WO2024040080A1 - Conjugués inhibiteurs de kras - Google Patents

Conjugués inhibiteurs de kras Download PDF

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Publication number
WO2024040080A1
WO2024040080A1 PCT/US2023/072251 US2023072251W WO2024040080A1 WO 2024040080 A1 WO2024040080 A1 WO 2024040080A1 US 2023072251 W US2023072251 W US 2023072251W WO 2024040080 A1 WO2024040080 A1 WO 2024040080A1
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compound
mmol
alkyl
methyl
carcinoma
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PCT/US2023/072251
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English (en)
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Hengmiao Cheng
Jean-Michael Vernier
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Erasca, Inc.
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Publication of WO2024040080A1 publication Critical patent/WO2024040080A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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 guaonnine 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, and the G12D mutation is among the most prevalent. Accordingly, there is a need to develop selective inhibitors of KRAS G12D.
  • the present embodiments meet this and other needs.
  • R 1 is Ci-Ce alkyl, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said Ci-Ce alkyl, heterocyclyl, cycloalkyl, aryl and heteroaryl are optionally substituted with OH, halo, CN, CF 3 , C 1-4 alkyl, CM alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and C 1-3 alkyl-OH;
  • X is C-H, C-halo, C-C 1-3 alkyl, C-CF3, C-C 1-3 haloalkyl, C- C 3-4 cycloalkyl, C- cyano, or N;
  • Y is O, NR 2 , S, or absent, wherein R 2 is H or C 1-4 alkyl;
  • Y’ is C 1-3 alkyl or absent
  • Z is O, NR Z , S, or absent; wherein R z is hydrogen or methyl;
  • Z’ is null, substituted or unsubstituted alkylene, substituted or unsubstituted heterocyclylalkylene, substituted or unsubstituted heterocyclyloxyalkylene, substituted or unsubstituted alkoxalkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylalkylene, substituted or unsubstituted aryloxyalkylene, substituted or unsubstituted heteroarylalkylene, substituted or unsubstituted heteroaryloxyalkylene, substituted or unsubstituted cycloalkylalkylene, or a substituted or unsubstituted cycloalkyloxyalkylene;
  • L is: bond, NH, S, O, C(O), C(O)O, OC(O), NHC(O), C(O)NH, NHC(O)NH, NHC(NH)NH, C(S), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted spirocycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted spiroheterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene or combinations thereof; and
  • UBM comprises a ubiquitin binding moiety structure of Formula (la): wherein W is aryl, heteroaryl, or -NH-;
  • R b is C1-C4 alkyl
  • G and G' are independently H, methyl, ethyl, isopropyl, or hydroxymethyl; or G and G' combine to form a cyclopropyl;
  • m is an integer from 0 to5;
  • each R T is independently halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, OH, - NH2, cyclopropyl, or cyclobutyl;
  • each of T 1 , T 2 , T 3 , T 4 , or T 5 is independently N, CH, or CR T ; wherein 0 to 3 of T 1 , T 2 , T 3 , T 4 , or T 5 are N.
  • the present embodiments provide a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present embodiments provide a method of treating a subject having cancer, the cancer characterized by the presence of a KRAS G12D mutation, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as disclosed herein.
  • the present embodiments provide a method for manufacturing a medicament for treating a subject having cancer, the cancer characterized by the presence of a KRAS G12D mutation, the medicament comprising a conjugate 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 conjugate disclosed herein, or a pharmaceutically acceptable salt thereof, or a a pharmaceutical composition as disclosed herein, for the manufacture of a medicament for the treatment of cancer in a subject, the cancer characterized by the presence of a KRAS G12D mutation.
  • the present embodiments provide the conjugates disclosed herein, or a pharmaceutically acceptable salt thereof, or a a pharmaceutical composition as disclosed herein, for use in the treatment of cancer in a subject, the cancer characterized by a KRAS G12D mutation.
  • the present embodiments provide conjugates of selective inhibitors of KRAS G12D exhibiting good selectivity over wild- type KRAS conjugated to ubiquitin binding moieties and are useful for treating a cancer characterized by a KRAS G12D mutation.
  • ‘A,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member.
  • the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
  • a cell includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so forth.
  • An “acetyl” group which is a type of acyl, refers to a (--C( C) )CH , ) group.
  • An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, without limitation, methylcarbonyl and ethylcarbonyl.
  • an “arylcarbonyl” or “aroyl” group refers to an aryl group attached to the parent molecular moiety through a carbonyl group.
  • examples of such groups include, without limitation, benzoyl and naphthoyl.
  • generic examples of acyl groups include alkanoyl, aroyl, heteroaroyl, and so on.
  • Specific examples of acyl groups include, without limitation, formyl, acetyl, acryloyl, benzoyl, trifluoroacetyl and the like.
  • alkenyl refers to a straightchain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms.
  • the alkenyl may comprise from 2 to 6 carbon atoms, or from 2 to 4 carbons, either of which may be referred to as “lower alkenyl.”
  • Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and Ce, and so on up to 20 carbon atoms.
  • Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1 -butenyl, 2-butenyl, isobutenyl, butadienyl, 1 -pentenyl,
  • Alkenyl groups can be substituted or unsubstituted. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups.
  • alkoxy refers to an alkyl ether radical, wherein the term alkyl is as defined below.
  • Alkoxy groups may have the general formula: alkyl-O-.
  • alkyl group alkoxy groups can have any suitable number of carbon atoms, such as Ci-6.
  • Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.
  • the alkoxy groups can be further optionally substituted as defined herein.
  • alkyl refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms.
  • the alkyl may comprise from 1 to 10 carbon atoms.
  • the alkyl may comprise from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms.
  • Alkyl can include any number of carbons, such as C1-2, C 1-3 , C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, Ci-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6.
  • Ci-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc.
  • Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.
  • alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (— CH 2 — ). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. When the alkyl is methyl, it may be represented structurally as CH3, Me, or just a single bond terminating with no end group substitution.
  • alkylamino refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N- methylamino (— NHMe), N-ethylamino (— NHEt), N,N-dimethylamino (— NMe2), N,N- ethylmethylamino (— NMeEt) and the like.
  • aminoalkyl refers to reverse orientation in which the amino group appears distal to the parent molecular moiety and attachment to the parent molecular moiety is through the alkyl group.
  • NH2(CH 2 )n — describes an aminoalkyl group with a terminal amine at the end of an alkyl group attached to the parent molecular moiety.
  • alkylamino and aminoalkyl can be combined to describe an “alkylaminoalkyl” group in which an alkyl group resides on a nitrogen atom distal to the parent molecular moiety, such as MeNH(CH 2 )n— .
  • an aryl group as defined herein, may combine in a similar fashion providing an arylaminoalkyl group ArNH(CH 2 )n— .
  • N- in the name, such as N-arylaminoalkyl, which is understood to mean that the aryl group is a substituent on the nitrogen atom of the aminoalkyl group, the alkyl being attached the parent molecular moiety.
  • alkylidene refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
  • alkylthio refers to an alkyl thioether (AlkS-) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.
  • alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.
  • arylthio refers to arylthioether (ArS-) radical wherein the term aryl is as defined herein and wherein the sulfur may be singly or double oxidized.
  • alkynyl refers to a straightchain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms.
  • alkynylene refers to a carbon-carbon triple bond attached at two positions such as ethynylene.
  • Alkynyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C34, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and Ce.
  • 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. Unless otherwise specified, the term “alkynyl” may include “alkynylene” groups.
  • acylamino as used herein, alone or in combination, refers to an amino group as described below attached to the parent molecular moiety through a carbonyl group.
  • acylamino as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group.
  • An example of an “acylamino” group is acetylamino (CH 3 C(O)NH-).
  • amino refers to — N(R)(R') or — N + (R)(R')(R"), wherein R, R' and R" are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted.
  • amino acid means a substituent of the form — NRCH(R')C(O)OH, wherein R is typically hydrogen, but may be cyclized with N (for example, as in the case of the amino acid proline), and R' is selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, amino, amido, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, thiol, thioalkyl, alkylthioalkyl, and alkylthio, any of which may be optionally substituted.
  • amino acid includes all naturally occurring amino acids as well as synthetic analogues.
  • aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, and biphenyl.
  • arylalkenyl or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
  • arylalkoxy or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
  • arylalkyl or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • arylalkynyl or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
  • arylalkanoyl or “aralkanoyl” or “aroyl,” as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl, phenylacetyl, 3 -phenylpropionyl (hydrocinnamoyl), 4- phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxy.
