WO2006112828A1 - Derives d’azaindole en tant qu’inhibiteurs de kinase p38 - Google Patents

Derives d’azaindole en tant qu’inhibiteurs de kinase p38 Download PDF

Info

Publication number
WO2006112828A1
WO2006112828A1 PCT/US2005/012969 US2005012969W WO2006112828A1 WO 2006112828 A1 WO2006112828 A1 WO 2006112828A1 US 2005012969 W US2005012969 W US 2005012969W WO 2006112828 A1 WO2006112828 A1 WO 2006112828A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
heteroalkyl
halo
independently
Prior art date
Application number
PCT/US2005/012969
Other languages
English (en)
Inventor
Sundeep Dugar
Bindu Goyal
Qing Lu
Gregroy R. Luedtke
Babu J. Mavunkel
Imad Nashashibi
John J. Perumattam
Xuefei Tan
Richland Tester
Dan Xiong Wang
Original Assignee
Scios, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scios, Inc. filed Critical Scios, Inc.
Priority to PCT/US2005/012969 priority Critical patent/WO2006112828A1/fr
Publication of WO2006112828A1 publication Critical patent/WO2006112828A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds, compositions, and methods for treating various disorders associated with undesirably high activity of p38 kinase. More specifically, it concerns compounds that are related to azaindole, wherein the azaindole-type ring is coupled through an azacyclic moiety to an additional cyclic group, which are useful in methods to treat such disorders.
  • cytokines A large number of chronic and acute conditions have been recognized to be associated with perturbations of the inflammatory response. Many different cytokines are known to participate in this response, including IL-I, IL-6, IL-8 and TNF. It appears that the activity of these cytokines in the regulation of inflammation rely at least in part on the activation of an enzyme in the cell signaling pathway, a member of the MAP kinase family generally known as p38, and alternatively known as CSBP and RK. This kinase is activated by dual phosphorylation after stimulation byphysiochemical stress, treatment with Hpopolysaccharides or with proinflammatory cytokines such as IL-I and TNF. Therefore, inhibitors of the kinase activity of p38 are useful anti-inflammatory agents.
  • p38 has been shown to comprise a group of MAP kinases designated p38- ⁇ , p38- ⁇ , p38- ⁇ and p38- ⁇ .
  • Jiang, Y., et al, J. Biol. Chem. (1996) 271 : 17920- 17926 reported characterization of p38- ⁇ as a 372-amino acid protein closely related to p38- ⁇ .
  • p38- ⁇ was preferentially activated by MAP kinase kinase-6 (MKK6) and preferentially activated transcription factor 2, thus suggesting that separate mechanisms for action may be associated with these forms.
  • MKK6 MAP kinase kinase-6
  • ATF-2 activated transcription factor-2
  • rheumatoid arthritis rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions
  • sepsis septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, stroke, reperfusion injury, CNS injuries such as neural trauma and ischemia, psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, cystic fibrosis, silicosis, pulmonary sarcosis, bone fracture healing, bone resorption diseases such as osteoporosis, soft tissue damage, graft- versus-host reaction, Crohn's Disease, ulcerative colitis including inflammatory bowel disease (IBD) and pyresis.
  • IBD inflammatory bowel disease
  • the invention is directed to methods and compounds useful in treating conditions that are characterized by excessive, or undesirably high, p38 kinase activity.
  • p38 kinase sometimes shortened to "p38" refers to all of the iso forms having p38 kinase activity.
  • the conditions characterized by undesirably high p38 kinase activity include those identified above, particularly inflammation related disorders sucH as arthritis.
  • p38 activity has been associated with pain, cardiovascular diseases such as acute coronary syndrome, osteolytic lesions and other cancers, myelodysplasia and multiple myeloma.
  • the compounds of the invention are useful in treating and alleviating these disorders as further described below.
  • ⁇ * represents a single or double bond
  • one of Z 1 and Z 2 is CQ or C R 1 Q and the other of Z 1 and Z 2 is CR 1 or C(R') 2 ;
  • Cy is a cyclic group having 3-7 ring members that is substituted with 0-5 substituents R 6 , wherein two R 6 substituents can form a ring that is fused to Cy, or
  • Cy can represent two cyclic groups having 3-7 ring members each, where both cyclic groups are bonded to a single atom of L 2 and where each of the two cyclic groups is optionally substituted with 0-5 substituents R 6 ; each R 3 and R 6 independently represents an optionally substituted C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl group, or it can be halo, OR, NR 2 , NROR, NRNR 2 , SR, SOR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCOOR, N
  • the compounds of formula (1) are useful in treating conditions which are characterized by excessive, or undesirably high, activity of p38 kinase, in particular the ⁇ -isoform.
  • Conditions "characterized by excessive p38 activity” include those where this enzyme is present in increased amount, or where the enzyme has been modified to increase its inherent activity, or both, as well as conditions where the enzyme activity or level is not abnormally high but a medical benefit can be provided to a subject by reducing the subject's p38 kinase activity.
  • excessive activity refers to any condition wherein the effectiveness or activity of these proteins is undesirably high, regardless of the cause.
  • the compounds of the invention are useful in conditions where p38 kinase exhibits excessive activity. These conditions are those in which fibrosis and organ sclerosis are caused by, or accompanied by, inflammation, oxidation injury, hypoxia, altered temperature or extracellular osmolality, conditions causing cellular stress, apoptosis or necrosis. These conditions include ischemia-reperfusion injury, congestive heart failure, progressive pulmonary and bronchial fibrosis, hepatitis, arthritis, inflammatory bowel disease, glomerular sclerosis, interstitial renal fibrosis, chronic scarring diseases of the eyes, bladder and reproductive tract, bone marrow dysplasia, chronic infectious or autoimmune states and traumatic or surgical wounds. These conditions, of course, would be benefited by compounds which inhibit p38. Methods of treatment with the compounds of the invention are further discussed below.
  • hydrocarbyl residue refers to a residue which contains only carbon and hydrogen.
  • the residue may be aliphatic or aromatic, straight-chain, cyclic, branched, saturated or unsaturated, or any combination of these.
  • the hydrocarbyl residue when so stated however, may contain heteroatoms in addition to or instead of the carbon and hydrogen members of the hydrocarbyl group itself.
  • the hydrocarbyl group when specifically noted as containing heteroatoms the hydrocarbyl group may contain heteroatoms within the "backbone" of the hydrocarbyl residue, and when optionally substituted, the hydrocarbyl residue may also have one or more carbonyl groups, amino groups, hydroxyl groups and the like in place of one or more hydrogens of the parent hydrocarbyl residue.
  • organic residue refers to a residue that does not contain carbon. Examples include, but are not limited to, halo, hydroxy, NO 2 or NH 2 .
  • alkyl straight-chain, branched-chain and cyclic monovalent hydrocarbyl radicals, and combinations of these, which contain only C and H when they are unsubstituted. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentyl ethyl, 2-propenyl, 3-butynyl, and the like.
  • the total number of carbon atoms in each such group is sometimes described herein, e.g., when the group can contain up to ten carbon atoms it can be represented as 1-1 OC or as Cl-ClO or Cl-10.
  • heteroatoms N, O and S typically
  • the numbers describing the group though still written as e.g. C1-C6, represent the sum of the number of carbon atoms in the group plus the number of such heteroatoms that are included as replacements for carbon atoms in the ring or chain being described.
  • the alkyl, alkenyl and alkynyl substituents of the invention contain 1-lOC (alkyl) or 2- 1OC (alkenyl or alkynyl). Preferably they contain 1-8C (alkyl) or 2-8C (alkenyl or alkynyl). Sometimes they contain 1-4C (alkyl) or 2-4C (alkenyl or alkynyl).
  • a single group can include more than one type of multiple bond, or more than one multiple bond; such groups are included within the definition of the term "alkenyl” when they contain at least one carbon- carbon double bond, and are included within the term "alkynyl" when they contain at least one carbon-carbon triple bond.
  • alkyl, alkenyl and alkynyl groups are often substituted to the extent that such substitution makes sense chemically.
  • Alkyl, alkenyl and alkynyl groups can also be substituted by C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl, each of which can be substituted by the substituents that are appropriate for the particular group.
  • Heteroalkyl “heteroalkenyl”, and “heteroalkynyl” and the like are defined similarly to the corresponding hydrocarbyl (alkyl, alkenyl and alkynyl) groups, but the 'hetero' terms refer to groups that contain 1-3 O, S or N heteroatoms or combinations thereof within the backbone residue; thus at least one carbon atom of a corresponding alkyl, alkenyl, or alkynyl group is replaced by one of the specified heteroatoms to form a heteroalkyl, heteroalkenyl, or heteroalkynyl group.
  • heteroforms of alkyl, alkenyl and alkynyl groups are generally the same as for the corresponding hydrocarbyl groups, and the substituents that may be present on the heteroforms are the same as those described above for the hydrocarbyl groups.
  • substituents that may be present on the heteroforms are the same as those described above for the hydrocarbyl groups.
  • such groups do not include more than two contiguous heteroatoms except where an oxo group is present on N or S as in a nitro or sulfonyl group.
  • alkyl as used herein includes cycloalkyl and cycloalkylalkyl groups
  • cycloalkyl may be used herein to describe a carbocyclic non-aromatic group that is connected via a ring carbon atom
  • cycloalkylalkyl may be used to describe a carbocyclic non-aromatic group that is connected to the molecule through an alkyl linker.
