Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—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
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • C07D487/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/08—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

• the present invention relates to compounds that inhibit KRas G12C.
• the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.
• KRas Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
• GTPas GTPase
• Ras Ras family of oncogenes
• KRas serves a molecular switch cycling between inactive (GDP -bound) and active (GTP -bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13 :394-401).
• KRAs The well-known role of KRAs in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large scale discovery efforts to develop inhibitors of KRas for treating cancer, no KRas inhibitor has demonstrated sufficient safety and/or efficacy to obtain regulatory approval (e.g., see
• KRas G12C e.g., see Ostrem et al., (2013) Nature 503 :548-551.
• KRas G12C e.g., see Ostrem et al., (2013) Nature 503 :548-551.
• compounds are provided that inhibit KRas G12C activity.
• the compounds are represented by formula (I):
• X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R 8 ;
• Y is a bond, O, S or R 5 ;
• R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl,
• Z is Cl - C4 alkylene
• each R 3 is independently CI - C3 alkyl, oxo, or haloalkyl;
• L is a bond, -C(O)-, or CI - C3 alkylene;
• R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R 6 or R 7 ;
• each R 5 is independently hydrogen or CI - C3 alkyl
• R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R 7 ;
• each R 7 is independently halogen, hydroxyl, CI - C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;
• R 8 is oxo, CI - C3 alkyl, C2 - C4 alkynyl, heteroalkyl, cyano, -C(0)OR 5 , -C(0)N(R 5 ) 2 , - N(R 5 ) 2 , wherein the CI - C3 alkyl may be optionally substituted with cyano, halogen, -OR 5 , - N(R 5 ) 2 , or heteroaryl
• each R 9 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, CI - C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the CI - C6 alkyl may be optionally substituted with cycloalkyl;
• each R 10 is independently hydrogen, acyl, CI - C3 alkyl, heteroalkyl or hydroxyalkyl;
• R A is absent, hydrogen, or CI - C3 alkyl
• each R B is independently hydrogen, CI - C3 alkyl, alkylaminylalkyl, dialkylaminylalkyl or heterocyclylalkyl;
• m is zero or an integer between 1 and 2;
• p is one or two; and wherein,
• R A , R B and the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl optionally substituted with one or more R 7 .
• R A , R B and the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl optionally substituted with one or more R 7 .
• R 1 , R 3 , R 4 , R 5 , R 10 , L and m are as defined for Formula I, R 11 is
• R 1 , R 3 , R 4 , R 9 , L and m are as defined for Formula I
• R 2 is heterocyclylalkyl optionally substituted with one or more R 9
• the piperidinyl ring is optionally substituted with R 8
• R 8 is as defined for Formula I.
• compositions comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
• methods for inhibiting KRas G12C activity in a in a cell comprising contacting the cell with a compound of Formula I, Formula I-A or Formula 1- B.
• the contacting is in vitro.
• the contacting is in vivo.
• Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula I, Formula I-A or Formula 1-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.
• Also provided are methods for treating cancer in a patient comprising administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.
• Also provided herein is a method of treating a KRas G12C -associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, Formula I-A or Formula 1-B, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.
• Also provided herein is a compound of Formula I, Formula I-A or Formula 1-B, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.
• Also provided herein is a compound of Formula I, Formula I-A or Formula 1-B, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.
• Also provided herein is a compound of Formula I, Formula I-A or Formula 1-B, or a pharmaceutically acceptable salt or solvate thereof for use in the inhibition of KRas G12C.
• a compound of Formula I, Formula I-A or Formula 1-B, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of a KRas G12C-associated disease or disorder.
• Also provided herein is a use of a compound of Formula I, Formula I-A or Formula 1-B, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of KRas G12C.
• Also provided herein is the use of a compound of Formula I, Formula I-A or Formula 1- B, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12C-associated disease or disorder.
• Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula I, Formula I-A or Formula 1-B or a
• a KRas G12C mutation e.g., a KRas G12C-associated cancer
• Also provided herein is a process for preparing a compound of Formula I, Formula I-A or Formula 1-B, or a pharmaceutically acceptable salt or solvate thereof.
• Also provided herein is a compound of Formula I, Formula I-A or Formula 1-B, or a pharmaceutically acceptable salt thereof obtained by a process of preparing the compound as defined herein.
• the present invention relates to inhibitors of KRas G12C.
• the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C,
• compositions comprising a therapeutically effective amount of the compounds and methods of use therefor.
• KRas G12C refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12.
• the assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variant p.Glyl2Cys.
• KRas G12C inhibitor refers to compounds of the present invention that are represented by formulae (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C.
• the KRas G12C inhibitors of the present invention interact with and irreversibly bind to KRas G12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12 resulting in the inhibition of the enzymatic activity of KRas G12C.
• KRas G12C-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation.
• a non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.
• the term "subject,” “individual,” or “patient,” used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
• the patient is a human.
• the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
• the subject has been identified or diagnosed as having a cancer having a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
• the subject has a tumor that is positive for a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit).
• the subject can be a subject with a tumor(s) that is positive for a KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
• the subject can be a subject whose tumors have a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
• the subject is suspected of having a KRas G12C gene-associated cancer.
• the subject has a clinical record indicating that the subject has a tumor that has a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
• an assay is used to determine whether the patient has KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated cancer, and/or a patient that has an increased risk of developing a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).
• the assays are typically performed, e.g., with at least one or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a
• regulatory agency is a country's agency for the approval of the medical use of pharmaceutical agents with the country.
• regulatory agency is the U.S. Food and Drug Administration (FDA).
• amino refers to -NH 2 ;
• acyl refers to -C(0)CH 3 .
• alkyl refers to straight and branched chain aliphatic groups having from 1 to 12 carbon atoms, 1-8 carbon atoms 1-6 carbon atoms, or 1-3 carbon atoms which is optionally substituted with one, two or three substituents.
• alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.
• haloalkyl refers to an alkyl chain in which one or more hydrogen has been replaced by a halogen.
• haloalkyls are trifluoromethyl, difluoromethyl and fluorom ethyl.
• haloalkyl oxy refers to -O-haloalkyl.
• An "alkylene,” group is an alkyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.
• alkoxy refers to -OC1 - C6 alkyl.
• cycloalkyl as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example 3 to 8 carbons, and as a further example 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted.
• cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl,
• cyclopentyl cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
• heteroalkyl refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are replaced by a heteroatom selected from the group consisting of O, S, and N.
• hydroxyalkyl refers to -alkyl-OH.
• dihydroxyalkyl refers to an alkyl group as defined herein wherein two carbon atoms are each substituted with a hydroxyl group.
• alkylaminyl refers to - R x -alkyl, wherein R x is hydrogen.
• R x is hydrogen
• dialkylaminyl refers to -N(R y ) 2 , wherein each R y is CI - C3 alkyl.
• alkylaminylalkyl refers to -alkyl- R x -alkyl, wherein R x is hydrogen. In one embodiment, R x is hydrogen.
• dialkylaminylalkyl refers to -alkyl-N(R y ) 2 , wherein each R y is CI - C4 alkyl, wherein the alkyl of the— alkyl -N(R y ) 2 may be optionally substituted with hydroxy or hydroxyalkyl.
• aryl group is a C 6 -Ci4 aromatic moiety comprising one to three aromatic rings, which is optionally substituted.
• the aryl group is a C 6 -Cio aryl group.
• aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
• an "aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted.
• An example of an aralkyl group is (Ci- C6)alkyl(C6-Cio)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
• An example of a substituted aralkyl is wherein the alkyl group is substituted with hydroxy alkyl.
• a “heterocyclyl” or “heterocyclic” group is a ring structure having from about 3 to about 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S, the remainder of the ring atoms being carbon.
• the heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic or a bridged ring system.
• the heterocyclic group is optionally substituted with R 7 on carbon or nitrogen at one or more positions, wherein R 7 is as defined for Formula I.
• the heterocyclic group is also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or on sulfur with oxo or lower alkyl.
• heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl,
• azabiocycloheptanes Specifically excluded from the scope of this term are compounds having adjacent annular O and/or S atoms.
• heterocyclylalkyl refers to a heterocyclyl group as defined herein linked to the remaining portion of the molecule via an alkyl linker, wherein the alkyl linker of the heterocyclylalkyl may be optionally substituted with hydroxy or hydroxyalkyl.
• heteroaryl refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms per ring selected from the group consisting of N, O, and S.
• heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,
• tetrahydroisoquinolinyl tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
• a "heteroarylalkyl” group comprises a heteroaryl group covalently linked to an alkyl group, wherein the radical is on the alkyl group, either of which is independently optionally substituted or unsubstituted.
• heteroarylalkyl groups include a heteroaryl group having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group.
• heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolyl ethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolyl ethyl, benzimidazolylmethyl, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenyl ethyl.
• compounds having adjacent annular O and/or S atoms are compounds having adjacent annular O and/or S atoms.
• an effective amount of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
• a "therapeutically effective amount" of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
• treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
• amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
• X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring is optionally substituted with one or more R 8 ;
• Y is a bond, O, S or R 5 ;
• R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl,
• heteroarylalkyl wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R 9 ;
• Z is Cl - C4 alkylene
• each R 3 is independently CI - C3 alkyl, oxo, or haloalkyl;
• L is a bond, -C(O)-, or CI - C3 alkylene;
• R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R 6 or R 7 ;
• each R 5 is independently hydrogen or CI - C3 alkyl
• R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R 7 ;
• each R 7 is independently halogen, hydroxyl, CI - C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;
• R 8 is oxo, CI - C3 alkyl, C2 - C4 alkynyl, heteroalkyl, cyano, -C(0)OR 5 , -C(0)N(R 5 ) 2 , - N(R 5 ) 2 , wherein the CI - C3 alkyl may be optionally substituted with cyano, halogen, -OR 5 , - N(R 5 ) 2 , or heteroaryl;
• each R 9 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, CI - C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the CI - C6 alkyl may be optionally substituted with cycloalkyl;
• each R 10 is independently hydrogen, acyl, CI - C3 alkyl, heteroalkyl or hydroxyalkyl; [0098] R A is absent, hydrogen, or CI - C3 alkyl;
• each R B is independently hydrogen, CI - C3 alkyl, alkylaminylalkyl, dialkylaminylalkyl or heterocyclylalkyl;
• m is zero or an integer between 1 and 2;
• p is one or two; and wherein,
• R A , R B and the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl optionally substituted with one or more R 7 .
• R*-X is:
• R 1 is defined for Formula I and the piperazinyl ring is optionally substituted with R 8 , where R 8 is as defined for Formula I.
• R 8 is CI - C3 alkyl wherein the alkyl is optionally substituted with cyano or OR 5 , or -C(0)N(R 5 )2, wherein each R 5 is independently hydrogen or CI - C3 alkyl.
• R 1 is -C(0)C(R A ) C(R B ) P , wherein is a triple bond and R A is absent, p is one and R B is CI - C3 alkyl.
• R 1 is -
• Y is O or NR 5 and R 2 is selected from the group consisting of alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, heterocyclyl,
• Y is O and R 2 is hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, or dialkylaminylalkyl, wherein the alkylaminylalkyl or dialkylaminylalkyl is optionally substituted with one or more R 9 .
• the optionally substituted alkylaminylalkyl or dialkylaminylalkyl is independently selected from methylaminylpropan-2-yl, dimethylaminylethyl, methylethylaminylethyl,
• Y is O or NR 5 and R 2 is heterocyclyl or heterocyclylalkyl optionally substituted with one or more R 9 .
• R 9 when R 2 is heterocyclyl or heterocyclylalkyl include CI - C3 alkyl, acyl, oxo, cyano, alkoxy, cycloalkyl, cycloalkylmethyl, halogen, and hydroxyl.
• R 2 heterocyclyls optionally substituted with one or more R 9 include azetidinyl, Cl-C3alkyl-substituted azetidinyl (e.g., methylazetidinyl), halo-substituted azetidinyl (e.g., difluoroazetidinyl), tetrahydropyran, pyrrolidinyl, C1-C3 alkyl- substituted pyrrolidinyl (e.g., methylpyrrolidinyl, dimethylpyrrolidinyl, and
• methylmorpholinyl, 1,4-oxazepanyl, piperdinyl, C1-C3 alkyl-substituted piperidinyl e.g., methylpiperidinyl
• acylpiperdinyl cyanopiperdinyl, cycloalkylpiperdinyl, halopiperdinyl (e.g., fluoropiperdinyl), dihalopiperdinyl (e.g., difluoropiperdinyl), alkoxypiperdinyl, pyrrolidonyl, piperidonyl, thiomorpholinyl- 1,1 -dioxide, 3-azabicyclo[3.1.0]hexanyl, oxa-5- azabicyclo[2.2.1]heptan-5-yl, and azabicyclo[2.2.1]heptan-2-yl.
• Y is O and R 2 is heteroarylalkyl optionally substituted with one or more R 9 .
• the heteroaryl portion of the heteroarylalkyl is pyridinyl.
• Y is O and R 2 is -ZR 5 R 10 .
• R 5 is CI - C3 alkyl and R 10 is independently selected from acyl, hydroxyalkyl or alkoxy.
• Y is a bond and R 2 is hydrogen, heterocyclyl or aryl, wherein said heterocyclyl and aryl are optionally substituted with one or more R 9 .
• Y is a bond and R 2 is hydrogen.
• Y is a bond and R 2 is heterocyclyl optionally substituted with one or more R 9 .
• Y is a bond and R 2 is heterocyclyl optionally substituted with methyl, halogen or dimethylamino.
• R 2 heterocyclyls include azetidinyl, piped dinyl, piperazinyl, morpholinyl, and pyrrolidinyl.
• Y is a bond and R 2 is aryl optionally substituted with one or more R 9 .
• the aryl is phenyl substituted with heterocyclylalkyl.
• R 4 is aryl.
• R 4 is selected from the group consisting of phenyl and naphthyl and is optionally substituted with one or more R 6 or R 7 .
• R 7 substituents include halogen, hydroxyl, CI - C6 alkyl (e.g., CI - C3 alkyl), cycloalkyl, haloalkyl, Q-haloalkyl, amino, cyano,
• the aryl is phenyl substituted with one or more R 7 groups independently selected from halogen, hydroxyl, CI - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy.
• the aryl is phenyl substituted with one or more R 7 groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl.
• the aryl is phenyl substituted with one or more R 7 groups independently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,
• the aryl is phenyl substituted with one to three R 7 groups independently selected from hydroxyl, fluorine and chlorine.
• the aryl is phenyl substituted with hydroxyl and CI - C3 alkyl or two CI - C3 alkyl.
• the aryl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine.
• R 4 is aryl wherein aryl is naphthyl optionally substituted with one or more R 7 .
• the aryl is naphthyl substituted with one or more R 7 groups independently selected from halogen, hydroxyl, CI - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy.
• the aryl is naphthyl substituted with one or more R 7 groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl.
