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WO2012101063A1 - Composés de n-acyl pyridine biaryl et leurs utilisations - Google Patents

Composés de n-acyl pyridine biaryl et leurs utilisations Download PDF

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Publication number
WO2012101063A1
WO2012101063A1 PCT/EP2012/050906 EP2012050906W WO2012101063A1 WO 2012101063 A1 WO2012101063 A1 WO 2012101063A1 EP 2012050906 W EP2012050906 W EP 2012050906W WO 2012101063 A1 WO2012101063 A1 WO 2012101063A1
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Prior art keywords
pyran
mmol
methyl
mixture
compound
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Inventor
Paul A. Barsanti
Cheng Hu
Xianming Jin
Simon C. Ng
Keith B. Pfister
Martin Sendzik
James Sutton
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Novartis AG
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Novartis AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with aberrant cellular signaling pathways that can be modulated by inhibition of kinases, particularly diseases or disorders that involve aberrant cellular signaling pathways that can be modulated by inhibition of CDK9.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. (Hardie, G. and Hanks, S. THE PROTEIN KINASE FACTS BOOK, I and II, Academic Press, San Diego, Calif.: 1995). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, efc.).
  • phosphorylate e.g., protein-tyrosine, protein-serine/threonine, lipids, efc.
  • diseases are associated with abnormal cellular responses triggered by the protein kinase-mediated events described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, viral diseases, and hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
  • the cyclin-dependent kinase (CDK) complexes are a class of kinases that are targets of interest. These complexes comprise at least a catalytic (the CDK itself) and a regulatory (cyclin) subunit. Some of the more important complexes for cell cycle regulation include cyclin A (CDK1-also known as cdc2, and CDK2), cyclin B1-B3 (CDK1) and cyclin D1-D3 (CDK2, CDK4, CDK5, CDK6), cyclin E (CDK2). Each of these complexes is involved in a particular phase of the cell cycle. Additionally, CDKs 7, 8, and 9 are implicated in the regulation of transcription.
  • the CDKs seem to participate in cell cycle progression and cellular transcription, and loss of growth control is linked to abnormal cell proliferation in disease (see e.g., Malumbres and Barbacid, Nat. Rev. Cancer 2001 , 1 :222). Increased activity or temporally abnormal activation of cyclin-dependent kinases has been shown to result in the development of human tumors (Sherr C. J., Science 1996, 274: 1672-1677). Indeed, human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators (Cordon-Cardo C, Am. J. Pat1/701. 1995; 147: 545-560; Karp J. E. and Broder S., Nat. Med. 1995; 1 : 309-320; Hall M. et al., Adv.
  • CDKs 7 and 9 seem to play key roles in transcription initiation and elongation, respectively (see, e.g., Peterlin and Price, Cell 23: 297-305, 2006; Shapiro, J. Clin. Oncol. 24: 1770-83, 2006;).
  • Inhibition of CDK9 has been linked to direct induction of apoptosis in tumor cells of hematopoietic lineages through down-regulation of transcription of antiapoptotic proteins such as Mcl1 (Chao, S.-H. et al. J. Biol. Chem. 2000;275:28345- 28348; Chao, S.-H. et al. J. Biol. Chem. 2001 ;276:31793-31799; Lam et. al. Genome
  • CDK9 transcriptional inhibition by downregulation of CDK9 activity synergizes with inhibition of cell cycle CDKs, for example CDK1 and 2, to induce apoptosis (Cai, D.-P., Cancer Res 2006, 66:9270.
  • Inhibition of transcription through CDK9 or CDK7 may have selective non-proliferative effect on the tumor cell types that are dependent on the transcription of mRNAs with short half lives, for example Cyclin D1 in Mantle Cell Lymphoma.
  • Some transcription factors such as Myc and NF-kB selectively recruit CDK9 to their promoters, and tumors dependent on activation of these signaling pathways may be sensitive to CDK9 inhibition.
  • CDK inhibitors may also be used in the treatment of
  • cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders that are due to aberrant cell proliferation.
  • Vascular smooth muscle proliferation and intimal hyperplasia following balloon angioplasty are inhibited by over-expression of the cyclin-dependent kinase inhibitor protein.
  • CDKs are important in neutrophil-mediated inflammation and CDK inhibitors promote the resolution of inflammation in animal models. (Rossi, A.G. et al, Nature Med. 2006, 12: 1056).
  • CDK inhibitors including CDK9 inhibitors, may act as antiinflammatory agents.
  • CDK inhibitors are useful as chemoprotective agents through their ability to inhibit cell cycle progression of normal untransformed cells (Chen, et al. J. Natl.
  • CDK9 inhibitors Pyridine compounds of the formula below have been identified as CDK9 inhibitors, and accordingly such compounds are useful for treating cancer and other conditions mediated by CDK9 activity:
  • Ri is d-8 alkyl, C 3 . 8 cycloalkyl, C 3 . 8 branched alkyl, -(CH 2 )o-3-0-Ci_ 4 alkyl,
  • R 2 is hydrogen, Ci -4 alkoxy, Ci -4 haloalkyl, Ci -4 -alkyl, or halogen;
  • a 4 is N or CR 6 , with the proviso that only one of Ai and A 4 is a N ;
  • R 3 is Ci-4 alkyl, H , or OCi -4 alkyl;
  • R 4 is hydrogen, halogen, 5 to 7 membered heterocyclyl-aryl, or A 6 -L-R 9 ;
  • R 5 is hydrogen, d -4 alkyl, or halogen
  • R 6 is hydrogen, Ci -4 alkyl, or halogen
  • R 7 is hydrogen, Ci -4 alkyl, or halogen
  • a 6 is NR 8 ;
  • L is Co-3-alkylene or C 3 . 8 branched alkylene
  • R 8 is hydrogen, Ci -4 alkyl; or -C 3 . 8 branched alkyl;
  • R 9 is hydrogen, Ci_ 6 alkyl, C 3 . 8 cycloalkyl, 4 to 8 member heterocycloalkyl, aryl, or heteroaryl, wherein said groups are optionally substituted with one to three substituents each independently selected from hydrogen, halogen, Ci -4 alkyl, Ci -4 haloalkyl, -OH, -O-C 1 .3 alkyl, -O-C 1 -3 haloalkyl, -0-(CH 2 ) 2 -3-0-Ci. 2 alkyl, -C(0)-Ci. 4 alkyl, and -NH-C(0)-Ci-4 alkyl.
  • the present invention provides novel kinase inhibitors, particularly inhibitors of CDK9, as further described below.
  • the present invention provides novel biaryl compounds having structural similarities to the pyridinyl compounds described above, which are also useful to treat cancer and other conditions based on their activity on CDK9.
  • novel compounds of the invention are represented by the following Formulas:
  • the invention includes pharmaceutically acceptable salts of compounds of any of Formulas l-VII. Further structural description of these compounds and of pharmaceutical compositions and methods of use of these compounds are described below.
  • the foregoing compounds are inhibitors of at least one CDK, specifically including CDK9, and are thereby useful for treating conditions mediated by excessive or undesired levels of CDK9 activity, such as the conditions described herein.
  • Another embodiment of the invention provides a method of treating a disease or condition mediated by CDK9 by using a compound of Formulas l-VII, or a
  • Also provided in another embodiment is a method for the manufacture of a medicament for the treatment of a disease or condition mediated by CDK9, said medicament comprising a compound of any of Formulas l-VII, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides a method of treating a disease or condition mediated by CDK9 using a compound of any of Formulas l-VII, or pharmaceutically acceptable salt thereof.
  • a preferred method comprises administering a therapeutically effective amount of a compound of any of Formulas l-VII, or a pharmaceutical composition comprising an effective amount of a compound of any of Formulas l-VI I.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of Formulas l-VI I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • a compound of any of Formulas l-VI I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition mediated by CDK9.
  • the present invention provides a method of regulating, modulating, or inhibiting protein kinase activity which comprises contacting a protein kinase with a compound of the invention.
  • Suitable protein kinases include CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, or any combination thereof.
  • the protein kinase is selected from the group consisting of CDK1 , CDK2 and CDK9, or any combination thereof.
  • the protein kinase is in a cell culture.
  • the protein kinase is in a mammal.
  • the invention provides a method of treating a protein kinase-associated disorder comprising administering to a subject in need thereof a
  • Suitable protein kinases include CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 or combinations thereof (preferably, the protein kinase is selected from the group consisting of CDK1 , CDK2 and CDK9, more preferably, the protein kinase is CDK9.)