  • heterocyclyl may be used to describe a non-aromatic cyclic group that contains at least one heteroatom as a ring member and that is connected to the molecule via a ring atom, which may be C or N; and “heterocyclylalkyl” may be used to describe such a group that is connected to another molecule through a linker.
  • the sizes and substituents that are suitable for the cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups are the same as those described above for alkyl groups. As used herein, these terms also include rings that contain a double bond or two, as long as the ring is not aromatic.
  • acyl encompasses groups comprising an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical attached at one of the two available valence positions of a carbonyl carbon atom
  • heteroacyl refers to the corresponding groups wherein at least one carbon other than the carbonyl carbon has been replaced by a heteroatom chosen from N, O and S.
  • Acyl and heteroacyl groups are bonded to any group or molecule to which they are attached through the open valence of the carbonyl carbon atom. Typically, they are C1-C8 acyl groups, which include formyl, acetyl, pivaloyl, and benzoyl, and C2-C8 heteroacyl groups, which include methoxyacetyl, ethoxycarbonyl, and 4-pyridinoyl.
  • the hydrocarbyl groups, aryl groups, and heteroforms of such groups that comprise an acyl or heteroacyl group can be substituted with the substituents described herein as generally suitable substituents for each of the corresponding component of the acyl or heteroacyl group.
  • Aromatic moiety or "aryl” moiety refers to a monocyclic or fused bicyclic moiety having the well-known characteristics of aromaticity; examples include phenyl and naphthyl.
  • heteroaryl refers to such monocyclic or fused bicyclic ring systems which contain as ring members one or more heteroatoms selected from O, S and N. The inclusion of a heteroatom permits aromaticity in 5-membered rings as well as 6-membered rings.
  • Typical heteroaromatic systems include monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, and imidazolyl and the fused bicyclic moieties formed by fusing one of these monocyclic groups with a phenyl ring or with any of the heteroaromatic monocyclic groups to form a C8-C 10 bicyclic group such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, quinazolinyl, quinoxalinyl, cinnolinyl, and the like.
  • monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidy
  • any monocyclic or fused ring bicyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition. It also includes bicyclic groups where at least the ring which is directly attached to the remainder of the molecule has the characteristics of aromaticity.
  • the ring systems contain 5-12 ring member atoms.
  • the monocyclic heteroaryls contain 5-6 ring members, and the bicyclic heteroaryls contain 8-10 ring members.
  • Aryl and heteroaryl moieties may be substituted with a variety of substituents including C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl, C1-C8 acyl, and heteroforms of these, each of which can itself be further substituted; other substituents for aryl and heteroaryl moieties include halo,OR, NR 2 , SR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, CONR 2 , 0OCR, COR, and NO 2 , wherein each R is independently H, C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, C5-C10
  • an arylalkyl substituent may be substituted on the aryl portion with substituents described herein as typical for aryl groups, and it may be further substituted on the alkyl portion with substituents described herein as typical or suitable for alkyl groups.
  • arylalkyl and “heteroarylalkyl” refer to aromatic and heteroaromatic ring systems which are bonded to their attachment point through a linking group such as an alkylene, including substituted or unsubstituted, saturated or unsaturated, cyclic or acyclic linkers.
  • the linker is C1-C8 alkyl or a hetero form thereof.
  • These linkers may also include a carbonyl group, thus making them able to provide substituents as an acyl or heteroacyl moiety.
  • An aryl or heteroaryl ring in an arylalkyl or heteroarylalkyl group may be substituted with the same substituents described above for aryl groups.
  • an arylalkyl group includes a phenyl ring optionally substituted with the groups defined above for aryl groups and a C1-C4 alkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl groups or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane.
  • a heteroarylalkyl group preferably includes a C5-C6 monocyclic heteroaryl group that is optionally substituted with the groups described above as substituents typical on aryl groups and a C1-C4 alkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl groups or heteroalkyl groups, or it includes an optionally substituted phenyl ring or C5-C6 monocyclic heteroaryl and a C1-C4 heteroalkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane.
  • substituents may be on either the alkyl or heteroalkyl portion or on the aryl or heteroaryl portion of the group.
  • the substituents optionally present on the alkyl or heteroalkyl portion are the same as those described above for alkyl groups generally; the substituents optionally present on the aryl or heteroaryl portion are the same as those described above for aryl groups generally.
  • Arylalkyl groups as used herein are hydrocarbyl groups if they are unsubstituted, and are described by the total number of carbon atoms in the ring and alkyl ene or similar linker.
  • a benzyl group is a C7-arylalkyl group
  • phenylethyl is a C8-arylalkyl.
  • Heteroarylalkyl refers to a moiety comprising an aryl group that is attached through a linking group, and differs from “arylalkyl” in that at least one ring atom of the aryl moiety or one atom in the linking group is a heteroatom selected from N, O and S.
  • the heteroarylalkyl groups are described herein according to the total number of atoms in the ring and linker combined, and they include aryl groups linked through a heteroalkyl linker; heteroaryl groups linked through a hydrocarbyl linker such as an alkylene; and heteroaryl groups linked through a heteroalkyl linker.
  • C7-heteroarylalkyl would include pyridylmethyl, phenoxy, and N-pyrrolylmethoxy.
  • Alkylene refers to a divalent hydrocarbyl group; because it is divalent, it can link two other groups together. Typically it refers to -(CH 2 ) n - where n is 1-8 and preferably n is 1 -4, though where specified, an alkylene can also be substituted by other groups, and can be of other lengths, and the open valences need not be at opposite ends of a chain. Thus -CH(Me)- and -C(Me) 2 - may also be referred to as alkylenes, as can a cyclic group such as cyclopropan-l,l-diyl. Where an alkylene group is substituted, the substituents include those typically present on alkyl groups as described herein.
  • any alkyl, alkenyl, alkynyl, acyl, or aryl or arylalkyl group or any heteroform of one of these groups that is contained in a substituent may itself optionally be substituted by additional substituents.
  • the nature of these substituents is similar to those recited with regard to the primary substituents themselves if the substituents are not otherwise described.
  • R 7 is alkyl
  • this alkyl may optionally be substituted by the remaining substituents listed as embodiments for R 7 where this makes chemical sense, and where this does not undermine the size limit provided for the alkyl per se; e.g., alkyl substituted by alkyl or by alkenyl would simply extend the upper limit of carbon atoms for these embodiments, and is not included.
  • each such alkyl, alkenyl, alkynyl, acyl, or aryl group may be substituted with a number of substituents according to its available valences; in particular, any of these groups may be substituted with fluorine atoms at any or all of its available valences, for example.
  • Heteroform or “heteroarom-containing form” as used herein refers to a derivative of a group such as an alkyl, aryl, or acyl, wherein at least one carbon atom of the designated hydrocarbyl group has been replaced by a heteroatom selected from N, O and S.
  • the heteroforms of alkyl, alkenyl, alkynyl, acyl, aryl, and arylalkyl are heteroalkyl, heteroalkenyl, heteroalkynyl, heteroacyl, heteroaryl, and heteroarylalkyl, respectively. It is understood that no more than two N, O or S atoms are ordinarily connected sequentially, except where an oxo group is attached to N or S to form a nitro or sulfonyl group.
  • the group takes up two available valences, so the total number of substituents that may be included is reduced according to the number of available valences.
  • Halo as used herein includes fluoro, chloro, bromo and iodo. Fluoro and chloro are often preferred.
  • Amino refers to NH 2 , but where an amino is described as “substituted” or “optionally substituted”, the term includes NR'R" wherein each R' and R" is independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl groups or heteroforms of one of these groups is optionally substituted with the substituents described herein as suitable for the corresponding group.
  • R' and R" are linked together to form a 3-8 membered ring which may be saturated, unsaturated or aromatic and which contains 1-3 heteroatoms independently selected from N, O and S as ring members, and which is optionally substituted with the substituents described as suitable for alkyl groups or, if NR'R" is an aromatic group, it is optionally substituted with the substituents described as typical for heteroaryl groups.
  • the compounds of the invention are derivatives of azaindoles: they are analogs of indole having at least one extra ring nitrogen, which is in the 6-membered ring.
  • they include ring systems where the ring labeled ⁇ in formula (1) is a pyridine or pyrazine ring, which is fused to a pyrrole or a partially saturated pyrrole ring that is labeled ⁇ in formula (1).
  • the positions of atoms in the ⁇ and ⁇ rings will be described using the numbering shown in formula (1).
  • the ring labeled ⁇ is a pyridine or pyrazine ring.
  • Z 4 or Z 5 is N
  • the other one of Z 4 and Z 5 is either CH or CR 3 , or it is C to which L 1 is attached.
  • the ring labeled ⁇ is a pyrazine, so both Z 4 and Z 5 are N.
  • Z 4 is CH and Z 5 is N; in still others, Z 4 is N and Z 5 is CH.
  • L 1 is CO and it is sometimes preferred that L 2 is CH 2 .