• R 4 is naphthyl optionally substituted with one or more R 7 substituents independently selected from hydroxyl, halogen, CI - C3 alkyl, amino, and haloalkyl. In one embodiment, R 4 is naphthyl optionally substituted with one to three R 7 substituents independently selected from difluoromethyl, methyl, hydroxyl, amino, fluoro, and chloro.
• the aryl is naphthyl optionally substituted with one or more halogen. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or CI - C3alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl.
• R 4 is heteroaryl optionally substituted with one or more R 7 .
• R 4 is heteroaryl optionally substituted with one or more R 7 independently selected from halogen, hydroxyl, CI - C3 alkyl, haloalkyl, Q-haloalkyl, alkoxy and amino.
• R 4 is indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl or benzo[d]thiazolyl optionally substituted with one or more R 7 .
• R 4 is indoyl, indazolyl, quinolinyl, isoquinolinyl, pyridinyl or benzo[d]thiazolyl optionally substituted with one or more R 7 independently selected from halogen, hydroxyl, CI- C3 alkyl, haloalkyl, Q-haloalkyl, alkoxy and amino.
• R 4 is heteroaryl, optionally an indoyl or an indazolyl, each of which may be substituted with one or more R 7 .
• R 4 is heteroaryl optionally substituted with one or more R 7 substituents independently selected from the group consisting of halogen, hydroxyl, CI- C3 alkyl, haloalkyl, Q-haloalkyl and alkoxy.
• the R 4 heteroaryl is indazolyl optionally substituted with one or two R 7 independently selected from alkoxy, haloalkyl, and C1-C6 alkyl.
• the R 4 heteroaryl is a quinolinyl or isoquinolinyl, each optionally substituted with one or more R 7 . In one
• the R 4 heteroaryl is a quinolinyl or isoquinolinyl, each optionally substituted with one or more R 7 independently selected from amino, hydroxyl, CI - C3 alkyl, and hydroxyl.
• the R 4 heteroaryl is a quinolinyl or isoquinolinyl, each optionally substituted with R 7 selected from hydroxyl and amino.
• the R 4 heteroaryl is a pyridinyl optionally substituted with one or more R 7 .
• the R 4 heteroaryl is pyridinyl optionally substituted with one or more R 7 independently selected from CI - C3 alkyl, halogen and haloalkyl.
• the R 4 heteroaryl is benzo[d]thiazolyl optionally substituted with one or more R 7 , such as hydroxyl, one or two CI - C3 alkyl, or hydroxyl and one or two CI - C3 alkyl.
• the R 4 heteroaryl is indolyl optionally substituted with one or more R 7 .
• the R 4 heteroaryl is indolyl optionally substituted with one or two R 7 independently selected from hydroxyl and CI - C3alkyl.
• R 4 is aralkyl.
• the aralkyl is benzyl.
• the alkyl of the benzyl group is optionally substituted with hydroxyalkyl.
• L is a bond
• m is one and R 3 is CI - C3 alkyl.
• m is one and R 3 is oxo.
• R 8 is heteroalkyl, C2-C4 alkynyl or CI - C3 alkyl optionally substituted with -OR 5 , cyano or heteroaryl.
• R 8 is methyl, cyanomethyl, methoxy methyl, hydroxymethyl.
• R 8 is methyl.
• R 8 is cyanomethyl.
• R 8 is hydroxymethyl.
• Formula I includes compounds having the Formula I- A:
• R 1 , R 3 , R 4 , R 5 , R 10 , L and m are as defined for Formula I
• R 11 is hydrogen, methyl or hydroxyalkyl
• the piperidinyl ring is optionally substituted with R 8 wherein R 8 is as defined for Formula I.
• L is a bond.
• R 4 is aryl or heteroaryl, each of which is optionally substituted with one or more R 6 or R 7 .
• R 4 is aryl or heteroaryl, each of which is optionally substituted with one or more R 7 .
• each R 7 is independently selected from hydroxyl, amino, halogen, CI - C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl and alkoxy.
• R 5 and R 10 are each CI - C3 alkyl.
• the aryl is phenyl substituted with one or more R 7 groups independently selected from halogen, hydroxyl, CI- C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy.
• the aryl is phenyl substituted with one or more R 7 groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, the aryl is phenyl substituted with one or more R 7 groups independently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl,
• the aryl is phenyl substituted with one to three R 7 groups independently selected from hydroxyl, fluorine and chlorine.
• the aryl is phenyl substituted with hydroxyl and CI - C3 alkyl or two CI - C3 alkyl.
• the aryl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine.
• the aryl is naphthyl substituted with one or more R 7 groups independently selected from halogen, hydroxyl, CI - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is naphthyl substituted with one or more R 7 groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl. In one embodiment, R 4 is naphthyl optionally substituted with one or more R 7 substituents independently selected from hydroxyl, halogen, CI - C3 alkyl, amino, and haloalkyl. In one embodiment, R 4 is naphthyl optionally substituted with one to three R 7 substituents independently selected from
• the aryl is naphthyl optionally substituted with one or more halogen. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or CI - C3alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl. In one embodiment, R 4 is heteroaryl, wherein the heteroaryl is indazolyl optionally substituted with one or two R 7 independently selected from alkoxy, haloalkyl, and C1-C6 alkyl.
• R 4 is heteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R 7 .
• R 4 is heteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R independently selected from amino, hydroxyl, CI - C3alkyl, and hydroxyl.
• the R 4 heteroaryl is a pyridinyl optionally substituted with one or more R 7 .
• the R 4 heteroaryl is pyridinyl optionally substituted with one or more R 7 independently selected from CI - C3 alkyl, halogen and haloalkyl.
• the R 4 heteroaryl is benzo[d]thiazolyl optionally substituted with one or more R 7 , such as hydroxyl, one or two CI - C3 alkyl, or hydroxyl and one or two CI - C3 alkyl.
• the R 4 heteroaryl is indolyl optionally substituted with one or more R 7 .
• the R 4 heteroaryl is indolyl optionally substituted with one or two R 7 independently selected from hydroxyl and CI - C3alkyl.
• R 11 is methyl.
• the piperidinyl ring is unsubstituted. In one embodiment, the piperidinyl ring is substituted with R 8 .
• R 8 is CI - C3 alkyl optionally substituted with cyano or hydroxyl. In one embodiment, R 8 is methyl, cyanomethyl or hydroxymethyl. In one embodiment, R 8 is methyl. In one embodiment, R 8 is cyanomethyl. In one embodiment, R 8 is hydroxymethyl.
• R 5 and R 10 are each CI - C3 alkyl, R 11 is methyl, R 8 is methyl, cyanomethyl or hydroxymethyl, L is a bond, and R 4 is aryl or heteroaryl, each optionally substituted with one or more R 6 or R 7 .
• Formula I includes compounds having the Formula I-B:
• R 2 is heterocyclylalkyl optionally substituted with one or more R 9
• the piperidinyl ring is optionally substituted with R 8 , where R 8 is as defined for Formula I.
• the heterocyclyl portion of the R 2 heterocyclylalkyl is a monocyclic, bicyclic, or bridged ring system having one or two ring heteroatoms independently selected from N and O.
• R 2 heterocyclyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, thiomorpholinyl-1,1- dioxide, 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, and
• each R 9 is selected from acyl, oxo, halogen, cyano, CI - C3 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, aralkyl and dialkylamidoalkyl.
• L is a bond.
• R 4 is aryl or heteroaryl, each of which is optionally substituted with one or more R 6 or R 7 .
• R 4 is aryl or heteroaryl, each of which is optionally substituted with one or more R 7 .
• each R 7 is independently selected from hydroxyl, amino, halogen, CI - C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl and alkoxy.
• the aryl is phenyl substituted with one or more R 7 groups independently selected from halogen, hydroxyl, CI - C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy.
• the aryl is phenyl substituted with one or more R 7 groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl.
• the aryl is phenyl substituted with one or more R 7 groups independently selected from methyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl and trifluoromethylthio.
• the aryl is phenyl substituted with one to three R 7 groups independently selected from hydroxyl, fluorine and chlorine.
• the aryl is phenyl substituted with hydroxyl and CI - C3 alkyl or two CI - C3 alkyl.
• the aryl is phenyl substituted with Q-haloalkyl and hydroxyl or fluorine. In one embodiment, the aryl is naphthyl substituted with one or more R 7 groups independently selected from halogen, hydroxyl, CI- C3 alkyl, haloalkyl, Q-haloalkyl, and alkoxy. In one embodiment, the aryl is naphthyl substituted with one or more R 7 groups independently selected from halogen, haloalkyl, methyl, isopropyl, methoxy, Q-haloalkyl and hydroxyl.
• R 4 is naphthyl optionally substituted with one or more R 7 substituents independently selected from hydroxyl, halogen, CI - C3 alkyl, amino, and haloalkyl. In one embodiment, R 4 is naphthyl optionally substituted with one to three R 7 substituents independently selected from difluoromethyl, methyl, hydroxyl, amino, fluoro, and chloro. In one embodiment, the aryl is naphthyl optionally substituted with one or more halogen. In one embodiment, the aryl is naphthyl substituted with hydroxyl and trifluoromethyl or CI - C3alkyl. In one embodiment, the aryl is naphthyl substituted with hydroxyl.
• R 4 is heteroaryl, wherein the heteroaryl is indazolyl optionally substituted with one or two R 7 independently selected from alkoxy, haloalkyl, and C 1-C6 alkyl.
• R 4 is heteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R 7 .
• R 4 is heteroaryl, wherein the heteroaryl is quinolinyl or isoquinolinyl, each optionally substituted with one or more R 7 independently selected from amino, hydroxyl, C I - C3 alkyl, and hydroxyl.
• the R 4 heteroaryl is a pyridinyl optionally substituted with one or more R 7 .
• the R 4 heteroaryl is pyridinyl optionally substituted with one or more R 7 independently selected from CI - C3 alkyl, halogen and haloalkyl.
• the R 4 heteroaryl is benzo[d]thiazolyl optionally substituted with one or more R 7 , such as hydroxyl, one or two CI - C3 alkyl, or hydroxyl and one or two C I - C3 alkyl.
• the R 4 heteroaryl is indolyl optionally substituted with one or more R 7 .
• the R 4 heteroaryl is indolyl optionally substituted with one or two R 7 independently selected from hydroxyl and C I - C3 alkyl.
• R 11 is methyl.
• the piperidinyl ring is unsubstituted.
• the piperidinyl ring is substituted with R 8 .
• the piperidinyl ring is unsubstituted.
• the piperidinyl ring is substituted with R 8 .
• R 8 is CI - C3 alkyl optionally substituted with cyano, hydroxyl or methoxy.
• R 8 is methyl, cyanomethyl, hydroxymethyl or methoxymethyl.
• X is a saturated bridged ring system.
• bridged ring systems include diazabicycloheptanes and diazabicyclooctanes.
• the bridged ring system is substituted with one or two groups independently selected from R 8 , where R 8 is as defined for Formula I.
• the bridged ring system is unsubstituted.
• the bridged ring system is
• l -X is:
• a and B are a spirocyclic ring system, wherein A and B are the same or different and independently represent a 4-6 membered saturated ring systems, wherein the rings are optionally substituted with one or more R 8 , wherein R 8 is as defined for Formula I.
• rings A and B are unsubstituted.
• the spirocyclic ring system is unsubstituted.
• spirocyclic ring systems include:
• R 2 is selected from the group consisting of
• R 2 is heterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl or heterocyclylalkyl are independently optionally substituted with one or more R 9 .
• R 2 is dialkylaminylalkyl optionally substituted with one or more R 9 .
• Non- limiting examples include dimethylaminylethyl, dimethylaminylpropanyl,
• dimethylaminylpropan-2-yl dimethylaminylbutanyl, dimethylaminylbutan-2-yl, 2- dimethylaminylpropanol, or diethylaminylethyl.
• Y is O and R 2 is selected from the group consisting of hydroxyalkyl, dialkylaminylalkyl, heterocyclyl, heterocyclylalkyl, and -ZR 5 R 10 , wherein R 5 and R 10 are as defined for Formula I.
• Y is O and R 2 is selected from the group consisting of hydroxyalkyl, dialkylaminylalkyl, heterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl or heterocyclylalkyl are independently optionally substituted with R 9 .
• R 2 is heterocyclyl and heterocyclylalkyl, wherein each of the heterocyclyl or heterocyclylalkyl are independently optionally substituted with one or more R 9 .
• R 9 include acyl, oxo, halogen, cyano, CI - C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, aralkyl or dialkylamidoalkyl.
• R 2 is dialkylaminylalkyl optionally substituted with one or more R 9 .
• Non-limiting examples include dimethylaminylethyl,
• R 4 is aryl optionally substituted with one or more R 6 or R 7 .
• R 4 is phenyl or naphthyl optionally substituted with one or more R 6 or R 7 .
• R 4 is phenyl or naphthyl optionally substituted with one or more R 7 .
• R 4 is phenyl or naphthyl optionally substituted with one or more R 7 substituents independently selected from halogen, hydroxyl, CI - C3alkyl, cycloalkyl, alkoxy, haloalkyl, or Q-haloalkyl wherein Q is O or S.
• R 4 is phenyl or naphthyl optionally substituted with one or more R 7 substituents independently selected from methyl, trifluoromethyl, hydroxyl, trifluoromethoxy, hydroxyl, fluoro, chloro, isopropyl, cyclopropyl and methylthio.
• R 4 is isoquinolinyl which is optionally substituted with amino.
• R 4 is aralkyl.
• the aralkyl is benzyl.
• the aralkyl is benzyl wherein the alkyl portion is substituted with hydroxyl or hydroxyalkyl.
• Nonlimiting examples of compounds of Formula (I), Formula I-A and Formula I-B are selected from the group consisting of:
• the compounds of Formula I include trifluoroacetic acid salts of the above compounds.
• the compounds of Formula (I), Formula I- A, or Formula I-B may be formulated into pharmaceutical compositions.
• the invention provides pharmaceutical compositions comprising a KRas G12C inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent.
• Compounds of the invention may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
• compounds of the invention are administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route.
• compositions according to the invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
• diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
• the preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
• the term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
• examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
• inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
• organic acids such as acetic acid, oxalic acid, tartaric acid
• the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula --NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methyl sulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
• R is hydrogen, alkyl, or benzyl
• Z is a counterion, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methyl sulfon
• the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated.
• a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, for example 0.1 to 100 mg/kg per day, and as a further example 0.5 to about 25 mg per kilogram body weight of the recipient per day.
• a typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier.
• the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
• compositions comprising compounds of the present invention may be used in the methods of use described herein.
• the invention provides for methods for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of Formula (I), Formula I- A, or Formula I-B, pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof.
• the contacting is in vitro. In one embodiment, the contacting is in vivo.
• contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
• "contacting" a KRas G12C with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12C, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12C.
• a cell in which inhibition of KRas G12C activity is desired is contacted with an effective amount of a compound of Formula (I), Formula I- A, or Formula I-B, to negatively modulate the activity of KRas G12C.
