EP2961750A1 - 7-oxo-pyrido [2, 3-d]pyrimidines substituées et leur utilisation dans le traitement de troubles associés à egfr/erbb2 - Google Patents

7-oxo-pyrido [2, 3-d]pyrimidines substituées et leur utilisation dans le traitement de troubles associés à egfr/erbb2

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Publication number
EP2961750A1
EP2961750A1 EP14710724.7A EP14710724A EP2961750A1 EP 2961750 A1 EP2961750 A1 EP 2961750A1 EP 14710724 A EP14710724 A EP 14710724A EP 2961750 A1 EP2961750 A1 EP 2961750A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
methyl
amino
pyrimidin
oxopyrido
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14710724.7A
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German (de)
English (en)
Inventor
Ryan Wurz
Andrew Tasker
Seifu Tadesse
Liping H. Pettus
Thomas T. Nguyen
Fang-Tsao Hong
Bradley J. Herberich
Essa HARRINGTON
Jian J. Chen
James Brown
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Amgen Inc
Original Assignee
Amgen Inc
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Filing date
Publication date
Application filed by Amgen Inc filed Critical Amgen Inc
Publication of EP2961750A1 publication Critical patent/EP2961750A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention is in the field of pharmaceutical agents and specifically relates to compounds, compositions, uses and methods for treating cancer.
  • Protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function.
  • a partial list of such kinases includes abl, Atk, bcr-abl, Blk, Brk, Btk, c-kit, c-
  • c-src CDKl, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDKIO, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70.
  • the ErbB receptor family belongs to the subclass I receptor tyrosine kinase superfamily and includes four distinct receptors including epidermal growth factor receptor (EGFR or ErbB 1). ⁇ 132 (HER22 or pl 85neu). Erbl33 (HER3), and Erbl34 (HER4 or rvro2). Over 60% of all solid tumors overexpress at least one of these proteins or their ligands.
  • EGFR or ErbBl has been implicated in human malignancy. Overexpression of EGFR is commonly found in breast, lung, head and neck, bladder tumors. Monoclonal antibodies directed against the EGFR, or its ligands TGF-alpha and EGF have been evaluated as therapeutic agents in the treatment of such malignancies.
  • the reversible inhibitors Tarceva (erlotinib) and Iressa (gefitinib) currently are first-line therapy for non- small cell lung cancer patients with activating mutations.
  • Activating mutations in the tyrosine kinase domain of EGFR have been identified in patients with non-small cell lung cancer (Lin, N. U.; Winer, E. P., Breast Cancer Res 6: 204-210, 2004). The most common activating mutations are L858R and delE746-A750. Another mutant, T790M, has been detected in at least half of such clinically resistant patients. Moreover, T790M may also be pre-existing, there may be an independent, oncogenic role for the T790M mutation. In addition, germline EGFR T790M mutations are linked with certain familial lung cancers.
  • the present invention comprises a new class of 7-oxo-pyrido[2,3-d]pyrimidines useful in the treatment of diseases, such as EGFR mutant-mediated diseases, for example cancer.
  • the invention also comprises pharmaceutical compositions comprising the compounds, methods for the treatment of EGFR mutant-mediated diseases and other maladies, such as treatment of solid tumors, for example breast, lung, head and neck, bladder cancers, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
  • the compounds of the invention are represented by the following general structure:
  • R; R n ; R 12 ; and R 14 are defined below.
  • One aspect of the current invention relates to compounds having the general structure of formula 1 :
  • Ring A is 5 membered heteroaryl
  • Ring T is phenyl or 6 membered heteroaryl
  • R 2 is H, F, CI or methyl
  • R 3 is H, C ⁇ -Ce alkyl or C ⁇ -Ce dialkylamino- C ⁇ -Ce alkyl;
  • R 5 is unsubstituted or substituted 5-6 membered saturated heterocyclyl or substituted 4-7 membered heterocyclylamino;
  • R 6 is H, C ⁇ -Ce alkoxy, C ⁇ -Ce haloalkoxy or halo;
  • X is CH or N
  • R 5 is not 4-morpholinyl
  • the group X is CH.
  • the group R 3 is H.
  • the group R 2 is H or methyl.
  • the group R 2 is methyl.
  • the group R 1 is substituted phenyl.
  • R 1 is substituted pyridyl or substituted pyrimidinyl.
  • R 5 is optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted diazepanyl, or optionally substituted azetidinylamino; wherein the piperazinyl, piperidinyl, pyrrolidinyl, diazepanyl, and azetidinyl rings are optionally substituted with one or more substituents selected from Cu alkyl, Cu haloalkyl, Ci_ 4 alkoxycarbonyl, Cu alkylamino, optionally substituted 5-6 membered heterocyclyl, C1.4 alkylcarbonyl, C1.4 alkylsulfonyl, aminosulfonyl, C1.4 hydroxyalkylcarbonyl, C1.4 alkylaminocarbonyl, and C1.4 haloalkylcarbonyl.
  • the group R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 5 is l-fluoroethylazetidin-3-ylamino.
  • R 6 is H, methoxy or chloro.
  • Another aspect of the current invention relates to compounds having the general structure of Formula II
  • R 2 is H or methyl
  • R a is optionally substituted piperazinyl, optionally substituted piperidinyl,
  • R b is H or methoxy
  • the group R 2 is methyl.
  • the group R b is located at position 3 on the phenyl ring.
  • the group R a is optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, or optionally substituted diazepanyl; wherein the piperazinyl, piperidinyl, pyrrolidinyl and diazepanyl rings are optionally substituted with one or more substituents selected from Cu alkyl, Q_ 3 haloalkyl, C1.4 alkoxycarbonyl, Cu alkylamino, optionally substituted 5-6 membered heterocyclyl, Ci_ 4 alkylcarbonyl, Ci_ 4 alkylsulfonyl, aminosulfonyl, C1
  • the group R a is azetidinylamino; wherein the azetindinyl is optionally substituted with one or more substituents selected from Cu alkyl, Cu haloalkyl, C1.4 alkoxycarbonyl, Cu alkylamino, optionally substituted 5-6 membered heterocyclyl, Ci_ 4 alkylcarbonyl, Ci_ 4 alkylsulfonyl, aminosulfonyl, C1
  • a family of specific compounds of particular interest within Formula 1 consists of compounds and pharmaceutically-acceptable derivatives thereof as follows:
  • R n is unsubstituted or substituted phenyl or unsubstituted or substituted 4-6
  • R 12 is H, or methyl
  • R 14 is H, Ci-C 6 alkyl, Ci-C 6 alkoxy or phenyl- Ci-C 6 alkyl;
  • R 17 is H or methyl
  • R n is not 3-methoxy-4-methylpiperazin-l -yl-phenyl or phenyl when R is benzacrylamide, R 12 is methyl and R 14 is H;
  • R n is not 3-methoxy-4-methylpiperazin-l -yl-phenyl when R is 3- benzacrylamide, R 12 is H and R 14 is benzyl;
  • R 14 is not methyl or methoxy when R 12 is H.
  • R is
  • R 14 is H, benzyl, or methoxy; and pharmaceutically acceptable salts thereof.
  • R 14 is H; and pharmaceutically acceptable salts thereof.
  • R 12 is methyl; and pharmaceutically acceptable salts thereof.
  • R n is or f V!_/ ; wherein
  • Ring A is 5 membered heteroaryl; wherein Ring T is phenyl; wherein R 15 is unsubstituted or substituted 6-membered nitrogen containing heterocyclyl, C1.4 alkylamino- C1.4 alkylamino, C1.4 hydroxylalkylamino, 5-membered nitrogen containing heterocyclyl-Ci.4 alkylamino, 5-membered nitrogen containing heterocyclyl-oxy, C1.4 alkylamino- C1.4 alkoxy, or C1.4 alkoxy- C1.4 alkoxy; wherein R 16 is one or more substituents selected from Ci_4 alkyl, C1.4 alkoxy, chloro, fluoro, H, C ⁇ haloalkoxy and C ⁇ haloalkyl; and wherein R 18 is Ci_4 alkyl, Ci_ 4 alkylamino- Ci_ 4 alkyl, unsubstituted or substituted 5-membered nitrogen containing heterocyclyl or unsubstituted or substituted 6-membered nitrogen
  • R n is substituted phenyl; and pharmaceutically acceptable salts thereof.
  • R n is substituted pyrazolyl; and pharmaceutically acceptable salts thereof.
  • R 15 is optionally substituted piperazinyl, optionally substituted piperidinyl, N-(N',N'-dimethylaminoethyl)-N-methylamino, N-hydroxyethyl- N-methylamino, N-(2-oxo-l -pyrrolidinylethyl)-N-methylamino, N-(l -pyrrolidinylethyl)- N-methylamino, l -methyl-3-pyrrolidinyoxy, ⁇ , ⁇ -dimethylaminopropoxy, N,N- dimethylaminoethoxy, or methoxyethoxy; wherein the piperazinyl, and piperidinyl rings are optionally substituted with one or more substituents selected from methyl, trifluoromethyl, 1 -hydroxy- 1-methylethyl and acetyl; and pharmaceutically acceptable salts thereof.
  • R 16 is methyl, methoxy, chloro, fluoro, H,
  • R 18 is methyl, ethyl, isopropyl, N,N- dimethylaminoethyl, 1 -methyl-pyrrolidinyl, or 1-methylpiperidinyl;
  • R n is
  • Another aspect of the current invention relates to compounds having the general structure of Formula Ila
  • R a is unsubstituted or substituted 6-membered nitrogen containing heterocyclyl; and wherein R bl is one or more substituents selected from C1.4 alkyl, C1.4 alkoxy, chloro, fluoro, H, C ⁇ haloalkoxy and C ⁇ haloalkyl; and pharmaceutically acceptable salts thereof;
  • R al is not 1 -methyl-4-piperazinyl when R bl is 3-methoxy.
