WO2012106448A1 - Composés hétérocycliques comme inhibiteurs de janus kinase - Google Patents

Composés hétérocycliques comme inhibiteurs de janus kinase Download PDF

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Publication number
WO2012106448A1
WO2012106448A1 PCT/US2012/023510 US2012023510W WO2012106448A1 WO 2012106448 A1 WO2012106448 A1 WO 2012106448A1 US 2012023510 W US2012023510 W US 2012023510W WO 2012106448 A1 WO2012106448 A1 WO 2012106448A1
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Prior art keywords
compound
alkyl
aryl
mmol
heteroaryl
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PCT/US2012/023510
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English (en)
Inventor
Yarlagadda S. Babu
Pravin L. Kotian
Krishnan RAMAN
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Biocryst Pharmaceuticals, Inc.
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Publication of WO2012106448A1 publication Critical patent/WO2012106448A1/fr

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    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/16—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07D487/22—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 four or more hetero rings

Definitions

  • Janus kinase 3 is a cytoplasmic protein tyrosine kinase associated with the common gamma chain (yc), which is an integral component of various cytokine receptors. Kudlacz et al. (2004) American Journal of Transplantation 4:51-57.
  • JAK3 While effective in the prevention of transplant rejection, commonly used immunosuppressants, such as calcineurin inhibitors, possess a number of significant dose- limiting toxicities, thereby prompting a search for agents with novel mechanisms of action.
  • the inhibition of JAK3 represents an attractive strategy for immunosuppression based upon its limited tissue distribution, lack of constitutive activation and the evidence for its role in immune cell function.
  • JAK3 is a viable target for immunosuppression and transplant rejection.
  • JAK3 specific inhibitors may also be useful for treatment of hematologic and other malignancies that involve pathologic JAK activation.
  • An aspect of the invention is a compound represented by formula Ic:
  • W is -NR e - or -NR e C(O)-;
  • V is CR;
  • R is H, -(Ci-C 6 )alkyl, carboxyl, or -C(0)0(Ci-C 6 )alkyl;
  • R 1 is aryl or heteroaryl, wherein any aryl or heteroaryl of R 1 is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, carboxyl, (Ci-Ce)alkyl, (Ci-C6)perfluoroalkyl,
  • R 2 is H or -(Ci-C 6 )alkyl
  • R 3 is selected from the group consisting of H, hydroxyl, carboxyl, -(Ci-C 6 )alkyl, -0(Ci-C 6 )alkyl, -C(0)OR 5 , -C(0)NHR 5 , aralkyl, acyl, aryl, heteroaryl, and amino;
  • each R 4 is independently selected from the group consisting of halogen, hydroxyl, carboxyl, -(Ci-C 6 )alkyl, -0(Ci-C 6 )alkyl, -C(0)OR 5 , -C(0)NHR 5 , aralkyl, aryl, heteroaryl, cyano, amino, and nitro;
  • each R 5 is H, -(Ci-C 6 )alkyl, or aralkyl;
  • Rs is selected from the group consisting of H, hydroxyl, carboxyl, -(Ci-C 6 )alkyl, -0(Ci-C 6 )alkyl, -C(0)OR 5 , -C(0)NHR 5 , aralkyl, acyl, aryl, heteroaryl, and amino;
  • R f is selected from the group consisting of H, halogen, hydroxyl, carboxyl,
  • n is an integer 0-4;
  • W is -NR e -.
  • R e is H.
  • W is -NHC(O)-.
  • R is H
  • R 1 in one embodiment, R 1
  • R 1 is optionally substituted aryl.
  • R 1 is optionally substituted phenyl.
  • R 1 is selected from the
  • the phenyl of R 1 comprises a 4-hydroxyl group.
  • R 2 is H.
  • R 3 is H.
  • R f is H.
  • n 0.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of: In one embodiment, the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of: n one embodiment, the compound is selected from the group consisting of:
  • the compound is represented by
  • the compound is represented by In one embodiment, the compound is selected from the group consisting of:
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a method for treating a disease or condition associated with pathologic JAK activation (e.g., a cancer, a hematologic malignancy or other malignancy) in a mammal (e.g., a human), comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to the mammal.
  • a mammal e.g., a human
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of a disease or condition associated with pathologic JAK activation (e.g., a cancer, a hematologic malignancy or other malignancy).
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in medical therapy (e.g., for use in treating a disease or condition associated with pathologic JAK activation such as cancer, a hematologic malignancy or other malignancy).
  • medical therapy e.g., for use in treating a disease or condition associated with pathologic JAK activation such as cancer, a hematologic malignancy or other malignancy.
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof ,for the manufacture of a medicament for the treatment of a disease or condition associated with pathologic JAK activation (e.g., a cancer, a hematologic malignancy or other malignancy) in a mammal (e.g., a human).
  • a disease or condition associated with pathologic JAK activation e.g., a cancer, a hematologic malignancy or other malignancy
  • a mammal e.g., a human
  • the invention also provides a method for suppressing an immune response in a mammal (e.g., a human), comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to the mammal.
  • a mammal e.g., a human
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic suppression of an immune response.
  • the invention also provides the use of a compound of formula I, or a
  • a pharmaceutically acceptable salt thereof for the manufacture of a medicament for suppressing an immune response in a mammal (e.g., a human).
  • the invention also provides novel processes and novel intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof, for example, those described in schemes 1-88.
