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WO2012101066A1 - Composés de pyridine biarylamine et utilisation de ceux-ci - Google Patents

Composés de pyridine biarylamine et utilisation de ceux-ci Download PDF

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Publication number
WO2012101066A1
WO2012101066A1 PCT/EP2012/050914 EP2012050914W WO2012101066A1 WO 2012101066 A1 WO2012101066 A1 WO 2012101066A1 EP 2012050914 W EP2012050914 W EP 2012050914W WO 2012101066 A1 WO2012101066 A1 WO 2012101066A1
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mmol
compound
mixture
pyran
stirred
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PCT/EP2012/050914
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English (en)
Inventor
William R. Antonios-Mccrea
Paul A. Barsanti
Cheng Hu
Xianming Jin
Xiaodong Lin
Eric J. Martin
Yue Pan
Keith B. Pfister
Paul A. Renhowe
Martin Sendzik
James Sutton
Lifeng Wan
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Novartis Ag
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Publication of WO2012101066A1 publication Critical patent/WO2012101066A1/fr

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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
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

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.
  • CDK cyclin-dependent kinase
  • CDK1-B3 cyclin B1-B3
  • CDK2 cyclin D1-D3
  • CDK4 CDK5
  • CDK6 cyclin E
  • 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.
  • 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). Thus 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 described as CDK9 inhibitors, and accordingly such compounds are useful for treating cancer and other conditions mediated by CDK9 activity:
  • Ri is Ci-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;
  • Ai is N or CR 3 ;
  • a 4 is N or CR 6 , with the proviso that only one of A ! 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, Ci -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.
  • CDK1 protein kinases
  • CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 protein kinases
  • the present invention provides novel biaryl pyridine compounds having structural similarities to the compounds described above, which are also useful to treat cancer and other conditions based on their activity on CDK9.
  • Compounds of the invention are of Formulas l-VI as further described herein.
  • the invention includes pharmaceutically acceptable salts of compounds of any of Formulas l-VI. 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 kinase, including at least CDK9, and are therefore useful for treating conditions mediated by excessive or undesired levels of CDK9 activity, such as the conditions described herein.
  • Another embodiment provides a method of treating a disease or condition mediated by CDK9 by using a compound of Formulas l-VI, or a pharmaceutically acceptable salt thereof. Also provided in another embodiment is 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-VI, 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-VI, or pharmaceutically acceptable salt thereof.
  • a preferred method comprises administering a therapeutically effective amount of a compound of any of Formulas l-VI, or a pharmaceutical composition comprising an effective amount of a compound of any of Formulas l-VI to a subject in need thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of Formulas l-VI, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • 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 includeCDKI , 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 HIV 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. Illustrative examples of cycloalkyl are 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- haloalkyi, 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-Ci_4 alkyl, -NHC(0)-Ci. 4 alkyl, -C(0)-0-Ci. 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 I I); 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 I I
  • 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 compounds having a bi-aryl core structure with a pyridine ring connected to a second heterocyclic ring, wherein each ring has an additional substituent attached at a position 'meta' to the biaryl linkage.
  • R is selected from the group consisting of d_ 6 alkyl, C 3 . 6 branched alkyl,
  • each heterocycloalkyi contains one or two heteroatoms selected from N, S and O as ring members,
  • R 3 is H, CI or F
  • L is a bond or Ci_ 3 alkylene
  • L 2 is Co-3 alkylene, CD 2 , CHD, or C 3 . 8 branched alkylene;
  • a 1 is O or -NR 8 - Z 2 is N or CR 2 ;
  • Z 4 is N or CR 4 ;
  • Z 5 is N or CR 5 ;
  • Z 6 is N or CR 6 ;
  • R 2 , R 4 , R 5 , R 6 , and R 7 are each independently selected from H, C C 4 alkyl, C C 4 alkoxy, C C 4 haloalkyi, C C 4 haloalkoxy, CN, F and CI;
  • R 8 is H or methyl
  • R 9 is an optionally substituted group selected from Ci_ 3 alkyl, C 3 . 6 branched alkyl, C 3 . 7 cycloalkyl, C 3 . 7 heterocycloalkyl having up to two heteroatoms selected from N, O and S as ring members, -(CH 2 )i- 3 -0-Ci. 4 alkyl, pyridyl, and phenyl,
  • R 9 wherein the optional substituents for R 9 are up to four groups independently selected from halo, oxo, CN, C C 4 haloalkyi, C C 4 haloalkoxy, - OH, R ⁇ OR', -C(0)R ⁇ CONH2, CONHR', NH 2 , NHR', -NH-C(0)-R', where each R' is independently C C 4 straight chain or branched chain alkyl or haloalkyi.
  • R 5 or R 6 or both will represent H .
  • R 5 or R 6 or both will represent H .
  • R 7 is H and R 2 and R 4 can be H also, when they are present.
  • a 1 is NR 8 .
  • R 8 is H.
  • L is a bond; in some embodiments, L 2 is CH 2 .
  • R 9 is a heterocyclic group selected from tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran-1 -dioxide, piperidine, pyrrolidine, dioxane, and tetrahydrofuran, oxepane, and dioxepane.