  • R bl is located at position 3 on the phenyl ring; and pharmaceutically acceptable salts thereof.
  • R al is piperidinyl or piperazinyl; wherein the piperidinyl or piperazinyl ring is optionally substituted with one or more substituents selected from Ci-3 alkyl, C1.4 alkylcarbonyl, or C1.4 hydroxyalkyl; and pharmaceutically acceptable salts thereof.
  • R al is
  • R bl is methyl, methoxy, chloro, fliioro, H, trifluoromethyl or difluormethoxy; and pharmaceutically acceptable salts thereof.
  • Another aspect of the current invention relates to compounds having the general structure of Formula Ilia
  • R 31 is substituted 5 membered heteroaryl
  • R 32 is H or methyl
  • R 34 is H, Ci-C 6 alkyl, Ci-C 6 alkoxy or phenyl-Ci-C 6 alkyl;
  • R 31 is substituted with one or more substituents selected from C1.4 alkyl, C1.4 alkoxy, chloro, fluoro, C ⁇ haloalkoxy, C ⁇ haloalkyl, C 1 .4 alky lamino-C 1.4 alkyl, unsubstituted or substituted 5 -membered nitrogen containing heterocyclyl and unsubstituted or substituted 6-membered nitrogen containing heterocyclyl; and and pharmaceutically acceptable salts thereof.
  • R 31 is optionally substituted pyrazolyl, optionally substituted isoxazolyl, optionally substituted thiadiazolyl, or optionally substituted imidazolyl; wherein the pyrazolyl, isoxazolyl, thiadiazolyl, or imidazolyl rings are substituted with one or more substituents selected from methyl, ethyl, isopropyl, methoxy, chloro, fluoro, trifluoromethyl, difluoromethoxy, ⁇ , ⁇ -dimethylaminoethyl, 1 - methyl-pyrrolidinyl or 1-methylpiperidinyl; and pharmaceutically acceptable salts thereof.
  • R 31 is optionally substituted pyrazolyl; wherein the pyrazolyl ring is substituted with one or more substituents selected from methyl, ethyl, isopropyl, methoxy, chloro, fluoro, trifluoromethyl, difluoromethoxy, N,N- dimethylaminoethyl, 1-methyl-pyrrolidinyl and 1 -methylpiperidinyl; and
  • R 31 is
  • R 34 is H, benzyl, or methoxy; and pharmaceutically acceptable salts thereof.
  • Another aspect of the current invention relates to compounds having the general structure of Formula IVa
  • R a is C1.4 alky lamino-C 1.4 alkylamino, C1.4 hydroxylalkylamino, 5-membered nitrogen containing heterocyclyl-Ci.4 alkylamino, 5-membered nitrogen containing heterocyclyl-oxy, C1.4 alkoxy, or C1.4 alkoxy-Ci.4 alkoxy; and wherein R is one or more substituents selected from Ci_ 4 alkyl, Ci_ 4 alkoxy, chloro, fluoro, H, and pharmaceutically acceptable salts thereof.
  • R a4 is N-(N',N'-dimethylaminoethyl)-N-methylamino, N-hydroxyethyl-N-methylamino, N-(2-oxo- 1 -pyrrolidinylethyl)-N-methylamino, N-( 1 - pyrrolidinylethyl)-N-methylamino, l-methyl-3-pyrrolidinyoxy, N,N- dimethylaminopropoxy, ⁇ , ⁇ -dimethylaminoethoxy, or methoxyethoxy; and pharmaceutically acceptable salts thereof.
  • R M is methyl, methoxy, chloro, fluoro, H,
  • a family of specific compounds of particular interest within Formula la consists of compounds and pharmaceutically-acceptable derivatives thereof as follows:
  • One aspect of the current invention relates to compounds having the general structure of formula lb:
  • X is CH or N
  • R 21 is unsubstituted or substituted phenyl or unsubstituted or substituted 4-6
  • R 22 is H, fluoro, chloro or methyl
  • R 24 is H, Ci-C 6 alkyl, Ci-C 6 alkoxy or phenyl- Ci-C 6 alkyl;
  • R 27 is H, Ci-C 6 alkyl or Ci-C 6 dialkylamino- Ci-C 6 alkyl;
  • R is or ; wherein Ring A is 5 membered heteroaryl; wherein Ring T is phenyl or 6 membered heteroaryl; wherein R 5 is unsubstituted or substituted 5-6 membered saturated heterocyclyl or substituted 4-7 membered heterocyclylamino; and wherein R 6 is H, alkoxy, haloalkoxy or halo.
  • R 21 is unsubstituted or substituted phenyl or unsubstituted or substituted 4-6 membered heterocyclyl.
  • R 22 is H, or methyl.
  • R 24 is H.
  • provided compounds are selective inhibitors of at least one mutation of EGFR. It has been surprisingly found that provided compounds are selective inhibitors of at least one mutation of EGFR as compared to wild-type ("WT") EGFR.
  • WT wild-type
  • the mutation of EGFR is T790M. In certain embodiments, the mutation of EGFR is a deletion mutation.
  • the mutation of EGFR is an activating mutation.
  • a compound of the invention selectively inhibits at least one resistant mutation and at least one activating mutation as compared to WT EGFR.
  • a compound of the invention selectively inhibits at least one deletion mutation and/or at least one point mutation, and is sparing as to WT EGFR inhibition.
  • a mutation of EGFR can be selected from T790M (resistant or oncogenic), L858R (activating), delE746-A750 (activating), G719S (activating), or a combination thereof.
  • the term "selectively inhibits,” as used in comparison to inhibition of WT EGFR, means that a provided compound inhibits at least one mutation of EGFR (i.e., at least one deletion mutation, at least one activating mutation, at least one resistant mutation, or a combination of at least one deletion mutation and at least one point mutation) in at least one assay described herein (e.g., biochemical or cellular).
  • the term "selectively inhibits,” as used in comparison to WT EGFR inhibition means that a provided compound is at least 20 times more potent, at least 25 times, at least 30, at least 35, at least 40, at least 45, or at least 50 times more potent as an inhibitor of at least one mutation of EGFR, as defined and described herein, as compared to WT EGFR.
  • the term “sparing as to WT EGFR” means that a selective inhibitor of at least one mutation of EGFR, as defined and described above and herein, inhibits EGFR at the upper limit of detection of at least one assay as described herein (e.g., biochemical or cellular as described in detail below).
  • the term “sparing as to WT EGFR” means that a provided compound inhibits WT EGFR with an IC50 of at least 1 ⁇ , at least 2 ⁇ , at least 5 ⁇ , or at least 10 ⁇ .
  • a provided compound selectively inhibits (a) at least one activating mutation; and (b) T790M; and (c) is sparing as to WT.
  • the activating mutation is a deletion mutation.
  • the activating mutation is a point mutation.
  • an activating mutation is delE746- A750.
  • an activating mutation is L858R.
  • an activating mutation is G719S.
  • the at least one mutation of EGFR is L858R and/or
  • the present invention provides a method for inhibiting an activating mutation in a patient comprising administering to the patient a provided compound or composition thereof, as described herein.
  • the present invention provides a method for inhibiting oncogenic T790M in a patient comprising administering to the patient a provided compound or composition thereof, as described herein.
  • Compounds of the present invention would be useful for, but not limited to, the prevention or treatment of EGFR mutant-mediated diseases.
  • the compounds of the invention have kinase inhibitory activity, such as T790M inhibitory activity.
  • Compounds of the invention are useful for the treatment of neoplasia including cancer and metastasis, including, but not limited to: carcinoma such as cancer of solid tumors, for example breast, lung, head and neck, bladder cancers.
  • these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • the present invention includes all pharmaceutically acceptable isotopically- labelled compounds of the present invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2 H and 3 H, carbon, such as n C, 13 C and 14 C, chlorine, such as 38 C1, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and ls O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopes of hydrogen such as 2 H and 3 H
  • carbon such as n C, 13 C and 14 C
  • chlorine such as 38 C1
  • fluorine such as 18 F
  • iodine such as 123 I and 125 I
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 0 and ls O
  • phosphorus such as 32 P
  • sulphur such as 35 S.
  • isotopically-labelled compounds of the present invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically -labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • the compounds of the present invention include the
  • treatment includes therapeutic treatment as well as prophylactic treatment (either preventing the onset of disorders altogether or delaying the onset of a preclinically evident stage of disorders in individuals).
  • prevention includes either preventing the onset of
  • a “pharmaceutically-acceptable derivative” denotes any salt, ester of a compound of this invention, or any other compound which upon administration to a patient is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by being therapeutically effective in vivo.
  • neoplastic therapeutic agents prolong the survivability of the patient, inhibit the rapidly-proliferating cell growth associated with the neoplasm, or effect a regression of the neoplasm.
  • H denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydro xyl radical.
  • alkyl is used, either alone or within other terms such as “haloalkyl” and “alkylamino”, it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, teri-butyl, pentyl, isoamyl, hexyl and the like.
  • alkylenyl embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having 1-6 carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perfluoroalkyl means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.
  • alkoxy embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and teri-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl.
  • Said "aryl” group may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.
  • heterocyclyl embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing - ⁇ - ⁇ -,- ⁇ -S- or -S-S- portions.
  • Said "heterocyclyl” group may have 1 to 3 substituents such as hydroxyl, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino.
  • saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • nitrogen atoms e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl
  • saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. morpholinyl
  • heterocyclyl radicals examples include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.
  • unsaturated heterocyclic radicals also termed "heteroaryl” radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to
  • heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5- b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl.
  • heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur, nitrogen and oxygen, selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.
  • Heterocycle means a ring comprising at least one carbon atom and at least one other atom selected from N, O and S. Examples of heterocycles that may be found in the claims include, but are not limited to, the following:
  • sulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO 2 -.
  • carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -C0 2 H.
  • alkylamino embraces "N-alkylamino” and “ ⁇ , ⁇ -dialkylamino” where amino groups are substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are “lower alkylamino” radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N- ethylamino, N,N-dimethylamino, ⁇ , ⁇ -diethylamino or the like.
  • heterocyclylamino embraces amino groups substituted with a heterocyclyl radical.
  • alkylcarbonyl denotes a carbonyl radical substituted with an alkyl group. Even more preferred are alkylcarbonyl radicals having alkyl lengths of one to four carbon atoms.
  • alkoxycarbonyl denotes an ester group, containing an alkoxy substituted carbonyl. Even more preferred are alkoxycarbonyl radicals having alkoxy lengths of one to four carbon atoms.
  • haloalkylcarbonyl denotes a carbonyl radical substituted with a haloalkyl group. Even more preferred are haloalkylcarbonyl radicals having haloalkyl lengths of one to four carbon atoms.
  • hydroxyalkylcarbonyl denotes a carbonyl radical substituted with an hydroxyalkyl group. Even more preferred are hydroxyalkylcarbonyl radicals having hydroxyalkyl lengths of one to four carbon atoms.
  • alkylaminocarbonyl denotes a carbonyl radical substituted with an alkylamino group. Even more preferred are alkylaminocarbonyl radicals having alkyl lengths of one to four carbon atoms.
  • alkylsulfonyl denotes a sulfonyl radical substituted with an alkyl group. Even more preferred are alkylsulfonyl radicals having alkyl lengths of one to four carbon atoms.
  • aminosulfonyl denotes a sulfonyl radical substituted with an amino group. This substituent is alternatively named sulfonamidyl or sulfamyl.
  • sulfinyl whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals -SO-.
  • aralkyl embraces aryl-substituted alkyl radicals.
  • Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are “phenylalkylenyl” attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • heterocyclyloxy embraces optionally substituted heterocyclyl radicals, as defined above, attached to an oxygen atom.
  • heterocyclylalkylamino embraces optionally substituted heterocyclyl radicals, as defined above, attached to an alkylamino group.
  • alkylaminoalkyl embraces alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl” radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N- methylaminomethyl, N,N-dimethyl-aminoethyl, ⁇ , ⁇ -diethylaminomethyl and the like.
  • alkylaminoalkylamino embraces alkylamino radicals, as defined above, attached to an alkylamino group.
  • alkylaminoalkoxy embraces alkylamino radicals, as defined above, attached to an alkoxy group.
  • hydroxyalkylamino denotes an amino radical substituted with an hydroxyalkyl group. Even more preferred are hydroxyalkylamino radicals having hydroxyalkyl lengths of one to four carbon atoms.
  • alkoxyalkoxy embraces alkoxy radicals attached through an oxygen atom to other alkoxy radicals, as described above. More preferred alkoxyalkoxy radicals are "lower alkoxyalkoxy" radicals having lower alkoxy radicals attached to other lower alkoxy radical.
  • “Saturated, partially-saturated or unsaturated” includes substituents saturated with hydrogens, substituents completely unsaturated with hydrogens and substituents partially saturated with hydrogens.
  • leaving group generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
  • Protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.
  • aralkyl examples include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts.
  • aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like.
  • Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like.
  • Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso- butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl, phthaloyl and the like.
  • a mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group.
  • Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example,
  • heterocyclic groups can further include adjoining aryl and cycloalkyl rings.
  • heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.
  • Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • an addition salt such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
  • Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups.
  • Alkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
  • Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, l,2-bis(dimethylsilyl)benzene, l,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl.
  • Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a ⁇ , ⁇ , ⁇ -trisilyl derivative.
  • silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group.
  • Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF.
  • Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art.
  • Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
  • Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like.
  • a preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
  • a t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HC1 or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine.
  • Carboxy protecting group such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.
  • the present invention also comprises the use of a compound of the invention, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment either acutely or chronically of an angiogenesis mediated disease state, including those described previously.
  • the compounds of the present invention are useful in the manufacture of an anti-cancer medicament.
  • the compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of EGFR mutants.
  • the present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas I-IVa in association with a least one pharmaceutically -acceptable carrier, adjuvant or diluent.
  • the present invention also comprises a method of treating EGFR mutant related disorders, such as cancer in a subject, the method comprising treating the subject having or susceptible to such disorder with a therapeutically-effective amount of a compound of Formulas I-IVa. This includes first line therapies and second line therapies.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.
  • co-therapy in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace coadministration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
  • the administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia, such as with radiation therapy or with cytostatic or cytotoxic agents.
  • Such combination products employ the compounds of this invention within the accepted dosage ranges.
  • Compounds of Formula I may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of Formula I may be administered either prior to, at the same time as, or after administration of the known anticancer or cytotoxic agent.
  • the typical chemotherapy regime consists of either DNA alkylating agents, DNA intercalating agents, CDK inhibitors, or microtubule poisons.
  • the chemotherapy doses used are just below the maximal tolerated dose and therefore dose limiting toxicities typically include, nausea, vomiting, diarrhea, hair loss, neutropenia and the like.
  • antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which would be selected for treatment of neoplasia by combination drug chemotherapy.
  • Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents.
  • a first family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antimetabolite-type/thymidilate synthase inhibitor antineoplastic agents.
  • Suitable antimetabolite antineoplastic agents may be selected from but not limited to the group consisting of 5 -FU- fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co.
  • EX-015 benzrabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT and uricy
  • a second family of antineoplastic agents which may be used in combination with compounds of the present invention consists of alkylating-type antineoplastic agents.
  • Suitable alkylating-type antineoplastic agents may be selected from but not limited to the group consisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil, cisplatin,
  • prednimustine Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol.
  • a third family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antibiotic-type antineoplastic agents.
  • Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoxi
  • a fourth family of antineoplastic agents which may be used in combination with compounds of the present invention consists of a miscellaneous family of antineoplastic agents, including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents, selected from but not limited to the group consisting of a-carotene, a-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisant
  • the present compounds may also be used in co-therapies with other anti-neoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol,
  • doxercalciferol doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil/oteracil/tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein,
  • melanoma oncolysate vaccine New York Medical College
  • viral melanoma cell lysates vaccine Royal Newcastle Hospital
  • valspodar melanoma oncolysate vaccine
  • the present compounds may also be used in co-therapies with other anti-neoplastic agents, such as other kinase inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP) and VEGFR inhibitors.
  • other anti-neoplastic agents such as other kinase inhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP) and VEGFR inhibitors.
  • compositions of this invention comprise a combination of a kinase inhibitor of the Formulas described herein and one or more additional therapeutic or prophylactic agents
  • both the kinase inhibitor and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 to 80% of the dosage normally administered in a monotherapy regimen.
  • additional kinase inhibitory agents were those which may modulate, regulate or otherwise affect kinase enzyme activity. Such effects may lead to modulation of disease pathology and/or symptoms.
  • Kinase inhibitory agents include, for example, small molecules, polypeptides, antibodies (including for example, monoclonals, chimeric, humanized, single chain, immunokines, etc.), and the like.
  • additional kinase inhibitory small molecule agents include, but were not limited to, CDK inhibitors and p38 inhibitors, including SU- 6668, SU-5416, ZD-4190, ZD-1839, STI-571, CP-358774, LY-333531 and the like.
  • compositions of this invention comprise an additional immunosuppression agent.
  • additional immunosuppression agents include, but were not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon and mizoribine.
  • compositions of this invention may additionally comprise antibodies (including for example, monoclonals, chimeric, humanized, single chain, immunokines, etc.), cytotoxic or hormonal anti-cancer agents or combinations thereof.
  • antibodies including for example, monoclonals, chimeric, humanized, single chain, immunokines, etc.
  • cytotoxic or hormonal anti-cancer agents or combinations thereof.
  • the present invention comprises a process for the preparation of a compound of Formulas I-IVa.
  • optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base.
  • appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydro lyzed to deliver the enantiomerically pure compound.
  • the optically active compounds of the invention can likewise be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • pharmaceutically-acceptable salts are also included in the family of compounds of Formulas I-IVa.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is
  • Suitable pharmaceutically-acceptable acid addition salts of compounds of Formulas I-IVa may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are acetic, adipic, algenic, anthranilic, ascorbic, aspartic, benzoic, benzenesulfonic, butyric, camphoric, camphorsulfonic, citric, cyclopentanepropionic, cyclohexylaminosulfonic, digluconic, dodecylsulfonic, ethanesulfonic, formic, fumaric, galactaric, galacturonic, glycolic, gluconic, glucuronic, glucoheptanoic, glutamic, glycerophosphonic, heptanoic, hexanoic, 4-hydroxybenzoic, 2 -hydroxy ethanesulfonic, ⁇ -hydroxybutyric, lactic, malic, male
  • Formulas I-IVa include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formulas I-IVa.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained. Additional examples of such salts can be found in Berge et al., J. Pharm. Sci., 66, 1 (1977).
  • the invention also relates to a method of making a compound of the formulas described herein, comprising synthesizing any one or more intermediates illustrated in the synthetic schemes herein and then converting that intermediate(s) to a compound of the formulas described herein.
  • the invention also relates to a method of making a compound of the formulas described herein, comprising synthesizing any one or more intermediates illustrated in the examples herein and then converting that intermediate(s) to a compound of the formulas described herein.
  • LiHMDS Lithium bis(trimethylsilyl)amide mg milligram g gram
  • Acrylamide substituted 7-oxo-pyrido[2,3-d]pyrimidines can be prepared according to the methods set out in Scheme 1.
  • 2-(Methylthio)-7-oxopyrido[2,3- djpyrimidines (I) is treated with an oxidizing agent such as MCPBA, in an appropriate solvent such as in DCM, to furnish 2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidines (II).
