WO2013033093A1 - Heterocyclic compounds as janus kinase inhibitors - Google Patents

Heterocyclic compounds as janus kinase inhibitors Download PDF

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Publication number
WO2013033093A1
WO2013033093A1 PCT/US2012/052657 US2012052657W WO2013033093A1 WO 2013033093 A1 WO2013033093 A1 WO 2013033093A1 US 2012052657 W US2012052657 W US 2012052657W WO 2013033093 A1 WO2013033093 A1 WO 2013033093A1
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Prior art keywords
tetraazadibenzo
dihydro
azulen
alkyl
aryl
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PCT/US2012/052657
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French (fr)
Inventor
Yarlagadda S. Babu
Pravin L. Kotian
Venkat R. CHINTAREDDY
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Biocryst Pharmaceuticals, Inc.
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Publication of WO2013033093A1 publication Critical patent/WO2013033093A1/en

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • kinases have become one of the most intensively pursued classes of drug targets. Deregulation of kinase function has been implicated not only in cancer but also in disorders which include immunological, neurological, metabolic and infectious disease. Compounds having protein kinase, particularly Janus kinase (JAK) inhibitory activity may be beneficial in various diseases which include, autoimmune diseases, atopic diseases, cancer, and in prevention of transplant rejection.
  • JAK Janus kinase
  • the mammalian JAK family has four members: Jakl, Jak2, Jak3, and tyrosine kinase (TYK2). Genetic knock out studies have shown that JAKs and STATs have highly specific function in the control of various immune responses.
  • 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.
  • yc common gamma chain
  • JAK is a viable target for immunosuppression and transplant rejection. JAK inhibitors may also be useful for the treatment of cancer including hematologic and other malignancies that involve pathologic JAK activation.
  • the invention provides a compound represented by formula I
  • A is a fused aryl or heteroaryl, wherein any aryl or heteroaryl of A is optionally substituted with one or more groups selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, (Ci-C 6 )alkyl, (Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -Cy)cycloalkyl,
  • X, Y, or V is N
  • R la is H, or -C(0)OR f ;
  • R 1 is H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl,
  • (C 3 -C 7 )cycloalkyl, -(Ci-C 6 )alkylaryl, -(Ci-C 6 )alkylheteroaryl or heterocycle of R 1 is optionally substituted with one or more groups selected from the group consisting of Z 1 , oxo, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, -(Ci-C 6 )alkylNRiRj, -(Ci-C 6 )alkylOR g , -(Ci-C 6 )alkylSR g , -(Ci-C 6 )alkylN 0 2 , -(Ci-C 6 )alkylCN and -(Ci-C 6 )alkylOH, and wherein any (Ci-C 6 )alkyl,
  • R 2 is H, halogen, (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, heterocycle, N0 2 , CN, -OH, -OR k , -NR m R n , N 3 ,
  • (C 2 -C 8 )alkynyl, aryl or heteroaryl of R 2 is optionally substituted with one or more Z 2 groups, and wherein any (C 3 -C 8 )cycloalkyl or heterocycle of R 2 is optionally substituted with one or more groups selected from the group consisting of Z 2 , oxo and
  • R 3 is H, OH, N0 2 , C0 2 H,
  • R 4 is H, OH, N0 2 , C0 2 H,
  • R 5 is H, halogen, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, heterocycle, N0 2 , CN, OH, -OR w , -NR U R V ,
  • each R a is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
  • each R b is independently (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
  • R c and R d are each independently selected from the group consisting of H,
  • each R e is independently H, (Ci-C 6 )alkyl, -(Ci-Ce)alkylaryl or -C(0)OR s i;
  • each R e i is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl,
  • each R f is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl,
  • each R g is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl,
  • each R is independently (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
  • Ri and R j are each independently selected from the group consisting of H,
  • R k is (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, heterocycle, heteroaryl or aryl;
  • R m and R n are each independently selected from the group consisting of H,
  • any (Ci-C 6 )alkyl of R m or R n is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of -C(0)OH and OH; or R m and R m together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino;
  • Ro is H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, heterocycle, heteroaryl or aryl;
  • R p and R q are each independently selected from the group consisting of H,
  • any (Ci-C 6 )alkyl of R p or R q is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of -C(0)OH and OH; or R p and R q together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
  • each R r is independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, aryl, -(Ci-Ce)alkylaryl, heterocycle and heteroaryl;
  • each R s is independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, aryl, -(Ci-Ce)alkylaryl, heterocycle and heteroaryl, wherein any (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, aryl, -(Ci-C 6 )alkylaryl, heterocycle or heteroaryl of R s is optionally substituted with one or more halogens;