  • R 9 is substituted with at least one group selected from CN, halo, and C1-C4 alkyl. In some preferred embodiments, R 9 is a cyclopropyl or
  • the compound is selected from the group consisting of:
  • L is a bond or CH 2
  • R is cyclohexyl
  • R 3 is F or CI
  • L 2 is CH 2 , CHD, or CD 2 ;
  • R 9 is selected from pyridyl, phenyl, tetrahydropyran, cyclopropane, and tetrahydrofuran, each of which can be substituted with up to three groups independently selected from F, CI, -OH, Me, ethyl, -OMe, CN, and CONH 2 .
  • a 1 is NH and L 2 is CH 2 .
  • R 9 is optionally substituted phenyl or substituted cyclopropane or tetrahydropyran.
  • R 0 and R and R 2 each independently represent H, F,
  • R 2 is preferably CN.
  • R 0 and R are typically H, F, CI,
  • a compound of any of embodiments 1-17, for use in therapy is a compound of any of embodiments 1-17, for use in therapy.
  • a method to treat cancer comprising administering to a subject in need thereof an effective amount of a compound according to any of embodiments 1-17.
  • 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.
  • the compound is administered, simultaneously or sequentially, with an antiinflammatory, antiproliferative,
  • a pharmaceutical composition comprising a compound according to any of embodiments 1-17 admixed with at least one pharmaceutically acceptable excipient.
  • composition of embodiment 25 which comprises at least one pharmaceutically acceptable carrier and at least one other pharmaceutically acceptable excipient.
  • additional therapeutic agent is an antiinflammatory, antiproliferative, chemotherapeutic agent, immunosuppressant, anti-cancer, cytotoxic agent or kinase inhibitor or a salt thereof.
  • Additional embodiments of the compounds of the invention include the following compounds and their pharmaceutically acceptable salts, as well as the novel compounds in the Tables herein. 30
  • 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, Wley, 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.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wsconsin, USA), Bachem (Torrance,
  • 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 XII 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,
  • 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.
  • Compounds enriched in deuterium are referred to herein as 'deuterated versions' of the compounds of Formula I.
  • 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.
  • stereoisomers 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. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, 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.
  • the term "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 or pharmaceutical compositions is contemplated.
  • 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. 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
  • compositions 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.
  • the invention further provides pharmaceutical 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 Formulas l-VI 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 suitable for use in therapy.
  • CDK inhibiting properties e.g. as indicated in vitro and in vivo tests as provided below
  • 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
  • Yet another aspect of the present invention provides a method of treating a disease or condition mediated by CDK9 comprising administration to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a
  • a compound of Formula I for use in a method of treating a disease or condition mediated by CDK9 is selected from cancer, cardiac hypotrophy, HIV and inflammatory diseases.
  • Another aspect of the present invention provides a method of treating a cancer 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 cancer 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.
  • Yet another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention provides a method of regulating, modulating, or inhibiting protein kinase activity which comprises contacting a protein kinase with a compound of the invention.
  • the protein kinase is selected from the group consisting of 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
  • the protein kinase is selected from the group consisting of CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9.
  • the protein kinase-associated disorder 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.
  • the protein kinase-associated disorder is inflammation.
  • the inflammation is related to rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, chronic
  • the protein kinase-associated disorder is a viral infection.
  • the viral infection is associated with the HIV virus, human papilloma virus, herpes virus, poxvirus virus, Epstein-Barr virus, Sindbis virus, or adenovirus.
  • the protein kinase-associated disorder is cardiac hypertrophy.
  • 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 such that the cancer is treated.
  • 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.
  • the invention provides a method of treating inflammation comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the inflammation is treated, wherein the compound is a compound of the invention.
  • the inflammation is related to rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, chronic inflammation, and organ transplant rejections.
  • the invention provides a method of treating cardiac
  • hypertrophy comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the cardiac hypertrophy is treated, wherein the compound is a compound of the invention.
  • the invention provides a method of treating a viral infection comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound such that the viral infection is treated, wherein the compound is a compound of the invention.
  • the viral infection is associated with the HIV virus, human papilloma virus, herpes virus, poxvirus virus, Epstein-Barr virus, Sindbis virus, or adenovirus.
  • the subject to be treated by the compounds of the invention is a mammal. In another embodiment, the mammal is a human.
  • the compounds of the invention is administered,
  • the compound, or salt thereof is
  • a PTK inhibitor administered, simultaneously or sequentially, with one or more of a PTK inhibitor, cyclosporin A, CTLA4-lg, antibodies selected from anti-ICAM-3, anti-IL-2 receptor, anti- CD45RB, anti-CD2, anti-CD3, anti-CD4, anti-CD80, anti-CD86, and monoclonal antibody OKT3, CVT-313, agents blocking the interaction between CD40 and gp39, fusion proteins constructed from CD40 and gp39, inhibitors of NF-kappa B function, nonsteroidal antiinflammatory drugs, steroids, gold compounds, FK506, mycophenolate mofetil, cytotoxic drugs, TNF-a inhibitors, anti-TNF antibodies or soluble TNF receptor, rapamycin, leflunimide, cyclooxygenase-2 inhibitors, paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin
  • the invention provides a packaged protein kinase-associated disorder treatment, comprising a protein kinase-modulating compound of the Formula I or Formula II, packaged with instructions for using an effective amount of the protein kinase-modulating compound to treat a protein kinase-associated disorder.