  • the 2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidines (II) is treated with a base, such as with DIEA, and heated at a temperature above RT, preferably above about 50 °C, more preferably at about 80 °C to yield the amino substituted 7-oxopyrido[2,3- d]pyrimidines (III).
  • a base such as with DIEA
  • a temperature above RT preferably above about 50 °C, more preferably at about 80 °C
  • Deprotection such as with treatment with acid, followed by treatment with an unsaturated acid chloride, such as acryloyl chloride yields the desired product (IV).
  • the acrylamide (V) is formed from the starting material (I) by a method similar to that described above.
  • the 2-(methylthio)-7-oxopyrido[2,3- djpyrimidinyl acrylamides (V) can be oxidized, by a method similar to that described above followed by amination to yield the desired product (IV).
  • Acrylamide substituted 7-oxo-pyrido[2,3-d]pyrimidines can be prepared from the di-Boc protected compound, according to the method set out in Scheme 2.
  • the 2- (methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidines (57) is treated with a base, such as with DIEA, and heated at a temperature above RT, preferably above about 50 °C, more preferably at about 80 °C to yield the amino substituted 7-oxopyrido[2,3-d]pyrimidines (VII).
  • Deprotection such as with treatment with acid, followed by treatment with an unsaturated acid chloride, such as acryloyl chloride yields the desired product (IV).
  • a solution of protected (R)- 3-((2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)methyl)pyrrolidine is treated with deprotected, such as with acid, for example TFA, yields the free amine.
  • deprotected such as with acid, for example TFA
  • base such as DIPEA and an acyl chloride at a temperature below RT, preferably at about 0 °C affords the acrylamide derivative VIIx.
  • the desired compounds of the invention VIIIx are prepared by coupling of the acrylamide derivative VIIx with a substituted amine.
  • One example of such coupling involves heating the reactants in the presence of acid, such as TFA, at a temperature above RT, preferably above about 50 °C and more preferably at about 100 °C.
  • the starting compounds defined in Schemes l-3a may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt- forming group is present and the reaction in salt form is possible. If so desired, one compound of formula I can be converted into another compound of formula I or a N- oxide thereof; a compound of formula I can be converted into a salt; a salt of a compound of formula I can be converted into the free compound or another salt; and/or a mixture of isomeric compounds of formula I can be separated into the individual isomers.
  • N-Oxides can be obtained in a known manner by reacting a compound of formula I with hydrogen peroxide or a peracid, e.g. 3-chloroperoxy-benzoic acid, in an inert solvent, e.g. CH 2 C1 2 , at a temperature between about -10 to about 35°C, such as about 0°C to about RT.
  • hydrogen peroxide or a peracid e.g. 3-chloroperoxy-benzoic acid
  • an inert solvent e.g. CH 2 C1 2
  • one or more other functional groups for example carboxy, hydroxy, amino, or mercapto, are or need to be protected in a compound of Formulas I-IVa, because they should not take part in the reaction, these are such groups as are usually used in the synthesis of peptide compounds, and also of cephalosporins and penicillins, as well as nucleic acid derivatives and sugars.
  • the protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products.
  • the specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned above and hereinafter.
  • functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned above under "protecting groups".
  • the protecting groups are then wholly or partly removed according to one of the methods described there.
  • Salts of a compound of formula I with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of formula I may thus be obtained by treatment with an acid or with a suitable anion exchange reagent. A salt with two acid molecules (for example a dihalogenide of a compound of formula I) may also be converted into a salt with one acid molecule per compound (for example a
  • this may be done by heating to a melt, or for example by heating as a solid under a high vacuum at elevated temperature, for example from about 130°C to about 170°C, one molecule of the acid being expelled per molecule of a compound of formula I.
  • Salts can usually be converted to free compounds, e.g. by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically K 2 CO 3 or NaOH.
  • suitable basic agents for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically K 2 CO 3 or NaOH.
  • All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically cation exchangers, for example in the H+ form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from about -100°C to about 190°C, preferably from about -80°C to about 150°C, for example at about -80°C to about 60°C, at RT, at about -20°C to about 40°C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.
  • Salts may be present in all starting compounds and transients, if these
  • the solvents from which those can be selected which are suitable for the reaction in question include for example water, esters, e.g EtOAc, ethers, typically aliphatic ethers, e.g. Et 2 0, or cyclic ethers, e.g. THF, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically MeOH, EtOH, iPOH or 1-propanol, nitriles, typically AcCN, halogenated hydrocarbons, typically CH 2 C1 2 , amides, e.g. DMF, bases, typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids, typically lower alkanecarboxylic acids, e.g.
  • esters e.g EtOAc
  • ethers typically aliphatic ethers, e.g. Et 2 0, or cyclic ethers, e.g. THF
  • liquid aromatic hydrocarbons typically benzene or toluene
  • carboxylic acid anhydrides typically lower alkane acid anhydrides, e.g. acetic anhydride, cyclic, linear, or branched hydrocarbons, typically cyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the process.
  • lower alkane acid anhydrides e.g. acetic anhydride
  • cyclic, linear, or branched hydrocarbons typically cyclohexane, hexane, or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the process.
  • the invention relates also to those forms of the process in which one starts from a compound obtainable at any stage as a transient and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention and processes the said compound in situ.
  • a compound of any of the formulas delineated herein may be synthesized according to any of the processes delineated herein.
  • the steps may be performed in an alternate order and may be preceded, or followed, by additional protection/deprotection steps as necessary.
  • the processes may further comprise use of appropriate reaction conditions including inert solvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine, K 2 C0 3 , and the like), catalysts, and salt forms of the above.
  • bases e.g., LDA, DIEA, pyridine, K 2 C0 3 , and the like
  • Purification methods include, for example, crystallization, chromatography (liquid and gas phase, simulated moving bed (“SMB”)), extraction, distillation, trituration, reverse phase HPLC and the like.
  • Reactions conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient) are known in the art and may be adjusted as appropriate for the reaction.
  • the compounds of formula I-IVa are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallization (present as solvates).
  • New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention.
  • such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
  • the compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, scalemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention.
  • the invention expressly includes all tautomeric forms of the compounds described herein.
  • the compounds may also occur in cis- or trans- or E- or Z- double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
  • Substituents on ring moieties may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to a specific atom (see below), whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H.
  • heterocyclic ring systems may be attached through a carbon atom or a heteroatom in the ring system.
  • a heterocyclic or heteroaryl ring system is stated to be attached at a heteroatom (e.g., nitrogen atom)
  • all materials were obtained from commercial suppliers and used without further purification. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures.
  • HPLC analyses were run on a HP- 1050 system with an HP Zorbax SB-Cis (5 ⁇ ) reverse phase column (4.6 x 150mm) run at 30°C with a flow rate of 1.00 mL/min.
  • the mobile phase used solvent A (H 2 O/0.1 % TFA) and solvent B (AcCN/0.1% TFA) with a 20 min gradient from 10% to 90% AcCN. The gradient was followed by a 2 min return to 10% AcCN and a 3 min flush.
  • the mobile phase used solvent A (H 2 O/0.1 % HOAc) and solvent B (AcCN/0.1 % HOAc) with a 5 min gradient from 10% to 90% AcCN. The gradient was followed by a 0.5 min return to 10% AcCN and a 1.5 min flush.
  • Preparative HPLC Where indicated, compounds of interest were purified via preparative HPLC using a Gilson workstation with a 20 x 50 mm column at 45 ml/min.
  • the mobile phase used solvent A (H 2 O/0.1% TFA) and solvent B (AcCN/0.1% TFA) with a 10 min gradient from 10% to 95% AcCN. The gradient was followed by a 2 min return to 20% AcCN.
  • Step 1 A mixture of N-Boc-m-phenylenediamine (50a, prepared according to the procedures reported in: Duceppe, J.-S. et al. Org. Process. Res. Dev. 2009, 13, 1156- 1160) (280 g, 1.35 mol) and ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (Sigma-Aldrich; 303.7 g, 1.32 mol) in DMF (200 mL) at RT was treated with K 2 C0 3
  • Step 2 To a suspension of ethyl 4-((3-((tert- butoxycarbonyl)amino)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (50c) (340 g, 0.84 mol) in THF (200 mL) at -40 °C was added LiAlH 4 (2.57 L of 1.0 M solution in THF, 2.57 mol) dropwise. The reaction mixture was stirred at 0 °C for 13 h, then cooled to -20 °C and carefully quenched with solid Na 2 S04* 10H 2 O. The reaction mixture was filtered and rinsed with 2 X 150 mL of EtOAc.
  • Step 3 At RT, manganese (IV) oxide (358 g, 4.1 mol) was added to a solution of teri-butyl (3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50d) (140 g, 386.8 mmol) in CHCI 3 . After 18 h, the reaction mixture was filtered through a pad of Celite washing with 3 x 100 mL of CHCI 3 .
  • LiHMDS (41.6 mL of 1.0 M in THF solution, 41.6 mmol) was added to 2- MeTHF (70 mL) at -78 °C and treated with EtOAc (4.34 mL, 44.4 mmol). The solution was stirred at -78 °C for 10 min, then solid teri-butyl (3-((5-formyl-2- (methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50) (5.00 g, 13.87 mmol) was added in one portion and the solution was stirred at -78 °C for 10 min then removed from the cooling bath warmed to RT for 3 h.
  • Step 1 A 3-necked 2 L RBF equipped with an addition funnel, temperature probe and nitrogen inlet was charged with teri-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4- yl)amino)phenyl)carbamate (50) (25.0 g, 69.4 mmol) and THF (400 mL). The mixture was cooled to 0.5 °C using an ice water bath. Methylmagnesium bromide (3.0 M in Et 2 0, 74.0 mL, 222 mmol) was added dropwise via an addition funnel over 35 min. The temperature was kept below 8 °C during the addition.