  • the ⁇ ring of the azaindole is necessarily substituted with L 1 at one of positions 4, 5, 6, and 7. In some of the preferred embodiments, L 1 is attached at position 5, and in others it is at position 6. Position 5 is more preferred as the attachment point for L 1 . Where both Z 4 and Z 5 are N, L 1 must attach at position 5 or position 6; it is often preferably attached at position 5 in these embodiments.
  • the bond connecting Z 1 to Z 2 represents a double bond; in such embodiments, one of Z 1 and Z 2 is CQ and the other is CR 1 . Typically, Z 1 is CQ and Z 2 is CR 1 in such embodiments.
  • compounds which contain a partially saturated ⁇ ring where the bond connecting Z 1 to Z 2 is a single bond are also included within the scope of the invention, and can often be made from the compounds having a double bond by, for example, reduction to introduce two hydrogen atoms; reduction followed by alkylation to introduce one H and one other substituent such as alkyl or alkylthio; or oxidation to introduce a carbonyl at Z 2 , optionally followed by further functionalization to introduce a new substituent at Z 1 .
  • one of Z 1 and Z 2 is CR 1 Q, and the other is CR' 2 ; frequently in such embodiments at least one R 1 is H or Cl-C4 alkyl.
  • R 1 can be H or an optionally substituted C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6- ClO aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl group, or it can be halo, OR, NR 2 , NROR, NRNR 2 , SR, SOR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, COR, OrNO 2 , wherein each R is independently H or C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkenyl,
  • R 1 Preferred embodiments of R 1 include hydrogen, alkyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkylaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H, C 1-8 alkyl, C 1-8 alkenyl, C1-C8 acyl or C5-12 aryl or C6-C12 arylalkyl or heteroforms of any of these, and two R can optionally be linked to form a 3-7 membered ring containing one or more heteroatoms selected from N, O
  • Q can be the same groups R 1 can represent, but often Q is preferably a polar group.
  • These polar embodiments of Q include forms of R which contain multiple heteroatoms, such as those comprising an amide or ester or sulfonyl group, and those containing a basic amine group, especially when it is in combination with at least one other heteroatom.
  • Q is -Wj-COXjY wherein Y is COR 2 or an isostere thereof, and R 2 is as defined below; each of W and X is an alkylene, alkenylene, alkynyl ene, or heteroalkyl ene linker up to four atoms in length, and optionally substituted with the typical substituents appropriate for such groups; and each of i and j is independently O or 1.
  • the Z 1 — Z 2 bond is a double bond
  • R 1 is H, or alkyl, such as methyl
  • Q is a polar group.
  • "Polar group” in this context refers to an optionally substituted alkyl, alkenyl, alkynyl, or acyl, group, or a heteroform of one of these, that contains two or more heteroatoms selected from N, O and S.
  • Such polar groups include alkyl substituted with an amide or ester or carbamate or urea, for example, and groups containing an amine nitrogen and at least one other heteroatom, and those containing a sulfonyl or sulfoxide.
  • Q represents -Wj-COXjY wherein Y is COR 2 or an isostere thereof, and R 2 is hydrogen or a suitable substituent as described herein; each of W and X is an alkylene, alkenyl ene, alkynyl ene, or heteroalkylene linking group up to four atoms in length and is optionally substituted, and each of i and j is independently 0 or 1.
  • Each of W and X may be, for example, optionally substituted alkylene or heteroalkylene.
  • W and X are unsubstituted alkylenes.
  • j is 0 so that the carbonyl group is adjacent to Y, which is a carbonyl or isostere thereof, and X is absent.
  • i is 0 so that W is absent, and the proximal CO of the group is adjacent to the ring.
  • compounds wherein the proximal CO is spaced from the ring can readily be prepared by selective reduction of a glyoxal substituted ⁇ ring, which can be prepared as exemplified herein, and compounds having j other than 0 are readily prepared by the same acylation reaction used to introduce a glyoxal moiety.
  • the dotted line bond between Z 1 and Z 2 often represents a double bond, and frequently Z 1 is CQ and Z 2 is CR 1 .
  • Q is a polar group, and preferably Q is WjCOX j Y as defined above. More
  • Q is COY or COCOR , where R is as defined below.
  • Q is COCOR 2 .
  • the substituent represented by R 2 in these embodiments, when R is other than H, may be a hydrocarbyl residue (1-20C) containing 0-5 heteroatoms selected from O, S and N or an inorganic residue.
  • R 2 can be an optionally substituted C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, C5-C12 heteroaryl, C7-C12 arylalkyl, or C6-C12 heteroarylalkyl group, or it can be halo, OR, NR 2 , NROR, NRNR 2 , SR, SOR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, COR, OrNO 2 , wherein each R is independently H or C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-
  • R 2 is straight or branched chain alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, each optionally substituted with halo, alkyl, heteroalkyl, SR, SO 2 R, SO 2 NR 2 , OR, NR 2 , OCOR, NRCOR, NRCONR 2, NRSO 2 R, NRSO 2 NR 2 , OCONR 2 , or CONR 2 , wherein each R is independently H, or C1-C8 alkyl, C1-C8 alkenyl, C1-C8 acyl, or C5-C10 aryl or the heteroatom-containing forms thereof.
  • R 2 is OR, NR 2, SR, NRCONR 2, OCONR 2, or NRSO 2 NR 2, wherein each R is independently H, C1-C8 alkyl, C1-C8 alkenyl, Cl- C8 acyl, or C5-C10 aryl or the heteroatom-containing forms thereof, and wherein two R may be linked together to form a 3-8 member ring which may contain up to three heteroatoms selected from N, O and S, and wherein said ring may further be substituted by C 1-6 alkyl, heteroalkyl, alkenyl, or alkynyl, or C6-12 aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted, or by halo, SR, SO 2 R, SO 2 NR 2 , OR, NR 2 , OCOR, NRCOR, NRCONR 2, NRSO 2 R, NRSO 2 NR 2 ,
  • R 2 are heteroarylalkyl, -NR 2 , heteroaryl, -COOR, -NRNR 2 , heteroaryl-COOR, heteroaryloxy, -OR, heteroaryl-NR 2 , -NROR and C1-C8 alkyl or heteroalkyl.
  • R 2 is an NR 2 group that is selected from the following: isopropyl piperazine, methyl piperazine, methylamine, dimethylamine, ethylamine, N-methyl-N- methoxyamine, pyrrolidine, isopropylamine, methoxyamine, piperazine, isobutyl carboxylate, oxycarbonylethyl, benzimidazolyl, aminoethyldimethylamine, isobutyl carboxylate piperazine, oxypiperazine, ethylcarboxylate piperazine, methyl, amine, aminoethyl pyrrolidine, aminopropanediol, piperidine, pyrrolidinyl-piperidine, pyrrolidine, pyrrolidinone, pyrroline, or methyl piperidine, wherein each ring listed may optionally be substituted with the substituents described above for R groups comprising R . Methoxy, ethoxy, hydroxy are also sometimes preferred embodiment
  • Y can also represent an isostere of COR 2 .
  • Isosteres of COR 2 as represented by Y have varying lipophilicity and may contribute to enhanced metabolic stability.
  • Y as shown, may be replaced by the isosteres in Table A.
  • isosteres include optionally substituted tetrazole, 1,2,3-triazole, 1 ,2,4-triazole and imidazole groups such as those shown in Table A, which may further be substituted on N by an optionally substituted alkyl or heteroalkyl group, preferably methyl or methoxymethyl.
  • bi cyclic 'azaindole' portions of some of the preferred embodiments of the invention have one of the following formulas:
  • L 1 links the azaindole ring system to another cyclic group, referred to herein as an azacyclic group, which contains N and Z 6 and is further described below.
  • the azacyclic group is then further linked by L 2 , which attaches at Z 6 in the azacyclic ring, to another cyclic group, Cy.
  • L and L is a linking group that comprises up to four serially connected atoms selected from C, N, O and S, and each is optionally substituted.
  • L 1 and L 2 are C1-C4 alkylene, or heteroalkylene groups containing 1 or 2 heteroatoms in the chain, which are also optionally substituted.
  • L 1 and L 2 are (CH 2 )i -3 (CO) 0-1 and CO(CH 2 ) O-3 , especially CH 2 , CO, and isosteres of these, including forms where the carbonyl has been converted into an oxime, an oximeether, an oximeester, or a ketal, or optionally substituted isosteres, or longer chain forms.
  • L in particular, may be alkylene, preferably 1-4C, or alkenylene, preferably 1-4C (a Cl alkenylene refers here to a C that is attached by a double bond to Z 6 , and thus requires Z 6 to be C), and is optionally substituted with the substituents set forth above.
  • L 1 or L 2 may be or may include a heteroatom such as N, S or O.
  • L 2 is CH 2 and in others it is (CH 2 ) 2 or CH 2 CO.
  • L is NR or S or it is CR 2 , where each R is independently H, C1-C4 alkyl, or Cl- C4 heteroalkyl, and where CR 2 can represent a 3-7 membered nonaromatic ring, optionally containing 1-2 heteroatoms selected from N, O and S.
  • L 1 CO is sometimes preferred and for L 2 methylene (CH 2 ) or substituted methylene, especially C1-C4 alkyl-substituted methylene such as CHMe or CMe 2 , is sometimes preferred.
  • L 1 is CO while L 2 is CH 2 , and in such embodiments Z is sometimes preferably N, and in other such embodiments Z 6 is preferably CH. Often in these embodiments, both k and p are 1 ; and Z 1 is CQ.
  • Z 3 is typically NR 7 and Cy is typically a mono-substituted or unsubstituted phenyl group, hi such embodiments, Z 2 is often CH or CMe.
  • L 1 and L 2 are an azacyclic moiety of the following formula:
  • Z is N or CR 5 wherein R 5 is H or a suitable substituent.
  • R 5 is H or a suitable substituent.
  • Each of p and k is an integer from 0-2 wherein the sum of p and k is 0-3.
  • the substituents R 5 include, without limitation, halo, alkyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, acyl, carboxy, amino, mono- and di-alkylamino, and hydroxy.
  • R 5 is one of the groups set forth above for R 1 .
  • R 5 can be joined with an R 4 substituent or a substituent on L 2 to form an optionally substituted non-aromatic saturated or unsaturated hydrocarbyl ring which contains 3-8 members and 0-3 heteroatoms such as O, N and/or S.
