WO2014194201A2 - Inhibiteurs de cdk8 et applications de ceux-ci - Google Patents

Inhibiteurs de cdk8 et applications de ceux-ci Download PDF

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WO2014194201A2
WO2014194201A2 PCT/US2014/040243 US2014040243W WO2014194201A2 WO 2014194201 A2 WO2014194201 A2 WO 2014194201A2 US 2014040243 W US2014040243 W US 2014040243W WO 2014194201 A2 WO2014194201 A2 WO 2014194201A2
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compound
ring
nitrogen
sulfur
oxygen
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PCT/US2014/040243
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English (en)
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Donna L. Romero
Divya Chaudhary
Shaughnessy Robinson
Craig E. Masse
Michael J. Morin
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Nimbus Iris, Inc.
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Publication of WO2014194201A2 publication Critical patent/WO2014194201A2/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to compounds and methods useful for inhibiting cell division protein kinase 8 ("CDK8").
  • CDK8 cell division protein kinase 8
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
  • 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. 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, etc.).
  • protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli.
  • Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H 2 0 2 ), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL- 8) and tumor necrosis factor a (TNF-a)), and growth factors (e.g., granulocyte macrophage- colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)).
  • An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.
  • kinase-mediated events 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, and hormone-related diseases. Accordingly, there remains a need to find protein kinase inhibitors useful as therapeutic agents.
  • Compounds of the present invention are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating CDK8 kinases. Such diseases, disorders, or conditions include those described herein.
  • Compounds provided by this invention are also useful for the study of CDK8 enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new CDK8 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo.
  • Compounds of the present invention, and compositions thereof, are useful as inhibitors of CDK8 protein kinase.
  • the binding pocket of CDK8 contains a plurality of hydration sites, each of which is occupied by a single molecule of water. Each of these water molecules has a stability rating associated with it.
  • stability rating refers to a numerical calculation which incorporates the enthalpy, entropy, and free energy values associated with each water molecule. This stability rating allows for a measurable determination of the relative stability of water molecules that occupy hydration sites in the binding pocket of CDK8.
  • provided compounds displace or disrupt one or more unstable water molecules.
  • a provided compound displaces or disrupts at least two unstable water molecules.
  • the present invention provides a method of inhibiting CDK8 kinase comprising contacting s a I:
  • Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • n 0-4;
  • each R 1 is independently -R, halogen, -CN, -N0 2 , -OR, -CH 2 OR, - SR, -N(R) 2 , -S0 2 R, -S0 2 N(R) 2 , -SOR, -C(0)R, -C0 2 R, -C(0)N(R) 2 , -C(0)N(R)-OR, - NRC(0)OR, -NRC(0)N(R) 2 , Cy, or -NRS0 2 R; or R 1 is selected from one of the following formulas:
  • R 1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci_ 6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • Ring B is a 4-8 membered partially unsaturated carbocyclic fused ring; or a 4-7 membered
  • Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;
  • W is N or -C(R 3 )-;
  • R z is R, CN, NO 2 , halogen, -C(0)N(R) 2 , -C(0)OR, -C(0)R, -N(R) 2 , -NH-[Ar], - N(R)C(0)OR, -NRC(0)N(R) 2 , -OR, or -S0 2 N(R) 2 ;
  • R 3 is hydrogen, halogen, -CN, Ci_ 4 aliphatic, Ci_ 4 haloaliphatic, -OR, -C(0)R, or -C(0)N(R) 2 ;
  • [Ar] is an optionally substituted phenyl or heteroaromatic ring;
  • L 1 is a covalent bond or a Ci_ 6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -NR-, -N(R)C(0)-, -C(0)N(R)- , -N(R)S0 2 -, -S0 2 N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO- or -S0 2 -;
  • each L 2 is independently a covalent bond or a Ci_ 6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -NR-, - N(R)C(0)-, -C(0)N(R)-, -N(R)S0 2 -, -S0 2 N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO- or -S0 2 -; and
  • each R 4 is independently halogen, -CN, -N0 2 , -OR,
  • two -L 2 (R 4 ) P -R 4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • cycloaliphatic (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a "bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a "bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:
  • lower alkyl refers to a Ci_ 4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a Ci_ 4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • Ci_g (or Ci_ 6 ) saturated or unsaturated, straight or branched, hydrocarbon chain
  • bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An "alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure:
  • halogen means F, CI, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin- 3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4- dihydro-2H-pyrrolyl), ⁇ (as in pyrrolidinyl), or (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono- or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain "optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an "optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0 2 R*, -(haloR*), -(CH 2 ) 0 2 OH, -(CH 2 ) 0 2 OR*, -(CH 2 ) 0 2 CH(OR*) 2 ; -O(haloR'), -CN, -N 3 , -(CH 2 ) 0 2 C(0)R*, -(CH 2 ) 0 2 C(0)OH, -(CH 2 ) 0 2 C(0)OR*, - (CH 2 )o 2 SR*, -(CH 2 )o 2 SH, -(CH 2 ) 0 2 NH 2 , -(CH 2 ) 0 2 NHR*, -(CH 2 ) 0 2 NR* 2 , -N0 2 , -SiR*
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR 2 ) 2 3 0-, wherein each independent occurrence of R is selected from hydrogen, Ci_6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R include halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2 , or
  • each R* is unsubstituted or where preceded by "halo” is substituted only with one or more halogens, and is independently Ci_ 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , -NR ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , C(0)CH 2 C(0)R ⁇ , -S(0) 2 R ⁇ , -S(0) 2 NR ⁇ 2 , -C(S)NR ⁇ 2 , -C(NH)NR ⁇ 2 , or -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, Ci_6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci_ 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • an R 1 group of a provided compound comprises one or more deuterium atoms.
  • Ring B of a provided compound may be substituted with one or more deuterium atoms.
  • an inhibitor is defined as a compound that binds to and /or inhibits CDK8 with measurable affinity.
  • an inhibitor has an IC 50 and/or binding constant of less than about 50 ⁇ , less than about 1 ⁇ , less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • a compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents.
  • a detectable moiety may be attached to a provided compound via a suitable substituent.
  • suitable substituent refers to a moiety that is capable of covalent attachment to a detectable moiety.
  • moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few.
  • moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain.
  • such moieties may be attached via click chemistry.
  • such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst.
  • Methods of using click chemistry are known in the art and include those described by Rostovtsev et al. , Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al, Bioconjugate Chem., 2006, 17, 52-57.
  • detecttable moiety is used interchangeably with the term “label” and relates to any moiety capable of being detected, e.g., primary labels and secondary
  • Primary labels such as radioisotopes (e.g., tritium, P, P, S, or C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications.
  • Detectable moieties also include luminescent and phosphorescent groups.
  • secondary label refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal.
  • the secondary intermediate may include streptavidin-enzyme conjugates.
  • antigen labels secondary intermediates may include antibody-enzyme conjugates.
  • fluorescent label refers to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength.
  • fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, carboxy
  • mass-tag refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques.
  • mass-tags include electrophore release tags such as N-[3-[4'-[(p- Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4 ' -[2,3 ,5 ,6- Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives.
  • mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition.
  • nucleotides dideoxynucleotides
  • oligonucleotides of varying length and base composition oligopeptides, oligosaccharides
  • other synthetic polymers of varying length and monomer composition.