  • Step 2 Tetrapropylammonium perruthenate (1.05 g, 2.99 mmol) was added to a heterogenous mixture of tert-butyl (3-((5-(l-hydroxyethyl)-2-(methylthio)pyrimidin-4- yl)amino)phenyl)carbamate (22.5 g, 59.8 mmol) and 4-methylmorpholine N-oxide (8.75 g, 74.7 mmol) in DCM (460 mL) at RT. The mixture was stirred at RT for 3 h and concentrated under reduced pressure. The dark solid was dissolved in 10%> MeOH in DCM and the material was adsorbed on to silica gel.
  • the material was purified by silica gel pad (2-L sintered medium frit filled halfway with silica gel) eluted with 10% EtOAc in DCM (2 L) followed by 20% EtOAc in DCM (2 L). The fractions containing the desired product was concentrated to afford a white solid. 1.2 L of 1/1 MeOH/EtOAc was added to the solid and the mixture was heated to reflux and cooled to RT slowly. The mixture sat at RT overnight.
  • tert-butyl (3-(5-methyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)carbamate (440 mg, 1.10 mmol) in DCM (10 mL) was treated with MCPBA (75 wt. %, 681 mg, 2.76 mmol) and stirred for 90 min. The reaction mixture was diluted with DCM (25 mL), treated with ice and 1 N NaOH (30 mL).
  • the DCM layer was separated and the aqueous layer was extracted with an additional amount of DCM (2 x 20 mL), dried over Na 2 S0 4 and concentrated to furnish tert-butyl (3-(5- methyl-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (451 mg, 1.05 mmol, 95% yield) as an off-white foam.
  • the crude material was used without purification, m/z (ESI, +ve ion) 453.0 (M+Na) + . ! H NMR (400 MHz, CDCl 3 ) ⁇ ppm 9.11 (1 H, s), 7.60 (1 H, br.
  • Step 1 In a 20 mL glass microwave tube, 2-(methylthio)pyrido[2,3-d]pyrimidin- 7(8H)-one (57a, Matrix Scientific; 500 mg, 2.59 mmol) was treated with K 2 C0 3 (715 mg, 5.18 mmol), Cul (99 mg, 0.52 mmol) and 4,7-dimethoxy-l,10-phenanthroline (Sigma Aldrich, 187 mg, 0.77 mmol) followed by purging with argon for 3 min. The solids were then treated with DMSO (6.0 mL) and 3-iodoaniline (0.31 mL, 2.59 mmol). The tube was sealed and heated to 110 °C for 20 h.
  • Step 2 At 0 °C, 8-(3-aminophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)- one 2,2,2-trifluoroacetate (57b) (150 mg, 0.38 mmol) in THF (5.0 mL), and treated with NaH (60 wt. % dispersion in mineral oil, 60 mg, 1.51 mmol) in one portion. It was stirred at this temperature for 30 min then treated with di-t-butyldicarbonate (205 mg, 0.94 mmol) and heated to 70 °C for 6 h.
  • reaction mixture was cooled to RT, quenched with ice water and extracted with EtOAc (2 x 30 mL), dried over MgS0 4 , concentrated and purified on silica gel column (10-90% EtOAc in hexanes) affording bis(teri-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)) carbamate (57c) (158 mg, 0.33 mmol, 87%o yield) as a yellow film, m/z (ESI, +ve ion) 485.1 (M+l) + .
  • a suspension of teri-butyl (4-fluoro-3-(2-(methylthio)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)carbamate (59) (270 mg, 0.67 mmol) in DCM (10 mL) was treated with MCPBA (77 wt. %, 161 mg, 0.72 mmol) in one portion and stirred at 0 °C for 1 h.
  • the reaction mixture was diluted with DCM (50 mL), and treated with ice and water (30 mL) followed by 10% Na 2 C0 3 (ca. 10 mL).
  • Step 1 A mixture of 5-bromo-2,4-dichloro-pyrimidine (180 g, 0.79 mol, Matrix Scientific), A-Boc-m-phenylenediamine (170 g, 0.82 mol, Synchem Inc), and Na 2 C0 3 (90 g, 0.85 mol) in THF (620 mL) and DMF (310 mL) was stirred at RT for 18 h under nitrogen. It was treated with water (6 L) and EtOAc (6 L). The insoluble solid containing the desired product [m/z (ESI, +ve ion) 400.9/422.9 (M+l) + ] was filtered and washed with EtOAc (2 x 1 L) and collected.
  • Step 2 To a 3 -L 3 -neck round-bottomed flask armed with a mechanical stirrer was added teri-butyl (3-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (100a, 92 g, 230 mmol), crotonic acid (78.95 g, 920 mmol), bis(benzonitrile)palladium(ii) chloride (4.41 g, 11.51 mmol, Sigma-Aldrich), tri(o-toly)lphosphine (3.50 g, 11.51 mmol, Sigma- Aldrich), THF (319 mL), DIPEA (400 mL, 2302 mmol).
  • the suspension was purged with argon for 5 min. It was stirred at 68 °C in an oil bath overnight.
  • the reaction mixture was cooled to RT, and treated in one portion with acetic anhydride (58.6 mL, 622 mmol).
  • the reaction mixture was stirred at 68 °C in an oil bath for 1 h. It was cooled to RT, diluted with 2.1 L of EtOAc.
  • the mixture was washed with 1.12 L of 1 N HC1 followed by 1.12 L of saturated NaHCC>3 solution.
  • the organic layer was dried over
  • Step 3 In a 3-L three-neck RBF equipped with a thermometer, a suspension of tert-butyl (3-(2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)phenyl)carbamate (100b, 31 g, 80 mmol) in 4.0 M hydrochloric acid in dioxane (200 mL, 801 mmol) was stirred at 50 °C for 2.5 h. LCMS indicated the completed removal of N-Boc protecting group.
  • the overall mixture was cooled in an ice bath, and treated with NaOH 10.0 N solution (88 mL, 882 mmol) in a rate that the internal temperature did not exceed 15 °C.
  • the resulting mixture was treated with acryloyl chloride (8.46 mL, 104 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 h.
  • Step 1 A mixture of N-Boc-m-phenylenediamine (280 g, 1.35 mol) and ethyl 4- chloro-2-(methylthio)pyrimidine-5-carboxylate ( Sigma -Aldrich; 303.7 g, 1.32 mol) in DMF (200 mL) at RT was treated with potassium carbonate (361 g, 2.6 mol). The mixture was stirred at 80 °C in an oil bath overnight. It was cooled to RT and treated with ice water. The resulting white suspension was filtered and washed with water. The white solid was collected and dried to afford crude ethyl 4-((3-((tert- butoxycarbonyl)amino)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (101a)
  • Step 3 At RT, manganese (IV) oxide (358 g, 4.1 mol) was added to a solution of tert-butyl (3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (101c) (140 g, 386.8 mmol) in CHCI 3 . After 18 h, the reaction mixture was filtered through a pad of celite washing with 3 x 100 mL of CHCI 3 .
  • Step 1 A 3-necked 2-L RBF equipped with an addition funnel, temperature probe and nitrogen inlet was charged with teri-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4- yl)amino)phenyl)carbamate (25.0 g, 69.4 mmol) and THF (400 mL). The mixture was cooled to 0.5 °C using an ice water bath. Methylmagnesium bromide (3.0 M in Et 2 0, 74.0 mL, 222 mmol) was added dropwise via an addition funnel over 35 min. The temperature was kept below 8 °C during the addition.
  • Step 2 Tetrapropylammonium perruthenate (1.05 g, 2.99 mmol) was added to a heterogeneous mixture of tert-butyl (3-((5-(l-hydroxyethyl)-2-(methylthio)pyrimidin-4- yl)amino)phenyl)carbamate (22.5 g, 59.8 mmol) and 4-methylmorpholine N-oxide (8.75 g, 74.7 mmol) in DCM (460 mL) at RT. The mixture was stirred at RT for 3 h and concentrated under reduced pressure. The dark solid was dissolved in 10% MeOH in DCM and the material was adsorbed on to silica gel.
  • the material was purified by silica gel pad (2-L sintered medium frit filled halfway with silica gel) eluted with 10% EtOAc in DCM (2 L) followed by 20% EtOAc in DCM (2 L). The fractions containing the desired product were concentrated to afford a white solid with black stripes. 1.2 L of 1/1 MeOH/EtOAc was added to the solid and the mixture was heated to reflux and cooled to RT slowly. The mixture was kept at RT overnight.
  • Step 1 In a RBF equipped a with magnetic stirrer was charged with tert-butyl (3- ((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (102) (49.5 g, 132 mmol) and THF (1300 mL). The mixture was stirred for 30 min at RT and filtered through a fritted funnel. The resulting filtrate containing 102 was charged to an addition funnel, degassed and purged with nitrogen. In a separate 5 L 3-necked RBF equipped with an overhead stirrer, a thermocouple and a nitrogen inlet was charged with THF (325 mL). The solvent was degassed and purged with nitrogen.
  • reaction mixture was poured into a biphasic mixture of EtOAc (1000 mL) and saturated NH 4 C1 solution (200 mL) cooled with an ice bath. The mixture was stirred for 30 min. The layers were separated. The organic layer was washed with brine (950 mL), dried over Na 2 S0 4 and concentrated to dryness upon which the desired product crystallized out of solution. MTBE was flushed in several times.
  • Step 2 To a suspension of tert-butyl (3-(5-methyl-2-(methylthio)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (103a, 6.52 g, 16.36 mmol) in DCM (50 mL) was added TFA (30 mL). The resulting homogeneous solution was stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and then under high vacuum for 20 min to give 103b as a viscous brown oil. m/z (ESI, +ve ion) 299.1 (M+H) + .