  • Suitable CDK combinations include CDK4 and CDK9; CDK1 , CDK2 and CDK9; CDK9 and CDK7; CDK9 and CDK1 ; CDK9 and CDK2; CDK4, CDK6 and CDK9; CDK1 , CDK2, CDK3, CDK4, CDK6 and CDK9.
  • the invention provides a method of treating cancer comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of the invention.
  • Suitable cancers for treatment by the compounds, compositions and methods described herein include bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal and pancreatic cancer.
  • protein kinase-associated disorder includes disorders and states (e.g., a disease state) that are associated with the activity of a protein kinase, e.g. , the CDKs, e.g., CDK1 , CDK2 and/or CDK9.
  • a protein kinase e.g., the CDKs, e.g., CDK1 , CDK2 and/or CDK9.
  • Non-limiting examples of protein kinase-associated disorders include abnormal cell proliferation (including protein kinase- associated cancers), viral infections, fungal infections, autoimmune diseases and neurodegenerative disorders.
  • treat includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
  • the treatment comprises the induction of a protein kinase-associated disorder, followed by the activation of the compound of the invention, which would in turn diminish or alleviate at least one symptom associated or caused by the protein kinase-associated disorder being treated.
  • treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
  • use includes one or more of the following embodiments of the invention, respectively: the use in the treatment of protein kinase-associated disorders; the use for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, e.g. , in the manufacture of a medicament; methods of use of compounds of the invention in the treatment of these diseases; pharmaceutical preparations having compounds of the invention for the treatment of these diseases; and compounds of the invention for use in the treatment of these diseases; as appropriate and expedient, if not stated otherwise.
  • diseases to be treated and are thus preferred for use of a compound of the present invention are selected from cancer, inflammation, cardiac hypertrophy, and H IV infection, as well as those diseases that depend on the activity of protein kinases.
  • compositions herein which bind to a protein kinase sufficiently to serve as tracers or labels, so that when coupled to a fluor or tag, or made radioactive, can be used as a research reagent or as a diagnostic or an imaging agent.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a fully saturated straight-chain (linear; unbranched) or branched chain, having the number of carbon atoms specified, if designated (i.e. C Ci 0 means one to ten carbons).
  • Illustrative "alkyl” group examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. If no size is designated, the alkyl groups mentioned herein contain 1 -10 carbon atoms, typically 1-8 carbon atoms, and preferably 1 -6 or 1-4 carbon atoms.
  • alkoxy refers to -O-alkyl, wherein the term alkyl is as defined above.
  • cycloalkyl by itself or in combination with other terms, represents, unless otherwise stated, cyclic versions of alkyl. Additionally, cycloalkyl may contain fused rings, but is not intended to describe fused fully aromatic aryl and heteroaryl groups. Cycloalkyl groups, unless indicated otherwise, are unsubstituted, but may be substituted with those groups typically suitable for alkyl group substitutions.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. If no ring size is specified, the cycloalkyl groups described herein generally contain 3-10 ring members, preferably 3-6 ring members.
  • heterocyclic or “heterocycloalkyl” or “heterocyclyl,” by itself or in combination with other terms, represents a cycloalkyl containing at least one annular carbon atom and at least one annular heteroatom selected from the group consisting of O, N, P, Si and S, preferably from N, O and S, wherein the ring is not aromatic but can contain unsaturations.
  • the nitrogen and sulfur atoms in a heterocyclic group may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heterocyclic groups discussed herein, if not otherwise specified, contain 3-10 ring members, and at least one ring member is a heteroatom selected from N, O, P, Si, and S.
  • heterocyclic group Preferably, not more than three of these heteroatoms are included in a heterocyclic group, and generally not more than two of these heteroatoms are present in a single ring of the heterocyclic group.
  • the heterocyclic group can be fused to an additional carbocyclic or heterocyclic ring.
  • a heterocyclic group can be attached to the remainder of the molecule at an annular carbon or annular heteroatom.
  • heterocyclic may contain fused rings, but excludes fused systems containing a heteroaryl group as part of the fused ring system.
  • heterocyclic groups include, 1- (1 ,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,
  • tetrahydrothien-3-yl 1 -piperazinyl, 2-piperazinyl, piperidin-2-one, azepane, tetrahydro- 2H-pyranyl, pyrrolidinyl, methylpyrrolidinone, alkylpiperidinyl, haloalkylpiperidinyl, 1- (alkylpiperidin-l-yl)ethanone, and the like.
  • substituents
  • 'heterocyclic' groups are piperidine, morpholine,
  • thiomorpholine piperazine, pyrrolidine, tetrahydrofuran, oxetane, oxepane, oxirane, tetrahydrothiofuran, thiepane, thiirane, and optionally substituted versions of each of these.
  • aryl represents an aromatic hydrocarbon group which can be a single ring or multiple rings (e.g., from 1 to 3 rings) which are fused together.
  • Aryl includes fused rings, wherein one or more of the fused rings is fully saturated (e.g. , cycloalkyl) or partially unsaturated (e.g. , cyclohexenyl), but not a heterocyclic or heteroaromatic ring.
  • Illustrative examples of aryl groups include, but are not limited to, phenyl, 1 -naphthyl, 2-naphthyl, and tetrahydronaphthyl.
  • heteroaryl refers to groups comprising a single ring, or a fused ring, where at least one of the rings is an aromatic ring that contain from one to four heteroatoms selected from N, O, and S as ring members (i.e., it contains at least one heteroaromatic ring), wherein the nitrogen and sulfur atoms can be oxidized, and the nitrogen atom(s) can be quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through an annular carbon or annular heteroatom, and it can be attached through any ring of the heteroaryl moiety, if that moiety is a bicyclic, tricyclic, or a fused ring system.
  • a heteroaryl group may contain fused rings, wherein one of the fused rings is aromatic or heteroaromatic, and the other fused ring(s) are partially unsaturated (e.g., cyclohexenyl, 2,3-dihydrofuran, tetrahydropyrazine, and 3,4-dihydro- 2H-pyran), or completely saturated (e.g., cyclohexyl, cyclopentyl, tetrahydrofuran, morpholine, and piperazine).
  • the term heteroaryl is also intended to include fused rings systems that include a combination of aromatic and heteroaromatic rings systems (e.g., indoles, quinoline, quinazolines, and benzimidazoles).
  • heteroaryl groups are 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2- benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3- quinolyl, and
  • halo or halogen
  • halo represents a fluorine, chlorine, bromine, or iodine atom. Commonly when present as a substituent, halo refers to F or CI or Br, preferably F or CI.
  • haloalkyi represents an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group are replaced by a halogen atom which may be the same or different.
  • haloalkyi thus includes mono-haloalkyl, di-haloalkyl, tri- haloalkyl, tetra-haloalkyl, and the like as well as per-haloalkyl.
  • perhalo refers to the respective group wherein all available valences are replaced by halo groups.
  • perhaloalkyl includes -CCI 3 , -CF 3 , -CCI 2 CF 3 , and the like.
  • perfluoroalkyl and “perchloroalkyl” are a subset of perhaloalkyl wherein all available valences are replaced by fluoro and chloro groups, respectively.
  • Illustrative examples of perfluoroalkyl include -CF 3 and -CF 2 CF 3
  • perchloroalkyl include -CCI 3
  • Optionally substituted indicates that the particular group or groups being described may have no non-hydrogen substituents (i.e., it can be unsubstituted), or the group or groups may have one or more non-hydrogen substituents. If not otherwise specified, the total number of such substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Typically, an optionally substituted group will contain up to four (1-4) substituents.
  • Suitable optional substituent groups include halo, d. 4 alkyl, -NH-C(0)-CH 2 -0-d. 4 alkyl, -NHC(0)-d. 4 alkyl, -C(0)-0-d. 4 alkyl,
  • the term "compounds of the present invention” refer to compounds of Formula I, prodrugs thereof, pharmaceutically acceptable salts of the compounds, and/or prodrugs, and hydrates or solvates of the compounds, salts, and/or prodrugs, as well as, all stereoisomers (including diastereoisomers and enantiomers), tautomers, and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties (e.g., polymorphs, solvates and/or hydrates).
  • salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. It is noted that salts of the novel compounds described herein are of course useful as precursors for the neutral species or for pharmaceutically acceptable salts.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by one or more CDK enzymes, or (ii) associated with one or more CDK enzyme activities, or (iii) characterized by activity of proteins regulated (directly or indirectly) by one or more CDK enzymes (e.g. RNA polymerase II); or (2) reducing or inhibiting the expression of proteins whose expression is dependent (directly or indirectly) on one or more CDK enzymes (e.g. Mcl-1 , Cyclin D, Myc etc.).
