H-1-thia-3a,5,8-triazaphenalen-6- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4, 15.4 mg, 0.024 mmol) was added hydrogen chloride (0.180 mL, 0.718 mmol, 4M in dioxane). The mixture was stirred at rt for 1 hour, aqueous sodium bicarbonate solution (saturated) was added to adjust pH to around 8 and the solvent was evaporated. Purification of the residue by reverse-phase chromatography (C₁₈ column, 5-80% acetonitrile in water + 0.1% formic acid) gave 6 (3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2,3- dihydro-4H-1-thia-3a,5,8-triazaphenalen-4-one (7) as off-white solid. Yield: 9.0 mg,

75%; MS: 500.0 [M+H]⁺; ¹H NMR (CH₃OH-d₄ , 400 MHz): δ 2.06-1.91 (4H, m), 3.20- 3.07 (2H, m), 3.48 (1H, s), 3.62 (1H, d, J= 13.6 Hz), 3.80 (1H, d , J= 13.4 Hz), 3.92 (2H, s, br), 4.12-4.06 (1H, m), 4.44-4.38 (1H, d, J= 13.4 Hz), 4.58-4.48 (1H, m), 4.77-4.70 (1H, m), 7.10 (1H, d, J= 2.6 Hz), 7.33-7.27 (2H, m), 7.86-7.80 (1H, dd, J= 9.1, 5.7 Hz), 8.66 (1H, s).

[0321] Example 8: 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-2,3-dihydro-4H-1-oxa-3a,5,8-triazaphenalen-4-one (8)

[0322] Step 1: Synthesis of 3-(2-((tert-butyl dimethylsilyl)oxy)ethoxy)-2-chloro-4- nitropyridine

[0323] To a mixture of 2-chloro-4-nitropyridin-3-ol (3.0 g, 17.2 mmol, 1 equiv.,

CAS: 15128-85-5), 2-((tert-butyl dimethylsilyl)oxy)ethan-1-ol (3.94 g, 22.4 mmol, 1.3 equiv.) and triphenylphosphine (6.76 g, 25.8 mmol, 1.5 equiv.) in THF (60 ml) was added dropwise diisopropylazidodicarboxylate (5.21 g, 25.8 mmol, 1.5 equiv.) under nitrogen at 20°C. After addition, the resulting mixture was stirred under N2 at 20°C for 3 hours. The reaction mixture was extracted with EA (150 mLx2)/H₂O (150 mL) and the organic phases were washed with brine. The organic phases were combined, dried over Na₂SO₄ , evaporated to dryness and the residue was purified by silica gel chromatography (PE/EA =5:1) to give 3-(2-(( tert-butyl dimethylsilyl)oxy)ethoxy)-2-chloro-4-nitropyridine (5.7 g, 98.8% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J= 5.2 Hz, 1H), 7.56 (d, J= 5.2 Hz, 1H), 4.30 (t, J= 4.9 Hz, 2H), 3.98 (t, J= 4.9 Hz, 2H), 0.86 (s,

9H), 0.05 (s, 6H). [0324] Step 2: Synthesis of 3-(2-((tert-butyl dimethylsilyl)oxy)ethoxy)-2-chloropyridin-4- amine

[0325] To a mixture of 3 -(2-(( tert-butyldimethylsilyl)oxy)ethoxy)-2-chloro-4- nitropyridine (2.0 g, 6.02 mmol, 1.0 equiv.) in EtOH (20 mL) and H₂O (20 mL) was added iron (3.36 g, 60.2 mmol, 10 equiv.) andNEECl (3.24 g, 60.2 mmol, 10 equiv.) at 20°C.

The mixture was stirred under nitrogen at 60°C for 2 hours. The mixture was cooled and extracted with DCM (200 mL×2) and 200 mL water. The organic phasse were washed with water followed by brine. The organic phases were dried over anhydrous Na₂SO₄.