  • a large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change in a CDK8 protein kinase activity between a sample comprising a compound of the present invention, or composition thereof, and a CDK8 protein kinase, and an equivalent sample comprising an CDK8 protein kinase, in the absence of said compound, or composition thereof.
  • the present invention provides a method of inhibiting CDK8 kinase, comprising contacting said kinase with a compound of formula I:
  • Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • n 0-4;
  • each R 1 is independently -R, halogen, -CN, -N0 2 , -OR, -CH 2 OR, - SR, -N(R) 2 , -S0 2 R, -S0 2 N(R) 2 , -SOR, -C(0)R, -C0 2 R, -C(0)N(R) 2 , -C(0)N(R)-OR, - NRC(0)OR, -NRC(0)N(R) 2 , Cy, or -NRS0 2 R; or R 1 is selected from one of the following formulas:
  • R 1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each Cy is an optionally substituted monocyclic or bicyclic ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic monocyclic or bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci_ 6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
  • Ring B is a 4-8 membered partially unsaturated carbocyclic fused ring; or a 4-7 membered
  • Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;
  • n 0-4;
  • p 0-2;
  • W is N or -C(R 3 )-;
  • R z is R, CN, N0 2 , halogen, -C(0)N(R) 2 , -C(0)OR, -C(0)R, -N(R) 2 , -NH-[Ar], - N(R)C(0)OR, -NRC(0)N(R) 2 , -OR, or -S0 2 N(R) 2 ;
  • R 3 is hydrogen, halogen, -CN, Ci_ 4 aliphatic, Ci_ 4 haloaliphatic, -OR, -C(0)R, or -C(0)N(R) 2 ;
  • [Ar] is an optionally substituted phenyl or heteroaromatic ring;
  • L 1 is a covalent bond or a Ci_ 6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -NR-, -N(R)C(0)-, -C(0)N(R)- , -N(R)S0 2 -, -S0 2 N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO- or -S0 2 -;
  • each L 2 is independently a covalent bond or a Ci_ 6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -NR-, - N(R)C(0)-, -C(0)N(R)-, -N(R)S0 2 -, -S0 2 N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO- or -S0 2 -; and
  • each R 4 is independently halogen, -CN, -N0 2 , -OR,
  • two -L 2 (R 4 ) P -R 4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the Ring A group of formula I is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring.
  • Ring A is a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ring A is a 3-7 membered saturated carbocyclic ring. In certain embodiments, Ring A is cyclopentyl or cyclohexyl. In some embodiments, Ring A is cyclohexyl.
  • Ring A when Ring A is a disubstituted cycloalkyl ring, said ring can have cis or trans relative stereochemistry.
  • Ring A is a trans- 1 ,4-disubstituted cycloalkyl ring.
  • Ring A a trans- 1 ,4-disubstituted cyclohexyl ring.
  • Ring A is a 4-7 membered saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, Ring A is a 5-6 membered saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, Ring A is piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, or tetrahydrofuranyl. In some embodiments, when Ring A is a 4-7 membered saturated heterocyclic ring, L 1 is a covalent bond.
  • n group of formula I is 0-4. In some embodiments, n is 0. In some embodiments, n is 1-4. In certain embodiments, n is 1. In some embodiments, n is 2.
  • each R 1 group of formula I is independently -R, halogen,
  • NRC(0)R NRC(0)R, -NRC(0)N(R) 2 , Cy, or -NRS0 2 R; or R 1 is selected from one of the following formulas:
  • R 1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 1 is R, -OR, -N(R) 2 , -C0 2 R, -C(0)N(R) 2 , -C(0)N(R)- OR, -S0 2 N(R) 2 , Cy, or -NRC(0)OR.
  • R 1 is -C(0)NH 2 , -C(0)NHCH 3 , - C(0)NH-OH, -CH 3 , -CH 2 CH 3 , -S0 2 t-butyl, -OH, -C(0)OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , - N(CH 2 CH 3 ) 2 , -NHC(0)CH 3 , or -CH 2 phenyl.
  • Rl is selected from one of the following formulas: ( CH 2)i-4 NR 2 (CH 2 ) 1-4 R
  • R 1 is
  • R 1 is -N(R) 2 .
  • Exemplary R 1 groups include those depicted in Table 1. In some embodiments R 1 is R only where R is not hydrogen.
  • the present invention provides a method utilizing a compound of formula I wherein two R 1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • two R 1 groups on adjacent carbon atoms are taken together to form an optionally substituted 4-7 membered ring fused to Ring A.
  • two R 1 groups on the same carbon atom are taken together to form an optionally substituted 4-7 membered spiro-fused ring.
  • Cy is an optionally substituted monocyclic or bicyclic ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic monocyclic or bicyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Cy is a 3-7 membered saturated carbocyclic ring. In certain embodiments, Cy is a 4-7 membered saturated heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In certain embodiments Cy is a spirobicyclic 7-membered ring. In some embodiments, Cy is 2-oxa-6-azaspiro[3.3]heptane. In certain embodiments, Cy is morpholinyl, pyrrolidinyl, azetidinyl, piperidinyl or piperazinyl.
  • an R 1 substituent on a saturated carbon of Ring A forms a chiral center.
  • that chiral center is in the (R) configuration.
  • that chiral center is in the (S) configuration.
  • the L 1 group of formula I is a covalent bond or a Ci_ 6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -NR-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S0 2 -, -S0 2 N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO- or -S0 2 -.
  • L 1 is a covalent bond.
  • L 1 is a Ci_ 6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -NR-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S0 2 - , -S0 2 N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO- or -S0 2 -.
  • L 1 is -NH- (i.e., a Ci bivalent hydrocarbon chain wherein the methylene unit is replaced by -NH-), -0-, -CH 2 0-, -OCH 2 -, -NHC(O)-, -CH 2 NH-, or -NHCH 2 -.
  • L 1 is -0-.
  • L 1 is -NR-.
  • L 1 is -OCH 2 -.
  • L 1 is -NRCH 2 -.
  • Exemplary L 1 groups include those depicted in Table 1.
  • the Ring B group of formula I is a 4-8 membered partially unsaturated carbocyclic fused ring; or a 4-7 membered partially unsaturated heterocyclic fused ring having 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups.
  • Ring B is a 4-8 membered partially unsaturated carbocyclic fused ring. In other embodiments, Ring B is a 4-7 membered partially unsaturated azacyclic fused ring having one or two nitrogens. In some embodiments, Ring B is a cyclohexo- or cyclopento-fused ring. In other embodiments, Ring B is a piperidino-fused ring. In some embodiments, Ring B is a tetrahydropyrano-fused ring. In some embodiments, Ring B is a pyrrolidino-fused ring.
  • a substituent on a saturated carbon of Ring B forms a chiral center.
  • that chiral center is in the (R) configuration.
  • that chiral center is in the (S) configuration.
  • the m group of formula I is 0-4. In some embodiments, m is 0. In some embodiments, m is 1-4. In some embodiments, m is 1.
  • each L 2 is independently a covalent bond or a Ci_ 6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -NR-, -N(R)C(0)-, -C(0)N(R)-, -N(R)S0 2 -, -S0 2 N(R)-, -0-, -C(O)-, -OC(O)-, -C(0)0-, -S-, -SO- or -S0 2 -.