  • Step 3 The crude residue of 103b was taken up in DCM (75 mL), cooled to 0 °C and treated with DIEA (14.23 mL, 82 mmol) followed by acryloyl chloride (1.60 mL, 19.63 mmol). The resulting yellow suspension was kept at 0 °C for 50 min. The reaction mixture was quenched by the addition of an aqueous solution of ca. 1.0 M K2CO3 (50 mL) and the resulting light yellow suspension was filtered through a medium porosity sintered glass frit washing with water and then with Et20 affording N-(3-(5-methyl-2-
  • Step 4 To a suspension of N-(3-(5-methyl-2-(methylthio)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide (103c, 5.46 g, 15.49 mmol) in DCM (100 mL) at 0 °C was treated with 3-chlorobenzoperoxoic acid (77% max. wt. from Aldrich) (3.72 g, 16.58 mmol) in 1 portion and stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM (150 mL) and treated with an ice cold solution of ca. 1.0 M K2CO3 (25 mL).
  • Step 1 LiHMDS (41.6 mL of 1.0 M in THF solution, 41.6 mmol) was added to 2-MeTHF (70 mL) at -78 °C and treated with EtOAc (4.34 mL, 44.4 mmol). The solution was stirred at -78 °C for 10 min, then solid tert-butyl (3-((5-formyl-2- (methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (101) (5.00 g, 13.87 mmol) was added in one portion and the solution was stirred at -78 °C for 10 min then removed from the cooling bath and warmed to RT for 3 h.
  • Step 2 To a suspension of tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)carbamate (104a, 3.30 g, 8.58 mmol) in DCM (30 mL) was added 20 mL of TFA. The resulting homogeneous solution was stirred at RT for 30 min, and concentrated under reduced pressure to afford 104b as a viscous orange oil. Step 3.
  • Step 4 To a suspension of N-(3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)acrylamide (104c, 2.20 g, 6.50 mmol) in DCM (100 mL) at 0 °C was treated with MCPBA (1.559 g, 6.96 mmol, 77% max. wt. from Aldrich) and stirred at 0 °C for 75 min. The reaction mixture was treated with crushed ice followed by saturated K 2 CO 3 solution (15 mL).
  • the mixture was cooled to 0 °C using an ice/brine bath and treated slowly dropwise via addition funnel with 10 N NaOH (8.79 mL, 88 mmol), keeping the temperature below 15 °C. After the addition was completed, the pH was checked to ensure basic. The mixture was stirred at 0 °C and treated dropwise via a syringe with (is)-crotonoyl chloride (Sigma Aldrich, 0.64 mL, 6.72 mmol) and progress was followed with LC/MS.
  • Step 1 To a mixture of 2-methoxy-4-(4-methylpiperazin-l-yl)aniline (Combi-Blocks Inc; 342 mg, 1.55 mmol) and tert-butyl (3-(2-(methylsulfmyl)-7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)carbamate (52) (521 mg, 1.30 mmol) in teri-butanol (10 mL, 105 mmol) was added DIEA (0.57 mL, 3.25 mmol). The reaction mixture was heated at 80 °C in an oil bath for 21 h.
  • Step 2 The crude la from above was treated with DCM (20 mL) and TFA (20 mL) and stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and purified on a silica gel column (1-20% 2M NH 3 /MeOH in DCM) affording 8-(3-aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-l- yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (lb) (470 mg, 1.03 mmol, 79% yield) as a brown amorphous solid, m/z (ESI, +ve ion) 458.0 (M+H) + .
  • Step 3 8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-l- yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (lb) (2.17 g, 4.74 mmol) in DCM (30 mL) and THF (30 mL) at 0 °C was treated with DIEA (1.66 mL, 9.49 mmol) and acryloyl chloride (0.46 mL, 5.69 mmol) dropwise over 15 min and stirred at 0 °C. After
  • Step 1 2- ⁇ 6 ⁇ 1 ⁇ -4- ⁇ 1 ⁇ 1 ⁇ 1 ⁇ 6 (Matrix Scientific, Columbia, SC; 135 mg, 0.65 mmol) and bis(teri-butyl (3-(2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl))carbamate (57) (167 mg, 0.32 mmol) were treated with teri-butanol (2.0 mL) and Et 3 N (0.14 mL, 0.97 mmol) and heated to 110 °C for 75 min.
  • Step 3 8-(3-Aminophenyl)-2-((2-methoxy-4-mo ⁇ holinophenyl)amino)- pyrido[2,3-d]pyrimidin-7(8H)-one 2,2,2-trifluoroacetate (2b, 63 mg, 0.11 mmol) was treated with DCM (5.0 mL), cooled to 0 °C and treated with DIEA (0.06 mL, 0.34 mmol) and acryloyl chloride (9.16 ⁇ L, 0.113 mmol) and stirred at 0 °C for 40 min. The mixture was treated with ice and water and then a saturated solution of NaHCC .
  • Step 1 To a suspension of teri-butyl (3-(5-methyl-2-(methylthio)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (54) (2.49 g, 6.25 mmol) in DCM (30 mL) at RT was added TFA (20 mL). The resulting homogeneous solution was stirred for 1 h then the reaction was concentrated under reduced pressure (rotary evaporator). The residue was dissolved in DCM (50 mL), cooled to 0 °C and treated with DIEA (5.43 mL, 31.2 mmol) followed by acryloyl chloride (0.61 mL, 7.50 mmol).
  • Steps 2 and 3 To a suspension of N-(3-(5-methyl-2-(methylthio)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5a; 5.15 g, 14.63 mmol) in DCM (100 mL) at 0 °C was added MCPBA (77 wt. %, 3.51 g, 15.65 mmol) in one portion. The resulting suspension was stirred at 0 °C for 1 h. The mixture was diluted with DCM (100 mL) and treated with an ice cold solution of 1.0 M K 2 CO 3 . The aqueous layer was extracted with DCM (2 x 100 mL).
  • Step 4 To a suspension of 2-methoxy-4-(4-methylpiperazin-l -yl)aniline (Green Chempharm; 3.45 g, 15.57 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b) (4.59 g, 12.46 mmol) in anhydrous teri-butanol (40 mL) and dioxane (5 mL) at RT was added DIEA (4.33 mL, 24.92 mmol). The mixture was heated at 100 °C for 40 h.
  • 2-methoxy-4-(4-methylpiperazin-l -yl)aniline Green Chempharm; 3.45 g, 15.57 mmol
  • Step 1 At 0 °C, a suspension of teri-butyl (3-(6-ethyl-2-(methylthio)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (55) (720 mg, 1.75 mmol) in DCM (15 mL) was treated with mCPBA (70 wt.%, 460 mg, 1.87 mmol) in one portion and stirred at 0 °C for 1 h. The mixture was diluted with DCM (15 mL), and treated with ice and a 10% solution of Na 2 C0 3 (ca. 10 mL).
  • the DCM layer was separated and the aqueous layer was extracted with an additional amount of DCM (2 x 50 mL), dried over Na 2 S0 4 and concentrated to give teri-butyl (3-(6-ethyl-2-(methylsulfinyl)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (6a) (682 mg, 1.59 mmol, 91% yield) as a light yellow amorphous solid, m/z (ESI, +ve ion) 451.0 (M+Na) + . The crude material was used in the subsequent step without further purification.
  • reaction mixture was concentrated under reduced presure (rotary evaporator) and purified on silica gel on an ISCO Combiflash RF (40 g Redisep column, 5-20% 2M NH 3 /MeOH in DCM) affording 8-(3-aminophenyl)-6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-l- yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (392 mg, 0.81 mmol, 51% yield) as a brown/yellow film, m/z (ESI, +ve ion) 486.0 (M+H) + . !
  • the solution was stirred 0 °C for 15 min. Two additional drops of acryloyl chloride were added and the mixture was stirred an additional 2 h at 0 °C.
  • the mixture was treated with silica gel and concentrated on the rotovap to dryness.
  • the material was purified on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 0-20%o MeOH in DCM) affording enriched product as a yellow powdery solid.
  • tert-butyl (3-(5-methyl-2- (methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (56) (150 mg, 0.35 mmol), 2-methoxy-4-mo holinoaniline (Matrix Scientific, Columbia, SC, 54 mg, 0.26 mmol) followed by purging with argon.
  • the solids were then treated with tert- butanol (2.0 mL) and DIEA (0.11 mL, 0.65 mmol).
  • the tube was sealed and heated to 85 °C for 20 h.
  • the crude reaction mixture was purified on silica gel on an I SCO
  • Step 1 Preparation of 4-methoxy-6-(4-methylpiperazin-l-yl)pyridin-3-amine (8a).
  • 2-Chloro-4-methoxy-5-nitropyridine (Frontier Scientific, Newark, DE; 1.02 g, 5.40 mmol) and K 2 C0 3 (895 mg, 6.48 mmol) were purged with argon, treated with DMF (10 mL) followed by 1-methylpiperazine (0.66 mL, 5.94 mmol). The reaction was then heated to 60 °C for 3 h.
  • Step 3 N-(3-(2-((4-Methoxy-6-(4-methyl-l-piperazinyl)-3-pyridinyl)amino)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)-2-propenamide (8) (14% overall yield for 2 steps) as a yellow crystalline solid was prepared according to the procedures described for Example 6, using teri-butyl (3-(2-((4-methoxy-6-(4-methylpiperazin-l-yl)pyridin-3- yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (8b) as the starting material, m/z (ESI, +ve ion) 512.9 (M+H) + .
  • reaction mixture was removed from the ice bath and stirred at RT for 30 min.
  • the reaction mixture was treated with silica gel, concentrated on the rotovap and purified on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 0-20% MeOH in DCM) affording enriched product as a yellow solid.
  • This sample was repurified on the Gilson preparatory HPLC (Gemini Phenomenex; 30 x 150 mm, 5 u, 10-95%
  • Nl -( 1 -(2-Fluoroethyl)azetidin-3-yl)-3-methoxybenzene-l ,4-diamine (1 lc) was prepared according to the procedures described in WO 2012064706.