  • the compound of the present invention is further characterized as a modulator of a protein kinase, including, but not limited to, protein kinases selected from the group consisting of abl, ATK, Bcr-abl, Blk, Brk, Btk, c-fms, e- kit, c-met, c-src, CDK, cRafl, CSFIR, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFRI, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1 , Fps, Frk, Fyn, GSK, Gst-Flkl, Hck, Her-2, Her-4, IGF- IR, INS-R, Jak, JNK, KDR, Lck, Lyn, MEK, p38, panHER,
  • protein kinases selected from the group consisting of
  • PDGFR PLK, PKC, PYK2, Raf, Rho, ros, SRC, TRK, TYK2, UL97, VEGFR, Yes, Zap70, Aurora-A, GSK3-alpha, HIPK1 , HIPK2, HIP3, IRAKI , JNK1 , JNK2, JNK3, TRKB, CAMKII, CK1 , CK2, RAF, GSK3Beta, MAPK1 , MKK4, MKK7, MST2, NEK2, AAK1 , PKCalpha, PKD, RIPK2 and ROCK-II.
  • the protein kinase is selected from the group consisting of CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 and any combination thereof, as well as any other CDK, as well as any CDK not yet identified.
  • the protein kinase is selected from the group consisting of CDK1 , CDK2 and CDK9.
  • the protein kinase is selected from the group consisting of CDK9.
  • CDK combinations of interest 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 compounds of the present invention are used for the treatment of protein kinase-associated disorders.
  • 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.
  • disorders and states e.g., a disease state
  • 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.
  • Non-limiting examples of protein-kinase associated disorders include proliferative diseases, such as viral infections, auto-immune diseases, fungal disease, cancer, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, chronic inflammation, neurodegenerative disorders, such as Alzheimer's disease, and post-surgical stenosis and restenosis.
  • proliferative diseases such as viral infections, auto-immune diseases, fungal disease, cancer, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, chronic inflammation
  • neurodegenerative disorders such as Alzheimer's disease, and post-surgical stenosis and restenosis.
  • Protein kinase-associated diseases also include diseases related to abnormal cell proliferation, including, but not limited to, cancers of the breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary passages, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenocarcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy
  • protein kinase-associated cancers include carcinomas, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma
  • pigmentosum pigmentosum
  • keratoctanthoma thyroid follicular cancer
  • Kaposi's sarcoma Kaposi's sarcoma
  • Protein kinase-associated disorders include diseases associated with apoptosis, including, but not limited to, cancer, viral infections, autoimmune diseases and neurodegenerative disorders.
  • Non-limiting examples of protein-kinase associated disorders include viral infections in a patient in need thereof, wherein the viral infections include, but are not limited to, HIV, human papilloma virus, herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus.
  • Non-limiting examples of protein-kinase associated disorders include tumor angiogenesis and metastasis.
  • Non-limiting examples of protein-kinase associated disorders also include vascular smooth muscle proliferation associated with
  • Atherosclerosis postsurgical vascular stenosis and restenosis, and endometriosis.
  • protein-kinase associated disorders include those associated with infectious agents, including yeast, fungi, protozoan parasites such as Plasmodium falciparum, and DNA and RNA viruses.
  • the compound of the present invention is further characterized as a modulator of a combination of protein kinases, e.g., the CDKs, e.g., CDK1 , CDK2 and/or CDK9.
  • a compound of the present invention is used for protein kinase-associated diseases, and/or as an inhibitor of any one or more protein kinases. It is envisioned that a use can be a treatment of inhibiting one or more isoforms of protein kinases.
  • the compounds of the invention are inhibitors of cyclin-dependent kinase enzymes.
  • inhibition of the CDK4/cyclin D1 complex blocks phosphorylation of the Rb/inactive E2F complex, thereby preventing release of activated E2F and ultimately blocking E2F-dependent DNA transcription. This has the effect of inducing G1 cell cycle arrest.
  • the CDK4 pathway has been shown to have tumor-specific deregulation and cytotoxic effects. Accordingly, the ability to inhibit the activity of combinations of CDKs will be of beneficial therapeutic use.
  • CDK9 inhibition may sensitize cells to TNFalpha or TRAIL stimulation by inhibition of NF-kB, or may block growth of cells by reducing myc-dependent gene expression. CDK9 inhibition may also sensitize cells to genotoxic chemotherapies, HDAC inhibition, or other signal transduction based therapies.
  • the compounds of the invention can lead to depletion of anti- apoptotic proteins, which can directly induce apoptosis or sensitize to other apoptotic stimuli, such as cell cycle inhibition, DNA or microtubule damage or signal transduction inhibition. Depletion of anti-apoptotic proteins by the compounds of the invention may directly induce apoptosis or sensitize to other apoptotic stimuli, such as cell cycle inhibition, DNA or microtubule damage or signal transduction inhibition.
  • the compounds of the invention can be effective in combination with chemotherapy, DNA damage arresting agents, or other cell cycle arresting agents.