  • CDK enzymes e.g. RNA polymerase II
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of proteins regulated by one or more CDK enzymes; or at least partially reducing or inhibiting the expression of proteins whose expression is dependent (directly or indirectly) on one or more CDK enzymes.
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans
  • the subject is a primate.
  • the subject is a human.
  • the invention provides pyrimidine compounds having a bi-aryl core structure with a pyrimidine ring connected to a second heterocyclic ring, wherein each ring has a nitrogen-containing substituent attached at a position 'meta' to the biaryl linkage.
  • the compound is of one of Formulas l-VII as described herein.
  • R is a heterocyclic or cycloalkyl group selected from piperidinyl, morpholinyl, 1 -methylpiperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, pyrrolidin-2-one, azepanyl, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, and 1 ,4-oxazepane.
  • R is selected from cyclohexyl, piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, and 1 ,4-oxazepanyl, preferably cyclohexyl, piperidinyl, or pyrrolidinyl.
  • R 2 can be selected from H, F and CI. In some embodiments, R 2 is F or CI. R 5 , when present, can be H, F or CI, and in some embodiments, it is H.
  • R 6 when present, is selected from H, F and CI; in preferred embodiments, R 6 is H.
  • R 7 when present, is typically H, F or CI, and is preferably H; except when R 2 is H, then R 7 is preferably F or CI.
  • R 8 is sometimes H and sometimes Me. Preferably, R 8 is H.
  • R 9 in these compounds is selected from Ci_ 3 alkyl, C 4 . 6 branched alkyl, - (CH 2 )i-3-0-Ci. 4 alkyl, -(CH 2 )-pyridyl, phenyl, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran-1 -dioxide, piperidinyl, pyrrolidin-2-one, dioxane, cyclopropyl, tetrahydrofuran, cydohexyl, and cycloheptyl, each of which can be substituted with up to three substituents, which substituents are selected from halo, -OCHF 2 , -C(0)-Me, -OH, - Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , and -NH-C(0)-Me.
  • L is CH 2 ; frequently, R 9 is selected from cyclopropyl, tetrahydropyranyl, and phenyl, and R 9 is often substituted with -OH, -Me, -OMe, -CN, -Ethyl, vinyl, or ethynyl.
  • -L-R 9 is
  • R 0 and R and R 2 each independently represent H, F, -OH, Me, vinyl, ethynyl, ethyl, -OMe and CN.
  • R 2 is present and is selected from Me, OMe, OH, and CN.
  • R 0 and R are selected from H, F, Me, and OMe.
  • R is selected from piperidinyl, morpholinyl, 1-methylpiperidinyl, tetrahydropyran, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, pyrrolidin-2-one, azepane, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, and 1 ,4-oxazepane,
  • R 2 is H, CI or F
  • L is C 0 - 3 alkylene, CD 2 , CHD, or C 3 . 8 branched alkylene;
  • R 6 is H, F or CI
  • R 7 is H, F or CI
  • R 8 is H or methyl
  • R 9 is selected from C1.3 alkyl, C 4 . 6 branched alkyl, -(CH2)i.3-0-Ci -4 alkyl, -(CH 2 )- pyridyl, phenyl, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran-1 -dioxide, piperidinyl, pyrrolidin-2-one, dioxane, cyclopropyl, tetrahydrofuran, cyclohexyl, and cycloheptyl, each of which can be substituted with up to three substituents, which substituents are selected from halo, -OCHF 2 , -C(0)-Me, -OH, -Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , and -NH-C(0)-Me.
  • R is substituted with 1-3 groups selected from F, - OH, cyano, -NH 2 , -C(0)Me, -NH-Me, ethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,
  • R 8 is H. In some preferred embodiments, at least one of R 6 and R 7 is H. In many embodiments, R 2 is CI or F. 2. The compound of embodiment 1 , wherein:
  • R is selected from piperidinyl, morpholinyl, pyrrolidinyl, azepane, and 1 ,4- oxazepane,
  • R 2 is F or CI
  • L is CH 2 , CHD, or CD 2 ;
  • R 9 is selected from pyridyl, phenyl, tetrahydropyran, dioxane, and
  • tetrahydrofuran each of which can be substituted with up to three groups independently selected from F, -OH, Me, vinyl, ethynyl, ethyl, -OMe and CN.
  • L is CH 2 .
  • R 9 is phenyl or tetrahydropyran, and often R 9 is substituted.
  • R 0 and R and R 2 each independently represent H, F, -OCHF 2 , - C(0)-Me, -OH, Me, -OMe, -CN, -Ethyl, -CONH 2 , or vinyl, ethynyl, -NH-C(0)-Me, preferably H, F, -OH, Me, ethyl, -OMe or CN.
  • R 2 is preferably CN.
  • R 0 and R are typically H, F, Me or OMe.
  • R is selected from piperidinyl, morpholinyl, 1-methylpiperidinyl, tetrahydropyran, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, pyrrolidin-2-one, azepane, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, and 1 ,4-oxazepane,
  • R 2 is H, CI or F
  • L is C 0 - 3 alkylene, CD 2 , CHD, or C 3 . 8 branched alkylene;
  • R 6 is H, F or CI
  • R 5 is H, F or CI
  • R 8 is H or methyl
  • R 9 is selected from d -3 alkyl, C 4 . 6 branched alkyl, -(CH 2 )i.3-0-Ci -4 alkyl, -(CH 2 )- pyridyl, phenyl, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran-1 -dioxide, piperidinyl, pyrrolidin-2-one, dioxane, cyclopropyl, tetrahydrofuran, cyclohexyl, and cycloheptyl, each of which can be substituted with up to three substituents, which substituents are selected from halo, -OCHF 2 , -C(0)-Me, -OH, -Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , and -NH-C(0)-Me.
  • R is substituted with 1-3 groups selected from F, - OH, cyano, -NH 2 , -C(0)Me, -NH-Me, ethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,
  • R 8 is H. In some preferred embodiments, at least one of R 6 and R 7 is H. In many embodiments, R 2 is CI or F. 7. The compound of embodiment 6, wherein:
  • R is selected from piperidinyl, morpholinyl, pyrrolidinyl, azepane, and 1 ,4- oxazepane,
  • R 2 is F or CI
  • L is CH 2 , CHD, or CD 2 ;
  • R 9 is selected from pyridyl, phenyl, tetrahydropyran, dioxane, and
  • tetrahydrofuran each of which can be substituted with up to three groups independently selected from F, -OH, Me, vinyl, ethynyl, ethyl, -OMe and CN.
  • R 0 and R and R 2 each independently represent H, F, -OCHF 2 , - C(0)-Me, -OH, Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , or -NH-C(0)-Me, preferably H, F, -OH, Me, ethyl, -OMe or CN.
  • R 2 is preferably CN.
  • R 0 and R are typically H, F, Me or
  • R is an optionally substituted cyclohexyl, piperidine, or pyrrolidine.
  • R is selected from piperidinyl, morpholinyl, 1-methylpiperidinyl, tetrahydropyran, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, pyrrolidin-2-one, azepane, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, and 1 ,4-oxazepane,
  • R 2 is H, CI or F
  • L is C 0 - 3 alkylene, CD 2 , CHD, or C 3 . 8 branched alkylene;
  • R 6 is H, F or CI
  • R 5 is H, F or CI
  • R 8 is H or methyl
  • R 9 is selected from d -3 alkyl, C 4 . 6 branched alkyl, -(CH 2 )i.3-0-Ci -4 alkyl, -(CH 2 )- pyridyl, phenyl, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran-1 -dioxide, piperidinyl, pyrrolidin-2-one, dioxane, cyclopropyl, tetrahydrofuran, cyclohexyl, and cycloheptyl, each of which can be substituted with up to three substituents, which substituents are selected from halo, -OCHF 2 , -C(0)-Me, -OH, -Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , and -NH-C(0)-Me.
  • R is substituted with 1-3 groups selected from F, - OH, cyano, -NH 2 , -C(0)Me, -NH-Me, ethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,
  • R 8 is H. In some preferred embodiments, at least one of R 6 and R 7 is H. In many embodiments, R 2 is CI or F. 12. The compound of embodiment 6, wherein:
  • R is selected from piperidinyl, morpholinyl, pyrrolidinyl, azepane, and 1 ,4- oxazepane,
  • R 2 is F or CI
  • L is CH 2 , CHD, or CD 2 ;
  • R 9 is selected from pyridyl, phenyl, tetrahydropyran, dioxane, and
  • tetrahydrofuran each of which can be substituted with up to three groups independently selected from F, -OH, Me, vinyl, ethynyl, ethyl, -OMe and CN.