  • each L 2 is independently a covalent bond.
  • each L 2 is a Ci_ 3 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(0)N(R)-, -0-, -C(O)-, -S-, -SO- or - S0 2 -.
  • L 2 is methylene.
  • L 2 is -CH 2 -C(0)-.
  • L 2 is a C 2 hydrocarbon chain substituted with a hydroxyl group (-CH 2 CH(OH)-).
  • each R 4 is independently halogen, -CN, -N0 2 , -OR, -SR, -N(R) 2 , -S0 2 R, -S0 2 N(R) 2 , -SOR, -C(0)R, -C0 2 R, -C(0)N(R) 2 , -NRC(0)R, - NRC(0)N(R) 2 , -C(0)N(R)OR, -N(R)C(0)OR, -N(R)S(0) 2 N(R) 2 , -NRS0 2 R, or an optionally substituted group selected from Ci_ 6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two -L 2 (R 4 ) P -R 4 groups
  • each R 4 is independently - CN, -OR, -SR, -SOR, -S0 2 R, -C(0)N(R) 2 , -NRC(0)R, or an optionally substituted group selected from Ci_ 6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • each R 4 is independently - CN, -OR, -SR, -SOR, -S0 2 R, -C(0)N(R) 2 , -NRC(0)R, or an optionally substituted group selected from Ci_ 6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or
  • R 4 is an optionally substituted group selected from Ci_ 6 aliphatic, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R 4 is hydroxyl.
  • R 4 is -C(0)N(R) 2 .
  • the present invention provides a method utilizing a compound of formula I wherein two -L 2 (R 4 ) P -R 4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • two -L 2 -R 4 groups on adjacent carbon atoms are taken together to form an optionally substituted 4-7 membered ring fused to Ring B.
  • two -L 2 (R 4 ) P -R 4 groups on the same carbon atom are taken together to form an optionally substituted 4-7 membered spiro-fused ring.
  • two -L 2 (R 4 ) P -R 4 groups on non-adjacent carbon atoms are taken together to form an optionally substituted bridged bicyclic ring with Ring B.
  • any one or more -L 2 (R 4 ) P -R 4 groups are independently selected from deuterium, an unsubstituted alkyl group, a -C0 2 R group, and an unsubstituted heterocyclyl group. In some embodiments, any one or more -L 2 (R 4 ) P -R 4 groups are not independently selected from deuterium, an unsubstituted alkyl group a -C0 2 R group, and an unsubstituted heterocyclyl group.
  • an -L 2 (R 4 ) P -R 4 substituent on a saturated carbon of Ring B forms a chiral center.
  • that chiral center is in the (R) configuration.
  • that chiral center is in the (S) configuration.
  • the R z group of formula I is -R, -CN, -N0 2 , halogen, - C(0)N(R) 2 , -C(0)OR, -C(0)R, -N(R) 2 , -NH-[Ar], -N(R)C(0)OR, -NRC(0)N(R) 2 , -OR, or - S0 2 N(R) 2 .
  • R z is hydrogen.
  • R z is CN, halogen, -N(R) 2 or -C(0)N(R) 2 .
  • R z is -NH-[Ar].
  • R z groups include those depicted in Table 1.
  • [Ar] is an optionally substituted phenyl or heteroaromatic ring.
  • [Ar] is an optionally substituted phenyl or 5-6 membered heteroaromatic ring.
  • [Ar] is an optionally substituted phenyl ring.
  • [Ar] is an optionally substituted heteroaromatic ring.
  • [Ar] is an optionally substituted 5-6 membered heteroaromatic ring.
  • [Ar] is an optionally substituted 5-membered heteroaromatic ring.
  • [Ar] is an optionally substituted 6-membered heteroaromatic ring.
  • [Ar] is an optionally substituted pyrazole ring.
  • p is 0-2. In some embodiments p is 0. In some embodiments p is 1. In certain embodiments, p is 2.
  • a provided method employs a compound of formula I, wherein Ring B is a cyclopento fused ring, and W is N, thereby forming a compound of formula
  • Ring A, L 1 , L 2 , R z , R 1 , R 4 , m, n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula II, wherein R 1 is one of the following formulas:
  • Ring A, L 1 , L 2 , R, R z , R 1 , R 4 , m, n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula II, wherein m is 1, thereby forming a compound of formula III:
  • Ring A, L 1 , L 2 , R z , R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula III, wherein Ring A is cyclohexyl, thereby forming a compound of formula IV:
  • each of, L 1 , L 2 , R z , R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula III, wherein n is 1 and the cyclohexyl ring has trans stereochemistry, thereby forming a compound of formula V:
  • V or a pharmaceutically acceptable salt thereof, wherein each of, L 1 , L 2 , R z , R 1 , R 4 , and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided present invention provides a compound of formula V, wherein R z is -N(R) 2 , thereby forming a compound of formula VI:
  • a provided method employss a compound of formula VII, wherein W 1 1 , W2% X 1 1 , Y 1 , Y2 and Z 1 1 are each independently hydrogen or deuterium:
  • each of L 1 , L 2 , R 1 , R z , and R 4 is as defined above for formula I and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula VIII, wherein W 1 1 , W2% X1 1 , Z1 1 and Z 2 are each independently hydrogen or deuterium:
  • a provided method employs a compound of formula I, wherein Ring B is cyclohexo, W is N, and R z is hydrogen, thereby forming a compound of formula IX:
  • Ring A, L 1 , L 2 , R 1 , R 4 , m, n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula IX, wherein m is 1 , and L 2 is attached a to the thiophene ring, thereby forming a compound of formula X:
  • Ring A, L 1 , L 2 , R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula IX, wherein m is 1 , and L 2 is attached ⁇ to the thiophene ring, thereby forming a compound of formula XI:
  • Ring A, L 1 , L 2 , R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula III, wherein R z is hydrogen, and L 2 is C 2 alkylene, thereby forming a compound of formula XII:
  • Ring A, L 1 , R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XII, wherein one instance of R4 is -C(0)NR 2 , thereby forming a compound of formula XIII:
  • Ring A, L 1 , R, R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XIII, wherein Ring A is 4-substituted cyclohexyl, thereby forming a compound of formula XIV:
  • each of L 1 , R, R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XIV, wherein n is 1 , and R 1 is -NR 2 , thereby forming a compound of formula XV:
  • each of L 1 , R, R 4 , and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XV, wherein the stereochemistry of the substituent on the cyclopento ring is (R), and the relative stereochemistry on the cyclohexyl rin is trans thereby forming a compound of formula XVI:
  • each of L 1 , R, R 4 , and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XVI wherein each R 4 is independently hydrogen, fluoro or -OR. [0094] In certain embodiments a provided method employs a compound of formula XVI wherein L 1 is -0-. In certain embodiments a provided method employs a compound of formula XVI wherein L 1 is -NH-.