• an effective amount of a compound of Formula (I), Formula I- A, or Formula I-B to negatively modulate the activity of KRas G12C.
• a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing the compound of Formula (I), Formula I- A, or Formula I-B may be used.
• the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12C activity within the cell.
• the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12C.
• the degree of covalent modification of KRas G12C may be monitored in vitro using well known methods, including those described in Example A below.
• inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphylated ERK, including those described in Example B below, to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.
• methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), Formula I-A, or Formula I-B, pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided.
• compositions and methods provided herein may be used for the treatment of a KRas G12C-associated cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), Formula I- A, or Formula I-B, pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided.
• the KRas G12C-associated cancer is lung cancer.
• compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
• tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
• these compounds can be used to treat: 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, insulinom
• kidney adenocarcinoma, Wilm's tumor
• liver nephroblastoma
• lymphoma lymphoma
• leukemia bladder and urethra
• squamous cell carcinoma transitional cell carcinoma, adenocarcinoma
• prostate adenocarcinoma, sarcoma
• testis seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma
• Liver Liver:
• hepatoma hepatocellular carcinoma
• cholangiocarcinoma hepatoblastoma
• angiosarcoma hepatocellular adenoma
• Biliary tract gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma
• Bone osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma,
• osteochronfroma osteocartilaginous exostoses
• benign chondroma chondroblastoma
• chondromyxofibroma osteoid osteoma
• giant cell tumors Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma,
• meningiosarcoma meningiosarcoma, gliomatosis
• brain astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma
• Gynecological uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous
• cystadenocarcinoma unclassified carcinoma
• granulosa-thecal cell tumors Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin:
• the cancer is non-small cell lung cancer.
• the concentration and route of administration to the patient will vary depending on the cancer to be treated.
• compositions comprising such compounds and salts also may be coadministered with other anti -neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
• other anti -neoplastic compounds e.g., chemotherapy
• other treatments such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.
• Also provided herein is a compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.
• Also provided herein is a compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or solvate thereof for use in the inhibition of KRas G12C.
• Also provided herein is a compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12C-associated disease or disorder.
• Also provided herein is a use of a compound of Formula (I), Formula I-A, or Formula I- B, or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of KRas G12C.
• Also provided herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
• a KRas G12C mutation e.g., a KRas G12C-associated cancer
• a regulatory agency-approved e.g., FDA-approved, assay or kit
• administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula I-A, or Formula I-B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
• the compounds of the present invention may be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art.
• compounds of the present invention may be prepared according to the General Reaction Schemes I and II.
• step A an appropriately functionalized dihydropyridopyrimidine (1) is coupled to a heterocycle containing one nucleophilic amine species, with the other bound to a protecting group to provide compound (2).
• This coupling proceeds in a solvent such as dichloromethane in the presence of a base such as triethylamine or Hunig's base.
• step B the Boc group of compound (2) is removed using conditions known in the art, for example with trifluoroacetic acid in a solvent such as dichloromethane, to provide compound (3).
• step C the substituent R 4 is introduced with a palladium coupling, using a suitable functionalized aryl or heteroaryl system, for example an aryl triflate, in the presence of a palladium catalyst such as Pd 2 DBA 3 /Xantphos in a solvent such as toluene with a base such as sodium tert-butoxide to provide compound (4).
• a palladium catalyst such as Pd 2 DBA 3 /Xantphos
• a solvent such as toluene
• a base such as sodium tert-butoxide
• step D the protecting group of ring X compound (4) is removed, for example hydrogenolysis by Pd/C in the presence of H 2 in a polar solvent such as EtOH/THF to provide compound (5).
• R 1 is an acryloyl group
• this reaction proceeds, for example, in a solvent such as methylene chloride in the presence of acryloyl chloride or an acryloyl anhydride and a base such as Hunig's base.
• the species R 4 will also contain a protecting group, which can be removed at a subsequent step in the synthetic sequence.
• step A an appropriately functionalized dihydropyridopyrimidine (6) is coupled to a heterocycle containing one nucleophilic amine species, with the other bound to a protecting group to provide compound (7).
• This coupling proceeds in a solvent such as dichloromethane in the presence of a base such as triethylamine or Hunig's base.
• step B the substituent -Y-R 2 is introduced by substitution of the chlorine by a nucleophile, for example (S)-l-(dimethylamino-propan-2-ol in a polar solvent such as dioxane to provide compound (8).
• step C the Boc group is removed using conditions known in the art, for example with trifluoroacetic acid in a solvent such as dichloromethane to provide compound (9).
• step D the substituent R 4 is introduced with a palladium coupling, using a suitable functionalized aryl or heteroaryl system, for example an aryl triflate, in the presence of a palladium catalyst such as Pd2DBA 3 /BINAP in a solvent such as toluene with a base such as sodium tert-butoxide to provide compound (10).
• a palladium catalyst such as Pd2DBA 3 /BINAP
• a solvent such as toluene with a base such as sodium tert-butoxide
• step E the protecting group of ring X is removed, for example hydrogenolysis by Pd/C in the presence of Fh in a polar solvent such as EtOH/THF to provide compound (11).
• R 1 is introduced to provide a compound of Formula I, for example by treating with an acid chloride having the formula C1-C(0)C(R A ) C(R B )p or C1-S0 2 C(R A ) C(R )p, or an anhydride having the formula C(R B ) P C(R A )C(0)OC(0)C(R A ) C(R B )p, where R A , R B and p are as defined for Formula I.
• R 1 is an acryloyl group
• this reaction proceeds, for example, in a solvent such as methylene chloride in the presence of acryloyl chloride acryloyl anhydride and a base such as Hunig's base.
• the species R 4 and R 2 may also contain protecting groups, which can be removed at a subsequent step in the synthetic sequence.
• the compounds of the present invention may have one or more chiral center and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space.
• the compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic FIPLC columns according to the manufacturer's instructions.
• compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Unless otherwise indicated, whenever the specification, including the claims, refers to compounds of the invention, the term "compound” is to be understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms.
• the concentrated material was loaded onto a 120 g RediSep® gold silica gel column with dichloromethane and purified by normal phase chromatography (CombiFlash®, 0%-20% ethyl acetate/hexanes as the eluent) to give 3- (methoxymethoxy)naphthalen-l-yl trifluoromethanesulfonate (11.785 g, 35.045 mmol, 78.171 % yield).
• Step A tert-butyl 4-hvdroxy-2-(methylthio)-5.8-dihvdropyridor3.4-d]pyrimidine-7(6H)- carboxylate: To a stirred solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-l,4-dicarboxylate (50.0 g, 184 mmol, 1.00 eq) in MeOH (1.00 L) at 25 °C under nitrogen was added NaOMe (49.8 g, 921 mmol, 5.00 eq), followed by 2-methylisothiourea (62.4 g, 331 mmol, 1.80 eq, H2SO4) as a solid.
• the reaction mixture was stirred at 25 °C for 16 hours.
• the reaction mixture was adjusted to pH 5 with HC1 (2 M), and the mixture was concentrated under reduced pressure to removed MeOH.
• the residue was suspended in 300 mL of ethyl acetate and 300 mL of water and stirred rapidly. The suspension was filtered and the white solid was collected. The filtrate was separated and the organic layer was washed with water (1 ⁇ 300 mL) and brine (1 ⁇ 200 mL).
• Step B fert-butyl 2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H- pyrido[3,4-d1pyrimidine-7-carboxylate: To a stirred suspension of tert-butyl 4-hydroxy-2- methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (51.0 g, 171 mmol, 1.00 eq) in DCM (500 mL) at 0 °C was added DIEA (44.3 g, 343 mmol, 59.9 mL, 2.00 eq), followed by trifluoromethanesulfonic anhydride (72.6 g, 257 mmol, 42.4 mL, 1.50 eq) under nitrogen.
• DIEA 44.3 g, 343 mmol, 59.9 mL, 2.00 eq
• Step C fert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-methylsulfanyl-6,8-dihydro- 5H-pyrido[3,4-d1pyrimidine-7-carboxylate: To a stirred solution of tert-butyl 2-methylsulfanyl- 4- (trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (46.0 g, 107 mmol, 1.00 eq) in DMF (500 mL) was added DIEA (27.7 g, 214 mmol, 37.4 mL, 2.00 eq) followed by benzyl piperazine-l-carboxylate (25.9 g, 117 mmol, 22.7 mL, 1.10 eq).
• reaction was heated to 100 °C for 1 hour under a nitrogen atmosphere.
• the reaction mixture was poured into ethyl acetate (300 mL), washed with H 2 0 (300 mL x 3) and brine (200 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under vacuum.
• Step D Benzyl 4-(2-methylsulfanyl-5.6.7.8-tetrahvdropyrido[3.4-d1pyrimidin-4-vn piperazine- 1 -carboxylate: To a solution of tert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2- methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (25.0 g, 50.0 mmol, 1.00 eq) in DCM (50.0 mL) was added TFA (85.6 g, 750 mmol, 55.6 mL, 15.0 eq).
• Step E Benzyl 4-r7-(3-benzyloxy-l-naphthvn-2-methylsulfanyl-6.8-dihvdro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: A mixture of 3-benzyloxy-l-bromo- naphthalene (16.3 g, 52.1 mmol, 1.30 eq), benzyl 4-(2-methylsulfanyl-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate (16.0 g, 40.1 mmol, 1.00 eq), Cs 2 C0 3 (32.6 g, 100 mmol, 2.50 eq), Pd 2 (dba) 3 (5.50 g, 6.01 mmol, 0.15 eq) and 2- dicyclohexylphosphin
• Step F Benzyl 4-[7-(3-benzyloxy-l-naphthvn-2-methylsulfinyl-6.8-dihvdro-5H-pyrido [3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate :To a stirred solution of benzyl 4-[7-(3- benzyloxy-l-naphthyl)-2- methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]piperazine-l-carboxylate (8.00 g, 12.7 mmol, 1.00 eq) in DCM (200 mL) was added m- CPBA (2.73 g, 12.7 mmol, 80.0 % purity, 1.00 eq) at 0 °C under nitrogen.
• reaction mixture was quenched by adding Na2S 2 03 (10.0 mL) at 0 °C, diluted with water (100 mL) and extracted with DCM (200 mL). The combined organic layers were washed with brine (200 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue.
• Step A l-[4-[(2R)-2-hvdroxypropyl1piperazin-l-vHethanone: (2R)-2-methyloxirane (1.00 g, 17.2 mmol, 1.20 mL, 1.00 eq) and 1-piperazin-l-ylethanone (8.00 g, 62.4 mmol, 3.62 eq) were taken up into a microwave tube. The sealed tube was heated at 150 °C for 1 hour under microwave. The mixture was dissolved in DCM (80.0 mL), added (Boc) 2 0 (3.62 eq, 13.6 g) and stirred at 20 °C for 1 hour.
• Step A l-benzyloxy-3,5-dibromo-benzene: To a mixture of 3,5-dibromophenol (1.50 g, 5.95 mmol, 1.00 eq) and K2CO3 (2.47 g, 17.9 mmol, 3.00 eq) in MeCN (30.0 mL) was added benzyl bromide (1.07 g, 6.25 mmol, 742 ⁇ L, 1.05 eq), the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered and concentrated.
• Step B l-benzyloxy-3-bromo-5-cvclopropylbenzene: To a mixture of l-benzyloxy-3,5- dibromobenzene (1.20 g, 3.51 mmol, 1.00 eq) and cyclopropylboronic acid (392 mg, 4.56 mmol, 1.30 eq) in H 2 0 (4.00 mL) and dioxane (20.0 mL) was added Pd(dppf)Cl 2 (513 mg, 702 ⁇ , 0.20 eq) and CS2CO3 (2.29 g, 7.02 mmol, 2.00 eq). The reaction mixture was stirred at 90 °C for 12 hours under N2.
• Step A fert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-(3-morpholinopropoxy)-6,8- dihydro-5H-pyrido[3,4-d1pyrimidine-7-carboxylate: To a mixture of 3-morpholinopropan-l-ol (5.46 g, 37.6 mmol, 2.00 eq) in THF (100 mL) was added NaH (2.26 g, 56.4 mmol, 60.0 % purity, 3.00 eq) in portions at 0 °C.
• Step B benzyl 4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d1pyrimidin-4- yl]piperazine-l-carboxylate: To a mixture of tert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)- 2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (7.70 g, 12.9 mmol, 1.00 eq) in DCM (80.0 mL) was added TFA (1 19 g, 1.04 mol, 76.9 mL, 80.6 eq), and the reaction mixture was stirred at 15 °C for 1 hour.
• Step A fert-butyl 3-fluoropyrrolidine-l-carboxylate: To a solution of tert-butyl 3- hydroxypyrrolidine-l-carboxylate (10.0 g, 53.4 mmol, 1.00 eq) in DCM (150.00 mL) was added diethylaminosulfur trifluoride (DAST) (12.9 g, 80.1 mmol, 10.6 mL, 1.50 eq) at -40 °C under a nitrogen atmosphere. After stirring at - 40 °C for 2 hours, the mixture was warmed to 20 °C and stirred for 16 hours.
• DAST diethylaminosulfur trifluoride
• Step B 3-fluoropyrrolidine: To a solution of tert-butyl 3-fluoropyrrolidine-l-carboxylate (4.30 g, 22.7 mmol, 1.00 eq) in DCM (50.00 mL) was added HCl/dioxane (4 M, 35.0 mL, 6.16 eq) dropwise at 0 °C. The mixture was warmed to 20 °C and stirred for 1 hour. The mixture was concentrated under vacuum.
• Step C methyl 2-(3 -fluoropyrrolidin- 1 -vDacetate: A suspension of 3-fluoropyrrolidine (2.70 g, 21.5 mmol, 1.00 eq, HC1) in DCM (27.00 mL) was cooled to 0° C. Triethylamine (5.44 g, 53.8 mmol, 7.45 mL, 2.50 eq) and methyl 2-bromoacetate (3.62 g, 23.7 mmol, 2.23 mL, 1.10 eq) were added and the reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with CH2CI2 (100 mL) and water (50 mL).
• Step D 2-(3-fluoropyrrolidin- 1 -vDethanol : To a solution of LiAlH 4 (706 mg, 18.6 mmol, 1.50 eq) in THF (20 mL) was added a solution of methyl 2-(3-fluoropyrrolidin-l-yl)acetate (2.00 g, 12.4 mmol, 1.00 eq) in THF (10 mL) dropwise at 0 °C. The mixture was warmed up to 20 °C and stirred for 3 hours. The mixture was quenched with saturated aqueous sodium sulfate solution (1 mL). The mixture was filtered and the filtrate was concentrated under vacuum.
