EP4347603A1 - Schwefelhaltige heteroaromatische tricyclische kras-hemmer - Google Patents

Schwefelhaltige heteroaromatische tricyclische kras-hemmer

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Publication number
EP4347603A1
EP4347603A1 EP22731929.0A EP22731929A EP4347603A1 EP 4347603 A1 EP4347603 A1 EP 4347603A1 EP 22731929 A EP22731929 A EP 22731929A EP 4347603 A1 EP4347603 A1 EP 4347603A1
Authority
EP
European Patent Office
Prior art keywords
trifluoromethyl
mmol
mixture
carcinoma
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22731929.0A
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English (en)
French (fr)
Inventor
Marcos GONZALEZ-LOPEZ
Jean-Michel Vernier
Jun Feng
Benjamin Jones
Nicholas A. ISLEY
Ping Chen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Erasca Inc
Original Assignee
Erasca Inc
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Publication date
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Publication of EP4347603A1 publication Critical patent/EP4347603A1/de
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Embodiments herein relate to compounds, compositions and methods for the treatment of RAS-mediated disease.
  • embodiments herein relate to compounds and methods for treating diseases such as cancer via targeting oncogenic mutants of the K- RAS isoform.
  • 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.
  • GEFs guanine nucleotide exchange factors
  • SOS most commonly son of sevenless
  • GAPs GTPase- activating proteins
  • 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.
  • K- Ras, N-Ras, or H-Ras mutation of any one of the three Ras isoforms
  • K- Ras mutations are by far the most common in human cancer.
  • K- Ras mutations are known to be often associated with pancreatic, colorectal and non-small-cell lung carcinomas.
  • H-Ras mutations are common in cancers such as papillary thyroid cancer, lung cancers and skin cancers.
  • N-Ras mutations occur frequently in hepatocellular carcinoma.
  • K-Ras is the most frequently mutated oncoprotein in human cancers. Accordingly, there is a need to develop selective inhibitors of KRAS mutants.
  • the present embodiments meet this and other needs.
  • the present embodiments provide compounds, or a pharmaceutically acceptable salt thereof, of Formula(Ia): wherein
  • R' is alkyl, cyano, cycloalkyl, halogen, haloalkyl, trifluoromethyl, and alkoxy.
  • the present embodiments provide a method of treating a subject having cancer, the cancer characterized by the presence of a KRAS G12C 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.
  • 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 G12C mutation, the medicament comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a a pharmaceutical composition as disclosed herein, is used.
  • 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 G12C mutation.
  • 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 G12C mutation.
  • the present embodiments provide inhibitors of KRAS G12C exhibiting good selectivity over wild-type KRAS and are useful for treating a cancer characterized by a KRAS G12C mutation.
  • Alkyl refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. 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 2-4 , 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 .
  • C 1-6 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.
  • Alkylene refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical.
  • the two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group.
  • a straight chain alkylene can be the bivalent radical of -(CH 2 ) n - where n is 1, 2, 3, 4, 5 or 6.
  • Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene sec-butylene, pentylene and hexylene.
  • Alkylene groups can be substituted or unsubstituted.
  • Alkenyl refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C 6 . Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more.
  • alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, lsopentenyl, 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.
  • Alkenylene refers to an alkenyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical.
  • the two moieties linked to the alkenylene can be linked to the same atom or different atoms of the alkenylene.
  • Alkenylene groups include, but are not limited to, ethenylene, propenylene, isopropenylene, butenylene, isobutenylene, sec-butenylene, pentenylene and hexenylene.
  • Alkenylen groups can be substituted or unsubstituted.
  • Alkynyl refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl can include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C6.
  • alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl. isopentynyl, 1,3-pentadiynyl,
  • Alkynyl groups can be substituted or unsubstituted.
  • Alkynylene refers to an alkynyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical.
  • the two moieties linked to the alkynylene can be linked to the same atom or different atoms of the alkynylene.
  • Alkynylene groups include, but are not limited to, ethynylene, propynylene, isopropynylene, butynylene, sec-butynylene, pentynylene and hexynylene. Alkynylene groups can be substituted or unsubstituted.
  • Alkoxy refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-.
  • alky l group alkoxy groups can have any suitable number of carbon atoms, such as C 1-6 .
  • Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc.
  • the alkoxy groups can be further substituted with a variety of substituents described within. Alkoxy groups can be substituted or unsubstituted.
  • Alkoxyalkyl refers to a radical having an alkyl component and an alkoxy component, where the alkyl component links the alkoxy component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the alkoxy component and to the point of attachment.
  • the alkyl component can include any number of carbons, such as C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , 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 .
  • the alkoxy component is as defined above. Examples of the alkoxyalkyl group include, but are not limited to, 2-ethoxy- ethyl and methoxy methyl.
  • Alkylhydroxy refers to an alkyl group, as defined above, where at least one of the hydrogen atoms is replaced with a hydroxy group.
  • alkylhydroxy groups can have any suitable number of carbon atoms, such as C1-6.
  • Exemplary alkylhydroxy groups include, but are not limited to, hydroxy-methyl, hydroxyethyl (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), hydroxypentyl (where the hydroxy is in the 1-, 2-, 3-, 4- or 5-position), hydroxyhexyl (where the hydroxy is in the 1-, 2-, 3-, 4-, 5- or 6-position), 1,2-dihydroxy ethyl, and the like.
  • Halogen or “halo” refers to fluorine, chlorine, bromine and iodine.
  • Haloalkyl refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms.
  • alkyl group haloalkyl groups can have any suitable number of carbon atoms, such as C 1-6 .
  • haloalkyl includes trifluoromethyl, flouromethyl, etc.
  • perfluoro can be used to define a compound or radical where all the hydrogens are replaced with fluorine.
  • perfluoromethyl refers to 1,1,1 -trifluoromethyl.
  • Haloalkoxy refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms.
  • haloalkoxy groups can have any suitable number of carbon atoms, such as C 1-6 .
  • the alkoxy groups can be substituted with 1, 2, 3, or more halogens. When all the hydrogens are replaced with a halogen, for example by fluorine, the compounds are per-substituted, for example, perfluorinated.
  • Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.
  • Cycloalkyl refers to a saturated or partially unsaturated, monocyclic, fused bi cyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl 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 .
  • Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • Saturated bicychc and polycyclic cycloalkyl rings include, for example, norbomane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane.
  • Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring.
  • Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cy clohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbomene, and norbomadiene.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.