  • the compounds of the invention can also be effective for use in chemotherapy-resistant cells.
  • the present invention includes treatment of one or more symptoms of cancer, inflammation, cardiac hypertrophy, and HIV infection, as well as protein kinase- associated disorders as described above, but the invention is not intended to be limited to the manner by which the compound performs its intended function of treatment of a disease.
  • the present invention includes treatment of diseases described herein in any manner that allows treatment to occur, e.g., cancer, inflammation, cardiac hypertrophy, and HIV infection.
  • the invention provides a pharmaceutical composition of any of the compounds of the present invention.
  • the invention provides a pharmaceutical composition of any of the compounds of the present invention and a pharmaceutically acceptable carrier or excipient of any of these compounds.
  • the invention includes the compounds as novel chemical entities.
  • the invention includes a packaged protein kinase- associated disorder treatment.
  • the packaged treatment includes a compound of the invention packaged with instructions for using an effective amount of the compound of the invention for an intended use.
  • the compounds of the present invention are suitable as active agents in pharmaceutical compositions that are efficacious particularly for treating protein kinase- associated disorders, e.g., cancer, inflammation, cardiac hypertrophy, and HIV infection.
  • the pharmaceutical composition in various embodiments has a pharmaceutically effective amount of the present active agent along with other pharmaceutically acceptable excipients, carriers, fillers, diluents and the like.
  • pharmaceutically effective amount indicates an amount necessary to administer to a host, or to a cell, issue, or organ of a host, to achieve a therapeutic result, especially the regulating, modulating, or inhibiting protein kinase activity, e.g., inhibition of the activity of a protein kinase, or treatment of cancer, inflammation, cardiac hypertrophy, and HIV infection.
  • the present invention provides a method for inhibiting the activity of a protein kinase.
  • the method includes contacting a cell with any of the compounds of the present invention.
  • the method further provides that the compound is present in an amount effective to selectively inhibit the activity of a protein kinase.
  • the present invention provides a use of any of the compounds of the invention for manufacture of a medicament to treat cancer, inflammation, cardiac hypertrophy, and HIV infection in a subject.
  • the invention provides a method of manufacture of a medicament, including formulating any of the compounds of the present invention for treatment of a subject.
  • 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
  • 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. The following abbreviations have the following meanings. If not specifically defined, abbreviations will have their generally accepted meanings.
  • 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
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • 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.
  • 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 starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka- Chemce or Sigma (St. Louis, Missouri, USA).
  • 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:
  • synthesis can start with a functionalized hyeterocyle I wherein X is Br, I, CI, OTf, and the like.
  • Compound I can be converted into boronic acid or boronic ester II by:
  • synthesis can start with a functionalized pyridine I wherein X can be a functional group like CI, Br, I, OTf, and the like.
  • Compound I can be converted into boronic acid or boronic ester II by:
  • synthesis can start with a functionalized pyridine I wherein X can be a functional group like CI, Br, I, OTf, and the like.
  • Compound I can be converted into boronic acid or boronic ester II by:
  • synthesis can start with a functionalized hyeterocyle I wherein X is Br, I, CI, OTf, and the like.
  • Compound I can be converted into boronic acid or boronic ester II by:
  • Step 3 Preparation of (R/S)-tert-butyl 6-bromopyridin-2-yl((2,2-dimethyltetrahydro-2H- pyran-4-yl)methyl)carbamate To a mixture of te/f-butyl 6-bromopyridin-2-ylcarbamate (686 mg, 2.51 mmol),
  • Step 4 Preparation of (R/S)-tert-butyl 5'-chloro-2'-fluoro-2,4'-bipyridin-6-yl((2,2- dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate
  • 2,3,6-Trifluoropyridine (17.91 ml, 188 mmol) was dissolved in anhydrous MeOH (300 ml) and the resulting mixture was placed under argon. This mixture then was treated with a 25wt% methanolic solution of sodium methoxide (43.0 ml, 188 mmol). The resulting mixture was then heated at about 65° C for 2 hr. The reaction mixture was cooled to ambient temperature, and concentrated in vacuo to yield a residue which then was mixed with brine (200 ml_), and extracted with Et20 (3 x 200 ml).
  • Step 2 Preparation of 3,6-difluoro-2-hydroxypyridine
  • sodium iodide 66.6 g, 445 mmol
  • chlorotnmethylsilane 56.8 ml, 445 mmol
  • the resulting mixture was heated at 80-85 °C for 2.5 hr.
  • the mixture was cooled to ambient temperature and diluted with EtOAc (300 ml_) and water (300 ml_) and vigorously stirred for another hr.
  • Step 5 Preparation of 5'-chloro-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4- yl)methyl)-2'-fluoro-2,4'-bipyridin-6-amine
  • 6-bromo-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl) pyridin-2-amine (1 10 mg, 0.36 mmol), 5-chloro-2-fluoro-pyridine-4-boronic acid (193 mg, 1.10 mmol), 0.55 ml 2.0M saturated sodium carbonate aqueous solution in 2 ml DME was purged with Argon for 3 min, PdCl 2 (dppf)CH 2 Cl 2 (30 mg, 0.037 mmol) was added to this purged .