  • R 0 and R and R 2 each independently represent H, F, -OCHF 2 , - C(0)-Me, -OH, Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , or -NH-C(0)-Me, preferably H, F, -OH, Me, ethyl, -OMe or CN.
  • R 2 is preferably CN.
  • R 0 and R are typically H, F, Me or
  • R is selected from piperidinyl, morpholinyl, 1-methylpiperidinyl, tetrahydropyran, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, pyrrolidin-2-one, azepane, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, and 1 ,4-oxazepane,
  • R 2 is H, CI or F
  • L is Co-3 alkylene, CD 2 , CHD, or C 3 . 8 branched alkylene;
  • R 6 is H, F or CI
  • R 5 is H, F or CI
  • R 8 is H or methyl
  • R 9 is selected from Ci -3 alkyl, C 4 . 6 branched alkyl, -(CH 2 )i-3-0-Ci -4 alkyl, -(CH 2 )- pyridyl, phenyl, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran-1 -dioxide, piperidinyl, pyrrolidin-2-one, dioxane, cyclopropyl, tetrahydrofuran, cyclohexyl, and cycloheptyl, each of which can be substituted with up to three substituents, which substituents are selected from halo, -OCHF 2 , -C(0)-Me, -OH, -Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , and -NH-C(0)-Me.
  • R is substituted with 1-3 groups selected from F, -
  • R 8 is H. In some preferred embodiments, at least one of R 6 and R 7 is H. In many embodiments, R 2 is CI or F.
  • R is selected from piperidinyl, morpholinyl, pyrrolidinyl, azepane, and 1 ,4- oxazepane,
  • R 2 is F or CI
  • L is CH 2 , CHD, or CD 2 ; and R 9 is selected from pyridyl, phenyl, tetrahydropyran, dioxane, and
  • tetrahydrofuran each of which can be substituted with up to three groups independently selected from F, -OH, Me, vinyl, ethynyl, ethyl, -OMe and CN.
  • R 0 and R and R 2 each independently represent H, F, -OCHF 2 , - C(0)-Me, -OH, Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , or -NH-C(0)-Me, preferably H, F, -OH, Me, ethyl, -OMe or CN.
  • R 2 is preferably CN.
  • R 0 and R are typically H, F, Me or
  • R is selected from piperidinyl, morpholinyl, 1-methylpiperidinyl, tetrahydropyran, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, pyrrolidin-2-one, azepane, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, and 1 ,4-oxazepane,
  • R 2 is H, CI or F
  • L is C 0 - 3 alkylene, CD 2 , CHD, or C 3 . 8 branched alkylene;
  • R 6 is H, F or CI
  • R is H or methyl
  • R 9 is selected from Ci -3 alkyl, C 4 . 6 branched alkyl, -(CH 2 )i-3-0-Ci -4 alkyl, -(CH 2 )- pyridyl, phenyl, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran-1 -dioxide, piperidinyl, pyrrolidin-2-one, dioxane, cyclopropyl, tetrahydrofuran, cyclohexyl, and cycloheptyl, each of which can be substituted with up to three substituents, which substituents are selected from halo, -OCHF 2 , -C(0)-Me, -OH, -Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , and -NH-C(0)-Me.
  • R is substituted with 1-3 groups selected from F, -
  • R 8 is H. In some preferred embodiments, at least one of R 6 and R 7 is H. In many embodiments, R 2 is CI or F.
  • R is selected from piperidinyl, morpholinyl, pyrrolidinyl, azepane, and 1 ,4- oxazepane,
  • R 2 is F or CI
  • L is CH 2 , CHD, or CD 2 ;
  • R 9 is selected from pyridyl, phenyl, tetrahydropyran, dioxane, and
  • tetrahydrofuran each of which can be substituted with up to three groups independently selected from F, -OH, Me, vinyl, ethynyl, ethyl, -OMe and CN.
  • R 0 and R and R 2 each independently represent H, F, -OCHF 2 , - C(0)-Me, -OH, Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , or -NH-C(0)-Me, preferably H, F, -OH, Me, ethyl, -OMe or CN.
  • R 2 is preferably CN.
  • R 0 and R are typically H, F, Me or OMe.
  • R is selected from piperidinyl, morpholinyl, 1-methylpiperidinyl, tetrahydropyran, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, pyrrolidin-2-one, azepane, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, and 1 ,4-oxazepane,
  • R 2 is H, CI or F
  • R 5 is H, F or CI
  • L is C 0 - 3 alkylene, CD 2 , CHD, or C 3 . 8 branched alkylene;
  • R 8 is H or methyl
  • R 9 is selected from Ci -3 alkyl, C 4 . 6 branched alkyl, -(CH 2 )i-3-0-Ci -4 alkyl, -(CH 2 )- pyridyl, phenyl, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran-1 -dioxide, piperidinyl, pyrrolidin-2-one, dioxane, cyclopropyl, tetrahydrofuran, cyclohexyl, and cycloheptyl, each of which can be substituted with up to three substituents, which substituents are selected from F, -OCHF 2 , -C(0)-Me, -OH, -Me, -OMe, -CN, vinyl, ethynyl, -Ethyl, and -NH-C(0)-Me.
  • R is substituted with 1-3 groups selected from F, - OH, cyano, -NH 2 , -C(0)Me, -NH-Me, ethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,
  • R 8 is H. In some preferred embodiments, at least one of R 6 and R 7 is H. In many embodiments, R 2 is CI or F.
  • R 2 is F or CI
  • L is CH 2 , CHD, or CD 2 ;
  • R 9 is selected from pyridyl, phenyl, tetrahydropyran, dioxane, and
  • tetrahydrofuran each of which can be substituted with up to three groups independently selected from F, -OH, Me, vinyl, ethynyl, ethyl, -OMe and CN.
  • R 0 and R and R 2 each independently represent H, F, -OCHF 2 , - C(0)-Me, -OH, Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , or -NH-C(0)-Me, preferably H, F, -OH, Me, ethyl, -OMe or CN.
  • R 2 is preferably CN.
  • R 0 and R are typically H, F, Me or
  • R is selected from piperidinyl, morpholinyl, 1-methylpiperidinyl, tetrahydropyran, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, pyrrolidin-2-one, azepane, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, and 1 ,4-oxazepane,
  • R 2 is H, CI or F
  • L is C 0 - 3 alkylene, CD 2 , CHD, or C 3 . 8 branched alkylene;
  • R 7 is H, F or CI
  • R is H or methyl
  • R 9 is selected from Ci -3 alkyl, C 4 . 6 branched alkyl, -(CH 2 )i-3-0-Ci -4 alkyl, -(CH 2 )- pyridyl, phenyl, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran-1 -dioxide, piperidinyl, pyrrolidin-2-one, dioxane, cyclopropyl, tetrahydrofuran, cyclohexyl, and cycloheptyl, each of which can be substituted with up to three substituents, which substituents are selected from halo, -OCHF 2 , -C(0)-Me, -OH, -Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , and -NH-C(0)-Me.
  • R is substituted with 1-3 groups selected from F, -
  • R 8 is H. In some preferred embodiments, at least one of R 6 and R 7 is H. In many embodiments, R 2 is CI or F.
  • R is selected from piperidinyl, morpholinyl, pyrrolidinyl, azepane, and 1 ,4- oxazepane,
  • R 2 is F or CI
  • L is CH 2 , CHD, or CD 2 ;
  • R 9 is selected from pyridyl, phenyl, tetrahydropyran, dioxane, and
  • tetrahydrofuran each of which can be substituted with up to three groups independently selected from F, -OH, Me, vinyl, ethynyl, ethyl, -OMe and CN.
  • R 0 and R and R 2 each independently represent H, F, -OCHF 2 , - C(0)-Me, -OH, Me, -OMe, -CN, -Ethyl, vinyl, ethynyl, -CONH 2 , or -NH-C(0)-Me, preferably H, F, -OH, Me, ethyl, -OMe or CN.
  • R 2 is preferably CN.
  • R 0 and R are typically H, F, Me or
  • the condition is cancer.
  • the cancer is selected from the group consisting of bladder, head and neck, breast, stomach, ovary, colon, lung, brain, larynx, lymphatic system, hematopoietic system, genitourinary tract, gastrointestinal, ovarian, prostate, gastric, bone, small-cell lung, glioma, colorectal, and pancreatic cancer.
  • a method to treat cancer comprising administering to a subject in need thereof an effective amount of a compound according to any of embodiments 1-35.