  • Cycloalkylene refers to a cycloalkyl group having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent radical.
  • the two moieties linked to the cycloalkylene can be linked to the same atom or different atoms of the cycloalkylene group.
  • Examples of cycloalkylene rings include cyclopropylene, cyclobutylene, cyclopentylene and cyclohexylene, among others.
  • Cycloalkylene groups can be linked 1,1, 1,2, 1,3, or 1,4.
  • the cyclohexylene ring for example, can adopt a number of conformations, including the boat and chair conformations.
  • the chair conformation of cyclohexylene can have substituents in an axial or equatorial orientation.
  • the divalent nature of the cycloalkylenes results in cis and tram formations where cis refers to both substituents being on the same side (top or bottom) of the cycloalkylene ring, and where tram refers to the substituents being on on opposite sides of the cycloalkylene ring.
  • cis- 1,2- and c/5-1, 4-cyclohexylene can have one substituent in the axial orientation and the other substituent in the equatorial orientation
  • tram- 1,2- and irons- 1.4-cyclohexylene have both substituents in the axial or equatorial orientation
  • 3 -cyclohexylene have both substituents in the axial or equatorial orientation
  • Irons- 1.3-cyclohexylene can have one substituent in the axial orientation and the other substituent in the equatorial orientation.
  • Cycloalkylene groups can be substituted or unsubstituted.
  • Alkyl-cycloalkyl refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the cycloalkyl component and to the point of attachment. In some instances, the alkyl component can be absent.
  • the alkyl component can include any number of carbons, such as C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , 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 .
  • the cycloalkyl component is as defined within.
  • Exemplary alkyl- cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl and methyl-cyclohexyl.
  • Heterocycloalkyl or “heterocyclyl” refers to a saturated ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. 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,
  • heterocycloalkyl groups such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4.
  • the heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, 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, di oxane, dithiane, and hexahydro-lH-pyrrolizine.
  • groups such as aziridine,
  • heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline.
  • Heterocycloalkyl groups can be unsubstituted or substituted.
  • the heterocycloalkyl groups can be linked via any position on the ring.
  • aziridine can be 1- or 2-azindme
  • 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-imidazolidine
  • piperazine can be 1-, 2-, 3- or 4-piperazine
  • tetrahydrofuran can be 1- or 2-tetrahydrofuran
  • oxazolidine can be
  • 2-, 3-, 4- or 5 -oxazolidine, isoxazolidine can be 2-, 3-, 4- or 5-isoxazolidine
  • thiazolidine can be 2-, 3-, 4- or 5 -thiazolidine
  • isothiazolidine can be 2-, 3-, 4- or 5- isothiazolidine
  • morpholine can be 2-, 3- or 4-morpholine.
  • 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, isoxzoalidine, 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, morpholine, and hexahydro-lH- pyrrolizine.
  • representative members including, but not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, and hexahydro-lH- pyrrolizine.
  • Heterocyclalkylene refers to a heterocyclalkyl group, as defined above, linking at least two other groups.
  • the two moieties linked to the heterocyclalkylene can be linked to the same atom or different atoms of the heterocyclalkylene.
  • Heterocycloalkylene groups can be substituted or unsubstituted.
  • Alkyl-heterocycloalkyl refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalk l component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heterocycloalkyl component and to the point of attachment.
  • the alkyl component can include any number of carbons, such as C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , 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 .
  • the alkyl component can be absent.
  • the heterocycloalkyl component is as defined above. Alkyl-heterocycloalkyl groups can be substituted or unsubstituted.
  • Aryl refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings.
  • Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members.
  • Aryl groups can be monocyclic, fused to form bi cyclic or tricyclic groups, or linked by a bond to form a biaryl group.
  • Representative aryl groups include phenyl, naphthyl and biphenyl. Other ary l groups include benzyl, having a methylene linking group.
  • aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.
  • Aryl groups can be substituted or unsubstituted.
  • Alkyl-aryl refers to a radical having an alkyl component and an aryl component, where the alkyl component links the ary l component to the point of attachment.
  • the alkyl component is as defined above, except that the alky l component is at least divalent, an alkylene, to link to the aryl component and to the point of attachment.
  • the alkyl component can include any number of carbons, such as Co-6, C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , 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 .
  • the alkyl component can be absent.
  • the aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene. Alkyl-ary l groups can be substituted or unsubstituted.
  • Arylene refers to an aryl group, as defined above, linking at least two other groups.
  • the two moieties linked to the aryl can be linked to the same atom or different atoms of the aryl.
  • Arylene groups can be substituted or unsubstituted.
  • Heteroaryl refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms can also be useful, including, but not limited to,
  • heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-.
  • Heteroaryl groups can include any number of ring atoms, such as,
  • heteroaryl groups 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,
  • 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.
  • 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.
  • the heteroaryl groups can be linked via any position on the ring.
  • 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-triazme
  • 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-
  • 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.
  • N, O or S such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,
  • 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.
  • 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.
  • 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.
  • 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.
  • heteroaryl groups include from 5 to 10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline.
  • Other heteroaryl groups include from 5 to 10 ring members and only oxygen heteroatoms, such as furan and benzofuran.
  • heteroaryl groups include from 5 to 10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Still other heteroaryl groups include from 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline.
  • Heteroarylene refers to a heteroaryl group, as defined above, linking at least two other groups. The two moieties linked to the heteroaryl are linked to different atoms of the heteroaryl. Heteroarylene groups can be substituted or unsubstituted.
  • Alkyl -heteroaryl refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heteroaryl component and to the point of attachment.
  • the alkyl component can include any number of carbons, such as Co-6, C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , 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 .
  • the alkyl component can be absent.
  • the heteroaryl component is as defined within. Alkyl-heteroaryl groups can be substituted or unsubstituted.
  • R’ R” and R”’ each independently refer to hydrogen, unsubstituted alkyl, such as unsubstituted C 1-6 alkyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • “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, lubncants, coatings, sweeteners, flavors and colors.
  • binders include, but are not limited to, binders, fillers, disintegrants, lubncants, coatings, sweeteners, flavors and colors.
  • 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.
  • 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.
  • a slow-release device e.g., a mini-osmotic pump
  • “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.
  • 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.