• Step A methyl piperazine-2-carboxylate: To a mixture of 1-tert-butyl 2-methyl piperazine- 1,2-dicarboxylate (5.0 g, 22.6 mmol, 1.00 eq) in MeOH (50.0 mL) was added HCl/dioxane (4.0 M, 134 mL). The reaction mixture was degassed and purged with nitrogen 3 times, and the mixture was stirred at 25 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to dryness to give methyl piperazine- 2-carboxylate (4.89 g, 2HC1, crude) as a white solid, which was used directly in the next step without further purification.
• HCl/dioxane 4.0 M, 134 mL
• Step B l-(tert-butyl) 3-methyl piperazine-L3-dicarboxylate: To a solution of methyl piperazine-2-carboxylate (4.30 g, crude) and TEA (8.02 g, 79.2 mmol, 11.0 mL) in MeOH (50.0 mL) was added di-tert-butyl dicarbonate (4.32 g, 19.8 mmol, 4.55 mL). After stirring at 25 °C for 12 hours, the reaction mixture was filtered and concentrated under reduced pressure to dryness.
• Step A 2,4-dibromonaphthalen- 1 -amine: To a solution of Br 2 (246 g, 1.54 mol, 79.3 mL, 2.18 eq) in AcOH (750 mL) was added a solution of naphthalen-1 -amine (101 g, 705 mmol, 99.0 mL, 1.00 eq) in AcOH (500 mL) at ambient temperature, and the reaction was stirred at 70 °C for 1 hour. The reaction mixture was cooled at room temperature and filtered. The filter cake was washed with AcOH (300 mL), then added to 20 % aqueous of NaOH (1.2 L). The mixture was stirred for 20 min and filtered.
• Step B 4-bromo- 1 -diazonio-naphthalen-2-olate : To a solution of 2,4-dibromonaphthalen- 1-amine (60.0 g, 199 mmol, 1.00 eq) in AcOH (900 mL) and propionic acid (150 mL) was added NaN0 2 (16.5 g, 239 mmol, 13.0 mL, 1.20 eq) portionwise at 5-8 °C over 30 min, and then the reaction mixture was stirred at 5-8 °C for 30 min.
• Step C 4-bromonaphthalen-2-ol : To a solution of 4-bromo-l-diazonio-naphthalen-2- olate (100 g, 402 mmol, 1.00 eq) in EtOH (2.00 L) was added portionwise NaBH 4 (30.4 g, 803 mmol, 2.00 eq) at 13-15 °C over 1 h, and the reaction mixture was stirred at 15-18 °C for 3 hrs. The reaction was filtered and concentrated to dryness. The residue was dissolved in DCM (1000 mL) and washed with water (500 mL ⁇ 2). The organic phase was dried over Na 2 S04 and concentrated to dryness.
• Step D 3 -benzyloxy- 1 -bromo-naphthalene: A mixture of 4-bromonaphthalen-2-ol (30.0 g, 134 mmol, 1.00 eq), benzyl bromide (25.3 g, 148 mmol, 17.6 mL, 1.10 eq) and K 2 C0 3 (55.7 g, 403 mmol, 3.00 eq) in MeCN (500 mL) was heated at 80 °C for 1 hr. The reaction mixture was filtered and concentrated to dryness.
• Step A 3 -methoxynaphthalen- 1 -ol : To a solution of naphthalene-l,3-diol (3.00 g, 18.7 mmol, 1.00 eq) in MeOH (60.0 mL) was added HCl/MeOH (4 M, 60.0 mL, 12.8 eq) at 0 °C. The mixture was stirred at 25 °C for 60 hours. The solvent was removed under vacuum.
• Step B (3-methoxy-l-naphthyl) trifluoromethanesulfonate: To a solution of 3- methoxynaphthalen-l-ol (2.10 g, 12.0 mmol, 1.00 eq) in DCM (40.0 mL) was added DIEA (7.79 g, 60.3 mmol, 10.5 mL, 5.00 eq) and trifluoromethanesulfonic anhydride (5.10 g, 18.1 mmol, 2.98 mL, 1.50 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour.
• Step A 7-benzyl-6.8-dihvdro-5H-pyrido[3.4-d]pyrimidine-2.4-diol: To EtOH (600 mL) was added Na (5.56 g, 241 mmol, 5.73 mL, 2.40 eq) in portions. The reaction mixture was stirred for 1 hour. To the mixture was added ethyl l-benzyl-3-oxo-piperidine-4-carboxylate (30.0 g, 100 mmol, 1.00 eq, HC1) and urea (14.5 g, 242 mmol, 13.0 mL, 2.40 eq).
• Step B 7-benzyl-2,4-dichloro-6,8-dihvdro-5H-pyrido[3,4-d1pyrimidine: To a solution of DIEA (30.1 g, 233 mmol, 40.7 mL, 3.00 eq) in POCh (330 g, 2.15 mol, 200 mL) was added 7- benzyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (20.0 g, 77.7 mmol, 1.00 eq). The reaction mixture was stirred at 110 °C for 5 hours. The reaction mixture was concentrated under vacuum.
• Step A fert-butyl4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine- 7-carboxylate: To a stirred solution of 1-tert-butyl 4-ethyl-3-oxopiperidine-l,4-dicarboxylate (44.0 g, 162 mmol, 1.00 eq) in MeOH (1.00 mL) at 25 °C under nitrogen was added a solution of NaOMe (35.0 g, 649 mmol, 4.00 eq) in MeOH (600 mL) by syringe followed by 2- methylisothiourea (61.1 g, 324 mmol, 2.00 eq, H 2 S0 4 ).
• Step B give fert-butyl 2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihvdro-5H- pyrido [3,4-d]pyrimidine-7-carboxylate: To a stirred suspension of tert-butyl 4-hydroxy-2- methylsulfanyl -6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (15.0 g, 50.4 mmol, 1.00 eq) in DCM (200 mL) was added DIEA (26.1 g, 202 mmol, 35.2 mL, 4.00 eq) at 0 °C under nitrogen and followed by trifluoromethanesulfonic anhydride (28.5 g, 101 mmol, 16.6 mL, 2.00 eq) by syringe.
• Step C fert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-methylsulfanyl-6,8- dihydro- 5H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a stirred solution of fer/-butyl2-methylsulfanyl- 4-(trifluoromethyl sulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (16.7 g, 38.9 mmol, 1.00 eq) in DMF (100 mL) was added DIEA (10.0 g, 77.9 mmol, 2.00 eq) and benzyl piperazine-l-carboxylate (9.41 g, 42.8 mmol, 1.10 eq).
• the reaction was heated to 100 °C and stirred for 1 hour under a nitrogen atmosphere.
• the reaction mixture was diluted with water (150 mL) and the reaction mixture was adjusted to pH 5 with HC1 (2 M) and extracted with DCM (3 x 200 mL).
• Step D tert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2- methylsulfonyl-6,8-dihydro- 5H-pyrido[3,4-d1pyrimidine-7-carboxylate: To a stirred solution of tert-butyl4-(4- benzyloxycarbonylpiperazin -l-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine- 7-carboxylate (14.4 g, 28.9 mmol, 1.00 eq) in DCM (150 mL) at 0 °C under nitrogen was added meta-chloroperoxybenzoic acid (17.4 g, 101 mmol, 3.50 eq) as a solid.
• reaction mixture was diluted with water (300 mL) and the reaction mixture was adjusted to pH 8 with saturated aqueous NaHCCb and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over Na 2 S04, filtered and concentrated under reduced pressure to dryness.
• Step A 3 -methoxynaphthalen- 1 -ol : To a solution of naphthalene-l,3-diol (40.0 g, 250 mmol, 1.00 eq) in MeOH (800 mL) was added HC1 (4 M, 750 mL, 12.0 eq, 4 M in MeOH) at 0 °C. The mixture was warmed up to 18 °C and stirred for 30 hours. The mixture was
• Step B fert-butyl-[(3-methoxy-l-naphthyl)oxy]-dimethyl-silane: To a solution of 3- methoxynaphthalen-l-ol (20.0 g, 115 mmol, 1.00 eq) and imidazole (23.5 g, 344 mmol, 3.00 eq) in THF (400 mL) was added TBSC1 (26.0 g, 172 mmol, 21.1 mL, 1.50 eq) dropwise at 0 °C. The mixture was warmed up to 25 °C and stirred for 16 hours.
• Step C fert-butyl-[[3-methoxy-6-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-vn-l- naphthyl]oxy]-dimethyl-silane and fert-butyl((3-methoxy-7-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)naphthalen-l-yl)oxy)dimethylsilane: A mixture of tert-butyl-[(3-methoxy-l- naphthyl) oxy]-dimethyl-silane (26.0 g, 90.1 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (45.8 g, 180 mmol, 2.00 eq), ( ⁇ Z
• Step D 8-[fert-butyl(dimethyl)silylloxy-6-methoxy- naphthalen-2-ol: To a solution of mixture (36.0 g, 86.9 mmol, 1.00 eq) of tert-butyl-[[3-methoxy-6-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-l- naphthyl]oxy]-dimethyl-silane and fert-butyl((3-methoxy-7-(4,4,5,5- tetramethyl-1,3, 2-dioxaborolan-2-yl)naphthalen-l-yl)oxy)dimethylsilanein in acetone (400 mL) was added a solution of Oxone (58.7 g, 95.6 mmol, 1.10 eq) in H 2 0 (400 mL) at 0 °C.
• Oxone 58.7 g, 9
• Step E r5-rte ⁇ butyl(dimetfayl)silyl1oxy-7-methoxy-2-naphthyl1
• Step F fert-butyl-[(3-methoxy-6-methyl-l-naphthyl)oxy]-dimethyl-silane: To a solution of [5-[tert-butyl(dimethyl)silyl]oxy-7-methoxy-2- naphthyl]trifluoromethanesulfonate (12.5 g, 28.6 mmol, 1.00 eq) and K2CO3 (11.9 g, 85.9 mmol, 3.00 eq) in dioxane (160 mL) was added Pd(PPh 3 )4 (3.31 g, 2.86 mmol, 0.10 eq) and trimethylboroxine (14.4 g, 57.3 mmol, 16.0 mL, 2.00 eq) under nitrogen atmosphere.
• the reaction was heated to 100 °C for 16 hours.
• the mixture was diluted with ethyl acetate (200 mL) and then washed with water (1 x 200 mL) and brine (1 ⁇ 200 mL).
• the separated organic layer was dried over sodium sulfate, filtered and concentrated under vacuum.
• the residue was purified by column chromatography over silica gel (petroleum ether/ethyl acetate 100/1 to 5/1).
• Step G 3 -methoxy-6-methyl-naphthalen- 1 -ol : To a solution of tert-butyl-[(3-methoxy-6- methyl-l-naphthyl) oxy]-dimethyl-silane (8.00 g, 26.5 mmol, 1.00 eq) in THF (100 mL) was added TBAF (10.4 g, 39.7 mmol, 1.50 eq) at 0 °C. The mixture was stirred at 0 °C for 3 hours. The mixture was diluted with water (100 mL) and ethyl acetate (200 mL).
• Step H 3-methoxy-6-methyl-l-naphthyl trifluoromethanesulfonate: To a solution of 3- methoxy-6-methyl-naphthalen-l-ol (4.70 g, 25.0 mmol, 1.00 eq) and DIEA (9.68 g, 74.9 mmol, 13.1 mL, 3.00 eq) in DCM (3.00 mL) was added Tf 2 0 (8.45 g, 30.0 mmol, 4.94 mL, 1.20 eq) dropwise at - 40 °C. The mixture was stirred for 1 hour.
• Step 1 3-fluoro-4-methylphenol (1.016 g, 8.055 mmol) was placed in Cs2 (3.9 mL, 64.44 mmol) and was cooled to 0°C. Br 2 (0.4150 mL, 8.055 mmol) was added and the mixture was stirred at room temperature for 2 hrs. 10% Na 2 S 2 0 2 was added and the mixture was extracted with DCM. The organic layers were combined, dried and filtered to provide 2-bromo-3-fluoro- 4-methylphenol (1.389 g, 6.775 mmol, 84.10 % yield) which was used directly in the next step.
• Step 2 2-bromo-3-fluoro-l-(methoxymethoxy)-4-methylbenzene was prepared according to the procedure for Intermediate 8 using 2-bromo-3-fluoro-4-methylphenol in place of 2-bromo-3-fluorophenol.
• Step 1 4-isopropoxyphenol (1.00 g, 6.57 mmol) and TEA (1.83 mL, 13.1 mmol) were placed in DCM (25 mL). Acetyl chloride (7.56 mL, 7.56 mmol) was added dropwise and the reaction was stirred at room temperature for 2hr. Water was added and the mixture was extracted with DCM. The organic layer was dried, filtered and concentrated to provide 4- isopropoxyphenyl acetate (1.24 g, 6.38 mmol, 97.2 % yield) which was directly in the next step.
• Step2 4-Isopropoxyphenyl acetate (1.24 g, 6.585 mmol) was placed in ACN (20 mL) and N-bromosuccinimide (1.173 g, 6.590 mmol) was added. The mixture was stirred for 18 hr. Water was added and the mixture was extracted with ether. The organic layers were combined, dried, and concentrated to provide 3-bromo-4-isopropoxyphenyl acetate (1.584 g, 5.800 mmol, 88.00 % yield) which was directly in the next step.
• Step 3 3-Bromo-4-isopropoxyphenyl acetate (500 mg, 1.83 mmol) was placed in MeOH (7 mL). A solution of KOH (111 mg, 1.98 mmol) in water (2 mL) was added to mixture and was stirred for 1 hr at room temperature. The reaction mixture was adjusted to pH 3 by the addition of IN HCl. The mixture was extracted with DCM. The extracts were combined, dried, filtered and concentrated to provide crude 3-bromo-4-isopropoxyphenol which was used directly the next reaction.
• Step 4 2-Bromo-l-isopropoxy-4-(methoxymethoxy)benzene was prepared according to the procedure for Intermediate 8 using 3-bromo-4-isopropoxyphenol in place of 2-bromo-3- fluorophenol
• Step 1 l-bromo-3-chloro-2-isopropyl-5-methoxybenzene (952 mg, 3.61 mmol) was placed in DCM (3 mL) and was cooled to 0°C. BBr3 (9030 ⁇ , 9.03 mmol) was added and the reaction was stirred at 0°C for 2 hr. Water was added and the mixture was extracted with DCM. The extracts were combined and concentrated. The resulting residue was purified by silica gel (0-20% EtOAc in hexane) to provide 3-bromo-5-chloro-4-isopropylphenol (575 mg, 2.30 mmol, 63.8 % yield)
• Step 2 l-bromo-3-chloro-2-isopropyl-5-(methoxymethoxy)benzene was prepared according to the procedure for Intermediate 8 using 3-bromo-5-chloro-4-isopropylphenol in place of 2-
• Step A 2.4-dibromonaphthalen-l-amine: To a solution of Br 2 (246 g, 1.54 mol, 79.3 mL) in AcOH (750 mL) was added a solution of naphthalen-1 -amine (101 g, 705 mmol, 99.0 mL) in AcOH (500 mL) at room temperature and the reaction stirred at 70 °C for 1 hour. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with AcOH (300 mL). The solid was next suspended in 20 % aqueous of NaOH (1.2 L). The mixture was stirred for 20 minutes and filtered.