  • Step 3 To a solution of (4-methoxytetrahydro-2H-pyran-4-yl) methanol (300 mg, 2.05 mmol) in pyridine (4 ml) at ambient temperature was added toluenesulfonic chloride (430 mg, 2.25 mmol) and the resulting mixture was stirred overnight at about 25 °C. The stirred mixture was concentrated and the solid residue was dissolved in DCM and purified by silica gel chromatography using a 12 g column, eluting with 0-30% ethyl acetate in heptane to yield the desired compound "O" as a light yellow solid (360 mg).1 H NMR (300 MHz, CHLOROFORM-d) .
  • reaction mixture was cooled to ambient temperature, diluted with EtOAc (20ml_), washed with saturated NaHC0 3 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 502 mg of a light brown crude liquid, which was purified by column chromatography ( 5 to 50% ethyl acetate in heptane)to yield the desired products.
  • Step 2a A mixture of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3- (trifluoromethyl)pyridin-2-amine(100 mg, 0.339 mmol), 5-chloro-2-fluoropyridin-4- ylboronic acid (89 mg, 0.509 mmol), PdCl 2 (dppf).CH 2 Cl 2 adduct (27.7 mg, 0.034 mmol), DME (1.5 mL) and 2M aqueous Na 2 C0 2 (0.5 mL, 1 mmol) was stirred in a sealed glass vessel at about 100 °C for about 3 hours.
  • Step 1 6-Bromo-2-aminopyridine (15 g, 87 mmol) and TEA (13.3 mL, 95 mmol) were dissolved in 173 mL of DCM. BOC-anhydride (20.8 g, 95 mmol) was then dissolved in 100 mL of DCM and added over 10 min using a syringe pump. The reaction mixture was stirred at ambient temperature for 72 hr. The solvents were evaporated and the resulting residue was purified by silica gel chromatography (heptane: EtOAc 1 :0 to 7:3) to give the product as a colorless solid (23.0 g, 97%).
  • Step 3 A solution of tert-Butyl 6-bromo-5-chloropyridin-2-ylcarbamate (2.32 g, 7.54 mmol) in DMF (25 mL) was mixed with sodium hydride (60% dispersion in mineral oil, 513 mg, 12.8 mmol), and the resulting mixture reaction mixture was stirred for 30 minutes at ambient temperature. (2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (3.15 g, 10.56 mmol), dissolved in 5 mL DMF, was then added and the resulting mixture was stirred at about 25 °C for 3 hours. The reaction mixture was partitioned between water and EtOAc.
  • Step 4 A mixture of tert-butyl 6-bromo-5-chloropyridin-2-yl((2,2- dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (1.86 g, 4.29 mmol), 5-chloro-2- fluoropyridin-4-ylboronic acid (1.50 g, 8.58 mmol), PdCI2(dppf)*DCM adduct (350 mg, 0.429 mmol), DME (15.6 mL) and 2 M aqueous sodium carbonate solution (5.4 mL) were combined in a glass bomb. The bomb was sealed and heated at about 98°C for 2 hours. The reaction mixture was cooled to ambient temperature and then diluted with EtOAc.
  • Step 1 To NaH (0.366 g, 9.16 mmol) in THF (12 mL) at 0 °C was added 1 ,3- dimethoxy-2-propanol (1 g, 8.32 mmol) in THF (8 mL) solution. The mixture was warmed to ambient temperature and stirred for 0.5 hour. To this was added tosyl chloride (1.587 g, 8.32 mmol) in one portion. The resulting white cloudy mixture then was stirred at ambient temperature for 16 hours. LC/MS showed complete conversion to 1 ,3- dimethoxypropan-2-yl 4-methylbenzenesulfonate. The reaction mixture was poured into water and extracted with EtOAc.
  • the organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo to yield 2 g of a colorless oil.
  • the crude mixture was purified by Analogix system (silica gel column 80 g, gradient: 0 min, 100%n-heptane; 5-12 min, 20% EtOAc in Heptane; 12-15 min. 30% EtOAc in Heptane and hold until 30 min).
  • the pure fractions were combined and concentrated in vacuo to yield 1.25 g of the tosylate product 1 ,3-dimethoxypropan-2-yl 4- methylbenzenesulfonate as a colorless oil, which solidified upon standing.
  • Step 2 To the tosylate obtained in Step 1 (0.8g, 2.92 mmol) in DMSO (8 ml) was added 1 ,4-trans-cyclohexane diamine (0.999 g, 8.75 mmol). The resulting brown mixture was heated in a capped vial to about 95 °C, with stirring, for 2 hours. The reaction mixture was poured into 10% HCI in water (10 ml_) at 0 °C (ice cubes in HCI) and extracted with DCM (1x20 ml_). The aqueous (light pink) was basified with 6N NaOH to a pH >12 and extracted with DCM (2x20ml_).