  • benzo and “benz,” as used herein, alone or in combination, refer to the divalent radical C 6 H 4 derived from benzene. Examples include benzothiophene and benzimidazole.
  • carbamate refers to an ester of carbamic acid (— NHCOO— ) which may be attached to the parent molecular moiety from either the nitrogen or acid (oxygen) end, and which may be optionally substituted as defined herein.
  • O-carbamyl as used herein, alone or in combination, refers to a — OC(O)NRR', group, with R and R' as defined herein.
  • N-carbamyl as used herein, alone or in combination, refers to a ROC(O)NR'— group, with R and R' as defined herein.
  • cyano as used herein, alone or in combination, refers to — CN.
  • cycloalkyl refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
  • a cycloalkyl may comprise from from 3 to 7 carbon atoms, or from 5 to 7 carbon atoms.
  • cycloalkyl radicals examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3- dihydro-lH-indenyl, adamantyl and the like.
  • “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[l.l.l]pentane, camphor, adamantane, and bicyclo[3.2.1]octane.
  • ether typically refers to an oxy group bridging two moieties linked at carbon atoms. “Ether” may also include polyethers, such as, for example, -RO(CH 2 )2O(CH 2 )2O(CH 2 )2OR', — RO(CH 2 )2O(CH 2 )2OR', -RO(CH 2 )2OR', and -RO(CH 2 ) 2 OH.
  • halo or halogen, as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl, trihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHC1— ) and the like.
  • heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized (i.e. bond to 4 groups).
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, - CH 2 NHOCH3.
  • the term heteroalkyl may include ethers.
  • heteroaryl refers to 3 to 7 membered unsaturated heteromonocyclic rings, or fused polycyclic rings, each of which is 3 to 7 membered, in which at least one of the fused rings is unsaturated, wherein at least one atom is selected from the group consisting of O, S, and N.
  • a heteroaryl may comprise from 5 to 7 carbon atoms.
  • the term also embraces fused polycyclic groups wherein heterocyclic radicals are fused with aryl radicals, wherein heteroaryl radicals are fused with other heteroaryl radicals, or wherein heteroaryl radicals are fused with cycloalkyl radicals.
  • heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chro
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.
  • the heteroaryl group can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • 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-triazine
  • 1 ,2,4-triazine includes 3-, 5- and 6-triazine
  • 1,3,5-triazine includes 2- triazine
  • thiophene includes 2- and 3 -thiophene
  • furan includes 2- and 3 -furan
  • thiazole includes 2-, 4- and 5-thiazole
  • 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
  • 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.
  • heterocycloalkyl and, interchangeably, “heterocycle,” or “heterocyclyl” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, spirocyclic, or tricyclic heterocyclic radical containing at least one heteroatom as ring members, wherein each heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • a heterocycloalkyl may comprise from 1 to 4 heteroatoms as ring members.
  • a heterocycloalkyl may comprise from 1 to 2 heteroatoms ring members.
  • a heterocycloalkyl may comprise from 3 to 8 ring members in each ring. In further embodiments, a heterocycloalkyl may comprise from 3 to 7 ring members in each ring. In yet further embodiments, a heterocycloalkyl may comprise from 5 to 6 ring members in each ring.
  • “Heterocycloalkyl” and “heterocycle” are intended to include sugars, sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
  • heterocycloalkyl groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro [1,3] oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1 ,4-dioxanyl, 1,3- dioxolanyl, epoxy, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, hexahydro- I H/-pyrrol izine and the like.
  • Heterocycloalkyl may refer to a saturated ring system having from 3 to 12 ring members and from 1 to 5 heteroatoms of N, O and S.
  • the heteroatoms can also be oxidized, such as, but not limited to, S(O) and S(O)2 .
  • Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 1 1, or 3 to 12 ring members.
  • heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4 or 3 to 5.
  • the heterocycloalkyl group can include any number of carbons, such as C3-6, C4-6, C5-6, C3-8, C4-8, C5-8, Ce-8, C3-9, C3-10, C3-11, and C3-12.
  • the heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, diazepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane.
  • groups such as aziridine, azetidine, pyrrolidine,
  • heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline, diazabicycloheptane, diazabicyclooctane, diazaspirooctane or diazaspirononane.
  • Heterocycloalkyl groups can be unsubstituted or substituted.
  • Heterocycloalkyl groups can also include a double bond or a triple bond, such as, but not limited to dihydropyridine or 1,2,3,6-tetrahydropyridine.
  • the heterocycloalkyl groups can be linked via any position on the ring.
  • aziridine can be 1- or 2-aziridine
  • azetidine can be 1- or 2- azetidine
  • pyrrolidine can be 1-, 2- or 3 -pyrrolidine
  • piperidine can be 1-, 2-, 3- or 4-piperidine
  • pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine
  • imidazolidine can be 1-, 2-, 3- or 4-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
  • 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, and morpholine.
  • hydrazinyl refers to two amino groups joined by a single bond, i.e., -N-N-.
  • the hydrazinyl group has optional substitution on at least one NH hydrogen to confer stability.
  • hydroxamic acid or its ester as used herein, refers to — C(O)ON(R)O(R'), wherein R and R' are as defined herein, or the corresponding “hydroxamate” anion, including any corresponding hydroxamic acid salt.
  • hydroxy refers to OH.
  • hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
  • “Hydroxyalkyl” or “alkylhydroxy” refers to an alkyl group, as defined above, where at least one of the hydrogen atoms is replaced with a hydroxy group.
  • alkyl group hydroxyalkyl or alkylhydroxy groups can have any suitable number of carbon atoms, such as C 1-6 .
  • Exemplary 4 1-6 hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (where the hydroxy is in the 1 or 2position), hydroxypropyl (where the hydroxy is in the 1, 2 or 3position), hydroxybutyl (where the hydroxy is in the 1, 2, 3 or 4position), 1 ,2dihydroxyethyl, and the like.
  • isocyanato refers to a — NCO group.
  • isothiocyanato refers to a — NCS group.
  • linear chain of atoms refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
  • linking group refers to any nitrogen containing organic fragment that serves to connect the pyrimidine or pyridone core of the compounds disclosed herein to the electrophilic moiety E, as defined herein.
  • exemplary linking groups include piperazines, aminoalkyls, alkyl- or aryl-based diamines, aminocycloalkyls, amine - containing spirocyclics, any of which may be optionally substituted as defined herein.
  • linking groups may comprise the substructure L-Q-L’-E wherein Q is a monocyclic 4 to 7 membered ring or a bicyclic, bridged, or fused, or spiro 6- 11 membered ring, any of which optionally include one or more nitrogen atoms, E is the electrophilic group, L is bond, Ci-6 alkylene, — O — C0-5 alkylene, — S — C0-5 alkylene, or — NH — C0-5 alkylene, and for C2-6 alkylene, — O — C2-5 alkylene, — S — C2-5 alkylene, and NH — C2-5 alkylene, one carbon atom of any of the alkylene groups can optionally be replaced with O, S, or NH; and L’ is bond when Q comprises a nitrogen to link to E, otherwise L’ is NR, where R is hydrogen or alkyl.
  • lower means containing from 1 to and including 6 carbon atoms, or from 1 to 4 carbon atoms.
  • mercaptyl as used herein, alone or in combination, refers to an RS— group, where R is as defined herein.
  • nitro refers to — NO2.
  • perhaloalkoxy refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
  • perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • phosphonate refers to a group of the form ROP(OR')(OR)O— wherein R and R' are selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted.
  • Phosphonate includes “phosphate [(OH)2P(O)O— ] and related phosphoric acid anions which may form salts.
  • sulfonate refers to the -SO3H group and its anion as the sulfonic acid is used in salt formation or sulfonate ester where OH is replaced by OR, where R is not hydrogen, but otherwise is as defined herein, and typically being alkyl or aryl.
  • thia and thio refer to a — S- group or an ether wherein the oxygen is replaced with sulfur.
  • the oxidized derivatives of the thio group namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
  • thiol refers to an — SH group.
  • thiocyanato refers to a — CNS group.
  • trihalomethanesulfonamido refers to a X 3 CSWOfiNR— group with X is a halogen and R as defined herein.
  • trimethoxy refers to a X 3 CO— group where X is a halogen.