  • Preferred embodiments include compounds wherein Z 6 is CH and those where it is N, and in such embodiments, both p and k are sometimes preferably 1, so the azacyclic ring is a piperidine or piperazine ring.
  • rings of other sizes as well as bridged rings and bicyclic systems are included within the scope of the invention.
  • the two R 4 groups are preferably in a trans orientation relative to each other, and they are typically positioned at least two atoms apart on the azacyclic ring.
  • R 4 represents a suitable substituent for an alkyl group, such as a hydrocarbyl residue (1-20C) containing 0-5 heteroatoms selected from O, S and N.
  • Each appropriate substituent is itself unsubstituted or substituted with 1-3 substituents.
  • the substituents are preferably independently selected from a group that includes alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2, CN, CF 3 , R 3 Si, and NO 2 , wherein each R is independently H, Cl -6 alkyl, C2-6 alkenyl or C5-12 aryl or arylalkyl, or heteroforms of any of these, and wherein two of R 4 on the same or adjacent positions can be joined
  • R 4 comprise alkyl (1-4C), straight chain or branched, and where m is 2, R 4 is often two alkyl substituents which may be further substituted. Most preferably m is 2, and the two R 4 groups comprise two methyl groups at positions 2 and 5 or positions 3 and 6 of a piperidine or piperazine ring. These substituted forms of the azacyclic group may be chiral and an isolated enantiomer may be preferred.
  • this azacyclic portion include a piperazine or piperidine having a 2,5-disubstitution pattern when the N to which L 1 is attached is defined as position 1, and the substituents are preferably in a trans orientation relative to each other.
  • 2R,5S-dimethylpiperazine where Z 6 is defined as position 4 for the purpose of numbering the ring atoms
  • the 2,5-dimethylpiperidine having the same absolute and relative stereochemistry as 2R, 5 S -dimethyl piperazine are preferred forms of this moiety, as are the corresponding racemic versions of these groups.
  • the absolute stereochemistry defined in the corresponding piperidine may change depending on what L is; so its stereochemistry is best defined by reference to the piperazine stereochemistry.
  • the azacyclic ring containing Z 6 is often one of the following:
  • [L 1 ] and [L 2 ] indicate the attachment points for the L 1 and L 2 groups, respectively, in formula (1).
  • L 1 is typically CO and L is frequently CH 2 or CHMe.
  • Cy is a cyclic moiety, or it may be two cyclic moieties on a single atom of L 2 .
  • the cyclic moieties of Cy include aryl, heteroaryl, cycloaliphatic and cycloheteroaliphatic groups that can be optionally substituted. Cy may be, for instance, cyclohexyl, piperazinyl, benzimidazolyl, morpholinyl, pyridyl, pyrimidyl, phenyl, naphthyl and the like.
  • Cy can represent a phenyl ring and a cyclohexyl ring both attached to one atom of the L 2 linker, or two phenyl rings attached in this fashion.
  • Cy is preferably substituted or unsubstituted aryl or heteroaryl, and more preferably is an optionally substituted phenyl or two optionally substituted phenyls.
  • Cy is a mono-substituted or disubstituted aryl group, preferably a phenyl group, and in others it is an unsubstituted phenyl or two unsubstituted phenyls.
  • Cy is a monosubstituted phenyl
  • the substituent is sometimes preferably at the para position.
  • Para-fluoro phenyl is one preferred embodiment of Cy; unsubstituted phenyl is another such embodiment; and two phenyl rings is another.
  • Each cyclic moiety comprising Cy is optionally substituted with up to five substituents R 6 .
  • Each substituent R 6 on Cy is independently a hydrocarbyl residue (1-20C) containing 0-5 heteroatoms selected from O, S and N, or is an inorganic residue.
  • R 6 is one of the same groups set forth for R 1 above.
  • R substituents include those selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkylaryl, NH-aroyl, arylacyl, heteroarylacyl, halo, OR, NR 2 , SR, SOR, SO 2 R, OCOR, NRCOR, NRCONR 2 , NRCOOR, OCONR 2 , RCO, COOR, alkyl-COOR, alkyl-OOCR, SO 3 R, CONR 2 , SO 2 NR 2 , NRSO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H, alkyl, alkenyl or aryl or heteroforms thereof, and wherein two of said optional substituents on the same or adjacent atoms can be joined to form a fused
  • Cy may be substituted by up to five substituents; typically it is substituted with 0-3 or 1-2 substituents R 6 . hi some preferred embodiments it is substituted once; in others it is unsubstituted. These R 6 substituents may occupy any available positions of the ring of Cy.
  • Cy comprises unsubstituted, mono-substituted, or disubstituted aryl or heteroaryl groups. In some preferred embodiments, Cy is disubstituted, and in more preferred embodiments it is unsubstituted or is mono-substituted. These substituents may themselves be optionally substituted with substituents similar to those listed above.
  • Cy is a para-halophenyl, especially para-fluorophenyl.
  • Cy is two optionally substituted or especially two unsubstituted phenyl rings.
  • Two substituents on a ring comprising Cy can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members and optionally contains 1-3 heteroatoms selected from N, O and S.
  • R 3 represents a substituent suitable for an aryl ring as set forth above.
  • R3 represents one of the groups set forth for R 1 above, other than hydrogen.
  • Preferred embodiments include hydrocarbyl residues (1-6C) containing 0-2 heteroatoms selected from O, S and/or N and inorganic residues, including halo.
  • R 3 may be present 'n' times, where n is an integer of 0-2, preferably 0 or 1.
  • the substituents represented by R 3 are independently halo, alkyl, heteroalkyl, OCOR, haloalkyl, OR, NRCOR, SR, or NR 2 , wherein R is H, alkyl, aryl, or heteroforms thereof.
  • R 3 substituents are selected from C1-C8 alkyl, CF 3 , Cl- C8 alkoxy and halo, and most preferably methoxy, ethoxy, methyl, and chloro.
  • n is 0 and the ⁇ ring is unsubstituted, except for L 1 , or n is 1 and R 3 is alkyl, halo or alkoxy, preferably chloro, methyl or methoxy.
  • R 3 is present it is preferably at position 6 when L 1 is attached at position 5, or it is at position 5 when L 1 is attached at position 6, though R 3 can also be at position 4 when Z 4 is C, or at position 7 when Z 5 is C.
  • L 1 is at position 5, n is 0 or 1, and R 3 , if present, is at position 6.
  • R 3 is typically methyl, methoxy, ethoxy, or chloro. If both Z 4 and Z 5 are N, n is 0 or 1, and typically in those embodiments, L 1 is attached at position 5 and R 3 , if present, must be at position 6.
  • Z 3 is sometimes preferably NR 7 , but can also be S or O.
  • Typical embodiments of R 7 are the same as those described above for R 1 .
  • Preferred embodiments of R 7 include H, optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, arylacyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroarylalkyl, heteroarylacyl, or R 7 can be SOR, SO 2 R, RCO, COOR, alkyl-COR, SO 3 R, CONR 2 , SO 2 NR 2 , CN, CF 3 , NR 2 , OR, alkyl-SR, alkyl-SOR, alkyl-SO 2 R, alkyl-OCOR, alkyl-COOR, alkyl-CN, or alkyl-CONR 2 , wherein each R is independently H, C1-C8 alky
  • R 7 is hydrogen or is alkyl (1-4C), preferably methyl, or it is acyl (1-4C), or it is COOR wherein R is H, C1-C4 alkyl, C2-C4 alkenyl or C5-C10 aryl or hetero forms thereof.
  • R 7 is also sometimes preferably a substituted alkyl wherein the preferred substituents are ether groups or carbonyl- or sulfonyl-containing moieties.
  • Other preferred R 7 embodiments include hydroxyl-, amino-, and sulfhydryl-substituted alkyl substituents.
  • Still other preferred embodiments include COR, COOR, and CONR 2 wherein R is defined as above.
  • Some embodiments include the features of formula (4c). Other embodiments include the features of (4b). Other embodiments include the features of (4c).
  • Z 6 represents N or CH or CR 5 ; Ph represents an optionally substituted phenyl; R represents H or lower alkyl, especially methyl; and R 3 , R 7 , R 1 , and R 2 are as defined for formula (1) except that R 3 can also be H in these formulas.
  • R 1 is typically H or methyl;
  • R 7 is typically H, methyl, or optionally substituted C1-C8 alkyl or C1-C8 heteroalkyl.
  • the invention includes each optically pure form as well as mixtures of stereoisomers or enantiomers, including racemic mixtures.
  • the azacyclic portion of these compounds in particular is often chiral, and single enantiomers are sometimes preferred while racemic mixtures or enantiomerically- enriched mixtures are also sometimes preferred.
  • the compounds of formula (1) may be supplied in the form of their pharmaceutically acceptable acid-addition salts including salts of inorganic acids such as hydrochloric, sulfuric, hydrobromic, or phosphoric acid and salts of organic acids such as acetic, tartaric, succinic, benzoic, salicylic, alkylsulfonic, or glucuronic acid and the like.
  • salts of inorganic acids such as hydrochloric, sulfuric, hydrobromic, or phosphoric acid
  • organic acids such as acetic, tartaric, succinic, benzoic, salicylic, alkylsulfonic, or glucuronic acid and the like.
  • suitable salts are provided in Stahl, P. Heinrich; Wermuth, Camille G. (Eds.), Handbook of Pharmaceutical Salts, 2002, Wiley- VCH, pp. 265-327.
  • the azaindole rings in the compounds of formula (1) are weakly basic, so the ring itself can be protonated by strong acids such as the inorganic acids listed above as well as the stronger organic acids such as the alkyl- and arylsulfonic acids, trifluoroacetic acid, and the like.
  • the protonated 7-azaindoles for example, have a pKa of about 3-5, and can thus be protonated by acids having a pKa below about 4 or 5.
  • salts are more often formed on the azacyclic group instead of the aromatic bicyclic azaindole ring.
  • Such acid addition salts readily form if the azacyclic group includes a nitrogen that is not acylated, as when the azacyclic group is piperazine and the L linker is an alkylene: the protonated forms of those compounds have a pKa of about 6-9.
  • Those compounds readily form salts from both organic and inorganic acids; the salts formed by addition of malonic acid, phosphoric acid, D- or L-tartaric acid, benzensulfonic acid, nitric acid, L-glutamic acid, D- or L- camphorsulfonic acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, maleic acid, hydrochloric acid, as well as those acids mentioned above are specifically contemplated.