  • Step 1 Synthesis of 4-((3,6-difluoropyridin-2-yl-amino)methyl)tetrahydro-2H-pyran-4- carbonitrile
  • Step 2 Synthesis of 4-((6-(benzyloxy)-3-fluoropyridin-2-yl-amino)methyl)tetrahydro-2H- pyran-4-carbonitrile
  • Benzyl alcohol (352 mg, 3.26 mmol) was dissolved in anhydrous DMF (2 ml) and placed under argon. This was then treated with a 60% dispersion in oil of SODIUM HYDRIDE (78.7 mg, 3.26 mmol). This resultant suspension was then stirred at room temperature for 15 min. At this time it was treated with a solution of 4-((3,6- difluoropyridin-2-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (275 mg, 1.09 mmol) dissolved in anhydrous DMF (2 ml). Once the addition was complete the reaction was stirred at 90°C for 5 hours. The reaction was allowed to cool to room temperature.
  • Step 3 Synthesis of 4-((3-fluoro-6-hydroxypyridin-2-yl-amino)methyl)tetrahydro-2H- pyran-4-carbonitrile
  • Step 4 Synthesis 6-((4-cyanotetrahydro-2H-pyran-4-yl) methyl)-amino-5-fluoropyridin-2- yl trifluoromethanesulfonate
  • Step 5 Synthesis of 4-((5'-chloro-2',5-difluoro-2,4'-bipyridin-6-yl- amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate AA)
  • Step 1 Synthesis of tert-butyl 6-bromopyridin-2-yl((4-methoxytetrahydro-2H-pyran-4- yl)methyl) carbamate
  • Step 2 Synthesis of tert-butyl 5'-chloro-2'-fluoro-2,4'-bipyridin-6-yl((4- methoxytetrahydro-2H-pyran-4-yl)methyl)carbamate
  • Step 3 Synthesis of 5'-chloro-2'-fluoro-N-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)- 2,4'-bipyridin-6-amine (Intermediate AC)
  • 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
  • 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 (6,6-dimethyl-1 ,4-dioxan-2-yl)methanamine
  • Step 1 Preparation of methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate
  • Step 1 Preparation of 1 ,6-dioxaspiro[2.5]octane
  • Step 3 Preparation of toluene-4-sulfonic acid 4-methoxy-tetrahydro-pyran-4- yl methyl ester
  • Step 1 Preparation of (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one
  • a solution of 2,6-dimethyl-4H-pyran-4-one (2 g, 16.1 mmol) in EtOH (20 mL) was stirred over Pd/C (10 wt.%, 0.2 g) under hydrogen (15 psi) for 16 hrs at ambient temperature.
  • the suspension was filtered off and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in dichloromethane (15 mL) and treated with Dess-Martin periodinane (2.3 g) at ambient temperature for 16 hrs.
  • reaction mixture was diluted with water (15 mL) and extracted with diethylether (2x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel,
  • Step 3 Preparation of (2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-carbaldehyde
  • the reaction mixture was cooled to 0 °C, neutralized with 1 N aqueous sodium hydroxide solution until pH ⁇ 6 and extracted with diethylether.
  • 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). The precipitate was filtered off and the solution was concentrated under reduced pressure providing crude trimethylsilyl ether, which was directly used in the next step without further purification.
  • 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 1 ,3-dimethoxypropan-2-yl 4-methylbenzenesulfonate
  • Step 1 Preparation of 1 -(trideuteromethoxy)propan-2-yl 4- methylbenzenesulfonate
  • Step 1 Preparation of 2-deutero-1 -methoxypropan-2-ol To 1-methoxypropan-2-one (5.26 mL, 56.8 mmol) in MeOH-d4 (10 mL) and THF (50.00 mL) at 0 °C was added NaBD 4 (2.375 g, 56.8 mmol) portion wise. Vigorous off-gassing was seen. The reaction mixture was warmed to room temperature and stirred under argon for 5 hrs. The reaction mixture was worked up by pouring saturated aqueous NaHC0 3 solution (10 mL) and stirred for 1 hr. The product was extracted with diethyl ether (100 mL), washed with brine, dried with sodium sulfate and concentrated under reduced pressure to give 3.53 g of colorless liquid. This was used in the next step without further purification.
  • Step 3 Preparation of trans-N1-(2-deutero-1 -methoxypropan-2-yl)cyclohexane-1 ,4- diamine
  • Step 1 Preparation of tert-butyl (trans-4-((2- methoxyethyl)amino)cyclohexyl)carbamate
  • Step 2 Preparation of tert-butyl (trans-4-(cyclopropyl(2-methoxyethyl)amino)- cyclohexyl)carbamate
  • Step 3 Preparation of trans-N1-cyclopropyl-N1 -(2-methoxyethyl)cyclohexane-1,4- diamine
  • Step 1 Preparation of (R)-3-(benzyloxy)-1 ,1 ,1-trifluoropropan-2-ol
  • Step 4 Preparation of (R)-3,3,3-trifluoro-2-methoxypropyl 4- methylbenzenesulfonate Sodium hydride (412 mg, 10.31 mmol) was added to a solution of (R)-3,3,3-trifluoro-2- methoxypropan-1-ol (495 mg, 3.44 mmol) in THF (10 ml) at ambient temperature. The mixture was stirred for 30 minutes.