  • the present embodiments provide compounds, and pharmaceutically acceptable salts thereof, of Formula (I): wherein m is 1 or 2; p is 1 or 2; L 1 is wherein k is an integer from 0 to 4; and each R 1 is independently selected from methyl, and cyanomethyl, C 2 -C 4 alkyl, cyano, cycloalkyl, halo, haloalkyl, trifluoromethyl, and alkoxy; or any two R 1 combine to form a fused ring, bridge or spirocycle structure optionally comprising a heteroatom in the bridge or spirocycle selected from S, SO 2 , O or N, and wherein the bridge or spirocycle structure is optionally substituted with oxo;
  • R 2 is is selected from the group consisting of alkyl, N-alkylamino, N, N- dialkylamino, alkylamidoalkyl, arylamidoalkyl, alkylsulfonamidoalkyl, arylsulfonamidoalkyl, N-alkyl aminoalkyl, N,N-dialkyl aminoalkyl, alkoxy, alkoxyalkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, any of which are optionally substituted; or when m is 2, two R 2 combine to form a spirocyclic 3-6-membered ring optionally containing 1 to 3 heteroatoms selected from N, O, or S;
  • R 3 , R 4 , R 5 , and R 6 are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, ammo, N-alkylamino, C-amide (-CONRR’), N-amides (- NHCOR), urea (-NHCONHR), ether (-OR), sulfonamide (-NHSO2R or -SO2NHR), and CF 3 ; wherein each R and R’ is independently hydrogen, alkyl, or cycloalkyl; or any two adjacent R 3 , R 4 , R 5 , or R 6 form an optionally substituted fused 5- or 6- membered ring comprising 0 to 3 heteroatoms selected fromN, 0 or S; provided that one of R 3 , R 4 , R 5 , or R 6 is a bond to the 2- quinazolinone; and
  • R 7 is alky l cyano, cycloalkyl, halogen, haloalkyl, trifluoromethyl, and alkoxy.
  • each R 10 is independently selected from alkyl, amino, cyano halogen, trifluoromethyl, heterocyclyl, or two R 10 combine to form a bicyclic fused heterocyle.
  • each R 10 is independently selected from alkyl, amino, cyano halogen, trifluoromethyl, heterocyclyl, or two R 10 combine to form a bicyclic fused heterocyle.
  • each R 10 is independently selected from alkyl, amino, cyano halogen, trifluoromethyl, heterocyclyl, or two R 10 combine to form a bicyclic fused heterocyle.
  • n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.
  • p is 1. In embodiments, p is 2.
  • L 1 selected from:
  • R 2 is selected from methoxy, amino, MeOCH 2 -, EtOCH 2 -, C-linked aryl or heteroaryl, N- linked heteroaryl or heterocyclyl, wherein R and R are independently selected from hydrogen, alkyl, and cycloalkyl.
  • R 3 , R 4 , R 5 , and R 6 define a thiophene selected from: , wherein X is hydrogen, chloro, methyl, or CF3,
  • compounds disclosed herein include the following compounds or pharmaceutically acceptable salt thereof:
  • compounds disclosed herein include the following further compounds, or pharmaceutically acceptable salt thereof:
  • 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.
  • base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, hydnodic, 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.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydnodic, or
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds disclosed herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds disclosed herein may be labeled with radioactive or stable isotopes, such as for example deuterium ( 2 H), tritium (3 ⁇ 4), iodine-125 ( 125 I), fluorine-18 ( 18 F), nitrogen-15 ( 15 N), oxygen-17 ( 17 0), oxygen-18 ( 18 0), carbon-13 ( 13 C), or carbon-14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the scope of the present embodiments.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions comprise a compound of any one of the compounds disclosed herein and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises an additional therapeutic agent.
  • the additional therapeutic agent is a chemotherapeutic agent.
  • 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.
  • the chemotherapeutic agent is cisplatm, carboplatin, doxorubicin, ionizing radiation, docetaxel or paclitaxel.
  • 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.
  • 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).
  • 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.
  • 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").
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • 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.
  • 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.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • 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.
  • 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.
  • 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.
  • a filler or binders such as lactose or starches
  • lubricants such as talc or magnesium stearate
  • stabilizers optionally, stabilizers.
  • 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.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • 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.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • 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 ahexi
  • 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.
  • preservatives such as ethyl or n-propyl p-hydroxybenzoate
  • coloring agents such as a coloring agent
  • flavoring agents such as aqueous suspension
  • sweetening agents such as sucrose, aspartame or saccharin.
  • Formulations can be adjusted for osmolarity.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • 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.
  • the pharmaceutical formulations can also be in the form of oil-in-water 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.
  • 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.
  • 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 transdermal and intradermal routes afford constant delivery for weeks or months.
  • 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.
  • the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%- 2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • the pharmaceutical preparation is preferably in unit dosage 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.
  • 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.
  • 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 ty pically 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.
  • 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) Pur. 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.
  • 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.
  • 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.
  • CSF cerebral spinal fluid
  • 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 ah, eds., De Gruyter, New York (1987).
  • 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.
  • 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.
  • Coadministration 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.
  • co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents.
  • the active agents can be formulated separately.
  • the active and/or adjunctive agents may be linked or conjugated to one another.
  • 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.
  • labeling would include, e.g., instructions concerning the amount, frequency and method of administration.
  • 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.
  • pharmaceutically acceptable carriers include water and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils can conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ligands specific for target cells or are otherwise preferentially directed to a specific organ.
  • a method of treating a disorder or condition in a subject 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.
  • a method for inhibiting KRAS G12C activity in a cell comprising contacting the cell in which inhibition of KRAS G12C activity is desired with an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting KRAS G12C activity in a cell comprising contacting the cell in which inhibition of KRAS G12C activity is desired with the pharmaceutical composition disclosed herein.
  • a method for treating a KRAS G12C- 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.
  • a method for treating a KRAS G12C- associated cancer comprising administering to a patient in need thereof the pharmaceutical composition disclosed herein.
  • a method of treating a subject having cancer, the cancer characterized by the presence of a KRAS G12C mutation 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.
  • a method for manufacturing a medicament for treating a subject having cancer the cancer characterized by the presence of a KRAS G12C mutation, the compound comprising Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.
  • a method for treating cancer in a patient in need thereof comprising (a) determining that the cancer is associated with a KRAS G12C mutation (e.g., a KRAS G12C- associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound disclosed herein.
  • a KRAS G12C mutation e.g., a KRAS G12C- associated cancer
  • a method for treating cancer in a patient in need thereof comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRAS G12C- associated cancer); and (b) administering to the patient the pharmaceutical composition disclosed herein.