  • chemotherapeutic agent chemotherapeutic agent, immunosuppressant, anti-cancer, cytotoxic agent or kinase inhibitor or salt thereof.
  • a pharmaceutical composition comprising a compound according to any of embodiments 1-35 admixed with at least one pharmaceutically acceptable excipient.
  • composition of embodiment 43 which comprises at least one pharmaceutically acceptable carrier and at least one other pharmaceutically acceptable excipient.
  • composition of embodiment 43 or 44 further comprising at least one additional therapeutic agent.
  • composition of embodiment 45 wherein the additional therapeutic agent is an antiinflammatory, antiproliferative, chemotherapeutic agent, immunosuppressant, anti-cancer, cytotoxic agent or kinase inhibitor or a salt thereof.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, PROTECTING GROUPS IN ORGANIC SYNTHESIS, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wsconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's REAGENTS FOR ORGANIC SYNTHESIS,
  • the various starting materials, intermediates, and compounds of the embodiments may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds may be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses.
  • the compounds of the present invention can be isolated and used per se or as their pharmaceutical acceptable salt.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate,
  • bromide/hydrobromide bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate,
  • Inorganic acids from which salts can be derived include, for example,
  • hydrochloric acid hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to VII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be any pharmaceutically acceptable salts of the present invention.
  • salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • the compounds of the present invention also include isotopically labeled forms of the compounds which may be synthesized using the processes described herein or modifications thereof known by those of skill in the art.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, C, 3 C, 4 C, 5 N, 8 F 3 P, 32 P, 35 S, 36 CI, 25 l respectively.
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 3 C, and 4 C, are present.
  • isotopically labeled compounds are useful in metabolic studies (with 4 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission
  • PET tomography
  • SPECT single-photon emission computed tomography
  • drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • 8 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available
  • isotopically labeled reagent for a non-isotopically labeled reagent isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopes particularly deuterium (i.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index.
  • deuterium in this context is regarded as a substituent of a compound of the formula (I).
  • concentration of such a heavier isotope, specifically deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Isotopically-labeled compounds of formula (I) 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 reagents in place of the non-labeled reagent previously employed.
  • the invention includes all enantiomers of any chiral compound disclosed, in either substantially pure levorotatory or dextrorotatory form, or in a racemic mixture, or in any ratio of enantiomers.
  • the compounds disclosed herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the embodiments, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the chemical structure or chemical name is intended to embrace all possible stereoisomers, conformers, rotamers, and tautomers of the compound depicted.
  • a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereomers (including (R,R), (S, S), (R,S), and (R, S) isomers).
  • solvates refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g. , water, ethanol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • solvates and hydrates of the compounds of the present invention are considered compositions, wherein the composition comprises a compound of the present invention and a solvent (including water).
  • the compounds of the present invention may exist in either amorphous or polymorphic form; therefore, all physical forms are considered to be within the scope of the present invention.
  • co-crystals i.e. compounds of the present invention that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
  • co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of formula (I).
  • pro-drugs convert in vivo to the compounds of the present invention.
  • a pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001).
  • bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action.
  • a transport moiety e.g., that improve uptake and/or localized delivery to a site(s) of action.
  • the linkage between the drug moiety and the transport moiety is a covalent bond
  • the prodrug is inactive or less active than the drug compound
  • any released transport moiety is acceptably non-toxic.
  • the transport moiety is intended to enhance uptake
  • the release of the transport moiety should be rapid.
  • it is desirable to utilize a moiety that provides slow release e.g., certain polymers or other moieties, such as cyclodextrins.
  • Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
  • lipophilicity can be increased by esterification of (a) hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) carboxylic acid groups with lipophilic alcohols (e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols).
  • prodrugs are, e.g., esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein.
  • Suitable prodrugs are often pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the -(amino, mono- or di- lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the -(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art
  • a typical pharmaceutical composition comprises a compound of the present invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • pharmaceutically acceptable carriers, diluents or excipients includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic agents, its use in the therapeutic agents, its use in the therapeutic agents, its use in the therapeutic agents, its use
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, and parenteral administration, etc.
  • the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • the pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose
  • Tablets may be uncoated, film coated, or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide
  • Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • Certain injectable compositions are aqueous isotonic solutions or suspensions, and
  • suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1-50%, of the active ingredient.
  • compositions and dosage forms that may comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose.
  • agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
  • the compounds of the invention in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, e.g. CDK inhibiting properties, e.g. as indicated in vitro and in vivo tests as provided below and are therefore indicated for therapy.
  • CDK inhibiting properties e.g. as indicated in vitro and in vivo tests as provided below and are therefore indicated for therapy.
  • an individual “in need thereof” may be an individual who has been diagnosed with or previously treated for the condition to be treated. With respect to prevention, the individual in need thereof may also be an individual who is at risk for a condition (e.g., a family history of the condition, life-style factors indicative of risk for the condition, etc.).
  • a step of administering a compound of the invention is disclosed herein, the invention further contemplates a step of identifying an individual or subject in need of the particular treatment to be
  • compounds of the invention can be synthesized using the methods described herein, or other methods known to one skilled in the art.
  • the compounds of the invention are readily prepared by the methods illustrated herein for making and using compounds of Formula (A).
  • the compounds and/or intermediates described herein were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2695 Separation Module (Milford, MA). The analytical columns were reversed phase
  • TLC thin layer chromatography
  • glass or plastic backed silica gel plates such as, for example, Baker-Flex Silica Gel 1 B2-F flexible sheets.
  • TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.
  • Mass spectrometric analysis was performed on LCMS instruments: Waters
  • GCMS analysis is performed on a Hewlett Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; injector volume: 1 L; initial column temperature: 50 °C; final column temperature: 250 °C; ramp time: 20 minutes; gas flow rate: 1 mL/min; column: 5 % phenyl methyl siloxane, Model No. HP 190915-443, dimensions: 30.0 m x 25 m x 0.25 m).
  • NMR Nuclear magnetic resonance
  • spectral reference was either TMS or the known chemical shift of the solvent.
  • Some compound samples were run at elevated temperatures (e.g., 75 oC) to promote increased sample solubility. Melting points are determined on a Laboratory Devices Mel-Temp apparatus (Holliston, MA).
  • Preparative separations are carried out using a Combiflash Rf system (Teledyne Isco, Lincoln, NE) with RediSep silica gel cartridges (Teledyne Isco, Lincoln, NE) or SiliaSep silica gel cartridges (Silicycle Inc., Quebec City, Canada) or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a Waters 2767 Sample Manager, C-18 reversed phase column, 30X50 mm, flow 75 mL/min.
  • Combiflash Rf system Teledyne Isco, Lincoln, NE
  • RediSep silica gel cartridges Teledyne Isco, Lincoln, NE
  • SiliaSep silica gel cartridges Sicycle Inc., Quebec City, Canada
  • HPLC Waters 2767 Sample Manager, C-18 reversed phase column, 30X50 mm, flow 75 mL/min.
  • Typical solvents employed for the Combiflash Rf system and flash column chromatography are dichloromethane, methanol, ethyl acetate, hexane, heptane, acetone, aqueous ammonia (or ammonium hydroxide), and triethyl amine.
  • Typical solvents employed for the reverse phase HPLC are varying concentrations of acetonitrile and water with 0.1 % trifluoroacetic acid.
  • BINAP 2,2'-bis(diphenylphosphino)-1 , 1'-binapthyl
  • DIPEA N,N-diisopropylethylamine
  • HATU 2-(7-aza-1 H-benzotriazole-1-yl)-1 , 1 ,3,3-tetramethyluronium
  • NBS N-bromosuccinimide
  • synthesis can start with a functionalized pyridine I wherein LG is a leaving group such as F, CI, OTf, and the like.
  • X can be a functional group like CI, Br, I or OTf.
  • Compound I can be converted into boronic acid or boronic ester II by:
  • Suzuki cross-coupling reaction between compound II and pyridine III then gives bi- heteroaryl intermediate IV.
  • the SN AR reaction between IV and ammonium hydroxide in a solvent such as DMF, THF, DMSO, NMP, dioxane with heating (30-130 °C) can give compound V.
  • Coupling of the nascent amino pyridine V with an acyl intermediate bearing a leaving group in the presence of a base such as Et 3 N, iPr 2 NEt or pyridine in a solvent such as DMF, THF, DMSO, NMP, dioxane can give compound VI.
  • Ri' is not identical to further functional manipulation is needed to obtain VII.
  • F is identical to compound VII will be the same as compound VI.