  • alkyl refers to alkyl groups having from 1 to 10 carbon atoms which are straight or branched monovalent groups.
  • (Ci-C 6 )alkyl refers to alkyl groups having from 1 to 6 carbon atoms which are straight or branched.
  • alkenyl or “alkene” as used herein refers to an alkenyl group having from 2 to 10 carbon atoms which are straight or branched and having at least one double bond. Such groups are exemplified by vinyl(ethen-l-yl), allyl, 1-propenyl, 2-propenyl(allyl), 1-methylethen-l-yl, 1-buten-l-yl, 2-buten-l-yl, 3-buten-l-yl, 1 -methyl- 1-propen-l-yl, 2- methyl-l-propen-l-yl, l-methyl-2-propen-l-yl, and 2-methyl-2-propen-l-yl, preferably 1- methyl-2-propen-l-yl and the like.
  • (C 2 -C 6 )alkenyl refers to alkenyl groups having from 2 to 6 carbon atoms which are straight or branched.
  • alkynyl or “alkyne” as used herein refers to an alkynyl group having from 2-10 carbon atoms which are straight or branched monovalent groups and having at least one triple bond. Such groups are exemplified by, but not limited to ethyn-l-yl, propyn- 1-yl, propyn-2-yl, l-methylprop-2-yn-l-yl, butyn-l-yl, butyn-2-yl, butyn-3-yl, and the like.
  • (C 2 -C 6 )alkynyl refers to alkynyl groups having from 2 to 6 carbon atoms which are straight or branched.
  • halogen refers to fluoro, chloro, bromo and iodo.
  • haloalkyl referes to an alkyl as described above wherein one one or more of the hydrogens of the alkyl is replaced with a halogen.
  • (Ci-C 6 )haloalkyl refers to alkyl groups having from 1 to 6 carbon atoms which are straight or branched wherein at least one and up to all of the hydrogens of the alkyl have been replaced with a halogen.
  • hydroxyalkyl referes to an alkyl as described above wherein one one or more of the hydrogens of the alkyl is replaced with a hydroxy.
  • (Ci-C 6 )hydroxyalkyl refers to alkyl groups having from 1 to 6 carbon atoms which are straight or branched wherein at least one and up to all of the hydrogens of the alkyl have been replaced with a hydroxy.
  • cycloalkyl refers to saturated or partially unsaturated cyclic hydrocarbon ring systems, such as those containing 1 to 3 rings and 3 to 8 carbons per ring wherein.
  • the rings in a multiple ring cycloalkyl can be connected through fused, spiro or bridging bonds.
  • Exemplary groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclohexenyl,
  • aryl refers to a ring structure of from 6 to 14 carbon atoms in the ring.
  • Aryl includes a single aromatic ring (e.g., phenyl).
  • Aryl also includes multiple condensed rings (e.g., bicyclic or multicyclic rings such as naphthyl or anthryl) wherein the condensed rings may be aromatic, saturated or partially saturated provided that at least one of the condensed rings is aromatic.
  • Such multiple condensed rings may be optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on on any non-aromatic portion (i.e., saturated or partially unsaturated) of the multiple condensed ring.
  • aryls include, but are not limited to phenyl, indanyl naphthyl, 1,2-dihydronaphthyl and 1,2,3,4- tetrahydronaphthyl.
  • heteroaryl refers to a ring structure of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the sulfur and nitrogen heteroatoms atoms may also be present in their oxidized forms.
  • Heteroaryl includes a single aromatic ring with at least one heteroatom (e.g., pyridyl, pyrimidinyl or furyl).
  • Heteroaryl also includes multiple condensed rings (e.g., bicyclic or multicyclic rings such as indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that at least one of the condensed rings is aromatic with at least one heteroatom.
  • Such multiple condensed rings may be optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any non- aromatic (i.e., saturated or partially unsaturated) portion of the condensed ring.
  • heteroaryl groups include, but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl,
  • heterocycle or “heterocyclic” or “heterocycloalkyl” as used herein refers to a single saturated or partially unsaturated ring (e.g., 3, 4, 5, 6, 7 or 8-membered ring) from about 1 to 7 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings.
  • the sulfur and nitrogen atoms may also be present in their oxidized forms.
  • Such rings include but are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl.
  • heterocycle also includes multiple condensed ring systems wherein a heterocycle group (as defined above) can be fused with another heterocycle (as defined above) (e.g., decahydronapthyridinyl), a cycloalkyl (e.g., decahydroquinolyl) or an aryl (e.g., 1,2,3,4-tetrahydroisoquinolyl) to form a multiple condensed ring.
  • a heterocycle group as defined above
  • another heterocycle as defined above
  • thiomorpholinyl piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl and dihydrooxazolyl .
  • a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I.
  • administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the invention provides a compound of the invention which is a compound of formula I:
  • A is aryl or heteroaryl, wherein any aryl or heteroaryl of A is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from halogen, aryl, heteroaryl, heterocycle, (Ci-C 6 )alkyl, -(Ci-Ce)haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, CN, -OR a , -OC(0)R b , -OC(0)NRcRd, -SRa, -S(0)R b , -S(0) 2 OH, -S(0) 2 R b , -S(0) 2 NR c R d , -NR c R d , -NR a COR b ,
  • W is -N-, V is C, R 1 is R la , and the bond represented by— is a double bond; or
  • W is -NR e -, -NR e C(O)- or -C(0)NR e -, V is CR lc , R 1 is R la and the bond represented by— is a single bond; or
  • R la is H, (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, -(Ci-C 6 )alkylaryl,
  • -(Ci-C 6 )alkylheteroaryl cycloalkyl, heterocycle, aryl or heteroaryl, wherein any cycloalkyl, -(Ci-Ce)alkylaryl, -(Ci-C 6 )alkylheteroaryl, heterocycle, aryl or heteroaryl of R la is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from Z 1 , (Ci-C 6 )alkyl, -(C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, -(Ci-C 6 )alkylNRiR j , -(Ci-C 6 )alkylOR g , -(Ci-C 6 )alkylSR g , -(Ci-C 6 )alkylN0 2 , -
  • R lb is aryl, heteroaryl or cycloalkyl, wherein any aryl, heteroaryl or cycloalkyl of R lb is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from Z 2 , (Ci-C 6 )alkyl, -(C 2 -C 6 )alkenyl, (C 2 -Ce)alkynyl,
  • (Ci-C 6 )haloalkyl -(Ci-C 6 )alkylNRêtR 0 , -(Ci-C 6 )alkylOR k , -(Ci-C 6 )alkylSR k , -(Ci-C 6 )alkylN0 2 , -(Ci-C 6 )alkylCN, and -(Ci-C 6 )alkylOH;
  • R ld is H, C(0)OR g i, OH or NH 2 ;
  • R 2 is H, halogen, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, N0 2 ,
  • any (Ci-C 6 )alkyl or (C 2 -C 6 )alkenyl of R 2 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from halogen, N0 2 , CN, -OR p , -NR q R r , -C(0)R p , -C(0)OR p , -C(0)NRqR r , -NRpCORs, -NR p S(0) 2 R s and -NR p CONRqR r ;
  • R 3 is H, (Ci-C 6 )alkyl or -C(0)OR p i;
  • each L is independently (Ci-C 6 )alkyl
  • each R a is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, heteroaryl or aryl;
  • each R b is independently (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -Ce)alkynyl, cycloalkyl, heterocycle, heteroaryl or aryl;
  • R c and R d are each independently selected from H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl; or R c and R d together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
  • R c is H, (Ci-C 6 )alkyl, aryl(Ci-C 6 )alkyl or -C(0)OR p2 ;
  • R f is H, halogen, (Ci-C 6 )alkyl, cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, heteroaryl, heterocycle, N0 2 , CN, -OR,, -NR U R V , N 3 , -SR,, -C(0)R,,
  • each R g i is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -Ce)alkynyl,
  • each R is independently (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -Ce)alkynyl, cycloalkyl, heterocycle, heteroaryl or aryl;
  • Ri and R j are each independently selected from H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl; or Ri and R j together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
  • each R k is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl,
  • each R m is independently (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 ) alkynyl, cycloalkyl, heterocycle, heteroaryl or aryl;
  • R n and RQ are each independently selected from H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl; or R n and R 0 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
  • each R p is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
  • each R p i is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -Ce)alkynyl,
  • each R P2 is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -Ce)alkynyl,
  • R q and R r are each independently selected from H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl; or R q and R r together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
  • each R s is independently (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, heteroaryl or aryl;
  • each R t is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -Ce)alkynyl, cycloalkyl, heterocycle, heteroaryl or aryl;
  • R u and R v are each independently selected from H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl; or R u and R v together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
  • each R w is independently (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, heteroaryl or aryl;
  • each R x is independently selected from halogen, cycloalkyl aryl, heteroaryl,
  • each R y is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, heteroaryl or aryl;
  • each R z i is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -Ce)alkynyl,
  • each R z2 is independently (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -Ce)alkynyl, cycloalkyl, heterocycle, heteroaryl or aryl;
  • R z3 and R z4 are each independently selected from H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, a (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl; or R z3 and R z4 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
  • R Z 5 and R z6 are each independently selected from H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, a (C 2 -C 6 )alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl; or R z3 and R z4 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino; each Z 1 is independently selected from halogen, aryl, heteroaryl, heterocycle, cycloalkyl, CN, -OR g , -OC(0)R h , -OC(0)NRiRj, -SR g , -S(0)R g , -S(0) 2 OH, -S(0) 2 R h , -S(0) 2 OR h , -8(0) 2 ⁇ 3 ⁇ 4 -NR,R j
  • each Z 2 is independently selected from halogen, aryl, heteroaryl, heterocycle,
  • radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
  • the specific values listed below are specific values for compounds of formula I as well as compounds of formula la, laa, lb, lal, Ia2, Ia3, Ia4, Ia5, Ia6, Ia7, Ia8, Ia9, IalO, Ial l, Ial2, Ial3, Ial4, Ial5, Ial6, Ial7, Ial8, Ial9, Ia20, Ia21, Ia22, Ia23, Ia24, Ia25, Ia26, Ia27, Ia28, Ia29, Ia30, lb, Ibl, Ib2, Ib3, Ib4, Ib5, Ib6, Ib7, Ib8, Ib9, IblO, Ibl 1, Ibl2, Ibl3, Ibl4, Ibl5, Ibl6, Ibl7, or Ibl8.