  • a provided method employs a compound of formula III, wherein R z is hydrogen, and L 2 is Ci alkylene, thereby forming a compound of formula XVII:
  • Ring A, L 1 , R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XVII, wherein one instance of R4 is -C(0)NR 2 , thereby forming a compound of formula XVIII:
  • Ring A, L 1 , R, R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XVIII, wherein Ring A is 4-substituted c clohexyl, thereby forming a compound of formula XIX:
  • a provided method employs a compound of formula XIX, wherein n is 1 , and R 1 is -NR 2 , thereb forming a compound of formula XX:
  • each of L 1 , R, R 4 , and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XX, wherein the stereochemistry of the substituent on the cyclopento ring is (R), and the relative stereochemistry on the cyclohexyl ring is trans thereby forming a compound of formula XXI:
  • each of L 1 , R, R 4 , and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XXI wherein each R 4 is independently hydrogen, fluoro or -OR.
  • a provided method employs a compound of formula XXI wherein L 1 is -0-. In certain embodiments a provided method employs a compound of formula XXI wherein L 1 is -NH-. [00102] In certain embodiments, a provided method employs a compound of formula I, wherein Ring B is piperidino, m is 1 , and R z is hydrogen, thereby forming a compound of formula XXII:
  • Ring A, L 1 , L 2 , R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XXII, wherein L 2 is a bond and p is 0, thereby forming a compound of formula XXIII:
  • Ring A, L 1 , R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XXIII wherein R 4 is -S(0) 2 R, -C(0)R, or -C(0)N(R) 2 .
  • a provided method employs a compound of formula II, wherein L 1 is -0-, thereby forming a compound of formula XXIV:
  • a provided method employs a compound of formula XXIV, wherein m is 1, thereby forming a :
  • Ring A, L 2 , R z , R 1 , R 4 , n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XXV, wherein Ring A is cyclohexyl, thereb forming a compound of formula XXVI:
  • a provided method employs a compound of formula I, wherein R z is -NH-[Ar], thereby forming a compound of formula XXVII:
  • a provided method employs a compound of formula XXVII, wherein n is 1 and Ring A is 1 ,4-trans-substituted cyclohexyl, thereby forming a compound of formula XXVIII:
  • [Ar] is an optionally substituted phenyl or heteroaromatic ring. In some embodiments, [Ar] is optionally substituted phenyl. In some embodiments, [Ar] is an optionally substituted heteroaromatic ring. In some embodiments, [Ar] is an optionally substituted 5-membered heteroaromatic ring. In some embodiments, [Ar] is an optionally substituted 6-membered heteroaromatic ring. In some embodiments, [Ar] is an optionally substituted pyrazole ring.
  • a provided method employs a compound of formula
  • a provided method employs a compound of formula XXVIII, wherein Ring B is cyclohexo, thereby forming a compound of formula XXIX:
  • a provided method employs a compound of formula XXVIII, wherein Ring B is a partially unsaturated tetrahydropyrano-fused ring, thereby forming a compound of one of formulae XXX-a, XXX-b, XXX-c, or XXX-d:
  • a provided method employs a compound of formula
  • Ring B is a partially unsaturated piperidino-fused ring, thereby forming compound of one of formulae XXXI-a, XXXI-b, XXXI-c, or XXXI-d:
  • a provided method employs a compound of formula
  • a provided method employs a compound of formula I, wherein n is 1 , Ring A is trans-substituted cyclohexyl, and Ring B is a partially unsaturated tetrahydropyrano-fused ring, thereby forming a compound of one of formulae XXXIII-a, XXXIII-b, XXXIII-c, or XXXIII-d:
  • each of L 1 , L 2 , R 1 , R 4 , R z , m, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula I, wherein n is 1 , Ring A is trans-substituted cyclohexyl, and Ring B is a partially unsaturated piperidino-fused ring, thereby forming a compound of one of formulae XXXIV-a, XXXIV-b, XXXIV-c, or XXXI -d:
  • a provided method employs a compound of formula I, wherein n is 1 , Ring A is trans-substituted cyclohexyl, and Ring B is a partially unsaturated pyrrolidino-fused ring, thereby forming a compound of one of formulae XXXV-a, XXXV-b, or XXXV-c:
  • each of L 1 , L 2 , R 1 , R 4 ,R Z , m, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula
  • each of L 1 , L 2 , R 1 , R 4 , m, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula
  • each of L 1 , L 2 , R 1 , R 4 , m, and p is as defined above and described in embodiments herein, both singly and in combination.
  • a provided method employs a compound of formula XXXV- a, XXXV-b, or XXXV-c, wherein R z is hydrogen, thereby forming a compound of one of formula -a, XXXVIII-b, or XXXVIII-c:
  • a provided method employs a compound of formula I, wherein W is N, and R z is hydrogen, thereby forming a compound of formula I-a:
  • Ring A, Ring B, L 1 , L 2 , W, R z , R 1 , R 4 , m, n, and p is as defined above and described in embodiments herein, both singly and in combination.
  • the method employs a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof.
  • a water molecule displaced or disrupted by an inhibitor compound, or pendant moiety of an inhibitor compound is an unstable water molecule.
  • the method employs a complex comprising CDK8 and an inhibitor, wherein at least one unstable water of CDK8 is displaced or disrupted by the inhibitor. In some embodiments, at least two unstable waters selected are displaced or disrupted by the inhibitor.
  • the compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.
  • compositions are provided.
  • the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit a CDK8 protein kinase, or a mutant thereof, in a biological sample or in a patient.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit a CDK8 protein kinase, or a mutant thereof, in a biological sample or in a patient.
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for oral administration to a patient.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropy
  • a "pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of a CDK8 protein kinase, or a mutant thereof.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • compositions of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • Compounds and compositions described herein are generally useful for the inhibition of kinase activity of one or more enzymes.
  • the kinase inhibited by the compounds and methods of the invention is CDK8
  • CDK8 is a member of the class of the cyclin-dependent kinase enzymes ("CDKs") that are an essential part of the regulation of cell growth. Tumor and malignant cell growth is often associated with mutation or disregulation of CDKs or their regulators, and thus inhibition of CDKs may be important in the treatment of cancer and other proliferative disorders.
  • CDKs cyclin-dependent kinase enzymes
  • cdk8 (the gene encoding the CDK8 enzyme) has been identified as an oncogene, with regulatory effects on beta-catenin activity.
  • Firestein et al “CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity” Nature (2008) 455(25), 547-551.
  • CDK8 has been identified as a key regulator of colon cancer cell proliferation.
  • the cdk8 gene is located at 13ql2.13, which has been found to be a region of recurrent copy number gain in a substantial fraction of colon cancers. Suppression of the hyperactivity of CDK8, inhibits the proliferation of colon cancers, as well as other cancers associated with overexpression and/or hyperactivity of CDK8 or beta-catenin, and associated members of the Wnt pathway.
  • Another key pathway for regulation of gene expression in colorectal cancer cells is the EGFR / KRAS pathway.
  • CDK8 inhibition leads to inhibition of proliferative activity even in cancers that have mutations in EGFR and KRAS, as well as those having mutations in APC or beta-catenin.
  • CDK8 inhibition leads to inhibition of proliferative activity even in cancers that have mutations in EGFR and KRAS, as well as those having mutations in APC or beta-catenin.
  • CDK8 inhibition leads to inhibition of proliferative activity even in cancers that have mutations in EGFR and KRAS, as well as those having mutations in APC or beta-catenin.
  • CDK8 inhibition By inhibiting CDK8, both Rzymski et al. "Antitumor activity of SEL120: orally available dual inhibitors of CDK8/CDK9, for standalone and combination therapy in colon cancer" AACR Annual Meeting 2012, poster #3845/26.