  • trimethysilyl as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • null When a group is defined to be “null,” what is meant is that said group is absent.
  • a “null” group occurring between two other group may also be understood to be a collapsing of flanking groups. For example, if in -(CH 2 ) X G 1 G 2 G 3 , the element G 2 were null, said group would become — (CH 2 ) X G 1 G 3 .
  • optionally substituted means the anteceding group or groups may be substituted or unsubstituted. Groups constituting optional substitution may themselves be optionally substituted. For example, where an alkyl group is embraced by an optional substitution, that alkyl group itself may also be optionally substituted.
  • the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: alkyl, alkenyl, alkynyl, alkanoyl, heteroalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, lower perhaloalkyl, perhaloalkoxy, cycloalkyl, phenyl, aryl, aryloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, alkylcarbonyl, carboxyester, carboxamido, cyano, hydrogen, halogen, hydroxy, amino, alkylamino, arylamino, amido, nitro, thiol, alkylthio, haloalkylthio, perhaloalkylthio, arylthi
  • optional substitution include, without limitation: (1) alkyl, halo, and alkoxy; (2) alkyl and halo; (3) alkyl and alkoxy; (4) alkyl, aryl, and heteroaryl; (5) halo and alkoxy; and (6) hydroxyl, alkyl, halo, alkoxy, and cyano.
  • an optional substitution comprises a heteroatom-hydrogen bond (-NH-, SH, OH)
  • further optional substitution of the heteroatom hydrogen is contemplated and includes, without limitation optional substitution with alkyl, acyl, alkoxymethyl, alkoxyethyl, arylsulfonyl, alkyl sulfonyl, any of which are further optionally substituted.
  • Optionally substituted may include any of the chemical functional groups defined hereinabove and throughout this disclosure. Two optional substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
  • An optionally substituted group may be unsubstituted (e.g., -CH 2 CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH 2 CF3).
  • a carbon chain may be substituted with an alkyl group, a halo group, and an alkoxy group.
  • substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed.
  • substituent is qualified as “substituted,” the substituted form is specifically intended.
  • different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.”
  • R or the term R' appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted.
  • R and R' groups should be understood to be optionally substituted as defined herein.
  • every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence.
  • substituent, or term e.g. aryl, heterocycle, R, etc.
  • its definition at each occurrence is independent of the definition at every other occurrence.
  • certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as — C(O)N(R)— may be attached to the parent moiety at either the carbon or the nitrogen.
  • substituents include, but are not limited to, halogen, haloalkyl, haloalkoxy, -OR’,
  • R’, R” and R’ each independently refer to hydrogen, unsubstituted alkyl, such as unsubstituted Ci-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.
  • Conjugate refers to compounds disclosed herein that are constructed by linking two components, a binder of KRAS having the G12D mutation and ubiquitin binding moiety.
  • conjugate and “compound” may be used interchangeably.
  • UBM Ubiquitin binding moiety
  • the UBM refers to a portion of the conjugates, as set forth herein, that is capable of binding to an E3 ubiquitin ligase.
  • the UBM is a monovalent form of a E3 ubiquitin ligase ligand that is covalently bonded in the conjugate.
  • the UBM is a divalent form of a E3 ubiquitin ligase ligand that is integrated into the conjugate.
  • the substrate recognition subunits of E3 ubiquitin ligases include, for example, Von Hippel-Lindau (VHL), cereblon (CRBN), inhibitor of apoptosis (IAP), and mouse double minute 2 homolog (MDM2) ligases.
  • VHL Von Hippel-Lindau
  • CRBN cereblon
  • IAP inhibitor of apoptosis
  • MDM2 mouse double minute 2 homolog
  • 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, lubricants, coatings, sweeteners, flavors and colors.
  • binders include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors.
  • ‘Treat”, “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom.
  • the treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.
  • 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.
  • R 1 is Ci-Ce alkyl, 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said Ci-Ce alkyl, heterocyclyl, cycloalkyl, aryl and heteroaryl are optionally substituted with OH, halo, CN, CF3, C 1-4 alkyl, CM alkoxy, C3-4 cycloalkyl, C3-4 cycloalkoxy, and C 1-3 alkyl-OH;
  • X is C-H, C-halo, C-C 1-3 alkyl, C-CF3, C-C 1-3 haloalkyl, C- C 3-4 cycloalkyl, C- cyano, or N;
  • Y is O, NR 2 , S, or absent, wherein R 2 is H or C 1-4 alkyl;
  • Y’ is C 1-3 alkyl or absent
  • Z is O, NR Z , S, or absent; wherein R z is hydrogen or methyl;
  • Z’ is null, substituted or unsubstituted alkylene, substituted or unsubstituted heterocyclylalkylene, substituted or unsubstituted heterocyclyloxyalkylene, substituted or unsubstituted alkoxalkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylalkylene, substituted or unsubstituted aryloxyalkylene, substituted or unsubstituted heteroarylalkylene, substituted or unsubstituted heteroaryloxyalkylene, substituted or unsubstituted cycloalkylalkylene, or a substituted or unsubstituted cycloalkyloxyalkylene;
  • L is: bond, NH, S, O, C(O), C(O)O, OC(O), NHC(O), C(O)NH, NHC(O)NH, NHC(NH)NH, C(S), substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted spirocycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted spiroheterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene or combinations thereof; and
  • UBM comprises a ubiquitin binding moiety structure of Formula (la): wherein W is aryl, heteroaryl, or -NH-;
  • R b is C1-C4 alkyl
  • G and G' are independently H, methyl, ethyl, isopropyl, or hydroxymethyl; or G and G' combine to form a cyclopropyl;
  • m is an integer from 0 to 5;
  • each R T is independently halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, OH, - NH2, cyclopropyl, or cyclobutyl;
  • each of T 1 , T 2 , T 3 , T 4 , or T 5 is independently N, CH, or CR T ; wherein 0 to 3 ofT 1 , T 2 , T 3 , T 4 , or T 5 are N.
  • W is isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiophenyl, pyrrolyl, imidazolyl, furanyl, triazolyl, furazanyl, thiadiazolyl, dioxazolyl, dithiazolyl, pyridyl, or phenyl.
  • W is isoxazolyl or triazolyl.
  • R b is n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or tert-butyl.
  • Formula (la) is (lb):
  • G is H, methyl, or hydroxymethyl.
  • Formula (la) is (Icl) or (Ic2): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (Id): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (lai ): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (Ia2): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (Ia3): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (Ia4): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (Ia5): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (Ia6): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (Ia7): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (Ia8): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (Ia9): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (laid): wherein G is H, methyl, or hydroxymethyl.
  • Formula (la) is (la1 1): wherein G is H, methyl, or hydroxymethyl.
  • W is isoxazolyl or triazolyl
  • R b is i-propyl
  • W is -NH- and R b is i-propyl or t-butyl.
  • Ar is selected from: wherein:
  • R 14 is H, halo, halo-Ci- 3 haloalkyl, Cfrialkoxy, Cfrihaloalkoxy, cyclopropyl, Ci- 3 alkylthio, or CF 3 ;
  • R 15 is H, halo, halo-Ci- 3 haloalkyl, Ci- 3 alkoxy, Ci- 3 haloalkoxy, cyclopropyl, Ci- 3 alkylthio, or CF 3 ; or
  • R 14 and R 15 together with the atoms to which they are each bonded, form 5 to 6 membered heteroaryl or 6 membered aryl, wherein the 5 to 6 membered heteroaryl and 6 membered aryl is optionally substituted with 1 to 4 substituents selected from the group consisting of halo, Ci- 3 alkyl, Ci- 3 alkoxy;
  • R 16 is H, halo, halo-Ci- 3 haloalkyl, Ci- 3 alkoxy, Ci- 3 haloalkoxy, cyclopropyl, Ci- 3 alkylthio, or CF 3 ;
  • R 17 is H or CIR; wherein each C 1-3 alkyl is independently optionally substituted with 1 to 5 halogens; and, each C 1-3 alkoxy is independently optionally substituted with 1 to 3 halogens.
  • (Al) is: [0134]
  • (A2) is:
  • (A2) is: [0136] In embodiments, (A2) is: wherein R c is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl.
  • (A2) is: wherein R c is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl.