• Step B 4-bromo- 1 -diazonio-naphthalen-2-olate : To a solution of 2,4-dibromonaphthalen- 1-amine (60.0 g, 199 mmol) in AcOH (900 mL) and propionic acid (150 mL) was added NaN0 2 (16.5 g, 239 mmol, 13.0 mL) portionwise at 5-8 °C over 30 minutes and the reaction mixture stirred at 5-8 °C for 30 minutes.
• Step C 4-bromonaphthalen-2-ol : To a solution of 4-bromo-l-diazonio-naphthalen-2- olate (100 g, 402 mmol) in EtOH (2.00 L) was added portion-wise NaBH 4 (30.4 g, 803 mmol) at 13-15 °C over 1 hour and the reaction stirred at 15-18 °C for 3 hours. The reaction was filtered and concentrated to dryness. The residue was dissolved in DCM (1000 mL) and washed with water (500 mL x 2). The organics were dried over Na 2 S04 and concentrated to dryness.
• Step D 3-benzyloxy-l-bromo-naphthalene: A mixture of 4-bromonaphthalen-2-ol (30.0 g, 134 mmol), BnBr (25.3 g, 148 mmol, 17.6 mL) and K 2 C0 3 (55.7 g, 403 mmol) in MeCN (500 mL) was heated at 80 °C for 1 hr. The reaction mixture was filtered and concentrated to dryness. The residue was purified by silica gel column eluting with PE/EA (100/1 to 60/1) to give 3-benzyloxy-l-bromo-naphthalene (40.0 g, 128 mmol, 95 % yield).
• Step A fert-butyl 4-hydroxy-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine- 7- carboxylate: To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-l,4-dicarboxylate (50.0 g, 184 mmol) in MeOH (1.00 L) under nitrogen was added NaOMe (49.8 g, 921 mmol) and 2- methylisothiourea (62.4 g, 331 mmol, H2SO4). The reaction mixture was stirred at 25 °C for 16 hours.
• Step B fert-butyl 2-methylsulfanyl-4-(trifluoromethylsulfonyloxy)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine-7-carboxylate: To a solution of tert-butyl 4-hydroxy-2-methylsulfanyl- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (51.0 g, 171 mmol) in DCM (500 mL) was added DIEA (44.3 g, 343 mmol, 59.9 mL) and Tf 2 0 (72.6 g, 257 mmol, 42.4 mL) sequentially at 0 °C under nitrogen.
• Step C fert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-methylsulfanyl -6,8-dihydro- 5H-pyrido[3,4-d]pyrimidine-7-carboxylate: To a solution of tert-butyl 2-methylsulfanyl-4- (trifluoromethylsulfonyloxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (46.0 g, 107 mmolin DMF (500 mL) was added DIEA (27.7 g, 214 mmol, 37.4 mL) and benzyl piperazine-1 -carboxylate (25.9 g, 117 mmol, 22.7 mL).
• the reaction was heated to 100 °C for one hour under N2 atmosphere.
• the reaction mixture was poured into ethyl acetate (300 mL).
• the mixture was washed with H2O (300 mL x 3).
• the organic phase was washed with brine (200 mL), dried over anhydrous Na 2 S04, concentrated in vacuo.
• Step D Benzyl 4-(2-methylsulfanyl-5.6.7.8-tetrahvdropyrido[3.4-d1pyrimidin-4- yl)piperazine-l -carboxylate: To a solution of tert-butyl 4-(4-benzyloxycarbonylpiperazin-l- yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate (25.0 g, 50 mmol) in DCM (50 mL) was added TFA (85.6 g, 750 mmol, 55.6 mL). The mixture was stirred at 25 °C for 1 hour.
• Step E benzyl 4-r7-(3-benzyloxy-l-naphthvn-2-methylsulfanyl-6.8-dihvdro-5H- pyrido[3,4-d] pyrimidin-4-yl]piperazine-l -carboxylate: A mixture of 3-benzyloxy-l-bromo- naphthalene (16.3 g, 52.1 mmol) , benzyl 4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazine-l -carboxylate (16.0 g, 40.1 mmol), CS2CO3 (32.6 g, 100 mmol), Pd 2 (dba) 3 (5.50 g, 6.01 mmol) and RuPhos (3.74 g, 8.01 mmol) in dioxane (300 mL) was degassed with
• reaction mixture was quenched by addition water (200 mL) at 0 °C, and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
• Step F benzyl 4-[7-(3-benzyloxy-l-naphthvn-2-methylsulfinyl-6.8-dihvdro-5H- pyrido[3,4-d1pyrimidin-4-vHpiperazine-l-carboxylate: To a solution of benzyl 4-[7-(3- benzyloxy-l-naphthyl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]piperazine-l -carboxylate (8.00 g, 12.7 mmol) in DCM (200 mL) was added m-CPBA (2.73 g, 12.7 mmol, 80.0 % purity) at 0 °C under nitrogen atmosphere.
• reaction mixture was stirred for two hours under 0 °C.
• the reaction mixture was quenched by addition Na 2 S 2 03 (10 mL) at 0 °C, and then diluted with water (100 mL) and extracted with DCM (200 mL). The combined organic layers were washed with brine (200 mL), dried over Na 2 S04, filtered and concentrated under reduced pressure.
• Step A fert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-methylsulfonyl-6,8-dihvdro- 5H-pyrido[3,4-d1pyrimidine-7-carboxylate: To a stirred solution of ter/-butyl4-(4- benzyloxycarbonylpiperazin -l-yl)-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine- 7-carboxylate (14.4 g, 28.9 mmol) in DCM (150 mL) was added m-CPBA solid (17.4 g, 101 mmol) at 0 °C under nitrogen.
• reaction mixture was diluted with water (300 mL) and basified with saturated NaHCCb aqueous solution to pH ⁇ 8 and then extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
• Step A 4-bromo-5-methyl-l-tetrahydropyran-2-yl-indazole: To a mixture of 4-bromo-5- methyl-lH-indazole (3 g, 14.2 mmol) and 3,4-dihydro-2H-pyran (2.39 g, 28.4 mmol, 2.60 mL) in DCM (30 mL) was added TsOH*H 2 0 (270 mg, 1.42 mmol) and the mixture stirred at 15 °C for 2 hours.
• Step A ethyl 2-methyl-3-oxo-4-phenyl-butanoate.
• ethyl 3-oxo-4-phenyl-butanoate 4.00 g, 19.4 mmoL
• THF 50.0 mL
• sodium hydride 931 mg, 23.3 mmoi
• a solution of methyl iodide (3.03 g, 21.3) was next added drop-wise. After addition was completed, the reaction mixture was warmed to 20 °C and stirred for two hours at 20°C.
• reaction mixture was quenched by addition of water (10.0 mL) at 20 °C and then diluted with ethyl acetate (20.0 mL) and the layers separated. The aqueous layer was next extracted with ethyl acetate (20.0 mL ⁇ 3). The combined organic layers were washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
• Step B 2-methylnaphthalene-L3-diol.
• a solution of ethyl 2-methyl-3-oxo-4-phenyl- butanoate (3.60 g, 16.3 mmol) in concentrated sulfuric acid (19.9 g, 203 mmol) was stirred at 15 °C for 12 hours.
• the reaction mixture was poured into ice-water (30.0 mL) and the resulting solid collected by filtration and dried under vacuum to afford 2-methylnaphthalene-l,3-diol (1.80 g, 10.3 mmol, 63.2% yield) as a red solid.
• Step C 3-methoxy-2-methyl-naphthalen-l-ol.
• 2-methylnaphthalene-1.3-diol (1.70 g, 9.76 mmol) was added to HCl/MeOH (2 M, 35.0 mL) and the result mixture was stirred at 30 °C for 3 days. The reaction was concentrated in vacuo and the residue purified by Prep-TLC
• Step D (3-methoxy-2-methyl-l-naphthyl)trifluoromethanesulfonate.
• 3- methoxy-2-methyl-naphthalen-l-ol 800 mg, 4.25 mmol.
• pyridine 504 mg, 6.38 mmol
• DCM DCM
• trifluoroacetic anhydride 1.44 g, 5.10 mmol
• Step E l-bromo-3-methoxy-2-methyl-naphthalene : In a sealed tube was added (3- methoxy-2-methyl-l-naphthyl)trifluoromethanesulfonate (466 mg, 1.45 mmol), t-Bu-Brettphos (154 mg, 290 umol), potassium bromide (259 mg, 2.17 mmol), PEG-200 (175 mg), 2-butanone (157 mg, 2.17 mmol) and Pd 2 (dba) 3 (133 mg, 145 umol) in toluene (10.0 mL) and the mixture de-gassed with N2 for
• Step F 4-bromo-3-methyl-naphthalen-2-ol: To a solution of l-bromo-3-methoxy-2- methyl -naphthalene (580 mg, 2.31 mmol) and tetrabutylammonium iodide (2.13 g, 5.78 mmol) in DCM (11.0 mL) cooled to -78 °C was added a solution of BC1 3 (1 M, 5.78 mL) dropwise over a period of 10 minutes while under N 2 . The reaction mixture was warmed to 0 °C and stirred for 2 hours at room temperature.
• Step G 3-benzyloxy-l-bromo-2-methyl-naphthalene.
• acetonitrile 3.00 mL
• potassium carbonate 310 mg, 2.24 mmol
• Step A (4-bromo-2-naphthyl) 2,2-dimethylpropanoate.
• 4- bromonaphthalen-2-ol 10 g, 44.8 mmol
• TEA 9.07 g, 89.7 mmol
• DCM 200 mL
• 2,2-dimethylpropanoyl chloride 8.11 g, 67.2 mmol
• T reaction mixture was quenched by addition of water (50 mL) and the layers separated. The organic layer was washed with brine (30 mL), dried over Na 2 SC"4 filtered and concentrated under vacuum.
• Step A 7-benzyl-6.8-dihvdro-5H-pyrido[3.4- ⁇ /lpyrimidine-2.4-diol.
• EtOH 600 mL
• Na 5.56 g, 241 mmol
• ethyl l-benzyl-3-oxo-piperidine-4-carboxylate 30.0 g, 100 mmol
• urea 14.5 g, 242 mmol
• Step B 7-benzyl-2,4-dichloro-6,8-dihvdro-5H-pyrido[3,4-d1pyrimidine.
• DIEA 30.1 g, 233 mmol
• POCh 30.1 g, 2.15 mol
• 7-benzyl-6,8-dihydro-5H- pyrido[3,4-d] pyrimidine-2,4-diol 20.0 g, 77.7 mmol
• the reaction mixture was concentrated under vacuum.
• the residue was dissolved in DCM (400 mL) and poured into sat.
• Step C fert-butyl 4-(7-benzyl-2-chloro-6.8-dihvdro-5H-pyrido[3.4-d1pyrimidin-4-vn piperazine- 1 -carboxylate.
• Step D fert-Butyl 4-[7-benzyl-2-(3-morpholinopropoxy)-6.8-dihvdro-5H-pyrido[3.4- dlpyrimidin-4- ⁇ piperazine- 1 -carboxylate.
• Step E fert-butyl 4-[2-(3-morpholinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-tinpyrimidin- 4-yl] piperazine- 1 -carboxylate.
• tert-butyl 4-[7-benzyl-2-(3- morpholinopropoxy)- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (14 g, 25.3 mmol) in MeOH (1 L) was added dry Pd/C (3 g, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times.
• Step A 4-bromo-l-tetrahvdropyran-2-yl-5-(trifluoromethyl)indazole: To a solution of 4- bromo-5-(trifluoromethyl)-lH-indazole (500 mg, 1.89 mmol, 1 eq) in DCM (10 mL) was added 3,4-dihydro-2H-pyran (476 mg, 5.66 mmol, 517 uL, 3 eq) and TsOH H 2 0 (35.9 mg, 188 umol, 0.1 eq). The mixture was stirred at 15 °C for 1 hour. The mixture was concentrated.
• 8-bromo-6-(methoxymethoxy)quinoline A stirred suspension of 8-bromoquinolin-6-ol (1.00 g, 4.46 mmol) in DCM (20 mL) was cooled to 0°C and diisopropylethylamine (1.2 mL, 6.7 mmol, 1.5 eq.) was added followed by chloro(methoxy)methane (0.41 mL, 5.4 mmol, 1.2 eq.) dropwise and the reaction mixture was warmed to room temperature overnight.
• Step A tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-5,8-dihydropyrido[3,4- d1pyrimidine-7(6H)-carboxylate: In 2 mL of dimethyl acetamide were combined tert-butyl 4- chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.0 g, 3.7 mmol), triethylamine (1.0 mL, 7.4 mmol), and benzyl 1-piperazinecarboxylate (0.86 mL, 4.4 mmol).
• reaction vessel was sealed and the reaction mixture was heated to 90 °C with stirring. After 5 hours, the reaction was diluted with brine and extracted with methyl t-butyl ether. The combined organic layers were washed sequentially with saturated ammonium chloride and brine, dried over MgSC"4, and concentrated under reduced pressure to a thick oil.
• Step B Benzyl 4-(5,6,7,8-tetrahvdropyrido[3,4-d1pyrimidin-4-yl)piperazine-l- carboxylate: To a solution of tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.58 g, 3.484 mmol) in dichloromethane (11.61 mL, 3.484 mmol) was added trifluoroacetic acid (2.668 mL, 34.84 mmol) and the reaction was stirred at room temperature for 3 hours.
• Step C benzyl 4-(7-(3-(methoxymethoxy)naphthalen-l-vn-5.6.7.8-tetrahvdropyrido[3.4- dlpyrimidin-4-vDpiperazine-l-carboxylate: To a vial was added
• Step D 7-( 3 -( methoxymethoxy)naphthalen- 1 - ⁇ -4-C piperazin- 1 -vQ-5.6.7.8- tetrahydropyrido[3,4-d]pyrimidine: To a solution of benzyl 4-(7-(3 -
• Step E 1 -( 4-(7-(3-( methoxymethoxy)naphthalen- 1 -ylV 5.6.7.8-tetrahvdropyrido[3.4- d1pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one : To a suspension of 7-(3- (methoxymethoxy)naphthalen- 1 -yl)-4-(piperazin- 1 -yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidine (0.046 g, 0.11 mmol) in dichloromethane (1.1 mL, 0.11 mmol) at ambient temperature was added acryloyl chloride (1.2 mL, 0.12 mmol) (freshly prepared 0.1 M solution in dichloromethane) followed by triethylamine (0.032 mL, 0.23 mmol).