  • a specific compound of formula I is a compound of formula la:
  • W is -N-, V is C, and the bond represented by— is a double bond;
  • W is -NR e -, -NR e C(O)- or -C(0)NRe-, V is CR lc , and the bond represented by— is a single bond;
  • a specific compound of formula I is a compound of formula laa:
  • W is -N-, V is C, and the bond represented by— is a double bond;
  • W is -NR e -, -NR e C(O)- or -C(0)NRe-, V is CR lc , and the bond represented by— is a single bond;
  • Another specific compound of formula I is a compound of formula lb:
  • Another s ecific compound of formula I is a compound of formula Ial, Ia2, or Ia3
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 3 ;
  • each Z 3 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl, -(Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, CN, -ORa, -OC(0)R b , -OC(0)NRcRd, -SRa, -S(0)R b , -S(0) 2 OH, -S(0) 2 R b , -S(0) 2 NRcRd, -NRcRj, -NRaCOR b , -NR a C0 2 R b , -NRaCONReRd, -NR a S(0) 2 R b , N0 2 , -CHO, -C(0)R a , -C(0)OR a
  • Another specific compound of formula I is a compound of formula Ia4, Ia5, or Ia6
  • Another specific compound of formula I is a compound of formula Ia7, Ia8, or Ia9 or a salt thereof.
  • Another specific compound of formula I is a compound of formula IalO, Ial 1, or
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 3 ;
  • each Z 3 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl, -(Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, CN, -OR a , -OC(0)R b , -OC(0)NR c R d , -SR a , -S(0)R b , -S(0) 2 OH, -S(0) 2 R b , -S(0) 2 NR c R d , -NR c R d , -NR a COR b , -NRaC0 2 R b , -NRaCONRcRd, -NRaS(0) 2 R b , N0 2 , -CHO, -C(0)Ra, -C(0)OR a or -C(0)NR c R d ;
  • a s ecific compound of formula I is a compound of formula Ial3, Ial4, or Ial5:
  • Another specific compound of formula I is a compound of formula Ial6, Ial7,
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 3 ;
  • each Z 3 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-C 6 )alkyl, -(Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, CN, -OR a , -OC(0)R b , -OC(0)NRcRd, -SRa, -S(0)R b , -S(0) 2 OH, -S(0) 2 R b , -S(0) 2 NRcRd, -NRcRj, -NRaCOR b , -NRaC0 2 R b , -NRaCONRcRd, -NRaS(0) 2 R b , N0 2 , -CHO, -C(0)Ra, -C(0)OR a or -C(0)NR c R d ;
  • Another specific compound of formula I is a compound of formula Ial9, Ia20, or
  • Another s ecific compound of formula I is a compound of formula Ia22, Ia23, or Ia24:
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 3 ;
  • each Z 3 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl,
  • Another specific compound of formula I is a compound of formula Ia25, Ia26, or
  • Another specific compound of formula I is a compound of formula Ia28, Ia29,
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 3 ;
  • each Z 3 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl, -(Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, CN, -OR a , -OC(0)R b , -OC(0)NR c R d , -SR a , -S(0)R b , -S(0) 2 OH, -S(0) 2 R b , -S(0) 2 NR c R d , -NR c R d , -NR a COR b , -NRaC0 2 R b , -NRaCONRcRd, -NRaS(0) 2 R b , N0 2 , -CHO, -C(0)Ra, -C(0)OR a or
  • Another specific compound of formula I is a compound of formula Ibl, Ib2, or Ib3:
  • Another specific compound of formula I is a compound of formula Ib4, Ib5, Ib6, Ib7, Ib8, Ib9, IblO, Ibl l, Ibl2, Ibl3, Ibl4, Ibl5, Ibl6, Ibl7, or Ibl8:
  • a specific value for A is aryl, wherein any aryl of A is optionally substituted with one or more groups selected from halogen, aryl, heteroaryl, heterocycle, (Ci-C 6 )alkyl, -(Ci- C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, CN, -ORa, -OC(0)R b ,
  • A is phenyl, wherein any phenyl of A is optionally substituted with one or more groups selected from halogen, aryl, heteroaryl, heterocycle, (Ci-C 6 )alkyl, -(Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, CN, -OR a , -OC(0)R b , -OC(0)NR c R d , -SR a , -S(0)R b , -S(0) 2 OH, -S(0) 2 R b , -S(0) 2 NR c R d , -NR c R d , -NRaCORb, -NR a C0 2 R b , -NRaCONRcRj, -NRaS(0) 2 R b , N0 2
  • A Another specific value for A is phenyl.
  • a specific group of compounds of formula I are compounds wherein W is -N-, V is C, and the bond represented by— is a double bond.
  • Another specific group of compounds of formula I are compounds wherein W is -NR e -, V is CR lc , and the bond represented by— is a single bond.
  • Another specific group of compounds of formula I are compounds wherein W is -NR e C(O)- or -C(0)NR s -, V is CR lc , and the bond represented by— is a single bond.
  • R s is H or -C(0)OR p2 .
  • Rg Another specific value for Rg is H.
  • R lc is H or -C(0)0(Ci-C 6 )alkyl.
  • R lc Another specific value for R lc is H.