  • the azacyclic group is relatively basic, it is possible to form di- salts by protonation of both the azacyclic and the azaindole moieties.
  • a strong acid such as HCl, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, trifluoroacetic acid, or an alkyl- or arylsulfonic acid, such compounds form di-salts.
  • the compounds of the invention will form salts such as the hydrochloric acid addition salt or a di-hydrochloride salt, and these salt forms are specifically within the invention scope.
  • the compound may also be supplied as a salt with a pharmaceutically acceptable cation such as lithium, sodium, potassium, or a substituted or unsubstituted ammonium species.
  • a pharmaceutically acceptable cation such as lithium, sodium, potassium, or a substituted or unsubstituted ammonium species.
  • suitable counterions are discussed in Stahl, P. Heinrich; Wermuth, Camille G. (Eds.), Handbook of Pharmaceutical Salts, 2002, Wiley-VCH.
  • pro-drugs Many techniques for producing pro-drugs are well known in the art, and the invention also includes pro-drug forms of the compounds of formula (1).
  • a compound of the invention has a carboxylic acid moiety, for example, the esters and readily- hydrolyzed amides of that carboxylic acid, such as amides formed by acylating the alpha-amine of an amino acid with that carboxylic acid are also within the scope of the invention.
  • the amides and esters formed with amino acids are examples of pro-drugs that are within the scope of the invention.
  • the compounds of the invention may be synthesized by art-known methods, by methods described herein, or combinations of the two.
  • the following reaction schemes are illustrative of approaches to synthesize particular embodiments. Those skilled in the art will appreciate that these approaches can be adapted to provide other compounds within the invention by using different available starting materials, or by making obvious changes to the sequence or order of reactions presented.
  • 2,6-difiuoropyridine can be converted to carboxylic acid Al through treatment with a base such as lithium diisopropylamide at -78 0 C in THF and then passing in a stream of dry CO 2 .
  • Carboxylic acid Al can be converted to amide Bl through treatment with standard coupling reagents such as TBTU or EDCI and the appropriately substituted amine.
  • Bl is dissolved in alcoholic solvent such as ethanol, methanol, or isopropanol whereupon ammonia gas is passed through the solution. The solution is sealed and heated until conversion to Cl 1 is complete.
  • Compound Dl is obtained by treating Cl with K-O 1 Bu in the desired alcoholic solvent. Heating Dl in DMF with iodine and sodium periodate yields El-. Acetyl chloride was added to a solution of El in a solvent such as THF and a base such as pyridine, yielding Fl. The trimethylsilyl acetylene group was installed through treatment of Fl- with trimethylsilyl acetylene in the presence of Pd(PPh 3 ) 2 C1 2 , CuI, and an amine base. Cyclization to Hl is accomplished by refluxing a solution of Gl and tetrabutylammonium fluoride.
  • Hl can be functionalized by treatment with a base such as NaH, KOH, or LiHMDS followed by addition of an appropriate electrophile to give II.
  • Il is then treated with oxalyl chloride in DCM, DCE, or chloroform.
  • To the resulting intermediate is then added the desired nucleophile to give Kl.
  • Hl can be converted to Jl in a similar manner.
  • Scheme 2 illustrates how 2-substituted azaindoles can be prepared from Dl-, which is obtained as shown in Scheme 1 , utilizing the method developed by Gassman (J. Amer. Chem. Soc, 96, 5495-5507 (1974)) wherein an appropriately substituted 2- aminopyridine is treated with N-chlorosuccinimide followed by the addition of a thiomethyl ketone and an amine base such as triethylamine to yield a 3 -methyl thio compound which is then reductively desulfurized using Raney nickel to provide L2.
  • L2 can then be converted to M2 and O2 as described in Scheme 1 for converting H
  • Scheme 2 illustrates how 2-substituted azaindoles can be prepared from Dl-, which is obtained as shown in Scheme 1 , utilizing the method developed by Gassman (J. Amer. Chem. Soc, 96, 5495-5507 (1974
  • the azaindole nitrogen of compounds within the invention can be aminated with an N-amination reagent, such as 2-nitro-4-(trifluoromethyl)phenyl hydroxylamine or 4-nitro-2-(trifluoromethyl)phenyl hydroxylamine, which are described in published patent application PCT/US2003/021888 (publication number WO2004/007462A1), and those described in Tetrahedron Lett, 23(37), 3835-3836 (1982), which are incorporated herein by reference.
  • Compound A3 reacts with an N-amination reactant to give the N- substituted indole compound B3.
  • N-aminating reagents are RONH 2 where R is an aromatic that is appropriately substituted with electron withdrawing groups such as one or two nitro groups; diarylphosphinyl; or a substituted sulfonyl group.
  • these reagents include but are not limited to (Ar)ONH 2 , (Ar 2 PO)ONH 2 , and (ROSO 2 )ONH 2 .
  • Cyclization is effected by heating D4 at reflux in the presence of tetrabutylammonium fluoride in a solvent such as THF, resulting in E4.
  • E4 can be converted to its corresponding carboxylic acid F4 by treatment with aqueous base.
  • Coupling of F4 with substituted amines under standard conditions using reagents like TBTU or EDCI results in compounds such as G4.
  • various 6-amino-2-alkoxy-nicotinic acid esters can be prepared from 2,6-dichloronicotinic acid, which is first converted into ester A5 by heating in the appropriate alcohol with catalytic amounts of acid, such as hydrochloric or sulfuric acid.
  • Compound B5 can be prepared by treating A5 with sodium alkoxides in a solvent such as dichloromethane or dichloroethane. By heating B ⁇ and 4-methoxybenzylamine in the presence of an amine base in a polar aprotic solvent such as N-methylpyrrolidinone compound C5 is obtained. C5 is converted into D5 by heating in TFA until deprotection is complete.
  • Another method to make the requisite 6-amino-2-alkoxy nicotinic acid derivatives involves treatment of 2,6-dichloro-3-trifluromethylpyridine with dibenzylamine and an amine base in N-methylpyrrolidinone at elevated temperatures resulting in compound A6. Heating A6 and an appropriate sodium alkoxide in a solvent such as DMF yields compound B6. Removal of the two benzyl protecting groups can be achieved by treating a solution of compound B6 in wet methanol with palladium hydroxide on carbon under hydrogen pressure to give C6. C6 can be converted to D6 by heating it in methanol in the presence of sodium methoxide. The ester, E6, is obtained through treatment of D6 with dilute hydrochloric acid in the appropriate alcoholic solvent.
  • Compound A7 can be prepared by heating 5-bromo-6-alkyl-2-aminopyridines with Zn(CN) 2 , l,l-bis(diphenylphosphino)- ferrocene, and Pd 2 (dba) 3 in a suitable solvent such as DMF.
  • B7 is prepared by heating A7 in concentrated sulfuric acid.
  • the carboxylic acid B7 can be converted to ester C7 by dissolving in the desired alcohol and treating with thionyl chloride.
  • C7 can be converted to 17 in a manner similar to that described in Scheme 4 for converting A7 to G7.
  • J7 can be prepared by treating 17 with a base such as NaH, KOH, or LiHMDS followed by addition of 2- (trirnethylsilyl)ethoxymethyl chloride. J is then treated with oxalyl chloride in DCM, DCE, or chloroform. To the resulting intermediate is then added the desired nucleophile to give K7. Upon treatment with tetrabutylammonium fluoride, L7 is obtained.
  • L7 can be converted to M7 by treating with a base such as NaH, KOH, or LiHMDS followed by the addition of the desired electrophile.
  • This method uses a 3-amino pyridine and adds an acetylene group at position 2, which can then be cyclized to form the fused five-membered ring.
  • 5-amino-2-cyanopyridine can thus be converted to 5-amino-2-nicotinic acid A8 by treating with sulfuric acid to provide the intermediate amide, which is then heated in water at 100 0 C until conversion to carboxylic acid A8 is achieved.
  • the ester B8 can be obtained by treating A8 with thionyl chloride in the desired alcoholic solvent.
  • Synthesis of compound C8 can be achieved by heating B8 in a solvent such as DMF with iodine and sodium periodate.
  • the trimethylsilylacetylene group can be installed through treatment of C8 with trimethylsilyl acetylene in the presence of Pd(PPh 3 ) 2 C1 2 , CuI, and an amine base.
  • Compound E8 can be obtained by adding acetyl chloride to D8 and pyridine in a solvent such as dichloromethane.
  • Cyclization to F8 can be performed by refluxing a solution of E8 and tetrabutylammonium fluoride.
  • F8 can be converted to its corresponding carboxylic acid by treatment with aqueous base.
  • Carboxylic acid G8 can be converted to amide H8 through treatment with standard coupling reagents such as TBTU or EDCI and the appropriately substituted amine.
  • H8 is then treated with AlCl 3 and ethyl oxalyl chloride in a solvent such as dichloromethane to yield 18, which can be converted to its corresponding carboxylic acid K8 by treatment with aqueous base.
  • 18 can be functionalized by treatment with base such as NaH, KOH, or LiHMDS followed by addition of an appropriate electrophile to give J8.
  • J8 can then be converted to carboxylic acid L8 by treatment with aqueous base.
  • K8 can then be converted to M8 using standard coupling reagents such as TBTU, EDCI, or DCC and the desired amine or alcohol.
  • L8 can be converted to N8 in a similar manner.
  • Scheme 9 illustrates the preparation of compounds within the scope of the invention having a halogen on the ring labeled ⁇ in formula (1).
  • 5,6-dichloronicotinic acid is treated with diphenylphosphoryl azide and triethylamine in t-butanol to form A9.
  • A9 is converted to B9 by heating with palladium acetate, l,3-bis(diphenylphosphino)propane, triethylamine, and carbon monoxide.
  • C9 is formed by treating B9 with trifluoroacetic acid in a solvent such as dichloromethane.
  • C9 can be converted to 19 in a manner similar to that described in Scheme 4 for converting A4 to G4 and in Scheme 8 for converting B8 to H8.