• Step F l-(4-(7-(3-hvdroxynaphthalen-l-vn-5.6.7.8-tetrahvdropyrido[3.4-d1pyrimidin-4- vDpiperazin- 1 -yl)prop-2-en- 1 -one : To a solution of l-(4-(7-(3-(methoxymethoxy)naphthalen-l- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one (0.034 g, 0.074 mmol) in ethyl acetate (0.74 mL, 0.074 mmol) was added hydrochloric acid (5 to 6 N solution in 2-propanol (0.44 mL, 2.2 mmol).
• Steps A-C benzyl 4-(7-(3-(methoxymethoxy)naphthalen-l-vn-6-methyl-5.6.7.8- tetrahvdropyrido[3,4-d1pyrimidin-4-yl)piperazine-l-carboxylate: Synthesized according to the method of Example 1, Steps A-C, using tert-butyl 4-chloro-6-methyl-5,8-dihydropyrido[3,4- d]pyrimidine-7(6H)-carboxylate in place of 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine- 7(6H)-carboxylate in Step A.
• Step Dl benzyl 4-(7-(3-hvdroxynaphthalen-l-vn-6-methyl-5.6.7.8- tetrahvdropyridor3,4-d1pyrimidin-4-yl)piperazine-l-carboxylate: To a solution of benzyl 4-(7- (3-(methoxymethoxy)naphthalen-l-yl)-6-methyl-5,6,7,8 etrahydropyrido[3,4-d]pyrimidin-4- yl)piperazine-l-carboxylate (0.05 g, 0.09 mmol) in isopropanol (10 mL) was added hydrogen chloride (5-6M in isopropanol) (0.02 mL, 0.09 mmol) and the reaction stirred at room temperature for 1 hour.
• Step D2 4-(7-(3-hydroxynaphthalen-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin-l-ol: Prepared according to the method of Example 1, Step D.
• Step E l-(4-(7-(3-hydroxynaphthalen-l-yl)-6-methyl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one: Prepared according to the method of
• Steps A-D benzyl 4-(7-(5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazol-4- yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate: Synthesized according to General Scheme 1, Steps A-C, using 4-bromo-5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-indazole in place of l-bromo-3- (methoxymethoxy)naphthalene in Step C [0294] Step Dl : benzyl 4-(7-(5-methyl-lH-indazol-4-vn-5.6.7.8-tetrahvdropyrido[3.4- dlpyrimidin-4-vDpiperazine-l-carboxylate: To a solution of benzyl 4-(7-(5
• Step D2 7-(5-methyl-lH-indazol-4-yl)-4-(piperazin-l-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidine: Prepared according to the method of Example 1, Step D.
• Step E l-(4-(7-(5-methyl-lH-indazol-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl)piperazin-l-yl)prop-2-en-l-one: Prepared according to the method of Example 1, Step E.
• Step A teit-butyl 4-(4-((benzyloxy)carbonvnpiperazin-l-vn-2-chloro-5.8- dihydropyridor3,4-d1pyrimidine-7(6H)-carboxylate: Benzyl 1-piperazinecarboxylate (1.268 mL, 6.575 mmol) and tert-Butyl 2,4-dichloro-5,6-dihydropyrido[3 4-d]pyrimidine-7(8H)- carboxylate (2 g, 6.575 mmol) were dissolved in dimethyl acetamide (10 mL) and treated with N-ethyl-N-isopropylpropan-2-amine (3.445 mL, 19.73 mmol).
• the reaction mixture was stirred at 85 °C for 2 hours.
• the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgS04, filtered and concentrated.
• the concentrate was purified by chromatography (CombiFlash®, 0%-50% ethyl acetate:Hexanes as the eluent to provide the product (2.69g, 83%).
• Step B tert-butyl (S)-4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-((l- (dimethylamino)propan-2-yl)oxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate: Tert-butyl 4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-chloro-5,8-dihydropyrido[3,4- d]pyrimidine-7(6H)-carboxylate (235 mg, 0.482 mmol), and (S)-l-(dimethylamino)propan-2-ol (497 mg, 4.82 mmol) were added to dioxane (0.5 mL) and heated to 100 °C for 3 days.
• Step C benzyl (S)-4-(2-((l-(dimethylamino)propan-2-yl)oxy)-5.6.7.8- tetrahvdropyridor3,4-d1pyrimidin-4-yl)piperazine-l-carboxylate: To a solution of tert-butyl (S)- 4-(4-((benzyloxy)carbonyl)piperazin-l-yl)-2-((l-(dimethylamino)propan-2-yl)oxy)-5,8- dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (200 mg, 0.3606 mmol) in dichloromethane (1202 ⁇ ., 0.3606 mmol) was added trifluoroacetic acid (828.3 ⁇ ., 10.82 mmol) and the reaction was stirred at room temperature for 3 hours.
• Step D benzyl (S)-4-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3- (methoxymethoxy)naphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-
• Step E (S)-2-((7-(3-(methoxymethoxy)naphthalen-l-yl)-4-(piperazin-l-yl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-2-yl)oxy)-N,N-dimethylpropan-l-amine: To a solution of benzyl (S)-4-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-l-yl)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate (68 mg, 0.11 mmol) in ethanol (1061 ⁇ ., 0.11 mmol) and tetrahydrofuran (1061 ⁇ ., 0.11 mmol) was added Palladium (113 mg, 0.053
• Step F (S)-l-(4-(2-((l-(dimethylamino)propan-2-yl)oxy)-7-(3-
• Step G l-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalen-l-yl)-5,6,7,8- tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one: (S)- 1 -(4-(2-((l - (dimethylamino)propan-2-yl)oxy)-7-(3-(methoxymethoxy)naphthalen-l-yl)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-l-yl)prop-2-en-l-one (51 mg, 0.091 mmol) was added to a vial containing 350 ⁇ _, of methanol and a few drops of tetrahydrofuran and the reaction vial was capped.
• Step A benzyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(l,l-dioxo-l,4-thiazinan-4- yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a mixture of benzyl 4-[7-(3-benzyloxy-l-naphthyl)-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate (300 mg, 463.12 ⁇ , 1.00 eq) and 2-(l,l-dioxo- l,4-thiazinan-4-yl)ethanol (166 mg, 926 ⁇ , 2.00 eq) in toluene (10.0 m
• Step B 4- ⁇ 2- ⁇ 2- ⁇ 1.1 -dioxo- 1.4-thiazinan-4-vnethoxy1-4-piperazin- 1 -yl-6.8-dihydro-5H- pyrido[3,4-d1pyrimidin-7-vHnaphthalen-2-ol: To a solution of benzyl 4-[7-(3-benzyloxy-l- naphthyl)-2-[2-(l,l-dioxo-l,44hiazinan-4-yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- 4-yl]piperazine-l-carboxylate (190 mg, 249 ⁇ , 1.00 eq) in MeOH (10.0 mL) was added Pd/C (100 mg) under N 2 .
• Step C l-[4-[2-[2-(l, l-dioxo-l,4-thiazinan-4-yl)ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a solution of 4-[2- [2-(l,l-dioxo-l,4-thiazinan-4-yl)ethoxy]-4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-7-yl]naphthalen-2-ol (90.0 mg, 167 ⁇ , 1.00 eq) and DIEA (64.8 mg, 501 ⁇ , 87.5 ⁇ , 3.00 eq) in DCM (2.00 mL) was added prop-2-enoyl prop-2-
• Step A benzyl 4-[2-[2-(4-acetylpiperazin-l-yl)ethoxy]-7-(3-benzyloxy-l-naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of l-[4-(2- hydroxyethyl)piperazin-l-yl]ethanone (277 mg, 1.61 mmol, 2.60 eq) in THF (8.00 mL) was added NaH (49.4 mg, 1.23 mmol, 60 % purity, 2.00 eq) at 0°C.The reaction mixture was stirred at 0 °C for 15 minutes.
• Step B l-[4-[2-[[7-(3-hydroxy-l-naphthyl)-4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-2-yl]oxy]ethyl]piperazin-l-yl]ethanone: To a solution of benzyl 4-[2-[2-(4- acetylpiperazin-l-yl)ethoxy]-7-(3-benzyloxy-l-naphthyl)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate (200 mg, 264 ⁇ , 1.00 eq) in THF (10.0 mL) was added Pd/C (100 mg, 10 % purity) under N 2 .
• Step C l-[4-[2-[2-(4-acetylpiperazin-l-yl)ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a solution of l-[4- [2-[[7-(3-hydroxy-l-naphthyl)-4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2- yl]oxy]ethyl]piperazin-l-yl]ethanone (80.0 mg, 150 ⁇ , 1.00 eq) and DIEA (58.3 mg, 451 ⁇ , 78.8 ⁇ L, 3.00 eq) in DCM (2.00 mL) was added prop-2-enoyl prop-2-
• reaction mixture was quenched with MeOH (1 mL) and diluted by DCM (20 mL) next washed with water (5 mL). The combined organic layers were washed with brine (5 mL), dried over Na 2 S0 4 and concentrated under vacuum.
• reaction mixture was purified by preparative HPLC : Phenomenex Gemini 150*25mm*, 10 ⁇ ; mobile phase: [water (0.05% ammonia hydroxide v/v) - ACN]; B%: 30%-55%, 10 min to give l-[4-[2-[2-(4-acetylpiperazin-l-yl)ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one (13.8 mg, 23.3 ⁇ , 15.5 % yield, 98.7 % purity) as a yellow solid.
• ESI MS m/z 586.3 [M+H] + .
• Step A 4-[7-(3-benzyloxy-5-cyclopropyl-phenyl)-2-(3- morpholinopropoxy)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a mixture of benzyl 4-[2- (3-mo holinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (400 mg, 805 ⁇ , 1.00 eq) and l-benzyloxy-3-bromo-5-cyclopropyl-benzene (268 mg, 886 ⁇ mol, 1.10 eq) in toluene (10.0 mL) was added 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (RuPhos) (75.2 mg, 161 ⁇ ,
• Step B 3-cvclopropyl-5-[2-(3-morpholinopropoxy)-4- piperazin-l-yl-6,8-dihydro-5H- pyrido[3,4-d1pyrimidin-7-yl]phenol
• benzyl 4-[7-(3-benzyloxy-5-cyclopropyl- phenyl)-2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l- carboxylate (150 mg, 209 ⁇ , 1.00 eq) in MeOH (10.0 mL) was added Pd/C (150 mg, 10 % purity) and CH3COOH (25.1 mg, 417.3 ⁇ , 23.9 ⁇ ⁇ , 2.00 eq).
• Step C l-[4-[7-(3-cyclopropyl-5-hydroxy-phenyl) -2-(3-mo holinopropoxy)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one
• Step A benzyl 4-[7-(3-methoxy-6-methyl-l-naphthyl)-2- (3-mo ⁇ holinopropoxy)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: A mixture of benzyl 4-[2-(3- mo holinopropoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (500 mg, 1.01 mmol, 1.00 eq), (3-methoxy-6-methyl-l-naphthyl)trifluoromethanesulfonate (483 mg, 1.51 mmol, 1.50 eq), CS2CO3 (820 mg, 2.52 mmol, 2.50 eq), 2-dicyclohexylphosphino- 2',6'-diisoprop
• Step B 4-r3-r[7-(3-methoxy-6-methyl-l-naphthvn-4-piperazin-l-yl-6.8-dihvdro-5H- pyrido[3,4-d1pyrimidin-2-yl1oxy1propyl1mo ⁇ holine: To a solution of benzyl 4-[7-(3-methoxy- 6-methyl-l-naphthyl) -2-(3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]piperazine-l-carboxylate (370 mg, 554 ⁇ , 1.00 eq) in MeOH (10.0 mL) was added Pd-C (100 mg, 10 % purity) and AcOH (66.6 mg, 1.11 mmol, 2.00 eq) under N 2 .
• Step C l-[4-[7-(3-methoxy-6-methyl-l-naphthyl)-2-(3-morpholinopropoxy) -6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a mixture of prop- 2-enoyl prop-2-enoate (56.8 mg, 450 ⁇ , 0.80 eq) and DIEA (727 mg, 5.63 mmol, 983 ⁇ ,, 10.0 eq) in DCM (2.00 mL) was added a solution of 4-[3-[[7-(3-methoxy-6-methyl-l-naphthyl)- 4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]propyl]morpholine (300 mg, 563 ⁇ ,
• Step D l-[4-[7-(3-hydroxy-6-methyl-l-naphthyl) -2-(3-morpholinopropoxy)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a solution of l-[4- [7-(3-methoxy-6-methyl-l-naphthyl)-2- (3-morpholinopropoxy)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one (100 mg, 170 ⁇ , 1.00 eq) in DCM (3.00 mL) was added BBn (213 mg, 852 ⁇ , 82.1 ⁇ ⁇ , 5.00 eq) at -78 °C.
• the mixture was stirred at 0 °C for 1 hour.
• the mixture was cooled to -78 °C and diluted with DCM (20.0 mL), quenched by addition of saturated sodium bicarbonate solution (5.00 mL) and stirred at -78 °C for 10 mins, then warmed to 0 °C.
• the mixture was extracted with DCM (2 x 15.0 mL), washed with brine (1 ⁇ 20.0 mL), dried over Na 2 S0 4 , filtered and concentrated under vacuum.
• Step A benzyl 4-[7-[5-methyl-l-(2-trimethylsilylethoxymethyl)indazol-4-yl]- 2-(3- mo holinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: A mixture of benzyl 4-[2-(3-mo holinopropoxy)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4- yl]piperazine-l-carboxylate (500 mg, 1.01 mmol, 1.00 eq), 2-[(4-bromo-5-methyl-indazol-l- yl)methoxy] ethyl-trimethylsilane (448 mg, 1.31 mmol, 1.30 eq), CS2CO3 (822 mg, 2.53 mmol, 2.50 eq), Pd 2 (d
• reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 ⁇ 100 mL). The combined organic layers were washed with brine (3 ⁇ 50.0 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure.
• Step B fert-butyl 4-[7-[5-methyl-l-(2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3- mo holinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of benzyl 4-[7-[5-methyl-l-(2-trimethylsilylethoxymethyl) indazol-4-yl]-2-(3- mo holinopropoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (370 mg, 488 ⁇ , 1.00 eq) in MeOH (10.0 mL) was added triethylamine (98.9 mg, 977 ⁇ , 135 ⁇ L, 2.00 eq), Pd/C(100 mg, 10
• Step C 4 3 [7-(5-methyl-lH-indazol-4-vn -4-piperazin-l-yl-6.8-dihydro-5H- pyrido[3,4-d1pyrimidin-2-yl1oxy1propyHmorpholine trifluoroacetate : To a solution of tert-butyl 4-[7-[5-methyl-l- (2-trimethylsilylethoxymethyl)indazol-4-yl]-2-(3-mo holinopropoxy)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (150 mg, 207 ⁇ , 1.00 eq) in DCM (500 ⁇ ) was added TFA (354 mg, 3.11 mmol, 230 ⁇ ., 15.0 eq).