  • (A2) is:
  • (A2) is:
  • (A2) is:
  • Ar is: wherein R 11 , R 12 , and R 13 , are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, and A-alkylamino; and, wherein R 14 is hydrogen, halogen, halo-C 1-3 haloalkyl, C 1-3 alkoxy, Ci-
  • (A4) is:
  • Ar is: wherein R 11 , R 12 , and R 13 , are independently selected from halogen, hydrogen, hydroxyl, alkoxy, alkyl, cycloalkyl, amino, and A-alkylamino; and, wherein R 14 is hydrogen, halogen, halo-C 1-3 haloalkyl, C 1-3 alkoxy, Ci- 3haloalkoxy, cyclopropyl, C 1-3 alkylthio, or CF3.
  • (A4) is:
  • (A3) is:
  • two V form a bridge: -CH 2 - or -CH 2 -CH 2 -.
  • UBM ubiquitin binding moiety
  • linker -L- is:
  • -L- is a structure according to formula (LO): wherein each k is independently 0 or 1; and, each g is independently 1 or 2. [0153] In embodiments, Z is O.
  • Z’ is C1-C3 alkylene.
  • the ubiquitin binding moiety structure of Formula (la) is:
  • R 1 is: substituted with OH, halo, CN, CF 3 , C1-4 alkyl, C1-4 alkoxy, and C 1-3 alkyl-OH.
  • Formula (I) is:
  • the compound of Formula (I) is:
  • the compound of Formula (I) is:
  • 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 include 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, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
  • 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 et al., "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 H), iodine- 125 ( 125 I), fluorine-18 ( 18 F), nitrogen-15 ( 15 N), oxygen-17 ( 17 O), oxygen-18 ( 18 O), 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.
  • 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.
  • compositions comprise a conjugate of any one of the compounds disclosed herein and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of a conjugate of Formula (A) 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 cisplatin, 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. Similarly, cachets and lozenges are included.
  • 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.
  • 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.
  • 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, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • 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 a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty
  • 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.
  • Oil suspensions can be formulated by suspending the compounds disclosed herein in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these.
  • the oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose.
  • These formulations can be preserved by the addition of an antioxidant such as ascorbic acid.
  • an injectable oil vehicle see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997.
  • the pharmaceutical formulations can also be in the form of oil-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 typically 10 mg to 500 mg, according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • 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. Sei. 84: 1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24: 103-108; the latest Remington's, supra).
  • the state of the art allows the clinician to determine the dosage regimen for each individual patient, GR and /or MR modulator and disease or condition treated.
  • 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 al., 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.
  • 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.
  • KRAS refers to Kirsten rat carcoma virus.
  • the KRAS or “K-Ras” protein is a GTPase, a class of enzymes that convert the nucleotide guanosine triphosphate into guanosine diphosphate.
  • KRAS is an intregral part of numerous signal transduction pathways.
  • KRAS G12D refers to the G12D mutation. Specifically, the amino acid position 12 of the KRAS protein is an cysteine instead of a glycine (wildtype).
  • the present application contemplates ligands that are KRAS G12D inhibitors. KRAS G12D inhibitors specifically bind to the KRAS G12D.
  • Example KRAS G12D inhibitors adaptable into a PROTAC degrader include those disclosed in WO/2022/105859, WO/2022/105855, WO/2022/105857, WO/2022/098625, WO/2022/066646, WG/2022/042630, WO/2022/031678, WO/2022/015375, WG/2022/002102, WO/2021/248079, WO/2021/248095, WO/2021/248082, WO/2021/248083, WO/2021/248090, WO/2021/215544, WG/2021/107160, WO/2021/106231, WO/2021/081212, and WO/2021/081212, all of which are incorporated herein by reference in their entirety.
  • KRAS G12C refers to the G12C mutation. Specifically, the amino acid position 12 of the KRAS protein is an aspartic acid instead of a glycine (wildtype). In other aspects of the application, ligands that are KRAS G12C inhibitors are contemplated. KRAS G12C inhibitors specifically bind to the KRAS G12C.
  • Example KRAS G12C inhibitors adaptable into a PROTAC degrader include those disclosed in WO/2022/119748, WO/2022/111513, WO/2022/115439, WO/2022/111527, WO/2022/11 1521, WO/2022/109485, WO/2022/109487, WO/2022/093856, WO/2022/087371, WO/2022/087624, WO/2022/087375, WO/2022/083569, WO/2022/081655, WO/2022/063297, WO/2022/037560, WO/2022/028492, WO/2021/259331, WO/2021/249563, WO/2021/252339, WO/2021/244603, WO/2021/248079, WO/2021/248095, WO/2021/248082, WO/2021/248083, WO/2021/248090, WO/2021/218110, WO/2021/219090, WO/2021/219091
  • a method for inhibiting KRAS G12D activity in a cell comprising contacting the cell in which inhibition of KRAS G12D activity is desired with an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.
  • a method for inhibiting KRAS G12D activity in a cell comprising contacting the cell in which inhibition of KRAS G12D activity is desired with the pharmaceutical composition disclosed herein.
  • a method for treating a KRAS G HD- 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 G HD- 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 G12D mutation comprising administering to the human a therapeutically effective amount of a compound of of Formula (I) 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 G12D mutation, the compound comprising Formula (I), 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 G12D mutation (e.g, a KRAS G12D- associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound disclosed herein.
  • a KRAS G12D mutation e.g, a KRAS G12D- associated cancer
  • a method for treating cancer in a patient in need thereof comprising (a) determining that the cancer is associated with a KRas G12D mutation (e.g., a KRAS G12D- associated cancer); and (b) administering to the patient the pharmaceutical composition disclosed herein.
  • a KRas G12D mutation e.g., a KRAS G12D- 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 a pharmaceutically acceptable salt thereof can be inhibitors of KRAS G12D.
  • the inhibition constant (Ki) of the compounds disclosed herein can be less than about 50 pM, or less than about 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than about 1 pM.
  • 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 G12D inhibition constant (IC50) of the compounds disclosed herein can be at least 2-fold less than the inhibition constant of one or more of KRAS wild-type, or NRAS, or HRAS, or at least 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100-fold less.
  • the KRAS gl2D inhibition constant (Ki) of the compounds disclosed herein can also be at least 100-fold less than the inhibition constant of one or more of KRAS wild-type, or NRAS, or HRAS, or at least 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 10,000-fold less.
  • 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-administering refers to either simultaneous administration, or any manner of separate sequential administration, of a compound disclosed herein or a salt thereof, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.
  • 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.
  • examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.
  • the treatment method includes the co-administration 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 iso
  • 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; HDAC 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), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5 -fluorouracil), leucovorin,
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, es
  • 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® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), F
  • 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 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as El .1 , E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6.
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659.439A2, Merck Patent GmbH).
  • EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451, W098/50038, W099/09016, and WO99/24037.
  • EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2- propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6- quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD 1839, gefitinib (IRESSA®) 4-(3’-Chloro- 4’-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3- chloro-4-fluoro-phenyl)-N2-(l-methyl-piperid
  • 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 GlaxoSmithKline), 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, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, opre
  • Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone- 17-butyrate, hydrocortisone- 17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone- 17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene
  • 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), cisplatin, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin,
  • 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 immunosuppressive agents
  • 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.
  • LiHMDS lithium bis(trimethylsilyl)amide mCPBA -3 -chloroperoxybenzoic acid
  • 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. For instance, compounds of the present application may be prepared according to the general reaction schemes set forth below.
  • step 2 Compound of formula 1 and compound of formula 2 are reacted to yield compound of formula 3.
  • step 2 compound of formula 3 is converted to compound of formula 4.
  • step 3 Compound of formula 4 is converted to compound of formula 5.
  • step 4 cyclopropyl group is installed on the core to produce compound of formula 6.
  • Ar group is coupled to compound of formula 6 to give compound of formula 7.
  • step 6 compound of formula 7 is oxidized to produce compound of formula 8.
  • step 7 compound of formula 8 is reacted with R 1 -YH to yield compound of formula 9.
  • step 8 compound of formula 9 is deprotected to generate compound of formula 10.
  • step 9 the ether bond in compound of formula 11 is generated from compound of formula 10 and a substituted benzyl alcohol.
  • Compound of formula A is coupled with compound of formula B to yield compound of formula C.
  • compound of formula C is subjected to deprotection conditions to generate compound of formula D.