  • 19 can be converted to N9 and O9 in a manner similar to that described in Scheme 8 for converting H8 to M8 and N8.
  • compounds within the invention having an alkoxy group on the ring labeled ⁇ in formula (1) can be prepared from 2,3-dihydroxypyridine.
  • the dihydroxypyridine is converted to AlO through treatment with NaOH and an alkylating agent such as dimethylsulfate.
  • the intermediate formed is then treated with concentrated sulfuric and nitric acid to form the nitro compound.
  • BlO can be prepared by heating AlO in a mixture of PCl 5 and POCl 3 .
  • the nitro compound can then be reduced with tin chloride in concentrated hydrochloric acid to yield ClO.
  • DlO is converted to JlO in a manner similar to that described in Scheme 4 for converting A4 to G4 and in Scheme 8 for converting B8 to H8.
  • JlQ can be converted to MlO or NlO as shown in Scheme 7 for converting 17 to LJ or M7.
  • 2,6-Dichloropyrazine can be converted to All by heating with the appropriate alkoxide in the corresponding alcoholic solvent.
  • Treatment of All with LDA in an appropriate anhydrous solvent such as THF followed by quenching with CO 2 gas results in BIl.
  • the ester CIl can be obtained by treating BIl with thionyl chloride in the desired alcoholic solvent.
  • Heating CIl and 4-methoxybenzylamine in the presence of an amine base in a polar aprotic solvent such as N-methylpyrrolidinone (NMP) results in DIl.
  • NMP N-methylpyrrolidinone
  • DIl can be converted to Ell by heating in TFA until deprotection is complete.
  • Synthesis of FIl can be achieved by heating Ell in a solvent such as DMF with iodine and sodium periodate.
  • the trimethylsilylacetylene group can be installed through treatment of FIl with trimethylsilyl acetylene in the presence of Pd(PPh 3 ) 2 C1 2 , CuI, and an amine base.
  • Compound HIl can be obtained by adding acetyl chloride to GIl and pyridine in a solvent such as dichloromethane.
  • Cyclization to in can be performed by refluxing a solution of HIl and tetrabutylammonium fluoride, in can be converted to its corresponding carboxylic acid by treatment with aqueous base.
  • Carboxylic acid JIl can be converted to amide KIl through treatment with standard coupling reagents such as TBTU or EDCI and the appropriately substituted amine.
  • the compounds of the invention are useful among other indications in treating conditions associated with cytokine regulation and inflammation.
  • the compounds of formula (1) or their pharmaceutically acceptable salts are used in the manufacture of a medicament for prophylactic or therapeutic treatment of mammals, including humans, in respect of conditions characterized by excessive production of cytokines and/or inappropriate or unregulated cytokine activity.
  • the compounds of the invention inhibit the production of cytokines such as TNF, IL-I, IL-6 and IL- 8, cytokines that are important proinflammatory constituents in many different disease states and syndromes. Thus, inhibition of these cytokines has benefit in controlling and mitigating many diseases.
  • the compounds of the invention are shown herein to inhibit a member of the MAP kinase family variously called p38 MAPK (or p38), CSBP, or SAPK-2. The activation of this protein has been shown to accompany exacerbation of the diseases in response to stress caused, for example, by treatment with lipopolysaccharides or cytokines such as TNF and IL-I.
  • Inhibition of p38 activity is predictive of the ability of a medicament to provide a beneficial effect in treating diseases such as Alzheimer's, coronary artery disease, congestive heart failure, cardiomyopathy, myocarditis, vasculitis, restenosis, such as occurs following coronary angioplasty, atherosclerosis, IBD, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, multiple sclerosis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), chronic pulmonary inflammatory disease, cystic fibrosis, silicosis, pulmonary sarcosis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, heart and brain failure (stroke) that are characterized by ischemia and reperfusion injury, surgical procedures, such as transplantation procedures and graft rejections, cardiopulmonary bypass, coronary artery
  • p38 MAP kinase plays a role in many biological processes. As mentioned above, it can act as a TNF mediator of the inflammatory process.
  • the compounds of the invention can be used to treat disorders such as rheumatoid arthritis, myelodysplasia, and psoriasis.
  • the compounds provided herein can be used to treat disorders such as Multiple myeloma, Hogkins and Non-Hodgkins lymphomas, renal carcinomas, and other cancers.
  • P38 kinase also plays a role in certain structural and regenerative aspects associated with bone disorders, including but not limited to the regulation of osteoblast and osteoclast cell differentiation.
  • the compounds provided herein can be used to treat such disorders as metastatic bone disease, osteolytic lesions, osteoarthritis, osteoporosis and improper bone healing.
  • inhibition of p38 kinase through administration of the compounds provided herein can be used to treat acute and chronic pain, including circumstances of neuropathy, diabetic or otherwise.
  • compositions useful in the invention and their related compounds will depend on the nature of the condition, the severity of the condition, the particular subject to be treated, and the judgment of the practitioner; formulation will depend on mode of administration.
  • the compounds of the invention are small molecules, they are conveniently administered by oral administration by compounding them with suitable pharmaceutical excipients so as to provide tablets, capsules, syrups, and the like.
  • suitable formulations for oral administration may also include minor components such as buffers, flavoring agents and the like.
  • the amount of active ingredient in the formulations will be in the range of 5%-95% of the total formulation, but wide variation is permitted depending on the carrier.
  • Suitable carriers include sucrose, pectin, magnesium stearate, lactose, peanut oil, olive oil, water, and the like.
  • the compounds useful in the invention may also be administered through suppositories or other transmucosal vehicles.
  • formulations will include excipients that facilitate the passage of the compound through the mucosa such as pharmaceutically acceptable detergents.
  • the compounds may also be administered topically, for topical conditions such as psoriasis, or in formulation intended to penetrate the skin. These include lotions, creams, ointments and the like which can be formulated by known methods.
  • the compounds may also be administered by injection, including intravenous, intramuscular, subcutaneous or intraperitoneal injection. Typical formulations for such use are liquid formulations in isotonic vehicles such as Hank's solution or Ringer's solution.
  • Alternative formulations include nasal sprays, liposomal formulations, slow-release formulations, and the like, as are known in the art.
  • the dosages of the compounds of the invention will depend on a number of factors which will vary from patient to patient. However, it is believed that generally, the daily oral dosage will utilize 0.001-100 mg/kg total body weight, preferably from 0.01-50 mg/kg and more preferably about 0.01 mg/kg-10 mg/kg.
  • the dose regimen will vary, however, depending on the particular compound(s) being used, the condition(s) being treated and the judgment of the practitioner.
  • the compounds of formula (1) can be administered as individual active ingredients, or as mixtures of several embodiments of this formula.
  • the inhibitors of p38 kinase can be used as single therapeutic agents or in combination with other therapeutic agents.
  • Drugs that could be usefully combined with these compounds include natural or synthetic corticosteroids, particularly prednisone and its derivatives, monoclonal antibodies targeting cells of the immune system, antibodies or soluble receptors or receptor fusion proteins targeting immune or non-immune cytokines, and small molecule inhibitors of cell division, protein synthesis, or mRNA transcription or translation, or inhibitors of immune cell differentiation or activation.
  • Compounds prepared and described herein are often characterized by high performance liquid chromatography (HPLC) using a mass spectrum detector (LC-MS).
  • HPLC high performance liquid chromatography
  • LC-MS mass spectrum detector
  • the LC provides information about the purity of the compound, and most new compounds were purified to at least about 95% purity by LC.
  • the mass spectrum obtained generally included a molecular ion having the mass of the expected product plus one, corresponding to a protonated species, and is reported as M+H or equivalently as M+l to indicate that the observed molecular ion corresponds to the molecular weight of the protonated species, as expected.
  • the LC-MS data thus provides evidence that the compound having the structure shown was produced by the reaction, as expected.
  • the HPLC retention time in minutes is reported for some compounds, often as Rf, and the HPLC conditions are then usually reported as Condition A or Condition B, which provides further characterization of the compounds.
  • HPLC Condition A uses a Phenomenex 30 x 4.6 mm column, model no. 00A-4097- EO.
  • the flow rate is 2.00 mL/min, beginning with 95:5 ratio of water to acetonitrile, with each solvent containing 0.1% trifluoroacetic acid (TFA).
  • the elution profile includes a linear gradient from a 95:5 water-acetonitrile ratio to a 5:95 ratio over the first 5 minutes, then 0.5 min at this ratio before returning to the 95:5 ratio.
  • HPLC Condition B uses a Merck AGA Chromolith Flash 25 x 4.6 mm column, model no. 1.51463.001.
  • the flow rate is 3.00 mL/min, beginning with 95:5 ratio of water to acetonitrile, with each solvent containing 0.1% trifluoroacetic acid (TFA).
  • the elution profile includes a linear gradient from a 95:5 water-acetonitrile ratio to a 5:95 ratio over the first 2.5 minutes, then 0.25 min at this ratio before returning to the 95:5 ratio.
  • 2,6-difluoropyridine-3-carboxylic acid (1) was prepared by using the method described by Rewcastle, G.W., et al., J. Med. Chem. (1996) 39:1823-1835.
  • the combined extract was washed with dilute sodium thiosulfate solution to remove the excess iodine.