  • Compound I can be converted into boronic acid or boronic ester II by:
  • Compound I can be converted into boronic acid or boronic ester II by:
  • Compound I can be converted into boronic acid or boronic ester II by:
  • Compound I can be converted into boronic acid or boronic ester II by:
  • Compound I can be converted into boronic acid or boronic ester II by: 1) PdCI 2 (dppf) DCM adduct, potassium acetate, bis(pinacolato)diboron heating from 30 - 120 °C in solvents such as THF, DMF, DME, DMA, toluene and dioxane; and 2) In a solvent such as THF or diethylether, anion halogen exchange by addition of nBuLi or LDA followed by quenching the anion with triisopropyl borate. Upon hydrolysis a boronic acid can be obtained. Suzuki cross-coupling reaction between compound II and functionalize pyridine III then gives bi-heteroaryl intermediate IV.
  • Compound I can be converted into boronic acid or boronic ester II by:
  • Compound I can be converted into boronic acid or boronic ester II by:
  • Compound I can be converted into boronic acid or boronic ester II by:
  • Compound I can be converted into boronic acid or boronic ester II by:
  • Compound I can be converted into boronic acid or boronic ester II by:
  • the SN AR reaction between IV and ammonium hydroxide in a solvent such as DMF, THF, DMSO, NMP, dioxane with heating (30-130 °C) can give compound V.
  • the SN AR reaction between V and a functionalized amine NH 2 Ri' under basic condition (DIEA, TEA, lutidine, pyridine) in a solvent such as DMF, THF, DMSO, NMP, dioxane with heating (30-180 °C) can give compound VI.
  • the SN AR reaction between IV and ammonium hydroxide in a solvent such as DMF, THF, DMSO, NMP, dioxane with heating (30-130 °C) can give compound V.
  • the SN AR reaction between V and a functionalized amine NH 2 Ri' under basic condition (DIEA, TEA, lutidine, pyridine) in a solvent such as DMF, THF, DMSO, NMP, dioxane with heating (30-180 °C) can give compound VI.
  • Step 1 Preparation of S'-chloro ⁇ '-fluoro-N-iS-fluorobenzy ⁇ '-bipyridin-e-amine
  • Step 2 Preparation of 5'-chloro-N6-(3-fluorobenzyl)-2,4'-bipyridine-2 ⁇ 6-diamine A mixture of 5'-chloro-2'-fluoro-N-(3-fluorobenzyl)-2,4'-bipyridin-6-amine (50 mg,
  • Step 1 Preparation of 5 , -chloro-2 , -fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine
  • Step 2 Preparation of S'-chloro-Ne-iitetrahydro ⁇ H-pyran ⁇ -y methyl) ⁇ , ⁇ - bipyridine-2',6-diamine
  • Step 1 Preparation of ⁇ 5'-chloro-6-[(tetrahydro-pyran-4-ylmethyl)-amino]- [2,4']bipyridinyl-2'-yl ⁇ -carbamic acid tert-butyl ester
  • Step 1 Preparation of 5 , -chloro-2 , -fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3,4'- bipyridin-5-amine
  • Step 2 Preparation of 5'-chloro-N5-((tetrahydro-2H-pyran-4-yl)methyl)-3,4'- bipyridine-2',5-diamine
  • Step 1 Preparation of S ⁇ e-dichloro ⁇ '-fluoro-N-iitetrahydro ⁇ H-pyran- ⁇ y methyl)- 3,4'-bipyridin-5-amine
  • N-bromo-2-chloro-N-((tetrahydro-2H-pyran-4- yl)methyl)pyridin-3-amine (1 g, 3.27 mmol
  • 2M aqueous sodium carbonate solution (4.25 mL, 8.51 mmol)
  • 5-chloro-2-fluoropyridin-4-ylboronic acid 0.975 g, 5.56 mmol
  • DME 20 mL
  • Step 2 Preparation of S' ⁇ -dichloro-NS-iitetrahydro ⁇ H-pyran ⁇ -y methy -S, ⁇ - bipyridine-2',5-diamine
  • Step 1 Preparation of S ⁇ '-dichloro ⁇ '-fluoro-N-iitetrahydro ⁇ H-pyran- ⁇ y methyl)- 2,4'-bipyridin-6-amine
  • Step 2 Preparation of S.S'-dichloro-Ne-tttetrahydro ⁇ H-pyran ⁇ -y methyl)- ⁇ - bipyridine-2',6-diamine
  • Step 1 Preparation of S j S'-dichloro ⁇ '-fluoro-N-iitetrahydro ⁇ H-pyran- ⁇ y methyl)- 2,4'-bipyridin-6-amine
  • Step 2 Preparation of S.S'-dichloro-Ne-tttetrahydro ⁇ H-pyran ⁇ -y methyl)- ⁇ - bipyridine-2',6-diamine
  • Step 1 Preparation of 6-bromo-3,5-dichloro-N-((tetrahydro-2H-pyran-4-yl)methyl)- pyridin-2-amine/ 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-pyridin-2- amine
  • Step 1 Preparation of S ⁇ S'-trichloro ⁇ '-fluoro-N-iitetrahydro ⁇ H-pyran ⁇ - yl)methyl)-2,4'-bipyridin-6-amine
  • Step 2 Preparation of 3,5,5 , -trichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4 , - bipyridine-2',6-diamine
  • a mixture of 3,5,5'-trichloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridin-6-amine (450 mg, 1.152 mmol) and ammonium hydroxide (aqueous solution 30- 35 wt.%, 10 mL) in DMSO (10 mL) was heated in a steel bomb at 135 °C for 16 hrs. The mixture was cooled to room temperature and diluted with EtOAc and brine.
  • tetrahydrofuran 27 mL was degassed by purging argon through the mixture for 10 min.
  • a 2M aqueous sodium carbonate solution 13.30 mL, 26.6 mmol
  • PdCI 2 (dppf) CH 2 CI 2 adduct 0.652 g, 0.798 mmol
  • the reaction mixture was stirred at 100 °C for 2 hrs in a sealed vessel.
  • the reaction mixture was cooled and diluted with EtOAc and water.
  • the separated organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure.
  • Step 1 Preparation of 3,6-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2- amine
  • Step 2 Preparation of 3-fluoro-6-methoxy-N-((tetrahydro-2H-pyran-4- yl)methyl)pyridin-2-amine
  • Step 1 Preparation of 5'-ch ⁇ oro-2 5-d ⁇ f ⁇ uoro-N- ⁇ tetrahydro-2H-pyran-4-y ⁇ )methy ⁇ )- 2,4'-bipyridin-6-amine
  • Step 1 Preparation of 3,5'-dichloro-2 ⁇ 5-difluoro-N-((tetrahydro-2H-pyran-4- yl)methyl)-2,4'-bipyridin-6-amine
  • Step 2 Preparation of 3,5'-clicando-5-fluoro-N6-((tetrariyclro-2H-pyran-4-yl)metriyl)- 2,4'-bipyridine-2',6-diamine
  • Step 1 Preparation of 5'-chloro-2'-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5- (trifluoromethyl)-2,4'-bipyridin-6-amine
  • Step 2 Preparation of 5'-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-5- (trifluoromethyl)-2,4'-bipyridine-2',6-diamine
  • reaction mixture was warmed to room temperature and stirring was continued for an additional hour.
  • the reaction mixture was diluted with aqueous sodium hydroxide solution (4 wt.%, 34 mL).
  • the mixture was extracted with EtOAc (3x 50 mL).
  • the combined organic layers washed with brine (50 mL), dried over sodium sulfate, filtered off and concentrated under reduced pressure.
  • the residue was triturated with diethylether to give 2,5-difluoropyridin-4-ylboronic acid (808 mg).
  • Step 2 Preparation of 3-chloro-2 , ,5'-difluoro- V-((tetrahydro-2H-pyran-4-yl)methyl)- 2,4'-bipyridin-6-amine
  • Step 3 Preparation of 3-chloro-5'-fluoro-N6-((tetrahydro-2H-pyran-4-yl)methyl)- 2,4'-bipyridine-2',6-diamine
  • Step 1 Preparation of 2 , -fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4'-bipyridin- 6-amine
  • Step 2 Preparation of N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4 , -bipyridine-2 , ,6- diamine
  • Step 1 Preparation of (R,E)-2-methyl-N-((tetrahydro-2H-pyran-4- yl)methylene)propane-2-sulfinamide
  • Step 2 Preparation of (R)-2-methyl-N-((S)-1 -(tetrahydro-2H-pyran-4- yl)ethyl)propane-2-sulfinamide
  • (R,E)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane- 2-sulfinamide (0.93 g, 4.28 mmol) in dichloromethane (21.4 mL) at 0 °C was added slowly methylmagnesium bromide (2.0 M in tetrahydrofuran, 4.28 mL, 8.56 mmol).