  • Step 1 -amino-4-bromo-5-chloro-3-fluoro-benzoic acid
  • Step 3 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline [0260] To a solution of 7-bromo-6-chloro-8-fluoro-lH-quinazoline-2, 4-dione (31 g, 105.6 mmol, 1 eq) in phosphoryl chloride (360 mL) was added N,N-diisopropylethylamine (310.0 mmol, 54 mL, 2.94 eq), the mixture was stirred at 110 °C for 16 hours. LCMS showed that the reactant was consumed completely. The mixture was concentrated under reduced pressure to give the crude product.
  • Step 1 tert-butyl N-(2-chloro-3-fluoro-4-pyridyl)carbamate
  • Step 4 ethyl 4-amino-6-chloro-5-fluoro- pyridine-3-carboxylate
  • Step 5 4-amino-6-chloro-5-fluoronicotinic acid
  • Step 6 7 -chloro-8-fluoro-2-sulfanyl-pyrido[4,3-d]pyrimidin-4-ol
  • Step 7 7-chloro-8-fluoro-2-methylsulfanyl-pyrido [4,3-d]pyrimidin-4-ol
  • Step 9 tert-butyl 3-(7-chloro-8-fluoro-2- methylsulfanyl-pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate
  • Step 1 tert-butyl (R)-(2-hydroxy-l-(2',3',6'-trifluoro-[l,r-biphenyl]-4- yl)ethyl)carbamate
  • Step 2 (R)-2-amino-2-(2',3',6'-trifluoro-[ 1 , 1 '-biphenyl]-4-yl)ethan- 1 -ol
  • Step 3 tert-butyl (2S,4R)-4-hydroxy-2-(((R)-2-hydroxy- 1 -(2',3',6'-trifluoro-[ 1 , 1 '- biphenyl]-4-yl)ethyl)carbamoyl)pyrrolidine- 1 -carboxylate
  • Step 4 (2S,4R)-4-hydroxy-N-((R)-2-hydroxy-l-(2',3',6'-trifluoro-[1,1- biphenyl]-4-yl)ethyl)pyrrolidine-2-carboxamide
  • Step 5 tert-butyl ((S)-l-((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(2',3',6'- trifluoro-[ 1 , 1 '-biphenyl]-4-yl)ethyl)carbamoyl)pyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-
  • Step 6 (2S,4R)-l-(L-valyl)-4-hydroxy-N-((R)-2-hydroxy-l-(2',3',6'-trifluoro-
  • Step 7 (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(2',3',6'-trifluoro-[ 1 , 1 '-biphenyl]-4-yl)ethyl)pyrrolidine-2-carboxamide
  • Step 2 (R)-2-amino-2-(4-(pyridin-3-yl)phenyl)ethan-l-ol
  • Step 3 tert-butyl (2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(4-(pyridin-3- yl)phenyl)ethyl) carbamoyl)pyrrolidine- 1 -carboxylate
  • reaction mixture was diluted with water (40 mL) and extracted with chloroform/isopropanol (10/1, 50 mL x 2), washed with brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered and then concentrated in vacuum to get a hresidue.
  • Step 4 (2S,4R)-4-hydroxy-N-((R)-2-hydroxy-l-(4-(pyridin-3- yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 5 tert-butyl ((S)- 1 -((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy- 1 -(4-(pyri din-3 - yl)phenyl) ethyl)carbamoyl)pyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)carbamate
  • Step 6 (2S,4R)-l-(L-valyl)-4-hydroxy-N-((R)-2-hydroxy-l-(4-(pyridin-3- yl)phenyl)ethyl) pyrrolidine-2-carboxamide
  • Step 7 (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- l-(4-(pyridin-3-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 2 (R)-2-amino-2-(2'-fluoro-[l , 1 '-biphenyl]-4-yl)ethan- 1 -ol
  • Step 3 tert-butyl (2S,4R)-2-(((R)-l-(2'-fluoro-[l,r-biphenyl]-4-yl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine- 1 -carboxylate
  • Step 4 (2S,4R)-N-((R)-l-(2'-fluoro-[l,l'-biphenyl]-4-yl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide
  • Step 5 tert-butyl ((S)-l-((2S,4R)-2-(((R)-l-(2'-fluoro-[l,T-biphenyl]-4-yl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)carbamate
  • Step 6 (2S,4R)- 1 -(L-valyl)-N-((R)- 1 -(2'-fluoro-[ 1 , 1 '-biphenyl]-4-yl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 7 (2S,4R)- 1 -((S)-2-azido-3 -methylbutanoyl)-N-((R)- 1 -(2'-fluoro-[ 1 , 1'- biphenyl]-4-yl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Example 1 (2S,4R)-l-((2S)-2-(4-(4-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1H- 1 ,2,3-triazol- 1 - yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(2',3',6'-trifluoro-[l , 1 '-biphenyl]-4- yl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 tert-butyl (lR,5S)-3-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3,8- diazabicyclo[3.2. l]octane-8-carboxylate
  • Step2 tert-butyl (lR,5S)-3-(7-bromo-6-chloro-8-fluoro-2-((tetrahydro-2H- pyran-4-yl)oxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate
  • the mixture was stirred at 50 °C for 12 h. LCMS showed the desired compound was detected.
  • the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 3 tert-butyl (lR,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 4 tert-butyl (lR,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-8-((4-ethynylbenzyl)oxy)-2-((tetrahydro-2H- pyran-4-yl)oxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2. l]octane-8-carboxylate
  • Step 5 tert-butyl (lR,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-6-chloro-8-((4-(l-((S)-l-((2S,4R)-4-hydroxy-2-(((R)-2- hydroxy- 1 -(2',3',6'-trifluoro-[ 1 , 1 '-biphenyl]-4-yl)ethyl)carbamoyl)pyrrolidin- 1 -yl)-3 - methyl- 1 -oxobutan-2-yl)- 1H- 1 ,2,3-triazol-4-yl)benzyl)oxy)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-4-yl)-3,8-diazabicyclo[
  • Step 6 (2S,4R)-l-((2S)-2-(4-(4-(((7-(2-amino-3-cyano-7- fluorobenzo[b]thiophen-4-yl)-4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1H- 1 ,2,3-triazol- 1 - yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(2',3',6'-trifluoro-[l , 1 '-biphenyl]-4- yl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 tert-butyl (lR,5S)-3-(7-chloro-8-fluoro-2-((tetrahydro-2H-pyran-4- yl)oxy) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [0340] To a solution of tert-butyl 3-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-
  • Step 3 tert-butyl (lR,5S)-3-(7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-((4-ethynylbenzyl)oxy)-2-((tetrahydro-2H-pyran-4- yl)oxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the reaction mixture was quenched by water (30 mL), 2% ethylenediamine tetraacetic acid disodium solution (30 mL), and then diluted with dichloromethane (30 mL). The mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 5 (2S,4R)-l-((S)-2-(4-(4-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-l-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)pyrido[4,3-d]pyrimidin-8-yl)oxy)methyl)phenyl)-lH-l,2,3-triazol-l-yl)-3- methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(2',3',6'-trifluoro-[l , 1 ’-biphenyl] -4- yl)ethyl)pyrrolidine-2-carboxamide 2H), 2.23 (br cl, ,7 - 7.2 Hz
  • Example 3 (2S,4R)- 1 -((2S)-2-(4-(4-(((4-(( 1 S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1H- 1 ,2,3-triazol- 1 - yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(2',3',6'-trifluoro-[l , 1 '-biphenyl]-4- yl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 tert-butyl (1 S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-
  • Step 2 tert-butyl (lS,4S)-5-(7-bromo-8-fluoro-6-iodo-2-((tetrahydro-2H-pyran- 4-yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 3 tert-butyl (lS,4S)-5-(8-(benzyloxy)-7-bromo-6-iodo-2-((tetrahydro-2H- pyran-4-yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate
  • reaction mixture was quenched by pouring into saturated aqueous ammonium chloride (200 mL), then extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to get a residue.
  • Step 4 tert-butyl (lS,4S)-5-(8-(benzyloxy)-7-bromo-6-cyclopropyl-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate
  • Step 5 tert-butyl (1 S,4S)-5-(8-(benzyloxy)-6-cyclopropyl-7-(6-fluoro-5-methyl-
  • the suspension was degassed and purged with nitrogen for three times. And the mixture was stirred at 90 °C for 2 h. LCMS showed the reaction was completed.
  • the reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (25 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum.