  • R la is (Ci-C 6 )alkyl, -(Ci-C 6 )alkylaryl, cycloalkyl, heterocycle, aryl or heteroaryl, wherein any cycloalkyl, -(Ci-C 6 )alkylheteroaryl, heterocycle, aryl or heteroaryl of R la is optionally substituted with one or more (e.g., 1 , 2, 3, 4 or 5) groups selected from halogen, aryl, heteroaryl, heterocycle, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl,
  • any (Ci-C 6 )alkyl of R la is optionally substituted with one or more (e.g., 1 , 2, 3, 4 or 5) groups selected from halogen, aryl, heteroaryl, heterocycle, cycloalkyl, CN, -OR g , -OC(0)R h , -OC(0)NR 1 R J , -SR g , -S(0)R g
  • R la is (Ci-C 6 )alkyl, -(Ci-C 6 )alkylaryl, cycloalkyl, heterocycle, aryl or heteroaryl, wherein any cycloalkyl, -(Ci-C 6 )alkylheteroaryl, heterocycle, aryl or heteroaryl of R la is optionally substituted with one or more (e.g., 1 , 2, 3, 4 or 5) groups selected from Z 1 , (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, -(Ci-C 6 )alkylNRiR j , -(Ci-C 6 )alkylOR g , -(Ci-C 6 )alkylSR g ,
  • any (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl of R la is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1 groups.
  • R la Another specific value for R la is (Ci-C 6 )alkyl, -(Ci-C 6 )alkylaryl, cycloalkyl, heterocycle, aryl or heteroaryl, wherein any cycloalkyl, -(Ci-C 6 )alkylaryl, heterocycle, aryl or heteroaryl of R la is optionally substituted with one or more groups selected from halogen, aryl, heteroaryl, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -OR g , -OC(0)NRiR j , -S(0) 2 R h , -NRiR j , -NR g C0 2 R h , -NR g S(0) 2 R h , N0 2 , -B(OH) 2 , -C(0)OR g and -C(0)NRiR j , and wherein any (Ci-C 6 )alkyl of
  • R la is aryl or heteroaryl, wherein any aryl or heteroaryl of R la is optionally substituted with one or more groups selected from halogen and -OR g .
  • R la is aryl, wherein any aryl of R la is optionally substituted with one or more groups selected from halogen and -OR g .
  • R la is aryl, wherein any aryl of R la is optionally substituted with one or more groups selected from F, CI and -OH.
  • R la Another specific value for R la is phenyl, wherein any phenyl of R la is optionally substituted with one or more groups selected from F, CI and -OH.
  • A is aryl or heteroaryl, wherein any aryl or heteroaryl of A is optionally substituted with one or more groups selected from -(Ci-Ce)hydroxyalkyl, -OR a , -S(0) 2 R b , -S(0) 2 NR c Rd, -NRcRd, -NRaCOR b , -NRaC0 2 R b , -NRaS(0) 2 R b , -C(0)ORa and -C(0)NR c R d .
  • A is aryl or heteroaryl, wherein any aryl or heteroaryl of A is optionally substituted with one or more groups selected from -CH 2 OH, -OH, -OCH 3 , -S(0) 2 CH 3 , -S(0) 2 NH 2 , -S(0) 2 NHCH 3 , -NH 2 , -NHCH 3 , -NHCOCH 3 , -NHC0 2 CH 3 , -NHS(0) 2 CH 3 , -C(0)OH -C(0)NHCH 3 and -C(0)NH 2 .
  • A is phenyl, pyridyl, pyrimidyl, furanyl or thienyl wherein any phenyl, pyridyl, pyrimidyl, furanyl or thienyl of A is optionally substituted with one or more groups selected from -CH 2 OH, -OH, -OCH 3 , -S(0) 2 CH 3 , -S(0) 2 NH 2 , -S(0) 2 NHCH 3 , -NH 2 , -NHCH 3 , -NHCOCH 3 , -NHC0 2 CH 3 , -NHS(0) 2 CH 3 , -C(0)OH -C(0)NHCH 3 and -C(0)NH 2 .
  • V Another specific value for V is NH.
  • Another specific group of compounds of formula I are compounds wherein when W is absent, the bond represented by— is absent, and the bond between A and W is absent, then V is CHOH.
  • V is NH
  • R lb is aryl, wherein any aryl of R lb is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from halogen, aryl, heteroaryl, heterocycle, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, CN, -OR k , -OC(0)R m , -OC(0)NR n Ro, -SR k , -S(0)R m , -S(0) 2 OH, -S(0) 2 R m , -S(0) 2 NR n Ro, -NR professionRo, -NR k C
  • R lb is aryl, wherein any aryl of R lb is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from Z 2 , (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, -(Ci-C 6 )alkylNR n R 0 , -(Ci-C 6 )alkylOR k , -(Ci-C 6 )alkylSR k , -(Ci-C 6 )alkylN0 2 , -(Ci-C 6 )alkylCN,
  • R lb is aryl, heteroaryl or cycloalkyl, wherein any aryl, heteroaryl or cycloalkyl of R lb is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from Z 2 , (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
  • R lb is aryl, wherein any aryl of R lb is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from Z 2 , (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, -(Ci-C6)alkylNR n R o ,
  • R lb is aryl, wherein any aryl, of R lb is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from Z 2 , (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, -(Ci-C 6 )alkylNRURIR 0 , -(Ci-C 6 )alkylOR k , -(Ci-C 6 )alkylSR k , -(Ci-C 6 )alkylN0 2 , -(Ci-C 6 )alkylCN, and
  • R lb is aryl, wherein any aryl, of R lb is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from halogen, aryl, heteroaryl, heterocycle, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, cycloalkyl, CN, -OR k , -OC(0)R m ,
  • R lb is aryl, wherein any aryl of R lb is optionally substituted with one or more groups selected from halogen, heteroaryl (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, -OR k , -OC(0)NR meaningRo, -S(0) 2 R m , -NR k C0 2 R m , -NR k S(0) 2 R m , N0 2 , and -C(0)OR k .