  • dichloromethane (21.4 mL) at 0 °C
  • methylmagnesium bromide 2.0 M in tetrahydrofuran, 4.28 mL, 8.56 mmol
  • Step 1 Preparation of (S)-3,5 , -dichloro-2'-fluoro-N-(1-(tetrahydro-2H-pyran-4- yl)ethyl)-2,4'-bipyridin-6-amine
  • Step 2 Preparation of (S)-3,5 , -dichloro-N6-(1 -(tetrahydro-2H-pyran-4-yl)ethyl)-2,4'- bipyridine-2',6-diamine
  • Step 1 Preparation of (S,E)-2-methyl-N-((tetrahydro-2H-pyran-4- yl)methylene)propane-2-sulfinamide
  • Step 2 Preparation of (S)-2-methyl-N-((R)-1 -(tetrahydro-2H-pyran-4- yl)ethyl)propane-2-sulfinamide
  • Step 4 Preparation of (R)-6-bromo-N-(1 -(tetrahydro-2H-pyran-4-yl)ethyl)pyridin-2- amine
  • Step 5 Preparation of (R)-6-bromo-5-chloro-N-(1-(tetrahydro-2H-pyran-4- yl)ethyl)pyridin-2-amine
  • acetonitrile 5 mL
  • N-chlorosuccinimide 94 mg, 0.701 mmol
  • Step 1 Preparation of (RJ-S ⁇ '-dichloro ⁇ '-fluoro-N-il -itetrahydro ⁇ H-pyran ⁇ - yl)ethyl)-2,4'-bipyridin-6-amine
  • Step 2 Preparation of (R)-3,5'-dichloro-N6-(1 -(tetrahydro-2H-pyran-4-yl)ethyl)-2,4'- bipyridine-2',6-diamine
  • Step 1 Preparation of (5 , -chloro-2 , -fluoro-[2,4 , ]bipyridinyl-6-yl)-(2,2-dimethyl- tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester
  • Step 2 Preparation of 5 , -chloro-N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)- 2'-fluoro-2,4'-bipyridin-6-amine
  • Amount 420 mg dissolved in isopropyl alcohol, 21 mg/mL.
  • Step 1 Preparation of tert-butyl 6-bromopyridin-2-ylcarbamate
  • Step 3 Preparation of tert-butyl (6-bromopyridin)-2-yl((2,2-dimethyltetrahydro-2H- pyran-4-yl)methyl)carbamate
  • Amount 150 g dissolved in isopropyl alcohol, 100 mg/mL.
  • Injection volume 10 ⁇ _.
  • Step l Preparation of tert-butyl 6-bromopyridin-2-ylcarbamate
  • Step 2 Preparation of tert-butyl 6-bromo-5-chloropyridin-2-ylcarbamate
  • Step 3 Preparation of (6-bromo-5-chloro-pyridin-2-yl)-(2,2-dimethyl-tetrahydro- pyran-4-ylmethyl)-carbamic acid tert-butyl ester
  • Step 1 Preparation of (3,5 , -dichloro-2 , -fluoro-[2,4 , ]bipyridinyl-6-yl)-(2,2-dimethyl- tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester
  • Step 2 Preparation of 3,5'-dichloro-N-((2,2-dimethyltetrahydro-2H-pyran-4- yl)methyl)-2'-fluoro-2,4'-bipyridin-6-amine
  • Amount 1.65 g dissolved in isobutanol, 200 mg/mL.
  • Solvent C0 2 /isopropyl alcohol/diethylamine 95 : 4.9 : 0.1.
  • Step 2 Preparation of 6-bromo-5-chloro-N-((2,2-dimethyltetrahydro-2H-pyran-4- yl)methyl)pyridin-2-amine
  • Step 3 Preparation of 3,5'-dichloro-N-((2,2-dimethyltetrahydro-2H-pyran-4- yl)methyl)-2'-fluoro-2,4'-bipyridin-6-amine
  • Step 4 Preparation of 3,5'-dichloro-N6-((2,2-dimethyltetrahydro-2H-pyran-4- yl)methyl)-2,4'-bipyridine-2',6-diamine
  • Step 3 Preparation of N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-3-fluoro-6- methoxy py ri d i n-2-am i ne
  • Step A-3 Preparation of N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-3- fluoro-6-(4-methoxybenzyloxy)pyridin-2-amine
  • Step 5 Preparation of 6-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-5- fluoropyridin-2-yl trifluoromethanesulfonate
  • Step 1 Preparation of 5'- ⁇ - ⁇ -((2,2- ⁇ 3 ⁇ -2 ⁇ - ⁇ - ⁇ 3 ⁇ -4- ⁇ ) ⁇ )- 2',5-difluoro-2,4'-bipyridin-6-amine
  • Step 2 Preparation of 5'-chloro-N6-((2,2-dimethyltetrahydro-2H-pyran-4- yl)methyl)-5-fluoro-2,4'-bipyridine-2',6-diamine
  • Step 4 Preparation of (6,6-dimethyl-1 ,4-dioxan-2-yl)methyl methanesulfonate
  • Step 5 Preparation of 6-bromo-N-((6,6-dimethyl-1 ,4-dioxan-2-yl)methyl)pyridin-2- amine
  • Step 1 Preparation of S'-chloro-N-iieje-dimethyl-l ⁇ -dioxan ⁇ -y methy ⁇ '-fluoro- 2,4'-bipyridin-6-amine
  • Step 2 Preparation of S'-chloro-Ne-iie ⁇ -dimethyl-l ⁇ -dioxan ⁇ -y methyl) ⁇ , ⁇ - bipyridine-2',6-diamine
  • dichloromethane 70 mL was added MCPBA ( ⁇ 77 wt.%, 15.71 g) at 0 °C. The suspension was stirred at 0 °C for 6.5 hrs before saturated aqueous sodium bicarbonate solution and aqueous sodium thiosulfate solution were added. The mixture was stirred at 0 °C for 15 min. The separated aqueous layer was extracted with dichloromethane (2x). The combined organic layers were dried over sodium sulfate, filtered off and
  • Step 1 Preparation of 5'-chloro-N-((5,5-dimethyl-1,4-dioxan-2-yl)methyl)-2'-fluoro- 2,4'-bipyridin-6-amine
  • Step 2 Preparation of (2R,6S)-4-(methoxymethylene)-2,6-dimethyltetrahydro-2H- pyran
  • tetrahydrofuran 8 ml_
  • sodium bis(trimethylsilyl) amide 1 M solution in tetrahydrofuran, 4.45 ml_
  • Step 4 Preparation of 6-bromo-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl) methyl) pyridin-2-amine
  • Step 1 Preparation of 5'-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4- yl)methyl)-2'-fluoro-2,4'-bipyridin-6-amine
  • Step 2 Preparation of 5'-chloro-N6-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4- yl)methyl)-2,4'-bipyridine ⁇ 6-diamine
  • a mixture of 5'-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)- 2'-fluoro-2,4'-bipyridin-6-amine 60 mg, 0.17 mmol
  • aqueous ammonium hydroxide solution 28 wt.%, 3 ml_
  • DMSO 3 ml_
  • Step 3 Preparation of 6-bromo-N-((4-methyltetrahydro-2H-pyran-4- yl)methyl)pyridin-2-amine
  • Step 1 Preparation of 5'-chloro-2'-fluoro-N-((4-methyltetrariydro-2l-l-pyran-4- yl)methyl)-2,4'-bipyridin-6-amine
  • Step 2 Preparation of 5'-chloro-N6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)- 2,4'-bipyridine-2 , ,6-diamine
  • Step 1a To a solution of DIPEA (6.12 mL, 35.0 mmol) in dichloromethane (80 mL) was added trimethylsilyl trifluoromethanesulfonate (7.79 g, 35.0 mmol) and slowly a solution of tetrahydro-2H-pyran-4-carbaldehyde (2 g, 17.52 mmol) in dichloromethane (80 mL) at 0 °C. Upon completion of the addition, the reaction mixture was stirred at room temperature for 2 hrs. The mixture was concentrated under reduced pressure and the residue was treated with hexane (200 mL).
  • Step 1 b To a solution of crude trimethylsilyl ether in dichloromethane (100 mL) was added dropwise a solution of N-fluorobenzenesulfonimide (5.53 g, 17.52 mmol), dissolved in dichloromethane (50 mL), at 0 °C. The mixture was stirred for 3 hrs at room temperature and the crude solution of 4-fluorotetrahydro-2H-pyran-4-carbaldehyde was directly used in the next reaction.