  • CDK8 is correlated to maintenance of tumor cell dedifferentiation, and maintaining embryonic stem cell pluripotency.
  • Adler et al. “CDK8 Maintains Tumor Dedifferentiation and Embryonic Stem Cell Pluripotency” Cancer Research (2012) 72; 2129-2139. Dedifferentiation of tumor cells is correlated to poor clinical outcome in cancers including colon cancer. Thus inhibition of CDK8 can lead to not only to decreased cancer cell proliferation, but also preventing cancer cells from maintaining their pluripotency, thereby improving clinical outcomes.
  • CDK8 expression and the de localization of ⁇ -catenin expression in tumor cells shows a significant positive correlation with carcinogenesis and tumor progression, especially lymph node metastasis. Kim et al. "Roles of cyclin-dependent kinase 8 and beta-catenin in the oncogenesis and progression of gastric adenocarcinoma" Intl. J. Oncology (2011) 38; 1375-1383.
  • CDK8 also leads to inhibition of Nuclear Factor kappa Beta (NFKB) transcriptional activity by both p21 and Tumor Necrosis Factor Alpha (TNF ). See WO2013/040153.
  • NFKB Nuclear Factor kappa Beta
  • CDK8 is also known to phosphorylate STAT1, STAT3, STAT4, and STAT5 in response to interferon-gamma (IFN- ⁇ ), and inhibition of CDK8 activity results in reduced expression of IFN-y-stimulated genes.
  • IFN- ⁇ interferon-gamma
  • CDK8 also plays a role, together with MED15, in regulating sterol regulatory element-binding protein (SREBP) transcription factors, which are master activators for genes that are responsible for lipid biosynthesis.
  • SREBP sterol regulatory element-binding protein
  • CDK8 has utility in treating obesity, cardiovascular disease (including atherosclerosis), metabolic disorders (such as Type II diabetes mellitus and hypertriglycemia), and other diseases implicating the MED 15 and SREBP transcription regulatory pathways (such as fatty liver, and non-alcoholic steatohepatitis).
  • CDK8 direct inhibition of enzymes such as CDK8 has advantages over other chemotherapies that target DNA replication or induce DNA damage by interacting with DNA directly, as the specific inhibition of a tumor-associated enzyme should lead to reduced side effects and reduced complications such as secondary tumor development associated with chemotherapy-induced mutations.
  • CDK8 has also been shown to be essential in early embryonic development, but not needed for mature cell proliferation. Westerling et al. "Cdk8 is essential for preimplantation mouse development" Mol. Cell. Biol. (2007) 27(17); 6177-6182. Accordingly, inhibition of CDK8 activity has selective antiproliferative effects in tumor cells featuring upregulated CDK8 activity over non-tumorigenic mature cells.
  • the activity of a compound utilized in this invention as an inhibitor of CDK8, or a mutant thereof may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of either the phosphorylation activity and/or the subsequent functional consequences, or ATPase activity of activated CDK8, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to CDK8. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/CDK8 complex and determining the amount of radiolabel bound.
  • inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with CDK8 bound to known radioligands.
  • Detailed conditions for assaying a compound utilized in this invention as an inhibitor of CDK8, or a mutant thereof, are set forth in the Examples below.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the present invention provides a method for treating a CDK8-mediated or beta-catenin-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.
  • the disorder is a CDK8-mediated disorder.
  • the disorder is a beta-catenin-mediated disorder.
  • CDK8-mediated disorders, diseases, and/or conditions means any disease or other deleterious condition in which CDK8 or a mutant thereof is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which CDK8, or a mutant thereof, is known to play a role.
  • CDK8-mediated disorders include but are not limited to cancers or other proliferative disorders.
  • the cancer or other proliferative disorder is selected from acute myeloid leukemia (also known as acute myelogenous leukemia), solid tumors, gliomas, myelodysplasia syndrome, renal cell carcinoma, glioblastoma, prostate cancer, melanoma, acute lymphoblastic leukemia, myeloproliferative disorder, nasopharyngeal carcinoma, breast tumors, thrombocytopenia, polycythemia vera, myelofibrosis, chronic myelocytic leukemia, lung tumors, colorectal tumors, and autoimmune diseases.
  • acute myeloid leukemia also known as acute myelogenous leukemia
  • solid tumors also known as acute myelogenous leukemia
  • gliomas also known as acute myelogenous leukemia
  • myeloproliferative disorder nasopharyngeal carcinoma
  • breast tumors thrombocytopenia
  • polycythemia vera myel
  • the disorder is selected from gliomas, myelodysplasia syndrome, acute lymphoblastic leukemia, myeloproliferative disorder, nasopharyngeal carcinoma, polycythemia vera, and myelofibrosis.
  • the disorder is a gastrointestinal cancer. In some embodiments, the disorder is a colon cancer. In some embodiments, the disorder is a gastric cancer. In some embodiments the disorder is an adenocarcinoma. In some embodiments, the adenocarcinoma is colon adenocarcinoma or gastric adenocarcinoma. In some embodiments, the cancer is associated with an overexpression or copy number gain of CDK8. In some embodiments, the cancer is associated with a mutation in one or more members of the Wnt signaling pathway. In some embodiments, the cancer is associated with a mutation in one or more members of the EGFR signaling pathway. In some embodiments, the cancer is associated with mutations in one or more members of both the Wnt signaling pathway and the EGFR signaling pathway. In some embodiments, the cancer is resistant to anti-EGFR therapy.
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition is a cancer, a neurodegenative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin- induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.
  • the disorder, disease, or condition is a cancer, a neurodegenative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thro
  • a human patient is treated with a compound of the current invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said compound is present in an amount to measurably inhibit CDK8 kinase activity or modulate CDK8 scaffold activity as it relates to cyclinC, MED 12, and MED 13
  • Compounds of the current invention are useful in the treatment of a proliferative disease selected from a benign or malignant tumor, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head,
  • Compounds according to the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression.
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "whez infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.
  • compounds of the invention are useful in treating ophthalmic diseases including age-related macular degeneration.
  • Compounds according to the invention are useful in the treatment of heteroimmune diseases.
  • heteroimmune diseases include, but are not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
  • Compounds of the current invention can be used for other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis anthracosis
  • asbestosis chalicosis
  • ptilosis ptilosis
  • siderosis silicosis
  • tabacosis tabacosis and byssinosis.
  • compounds of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g.
  • eosinophilic infiltration of pulmonary tissues including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil- related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
  • Compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.
  • Compounds of the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g.
  • hemolytic anemia aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g.
  • idiopathic nephrotic syndrome or minal change nephropathy chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget' s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity
  • the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.
  • Cardiovascular diseases which can be treated according to the methods of this invention include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, and deep venous thrombosis.
  • the neurodegenerative disease which can be treated according to the methods of this invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation and graft versus host disease.
  • the invention provides a method of treating, preventing or lessening the severity of Alzheimer's disease comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt or composition thereof.
  • the invention provides a method of treating a disease or condition commonly occurring in connection with transplantation.
  • the disease or condition commonly occurring in connection with transplantation is selected from organ transplantation, organ transplant rejection, and graft versus host disease.
  • the invention provides a method of treating a metabolic disease.
  • the metabolic disease is selected from Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity.
  • the invention provides a method of treating a viral disease.