  • R lb is aryl, wherein any aryl of R lb is optionally substituted with one or more groups selected from halogen and -OR k .
  • R lb is phenyl, wherein any phenyl of R lb is optionally substituted with one or more groups selected from F, CI and OH.
  • R is phenyl, wherein any phenyl of R is optionally substituted with one or more OH groups.
  • R is heteroaryl, wherein any heteroaryl, of R is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from Z 2 , (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, -(Ci-C 6 )alkylNRêtR 0 , -(Ci-C 6 )alkylOR k , -(Ci-C 6 )alkylSR k , -(Ci-C 6 )alkylN0 2 , -(Ci-C 6 )alkylCN, and
  • R is heterocycle, wherein any heterocycle, of R is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from Z 2 , (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, -(Ci-C 6 )alkylNRêtR 0 , -(Ci-C 6 )alkylOR k , -(C C 6 )alkylSR k , -(C C 6 )alkylN0 2 , -(Ci-C 6 )alkylCN, and
  • R is cycloalkyl, wherein any cycloalkyl, of R is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from Z 2 ,
  • (Ci-C 6 )alkyl (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, -(Ci-C 6 )alkylNRêtR 0 , -(Ci-C 6 )alkylOR k , -(Ci-C 6 )alkylSR k , -(Ci-C 6 )alkylN0 2 , -(Ci-C 6 )alkylCN, and
  • R 2 is H or (Ci-C 6 )alkyl .
  • R 2 Another specific value for R 2 is H.
  • R 3 is H or -C(0)0(Ci-C 6 )alkyl.
  • R 3 Another specific value for R 3 is H.
  • a specific value for X is N or CR f .
  • R f is H, halogen, (Ci-C6)alkyl, cycloalkyl, aryl, heteroaryl, CN, -C(0)NR u R v , or -S(0) 2 R w , wherein any aryl or heteroaryl of R f is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) R x or (Ci-C 6 )alkyl groups, and wherein any
  • Rf is H or -C(0)NR u R v .
  • R f is H or -C(0)NH 2 .
  • a specific compound of formula I is:
  • Another compound of formula I is:
  • An aspect of the invention is a compound represented by formula Ic:
  • V is CR
  • R is H, -(Ci-C 6 )alkyl, carboxyl, or -C(0)0(Ci-C 6 )alkyl;
  • R 1 is aryl or heteroaryl, wherein any aryl or heteroaryl of R 1 is optionally substituted with one or more groups selected from the group consisting of halogen, hydroxyl, carboxyl, (Ci-Ce)alkyl, (Ci-C6)perfluoroalkyl,
  • R 2 is H or -(C C 6 )alkyl
  • R 3 is selected from the group consisting of H, hydroxyl, carboxyl, -(Ci-C 6 )alkyl, -0(Ci-C 6 )alkyl, -C(0)OR 5 , -C(0)NHR 5 , aralkyl, acyl, aryl, heteroaryl, and amino;
  • each R 4 is independently selected from the group consisting of halogen, hydroxyl, carboxyl, -(Ci-C 6 )alkyl, -0(Ci-C 6 )alkyl, -C(0)OR 5 , -C(0)NHR 5 , aralkyl, aryl, heteroaryl, cyano, amino, and nitro;
  • each R 5 is H, -(C i-C 6 )alkyl, or aralkyl;
  • Rs is selected from the group consisting of H, hydroxyl, carboxyl, -(Ci-C 6 )alkyl, -0(Ci-C 6 )alkyl, -C(0)OR 5 , -C(0)NHR 5 , aralkyl, acyl, aryl, heteroaryl, and amino;
  • Rf is selected from the group consisting of H, halogen, hydroxyl, carboxyl,
  • n is an integer 0-4;
  • W is -NR e -.
  • R e is H.
  • W is -NHC(O)-.
  • R is H
  • R is -C(0)0(Ci- C 6 )alkyl.
  • R 1 is optionally substituted aryl.
  • R 1 is optionally substituted phenyl.
  • the phenyl of R 1 comprises a 4-hydroxyl group.
  • R 2 is H.
  • R 3 is H.
  • R f is H.
  • n 0.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is represented by
  • the compound is represented by 14T
  • the compound is selected from the group consisting of:
  • Heterocycles and hetereoaryls can be prepared from know methods as reported in the literature (a. Ring system handbook, published by American Chemical Society edition 1993 and subsequent supplements, b. The Chemistry of Heterocyclic Compounds; Weissberger, A., Ed.; Wiley: New York, 1962. c. Nesynov, E. P.; Grekov, A. P. The chemistry of 1,3,4- oxadiazole derivatives. Russ. Chem. Rev. 1964, 33, 508-515. d. Advances in Heterocyclic Chemistry; Katritzky, A. R., Boulton, A. J., Eds.; Academic Press: New York, 1966. e.
  • Lv is an appropriate leaving group
  • a compound lb boronic acid, Suzuki coupling
  • catalyst typically transition metal using a ligand and an appropriate base such as (Na 2 C0 3 , Ba(OH) 2 , K3PO4, NaHC0 3 , Cs 2 C0 3 , K 2 C0 3 , KHC0 3 , TiOH, KF, or
  • compound lb, 2a, 4d, 5a, and 6c boronic acids can be replaced with compounds of formulae 1 'b, 2'a, 4'd, 5'a, and 6'c in the appropriate schemes where Z is a boranate esters (Suzuki coupling), trialkyltin (Stille coupling), trialkylsilyl (Hiyama coupling), metal halides like Mg (Kumada coupling), Zn (Negishi coupling) Cu and ZrCp 2 or AlMe 2 (1.