The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE/EA =3: 1) to give 3-(2 -((tert- butyldimethylsilyl)oxy)ethoxy)-2-chloropyridin-4-amine (1.6 g, 88.3% yield) as colorless oil. ESI-MS m/z = 303.1 [M+H]⁺. Calculated MW: 302.12. [0326] Step 3: Synthesis of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-chloro-5- iodopyridin-4-amine

[0327] To a mixture of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-chloropyridin-4- amine (4.4 g, 14.5 mmol, 1 equiv.) in ACN (60 ml) was added NIS (4.89 g, 21.7 mmol, 1.5 equiv.) and TsOH (0.25 g, 1.45 mmol, 0.1 equiv.). The flask was purged with nitrogen for 3 times and the resulting mixture was stirred under nitrogen at 50°C for 5 hours. The reaction mixture was cooled, concentrated and extracted with EA (100 mLx2)/ H₂O (100 mL). The organic phases were washed with water followed by sodium thiosulfate solution. The organic phases were combined, dried over Na₂SO₄, evaporated to dryness and the residue was purified by silica gel chromatography (PE/EA =3:1) to give 3-(2- ((tert-butyldimethylsilyl)oxy)ethoxy)-2-chloro-5-iodopyridin-4-amine (5.8 g, 93.1% yield) as oil. ESI-MS m/z = 429.1 [M+H]⁺. Calculated MW: 428.02.

[0328] Step 4: Synthesis of methyl 4-amino-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6- chloronicotinate

[0329] To a mixture of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-chloro-5-iodopyridin-

4-amine (5.8 g, 13.5 mmol, 1 equiv.) and TEA (4.09 g, 40.5 mmol, 3.0 equiv.) in MeOH (80 ml) was added Pd(dppf)Cl₂ (0.99 g, 1.35 mmol, 0.1 equiv.) in autoclave. The autoclave was purged with CO 3 times and the resulting mixture was stirred under 1.5 MPa CO at 80°C for 16 hours. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography (PE/EA =3:1) to give methyl 4-amino-

5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloronicotinate (4.5 g, 92.6% yield) as oil. ESI-MS m/z = 361.1 [M+H]⁺. Calculated MW: 360.13. [0330] Step 5: Synthesis of methyl 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloro-4-

(3-(2,2,2-trichloroacetyl)ureido)nicotinate

[0331] To a mixture of methyl 4-amino-5-(2-((tert-butyldi methyl silyl)oxy )ethoxy)-6- chloronicotinate (1.0 g, 4.14 mmol, 1 equiv.) in THF (20 ml) was added dropwise 2,2,2- trichloroacetyl isocyanate (0.68 g, 3.36 mmol, 1.2 equiv.) slowly at 20°C. The resulting mixture was stirred under nitrogen at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give methyl 5 -(2 -((tert- butyldimethylsilyl)oxy)ethoxy)-6-chloro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate (1.3 g, crude) as oil, which was used directly next step without further purification. ESI-MS m/z = 548.0 [M+H]⁺. Calculated MW: 547.03.

[0332] Step 6: Synthesis of 8-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-7-chloro-4- hydro\ypyrido|4.3-d|pyrimidin-2(1H)-one

[0333] To a mixture of methyl 5-(2-((tert-butyl dimethylsilyl)oxy)ethoxy)-6-chloro-4-(3- (2,2,2-trichloroacetyl)ureido)nicotinate (1.3 g, crude) in MeOH (5 ml) was added 4 M NH₃/MeOH (20 mL) at 20°C. The resulting mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to dryness. The residue was triturated with 20 mL EA and stirred for 5 min. The mixture was filtered and collected filtrate cake gave 8-(2 -((tert- butyldimethylsilyl)oxy)ethoxy)-7-chloro-4-hydroxypyrido[4,3-d]pyrimidin-2(1H)-one (810 mg, 78.6% yield, 2 steps) as white solid. ESI-MS m/z = 372.1 [M+H]⁺. Calculated MW: 371.11.

[0334] Step 7: Synthesis of 7-chloro-4-hydroxy-8-(2-hydroxyethoxy)pyrido[4,3- d|pyrimidin-2(1H)-one