  • the viral infection is HIV infection.
  • the invention provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof for the preparation of a medicament for the treatment of a proliferative disease, an inflammatory disease, an obstructive respiratory disease, a cardiovascular disease, a metabolic disease, a neurological disease, a neurodegenerative disease, a viral disease, or a disorder commonly occurring in connection with transplantation.
  • additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as "appropriate for the disease, or condition, being treated.”
  • a provided combination, or composition thereof is administered in combination with another therapeutic agent.
  • MS Multiple
  • combination therapies of the present invention are administered in combination with a monoclonal antibody or an siR A therapeutic.
  • Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents.
  • the therapeutic agent may be administered together with a compound of formula I, or may be administered prior to or following administration of a compound of formula I. Suitable therapeutic agents are described in further detail below.
  • a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent.
  • a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.
  • the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents.
  • additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrex
  • NSAIDS non
  • the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from non-steroidal antiinflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofm (Ridaura®), D-penicill
  • NSAIDS non-
  • the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal antiinflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.
  • NSAIDS non-steroidal antiinflammatory drugs
  • the present invention provides a method of treating lupus comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).
  • NSAIDS non-steroidal anti
  • the present invention provides a method of treating inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.
  • mesalamine Asacol®
  • Amulfidine® antidiarrheals
  • the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (A)
  • the present invention provides a method of treating COPD comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, pre
  • the present invention provides a method of treating HIV comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and
  • the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
  • the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
  • additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,
  • the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I and a Hedgehog (Hh) signaling pathway inhibitor.
  • the hematological malignancy is DLBCL (Ramirez et al "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma" Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).
  • the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.
  • rituximab Renuxan®
  • Cytoxan® cyclophosphamide
  • doxorubicin Hydrodaunorubicin®
  • vincristine Oncovin®
  • prednisone a hedgehog signaling inhibitor
  • the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
  • additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
  • the present invention provides a method of treating Waldenstrom's macroglobulinemia comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from chlorambucil ( Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor,
  • additional therapeutic agents selected from chlorambucil ( Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, a B
  • the present invention provides a method of treating Alzheimer's disease comprising administering to a patient in need thereof a compound of formula ⁇ and one or more additional therapeutic agents selected from donepezil (Aricept ® ), rivastigmine (Excelon ® ), galantamine (Razadyne ® ), tacrine (Cognex ® ), and memantine (Namenda ® ).
  • the present invention provides a method of treating organ transplant rejection or graft vs. host disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from a steroid, cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan- JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.
  • additional therapeutic agents selected from a steroid, cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan- JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylos
  • the disease is selected from
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a C S disorder.
  • the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immuno
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of .fb.rm.ul I and a PI3 . inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a n
  • hemolytic anemia aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
  • idiopathic nephrotic syndrome or minal change nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer, an autoimmune disorder, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone- related disorder, liver disease, or a cardiac disorder.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • the expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention relates to a method of inhibiting CDK8, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention relates to a method of irreversibly inhibiting CDK8, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention provides a method of simultaneously inhibiting both CDK8 and one or more other protein kinases selected from FLT3, IRAK-1, IRAK-2, and IRAK-4, CLK1, CLK2, or mutants thereof.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of protein kinase, or a protein kinase selected from CDK8, or a mutant thereof, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • Another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of inhibiting activity of CDK8, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of reversibly or irreversibly inhibiting one or more of CDK8, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the present invention provides a method for treating a disorder mediated by CDK8, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof.
  • a disorder mediated by CDK8, or a mutant thereof in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof.
  • additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as "appropriate for the disease, or condition, being treated.”
  • a compound of the current invention may also be used to advantage in combination with other therapeutic compounds.
  • the other therapeutic compounds are antiproliferative compounds.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative
  • aromatase inhibitor as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane is marketed under the trade name AromasinTM.
  • Formestane is marketed under the trade name LentaronTM.
  • Fadrozole is marketed under the trade name AfemaTM.
  • Anastrozole is marketed under the trade name ArimidexTM.
  • Letrozole is marketed under the trade names FemaraTM or FemarTM.
  • Aminoglutethimide is marketed under the trade name OrimetenTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
  • antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen is marketed under the trade name NolvadexTM.
  • Raloxifene hydrochloride is marketed under the trade name EvistaTM.
  • Fulvestrant can be administered under the trade name FaslodexTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CasodexTM).
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name ZoladexTM.
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148.
  • Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CamptosarTM.
  • Topotecan is marketed under the trade name HycamptinTM.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CaelyxTM), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide is marketed under the trade name EtopophosTM.
  • Teniposide is marketed under the trade name VM 26-Bristol
  • Doxorubicin is marketed under the trade name AcriblastinTM or AdriamycinTM.
  • Epirubicin is marketed under the trade name FarmorubicinTM.
  • Idarubicin is marketed, under the trade name ZavedosTM.
  • Mitoxantrone is marketed under the trade name Novantron.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
  • Paclitaxel is marketed under the trade name TaxolTM.
  • Docetaxel is marketed under the trade name TaxotereTM.
  • Vinblastine sulfate is marketed under the trade name Vinblastin R.PTM.
  • Vincristine sulfate is marketed under the trade name FarmistinTM.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name CyclostinTM. Ifosfamide is marketed under the trade name HoloxanTM.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • SAHA suberoylanilide hydroxamic acid
  • antimetabolite includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine is marketed under the trade name XelodaTM.
  • Gemcitabine is marketed under the trade name GemzarTM.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CarboplatTM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark EloxatinTM.
  • the term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds” as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (I
  • BCR-Abl kinase and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD 180970; AG957; NSC 680410; PD 173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin;
  • c-Met receptor compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF
  • PI3K inhibitor includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to ⁇ , ⁇ , ⁇ , ⁇ , PI3K-C2a, PBK-C2P, ⁇ - C2y, Vps34, pl l0-a, ⁇ 110- ⁇ , ⁇ 110- ⁇ , ⁇ 110- ⁇ , ⁇ 85- ⁇ , ⁇ 85- ⁇ , ⁇ 55- ⁇ , ⁇ 150, plOl, and ⁇ 87.
  • ⁇ inhibitors useful in this invention include but are not limited to ATU-027, SF- 1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
  • BTK inhibitor includes, but is not limited to compounds having inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.
  • SYK inhibitor includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib [00239] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
  • PI3K inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.
  • JAK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (ThalomidTM) and TNP-470.
  • ThilomidTM thalidomide
  • TNP-470 TNP-470.
  • proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP- 18770, and MLN9708.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, ⁇ - ⁇ - or ⁇ - tocopherol or a- ⁇ - or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CelebrexTM), rofecoxib (VioxxTM), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • Cox- 2 inhibitors such as celecoxib (CelebrexTM), rofecoxib (VioxxTM), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid is marketed under the trade name DidronelTM.
  • Clodronic acid is marketed under the trade name BonefosTM.
  • Tiludronic acid is marketed under the trade name SkelidTM.
  • Pamidronic acid is marketed under the trade name ArediaTM.
  • Alendronic acid is marketed under the trade name FosamaxTM.
  • Ibandronic acid is marketed under the trade name BondranatTM.
  • Risedronic acid is marketed under the trade name ActonelTM.