  • Step j tert-butyl (1 S,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2H-indazol-4- yl)-8-hydroxy-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 7 tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-hydroxy-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 8 tert-butyl (lS,4S)-5-(6-cyclopropyl-8-((4-ethynylbenzyl)oxy)-7-(6- fluoro-5-methyl-2-trityl-2H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4- yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 9 tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-((4-(l-((S)-l-((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(2',3',6'-trifluoro- [1,1 ' -biphenyl] -4-yl)ethyl)carbamoyl)pyrrolidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)- 1H- l,2,3-triazol-4-yl)benzyl)oxy)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 10 (2S,4R)-l-((2S)-2-(4-(4-(((4-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol- 1 -yl)-3-methylbutanoyl)-4- hydroxy-N-((R)-2-hydroxy- 1 -(2',3',6'-trifluoro-[ 1 , 1 '-biphenyl]-4-yl)ethyl)pyrrolidine-2- carboxamide
  • Step 1 tert-butyl (lS,4S)-5-(7-bromo-2-chloro-8-fluoro-6-
  • Step 2 tert-butyl (lS,4S)-5-(7-bromo-8-fluoro-2-((S)-2-methoxypropoxy)-6- (trifluoromethyl) quinazolin-4-yl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate
  • Step 3 tert-butyl (lS,4S)-5-(8-fluoro-7-(6-fluoro-5-methyl-2-trityl-2H-indazol- 4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 4 tert-butyl (lS,4S)-5-(8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2- trityl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • the reaction mixture was diluted with saturated aqueous ammonium chloride (50 mL), and then extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified with by silica gel column chromatography (S1O2, Petroleum ether/Ethyl acetate 3/ 1 to 2/1) to afford the product (300 mg, 0.29 mmol, 53% yield) as a yellow solid.
  • Step 5 tert-butyl (lS,4S)-5-(7-(6-fluoro-5-methyl-2-trityl-2H-indazol-4-yl)-8- ((4-( 1 -((S)- 1 -((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy- 1 -(4-(pyridin-3- yl)phenyl)ethyl)carbamoyl)pyrro lidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)- 1H- 1 ,2,3-triazol-4- yl)benzyl)oxy)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • the mixture was stirred at 50 °C for 5 h. LCMS showed the starting material was consumed completely and one main peak with desired mass was detected.
  • the reaction mixture was diluted with dichloromethane (20 mL) and added 2% aqueous disodium ethylenediamine tetraacetate (20 mL), then the mixture was stirred at 25 °C for 30 min before extracting with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 6 (2S,4R)-l-((2S)-2-(4-(4-(((4-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6- (trifluoromethyl)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol- 1 -yl)-3 - methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(4-(pyridin-3- yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Example 5 (2S,4R)-l-((S)-2-(4-(4-(((4-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan- 2-yl)-6-chloro-7-(6-fluoro-5-methyl-2H-indazol-4-yl)-2-((S)-2- methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol- 1 -yl)-3 - methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(4-(pyridin-3- yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 tert-butyl (1 S,4S)-5-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate [0385] To a solution of tert-butyl (lS,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 2 tert-butyl (lS,4S)-5-(7-bromo-6-chloro-8-fluoro-2-((S)-2- methoxypropoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • the mixture was stirred at 50 °C for 5 h. LCMS showed the desired compound was detected.
  • the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over sodium sulfate, filtered and
  • Step 4 tert-butyl (1 S,4S)-5-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7- fluorobenzo[b] thiophen-4-yl)-6-chloro-8-((4-ethynylbenzyl)oxy)-2-((S)-2- methoxypropoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 5 tert-butyl (lS,4S)-5-(6-chloro-7-(6-fluoro-5-methyl-2-trityl-2H-indazol- 4-yl)-8-((4-( 1 -((S)- 1 -((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy- 1 -(4-(pyridin-3- yl)phenyl)ethyl)carbamoyl)pyrro lidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)- 1H- 1 ,2,3-triazol-4- yl)benzyl)oxy)-2-((S)-2-methoxypropoxy) quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • the mixture was stirred at 50 °C for 4 h. LCMS showed the starting material was consumed completely and one main peak with desired mass was detected.
  • the reaction mixture was diluted with dichloromethane (20 mL) and added 2% aqueous disodium ethylenediamine tetraacetate (20 mL). Then the mixture was stirred at 25 °C for 30 min. Color of the mixture turned to blue, then the mixture was extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 6 (2S,4R)-l-((S)-2-(4-(4-(((4-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-6-chloro-7-(6-fluoro-5-methyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin- 8-yl)oxy)methyl)phenyl)- 1H- 1 ,2,3-triazol- 1 -yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2- hydroxy- 1 -(4-(pyridin-3-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [0396]
  • Example 6 (2S,4R)-l-((2S)-2-(4-(4-(((4-((lS,4S)-2,5- diazabicyclo[2.2.1
  • Step 1 tert-butyl (1 S,4S)-5-(7-(6-fluoro-5-methyl-2-trityl-2H-indazol-4-yl)-8- ((4-( 1 -((S)- 1 -((2S,4R)-2-(((R)- 1 -(2'-fluoro- [ 1 , l'-biphenyl]-4-yl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)- 1H- 1 ,2,3- triazol-4-yl)benzyl)oxy)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Boc
  • Step 2 (2S.4R)-l-((2S)-2-(4-(4-(((4-((lS.4S)-2.5-diazabicvclor2.2.11heptan-2- yl)-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6- (trifluoromethyl)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol- 1 -yl)-3 - methylbutanoyl)-N-((R)- 1 -(2'-fluoro-[l , 1 ’-biphenyl] -4-yl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide
  • Step 1 tert-butyl (lS,4S)-5-(7-bromo-8-fluoro-6-iodo-2-((S)-2- methoxypropoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [0403] To a solution of tert-butyl (lS,4S)-5-(7-bromo-2-chloro-8-fluoro-6- iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.
  • Step 2 tert-butyl (lS,4S)-5-(7-bromo-6-cyclopropyl-8-fluoro-2-((S)-2- methoxypropoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • reaction mixture was diluted with water (100 mL), then extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to get a residue.
  • Step 3 tert-butyl (lS,4S)-5-(8-(benzyloxy)-7-bromo-6-cyclopropyl-2-((S)-2- methoxypropoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 4 tert-butyl (1 S,4S)-5-(8-(benzyloxy)-6-cyclopropyl-7-(6-fluoro-5-methyl- 2-trityl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate [0409] To a solution of 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-2-trityl-2H-indazole (1.96 g, 3.78 mmol, 1.1 eq), tert-butyl (lS,4S)-5-(8-(benzyloxy)- 7-bromo-6-cyclopropyl-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2
  • Step 5 tert-butyl (1 S,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2H-indazol-4- yl)-8-hydroxy-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate
  • Step 6 tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 7 tert-butyl (lS,4S)-5-(6-cyclopropyl-8-((4-ethynylbenzyl)oxy)-7-(6- fluoro-5-methyl-2-trityl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 1 tert-butyl (/? )-(2- hydroxy- 1 -(4-(3 -methyl pyri di n-4- yl)phenyl)ethyl)carbamate
  • Step 2 (R)-2-amino-2-(4-(3-methylpyridin-4-yl)phenyl)ethan-l-ol
  • Step 3 tert-butyl (2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(4-(3-methylpyridin- 4-yl)phenyl)ethyl) carbamoyl)pyrrolidine- 1 -carboxylate
  • the mixture was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed completely and one main peak with desired mass was detected.
  • the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 4 (2S,4R)-4-hydroxy-N-((R)-2-hydroxy- 1 -(4-(3-methylpyridin-4- yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 5 tert-butyl ((S)- 1 -((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy- 1 -(4-(3- methylpyridin-4-yl)phenyl)ethyl)carbamoyl)pyrro lidin- 1 -yl)-3 -methyl- 1 -oxobutan-2- yl)carbamate
  • the mixture was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed completely and one main peak with desired mass was detected.