[0335] To a mixture of 8-(2-((tert-butyl dimethylsilyl)oxy)ethoxy)-7-chloro-4- hydro\ypyrido|4.3-d|pyrimidin-2(1H)-one (900 mg, 2.42 mmol, 1 equiv.) in THF (20 ml) was added TBAF (1.17 g, 4.84 mmol, 2 equiv.) at 20°C. The flask was purged with nitrogen 3 times and the resulting mixture was stirred under nitrogen at 20°C for 1 hour. The reaction mixture was concentrated to dryness. The residue was triturated with 50 mL H₂O and stirred for 5 min. The mixture was filtered and the resulting filter cake was dried to give 7-chloro-4-hydroxy-8-(2-hydroxyethoxy)pyrido|4.3-d|pyrimidin-2(1H)-one (600 mg, 96.2% yield) as white solid. ESI-MS m/z = 258.1 [M+H]⁺. Calculated MW: 257.02. [0336] Step 8: Synthesis of 9-chloro-6-hydroxy-2,3-dihydro-4H-1-oxa-3a,5,8- triazaphenalen-4-one

[0337] To a mixture of 7-chloro-4-hydroxy-8-(2-hydroxyethoxy)pyrido[4,3-d]pyrimidin- 2(1H)-one (450 mg, 1.75 mmol, 1 equiv.) and triphenylphosphine (595 mg, 2.27 mmol,

1.3 equiv.) in DMF (50 ml) was dropwise added DIAD (459 mg, 2.27 mmol, 1.3 equiv.) under nitrogen at 20°C. After addition, the resulting mixture was stirred under nitrogen at 20°C for 3 hours. The reaction mixture was extracted with EA (300 mLx2)/H₂O (200 mL) and washed with brine. The organic phases were combined, dried over Na₂SO₄, and evaporated to dryness. The residue was triturated with 20 mL EA and stirred for 5 min. The mixture was filtered and the resulting filtrate cake was dried to give 9-chloro-6- hydro\y-2.3-dihydro-4H-1-oxa-3a,5,8-triazaphenalen-4-one (510 mg, P=60%, 73.1% yield) as white solid. ¹H NMR (400 MHz, DMSO) δ 11.89 (s, 1H), 8.44 (s, 1H), 4.48 (t, J = 4.7 Hz, 2H), 3.98 (t, J = 4.7 Hz, 2H).

[0338] Step 9: Synthesis of 6.9-di chloro-2.3-di hydro-4H-1-oxa-3a,5,8-triazaphenalen-4- one

[0339] To a mixture of 9-chloro-6-hydroxy-2.3-dihydro-4H-1-oxa-3a,5,8-triazaphenalen-

4-one (250 mg, 1.04 mmol, 1.0 equiv.) in toluene (15 ml) was added POCl₃ (1.60 g, 10.4 mmol, 10 equiv.) and DIEA (1.34 g, 10.4 mmol, 10 equiv.) at 20°C. The resulting mixture was stirred under nitrogen at 60°C for 3 hours. The reaction mixture was concentrated to dryness and diluted with 30 mL DCM. The mixture was added into 50 mL ice-water, extracted with DCM (50 mL×2) and 50 mL water. The organic phases were dried over anhydrous Na₂SO₄. The filtrate was concentrated under reduced pressure to give 6,9- dichloro-2.3-dihydro-4H-1-oxa-3a,5,8-triazaphenalen-4-one (712 mg, crude) as yellow solid, which was used directly next step without further purification. ESI-MS m/z = 258.0 [M+H]⁺. Calculated MW: 256.98.

[0340] Step 10: Synthesis of tert-butyl-3-(9-chloro-4-oxo-2,3-dihydro-4H-1-oxa-3a,5,8- triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0341] To a mixture of 6.9-dichloro-2.3-dihydro-4H-1-oxa-3a,5,8-triazaphenalen-4-one (712 mg, crude) and tert-butyl-3.8-diazabicyclo[3.2.1]octane-8-carboxylate (443 mg, 2.09 mmol, 2.0 equiv.) in dioxane (15 ml) was added DIEA (541 mg, 4.18 mmol, 4 equiv.). The resulting mixture was stirred under nitrogen at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (EA) to give tert-butyl -3-(9-chloro-4-oxo-2,3-dihydro-4H-1-oxa-3a,5,8- triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (410 mg, yield: 90.5%, 2 steps) as light yellow solid. ESI-MS m/z = 434.1 [M+H]⁺. Calculated MW: 433.15. [0342] Step 11: Synthesis of tert-butyl -3-(9-(7-fluoro-3-(methoxymethoxy)-8-