  • Zoledronic acid is marketed under the trade name ZometaTM.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CerticanTM), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation.
  • the term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons.
  • inhibitor of Ras oncogenic isoforms such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a “farnesyl transferase inhibitor” such as L-744832, DK8G557 or Rl 15777 (ZarnestraTM).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.
  • methionine ammopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine ammopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine ammopeptidase include, but are not limited to, bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VelcadeTM) and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251 , BAY 12-9566, TAA211 , MMI270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, ⁇ - ⁇ -D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HerceptinTM), Trastuzumab-DMl, erbitux, bevacizumab (AvastinTM), rituximab (Rituxan ® ), PR064553 (anti-CD40) and 2C4 Antibody.
  • trastuzumab HerceptinTM
  • Trastuzumab-DMl erbitux
  • bevacizumab AvastinTM
  • rituximab Rasteran ®
  • PR064553 anti-CD40
  • the present invention provides a method of treating a cancer or other proliferative disorder comprising administering to a patient in need thereof a compound of the invention together with another CDK inhibitor.
  • the CDK inhibitor is a CDK8, CDK9 and/or CDK19 inhibitor.
  • the other CDK inhibitor is selected from Senexin A, SNX2, SNX14, SNX2-1-108, SNS-032, fiavopiridol, staurosporine, staurosporine derivatives, SEL120-1 and SEL120-34.
  • HDAC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl) ⁇ 2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • the term "ionizing radiation” referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X- rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al, Eds., 4 th Edition, Vol. 1 , pp. 248-275 (1993).
  • EDG binders and ribonucleotide reductase inhibitors.
  • EDG binders refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.
  • VEGF vascular endothelial growth factor
  • l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate
  • AngiostatinTM EndostatinTM
  • anthranilic acid amides ZD4190; ZD6474; SU5416; SU6668
  • bevacizumab or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab
  • VEGF aptamer such as Macugon
  • FLT-4 inhibitors, FLT-3 inhibitors VEGFR-2 IgGI antibody
  • Angiozyme RI 4610)
  • Bevacizumab AvastinTM
  • Angiostatic steroids refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • angiogenesis such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fiuocinolone and dexamethasone.
  • chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • the compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • a compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes a combination of a compound of the invention as hereinbefore described with an antiinflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical composition.
  • Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such cilomilast (Arifio® GlaxoSmithKline), Rofiumilast (Byk Gulden), V-l 1294A (Napp), BAY 19-8004 (Bayer), SCH- 351591 (Schering- Plough), Arofylline (Almirall Prodesfarma), PD 189659 / PD 168787 (Parke-
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.
  • chemokine receptors e.g. CCR-1 , CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10
  • CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH- 55700 and SCH-D
  • Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)- 5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H- pyran-4- aminium chloride (TAK-770).
  • a compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • a compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
  • a compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
  • Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen.
  • those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.
  • compositions which comprise an additional therapeutic agent that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 ⁇ g/kg body weight/day of the additional therapeutic agent can be administered.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • Vascular stents for example, have been used to overcome restenosis (re -narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • the ee of 1.8 (98.5%>) and of 1.9 (100%) were determined by analytical chiral SFC under the following conditions: Column: phenomenex Lux 5u Cellulose-3, 4.6*250 mm, 5 ⁇ ; mobile phase: 90% C0 2 and 10% MeOH (0.01 DEA); flow rate: 4 mL/min; UV detection at 254 ⁇ .
  • Example 2 Synthesis of (12S)-3-[[(lr,4r)-4-(morpholin-4-yl)cyclohexyl]oxy]-8- thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-l(9),2(7),3,5-tetraene-12-carboxylic acid. (1-15)
  • Example 4 Synthesis of 12-N-[4-(morpholin-4-yl)cyclohexyl]-10-N-[4-(piperidin- 4-yl)phenyl]-7-thia-9,ll-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,ll-tetraene-10,12- diamine hydrochloride (1-12).
  • Compound 5.1 was prepared in a manner analogous to intermediate 3.4, substituting l-N,l-N-dimethylcyclohexane-l,4-diamine hydrochloride for 4-(morpholin-4-yl)cyclohexan-l- amine dihydrochloride. Isolated 5.1 (300 mg, 79%) as a yellow solid. MS (ES): m/z 252 (M+H) + .
  • Example 6 Synthesis of 10-N-[l-(propan-2-yl)-lH-pyrazol-4-yl]-12-N-[trans-4- (morpholin-4-yl)cyclohexyl]-7-thia-9,ll-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,ll- tetraene-10 -diamine 1-10 .
  • Example 7 Synthesis of 2-[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-10-[(l- methyl-lH-pyrazol-4-yl)amino]-7-thia-9, ll-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9, 1 l-tetraen-3- l acetamide 1-25 .
  • Example 8 Synthesis of 2-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-10-[(l- methyl-lH-pyrazol-4-yl)amino]-7-thia-9,ll-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9, 11- tetraen-3-yl]acetamide (1-14).
  • Example 9 Synthesis of 12-N-[4-(dimethylamino)cyclohexyl]-10-N-(l-methyl- lH-pyrazol-4-yl)-7-thia-9,ll-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,ll-tetraene-10,12- diamine (1-13).
  • Example 10 Synthesis of 10-N-(l-ethyl-lH-pyrazol-4-yl)-12-N-[trans-4- (morpholin-4-yl)cyclohexyl]-7-thia-9,ll-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,ll- tetraene-10,12-diamine (1-9)
  • Compound 1-9 was prepared from 3.4 in a manner analogous to the synthesis of 1-10, substituting 1 -ethyl- lH-pyrazol-4-amine for l-(propan-2-yl)-lH-pyrazol-4-amine.
  • Example 11 Synthesis of 5-N-(l-methyl-lH-pyrazol-4-yl)-3-N-[trans-4- (morpholin-4-yl)cyclohexyl] - 1 l-oxa-8-thia-4,6-diazatricyclo [7.4.0.0 A [2,7] ] trideca- l(9),2(7),3,5-tetraene-3,5-diamine (1-8)
  • Example 12 Synthesis of 12-N-[4-(dimethylamino)cyclohexyl]-10-N-phenyl-7- thia-9,ll-di (1-11)
  • Example 13 Synthesis of 10-N-(l-methyl-lH-pyrazol-4-yl)-12-N-[4-(morpholin- 4-yl)cyclohexyl]-7-thia-9,ll-diazatricyclo [6.4.0.0 [2,6]]dodeca-l(8),2(6),9,ll-tetraene-10,12- diamine (1-
  • Example 17 Synthesis of (S)-2-hydroxy-3-((R)-4-(((lr,4R)-4-(pyrrolidin-l- yl)cyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5- yl)propanamide (1-21).
  • Example 19 Synthesis of (2S)-3-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7- thia-9,11-diazatricyclo [6.4.0.0 [2,6] ] dodeca-l(8),2(6),9,l l-tetraen-3-yl]-2- hydroxypropanamide formate (1-18).
  • Example 20 Synthesis of (S)-2-hydroxy-3-((R)-4-(((lr,4R)-4-(piperidin-l- yl)cyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5- yl)propanamide (1-17).
  • step 3 Mol. Wt.: 560.82 step 4 Mol. Wt.:
  • Example 23 Synthesis of (S)-2-hydroxy-3-((R)-4-(((lr,4R)-4- morpholinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5- yl)propanamide (1-3).