  • a KRas G12C mutation e.g., a KRAS G12C- associated cancer
  • 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, insulino
  • sarcoma an
  • the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.
  • 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.
  • the compounds of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof can be inhibitors of KRAS G12C.
  • the inhibition constant (Ki) of the compounds disclosed herein can be less than about 50 mM, or less than about 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than about 1 mM.
  • 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.
  • KRAS G12C 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. orNRAS, 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 G12C 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.
  • the compounds disclosed herein or salts thereof may be employed alone or in combination with other agents for treatment.
  • 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.
  • a compound or a pharmaceutically acceptable salt can be co administered with a cytotoxic agent to treat proliferative diseases and cancer.
  • co-admmistering 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.
  • Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen.
  • 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.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with embodiments herein.
  • 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.
  • 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.
  • 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.
  • any agent that has activity against a disease or condition being treated may be co-administered.
  • agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Heilman (editors), 6 th edition (February 15,
  • the treatment method includes the co-admimstration of a compound disclosed herein or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent.
  • cytotoxic agent 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., At 211 , 1 131 , 1 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 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.
  • radioactive isotopes e.g., At 211 , 1 131 , 1 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu
  • chemotherapeutic agents e.g., At 211 , 1 131 , 1 125
  • 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.
  • chemotherapeutic agent includes chemical compounds useful in the treatment of cancer.
  • 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), oxaliplatm (ELOXATIN ® , Sanofi),
  • 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-doxombicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxombicin), epirubicin, esombicin A; bisphosphonates, such as clodronate; an
  • TAXOTERE ® docetaxel, doxetaxel; Sanofi-Aventis
  • chloranmbucil GEMZAR ®
  • 6-thioguanine mercaptopurine
  • methotrexate platinum analogs such as cisplatm 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; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.
  • 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 ® (
  • Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen pie), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RIT
  • 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, nolovizum
  • 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.”
  • EGFR inhibitors refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity
  • Examples of such agents include antibodies and small molecules that bind to EGFR.
  • 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.
  • EMD 55900 Stragliotto et al. Eur. J. Cancer 32A: 636-640 (1996)
  • EMD7200 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 HuMax-EGFR
  • 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,
  • 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-qumazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4 , -fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methyl
  • 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
  • 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, demleukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprel
  • Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcmonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone- 17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene a
  • celecoxib or etoricoxib proteosome inhibitor
  • CCI-779 tipifamib (R11577); orafenib, ABT510
  • Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®)
  • pixantrone famesyltransferase inhibitors such as lonafamib (SCH 6636, SARASARTM)
  • 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
  • FOLFOX an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.
  • ELOXATINTM oxaliplatin
  • 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, lumiracoxi
  • 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.
  • 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.
  • 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), cisplatm, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D, dolastatm 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin,
  • taxanes e.
  • 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, dex
  • 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 immunosup
  • 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.
  • the compounds of Formula I 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.
  • compounds of the present invention may be prepared according to the general reactions in Scheme I and II utilizing conventional cross-coupling chemistry :
  • X is halogen or pseudo-halogen such as mesylate, triflate or the like.
  • Step 3 methyl 2-amino-4-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-5- (frifluoromethyl)benzoate
  • Step 4 methyl 2-amino-4-(4-chlorothiophen-2-yl)-5-(trifluoromethyl)benzoate [0153] TBAF (14.7 mmol) was a added over a solution of methyl 2-amino-4-(4-chloro-5- (triisopropylsilyl)thiophen-2-yl)-5-(trifluoromethyl)benzoate (4.9 mmol) in THF (30 mL).
  • Step 5 methyl 2-amino-4-(4-chlorothiophen-2-yl)-3-iodo-5-(trifluoromethyl)benzoate [0154] To a mixture of methyl 2-amino-4-(4-chlorothiophen-2-yl)-5- (trifluoromethyl)benzoate (27.1 mmol) in AcOH (100 mL) was added N-iodosuccinamide (44.4 mol). The reaction was stirred at room temperature for 36 hours and the volatiles removed under reduced pressure. The resulting residue was redissolved in ethyl acetate and sequentially washed with saturated aqueous Na 2 S 2 O 3 , water and brine.
  • Step 7 7-(4-chlorothiophen-2-yl)-8-iodo-6-(trifluoromethyl)quinazoline-2.4( l H.3H)-dione
  • a mixture of 2-amino-4-(4-chlorothiophen-2-yl)-3-iodo-5-(trifluoromethyl)benzoic acid (20.4 mmol) and urea (1.67 mol) was heated at 200 °C for 2 hours.
  • the reaction was cooled down to 90 °C and diluted with 600 mL of methanol: ethyl acetate (1:1). The mixture was allowed to cool down to room temperature slowly and stirred for another 3 hours.
  • Step 8 (S)-7-(4-chlorothiophen-2-yl)-8-((3-hvdroxy-2-methoxypropyl)thio)-6- (trifluoromethyl)quinazoline-2.4(lH.3H)-dione
  • Step 9 (S)-ll-(4-chlorothiophen-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4-dihydro-2H,6H- 11.41thiazepinol2.3.4-iilquinazoline-6.8(7H)-dione
  • Step 10 (S)-l l-(4-chlorothiophen-2-yl)-8-((3S.5R)-3.5-dimethylpiperazin-l-yl)-3-methoxy- 10-(trifluoromethyl)-3,4-dihvdro-2H,6H-[T41thiazepino[2.3,4-ii1quinazolin-6-one [0159] To a solution of (S)-ll-(4-chlorothiophen-2-yl)-3-methoxy-10-(trifluoromethyl)-3,4- dihydro-2H,6H-[l,4]thiazepino[2,3,4-ij]quinazoline-6,8(7H)-dione (0.05 mmol) in toluene (1 mL) were added N,N - di isopropyl ethyl ami ne (1.0 mmol) and POC13 (1 mL).
  • reaction mixture was stirred at 120 °C for 1.5 hours, cooled down to room temperature and concentrated to afford a residue that was dissolved in dichloroethane (1 mL) and added to a solution of (2R,6S)-2,6-dimethylpiperazine (0.35 mmol) and N,Ndiisopropylethylamine (1.0 mmol) in dichloroethane (1 mL).