  • Z is a boranate esters (Suzuki coupling), trialkyltin (Stille coupling), trialkylsilyl (Hiyama coupling), metal halides like Mg (Kumada coupling), Zn (Negishi coupling) Cu and ZrCp 2 or AlMe 2 (1.
  • Schemes 17 and 18 outline methods to synthesize intermediates useful for preparing compounds of formula 1.
  • Methods to prepare starting materials or intermediates of Schemes 17 and 18 and reaction conditions for performing the synthetic steps of Schemes 17 and 18 are known (for example see: Scheme 17: 1. De Rosa, Michael; Issac, Roy P.; Houghton, Gregory, Tetrahedron Letters (1995) 36(51):9261-4. 2. Turilli, Oreste; Gandino, Mario, Annali di Chimica (Rome, Italy) (1963) 53(11): 1687-96. 3. Youssef, Mohamed S. K.; El- Dean, Adel M. Kamal; Abbady, Mohamed S.; Hassan, Khairy M., Collection of
  • Schemes 19-21 outline methods to synthesize intermediates useful for preparing compounds of formula 1.
  • Methods to prepare starting materials or intermediates of Schemes 19-21 and reaction conditions for performing the synthetic steps of Schemes 19-21 are known (for example see: Scheme 19: 1. Morgentin, Remy; Jung, Frederic; Lamorlette, Maryannick; Maudet, Mickael; Menard, Morgan; Pie, Patrick; Pasquet, Georges; Renaud, Fabrice, Tetrahedron (2009) 65(4): 757-764. 2.
  • Scheme 19 1. Morgentin, Remy; Jung, Frederic; Lamorlette, Maryannick; Maudet, Mickael; Menard, Morgan; Pie, Patrick; Pasquet, Georges; Renaud, Fabrice, Tetrahedron (2009) 65(4): 757-764. 2.
  • Valentina De Logu, Alessandro; Cocco, Maria T.; Fadda, Roberta; Meleddu, Rita; Congiu, Cenzo, European Journal of Medicinal Chemistry (2009) 44(3):
  • Scheme 22 outlines a method to synthesize an intermediate useful for preparing compounds of formula 1.
  • Methods to prepare starting materials and reaction conditions for performing the synthetic steps of Scheme 22 are known (for example see: 1. Sonoda, Miki, et al, Chemical & Pharmaceutical Bulletin (1982) 30(7):2357-63. 2. Mohamed, Mosaad Sayed, et al, Acta Pharmaceutica (Zagreb, Croatia) (2009) 59(2): 145-158. 3. FR 2881742 Al to Ronan, Baptiste, et al., Fr. Demande (2006). Compound 22a can be converted to intermediate 22f using the procedure reported in 1. European Journal of Medicinal Chemistry (2003) 38:265-275 and Canadian Journal of Chemistry (1976) 54(2):290-6.
  • the invention provides a method for preparing a salt of a compound of formula I, comprising reacting the compound of formula I with an acid under conditions suitable to provide the salt.
  • the invention provides a method for preparing a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier, comprising combining the compound of formula I, or the pharmaceutically acceptable salt thereof, with the pharmaceutically acceptable diluent or carrier to provide the pharmaceutical
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following diluents and carriers: binders such as gum tragacanth, acacia, corn starch or gelatin;
  • excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form.
  • tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • Compounds of the invention can also be administered in combination with other therapeutic agents, for example, other agents that are useful for immunosuppression.
  • the invention also provides a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier.
  • the invention also provides a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of formula I or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to suppress an immune response in the animal.
  • Compounds of the invention may also be useful in the treatment of other diseases, conditions or disorders associated with the function of a kinase such as a Janus kinase (e.g., JAK1, JAK2 or TYK2) including the pathological activation of a kinase such as a Janus kinase (e.g., JAK1, JAK2 or TYK2).
  • a kinase such as a Janus kinase (e.g., JAK1, JAK2 or TYK2)
  • a kinase such as a Janus kinase (e.g., JAK1, JAK2 or TYK2))-related disease, condition or disorder.
  • the ability of a compound of the invention to bind to JAK3 can be determined using pharmacological models which are well known to the art, or using Test A described below.
  • Inhibition constants were determined against JAK3 (JH1 domain-catalytic) kinase and other members of the JAK family. Assays were performed as described in Fabian et al. (2005) Nature Biotechnology 23:329-36 and in Karaman et al. (2008) Nature Biotechnology 26: 127-32. Inhibition constants were determined using 11-point dose response curves which were performed in triplicate. Representative compounds of the invention displayed IC 50 S of ⁇ 1 ⁇ against JAK3.
  • the ability of a compound of the invention to provide an immunomodulatory effect can also be determined using pharmacological models which are well known to the art.
  • the ability of a compound of the invention to provide an anti-cancer effect can also be determined using pharmacological models which are well known to the art.
  • Step 1
  • reaction mixture was stirred for additional 30 min poured into ice water (2000 mL) and extracted with ethyl acetate (3 x 500 mL), the ethyl acetate layers were combined washed with water (2 x 500 mL), brine (1 x 250 mL), dried and concentrated in vacuum. The residue was triturated with hexane (500 mL), and the solid obtained was collected by filtration to afford l-(4-acetyl-lH- pyrrol-2-yl)-2,2,2-trichloroethanone 11c, (51.7 g, 86 %) as a colorless solid.