  • the ethyl acetate extract was dried over sodium sulfate and evaporated.
  • the residue was purified on a column of silica gel eluting with ethyl acetate-hexane (20-40% ethyl acetate, gradient) to yield 6.46g (86.8%) of the desired product.
  • reaction mixture was removed from ice- bath and stirring continued for 20 h at RT.
  • the reaction mixture was filtered to remove the solids and the filtrate was evaporated to dryness.
  • the residue was purified on a column of silica gel eluting it with ethyl acetate-hexane ( 20-50% ethyl acetate, gradient), to yield 4.24g (92%) of the desired compound.
  • N- ⁇ 5-[4-(4-Fluoro-benzyl)-piperidine-l-carbonyl]-6-methoxy-3- trimethylsilanylethynyl-pyridin-2-yl ⁇ -acetamide (4.24 g, 8.8 mmol) was dissolved in dry THF (50 mL). Tetrabutylammonium fluoride (IM solution in THF, 17.6 niL, 17.6 mmol) was added and the mixture refluxed with stirring for 3 h. The solvent was removed under reduced pressure and the residue was taken in water and extracted with dichloromethane (3 x 75 mL). The combined extracts were dried over sodium sulfate and evaporated. The residue was purified in a column of silica gel, eluting it with ethyl acetate-hexane (20-50% ethyl acetate, gradient) to yield 2.7g of the desired product.
  • IM solution in THF 17.6 niL,
  • Trans-2,5-dimethylpiperazine (75.0 g) and trans-2,5-dimethylpiperazine dihydrochloride (122.83 g) are reacted together in equimolar quantities in methanol (370 mL) and the temperature raised to 68 °C and held for 30 min to generate two equivalents of trans-2,5- dimethylpiperazine monohydrochloride salt.
  • This is treated with 1.005 molar equivalent of 4- fluorobenzyl chloride (100.4 g), added over Ih with continued heating at reflux for 4 h, to give the monohydrochloride (1 equivalent) and trans-2,5-dimethylpiperazine dihydrochloride (1 equivalent).
  • the mixture is cooled and the dihydrochloride trans-2,5-dimethylpiperazine salt is filtered off.
  • the majority of the methanol is removed by distillation and heptane (300 mL) is added.
  • the majority of the heptane was removed by distillation and then heptane (300 mL) was added again. This mixture was distilled until a temperature of 90 0 C was reached.
  • the mix was then cooled and water (390 mL) was added.
  • Method 1 To a solution of (6-Amino-2-methoxy-pyridin-3-yl)-[4-(4-fluoro-benzyl)- 2R,5S-dimethyl-piperazin-l-yl]-methanone (800 mg, 2.15 mmol) in anhydrous DMF (20 mL) was added iodine (557 mg, 2.15 mmol) and sodium periodate (238 mg, 1.11 mmol). The reaction mixture was heated up at 5O 0 C overnight. The reaction mixture was poured into ice water and a solution of sodium thiosulfate (10%) was added to destroy the excess iodine. The precipitate formed was filtered.
  • the mixture can be cooled and approximately half the solvent removed before purifying on a silica gel column, eluting with THF.
  • the fractions containing the product are concentrated and then purified once again on a silica gel column, eluting with ethyl acetate / heptane (17:8).
  • the reaction was then cooled to 85 0 C and diluted with 90 mL NH 4 Cl (saturated), 90 mL H 2 O and 22.5 niL NH 4 OH (4 : 4 : 1). The mixture was then stirred overnight at 85 0 C. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The two layers were then filtered through Celite®. The organic layer was separated, washed with water, brine, and then dried over Na 2 SO 4 . After removing the volatiles, the residue was triturated with ethyl acetate. The solid thus separated was filtered and dried under high vacuum overnight.
  • the filtrate was purified by silica gel chromatography eluting with 30 to 100% ethyl acetate in hexane (Yield: 13 g, R f : 0.273 min, Condition B, M+H + : 134).
  • Step B cone. H 2 SO 4 /H 2 O
  • Tetrabutylammonium fluoride (8 mL, 1.0 M/THF) was added to the tetrahydrofuran (5 mL) solution of 6-acetylamino-2-methyl-5-trimethylsilanylethynyl-nicotinic acid methyl ester (1.5 g). The reaction was stirred at 70 0 C for 4 h. The reaction mixture was cooled to room temperature and was concentrated. The residue obtained was diluted with water. The solid thus separated was filtered and was washed with water. The solid was dried under high vacuum and was used as such for the next step without any purification (Yield: 0.85 g, R f : 0.8 min, Condition B, M+H + : 191).
  • Tetrabutylammonium fluoride (5 mL, 1.0M/THF) was added to the 2-[5-[4-(4-Fluoro- benzyl)-2R,5S-dimethyl-piperazine-l-carbonyl]-6-methyl-l-(2-trimethylsilanyl-ethoxymethyl)- lH-pyrrolo[2,3-b]pyridin-3-yl]-N-methyl-2-oxo-acetamide (0.1 g). Reaction was stirred at 60 0 C for 3 h. The reaction mixture was cooled to room temperature and was concentrated. The residue obtained was diluted with water. The solid thus separated was filtered and washed with water. The solid was purified by preparative HPLC (Yield: 0.045 g, Rf: 0.887min, Condition B, M+H + : 466).
  • the starting material was prepared as in Step D in Example 1.
  • the azaindole was synthesized using the method of Gassman (Paul G. Gassman et. al. J. Amer. Chem. Soc. (1974), 96, 5495-5507).
  • 6-Methoxy-2-amino pyridine carboxamide (0.9 g, 2.63 mMol) was dissolved in CH 2 Cl 2 (10 mL) and was treated with N-chlorosuccinimide (NCS) (0.42 g, 3.16 mMol) at -40 0 C for 3 h.
  • Thiomethylacetone was added (0.27g, 2.63 mMol) followed by Et 3 N (0.32 g, 3.1 mmol).
  • Tetrabutylammonium fluoride (6 mL, 1.0 M in THF) was added to the tetrahydrofuran (7 mL) solution of 5-acetylamino-5-trimethylsilanylethynyl-2 -nicotinic acid methyl ester (1.46 g). The reaction was stirred at 70 0 C for 4 h then the reaction mixture was cooled to room temperature and was concentrated. The residue obtained was diluted with water. The solid thus separated was filtered and was washed with water. The solid was dried under high vacuum and was used as such for the next step without any purification (Yield: 0.69 g, R f : 0.37 min, Condition B, M+H + : 177).
  • Tetrabutylammonium fluoride (TBAF, 11 mL, 1.0 M/THF) was added to the tetrahydrofuran (7 mL) solution of 3-chloro-5-acetylamino-6-trimethylsilanylethynyl-2-pyridine ethyl ester (1.3 g, 3.8 mmol). Reaction was stirred at 70 0 C for 4 h. The reaction mixture was cooled to room temperature and was concentrated. The residue obtained was diluted with water. The solid thus separated was filtered and was washed with water. The solid was purified using silica gel chromatography with hexane/ethyl acetate. (Yield: 0.72 g).
  • Tetrabutylammonium fluoride (3 mL, 1.0 M in THF) was added to 3-methoxy-5- acetylamino-6-trimethylsilanylethynyl-2-pyridine ethyl ester (290 mg, 0.86 mmol). The reaction was stirred at 70 0 C for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue obtained was diluted with water. The solid thus separated was filtered and was washed with water. The solid was purified using silica gel column chromatography with hexane/ethyl acetate mixture (Yield: 97 mg).
  • step K The product from step K (20 mg, 1.0 equiv.) was treated with 2 M oxalyl chloride in methylene chloride (6.0 equiv.) and allowed to stir overnight. The volatiles were then evaporated and the residue dried under vacuum. The residue was dissolved in THF and treated with excess methylamine in THF. Upon complete reaction, the mixture was concentrated and the product was purified by preparative TLC to obtain 6 mg of the desired compound.
  • Tetrabutylammonium fluoride (2 mL, 1.0 M in THF) was added to the tetrahydrofuran (1 mL) solution of 2-acetylamino-3-trimethylsilanylethynyl-6-methoxy- pyrazine-4-methyl ester (60 mg). The reaction was stirred at 70 0 C for 2 h and then cooled to room temperature and concentrated. The residue obtained was diluted with water and was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue obtained was dried under high vacuum and was used as such for the next step without any purification (Yield: 40 mg, R f : 0.773 min, Condition B, M+H + : 208).
  • the activity of the compounds of the invention can be determined with the in vitro assay described below. Table 1 shows the activity data for a number of such compounds.
  • the compounds to be tested were solubilized in DMSO and diluted with water to the desired concentrations.
  • the p38 kinase was diluted to 20 nM into a buffer containing 20 mM MOPS, pH 7.0, 25 mM beta-glycerol phosphate, 2 mg/ml gelatin, 0.5 mM EGTA (ethylene-bis- (oxyethylenenitrilo)-tetraacetic acid), and 4 mM dithiothreitol (DTT).
  • the reaction was carried out by mixing 20 ⁇ l test compound with 10 ⁇ l of a substrate cocktail containing 0.2 mM biotinylated peptide substrate and 0.6 mM ATP (+100 ⁇ Ci/ml gamma- 33 P-ATP) in a 5x assay buffer. The reaction was initiated by the addition of 10 ⁇ l of p38 kinase.
  • Final assay conditions were 25 mM MOPS, pH 7.0, 26.25 mM beta-glycerol phosphate, 80 mM KCl, 22 mM MgCl 2 , 3 mM MgSO 4 , 1 mg/ml gelatin, 0.625 mM EGTA, 1 mM DTT, 0.05 mM peptide substrate, 150 ⁇ M ATP, and 5 nM enzyme. After a 60 minute incubation at 30° Celsius, the reaction was stopped by the addition of 10 ⁇ l per reaction of 0.25 M phosphoric acid.
  • Counts incorporated are determined on a scintillation counter. Relative enzyme activity was calculated by subtracting background counts (counts measured in the absence of enzyme) from each result, and comparing the resulting counts to those obtained in the absence of inhibitor. IC 50 values were determined with curve-fitting plots available with common software packages. The IC 50 was expressed as the concentration of compound which inhibited the enzyme activity by 50%.
  • the compounds of the invention exhibit varying levels of activity towards p38 ⁇ kinase.
  • Table 1 provides in vitro activity data generated using the assay described above.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L’invention concerne des procédés d’inhibition de kinase p38, de préférence des composés utilisant p38-α qui sont des azaindoles, lesdits azaindoles étant couplés à un autre groupe caractéristique cyclique par le biais d’un lieur azacyclique.
PCT/US2005/012969 2005-04-15 2005-04-15 Derives d’azaindole en tant qu’inhibiteurs de kinase p38 WO2006112828A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2005/012969 WO2006112828A1 (fr) 2005-04-15 2005-04-15 Derives d’azaindole en tant qu’inhibiteurs de kinase p38