  • each R t is independently selected from the group consisting of (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, aryl, -(Ci-Ce)alkylaryl, heterocycle and heteroaryl;
  • R u and R v are each independently selected from the group consisting of H,
  • any (Ci-C 6 )alkyl of R u or R v is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of -C(0)OH and OH; or R u and R v together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino ring;
  • each R w is independently selected from the group consisting of H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, aryl, -(Ci-C 6 )alkylaryl, heterocycle and heteroaryl;
  • each Z 1 is independently selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, (C 3 -Cy)cycloalkyl,
  • (C3-Cy)cycloalkyl of Z 1 is optionally substituted with one or more groups selected from the group consisting of NH 2 , -NH(Ci-C4)alkyl, -N(Ci-C4)alkyl 2 , halogen,
  • each Z 2 is independently selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, R z , OH, CN, -OR z , -Oaryl, -OC(0)R z , -OC(0)NR z iR z2 ,
  • each Z 4 is independently selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, R z , OH, CN, -OR z , -Oaryl, -OC(0)R z , -OC(0)NR z iR z2 ,
  • each Z 5 is independently halogen, aryl, R z , OH, CN,
  • each R z is independently (Ci-C 6 )alkyl or (C 3 -C 6 )cycloalkyl, wherein any
  • (Ci-C 6 )alkyl of R z is optionally substituted with one or more R z4 groups, and wherein any (C3-C 6 )cycloalkyl of R z is optionally substituted with one or more groups selected from the group consisting of R z4 , (C 1 -C 6 )alkyl, -(C 1 -C 6 )alkylCN and -(Ci-C 6 )alkylOH;
  • R z i and R z2 are each independently selected from the group consisting of H,
  • each R z3 is independently selected from the group consisting of halogen, CN, CF 3 , NR z5 R z6 , OH, -0(Ci-C 6 )alkyl, -C(0)NR z5 R z6 , -C(0)(Ci-C 6 )alkyl, aryl, heterocycle and heteroaryl, wherein any heterocycle of R z3 is substituted with one or more (Ci-C 6 )alkyl; each R z4 is independently selected from the group consisting of halogen, CN, OH, -NR z5 R z6 , -SCN, -0(Ci-C 6 )alkyl, -Sheteroaryl, -S(0)aryl, -S(0) 2 aryl, -Oaryl, -C(0)NR z5 R Z 6, (C 3 -C 6 )cycloalkyl, -CH 2 NHCOaryl, -CH 2 OCH 2
  • Sheteroaryl, -S(0)aryl, -S(0) 2 aryl, -Oaryl, -CH 2 NHCOaryl, -CH 2 OCH 2 aryl, biphenyl or heterocycle of R z4 may be optionally substituted with one or more halogen,
  • R Z 5 and R z6 are each independently selected from the group consisting of H and (Ci-C 6 )alkyl, wherein (Ci-C 6 )alkyl is optionally substituted with NH 2 ;
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and 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 to a mammal in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to treat the disease or condition associated with pathologic JAK activation.
  • 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 treating a cancer (e.g., a hematologic malignancy or other malignancy) in a mammal (e.g., a human), comprising administering to a mammal in need thereof an effective amount of a compound of formula I, or a
  • 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).
  • 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 the prophylactic or therapeutic treatment of a cancer (e.g., a hematologic malignancy or other malignancy).
  • a cancer e.g., 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 compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer (e.g., a hematologic malignancy or other malignancy) in a mammal (e.g., a human).
  • cancer e.g., a hematologic malignancy or other malignancy
  • 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 to a mammal in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to suppress the immune response.
  • 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 1-55.
  • alkyl refers to alkyl groups having from 1 to 10 carbon atoms which are straight or branched groups.
  • (Ci-C 6 )alkyl refers to alkyl groups having from 1 to 6 carbon atoms which are straight or branched.
  • (Ci-Cg)alkyl refers to alkyl groups having from 1 to 8 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,
  • (C 2 -C 6 )alkenyl refers to alkenyl groups having from 2 to 6 carbon atoms which are straight or branched.
  • (C 2 -C 8 )alkenyl refers to alkenyl groups having from 2 to 8 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 groups and having at least one triple bond. Such groups are exemplified by, but not limited to ethyn-l-yl, propyn-l-yl, propyn-2-yl, l-methylprop-2-yn-l-yl, butyn-l-yl, butyn-2-yl, butyn-3-yl and the like.
  • (C 2 -Ce)alkynyl refers to alkynyl groups having from 2 to 6 carbon atoms which are straight or branched.
  • (C 2 -C 8 )alkynyl refers to alkynyl groups having from 2 to 8 carbon atoms which are straight or branched.
  • halogen or "halo”as used herein 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-C6)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 .
  • 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, cyclooctadienyl, decahydronaphthalene and spiro[4.5]decane.
  • 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 any non-aromatic portion (i.e., saturated or partially unsaturated) of the multiple condensed ring.