  • Step 5 Preparation of N1 -((R)-3,3,3-trifluoro-2-methoxypropyl)cyclohexane-trans- 1,4-diamine
  • Step 3 Preparation of trans-N1,N1 -dibenzylcyclohexane-1 ,4-diamine
  • Step 5 Preparation of 3-((trans-4-(dibenzylamino)cyclohexyl)amino)-1 ,1,1- trifluoro-2-methylpropan-2-ol
  • Step 6 Preparation of 3-((trans-4-aminocyclohexyl)amino)-1,1,1-trifluoro-2- methylpropan-2-ol (racemic m
  • Step 1 Preparation of (S)-benzyl (4-(3-methoxypyrrolidin-1- yl)cyclohexyl)carbamate
  • Step 1 Preparation of ethyl 2-(((trans)-4-aminocyclohexyl)amino)-2- methylpropanoate
  • Step 1 Preparation of rac benzyl ((1S,3S,4S)-3-hydroxy-4-((2- methoxyethyl)amino)cyclohexyl)carbamate
  • Step 2 Preparation of rac tert-butyl ((1S,2S,4S)-4-(((benzyloxy)carbonyl)amino)-2- hydroxycyclohexyl)(2-methoxyethyl)carbamate
  • Step 3 Preparation of rac tert-butyl ((1 S,2S,4S)-4-amino-2-hydroxycyclohexyl)(2- methoxyethyl)carbamate
  • Step 1 Preparation of rac (1S,3S,6R)-(7-Oxa-bicyclo[4.1.0]hept-3-yl)-carbamic acid benzyl ester
  • Step 3 Preparation of rac ((1 S,3R,4R)-3-azido-4-methoxy-cyclohexyl)-carbamic acid benzyl ester
  • Step 5 Preparation of rac ((1 S,3R,4R)-3-tert-butoxycarbonylamino-4-methoxy- cyclohexyl)-carbamic acid benzyl ester
  • Step 6 Preparation of rac ((1 R,2R,5S)-5-amino-2-methoxy-cyclohexyl)-carbamic acid tert-butyl ester
  • a mixture of rac ((1S,3R,4R)-3-tert-butoxycarbonylamino-4-methoxy-cyclohexyl)- carbamic acid benzyl ester (170 mg, 0.45 mmol), Pd/C (10%. 15 mg) in methanol (10 mL) was stirred at room temperature for 2 hr. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure.
  • Step 1 Preparation of rac (1S,3S,6R)-(7-oxa-bicyclo[4.1.0]hept-3-yl)-carbamic acid benzyl ester
  • Step 2 Preparation of rac ((1 S,3S,4S)-4-azido-3-hydroxy-cyclohexyl)-carbamic acid benzyl ester
  • Step 3 Preparation of rac ((1 S,3S,4S)-4-azido-3-methoxy-cyclohexyl)-carbamic acid benzyl ester
  • Step 5 Preparation of rac ((1 S,2S,4S)-4-benzyloxycarbonylamino-2-methoxy- cyclohexyl)-carbamic acid tert-butyl ester
  • Step 6 Preparation of rac ((1 S,2S,4S)-4-amino-2-methoxy-cyclohexyl)-carbamic acid tert-butyl ester
  • Step 1 Preparation of rac ((1 R,3S,4S)-4-hydroxy-3-methoxy-cyclohexyl)-carbamic acid benzyl ester
  • Step 3 Preparation of rac ((1 R,3S,4R)-4-azido-3-methoxy-cyclohexyl)-carbamic acid benzyl ester
  • Step 4 Preparation of rac ((1 R,3S,4R)-4-amino-3-methoxy-cyclohexyl)-carbamic acid benzyl ester
  • Step 5 Preparation of rac ((1 R,3S,4R)-4-tert-butoxycarbonylamino-3-methoxy- cyclohexyl)-carbamic acid benzyl ester
  • Step 6 Preparation of rac ((1 R,2S,4R)-4-amino-2-methoxy-cyclohexyl)-carbamic acid tert-butyl ester
  • the TFA salt was free- based using 200 ml of ethyl acetate and washed with saturated sodium bicarbonate 35 ml (1x), water (2x), saturated brine (1x), dried over sodium sulfate, filtered and concentrated to yield a solid. The solid was dissolved in (1 :1 ACN/ water), filtered, and lyophilized to yield 80 mg of the title compound as free-base.
  • the crude reaction mixture was cooled to room temperature, diluted with 3 ml DMSO, filtered, and purified by prep HPLC. (there is a general HPLC conditions in the general experimental session).
  • the fractions were concentrated, mixed with 500 ml ethyl acetate, and basified with saturated sodium bicarbonate 120 ml.
  • the ethyl acetate layer was separated, and the basic water layer was extracted with 300 ml ethyl acetate.
  • the ethyl acetate layers were combined and washed with water (3x), saturated salt solution (1x), dried with sodium sulfate, filtered and concentrated to yield a solid.
  • Step 1 Preparation of frans-N1-(4-bromopyridin-2-yl)cyclohexane-1 ,4-diamine
  • 4-bromo-2-chloropyridine (1500 mg, 7.79 mmol)
  • DMSO 15 ml
  • frans-cyclohexane-1 ,4-diamine 4450 mg, 39.0 mmol
  • the reaction mixture was cooled to room temperature, filtered and purified by prep LC, and lyophilized to yield 393mg of the title compound as a TFA salt.