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2005/012969 WO2006112828A1 (fr) 2005-04-15 2005-04-15 Derives d’azaindole en tant qu’inhibiteurs de kinase p38

Publications (1)

Publication Number Publication Date
WO2006112828A1 true WO2006112828A1 (fr) 2006-10-26

Family

ID=37115431

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/012969 WO2006112828A1 (fr) 2005-04-15 2005-04-15 Derives d’azaindole en tant qu’inhibiteurs de kinase p38

Country Status (1)

Country Link
WO (1) WO2006112828A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
WO2009005672A1 (fr) * 2007-06-29 2009-01-08 Merck & Co., Inc. Azaindoles et diazaindoles antidiabétiques
WO2009106443A1 (fr) * 2008-02-25 2009-09-03 F. Hoffmann-La Roche Ag Inhibiteurs de kinase pyrrolopyrazine
DE102008052943A1 (de) 2008-10-23 2010-04-29 Merck Patent Gmbh Azaindolderivate
EP2725903A4 (fr) * 2011-06-30 2015-06-24 Dow Agrosciences Llc Picolinates 3-alkoxy, thioalkyle et amino-4-amino-6-substitués et leur utilisation comme herbicides
EP3305786A2 (fr) 2018-01-22 2018-04-11 Bayer CropScience Aktiengesellschaft Dérivés d'hétérocyclène bicycliques condensés en tant que pesticides
WO2022189636A1 (fr) 2021-03-12 2022-09-15 Biomedcode Hellas Sa Dérivés de carboxamide anti-inflammatoires

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004032874A2 (fr) * 2002-10-09 2004-04-22 Scios Inc. Derives d'azaindole utilises en tant qu'inhibiteurs de la kinase p38

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004032874A2 (fr) * 2002-10-09 2004-04-22 Scios Inc. Derives d'azaindole utilises en tant qu'inhibiteurs de la kinase p38

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
WO2009005672A1 (fr) * 2007-06-29 2009-01-08 Merck & Co., Inc. Azaindoles et diazaindoles antidiabétiques
WO2009106443A1 (fr) * 2008-02-25 2009-09-03 F. Hoffmann-La Roche Ag Inhibiteurs de kinase pyrrolopyrazine
US7902197B2 (en) 2008-02-25 2011-03-08 Roche Palo Alto Llc Pyrrolopyrazine kinase inhibitors
CN101952294B (zh) * 2008-02-25 2014-11-26 霍夫曼-拉罗奇有限公司 吡咯并吡嗪激酶抑制剂
DE102008052943A1 (de) 2008-10-23 2010-04-29 Merck Patent Gmbh Azaindolderivate
EP2725903A4 (fr) * 2011-06-30 2015-06-24 Dow Agrosciences Llc Picolinates 3-alkoxy, thioalkyle et amino-4-amino-6-substitués et leur utilisation comme herbicides
EP3305786A2 (fr) 2018-01-22 2018-04-11 Bayer CropScience Aktiengesellschaft Dérivés d'hétérocyclène bicycliques condensés en tant que pesticides
WO2022189636A1 (fr) 2021-03-12 2022-09-15 Biomedcode Hellas Sa Dérivés de carboxamide anti-inflammatoires

Similar Documents

Publication Publication Date Title
JP7372255B2 (ja) 免疫調節剤としての複素環式化合物
US7393851B2 (en) Azaindole derivatives as inhibitors of p38 kinase
JP6494622B2 (ja) カゼインキナーゼ１ｄ／ｅ阻害剤としての置換された４，５，６，７−テトラヒドロピラゾロ［１，５−ａ］ピラジン誘導体
EP1353905B1 (fr) Inhibiteurs du type pip ridine/pip razine de la kinase p38
RU2629194C2 (ru) Производные 1,5- и 1,7-нафтиридина, полезные при лечении заболеваний, опосредованных fgfr
KR0163371B1 (ko) 5-아릴인돌 유도체
TWI782525B (zh) 新穎雜環化合物、其製備方法和包含該雜環化合物之醫藥組成物
JP2008534664A (ja) 置換複素環およびｃｈｋ１、ｐｄｋ１及びｐａｋ阻害剤としてのそれらの使用
WO2005080330A1 (fr) Dérivé d'hétéroarylphénylurée
EA017187B1 (ru) Конденсированные производные тиазола в качестве ингибиторов киназ
JP2009531274A (ja) キナーゼ阻害性ピロロピリジン化合物
JP2009542638A (ja) グリコーゲン・シンターゼ・キナーゼ（ｇｓｋ３）に関連する疾患の治療のためのイミダゾール−ピリミジン誘導体
JP6746613B2 (ja) ウレア誘導体、またはその薬理学的に許容される塩
WO2006112828A1 (fr) Derives d’azaindole en tant qu’inhibiteurs de kinase p38
JP6268276B2 (ja) ＰＥＲＫ阻害剤としての新規なＮ（２，３−ジヒドロ−１Ｈ−ピロロ［２，３−ｂ］ピリジン−５−イル）−４−キナゾリンアミン誘導体およびＮ−（２，３−ジヒドロ−１Ｈ−インドール−５−イル）−４−キナゾリンアミン誘導体
TWI671299B (zh) 作為ｒｓｖ抗病毒化合物之螺脲化合物
US20050288299A1 (en) Azaindole derivatives as inhibitors of p38 kinase
CN113518779B (zh) 噻吩并杂环类衍生物、其制备方法及其在医药上的应用
KR101651722B1 (ko) 질소-함유 포화 헤테로시클릭 화합물
JP2009504736A (ja) 代謝調節型グルタミン酸レセプターアンタゴニストとしてのアセチレン型ピペラジン
TW202334167A (zh) 作為ｅｒｂｂ２抑制劑之稠合四環喹唑啉衍生物
WO2019013562A1 (fr) Nouveau dérivé de 1h-pyrazolopyridine et composition pharmaceutique le contenant
JP2010540422A (ja) チエノピリミジン化合物類
JPH09165387A (ja) 非古典的抗葉酸剤
CN117321046A (zh) 基于吲唑的化合物和相关使用方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 05737673

Country of ref document: EP

Kind code of ref document: A1