  • the point(s) of attachment of a bicyclic or multicyclic aryl can be at any position of the ring system including an aromatic or non-aromatic portion of the ring.
  • aryls include, but are not limited to phenyl, indanyl, naphthyl,
  • 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, benzoxazolyl, indazolyl, indolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinoline and the like.
  • 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.
  • cyclic amino as used herein is a subgroup of heterocycles and refers to a 3-membered to 8-membered saturated or partially unsaturated, single ring which has at least one nitrogen atom, and may have one or more identical or different hetero atoms selected from the group consisting of nitrogen, oxygen, and sulfur wherein the nitrogen or sulfur atoms may be oxidized.
  • Cyclic amino includes but is not limited to values such as aziridino, azetidino, pyrrolidino, piperidino, homopiperidino, morpholino, thiomorpholino, and piperazino.
  • 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.
  • Pharmaceutically acceptable 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.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • a specific compound of formula I is a compound of formula Ia3 :
  • Another specific compound of formula I is a compound of formula Ia4 - Ia9:
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
  • Another specific compound of formula I is a compound of formula la 10 - Ial4:
  • Another specific compound of formula I is a compound of formula Ial5:
  • Another specific compound of formula I is a compound of formula Ia22 or Ia23:
  • Another specific compound of formula I is a compound of formula Ia24 - Ia29:
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-C 6 )alkyl,
  • a specific compound of formula I is a compound of formula Ia36 or Ia37:
  • Another specific compound of formula I is a compound of formula Ia38 - Ia43:
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
  • Another specific com ound of formula I is a compound of formula Ia50 or Ia51 :
  • Another s ecific compound of formula I is a compound of formula Ia52 - Ia57:
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
  • Another spe ific compound of formula I is a compound of formula Ia64 or Ia65:
  • Another specific compound of formula I is a compound of formula Ia66 - Ia71 :
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
  • Another spe ific compound of formula I is a compound of formula Ia78 or Ia79:
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
  • Another specific com ound of formula I is a compound of formula Ia92 or Ia93:
  • Another specific compound of formula I is a compound of formula Ia94 - Ia99
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
  • Another specific compound of formula I is a compound of formula la 106 or la 107:
  • Ial06 Ial07 or a pharmaceutically acceptable salt thereof.
  • Another specific compound of formula I is a compound of formula Ial08 - Ial 13:
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
  • Another specific compound of formula I is a compound of formula la 120 or Ial21 :
  • Ial20 Ial21 or a pharmaceutically acceptable salt thereof.
  • Another specific compound of formula I is a compound of formula la 122 - la 127:
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
  • Another spe ific compound of formula I is a compound of formula Ial34 or Ial35:
  • Another s ecific compound of formula I is a compound of formula la 136 - la 141 :
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-C 6 )alkyl,
  • Another specific compound of formula I is a compound of formula Ial48 or Ial49:
  • Another s ecific compound of formula I is a compound of formula Ial50 - Ial55:
  • each Y 1 , Y 2 , Y 3 and Y 4 is independently N, CH or CZ 7 ;
  • each Z 7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
  • a specific value for X is CR 3 .
  • a specific value for Y is CR 4 .
  • a specific value for R 3 is H.
  • a specific value for R 4 is H.
  • a specific group of compounds of formula I are compounds wherein W and Y are each CH.
  • a specific group of compounds of formula I are compounds of formula Ia3 :
  • a specific value for A is a fused 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, (C 3 -C 7 )cycloalkyl,
  • A is fused phenyl, wherein phenyl 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, (C 3 -C 7 )cycloalkyl, CN, -ORa, -OC(0)R b , -OC(0)NR c Rd, -SRa, -S(0)R b , -S(0) 2 OH, -S(0) 2 R b , -S(0) 2 NR c R d , - NRcRd, -NRaCORb, -NR a C0 2 R b , -NRaCONRcRd, -NRaS(0) 2 R b ,
  • Another specific group of compounds of formula I are compounds wherein W is -N-, Z is C, and the bond represented by— is a double bond; or W is -NRe-, Z is CR la , and the bond represented by— is a single bond; or W is -NR e C(O)- or -C(O)-, Z is CR la or N and the bond represented by— is a single bond.
  • Another specific group of compounds of formula I are compounds wherein W is -N-, Z is C and the bond represented by— is a double bond; or W is -NR e -, Z is CR la and the bond represented by— is a single bond; or W is -NR e C(0)-, Z is CR la and the bond represented by— is a single bond.
  • R e is H.
  • R la is H or -C(0)0(Ci-C 6 )alkyl.
  • R la Another specific value for R la is H.
  • R 2 is H or -NR m R n .
  • R 2 is H or -NH 2 .
  • V is N or CC(0)NR u R v .
  • V is N, CC(0)NH 2 or CC(0)NHCH 2 C0 2 H.