• Step D l-[4-[7-(5-methyl-lH-indazol-4-yl) -2-(3-morpholinopropoxy)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one : To a mixture of 4-[3-[[7-(5- methyl-lH-indazol-4-yl)-4-piperazin -l-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2- yl]oxy]propyl]morpholine trifluoroacetate (120 mg, 197 ⁇ , 1.00 eq, TFA) and DIEA (255 mg, 1.98 mmol, 345 ⁇ ⁇ , 10.0 eq) in dichloromethane (2.00 mL) was added a solution of prop-2- enoyl prop-2-
• Step A fert-butyl 3-(7-benzyl-2-chloro-6.8-dihvdro-5H-pyrido[3.4-d]pyrimidin-4-vn- 3 , 8 -di azabi cycl o [3.2.11 octane- 8 -carb oxyl ate : To a mixture of 7-benzyl-2,4-dichloro-6,8- dihydro-5H-pyrido[3,4-d]pyrimidine (920 mg, 3.13 mmol, 1.00 eq) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (677 mg, 3.19 mmol, 1.02 eq) in DMSO (18.0 mL) was added DIEA (1.21 g, 9.39 mmol, 1.64 mL, 3.00 eq).
• reaction mixture was stirred at 60 °C for 1 hour.
• the mixture was diluted with extracted with EtOAc (3 x 20 mL), washed with water (10 mL), IN HC1 (5 mL), NaHCCb (15 mL), and brine (15 mL).
• Step B fert-butyl 3-[7-benzyl-2-[2-(dimethylamino)-l-methyl-ethoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of 1- (dimethylamino)propan-2-ol (857 mg, 8.31 mmol, 942 ⁇ , 3.00 eq) in THF (40.0 mL) was added NaH (222 mg, 5.54 mmol, 60.0 % purity, 2.00 eq) at 15 °C under N2.
• Step C fert-butyl 3-[2-[2-(dimethylamino)-l-methyl-ethoxy]-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate : To a solution of tert-butyl 3-[7-benzyl-2-[2-(dimethylamino)-l-methyl-ethoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (700 mg, 1.30 mmol, 1.00 eq) in MeOH (30.0 mL) was added Pd/C (200 mg) under N2.
• Step D fert-butyl 3-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)-l-methyl- ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8- carboxylate: Pd 2 (dba) 3 (84.1 mg, 91.8 ⁇ , 0.10 eq) was added to a solution of tert-butyl 3-[2- [2-(dimethylamino)-l-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (410 mg, 918 ⁇ , 1.00 eq), 3-benzyloxy-l-bromo- n
• reaction mixture was stirred at 100 °C for 7 hours under N2 and then concentrated under vacuum.
• the residue was diluted with water (5 mL) and extracted with DCM (2 x 20 mL). The organic layers were dried over Na 2 S04, filtered and concentrated under vacuum.
• Step E tert-butyl 3-[2-[2-(dimethylamino)-l-methyl-ethoxy]-7-(3-hydroxy-l-naphthyl)- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of tert-butyl 3-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)-l-methyl-ethoxy]- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (340 mg, 501 ⁇ , 1.00 eq) in MeOH (6.80 mL) was added Pd/C (120 mg).
• Step F 4-[4-(3,8-diazabicyclo[3.2. l]octan-3-yl)-2-[2-(dimethylamino)-l-methyl-ethoxy]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol trifluoroacetate : To a solution of tert- butyl 3-[2-[2-(dimethylamino)-l-methyl-ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (180 mg, 306 ⁇ , 1.00 eq) in DCM (230 iV) was added TFA (349 mg, 3.06 mmol, 226 ⁇ , 10.0 eq).
• Step G l-[3-[2-[2-(dimethylamino)-l-methyl-ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]prop-2-en-l-one: To a solution of 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[2-(dimethylamino)-l-methyl- ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol trifluoroacetate (149 mg, 306 ⁇ , 1.00 eq) and DIE A (1.36 g, 10.5 mmol, 1.84 mL, 34.5 eq) in DCM (1
• Step A ethyl 2-(benzylamino)propanoate: To a solution of ethyl 2-bromopropanoate (30.0 g, 165 mmol, 21.6 mL, 1.00 eq), Bn H 2 (23.1 g, 215 mmol, 23.6 mL, 1.30 eq) in MeCN (600 mL) was added K 2 C0 3 (45.8 g, 331 mmol, 2.00 eq). The mixture was stirred at 80 °C for 2 hour. The reaction mixture was filtered and the filter cake was washed with DCM (300 mL). The filtrated was concentrated under vacuum.
• Step B ethyl 4-[benzyl-(2-ethoxy- 1 -methyl-2-oxo-ethvDaminolbutanoate: To a solution of ethyl 2-(benzylamino)propanoate (31.0 g, 150 mmol, 1.00 eq) and ethyl 4-bromobutanoate (87.5 g, 449 mmol, 64.4 mL, 3.00 eq) in MeCN (600 mL) and water (60.0 mL) was added Cs 2 C0 3 (97.5 g, 299.12 mmol, 2.00 eq) and KI (4.97 g, 29.9 mmol, 0.20 eq).
• the reaction mixture was stirred at 80-90 °C for 40 hours.
• the reaction mixture was filtered and the filter cake was washed with DCM (2 ⁇ 100 mL).
• the filtrate was concentrated under vacuum.
• the residue was dissolved in DCM (300 mL) and washed with brine (80 mL), dried over Na 2 S0 4 and concentrated under vacuum.
• Step C ethyl l-benzyl-2-methyl-3-oxo-piperidine-4-carboxylate: To a solution of ethyl 4-[benzyl-(2-ethoxy-l-methyl-2-oxo-ethyl)amino]butanoate (28.0 g, 87.1 mmol, 1.00 eq) in THF (600 mL) was added tBuOK (19.6 g, 174 mmol, 2.00 eq). The reaction mixture was stirred at 18 °C for 1 hour. The reaction mixture was quenched with water (100 mL) and extracted with MTBE (3 x 300mL) and DCM (2 200 mL).
• Step D 7-benzyl-8-methyl-6.8-dihvdro-5H-pyrido[3.4-d1pyrimidine-2.4-diol: To EtOH (400 mL) was added Na (3.76 g, 163 mmol, 3.88 mL, 2.50 eq). The reaction mixture was stirred at 20 °C for 0.5 hour.
• Step E benzyl-2,4-dichloro-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: A mixture of 7-benzyl-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (5.00 g, 18.4 mmol, 1.00 eq) in POCh (305 g, 1.99 mol, 185 mL, 108 eq) was heated to 110 °C for 12 hours. The solvent was removed under vacuum. The residue was dissolved in DCM (500 mL) and poured into saturated NaHCCb (200 mL) while keeping the pH greater than 7.
• Step F 4-(7-benzyl-2-chloro-8-methyl-6.8-dihvdro-5H-pyrido[3.4-d]pyrimidin-4- yl)piperazine-l-carboxylate: To a solution of 7-benzyl-2,4-dichloro-8-methyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine (3.00 g, 9.73 mmol, 1.00 eq) and DIEA (2.52 g, 19.5 mmol, 3.40 mL, 2.00 eq) in dioxane (60.0 mL) was added tert-butyl piperazine-l-carboxylate (1.90 g, 10.2 mmol, 1.05 eq).
• Step G tert-butyl-4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of 2- (dimethylamino)ethanol (583 mg, 6.54 mmol, 655 ⁇ ⁇ , 3.00 eq) in toluene (20.0 mL) was added Pd(OAc) 2 (48.9 mg, 218 ⁇ , 0.10 eq), tert-butyl-4-(7-benzyl-2-chloro-8-methyl-6,8-dihydro- 5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-l-carboxylate (1.00 g, 2.18 mmol, 1.00 eq), CS2CO3 (2.13 g, 6.54 mmol
• reaction mixture was stirred at 110 °C for 3 hours under N2.
• the reaction mixture was concentrated under vacuum.
• the residue was dissolved in water (10 mL) and extracted with DCM (3 ⁇ 40 mL). The combined organic layers were washed with brine, dried over Na 2 S04 and concentrated under vacuum.
• Step H tert-butyl 4-[2-[2-(dimethylamino)ethoxy1-8-methyl-5.6.7.8- tetrahvdropyrido[3.4-d1pyrimidin-4-vHpiperazine-l-carboxylate :To a solution of tert-butyl 4- [7-benzyl-2-[2-(dimethylamino)ethoxy]-8-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]piperazine-l-carboxylate (800 mg, 1.57 mmol, 1.00 eq) in MeOH (20.0 mL) was added Pd/C (100 mg) under N2.
• Step I tert-butyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy]-8-methyl- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a mixture of tert- butyl 4-[2-[2-(dimethylamino)ethoxy]-8-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl]piperazine-l-carboxylate (380 mg, 904 ⁇ , 1.00 eq) and 3-benzyloxy-l-bromo- naphthalene (311 mg, 994 ⁇ , 1.10 eq) in dioxane (8.00 mL), CS2CO3 (883 mg, 2.71 mmol, 3.00 eq) and 2-dicyclo
• the reaction mixture was stirred at 90 °C for 12 h under N2. The reaction mixture was concentrated under vacuum. The residue was partitioned between DCM (50 mL) and water (20 mL). The reaction mixture was extracted with DCM (50 mL). The combined organic layers were washed with brine (10 mL), dried over Na 2 S04 and concentrated under vacuum.
• Step J 4-[2-[2-(dimethylamino)ethoxy1-8-methyl-4-piperazin-l-yl-6.8-dihvdro-5H- pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol bis-trifluoroacetate:To a solution of tert-butyl 4- [2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-8-methyl-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate (100 mg, 177 ⁇ , 1.00 eq) in DCM (130.00 ⁇ L) was added TFA (202 mg, 1.78 mmol, 132 ⁇ L, 10.00 eq).
• reaction mixture was stirred at 20 °C for 1 hour.
• the solvent was removed under vacuum to provide 4-[2-[2- (dimethylamino)ethoxy]-8-methyl-4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7- yl]naphthalen-2-ol bis-trifluoroacetate (175.00 mg) as a brown oil which was used in the next step without further purification.
• Step K l-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-8-methyl-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a solution of 4-[2- [2-(dimethylamino)ethoxy]-8-methyl-4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- 7-yl]naphthalen-2-ol bis-trifluoroacetate (97.4 mg, 141 ⁇ , 1.00 eq) in DCM (500.00 ⁇ ) was added DIEA (222 mg, 1.72 mmol, 300 ⁇ , 12.2 eq) and prop-2-enoyl prop-2-enoate (14.2 mg, 113 ⁇ , 0.80 eq
• Step A ethyl 4-[benzyl-(2-ethoxy-2-oxo-ethyl)amino]pentanoate: A solution of ethyl 4- oxopentanoate (47.0 g, 326 mmol, 46.5 mL, 1.50 eq), ethyl 2-(benzylamino)acetate (42.0 g, 217.3 mmol, 1.00 eq) and AcOH (13.0 g, 217 mmol, 12.4 mL, 1.00 eq) in DCM (800 mL) was stirred at 12-18 °C for 30 min, then cooled at 0-5 °C, NaBH(OAc) 3 (138 g, 652 mmol, 3.00 eq) was added portion-wise.
• ethyl 4- oxopentanoate (47.0 g, 326 mmol, 46.5 mL, 1.50 eq)
• Step B ethyl l-benzyl-2-methyl-5-oxo-piperidine-4-carboxylate: A solution of ethyl 4- [benzyl-(2-ethoxy-2-oxo-ethyl)amino]pentanoate (37.00 g, 115.12 mmol, 1.00 eq) and t-BuOK (16.8 g, 150 mmol, 1.30 eq) in toluene (30.0 mL) was stirred at 25 °C for 5 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2 x 30 mL).
• Step C 7-benzyl-6-methyl-6.8-dihvdro-5H-pyrido[3.4-d1pyrimidine-2.4-diol: Na (3.05 g, 133 mmol, 3.14 mL, 2.50 eq) was dissolved in EtOH (280 mL), and then ethyl l-benzyl-2- methyl-5-oxo-piperidine-4-carboxylate (14.6 g, 53.0 mmol, 1.00 eq) and urea (7.96 g, 133 mmol, 7.11 mL, 2.50 eq) were added. The reaction mixture was heated to reflux (78 °C) for 16 hrs under N 2 .
• reaction mixture was concentrated to dryness.
• the residue was dissolved in water (100 mL), washed with MTBE (100 mL).
• the pH of the water phase was adjusted to pH 6-7 with 6N HC1 (2 mL).
• the resulting solid was collected by filtration and dried under vacuum at 60 °C to provide 7-benzyl-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-2,4-diol (5.00 g, 17.1 mmol, 32.3 % yield, 93 % purity) as light yellow solid.
• Step D 7-benzyl-2.4-dichloro-6-methyl-6.8-dihvdro-5H-pyrido[3.4-d]pyrimidine: POCh (49.5 g, 323 mmol, 30.0 mL, 58.4 eq) and 7-benzyl-6-methyl-6,8-dihydro-5H-pyrido[3,4- d]pyrimidine-2,4-diol (1.50 g, 5.53 mmol, 1.00 eq) were heated to 100 °C under reflux for 12 hours. The reaction was concentrated to dryness to remove POCh.
• Step E 4-(7-benzyl-2-chloro-6-methyl-6,8-dihvdro-5H-pyrido[3,4-d1pyrimidin-4- vDpiperazine-l-carboxylate :To a mixture of 7-benzyl-2,4-dichloro-6-methyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine (2.50 g, 8.11 mmol, 1.00 eq) and tert-butyl piperazine-l-carboxylate (1.54 g, 8.27 mmol, 1.02 eq) in dioxane (50.0 mL) was added DIEA (3.14 g, 24.3 mmol, 4.25 mL, 3.00 eq).
• Step F fert-butyl 4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of 2- (dimethylamino)ethanol (701 mg, 7.86 mmol, 788 ⁇ ⁇ , 3.00 eq) in THF (45.0 mL) was added NaH (210 mg, 5.24 mmol, 60.0 % purity, 2.00 eq) at 15 °C under N 2 .
• Step G fert-butyl 4-[2-[2-(dimethylamino)ethoxy1-6-methyl-5.6.7.8- tetrahydropyrido[3.4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of tert-butyl 4- [7-benzyl-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]piperazine-l-carboxylate (1.50 g, 2.94 mmol, 1.00 eq) in MeOH (80.0 mL) was added Pd/C (450 mg) under N 2 .
• Step H fert-butyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy]-6- methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: Pd 2 (dba) 3 (109 mg, 119 ⁇ , 0.10 eq) was added to a solution of tert-butyl 4-[2-[2-(dimethylamino)ethoxy]-6- methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (500 mg, 1.19 mmol, 1.00 eq), 3-benzyloxy-l-bromo-naphthalene (410 mg, 1.31 mmol, 1.10 eq), 2- dicyclohexylphosphin
• the reaction mixture was stirred at 90 °C for 12 hours under N2. The mixture was concentrated under vacuum. The residue was diluted with water (5 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na 2 S04, filtered and concentrated under vacuum.