  • Example 24 Synthesis of (12S)-3-[[4-(morpholin-4-yl)cyclohexyl]oxy]-8-thia-4,6- diazatricyclo[7.4.0.0[2,7]]trideca-l(9),2(7),3,5-tetraene-12-carboxamide. (1-4).
  • Example 25 Synthesis of (12S)-3-[[4-(dimethylamino)cyclohexyl]oxy]-8-thia-4,6- diazatricyclo[7.4.0.0[2,7]]trideca-l(9),2(7),3,5-tetraene-12-carboxamide. (1-19).
  • Example 27 Synthesis of 12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,ll- diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,ll-tetraene (1-27).
  • Example 28 Synthesis of (lr,4r)-Nl-(6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3- d]pyrimidin-4-yl)-N4,N4-dimethylcyclohexane-l,4-diamine (1-1).
  • Compound 29.1 was prepared from 18.3 in a manner analogous to the synthesis of 26.1 from 21.2. Isolated 0.9 g (76%) as a colourless oil.
  • Example 31 Synthesis of 2-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7- thia-9,11-diazatricyclo [6.4.0.0 [2,6] ] dodeca-l(8),2(6),9,l l-tetraen-3-yl] acetamide 1-22.
  • Example 33 Synthesis of N-((ls,4s)-4-morpholinocyclohexyl)-6,7-dihydro-5H- cyclopenta [4,5] thieno [2,3-d] pyrimidin-4-amine (1-24).
  • Example 34 Synthesis of 2-((R)-4-(((lr,4R)-4-morpholinocyclohexyl)oxy)-6,7- dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5-yl)acetamide (1-2).
  • Example 35 Synthesis of 2-((R)-4-(((lr,4R)-4-morpholinocyclohexyl)oxy)-6,7- dihydro-5H-cyclopenta [4,5] thie -d] pyrimidin-5-yl)acetamide (1-20).
  • Example 36 Synthesis of 3-[[trans-4-(morpholin-4-yl)cyclohexyl]oxy]-8-thia- 4,6,12-triazatricyclo[7.4.0.0[2,7]]trideca-l(9),2(7),3,5-tetraene-12-sulfonamide (1-6).
  • Example 37 Synthesis of 5-N-(l-methyl-lH-pyrazol-4-yl)-3-N-[(lr,4r)-4- (morpholin-4-yl)cyclohexyl]-8-thia-4,6-diazatricyclo[7.4.0.0 A [2,7]]trideca-l(9),2(7),3,5- tetraene-3,5-diamine (1-7).
  • Example 38 Synthesis of 10-N-(5-methyl-lH-pyrazol-3-yl)-12-N-[trans-4- (morpholin-4-yl)cyclohexyl]-7-thia-9,ll-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,ll- tetraene-10,12-diamine (1-16).
  • Example 39 Synthesis of (R)-2-hydroxy-3-((R)-4-(((lr,4R)-4-morpholin- ocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5-yl)propan- amide, 1-28.
  • Example 40 Synthesis of N2-(l-ethyl-lH-pyrazol-4-yl)-N4-((lr,4r)-4-morpho- linocyclohexyl)-6,8-dihydr o-5H-pyrano [4 ',3 ' :4,5] thieno [2,3-d] pyrimidine-2,4-diamine, 1-29.
  • Example 41 Synthesis of N4-((lr,4r)-4-morpholinocyclohexyl)-N2-(l- (tetrahydro-2H-pyr an-4-yl)- IH-pyr azol-4-yl)-6,8-dihydro-5H-pyrano [4 ',3 ' : 4,5] thieno [2,3- d]pyrimidine-2,4-diamine, 1-30.
  • Example 42 Synthesis of 2-[(3R)-12-[[trans-4-[morpholin-4-yl]cyclohexyl]oxy]- 7-thia-9,ll-diazatricyclo[6.4.0.0 A [2,6]]dodeca-l(8),2(6),9,ll-tetraen-3-yl]acetamide-d 8 , 1-31.
  • the aqueous Kinase Buffer was freshly prepared using 50 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, and 0.01% Brij-35.
  • the test compounds were dissolved in 4 uL of Kinase Buffer at 4x concentration.
  • 3-fold serial dilutions were conducted from the starting concentration.
  • CDK8/cyclin C kinase and Eu-anti-His (“Kinase/Antibody Mixture”) (LanthaScreen® Eu, Life Technologies) was diluted to a 2x working concentration in the Kinase Buffer.
  • the ATP-competitive Tracer (4X AlexaFluor® Tracer 236, Life Technologies) was prepared in Kinase Buffer. 4.0 uL of 4X test compound in Kinase Buffer was added to each well of a 384 well bar-coded, low volume plate (Greiner Cat. #784207). 8.0 uL of 2X Kinase/Antibody Mixture was added for a total CDK8 concentration of 5 nM and a total antibody concentration of 2 nM. 4.0 uL of the 4X Tracer was then added to each well for a total concentration of 10 nM of the Tracer. As a negative control, test compound was used, and as a positive control Staurosporine (10.6 nM IC50) was used. The plates were shaken for 30 seconds followed by a 60 minute incubation at room temperature. The plates were read on a fluorescence plate reader and the data analyzed and converted to displacement curves.
  • Table 2 shows the activity of selected compounds of this invention in the CDK8 FRET assay.
  • the compound numbers correspond to the compound numbers in Table 1.
  • Compounds having an activity designated as "A” provided an IC 50 ⁇ 1 ⁇ ; compounds having an activity designated as “B” provided an IC 50 of 1-2.5 ⁇ ; compounds having an activity designated as “C” provided an IC 50 of 2.5-5 ⁇ ; and compounds having an activity designated as "D” provided an IC 50 > 5 ⁇ .
  • “NA” stands for "not assayed.”
  • Example 44 Mass Spectrometry CDK8 Inhibition Assay
  • KiNativTM is based on biotinylated acyl phosphates of ATP and ADP that irreversibly react with protein kinases on conserved lysine residues in the ATP -binding pocket.
  • Lys2 of the conserved kinase binding pocket is the relevant residue.
  • PBMC peripheral blood mononuclear cells
  • PBMC lysate A549 adenocarcinomic human alveolar basal epithelial cells
  • A549 cell lysate A549 cell lysate
  • Mass spectrometry is then used to determine the amount of covalent modification of the target enzyme. Less covalent probe attached is correlated with a higher degree of inhibition by the test compound, and an inhibition curve was generated from the results over multiple concentrations, from which the IC 50 was calculated. Results of the Mass Spectrometry assay for compound 1-2 are depicted in Table 3 below. Table 3. CDK8 Activity Inhibition Data for Compound 1-2

Abstract

La présente invention concerne des procédés d'utilisation des composés représentés par la formule (I) et de compositions de ceux-ci, en vue d'inhiber CDK8 et de traiter des troubles induits par CDK8.
PCT/US2014/040243 2013-05-31 2014-05-30 Inhibiteurs de cdk8 et applications de ceux-ci WO2014194201A2 (fr)

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JP2018532784A (ja) * 2015-11-03 2018-11-08 エルユー ライセンス エービーＬｕ Ｌｉｃｅｎｓｅ Ａｂ 低増殖性障害の治療のための化合物
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