((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-oxo-2,3-dihydro-4H-1-thia-3a,5,8- triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0343] To a mixture of tert-butyl-3-(9-chloro-4-oxo-2,3-dihydro-4H-1-oxa-3a,5,8- triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (450 mg, 1.34 mmol, 1 equiv.) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilane (797 mg, 1.56 mmol, 1.5 equiv., CAS:2621932-37-2) in dioxane/H₂O (40 ml, V:V=4:1) was added Cs₂CO₃ (674 mg, 2.07 mmol, 2.0 equiv.) and Pd(dppl)Cl₂ (76 mg, 0.104 mmol, 0.1 equiv.). The flask was purged with nitrogen 3 times and the resulting mixture was stirred under nitrogen at 90°C for 16 hours. The reaction mixture was cooled and extracted with EA (100 mLx2)/H₂O (100 mL). The organic phases were washed with water followed by brine. The organic phases were combined, dried over Na₂SO₄, evaporated to dryness and the residue was purified by silica gel chromatography (EA) to give tert-butyl -3-(9-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-oxo-2,3-dihydro-4H- l-oxa-3a,5,8-triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (405 mg, 49.8% yield) as white solid. ¹H NMR (400 MHz, MeOD) δ 8.75 (s, 1H), 7.97 (dd, J= 9.1,

5.8 Hz, 1H), 7.65 (d, J= 2.5 Hz, 1H), 7.41 (t, J= 8.9 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 5.36 (s, 2H), 4.93 (s, 1H), 4.52 - 4.46 (m, 1H), 4.42 (d, J= 10.7 Hz, 2H), 4.32 (dd, J = 15.3, 7.2 Hz, 2H), 4.16 - 4.09 (m, 2H), 4.07 - 4.00 (m, 1H), 3.84 (d, J= 11.3 Hz, 1H),

3.52 (s, 3H), 3.41 (d, J= 13.1 Hz, 1H), 2.03 (s, 4H), 1.77 (d, J= 7.8 Hz, 1H), 1.55 (s, 10H), 0.98 (dd, J= 9.3, 7.6 Hz, 18H).

[0344] Step 12: Synthesis of tert-butyl-3-(9-(8-ethynyl-7-fluoro-3-

(methoxymethoxy)naphthalen-1-yl)-4-oxo-2,3-dihydro-4H-1-oxa-3a,5,8-triazaphenalen-6- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0345] To a mixture of tert-butyl-3-(9-(7-fluoro-3-(methoxymethoxy)-8-

((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-oxo-2,3-dihydro-4H-1-oxa-3a,5,8- triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (405 mg, 0.517 mmol, 1 equiv.) in DMF (20 ml) was added CsF (393 mg, 2.58 mmol, 5.0 equiv.). The resulting mixture was stirred under nitrogen at 20°C for 0.5 hours. The reaction mixture was extracted with EA (100 mLx2)/H₂O (100 mL). The organic phases were washed with water followed by brine, combined, dried over Na₂SO₄, and evaporated to dryness. The resulting residue was purified by silica gel chromatography (EA) to give tert-butyl -3-(9- (8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-oxo-2,3-dihydro-4H-1-oxa- 3a,5,8-triazaphenalen-6-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (310 mg, 95.6% yield) as light yellow solid. ESI-MS m/z = 628.2 [M+H]⁺. Calculated MW: 627.25. [0346] Step 13: Synthesis of 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(8-ethynyl-7-fluoro-

34iydroxynaphthalen-1-yl)-2.3-dihydro-4H-1-oxa-3a,5,8-triazaphenalen-4-one

[0347] To a mixture of tert-butyl -3-(9-(8-ethynyl-7-fluoro-3-

(methoxymethoxy)naphthalen-1-yl)-4-oxo-2.3-dihydro-4H-1-oxa-3a,5,8-triazaphenalen-6- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.191 mmol, 1.0 equiv.) in