• Step I tert-butyl 4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6-methyl- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: To a solution of tert- butyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy]-6-methyl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (340 mg, 521 ⁇ , 1.00 eq) in MeOH (6.80 mL) was added Pd/C (120 mg) under N2.
• Step J 4-[2-[2-(dimethylamino)ethoxy]-6-methyl-4-piperazin-l-yl-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-7-yl]naphthalen-2-ol trifluoroacetate : To a solution of tert-butyl 4-[2- [2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6-methyl-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate (180 mg, 320 ⁇ , 1.00 eq) in DCM (240 ⁇ L) was added TFA (365 mg, 3.20 mmol, 237 ⁇ L, 10.0 eq).
• Step K l-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6-methyl-6,8-dihydro- 5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a solution of 4-[2-[2- (dimethylamino)ethoxy]-6-methyl-4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- yl]naphthalen-2-ol trifluoroacetate (148 mg, 320 ⁇ , 1.00 eq) and DIEA (494 mg, 3.83 mmol, 668 ⁇ ., 12.0 eq) in DCM (500 ⁇ .) was added prop-2-enoyl prop-2-enoate (32.3 mg, 256 ⁇ , 0.80 eq) dropwise at
• Step A tert-butyl 4-(4-benzyloxycarbonylpiperazin-l-yl)-2-[2-(3-fluoropyrrolidin-l- yl)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate :A mixture of 2-(3- fluoropyrrolidin-l-yl)ethanol (401 mg, 3.01 mmol, 1.60 eq), tert-butyl 4-(4- benzyloxycarbonylpiperazin-l-yl)-2-methylsulfonyl- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidine- 7-carboxylate (1.00 g, 1.88 mmol, 1.00 eq), CS2CO3 (1.84 g, 5.64 mmol, 3.00 eq), Pd(OAc) 2 (42.2 mg, 188 ⁇ , 0.10
• Step B benzyl 4-r2-r2-(3-fluoropyiTolidin-l-vnethoxy1-5.6.7.8-tetrahvdropyrido ⁇ 3.4- dlpyrimidin-4-vHpiperazine-l-carboxylate: To a solution of tert-butyl 4-(4- benzyloxycarbonylpiperazin-1- yl)-2-[2-(3-fluoropyrrolidin-l-yl)ethoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidine-7-carboxylate (1.20 g, 2.05 mmol, 1.00 eq) in DCM (10.00 mL) was added TFA (3.51 g, 30.8 mmol, 2.28 mL, 15.00 eq) at 0 °C.
• the mixture was warmed to 25 °C and stirred for 16 hours.
• the mixture was diluted with water (100 mL) and the solution was extracted with ethyl acetate (2 ⁇ 100 mL).
• the water layer was basified with saturated aqueous sodium carbonate solution (50 mL) and then extracted with ethyl acetate (2 x 100 mL).
• the combined organic layers were washed with brine (1 ⁇ 100 mL), dried over sodium sulfate, and filtered.
• Step C benzyl 4-[2-[2-(3-fluoropyrrolidin-l-yl)ethoxy]-7-(3-methoxy-l-naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate: A mixture of benzyl 4-[2-[2- (3-fluoropyrrolidin-l-yl)ethoxy]- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l- carboxylate (750 mg, 1.55 mmol, 1.00 eq), (3-methoxy-l-naphthyl) trifluoromethanesulfonate (949 mg, 3.10 mmol, 2.00 eq), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuP
• Step D 2- [2-(3 -fluoropy rrolidin- 1 -yPethoxy ]-7-(3 -methoxy- 1 -naphthyl)-4-piperazin- 1 - yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: A mixture of benzyl 4-[2-[2-(3-fluoropyrrolidin-l- yl)ethoxy]-7- (3 -methoxy- l-naphthyl)-6, 8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine- 1-carboxylate (700.00 mg, 1.09 mmol, 1.00 eq) in MeOH was hydrogenated (15 psi) at 40 °C with dry Pd/C (140 mg,) as a catalyst for 4 hours.
• the catalyst was filtered through a Celite® pelt and the filtrate was concentrated under vacuum to provide 2-[2-(3-fluoropyrrolidin-l- yl)ethoxy]-7-(3-methoxy-l-naphthyl)-4-piperazin-l-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (500 mg, 987 ⁇ , 90.6 % yield) as a brown solid.
• Step E l-[4-[2-[2-(3-fluoropyrrolidin-l-yl)ethoxy]-7-(3-methoxy-l-naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a mixture of 2-[2- (3 -fluoropyrrolidin- 1 -yl)ethoxy]-7- (3 -methoxy- 1 -naphthyl)-4-piperazin- 1 -yl-6, 8-dihydro-5H- pyrido[3,4-d]pyrimidine (500 mg, 987 ⁇ , 1.00 eq) and DIEA (255 mg, 1.97 mmol, 345 ⁇ , 2.00 eq) in dichloromethane (8 mL) was added a solution of prop-2-enoyl prop-2-en
• the mixture was warmed to 25 °C and stirred for 1 hour.
• the mixture was diluted with water (20 mL) and dichloromethane (30 mL).
• the separated organic layer was washed with brine (1 x 30 mL), dried over magnesium sulfate, filtered and concentrated under vacuum.
• the residue was purified by column chromatography over silica gel (dichloromethane/methanol 100/1 to 10/1).
• Step F l-[4-[2-[2-(3-fluoropyrrolidin-l-yl)ethoxy]-7- (3-hydroxy-l-naphthyl)-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one: To a solution of l-[4- [2-[2-(3-fluoropyrrolidin-l-yl) ethoxy]-7-(3 -methoxy- l-naphthyl)-6,8-dihydro-5H-pyrido[3, 4- d]pyrimidin-4-yl]piperazin-l-yl]prop-2-en-l-one (400 mg, 713 ⁇ , 1.00 eq) in DCM (2.00 mL) was added BBn (1.30 g, 5.19 mmol, 500 ⁇ ⁇ , 7.27 eq
• the mixture was warmed to 0 °C and stirred for 1 hour.
• the mixture was diluted with dichloromethane (20 mL), and then quenched with saturated aqueous sodium bicarbonate solution (20 mL).
• the separated organic layer was washed with brine (1 x 10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by
• Step A 1-tert-butyl 2-methyl4-(7-benzyl-2-chloro-6.8-dihvdro-5H-pyrido[3.4- dlpyrimidin -4-yl)piperazine- 1 ,2-dicarboxylate :To a solution of 7-benzyl-2,4-dichloro-6,8- dihydro-5H-pyrido[3,4-d] pyrimidine (2.00 g, 6.80 mmol, 1.00 eq) in DMSO (40.0 mL) was added DIEA (1.76 g, 13.6 mmol, 2.38 mL, 2.00 eq) and 1-tert-butyl 2-methylpiperazine-l,2- dicarboxylate (1.74 g, 7.14 mmol, 1.05 eq).
• the mixture was stirred at 55 °C for 16 hours.
• the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL).
• the combined organic layers were washed with brine (3 ⁇ 100 mL), dried over Na 2 S04, filtered and concentrated to dryness.
• Step B 1-tert-butyl 2-methyl4-[7-benzyl-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H- pyrido[3,4-d] pyrimidin-4-yl]piperazine-l,2-dicarboxylate: A mixture of 1-tert-butyl 2-methyl- 4-(7-benzyl-2-chloro-6,8-dihydro -5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-l,2- dicarboxylate (3.00 g, 5.98 mmol, 1.00 eq), 2-(dimethylamino)ethanol (1.07 g, 12.0 mmol, 1.20 mL, 2.00 eq), CS2CO3 (4.87 g, 15.0 mmol, 2.50 eq), Pd(OAc) 2 (201 mg, 897 ⁇ , 0.15 eq) and BINAP (744 mg,
• reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic layers were washed with brine (3 ⁇ 50 mL), dried over Na 2 S0 4 , filtered and concentrated to dryness.
• Step C 1-tert-butyl 2-methyl4-[2- [2-(dimethylamino)ethoxy1-5.6J.8- tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-L2-dicarboxylate:To a solution of 1-tert- butyl 2-methyl-4-[7-benzyl-2-[2-(dimethyl amino)ethoxy]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazine-l,2-dicarboxylate (2.33 g, 4.20 mmol, 1.00 eq) in MeOH (50.0 mL) was added Pd/C (233 mg) under N 2 .
• Step D l-tert-butyl2-methyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2- (dimethylamino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l,2- dicarboxylate: A mixture of l-tert-butyl-2-methyl4-[2-[2-(dimethylamino)ethoxy] -5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l,2-dicarboxylate (1.50 g, crude), 3- benzyloxy- 1-bromo-naphthalene (1.49 g, 4.76 mmol, 1.30 eq), CS2CO3 (2.98 g, 9.15 mmol, 2.50 eq), Pc (dba)3 (503 mg, 549
• reaction mixture was quenched by adding water (50 mL) at 0 °C, and extracted with DCM (3 ⁇ 100 mL). The combined organic layers were washed with brine (3 ⁇ 150 mL), dried over Na 2 S04, filtered and concentrated under reduced pressure to dryness.
• Step E methyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-di hydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-2-carboxylate: To a solution of 1-tert-butyl 2- methyl4-[7-(3-benzyloxy-l -naphthyl) -2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazine-l,2-dicarboxylate (1.32 g, 1.89 mmol, 1.00 eq) in DCM (20.0 mL) was added TFA (4.31 g, 37.8 mmol, 2.80 mL, 20.0 eq) at 0 °C and the reaction mixture was stirred for 2 hours
• Step F ⁇ 4- ⁇ 7- ⁇ 3 -benzyloxy- 1 -naphthyl)-2-[2-( dimethylamino)ethoxy1-6.8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]methanol: A mixture of methyl-4-[7-(3-benzyloxy- l-naphthyl)-2-[2-(dimethyl amino)ethoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]piperazine-2-carboxylate (400 mg, 0.670 mmol) in THF (5.00 mL) was added LiAlFL (102 mg, 2.68 mmol, 4.00 eq) at 0 °C.
• reaction mixture was degassed and purged with nitrogen 3 times, and stirred at 0 °C for 2 hours under a nitrogen atmosphere.
• the reaction mixture was quenched by addition of NaiSO 10 H 2 0 (0.5 g) at 0 °C, and then diluted with DCM (50 mL).
• Step G 2-[[7-(3-benzyloxy-l-naphthyl)-4-[3-[[tert-butyl(dimethyl)silyl]oxymethyl] piperazin-l-yl]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl]oxy]-N,N-dimethyl-ethanamine: To a stirred solution of [4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethyl amino)ethoxy]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]methanol (250 mg, 440 ⁇ , 1.00 eq) and NaH (176 mg, 4.40 mmol, 60.0 % purity, 10.0 eq) in THF (10.0 mL) was added tert- butyldimethylsilyl
• the mixture was stirred at 25 °C for 12 hours under a nitrogen atmosphere.
• the reaction mixture was quenched by addition of water (25 mL) at 0 °C and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (3 ⁇ 30 mL), dried over Na 2 S0 4 , filtered and
• Step H l-[4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino) ethoxy]-6,8-dihydro- 5H-pyrido[3,4-d]pyrimidin-4-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-l-yl]prop-2- en-l-one; To a solution of 2-[[7-(3-benzyloxy-l-naphthyl)-4-[3-[[tert-butyl
• Step I l-[4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-2-(hydroxymethyl)piperazin-l-yl]prop-2-en-l-one: A mixture of l-[4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino) ethoxy]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]-2-[[tert-butyl(dimethyl)silyl]oxymethyl]piperazin-l-yl]prop-2-en-l-one (92.0 mg, 125 ⁇ , 1.00 eq) in DCM (8.00 mL) was added BBr 3 (17.0 mg, 67.8
• Step A 4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-l-tert-butoxycarbonyl-piperazine-2-carboxylic acid: To a solution of 1-tert-butyl 2-methyl 4-[7-(3-benzyloxy-l-naphthyl) -2-[2-(dimethylamino)ethoxy]-6,8- dihydro-5H-pyrido[3,
• Step B tert-butyl4-[7-(3-benzyloxy-l-naphthyl)-2-[2-(dimethylamino)ethoxy]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-l-carboxylate
• N-methylmethanamine 130 mg, 1.59 mmol, 146 ⁇ L, HC1 was added in one portion.
• the reaction mixture was degassed and purged with nitrogen 3 times. After stirring at 25 °C for 12 hours under a nitrogen atmosphere, the reaction mixture was diluted with water (50 mL) at 0 °C and extracted with DCM (3 x 50 mL).
• Step C tert-butyl 4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8- dihydro-5H-pyrido [3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-l-carboxylate: To a solution of tert-butyl 4-[7-(3-benzyloxy-l-naphthyl)-2-[2- (dimethylamino)ethoxy]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-l-carboxylate (345 mg, 486 ⁇ , 1.00 eq) in MeOH (5.00 mL) was added Pd/C (80.0 mg) under N 2 .
• Step D 4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-piperazine-2-carboxamide: A mixture of tert-butyl 4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]-2-(dimethylcarbamoyl)piperazine-l-carboxylate (197 mg, crude) in DCM (5.00 mL) was added HCl/dioxane (4 M, 1.61 mL) at 0 °C.
• reaction mixture was degassed and purged with nitrogen 3 times and stirred at 25 °C for 2 hours under a nitrogen atmosphere.
• the reaction mixture was concentrated under reduced pressure to dryness.
• the residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25*, 10 ⁇ ; mobile phase: [water (0.05 % HC1) - ACN]; B %: 10 % - 30 %, 7.8 min).
• Step E 4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-l-prop-2-enoyl-piperazine-2-carboxamide: To a solution of 4-[2-[2-(dimethylamino)ethoxy]-7-(3-hydroxy-l-naphthyl)-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-N,N-dimethyl-piperazine-2-carboxamide (70.0 mg, 135 ⁇ , 1.00 eq) in DMAC (500 ⁇ ) was added triethylamine (40.9 mg, 404 ⁇ , 56.0 ⁇ , 3.00 eq) at 0 °C and then prop-2-enoyl prop-2-en
• Step A tert-butyl 4-r7-benzyl-2-r2-(l-piperidyl)ethoxy1-6.8-dihvdro- 5H-pyrido[3.4- d]pyrimidin-4-yl]piperazine-l -carboxylate: To a solution of 2-(l-piperidyl)ethanol (872 mg, 6.75 mmol, 899 ⁇ , 3.00 eq) in toluene (40.0 mL) was added Pd(OAc) 2 (50.5 mg, 225 ⁇ , 0.10 eq), Cs 2 C0 3 (2.20 g, 6.75 mmol, 3.00 eq), BINAP (280 mg, 450 ⁇ , 0.20 eq) and tert- butyl 4-(7-benzyl-2-chloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl)piperazine-l- carboxylate (1.00
• Step B tert-butyl 4-r2-r2-(l-piperidvnethoxy1-5.6J.8-tetrahvdropyrido[3.4-d1pyrimidin-

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