  • Step 2 Preparation of 6-bromo-N-((4-fluorotetrahydro-2H-pyran-4- yl)methyl)pyridin-2-amine
  • Step 1 Preparation of 5'-chloro-2'-fluoro-N-((4-fluorotetrariydro-2l-l-pyran-4- yl)methyl)-2,4'-bipyridin-6-amine
  • Step 2 Preparation of 5 , -chloro-N6-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-2,4'- bipyridine-2',6-diamine
  • Step 1 Preparation of 4-((5'-chloro-2'-fluoro-2,4 , -bipyridinyl-6- ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile
  • Step 2 Preparation of 4-((2 , -amino-5'-chloro-2,4 , -bipyridinyl-6- ylamino)methyl)tetrahydro- -pyran-4-carbonitrile
  • Step 1 Preparation of 1 ,6-dioxaspiro[2.5]octane
  • Step 4 Preparation of (6-bromo-5-chloro-pyridin-2-yl)-(4-methoxy-tetrahydro- pyran-4-ylmethyl)-carbamic acid tert-butyl ester
  • Step 1 Preparation of (S j S'-dichloro ⁇ '-fluoro- ⁇ 'lbipyridinyl-e-y -i ⁇ methoxy- tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester
  • Step 1 Preparation of 3,6-difluoro-N-((4-methyltetrahydro-2H-pyran-4- yl)methyl)pyridin-2-amine
  • Step 2 Preparation of 3-fluoro-6-methoxy-N-((4-methyltetrahydro-2H-pyran-4- yl)methyl)pyridin-2-amine
  • Step 3 Preparation of 5-fluoro-6-(((4-methyltetrahydro-2H-pyran-4- yl)methyl)amino)pyridin-2-ol
  • Step 2-a Preparation of 6-(benzyloxy)-3-fluoro-N-((4-methyltetrahydro-2H-pyran-4- yl)methyl)pyridin-2-amine
  • Step 3-a Preparation of 5-fluoro-6-(((4-methyltetrahydro-2H-pyran-4- yl)methyl)amino)pyridin-2-ol
  • Step 1 Preparation of 5'-chloro-2 ⁇ 5-difluoro-N-((4-methyltetrahydro-2H-pyran-4- yl)methyl)-2,4'-bipyridin-6-amine
  • Step 1 Preparation of N-((4-ethyltetrahydro-2H-pyran-4-yl)methyl)-3,6- difluoropyridin-2-amine
  • Step 2 Preparation of N-((4-ethyltetrahydro-2H-pyran-4-yl)methyl)-3-fluoro-6- methoxy py ri d i n-2-am i ne
  • Step 4 Preparation of 6-(((4-ethyltetrahydro-2H-pyran-4-yl)methyl)amino)-5- fluoropyridin-2-yl trifluoromethanesulfonate
  • Step 1 Preparation of 5 , -chloro-N-((4-ethyltetrahydro-2H-pyran-4-yl)methyl)-2',5- difluoro-2,4'-bipyridin-6-amine
  • Step 2 Preparation of 5'-chloro-N6-((4-ethyltetrahydro-2H-pyran-4-yl)methyl)-5- fluoro-2,4'-bipyridine-2',6-diamine

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Abstract

L'invention concerne un composé de formule générale : dans laquelle Z2-Z6 comportent un ou deux atomes d'azote selon le descriptif, comprenant des sels pharmaceutiquement acceptables, des énantiomères, des stéréoisomères, des rotamères, des tautomères, des diastéréomères, ou des racémates de ceux-ci. Ces composés inhibent l'activité de CDK9 et sont par conséquent utiles comme produits pharmaceutiques. L'invention concerne en outre des procédés de traitement d'une maladie ou d'un état médié par CDK9 en utilisant les composés de la formule I et des isomères de ceux-ci, ainsi que des compositions pharmaceutiques comprenant ces composés.
PCT/EP2012/050906 2011-01-28 2012-01-20 Composés de n-acyl pyridine biaryl et leurs utilisations Ceased WO2012101063A1 (fr)

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WO2016061144A1 (fr) 2014-10-14 2016-04-21 The Regents Of The University Of California Utilisation d'inhibiteurs de cdk9 et d'inhibiteurs de brd4 pour inhiber une inflammation
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TWI613193B (zh) * 2012-11-15 2018-02-01 拜耳製藥公司 包含磺醯亞胺基團之５－氟－ｎ－（吡啶－２－基）吡啶－２－胺衍生物
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WO2018177889A1 (fr) 2017-03-28 2018-10-04 Bayer Aktiengesellschaft Nouveaux composés macrocycliques inhibiteurs de ptefb
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US9498471B2 (en) 2011-10-20 2016-11-22 The Regents Of The University Of California Use of CDK9 inhibitors to reduce cartilage degradation
US10639302B2 (en) 2011-10-20 2020-05-05 The Regents Of The University Of California Use of CDK9 inhibitors to reduce cartilage degradation
US10172844B2 (en) 2011-10-20 2019-01-08 The Regents Of The University Of California Use of CDK9 inhibitors to reduce cartilage degradation
US11351161B2 (en) 2011-10-20 2022-06-07 The Regents Of The University Of California Use of CDK9 inhibitors to reduce cartilage degradation
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WO2014060376A1 (fr) 2012-10-18 2014-04-24 Bayer Pharma Aktiengesellschaft 4-(ortho)-fluorophényl-5-fluoropyrimidin-2-yl amines contenant un groupe sulfone
TWI613193B (zh) * 2012-11-15 2018-02-01 拜耳製藥公司 包含磺醯亞胺基團之５－氟－ｎ－（吡啶－２－基）吡啶－２－胺衍生物
WO2014076111A1 (fr) 2012-11-15 2014-05-22 Bayer Pharma Aktiengesellschaft Dérivés n-(pyridin-2-yl)pyrimidin-4-amines contenant un groupe sulfoximine
US9650361B2 (en) 2012-11-15 2017-05-16 Bayer Pharam Aktiengesellschaft N-(pyridin-2-yl)pyrimidin-4-amine derivatives containing a sulfoximine group
CN105189481A (zh) * 2013-03-13 2015-12-23 艾伯维公司 吡啶cdk9激酶抑制剂
WO2014160017A1 (fr) * 2013-03-13 2014-10-02 Abbvie Inc. Inhibiteurs de pyridine cdk9 kinase
US10300073B2 (en) 2014-10-14 2019-05-28 The Regents Of The University Of California Use of CDK9 and BRD4 inhibitors to inhibit inflammation
US11020404B2 (en) 2014-10-14 2021-06-01 The Regents of the University of California, Davis Use of CDK9 and BRD4 inhibitors to inhibit inflammation
WO2016061144A1 (fr) 2014-10-14 2016-04-21 The Regents Of The University Of California Utilisation d'inhibiteurs de cdk9 et d'inhibiteurs de brd4 pour inhiber une inflammation
WO2016059011A1 (fr) 2014-10-16 2016-04-21 Bayer Pharma Aktiengesellschaft Dérivés de benzofuranyle-pyrimidine fluorés contenant un groupe sulfone
CN107873028A (zh) * 2015-06-29 2018-04-03 阿斯利康(瑞典)有限公司 用作cdk9抑制剂的多环酰胺衍生物
WO2017001354A1 (fr) * 2015-06-29 2017-01-05 Astrazeneca Ab Dérivés d'amides polycycliques comme inhibiteurs de la cdk9
US9845331B2 (en) 2015-06-29 2017-12-19 Astrazeneca Ab Chemical compounds
JP2018522869A (ja) * 2015-06-29 2018-08-16 アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ Ｃｄｋ９阻害剤としての多環式アミド誘導体
KR102663113B1 (ko) 2015-06-29 2024-05-02 아스트라제네카 아베 Cdk9 저해제로서의 폴리사이클릭 아미드 유도체
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CN106632021A (zh) * 2016-09-27 2017-05-10 中国药科大学 2‑取代异烟酸类化合物、其制备方法及其用途
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US10377714B2 (en) 2017-08-11 2019-08-13 Taigen Biotechnology Co., Ltd. Trans-isomeric heterocyclic compounds and preparation thereof
US11701347B2 (en) 2018-02-13 2023-07-18 Bayer Aktiengesellschaft Use of 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{4-[(S-methylsulfonimidoyl)methyl]pyridin-2-yl}pyridin-2-amine for treating diffuse large B-cell lymphoma
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