  • Step 2 Methyl 2-acetamido-4-chloro-5-(trifluoromethyl)benzoate [0162] To a mixture of methyl 2-acetamido-4-chloro-5-iodobenzoate (99 mmol) in DMF (350 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (396 mmol), HMPA (396 mmol) and Cul (79 mmol). The mixture was stirred at 90 °C for 16 hours, poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 4 Methyl 2-amino-4-chloro-3-iodo-5-(trifluoromethyl)benzoate [0164] To a solution of methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate (110 mmol) in acetic acid (280 mL) was added A-iodosuccinimide (143 mmol). The mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water, extracted with ethyl acetate three times and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was washed with hexanes to afford the title compound as a white solid in quantitative yield.
  • Step 6 7-Chloro-8-iodo-6-(trifluoromethyl)quinazoline-2.4( lH.3H)-dione
  • Step 7 ( j ?)-7-chloro-8-((2-hvdroxy-3-methoxypropyl)thio)-6-(trifluoromethyl)quinazoline-
  • Step 8 (M-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H-[1.4]thiazino[2.3.4- ij ] quinazoline-5 ,7(3H.6H)-dione
  • Step 9 (2S,6R)-tert-bxxtv ⁇ 4-((S)-10-chloro-3-(methoxymethyl)-5-oxo-9-(trifluoromethyl)- 3.5-dihvdro-2H-l 1 ,41 thiazino 12,3 ,4-ii 1 quinazolin-7 -yl 1-2.6-dimethylpiperazine- 1 -carboxyl ate [0169] To a mixture of ( ⁇ S)-10-chloro-3-(methoxymethyl)-9-(trifluoromethyl)-2H- [l,4]thiazino[2,3,4-ij]quinazoline-5,7(3H,6H)-dione (27.32 mmol) and potassium carbonate (273.2 mmol) in acetonitrile (500 mL) was added 4-methylbenzenesulfonic anhydride (40.98 mmol) at 0 °C.
  • Step 10 fe/T-butyl (2S.GR)-4-((S)- 10-(4-chlorothiophen-2-yl lA-tmelhowmelhyl )-5-o ⁇ o-9- (trifluoromethyl)-2.3-dihvdro-5H-[1.41thiazino[2.3.4-iilquinazolin-7-yl)-2.6- dimethylpiperazine- 1 -carboxylate
  • Step 11 (S)- 10-(4-chlorothiophen-2-yl )-7-((3ri ' .5//)-3.5-di methylpiperazin- 1 -yl )-3- (methoxymethvD-9-(trifluoromethyl)-2.3-dihvdro-5H-fl.41thiazino[2.3.4-ii1quinazolin-5-one [0171] To a stirred solution of tert-butyl (2,Y.6//)-4-
  • Step 1 tert-butyl (2S.6R)-4-((S)-l l-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3- (pyrimi din-2 -Yloxy)-10-(trifluoromethyl)-3.4-dihv dro-2H.6H-[l.41thi azepino[2.3.4- iilquinazolin-8-yl)-2.6-dimethylpiperazine-l-carboxylate
  • Step 2 tert-butyl (2S.6R)-4-((S)-ll-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10- (trifluoromethyl)-3.4-dihvdro-2H.6H-ri.41thiazepinor2.3.4-iilqumazolin-8-yl)-2.6- dimethylpiperazine- 1 -carboxylate
  • Step 3 (S)-ll-(4-chlorothiophen-2-yl)-8-((3S.5R)-3.5-dimethylpiperazin-l-yl)-3-(pyrimidin- 2-yloxyV10-(trifluoromethylV3.4-dihvdro-2H.6H-[1.41thiazepino[2.3.4-iilquinazolin-6-one
  • Step 4 (S)-8-((3S.5R)-4-acryloyl-3.5-dimethylpiperazin-l-yl)-l 1 -(4-chlorothiophen-2-yl)-3- (pyrimi din-2 -yloxy)-10-(trifluoromethyl)-3.4-dihv dro-2H.6H-[l.41thi azepino[2.3.4- iilquinazolin-6-one
  • Example 24 (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-l-yl)-ll-(4- chlorothiopheii-2-yl)-3-(IH-pyrazolo
  • Lithium diisopropylamide (10.91 mL, 21.83 mmol, 2.0 M solution in tetrahydrofuran/n- heptane) was slowly added to a solution of (3-chlorothiophen-2-yl)triisopropylsilane (2) (5 g, 18.19 mmol) in tetrahy drofuran (90 mL) at -78 °C under nitrogen atmosphere.
  • the mixture was stirred at -78 °C for 1 hour, then trimethyl borate (2.27 g, 21.83 mmol) was added.
  • the mixture was slowly warmed to room temperature and stirred for 1 hour. After completion, aqueous saturated ammonium chloride solution (10 mL) was slowly added.
  • Example 28 (S)-8-(Y3S,5R)-4-acryloyl-3,5-dimethylninerazin- l-yl)-l 1-14- chlorothiophen-2-yl)-3-(lH-l, 2, 3-triazol-l-yl)-10-(trifluoromethyl)-3, 4-dihydro-
  • Example 29 tS)-8- 4-acryloyl-3.5-dimethylpiperazin-l-yl)-ll-(4- chlorothiophen-2-yl)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
  • Step 2 (S)-3-((tert-butyldiphenylsilyl)oxy)-2-(pyrazin-2-yloxy)propane-l -thiol
  • Triethylsilane (37 mmol) was added to a 0 °C solution of (S)-2-((l -((tert- butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyrazine (19 mmol) in TFA (30 mL) and dichloromethane (90 mL). The reaction was allowed to reach room temperature over 60 minutes and at that time water was added.