  • Step 3 To a stirred solution of l-(4-acetyl-5-nitro-lH-pyrrol-2-yl)-2,2,2-trichloroethanone l id (53.57 g, 180.09 mmol) from above step in methanol (200 mL) was added sodium methoxide (42.80 g, 198.09 mmol, 25 % solution in methanol) at 20 °C. The reaction mixture was stirred at room temperature for 30 min and quenched carefully with a mixture of water and dilute HC1 (200 mmol). The solid separated was collected by filtration. The filtrate was extracted with ethyl acetate (2 x 1000 mL).
  • Step 1
  • tetraazadibenzo[cd,f]azulene 3-carboxylate 14d (100 mgs, 0.27 mmol) in methanol (20 mL) was added aqueous 6 N HC1 (0.5 mL) and Pd(C) (10%> by weight, 40 mgs). The slurry was hydrogenated at 50 psi until complete as analyzed by TLC analysis of the reaction mixture. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuum.
  • Inhibition constants (IC 5 os) were determined against JA 3 (JH1 domain-catalytic) kinase and other members of the JAK family. Assays were performed essentially as described in Fabian et al. (2005) Nature Biotechnology 23:329 and in Karaman et al. (2008) Nature Biotechnology 26: 127. Inhibition constants were determined using 11 -point dose response curves which were performed in triplicate. Results are shown in Table 1. A number of representative compounds of the invention displayed IC 50 S of ⁇ 1 ⁇ against JAK3. Table 1
  • IC 5 o > 1 ⁇ represents 1 ⁇ ⁇ IC 5 o ⁇ 10 ⁇

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Abstract

L'invention concerne des composés de formule I : ou l'un de leurs sels tels que décrits ici. L'invention concerne également des compositions pharmaceutiques comprenant un composé de formule I, des procédés pour préparer des composés de formule I, des intermédiaires utiles pour préparer des composés de formule I et des procédés thérapeutiques pour supprimer une réponse immunitaire ou traiter un cancer ou une malignité hématologique au moyen des composés de formule I.
PCT/US2012/023510 2011-02-02 2012-02-01 Composés hétérocycliques comme inhibiteurs de janus kinase WO2012106448A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN107739387A (zh) * 2017-10-16 2018-02-27 上海皓元生物医药科技有限公司 一种制备曲贝替定的关键中间体化合物的方法
WO2020161209A1 (fr) 2019-02-06 2020-08-13 Syngenta Crop Protection Ag Composés pyridazine fusionnés herbicides
WO2020161208A1 (fr) 2019-02-06 2020-08-13 Syngenta Crop Protection Ag Composés pyridazine fusionnés herbicides
WO2021121276A1 (fr) * 2019-12-17 2021-06-24 江苏恒瑞医药股份有限公司 Dérivé tétracyclique fusionné, son procédé de préparation et son utilisation médicale

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US20060111419A1 (en) * 2002-02-28 2006-05-25 Norihito Ohi Novel fused indazole compounds
US20080293694A1 (en) * 2007-03-13 2008-11-27 Biovitrum Ab (Publ.) New compounds
US20090325937A1 (en) * 2005-07-12 2009-12-31 Abbott Gmbh & Co. Kg Pyridazine Compounds as Glycogen Synthase Kinase 3 Inhibitors
US20100210581A1 (en) * 2007-09-24 2010-08-19 Istitute de Ricerche di Biologia Molecolare P. Angeletti Nucleoside Derivatives as Inhibitors of Viral Polymerases
WO2011031554A2 (fr) * 2009-08-27 2011-03-17 Biocryst Pharmaceuticals, Inc. Composés hétérocycliques en tant qu'inhibiteurs de janus kinase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060111419A1 (en) * 2002-02-28 2006-05-25 Norihito Ohi Novel fused indazole compounds
US20090325937A1 (en) * 2005-07-12 2009-12-31 Abbott Gmbh & Co. Kg Pyridazine Compounds as Glycogen Synthase Kinase 3 Inhibitors
US20080293694A1 (en) * 2007-03-13 2008-11-27 Biovitrum Ab (Publ.) New compounds
US20100210581A1 (en) * 2007-09-24 2010-08-19 Istitute de Ricerche di Biologia Molecolare P. Angeletti Nucleoside Derivatives as Inhibitors of Viral Polymerases
WO2011031554A2 (fr) * 2009-08-27 2011-03-17 Biocryst Pharmaceuticals, Inc. Composés hétérocycliques en tant qu'inhibiteurs de janus kinase

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107739387A (zh) * 2017-10-16 2018-02-27 上海皓元生物医药科技有限公司 一种制备曲贝替定的关键中间体化合物的方法
CN107739387B (zh) * 2017-10-16 2020-01-03 上海皓元生物医药科技有限公司 一种制备曲贝替定的关键中间体化合物的方法
WO2020161209A1 (fr) 2019-02-06 2020-08-13 Syngenta Crop Protection Ag Composés pyridazine fusionnés herbicides
WO2020161208A1 (fr) 2019-02-06 2020-08-13 Syngenta Crop Protection Ag Composés pyridazine fusionnés herbicides
WO2021121276A1 (fr) * 2019-12-17 2021-06-24 江苏恒瑞医药股份有限公司 Dérivé tétracyclique fusionné, son procédé de préparation et son utilisation médicale

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