  • LCMS (m/z): 270.2/272.2 (MH+), retention time 0.31 min.
  • Step 1 Preparation of 2,5-dichloro-4-(6-fluoropyridin-2-yl)pyrimidine
  • 2,4,5-trichloropyrimidine 49.3 mg, 0.269 mmol
  • 2-fluoro-6-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine 50 mg, 0.224 mmol
  • PdCl 2 dppf
  • CH 2 Cl 2 adduct (18.31 mg, 0.022 mmol
  • DME 0.7 ml
  • 2M sodium carbonate 0.247 ml, 0.493 mmol
  • cyclohexylmethanamine was removed under vacuum to yield a residue.
  • the residue was mixed with 0.5 ml DMSO, filtered, purified by prep HPLC and then lyophilized to yield 9.4 mg of the title compound as a TFA salt.
  • Example 5 (Compound 5) (5'-chloro-N6-(3-fluorobenzyl)-N2'-(piperidin-4-yl)-2,4'-bipyridine-2 ⁇ 6-diarnine
  • Step 3 Preparation of frans-4-(5'-chloro-6-(piperidin-4-yl-amino)-2,4'-bipyridin-2'-yl- amino)cyclohexanol
  • the Boc protecting group was removed from the intermediate by adding HCL 6M aq (140 ⁇ , 0.840 mmol) to the crude reaction mixture, followed by stirring the mixture at 90 °C for 45 minutes.
  • the reaction mixture was cooled, 0.5 ml of DMSO was added, filtered and purified by prep LC. Lyophilization of the material yielded 9.8 mg of the title compound, as a TFA salt.
  • Step 1 Preparation of 6-chloro-N-(3-fluorobenzyl)pyrazin-2-amine: To 2,6- dichloropyrazine (175 mg, 1.175 mmol) was added DMSO (1.5 ml), TEA (0.196 ml, 1.410 mmol) and (3-fluorophenyl)methanamine (368 mg, 2.94 mmol)l. The reaction mixture then was stirred at 90 °C until completion as indicated by LCMS, about 1 hour. To the reaction mixture was added 3 ml of DMSO, filtered and the residue was purified by prep LC. After lyophilization, 160 mg of the title compound was obtained as a TFA.
  • Step 2 Preparation of N-(3-fluorobenzyl)-6-(2-fluoropyridin-4-yl)pyrazin-2-amine: To 6-chloro-N-(3-fluorobenzyl)pyrazin-2-amine (140 mg, 0.589 mmol) was added 2- fluoropyridin-4-ylboronic acid (125 mg, 0.884 mmol), PalladiumTetrakis (82 mg, 0.071 mmol), DME (3.3 ml), and 2M sodium carbonate (1.031 ml, 2.062 mmol) . The resulting reaction mixture was stirred at 1 10 °C until completion as indicated by LCMS, about 3 hours. The reaction mixture was cooled to room temperature, diluted with 20 ml of ethyl acetate, filtered and concentrated to yield a crude solid. The solid was dissolved in
  • Step 2 Preparation of 3-fluoro-/V-(3-fluorobenzyl)-6-methoxypyridin-2-amine: 3,6-difluoro-A/-(3-fluorobenzyl)pyridine-2-amine (0.5209 g, 2.19 mmol), was dissolved in anhydrous MeOH ( 6.6 mL) and placed under argon. This mixture then was treated with sodium methoxide (0.500 mL, 0.473 g, 2.19 mmol, 25% in MeOH) by slow addition. The resulting mixture was then heated in the microwave at 150°C for four 30 min. The reaction mixture was then poured into brine (25 mL).
  • Step 3 Preparation of 5-fluoro-6-(3-fluorobenzylamino)pyridine-2-ol: 3-fluoro-/V- (3-fluorobenzyl)-6-methoxypyridin-2-amine (0.100 g, 0.400 mmol) was dissolved in anhydrous CH 3 CN (1.6 mL). This mixture was treated with sodium iodide (0.301 g, 2.01 mmol) followed by trimethylsilylchloride (0.257 mL, 0.218 g, 2.01 mmol). The resulting reaction mixture was then heated at reflux for 2 hr.

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Abstract

L'invention concerne un composé représenté par la formule (I), et des sels, des énantiomères, des stéréoisomères, des rotamères, des tautomères, des diastéréomères ou des racémates pharmaceutiquement acceptables de ceux-ci. Ces composés inhibent l'activité de CDK9 et sont par conséquent utiles comme produits pharmaceutiques. L'invention se réfère également à des méthodes de traitement d'une maladie ou d'un état pathologique dans lequel intervient la CDK9, au moyen des composés représentés par la formule I et d'isomères de ceux-ci, et à des compositions pharmaceutiques comprenant de tels composés.
PCT/EP2012/050914 2011-01-28 2012-01-20 Composés de pyridine biarylamine et utilisation de ceux-ci WO2012101066A1 (fr)

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US9751854B2 (en) 2014-01-14 2017-09-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
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US11591322B2 (en) 2020-05-15 2023-02-28 Algen Biotechnologies, Inc. Certain chemical compositions and methods of use thereof
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