  • the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 6 (25,4R )- l-(£-valyl)-4-hydroxy-N-((R )-2-hydroxy-l-(4-(3-methylpyridin- 4-yl)phenyl)ethyl) pyrrolidine-2-carboxamide
  • Step 7 (25,4R )- 1 -((5)-2-azido-3 -methylbutanoyl)-4-hydroxy-N-((R )-2-hydroxy- l-(4-(3-methylpyridin-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 tert-butyl (R)-(2-hydroxy-l-(4-(2-methylpyridin-3- yl)phenyl)ethyl)carbamate
  • Step 2 (R)-2-amino-2-(4-(2-methylpyridin-3-yl)phenyl)ethan-l-ol
  • Step 3 tert-butyl (2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(4-(2-methylpyridin- 3 -yl)phenyl) ethyl)carbamoyl)pyrrolidine- 1 -carboxylate
  • Step 4 (2S,4R)-4-hydroxy-N-((R)-2-hydroxy-l-(4-(2-methylpyridin-3- yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 5 tert-butyl ((S)-l-((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(4-(2- methylpyridin-3-yl)phenyl)ethyl)carbamoyl)pyrro lidin- 1 -yl)-3 -methyl- 1 -oxobutan-2- yl)carbamate
  • Step 6 (2S,4R)-l-(L-valyl)-4-hydroxy-N-((R)-2-hydroxy-l-(4-(2-methylpyridin- 3-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 7 (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- l-(4-(2-methylpyridin-3-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 tert-butyl (R)-(l-(4-(2-chloropyridin-3-yl)phenyl)-2- hydroxyethyl)carbamate
  • Step 2 (R)-2-amino-2-(4-(2-chloropyridin-3-yl)phenyl)ethan-l-ol
  • Step 3 tert-butyl (2S,4R)-2-(((R)-l-(4-(2-chloropyridin-3-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine- 1 -carboxylate
  • Step 5 tert-butyl ((S)-l-((2S,4R)-2-(((R)-l-(4-(2-chloropyridin-3-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)carbamate , -3-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (2.59 g, 6.50 mmol, 1.00 eq, hydrochloride) and (tert-butoxycarbonyl)-L-valine (1.70 g, 7.80 mmol, 1.20 eq) in N,N- dimethylformamide (40 mL) was added N,N-diisopropylethylamine (2.52 g, 19.51 mmol, 3.40 mL, 3.00 eq) and
  • Step 6 (2S,4R)-l-(L-valyl)-N-((R)-l-(4-(2-chloropyridin-3-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 7 (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-N-((R)-l-(4-(2-chloropyridin- 3-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 2 (R)-2-amino-2-(4-(3-fluoropyridin-4-yl)phenyl)ethan-l-ol
  • Step 3 tert-butyl (2S,4R)-2-(((R)-l-(4-(3-fluoropyridin-4-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine- 1 -carboxylate
  • Step 5 tert-butyl ((S)- 1 -((2S,4R)-2-(((R)- 1 -(4-(3-fluoropyridin-4-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)carbamate
  • Step 6 (2S,4R)- l-(L-valyl)-N-((R)- 1 -(4-(3-fluoropyridin-4-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 7 (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-N-((R)-l-(4-(3-fluoropyridin- 4-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 1 tert-butyl (R)-(l-(4-(3-chloropyridin-4-yl)phenyl)-2- hydroxyethyl)carbamate
  • Step 2 (R)-2-amino-2-(4-(3-chloropyridin-4-yl)phenyl)ethan-l-ol
  • Step 3 tert-butyl (2S,4R)-2-(((R)-l-(4-(3-chloropyridin-4-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine- 1 -carboxylate
  • Step 4 (2S,4R)-N-((R)- 1 -(4-(3-chloropyridin-4-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide
  • Step 5 tert-butyl ((S)-l-((2S,4R)-2-(((R)-l-(4-(3-chloropyridin-4-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)carbamate
  • Step 6 (2S,4R)-l-(L-valyl)-N-((R)-l-(4-(3-chloropyridin-4-yl)phenyl)-2- hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 7 (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-N-((R)-l-(4-(3-chloropyridin- 4-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide
  • Step 2 tert-butyl (2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(4-(pyrimidin-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine- 1 -carboxylate
  • Step 5 tert-butyl ((S)-l-((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(4-(pyrimidin- 5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate
  • Step 7 (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- l-(4-(pyrimidin-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Example 7 (2S,4R)-l-((2S)-2-(4-(4-(((4-((lS,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1H- 1 ,2,3-triazol- 1 - yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-l-(4-(2-methylpyridin-3- yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Step 1 tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-((4-( 1 -((S)- 1 -((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy- 1 -(4-(2- methylpyridin-3-yl)phenyl)ethyl)carbamoyl)pyrro lidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)- lH-l,2,3-triazol-4-yl)benzyl)oxy)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • the mixture was stirred at 50 °C for 5 h under nitrogen. TLC showed the desired compound was detected.
  • the reaction mixture was diluted with dichloromethane (20 mL) and added 2% aqueous disodium ethylenediamine tetraacetate (20 ml), then the mixture was stirred at 25 °C for 30 min, it was observed that the color of the mixture changed from green to blue, extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 (2S,4R)-l-((2S)-2-(4-(4-(((4-((l S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol- 1 -yl)-3-methylbutanoyl)-4- hydroxy-N-((R)-2-hydroxy-l-(4-(2-methylpyridin-3-yl)phenyl)ethyl)pyrrolidine-2- carboxamide
  • Example 8 (2S,4R)-l-((S)-2-(4-(4-(((4-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan- 2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-2H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol- 1 -yl)-3-methylbutanoyl)-4- hydroxy-N-((R)-2-hydroxy-l-(4-(3-methylpyridin-4-ylg)phenyl)ethyl)pyrrolidine-2- carboxamide
  • Step 1 tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-((4-(l-((S)-l-((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(4-(3- methylpyridin-4-yl)phenyl)ethyl)carbamoyl)pyrro lidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)- lH-l,2,3-triazol-4-yl)benzyl)oxy)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • the mixture was stirred at 50 °C for 12 h. LCMS showed the starting material was consumed completely and one main peak with desired mass was detected.
  • the reaction mixture was quenched by water (30 mL), 2% disodium ethylenediamine tetraacetate solution (30 mL), and then diluted with dichloromethane (30 mL). The mixture was stirred at 20 °C for 0.5 h before extracting with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product.
  • Step 2 (2S,4R)- 1 -((S)-2-(4-(4-(((4-(( 1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)- 6-cyclopropyl-7-(6-fluoro-5-methyl-2H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol- 1 -yl)-3-methylbutanoyl)-4- hydroxy-N-((R)-2-hydroxy-l-(4-(3-methylpyridin-4-yl)phenyl)ethyl)pyrrolidine-2- carboxamide
  • Example 9 (2S,4R)-l-((2S)-2-(4-(4-(((4-((lS,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2- ((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3 -triazol- 1 -yl)-3 - methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(4-(2-methylpyridin-3 - yl)phenyl)ethyl)pyrrolidine-2-carboxamide.
  • Step 1 tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-((4-( 1 -((S)- 1 -((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy- 1 -(4-(2- methylpyridin-3-yl)phenyl)ethyl)carbamoyl)pyrro lidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)- lH-l,2,3-triazol-4-yl)benzyl)oxy)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • the mixture was stirred at 50 °C for 5 h under nitrogen. LCMS showed the desired compound was detected.
  • the reaction mixture was diluted with dichloromethane (20 mL) and added 2% aqueous disodium ethylenediamine tetraacetate (20 mL), then the mixture was stirred at 25 °C for 30 min before extracting with dichloromethane (15 mL x 3).
  • the combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 2 (2S,4R)-l-((2S)-2-(4-(4-(((4-((l S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-((S)-2- methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol- 1 -y l)-3 - methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(4-(2-methylpyridin-3 - yl)phenyl)ethyl)pyrrolidine-2-carboxamide (ERAS-9271 )
  • Example 10 (2S,4R)-l-((2S)-2-(4-(4-(((4-((lS,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2- ((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3 -triazol- 1 -yl)-3 - methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(4-(pyridin-3- yl)phenyl)ethyl)pyrrolidine-2-carboxamide.
  • Step 1 tert-butyl (1 S,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-((4-(l-((S)-l-((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(4-(pyridin-3- yl)phenyl)ethyl)carbamoyl) pyrro lidin- 1 -yl) -3 -methyl- 1 -oxobutan-2-yl)- 1H- 1 ,2,3-triazol- 4-yl)benzyl)oxy)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • Step 2 (2S,4R)-l-((2S)-2-(4-(4-(((4-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-((S)-2- methoxypropoxy)quinazolin-8-yl)oxy)methyl) phenyl)- 1H- 1 ,2,3-triazol- 1 -yl)-3 - methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(4-(pyridin-3- yl)phenyl)ethyl)pyrrolidine-2-carboxamide
  • Example 11 Synthesis of (2S,4R)-l-((2S)-2-(4-(4-(((4-((lS,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2- ((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3 -triazol- 1 -yl)-3 - methylbutanoyl)-N-((R)-l-(4-(2-chloropyridin-3-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide.