MeCN (5 mL) was added dropwise of 6 M HCl/dioxane (5 mL) at 0°C. The mixture was stirred for 0.5 hours at 0°C. The mixture was added into 20 mL saturated NaHCO₃ solution at 0°C. The mixture was extracted with DCM (50 mLx2) and 100 mL water. The organic phases were washed with water followed by brine. The organic phases were dried over anhydrous Na₂SO₄. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative-HPLC (Mobile Phase: ACN—H₂O (0.1%FA), Gradient:20-50) to give 6-(3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-2.3-dihydro-4H-1-oxa-3a,5,8-triazaphenalen-4-one (30 mg, purity: 99.11%, yield:32.1%) as yellow solid. ESI-MS m/z = 484.1 [M+H]⁺. Calculated MW: 483.17. ¹H NMR (400 MHz, MeOD) δ 8.67 (s, 1H), 8.52 (s, 2H), 7.86 (d, J= 3.6 Hz, 1H), 7.33 (s, 2H), 7.17 (s, 1H), 4.80 (d, J= 13.7 Hz, 1H), 4.64 (d, J= 13.6 Hz, 1H), 4.45 - 4.31 (m, 2H), 4.18 (d, J= 13.5 Hz, 1H), 4.02 (s, 3H), 3.78 (dd, J= 36.8, 13.1 Hz, 2H), 3.56 (s, 1H), 2.04 (s, 4H). Assays & Activity Data

[0348] KRAS G12D and Wild-type KRAS enzyme assays were carried out as follows:

Example 2. KRAS G12D and Wild-type KRAS- In-Vitro RAS-RAF Binding Assay (RRB)

[0349] Biotinylated KRAS protein amino acids 1-169 (produced at Erasca) was labeled with streptavidin-terbium (lanthanide cryptate donor fluorophore) in assay buffer (50 mM HEPES, pH 7.5, 100 mM NaCl, 1 mM MgCl₂, 1 mM DTT) at a final concentration of 30nM. In a separate reaction mixture, 30nM cRAF (RBD) (Abeam, Cambridge MA) was labeled with anti-GST d2 (acceptor fluorophore). Labeling reactions were incubated for one hour at room temperature.

[0350] Compounds of interest were incubated with the labeled-KRAS for 60 minutes at room temperature at a final DMSO concentration of 5% in a black ½ area microtiter plate (50uL final reaction volume). Following the compound incubation, SOS1 catalytic domain (produced at Erasca) and GTPgS were added to the reaction to initiate nucleotide exchange (60 minutes exchange reaction). Once in the GTP state KRAS will bind to cRAF. No binding will occur if KRAS remains in the GDP state. Compounds may block nucleotide exchange or may create a steric obstruction to cRAF-KRAS interaction by binding to the RAS effector site.

[0351] Following the exchange reaction, the labeled KRAS and cRAF were mixed in equal volume (30uL each) and incubated for 30-60 minutes at room temperature. A portion of this mixture was transferred to a white 384-well plate (20uL per well in duplicate) and read on an HTRF compatible plate reader (ClarioSTAR). Fluorescent resonance energy transfer (FRET) was measured at equilibrium. FRET signal will be high if KRAS-cRAF binding occurs. FRET signal will be low if KRAS-cRAF binding is inhibited by the test compound. The results for exemplary compounds are shown below in Table 1. Table 1

Inhibition of RAS-RAF Binding ( in-vitro )

[0352] Although the foregoing embodiments have been described in some detail by way of illustration and Example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

WHAT IS CLAIMED IS:

1. A compound, or a pharmaceutically acceptable salt thereof, of Formula(I):

wherein R³, R⁴, R⁵, and R⁶ are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino, C-amide (- CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), sulfonamide (- NHSO₂R or -SO₂NHR), and CF₃; wherein each R and R’ is independently hydrogen, alkyl, or cycloalkyl; or any two adjacent R³, R⁴, R⁵, or R⁶ form an optionally substituted fused 5- or 6-membered ring comprising 0 to 3 heteroatoms selected fromN, O or S; provided that one of R³, R⁴, R⁵, or R⁶ is the bond representing the link between A and the tricyclic ring system;

wherein G¹ and G² are independently selected from S, O, CH, - CH=CH-, -CH=N-, N, NH, NMe or -CE, where E is CN, halogen, OH, OMe, alkyl- or aryl sulfonamide, alkyl- or aryl sulfone, acyl, formyl, amide, ester, carboxylic acid, or CF₃; wherein either G¹ or G² forms a double bond with carbon of the -CR¹⁰ moiety; wherein R⁷, R⁸, and R⁹, are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino; and R¹⁰ is hydrogen, hydroxyl, alkoxy, amino, N-alkylamino, C-amide (-CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), or sulfonamide (-NHSO₂R or -SO₂NHR)₃;