  • the reaction was sonicated for 10 min to help dissolve the substrate and another 2 drops of 2-chloroacetyl chloride was added. After 30 min, 2 more drops of 2-chloroacetyl chloride were added and the solution stirred for another 75 min resulting in clean conversion to the desired product.
  • the mixture was concentrated, treated with DMSO (8 mL) and purified on a Gilson preparatory HPLC (Gemini Phenomenex; 30 x 150 mm, 5 ⁇ , 10-95% 0.1%TFA/CH 3 CN in 0.1 %TFA/water).
  • Example 13 3-(dimethylamino)-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propanamide
  • Step 1 8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-l- yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (lb; 200 mg, 0.44 mmol) in DCM (5 mL) at 0 °C was treated with DIEA (0.19 mL, 1.09 mmol) and cooled in an ice bath at 0 °C. The solution was then treated with 3-chloropropionyl chloride (Sigma Aldrich, St.
  • the mixture was purified by chromatography on silica gel on an ISCO Combiflash RF (24 g Redisep HP (Gold), using a gradient of 0-20% 2M NH 3 /MeOH in DCM) affording 3-(dimethylamino)-N-(3-(2-((2-methoxy-4-(4- methylpiperazin-l-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)phenyl)propanamide (44.6 mg, 0.066 mmol, 76%o yield) as a yellow-orange amorphous foam, m/z (ESI, +ve ion) 557.0 (M+H) + .
  • Example 17 N-(3-(5-methyl-2-((4-(4-methylpiperazin-l-yl)phenyl)amino)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • a microwave tube was charged with N-(3-(5-methyl-2-(methylsulfmyl)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 210 mg, 0.57 mmol), 4-(4- methylpiperazino)aniline (136 mg, 0.71 mmol) and DIEA (0.20 mL, 1.14 mmol) in tert- butanol (5.5 mL). The tube was sealed and the mixture was heated to 100 °C for 3 d. The mixture was concentrated and then the brown solid was suspended in Et 2 0 and collected by filtration. The brown solid was washed with Et 2 0 to afford 270 mg of crude material.
  • the crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0-20%o MeOH in DCM.
  • This enriched product was repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30 x 150 mm, 5 ⁇ , 10-95% 0.1 %TFA/CH 3 CN in 0.1%TFA/water).
  • the product containing fractions were combined and concentrated.
  • a saturated solution of aqueous NaHCC was added and the mixture was extracted with 3 : 1 CHCI 3 /IPA (3 x 30 mL).
  • the reaction mixture was concentrated on the rotovap and the crude residue was suspended in Et 2 0 and filtered. The greenish brown amorphous solid was washed with Et 2 0 (3 x 20 mL) and this removed most of the aniline starting material (18a).
  • the crude material contained roughly 19% of the desired product (18b) along with recovered 5b. m/z (ESI, +ve ion) 611.9 (M+H) + .
  • the crude residue was used in the subsequent step without further purification.
  • the solids were purged with argon and treated with 1,4-dioxane (12 mL) and water (4 mL), sealed and heated at 1 10 °C in a heating block for 1 h.
  • the reaction mixture was treated with 1 N NaOH and extracted with EtOAc (3 x 30 mL), dried over MgSO t, filtered and concentrated.
  • the reaction mixture was transferred to a 1-L RBF using water (ca. 50 mL) and concentrated on the rotovap to remove most of the EtOH and treated with water (350 mL) and EtOAc (300 mL). The organic layer was separated and discarded. The aqueous layer was extracted with EtOAc (2 x 300 mL) and discarded. The aqueous layer was treated with NaOAc (ca. 18 g) (pH ca. 5-6) and extracted with CHCl 3 /5% IPA (3 x 300 mL) then treated with 1 N NaOH (10 mL) and extracted with CHC3 ⁇ 4/5% IPA (1 x 300 mL) again.
  • Example B2 N-(3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5- methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • Nl-(2-(Dimethylamino)ethyl)-Nl-methylbenzene-l,4-diamine (335 mg, 1.733 mmol) and N-(3-(5-methyl-2-(methylsulfmyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide (103, 350 mg, 0.950 mmol) was treated with DMAc (4.0 mL) and heated to 100 °C for 3.5 h.
  • the crude mixture was added directly to a silica gel column and the material was purified on the ISCO Combiflash RF (40 g Silicycle column, using a gradient of 0-20% 2M NH 3 /MeOH in DCM) affording enriched product.
  • the material was purified on the Gilson (Gemini Phenomenex; 30 x 150 mm, 5 u, 10-95%o
  • Example B3 N-(3-(2-((3-fluorophenyl)amino)-5-methyl-7-oxopyrido[2,3- d] py rimidin-8(7H)-yl)phenyl)acrylamide
  • Example B4 N-(3-(5-methyl-2-((l-methyl-lH-pyrazol-4-yl)amino)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)-2-propenamide
  • Example B6 8-(((3S)-l-acryloyl-3-pyrrolidinyl)methyl)-2-((2-methoxy-4-(4-methyl- l-piperazinyl)phenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one
  • Step 1 A solution of l -(2,4-dichloropyrimidin-5-yl)ethanone (800 mg, 4.19 mmol, Princeton Bio) in 3 mL of THF and 18 mL of cyclohexane at RT was treated with ( ?)-tert-butyl 3-(aminomethyl)pyrrolidine-l -carboxylate (923 mg, 4.61 mmol, Astatech Inc.) followed by NaHCC (387 mg, 4.61 mmol). It was stirred at RT for 2 h, and diluted with 150 mL of EtOAc. The mixture was filtered through a pad of Celite. The solid was discarded.
  • Step 2 At -78 °C, EtOAc (329 xL, 3.36 mmol) was added dropwise to a solution of LiHMDS (3.48 mL of 1.0 M solution in THF, 3.48 mmol) in 5 mL of THF. It was stirred at -78 °C for 15 min then treated with a solution of ( ?)-tert-butyl 3-(((5-acetyl-2- chloropyrimidin-4-yl)amino)methyl)pyrrolidine-l-carboxylate (398 mg of B6a that was about 85% pure, 1.12 mmol) in THF (6 mL) dropwise.
  • Step 3 A solution of (R)-tert-butyl 3-((2-chloro-5-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)methyl)pyrrolidine-l -carboxylate (340 mg of 6b that was about 40% pure, 0.90 mmol) in 3 mL of DCM at RT was treated with TFA (667 xL, 8.97 mmol) and stirred at RT for 45 min. It was concentrated under reduced pressure.
  • Step 4 A mixture of (.S)-8-((l-acryloylpyrrolidin-3-yl)methyl)-2-chloro-5- methylpyrido[2,3-d]pyrimidin-7(8H)-one (B6c, 185 mg, 0.55 mmol), 2-methoxy-4-(4- methylpiperazin-l-yl)aniline (148 mg, 0.66 mmol, GreenchemPharm) and TFA (0.045 mL, 0.61 mmol) in 2-butanol (2 mL, 21.80 mmol) was heated in an oil bath at 100 °C for 3 h.
  • Example B7 N-(3-(2-((l,3-dimethyl-lH-pyrazol-4-yl)amino)-5-methyl-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • Example B8 N-(3-(2-((l-ethyl-lH-pyrazol-5-yl)amino)-5-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide.
  • Example B9 N-(3-(2-((4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)amino)-5- methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • the organic extracts were washed with brine and dried over Na 2 S0 4 .
  • the solution was filtered and concentrated in vacuo to give the crude material as a yellow oil.
  • the crude material was absorbed onto silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0-3% 2 M NH 3 MeOH in CH 2 C1 2 , to provide 2-(3-fluoro-4-nitrophenoxy)-A ⁇ ,A ⁇ -dimethylethanamine (B9a, 0.392 g, 21% yield) as yellow oil.
  • Example Bll N-(3-(2-((l,3-dimethyl-lH-pyrazol-4-yl)amino)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • Example B12 N-(3-(5-methyl-2-((l-methyl-3-(trifluoromethyl)-lH-pyrazol-4- yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • Example B13 N-(3-(5-methyl-2-((4-(l-methylpiperidin-4-yl)phenyl)amino)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • Example B14 N-(3-(2-((4-(2-(dimethylamino)ethoxy)-2-methoxyphenyl)amino)-5- methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • the remaining solid was purified on a silica gel column (5% MeOH in DCM followed by 5-10% of 2 M NH3 in MeOH in DCM) to provide an enriched material (about 580 mg of yellow solid).
  • the yellow solid was stirred in 10 mL of ether for 30 min. The yellow solid was filtered, and washed with 3 x 10 mL of ether. The ether filtrate was discarded.
  • Example B15 A mixture of l,3-dimethyl-lH-pyrazol-5-amine (0.024 g, 0.220 mmol, FSSI), N-
  • Example B16 N-(3-(2-((4-(2-methoxyethoxy)phenyl)amino)-5-methyl-7- oxopyrido [2,3-d] pyrimidin-8(7H)-yl)phenyl)acrylamide.
  • Example B17 N-(3-(2-((4-((2-hydroxyethyl)(methyl)amino)-2- methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide
  • Example B17 Preparation of Example B17. To a stirred mixture of 7V-(3-(2-chloro-5-methyl-7- oxopyrido[2,3-d]pyrimidin-8(7//)-yl)phenyl)acrylamide (510 mg, 1.497 mmol) (100) and crude 2-((4-amino-3-methoxyphenyl)(methyl)amino)ethanol (382 mg, 1.946 mmol) in 2- butanol (5.00 mL) was added TFA (0.15 mL, 1.95 mmol) and the heterogeneous mixture was stirred at 110 °C overnight.