  • Step 4 (S)-7-chloro-8-((3-hvdroxy-2-(pyrazin-2-yloxy)propyl)thio)-6- (trifluoromethyl)quinazoline-2.4(lH.3H)-dione
  • Step 5 (S)-ll-chloro-3-tpyrazin-2-yloxyl-10-(trifluoromethyl)-3.4-dihvdro-2H.6H- n.41thiazepinor2.3.4-iilquinazoline-6.8(7H)-dione
  • Step 6 tert-butyl (2S.6R)-4-((S)-ll-chloro-6-oxo-3-(pyrazm-2-yloxy)-10-(trifluoromethyl)-
  • Step 7 tert-butyl (2S.6R)-4-((S)-l l-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3-
  • Step 8 (S)-ll-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-8-((3S.5R)-3.5- dimethylpiperazin-l-yl)-3-(pyrazin-2-yloxy)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H- ri.41thiazepinor2.3.4-iilquinazolin-6-one
  • Step 9 (S)-ll-(4-chlorothiophen-2-yl)-8-((3S.5R)-3.5-dimethylpiperazin-l-yl)-3-(pyrazin-2- Yloxy)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-ri.41thiazepmor2.3.4-iilquinazolin-6-one
  • Step 10 (S)-8-((3S.5R)-4-acryloyl-3.5-dimethylpiperazin-1 -yl)-ll-(4-chlorothiophen-2-yl)- 3-rpyrazm-2-yloxy)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepino[2.3.4- iilquinazolin-6-one
  • Step 2 (S)-l-((tert-butyldiphenylsilylloxy)-3-(tritylthio)propan-2-ol
  • Step 3 (S)-2-((l-((tert-butyldiphenylsilyl)oxy)-3-(tritylthio)propan-2-yl)oxy)pyridine
  • Step 4 (S)-2-(Pyridin-2-yloxy)-3-(tritylthio)propan-l-ol
  • Step 7 (S)-ll-chloro-3-(pyridin-2-yloxy)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H- ri.41thiazepinor2.3.4-iilquinazoline-6.8(7H)-dione
  • Step 9 tert-butyl (2S.6R)-4-((S)-ll-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3- (pyridin-2-yloxy)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepino[2.3.4- i ylpipera/ine-l -carbowlale
  • Step 10 tert-butyl (2S.6R)-4-((S)-ll-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-2-yloxy)-10- (trifluoromethyl)-3.4-dihvdro-2H.6H-11.41thiazepinol2.3.4-iilqumazolin-8-yl)-2.6- dimethylpiperazine- 1 -carboxylate
  • Step 11 (S)-l l-(4-chlorothiophen-2-yl)-8-((3S.5R)-3.5-dimethylpiperazin-l-yl)-3-(pyridin-2- yloxy)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepino[2.3.4-iilquinazolin-6-one [0262]
  • the title compound was prepared analogously to Example 23, step 3 where tert- butyl (2S,6R)-4-((S)-ll-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[l,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-l-carboxylate was replaced with tert
  • Step 12 (S)-8-((3S.5R)-4-acryloyl-3.5-dimethylpiperazin-l-yl)-l l-(4-chlorothiophen-2-yl)- 3-(pyri din-2 -yloxy)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepino[2.3.4- iilquinazolin-6-one
  • Example 33 (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-l-yl)-l 1-14- chlorothiophen-2-yl)-3-tpynmidin-4-yloxy)-10-ttnfluoromethyl)-3,4-dihvdro-2H,6H- [ 1 ,41 thiazepino [ 2,3,4-ii ] quinazolin-6-one [0265]
  • the title compound was prepared analogously to Example 29, where 2- fluoropyrazine was replaced with 4-chloropyrimidine in step 1.
  • the title compound was isolated as a yellow oil.
  • MS (ESI) m/z: 690.0 [M+Na]+.
  • Step 3 tert-Butyl (2S.6R)-4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)-1.2- dihvdroquinazolin-4-yl)-2.6-dimethylpiperazine- 1 -carboxylate
  • Step 6 S-(3-Hvdroxy-2-(pyridin-4-yl)propyl) ethanethioate
  • Step 7 tert-butyl (2S.6R)-4-(7-chloro-8-((3-hvdroxy-2-(pyridin-4-yl)propyl)thio)-2-oxo-6- (trifluoromethyl)-1.2-dihvdroquinazolin-4-yl)-2.6-dimethylpiperazine-l-carboxylate
  • Step 8 tert-Butyl (2S.6R)-4-((R)-l l-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3.4- dihvdro-2H.6H-[1.41thiazepinoi2.3.4-ii1quinazolin-8-yl)-2.6-dimethylpiperazine-l- carboxylate (Int-la) and tert-butyl (2S.6R)-4-((S)-ll-chloro-6-oxo-3-(pyridin-4-vD-10- (trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepino[2.3.4-iilqumazolin-8-yl)-2.6- dimethylpiperazine- 1 -carboxylate (Int- 1 b)
  • Step 10 tert-butyl (2S.6R)-4-((S)-ll-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-4-yl)-10- (trifluoromethyl)-3.4-dihvdro-2H.6H-[1.4]thiazepino[2.3.4-ij]qumazolin-8-Yl)-2.6- dimethylpiperazine- 1 -carboxylate
  • Step 11 (S)-l l-(4-chlorothiophen-2-yl)-8-((3S.5R)-3.5-dimethylpiperazin-l-yl)-3-(pyridin-4- yl)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepinor2.3.4-iilquinazolin-6-one
  • Step 12 (S)-8-((3S.5R)-4-acryloyl-3.5-dimethylpiperazin-l -yl )- 1 l-(4-chlorothiophen-2-yl)- 3-(pyridin-4-yl)- 10-(lrinuoromelhyl)-3.4-dihvdro-2H.6H-! 1.41lhiazepinoi2.3.4-iilquina/olin- 6-one
  • Step 1 tert-butyl (2S,6R)-4-((Sl-ll-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4- dihvdro-2H.6H-11.41thiazepino[2,3.4-ii1quinazolin-8-yl)-2.6-dimethylpiperazine-l- carboxylate (Int-2a) and tert-butyl (2S.6R)-4-((R)-ll-chloro-6-oxo-3-(pyridin-2-yl)-10- (trifluoromethyl)-3.4-dihvdro-2H.6H-ri.41thiazepinor2.3.4-iilqumazohn-8-yl)-2.6- dimethylpiperazine- 1 -carboxylate (Int-2b)
  • Step 2 tert-butyl (2S.6R]-4- ll-(4-chloro-5-(triisopropylsilyl]thiophen-2-yl)-6-oxo-3- (pyridin-2-yl)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepino[2.3.4-iilquinazolin-8- yl)-2.6-dimethylpiperazme- 1 -carboxylate
  • Step 3 tert-butyl (2S.6R)-4-((R)- 1 l-(4-chlorolhiophen-2-yl)-6-o ⁇ o-3-(pyndin-2-yl)-10- (trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepinor2.3.4-iilquinazolin-8-yl ' )-2.6- dimethylpiperazine- 1 -carboxylate