  • Step 1 tert-butyl (lS,4S)-5-(8-((4-(l-((S)-l-((2S,4R)-2-(((R)-l-(4-(2- chloropyridin-3-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin- 1 -yl)-3 - methyl- 1 -oxobutan-2-yl)- 1H- 1 ,2,3-triazol-4-yl)benzyl)oxy)-6-cyclopropyl-7-(6-fluoro-5- methyl-2-trityl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • cuprous iodide (4.59 mg, 0.02 mmol, 0.5 eq) and sodium ascorbate (14 mg, 0.07 mmol, 1.5 eq) were added. The mixture was stirred at 50 °C for 5 h under nitrogen. LCMS showed the desired compound was detected.
  • the reaction mixture was diluted with dichloromethane (20 mL) and added 2% disodium ethylenediamine tetraacetate solution (20 ml), extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 2 (2S,4R)-l-((2S)-2-(4-(4-(((4-((l S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-((S)-2- methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol- 1 -y l)-3 - methylbutanoyl)-N-((R)-l-(4-(2-chloropyridin-3-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide (ERAS-9256)
  • Example 12 (2S,4R)-l-((S)-2-(4-(4-(((4-((lS,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-2H-indazol-4-yl)-2- ((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3 -triazol- 1 -yl)-3 - methylbutanoyl)-N-((R)-l-(4-(3-fluoropyridin-4-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide
  • Step 1 tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-((4-(l-((S)-l-((2S,4R)-2-(((R)-l-(4-(3-fluoropyridin-4-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)- 1H- 1 ,2,3- triazol-4-yl)benzyl)oxy)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate Boc i
  • Step 2 (2S,4R)- 1 -((S)-2-(4-(4-(((4-(( 1 S,4S)-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)- 6-cyclopropyl-7-(6-fluoro-5-methyl-2H-indazol-4-yl)-2-((S)-2- methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol-l-yl)-3- methylbutanoyl)-N-((R)-l-(4-(3-fluoropyridin-4-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide
  • Examples 84a and 84b (2S,4R)-l-((S)-2-(4-(4-((((S)-4-((lS,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2- ((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3 -triazol- 1 -yl)-3 - methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(4-(2-methylpyridin-3 - yl)phenyl)ethyl)pyrrolidine-2-carboxamide (84a) and (2S,4R)-l-((S)-2-(4-(4-((((R)-4- ((lS,
  • Step 1 tert-butyl (1 S,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-((4-( 1 -((S)- 1 -((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy- 1 -(4-(2- methylpyridin-3 -yl)phenyl)ethyl)carbamoyl)pyrro lidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)- lH-l,2,3-triazol-4-yl)benzyl)oxy)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • the mixture was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 50 °C for 5 h under nitrogen. LCMS showed the reaction was completed.
  • the reaction mixture was diluted with dichloromethane (20 mL) and added 2% disodium ethylenediamine tetraacetate solution (20 mL), extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 2 (2S,4R)-l-((S)-2-(4-(4-((((S)-4-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan-
  • Examples 85a and 85b (2S,4R)-l-((S)-2-(4-(4-((((S)-4-((lS,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2- ((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3 -triazol- 1 -yl)-3 - methylbutanoyl)-N-((R)-l-(4-(3-fluoropyridin-2-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide and (2S,4R)-l-((S)-2-(4-(4-((((R)-4-((l S,4S)-2,
  • Step 1 tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-((4-(l-((S)-l-((2S,4R)-2-(((R)-l-(4-(3-fluoropyridin-2-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)- 1H- 1 ,2,3- triazol-4-yl)benzyl)oxy)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate [0543] A mixture of tert-butyl (lS,4S)-5-(6-
  • the reaction mixture was diluted with dichloromethane (20 mL) and added 2% disodium ethylenediamine tetraacetate solution (20 mL), extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 2 (2S,4R)-l-((S)-2-(4-(4-((((S)-4-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan- 2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-((S)-2- methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3-triazol- 1 -yl)-3 - methylbutanoyl)-N-((R)- 1 -(4-(3 -fluoropyridin-2-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide and (2S,4R)-l-((S)-2-(4-(4-((((R)-4-((l S,4S)-2,5-
  • Examples 86a and 86b (2S,4R)-l-((S)-2-(4-(4-((((S)-4-((lS,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2- ((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)- 1 H- 1 ,2,3 -triazol- 1 -yl)-3 - methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(4-(pyridin-3- yl)phenyl)ethyl)pyrrolidine-2-carboxamide and (2S,4R)-l-((S)-2-(4-(4-((((R)-4-((lS,4S)- 2,5-
  • Step 1 tert-butyl (lS,4S)-5-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H- indazol-4-yl)-8-((4-(l-((S)-l-((2S,4R)-4-hydroxy-2-(((R)-2-hydroxy-l-(4-(pyridin-3- yl)phenyl)ethyl)carbamoyl) pyrro lidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)- 1 H- 1 ,2,3-triazol- 4-yl)benzyl)oxy)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate
  • the mixture was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 50 °C for 5 h under nitrogen. LCMS showed the reaction was completed.
  • the reaction mixture was diluted with dichloromethane (20 mL) and added 2% disodium ethylenediamine tetraacetate solution (20 mL), extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 2 (2S,4R)-l-((S)-2-(4-(4-((((S)-4-((lS,4S)-2,5-diazabicyclo[2.2.1]heptan- 2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-((S)-2- methoxypropoxy)quinazolin-8-yl)oxy)methyl) phenyl)- 1H- 1 ,2,3-triazol- 1 -yl)-3 - methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy- 1 -(4-(pyridin-3- yl)phenyl)ethyl)pyrrolidine-2-carboxamide and (2S,4R)-l-((S)-2-(4-(4-((((R)-4-((lS,4S)- 2,5-diazabicy
  • Step 1 tert-butyl (R)-(l-(4-(3-fluoropyridin-2-yl)phenyl)-2- hydroxyethyl)carbamate
  • Step 2 (R)-2-amino-2-(4-(3-fluoropyridin-2-yl)phenyl)ethan- 1 -ol
  • Step 3 tert-butyl (2S,4R)-2-(((R)-l-(4-(3-fluoropyridin-2-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine- 1 -carboxylate
  • Step 4 (2S,4R)-N-((R)- 1 -(4-(3-fluoropyridin-2-yl)phenyl)-2-hydroxyethyl)-4- hydroxypyrrolidine-2-carboxamide
  • Step 5 tert-butyl ((S)- 1 -((2S,4R)-2-(((R)- 1 -(4-(3-fluoropyridin-2-yl)phenyl)-2- hydroxyethyl)carbamoyl)-4-hydroxypyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)carbamate

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Abstract

Les présents modes de réalisation concernent des composés de formule I, des compositions des composés, et des méthodes de traitement de maladies telles que le cancer.
PCT/US2023/072251 2022-08-19 2023-08-15 Conjugués inhibiteurs de kras WO2024040080A1 (fr)

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Citations (5)

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WO2016149668A1 (fr) * 2015-03-18 2016-09-22 Arvinas, Inc. Composés et procédés de dégradation accrue de protéines ciblées
US10730862B2 (en) * 2012-01-12 2020-08-04 Yale University Compounds and methods for the enhanced degradation of targeted proteins and other polypeptides by an E3 ubiquitin ligase
WO2021207172A1 (fr) * 2020-04-06 2021-10-14 Arvinas Operations, Inc. Composés et procédés de dégradation ciblée de kras
WO2022105857A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022266206A1 (fr) * 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras

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US10730862B2 (en) * 2012-01-12 2020-08-04 Yale University Compounds and methods for the enhanced degradation of targeted proteins and other polypeptides by an E3 ubiquitin ligase
WO2016149668A1 (fr) * 2015-03-18 2016-09-22 Arvinas, Inc. Composés et procédés de dégradation accrue de protéines ciblées
WO2021207172A1 (fr) * 2020-04-06 2021-10-14 Arvinas Operations, Inc. Composés et procédés de dégradation ciblée de kras
WO2022105857A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
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