  • TFA 0.15 mL, 1.95 mmol
  • Example B18 N-(3-(5-methyl-7-oxo-2-((4-(piperidin-4-yl)phenyl)amino)pyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • reaction mixture was concentrated on the rotovap and chromatographed on the ISCO Combiflash RF (40 g Thompson SingleStep column, using a gradient of 0-10% MeOH in DCM) affording N-(3-(2-((l-isopropyl-lH-pyrazol-4-yl)amino)-5-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide (59 mg, 0.138 mmol, 46% yield) as a yellow crystalline solid, m/z (ESI, +ve ion) 430.0 (M+H) + . !
  • Example B20 N-(3-(2-((2-chloro-4-((2- (dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-methyl-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)-2-propenamide
  • reaction mixture was filtered over Celite, washed with MeOH/THF (2 x 20 mL of 1 : 1 solution). The filtrate was evaporated to dryness to give a viscous blue oil containing a mixture of 3-chloro-Nl-(2- (dimethylamino)ethyl)-Nl -methylbenzene-l,4-diamine (1.15 g, about 80%) and Nl-(2- (dimethylamino)ethyl)-5-fluoro-Nl-methylbenzene-l ,2-diamine (about 20%).
  • a heterogeneous mixture of N-(3-(2-chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)acrylamide (100, 194 mg, 0.57 mmol), 3-chloro-Nl -(2- (dimethylamino)ethyl)-Nl-methylbenzene-l,4-diamine hydrochloride (20b, 188 mg, 0.71 mmol, in about 90% pure) contaminated with 10% of N-(3-(2-chloro-5-methyl-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide in 2.5 mL of EtOH was treated with HOAc (32.9 xL, 0.57 mmol) and heated in an oil bath at 100 °C for 30 min.
  • the reaction mixture was heated in a microwave at 120 °C for 1 h.
  • the resulting dark mixture was loaded on a silica gel column and eluted with 2% MeOH in DCM followed by 5-10% of 2 M NH 3 in MeOH in DCM.
  • the residue was stirred in 5 mL of ether for 10 min.
  • the precipitated yellow solid was filtered, rinsed with 2 x 2 mL of ether. The filtrate was discarded.
  • Example B21 N-(3-(5-methyl-2-((3-methyl-l-(l-methylpiperidin-4-yl)-lH-pyrazol-4- yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide and N-(3-(5- methyl-2-((5-methyl-l-(l-methylpiperidin-4-yl)-lH-pyrazol-4-yl)amino)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • Example 21 The 3-methyl-l-(l-methylpiperidin-4-yl)-lH- pyrazol-4-amine hydrochloride and 5 -methyl- l-(l-methy lpiperidin-4-yl)-lH-pyrazol-4- amine hydrochloride mixture (21b, 0.10 g, 0.43 mmol) was combined with N-(3-(2- chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (100) (0.137 g, 0.40 mmol) and suspended in EtOH (1 mL) in a microwave vial.
  • the mixture was stirred at 0 °C for 10 min and then at RT for 1 h.
  • the reaction mixture was quenched with water (5 mL) and the resulting fine white precipitate was filtered using a medium porosity sintered glass frit and the filter cake was washed Et20.
  • N-(3-(6-benzyl-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin- 8(7H)-yl)phenyl)acrylamide (531 mg, 1.24 mmol) was treated with DCM (20 mL), cooled to 0 °C in an ice bath and treated with 3-chloroperoxybenzoic acid (77% max., 278 mg, 1.239 mmol) in one portion. The solution was stirred at 0 °C for 1 h 30 min.
  • Example B23 (5)-N-(3-(2-((2-methoxy-4-((l-methylpyrrolidin-3- yl)oxy)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide
  • the first eluent was N-(3-(2-((2-chloro-4-(2-(dimethylamino)ethoxy)- phenyl)amino)-5 -methyl-7-oxopyrido [2,3 -d]pyrimidin-8(7H)-yl)phenyl)acrylamide (Example B25, 50 mg, 15% yield) as a yellow crystalline solid. !
  • Example B27 N-(3-(5-methyl-2-((3-methyl-4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • Reaction mixture was directly purified by Gilson HPLC (Gemini-NX, lOu, Ci 8 , 100x50 mm; 0.1% TFA/water, 0.1% TFA/AcCN). Fractions azeotroped with AcCN. The residue was resolubilized with MeOH and neutralized with Silicycle SiliaPrep Carbonate cartridge.
  • Comparator Example 28 N-(3-(6-methoxy-2-((2-methoxy-4-(4-methylpiperazin-l- yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide.
  • N-(3-(6-methoxy-2-(methylthio)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide (1.02 g, 2.78 mmol) was treated with DCM (50 mL), cooled to 0 °C in an ice bath and treated with 3-chloroperoxybenzoic acid (77% max.; 0.623 g, 2.78 mmol) in one portion. The solution was stirred at 0 °C for 1 h.
  • Example B29 N-(3-(2-((4-(4-(2-hydroxypropan-2-yl)piperidin-l-yl)phenyl)amino)-5- methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • Reaction mixture was directly purified by Gilson HPLC (Gemini-NX, lOu, CI 8, 100x50 mm; 0.1% TFA/water, 0.1% TFA/AcCN). The clean fractions were azeotroped with AcCN. The residue was resolubilized with MeOH and neutralized with Silicycle SiliaPrep Carbonate cartridge to afford N-(3-(2-((4-(4-(2-hydroxypropan-2-yl)piperidin-l -yl)phenyl)amino)-5-methyl-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (Example B29, 45.3 mg, 0.84 mmol, 29% yield).
  • Example B30 N-(3-(6-Methoxy-2-((2-methoxy-4-(4-methylpiperazin-l- yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide.
  • LiHMDS (1.0 M in THF, 2.00 mL, 2.00 mmol) was added to THF (10 mL) at -78 °C and treated with methyl methoxyacetate (Sigma Aldrich, 0.145 mL, 1.469 mmol) slowly dropwise. The solution was stirred at -78 °C for 25 min, then tert-butyl (3-((5- acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (102, 250 mg, 0.668 mmol) was added in one portion and the solution was removed from the cooling bath, warmed to RT and stirred for 2 h.
  • Martin sulfurane dehydrating agent (Sigma Aldrich, 449 mg, 0.668 mmol) was added in one portion to the reaction mixture and stirred for 3 h. The reaction was quenched with a saturated solution of NH 4 C1 and extracted with EtOAc (2 x 15 mL), dried over MgS0 4 , filtered and concentrated.
  • tert-butyl (3-(6-methoxy-5-methyl-2-(methylthio)-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (30a; 163 mg, 0.38 mmol) was treated with HC1 (4 M in 1,4-dioxane, 1.90 mL, 7.61 mmol) and heated to 50 °C for 45 min. The volatiles were removed under reduced pressure and the crude material was treated with 1,4-dioxane (4 mL), cooled to 0 °C and treated with NaOH (10 N, 0.84 ml, 8.37 mmol) in an ice bath.
  • N-(3-(6-methoxy-5-methyl-2-(methylthio)-7-oxopyrido[2,3- d]pyrimidin-8(7H)-yl)phenyl)acrylamide (30b; 101 mg, 0.26 mmol) was treated with DCM (20 mL), cooled to 0 °C in an ice bath and treated with 3-chloroperoxybenzoic acid (59 mg of 77% max., 0.26 mmol) in one portion. The solution was stirred at 0 °C for 50 min.
  • Example B31 A solution of l -(4-(4-amino-3- chlorophenyl)piperazin-l-yl)ethanone (31b, 0.135 g, 0.53 mmol), N-(3-(2-chloro-5- methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (0.165 g, 0.484 mmol), TFA (0.036 mL, 0.48 mmol) in 2-butanol (20 mL, 109 mmol) was stirred at 1 10 °C overnight. After cooled to RT, the crude was was concentrated down and
  • Example B32 (R) and (S) N-(3-(2-((4-(3,4-dimethylpiperazin-l-yl)-2- methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide
  • Example B33 N-(3-(2-((4-(3-(dimethylamino)propoxy)phenyl)amino)-5-methyl-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide
  • Reaction mixture was directly purified by Gilson HPLC (Gemini-NX, lOu, Ci 8 , 100 x 50 mm column; 0.1% TF A/water, 0.1% TFA/AcCN). The clean fraction was azeotroped with AcCN. The residue was resolubilized with MeOH and neutralized with Silicycle SiliaPrep Carbonate cartridge to afford N-(3-(2-((4-(3-(dimethylamino)propoxy)phenyl)amino)-5-methyl-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (Example B33, 16.1 mg, 0.032 mmol, 11% yield). !
  • Example B34 N-(3-(2-((2-methoxy-4-(methyl(2-(2-oxopyrrolidin-l- yl)ethyl)amino)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)- yl)phenyl)acrylamide
  • Example B34 Preparation of Example B34. l-(2-((4-Amino-3-methoxyphenyl)(methyl)amino)- ethyl)pyrrolidin-2-one (34c, 0.64 g, 2.430 mmol), N-(3-(2-chloro-5-methyl-7- oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (100) (0.828 g, 2.43 mmol), HOAc (Sigma-Aldrich; 0.14 mL, 2.43 mmol), and EtOH (5 mL) were combined in a pressure vessel under argon and heated in a 120 °C oil bath.

Abstract

La présente invention concerne des composés représentés par les formules générales suivantes : formule (I) et formule (II), dans lesquelles X ; R1-R3 ; R11 ; R12 ; et R14 sont tels que définis dans les revendications et des sels pharmaceutiquement acceptables de ceux-ci, des compositions pharmaceutiques, des utilisations et des méthodes de prophylaxie et de traitement du cancer.
EP14710724.7A 2013-03-01 2014-02-27 7-oxo-pyrido [2, 3-d]pyrimidines substituées et leur utilisation dans le traitement de troubles associés à egfr/erbb2 Withdrawn EP2961750A1 (fr)

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