wherein G¹ and G² are independently selected from S, O, CH, -

CH=CH-, -CH=N-, N, NH, NMe or -CE, where E is CN, halogen, OH, OMe, alkyl- or aryl sulfonamide, alkyl- or aryl sulfone, acyl, formyl, amide, ester, carboxylic acid, or CF₃; wherein either G¹ or G² forms a double bond with carbon of the -CR¹¹ moiety; R¹¹ is hydroxyl, alkoxy, amino, N-alkylamino, C-amide (-CONRR’), N-amides (-NHCOR), urea (-NHCONHR), ether (-OR), or sulfonamide (-NHSO₂R or -SO₂NHR)₃, wherein R and R’ are independently alkyl or hydrogen;wherein X¹ is selected from CH, or N; and X² is selected from O, S, NH, and NMe; or

wherein Z¹, Z², Z³, and Z⁴ are independently selected from

wherein Z¹, Z², Z³, and Z⁴ are each independently selected from CH and -CE, wherein E is CN, -C≡CH, halogen, OH, OMe, alkyl- or aryl sulfonamide, alkyl- or aryl sulfone, acyl, formyl, amide, ester, carboxylic acid, or CF₃; and, R¹³, are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, N-alkylamino; each V is independently selected from methyl, cyanomethyl, or any two V combine to form a bridge or spirocycle structure optionally comprising a heteroatom in the bridge or spirocycle selected from S, SO₂, O or N, and wherein the bridge or spirocycle structure is optionally substituted with oxo; X is O or S;

2. The compound of claim 1, wherein the compound is a single atropisomer.

3. The compound of claim 1 or 2, wherein X is O.

4. The compound of claim 1 or 2, wherein X is S.

5. The compound of any one of claims 1 to 4, wherein (Al) is selected from:

6. The compound of any one of claims 1 to 4, wherein (A1) is selected from:

7. The compound of any one of claims 1 to 4, wherein (A2) is selected from:

8. The compound of claim 7, wherein (A2) is:

9. The compound of any one of claims 1 to 4, wherein (A3) is selected from:

10. The compound of any one of claims 1 to 4, wherein (A4) is selected from:

11. The compound of any one of claims 1 to 4, wherein (A5) is selected from

12. The compound of any one of claims 1 to 11, wherein R₁ is F.

13. The compound of any one of claims 1 to 11, wherein R₁ is methyl.

14. The compound of any one of claims 1 to 11, wherein R₁ is Cl.

15. The compound of any one of claims 1 to 11, wherein R₁ is H.

16. The compound of any one of claims 1 to 11, wherein R₁ is CF₃.

17. The compound of any one of claims 1 to 16, wherein R² is selected from:

MeOCH₂-, EtOCH₂-, MeO(CH₂)₂NH-,

wherein R and R’ are independently selected from hydrogen, alkyl, and cycloalkyl; and wherein R¹⁵ and R¹⁶ is selected from hydrogen, hydroxyl, CN, Cl, F, CF₃, C_1-3 alkyl or C_1-3 alkoxy, methoxy, and amino.

18. The compound of any one of claims 1 to 17, wherein two V form a bridge: -CH₂-CH₂-.

19. The compound of any one of claims 1 to 17, wherein two V form a bridge: -CH₂-CH₂-CH₂-.

20. The compound of any one of claims 1 to 17, wherein two V form a bridge:

-CH₂-.

21. The compound of any one of claims 1 to 20, wherein m is 1.

22. The compound of any one of claims 1 to 20, wherein m is 2.

23. The compound of claim 1, wherein the compound is:

24. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

25. The pharmaceutical composition of claim 24, further comprising an additional therapeutic agent.

26. A method of treating a subject having cancer, the cancer characterized by the presence of a KRAS G12D mutation, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

27. The method of claim 26, wherein the cancer is Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm’s tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial ‘carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin’s disease, non-Hodgkin’s lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; or Adrenal glands: neuroblastoma.

28. The method of claim 26, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

29. Use of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or a a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cancer in a subject, the cancer characterized by the presence of a KRAS G12D mutation.

30. The use of claim 29, wherein the cancer is Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm’s tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial ‘carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin’s disease, non-Hodgkin’s lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; or Adrenal glands: neuroblastoma.

31. The method of claim 29, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.