  • Step 5 (R)-8-((3S.5R)-4-acryloyl-3.5-dimethylpiperazin-l-yl)-l l-(4-chlorothiophen-2-yl)-3- (pyridin-2-yl)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-ri.41thiazepinor2.3.4-iilquinazolin-6- one
  • Step 3 3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propan-l-ol
  • Step 4 S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl) ethanethioate
  • Step 6 tert-butyl (2S,6R)-4-(7-chloro-8-((3-hvdroxy-2-(pyridin-3-yl)propyl)thio)-2-oxo-6- (trifluoromethyl)-1.2-dihvdroquinazolin-4-yl)-2.6-dimethylpiperazine-l-carboxylate
  • Step 7 tert-butyl (2S.6R)-4-((S)-l l-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluoromethyl)-3.4- dihvdro-2H.6H-[1.41thiazepino[2.3.4-iilquinazolin-8-yl)-2.6-dimethylpiperazine-1 - carboxylate (int-3a) and tert-butyl 12S.6R)-4-ttR)- 1 1 -chloro-6-oxo-3-tpyridin-3-yl )- 10- (trinuoromethyl)-3.4-dihvdro-2H.6H-l 1.4lthiazepinol2.3.4-ii lqumazolin-8-yl)-2.6- dimethylpiperazine-1 -carboxylate (int-3b)
  • Step 8 tert-butyl (2S.6R)-4-((SVl l-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-6-oxo-3- (pYridin-3-yl ' )-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-ri.41thiazepinor2.3.4-iilquinazolin-8- yl)-2.6-dimethylpiperazme- 1 -carboxylate
  • Step 9 tert-butyl (2S.6R)-4-((S)-11-(4-chlorothiophen-2-yl)-6-oxo-3-(pyridin-3-yl)-10- (trifluoromethyl)-3,4-dihvdro-2H.6H-[l,41thiazepino[2,3,4-iilquinazolin-8-yl)-2,6- dimethylpiperazine- 1 -carboxylate
  • Step 10 (S)-l l-(4-chlorothiophen-2-vl)-8-((3S.5R)-3.5-dimethylpiperazin-l-yl)-3-(pyridin-3- yl)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepinor2.3.4-ij]quinazolin-6-one
  • Step 11 (S)-8-((3S.5R)-4-acryloyl-3.5-dimethylpiperazin-l -yl )- 1 l-(4-chlorothiophen-2-yl)- 3-(pyridin-3-yl)- l()-(lrinuoromelhyl)-3.4-dihvdro-2H.6H-[ 1.41thiazepinoi2.3.4-iilquina/olin- 6-one
  • Step 2 2-(pyrimidin-2-yl)propane-1.3-diol
  • a 1M solution of DIBALH in THF (380 mL) was added to a -40 °C solution of 1,3- dimethyl 2-(pyrimi din-2 -yl)propanedioate (95.2 mmol) in THF (200 mL).
  • the reaction was quenched with sodium sulfate decahydrate, diluted with water and extracted with ethyl acetate three times.
  • the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as yellow oil.
  • MS (ESI) m/z 155.1 (M+H)+.
  • Step 3 3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yl)propan-l-ol
  • Step 5 3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimi din-2 -yl)propane-l -thiol
  • Step 6 8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyrimidin-2-yl)propyl)thio)-7-chloro-6- (trifluoromethyl)quinazoline-2.4(lH.3H)-dione
  • Step 7 7-chloro-8-((3-hvdroxy-2-(pyrimidin-2-yl)propyl)thio)-6- (trifluoromethyl)quinazoline-2.4(lH.3H)-dione
  • Step 11 1 l-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-8-((3S.5R)-3.5-dimethylpiperazin-1 - yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3.4-dihvdro-2E[.6H-[1.41thiazepino[2.3.4- iilquinazolin-6-one
  • Step 12 1 l-(4-chlorothiophen-2-yl)-8-((3S.5R)-3.5-dimethylpiperazin-l-yl)-3-(pyrimidin-2- yl)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepinor2.3.4-iilquinazolin-6-one
  • Step 13 (S)-8-((3S.5R)-4-acryloyl-3.5-dimethylpiperazin-l-yl)-ll-(4-chlorothiophen-2-yl)- 3-(pyrimi din-2 -yl)-10-(trifluoromethyl)-3,4-dihy dro-2H,6H-[T41thiazepino iilquinazolin-6-one and (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-l-yl)-ll-(4- chlorothiophen-2-yl)-3-(pyrimidin-2-yl)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H- [1.41thiazepino[2.3.4-iilquinazolin-6-one
  • Detector Photodiode-array).
  • Step 1 tert-butyl (2S.6R)-4-((R)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10- (trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepino[2.3.4-iilquinazolin-8-yl)-2.6- dimethylpiperazine-l-carboxylate (int-4a) and tert-butyl (2S.6R)-4-((S)-11-chloro-3-(5- fluoropyndin-3-yl)-6-oxo-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-[1.41thiazepino[2.3.4- ij]quinazolin-8-YlV2.6-dipiethylpiperazine-l-carboxYlate (int-4b)
  • Step 2 tert-butyl (2S.6R)-4-((S)-l l-(4-chloro-5-(tnisopropylsilyl)thiophen-2-yl)-3-(5- fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-ri.41thiazepinor2.3.4- iilquinazolin-8-yl)-2.6-dimethylpiperazine-l-carboxylate
  • Step 4 (S)-ll-(4-chlorothiophen-2-yl)-8-((3S.5R)-3.5-dimethylpiperazin-l-yl)-3-(5- fluoropyridin-3-yl)-10-(trifluoromethyl)-3.4-dihvdro-2H.6H-ri.41thiazepinor2.3.4- iilquinazolin-6-one [0312] The title compound was prepared analogously to Example 23, step 3 where tert- butyl (2S,6R)-4-((S)-ll-(4-chlorothiophen-2-yl)-6-oxo-3-(pyrimidin-2-yloxy)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[l,4]thiazepino[2,3,4-ij]qumazohn-8-yl)-2,6- dimethylpiperazine-l-carboxylate was replaced with tert-but
  • Step 5 (S)-8-((3S.5R)-4-acryloyl-3.5-dimethylpiperazin-l-yl)-l 1 -(4-chlorothiophen-2-yl)-3-
  • Step 2 3-fluoro-5-iodothiophene-2-carboxylic acid
  • Sodium hydroxide 42 mmol was added to a solution of methyl 3-fluoro-5- iodothiophene-2-carboxylate (14.0 mmol) in THF (10 mL) and the mixture was stirred at room temperature for four hours. Most volatiles were removed under reduced pressure and the resulting aqueous solution was treated with a 1M aqueous solution of HC1 (10 mL) to induce the precipitation of the title compound which was filtered and dried. The title compound was isolated in 79% yield as a white solid.
  • Step 4 tert-butyldimethvh(2-(4.4.5.5-tetramethyl-L3.2-dioxaborolan-2-yllallyl ' )oxylsilane
  • Step 6 3-((tert-butyldimethylsilyl)oxy)-2-(4-fluorothiophen-2-yl)propan-l-ol
  • Step 7 S-(3-((tert-butyldimethylsilyl)oxy)-2-(4-fluorothiophen-2-yl)propyl) ethanethioate
  • Step 8 tert-butyl (2S.6R)-4-(8-((3-((tert-butyldimethylsilyl)oxy)-2-(4-fluorothiophen-2- yl)propyl)thio)-7-chloro-2-oxo-6-itrifluoromethyl)-1.2-dihvdroquinazohn-4-yl)-2.6- dimethylpiperazine- 1 -carboxylate
  • Step 9 tert-butyl (2S.6R)-4-(7-chloro-8-((2-(4-fluorothiophen-2-yl)-3-hvdroxypropyl)thio)-2- oxo-6-(trifluoromethyl)-1.2-dihvdroquinazolin-4-yl)-2.6-dimethylpiperazine-l -carboxylate
  • Mobile phase A: C02 and mobile phase B: 40% methanol in acetonitrile containing 0.05% diethylamine, flow rate 3 mL/min.
  • Detector Photodiode-array).
  • Step 11 tert-butyl (2S.6R)-4-((S)-ll-(4-chloro-5-(triisopropylsilyl)thiophen-2-yl)-3-(4- fluorothiophen-2-yl)-6-oxo-l 0-(trifluoromethyl)-3.4-dihydro-2H.6H-r 1.4]thiazepino[2.3.4- iilquinazolin-8-yl)-2.6-dimethylpiperazine-l-carboxylate
  • Step 12 tert-butyl (2S,6R)-4-((S)-ll-(4-chlorothiophen-2-yl)-3-(4-fluorothiophen-2-yl)-6- oxo-10-(trifluoromethyl)-3.4-dihvdro-2H,6H-[l .41thiazepino[2.3.4-ii1quinazolin-8-yl)-2.6- dimethylpiperazine- 1 -carboxylate
  • Step 13 (S)-l l-(4-chlorolhiophen-2-yl)-8-(Y3S.5R)-3.5-dimelhylpipera/in-l-yl)-3-(4- fluorothiophen-2-yll-l 0-(trifluoromethyl ' )-3.4-dihvdro-2H.6H-l 1.41thiazepino[2,3.4- iilquinazolin-6-one
  • Step 14 (S)-8-((3S.5R)-4-acryloyl-3.5-dimethylpiperazin-l-yl)-l l-(4-chlorothiophen-2-yl)-
  • KRAS G12C covalent binding assays are carried out as follows:
  • This Example provides a protocol for assessing covalent adduct formation (CAF) between the compounds of Formula (I) and KRAS.
  • CAF Covalent adduct formation
  • Recombinant Human KRAS 4B protein containing the G12C mutation is used in compound screening experiments.
  • This protein contained 188 amino acids in total, including an N-terminal 6-Histidine tag, followed by a Tobacco Etch Vims (TEV) tag, followed by residues 1-169 of the native KRAS 4B sequence.
  • TSV Tobacco Etch Vims
  • the exact mass of the protein is 21,310 Da as determined by mass spectrometry.
  • the full amino acid sequence is shown below:
  • the assay can be conducted using a KRAS 4b G12C protein having 170 amino acids, a mass of 19,336 Da, and the amino acid sequence SMTEYKLVVVGA CGVGKSALTI QLIQNHFVDE YDPTIEDSYR KQVVIDGETC LLDILDTAGQ EEYSAMRDQY MRTGEGFLCV FAINNTKSFE DIHHYREQIK RVKDSEDVPM VLVGNKCDLP SRTVDTKQAQ DLARSYGIPF IETSAKTRQG VDDAFYTLVR EIRKHKEK (SEQ ID NO: 2).
  • the recombinant protein is expressed in E. coli BL21 cells and purified using affinity chromatography via a Ni-NTA column. Protein stocks are nucleotide-exchanged to >95 % GDP, concentrated to 4 mg/mL, and stored at -80 °C in storage buffer (50 mM HEPES pH 7.4, 50 mM NaCl, 5 mM MgC12, 1 mM DTT). Pure KRAS 4B G12C protein is diluted to a concentration of 5 mM in Tris Buffered Saline, pH 7.4. The compounds are dissolved in DMSO and added to the diluted protein to make a 10 mM concentration. The total DMSO concentration in the reaction is 4%.
  • the reaction is mixed by pipetting and incubated at 22 °C for one hour. Aliquots of the reaction are taken over time and diluted 2: 1 in 0.1% formic acid.
  • the intact mass of the protein samples is measured by LC-MS using a QExactive+ mass spectrometer (Thermo Scientific). An amount of 500 ng total protein is injected onto a C8 reverse phase column, eluted with a seven-minute gradient of 30%-90% acetonitrile/0.1% formic acid, and analyzed for intact mass by the mass spectrometer. Adducts identified are confirmed to be within 1 Dalton of the expected mass, and the relative ratios of free: adduct protein were used to quantify the percentage of protein bound by the compound. CAF reactions are run in duplicate, with a typical variability of ⁇ 5%.
  • KRAS G12C mutant cell lines NCI H358 (ATCC, CRL-5807), and Ras Initiative (RI) KRAS G12C were cultured according to published protocols and maintained at 37 °C in 5% CO 2 .
  • the phospho-ERK HTRF assay was executed following provider’s protocol (CisBio #64AERPEH).
  • NCI-H358 or RI KRAS G12C cells were plated at a density of 50,000 cells per well in a 96-well plate (Coming #3903) in respective medias (for NCI-H358, RPMI +
  • lysis buffer (lx) supplemented with lx Pierce Halt Protease and Phosphatase inhibitor and incubated for 30 minutes at 4 °C with shaking. After lysis, 16 pL of cell lysate from the 96-well cell-culture plate was transferred to a 384- well plate (Perkin Elmer #6007290).
  • the premixed antibody solution was prepared by mixing (vol/vol) advanced phospho-ERKl/2 d2 antibody and advanced phospho-ERKl/2 Eu Cryptate antibody. The premixed antibody solution (4 pL) was added to the detection plate containing cell lysate.
EP22731929.0A 2021-05-25 2022-05-25 Schwefelhaltige heteroaromatische tricyclische kras-hemmer Pending EP4347603A1 (de)

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