  • a specific value for V is N.
  • a specific value for R 1 is (C 3 -Cy)cycloalkyl, heterocycle, aryl or heteroaryl, wherein any aryl or heteroaryl of R 1 is optionally substituted with one or more 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 )alkylN 0 2 , -(C C 6 )alkylCN and -(Ci-C 6 )alkylOH.
  • R 1 is phenyl, wherein phenyl is optionally substituted with one or more 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 )alkylN 0 2 , -(C C 6 )alkylCN and -(Ci-C 6 )alkylOH.
  • R 1 Another specific value for R 1 is phenyl, wherein phenyl is optionally substituted with one or more groups selected from halogen, CN, -OR g , -NRiR j , N0 2 , -B(OR g ) 2 , (Ci-C 6 )alkyl and (C 2 -C 6 )alkenyl.
  • R 1 Another specific value for R 1 is phenyl, wherein phenyl is optionally substituted with one or more groups selected from halogen, -OR g and N0 2 .
  • An aspect of the invention is a compound of formula I which is:
  • An aspect of the invention is a compound of formula I which is:
  • An aspect of the invention is a compound of formula I which
  • An aspect of the invention is a compound of formula I which
  • An aspect of the invention is a compound of formula I which is:
  • An aspect of the invention is a compound of formula I which is:
  • An aspect of the invention is a compound of formula I which is:
  • An aspect of the invention is a compound selected from the group consisting of: 4-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol,
  • An aspect of the invention is a compound selected from the group consisting of:
  • An aspect of the invention is a compound selected from the group consisting of: 2-Chloro-4-(3 ,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-6-methoxyphenol,
  • An aspect of the invention is a compound selected from the group consisting of: 3-(2,4-Dichlorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
  • An aspect of the invention is a compound selected from the group consisting of: 3-(2,3,6-Trifluorophenyl)-3,4-dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulene,
  • An aspect of the invention is a compound selected from the group consisting of: Methyl (3-(4-hydroxy-2-methylphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo
  • Methyl (3-(2,5-dihydroxyphenyl)-4,9,l 1,1 la-tetraazadibenzo[cd,fjazulen-10-yl)carbamate, Methyl (3-(3-bromo-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo
  • An aspect of the invention is a compound selected from the group consisting of: 4-(4,9, 11 , 11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-fluorophenol,
  • An aspect of the invention is a compound selected from the group consisting of: 3-(2,3-Dihydrobenzofuran-5-yl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo [cd,f]azulene, 3-(2,6-Difluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
  • An aspect of the invention is a compound selected from the group consisting of: 4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-chlorophenol, 4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
  • An aspect of the invention is a compound selected from the group consisting of: 4-(9-Amino-3,4-dihydro-5-thia-4,8,10,10a-tetraazabenzo[cd]cyclopenta[fJazulen-3-yl)-3- fluorophenol,
  • Heterocycles and hetereoaryls can be prepared from know methods as reported in the literature (a. Ring system handbook, published by American Chemical Society edition
  • An aspect of the invention is a pharmaceutical composition, comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical composition can be prepared by combining a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • Pharmaceutical compositions of the invention can be prepared in any of various suitable formulations, such as are discussed below.
  • An aspect of the invention is a method of treating a disease or condition associated with Janus kinase (JAK) activation in a mammal.
  • the method includes the step of administering to a mammal in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to treat the disease or condition associated with Janus kinase (JAK) activation.
  • the JAK activation is pathologic JAK activation.
  • the mammal is a human.
  • the disease or condition associated with JAK activation is selected from the group consisting of cancer, leukemia, T-cell prolymphocytic leukemia, lymphoma, cutaneous T-cell lymphoma, lymphoproliferative disorders, multiple myeloma, myleoproliferative disorders, acute and chronic allograft transplant rejection, graft-versus- host disease (GvHD), Alzheimer's disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, autoimmune thyroid disorders, Type I diabetes mellitus and complications from diabetes, lupus erythematosus, multiple sclerosis, T-cell autoimmune disease, asthma, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), psoriasis, chronic obstructive pulmonary disease (COPD), allergy, other inflammatory diseases, and sepsis.
  • cancer leukemia, T-cell prolymphocytic leukemia, lymphoma, cutaneous T-cell lympho
  • the disease or condition associated with JAK activation is cancer.
  • the cancer is a hematologic malignancy, e.g., leukemia, lymphoma.
  • the disease or condition associated with JAK activation is an undesirable immune response.
  • An undesirable immune response includes, without limitation, an autoimmune disease (e.g., rheumatoid arthritis, autoimmune thyroid disorders, Type I diabetes mellitus, lupus erythematosus, multiple sclerosis, and
  • JAK activation refers to activation of any one or more of Jakl, Jak2, Jak3, and TYK2.
  • JAK activation refers to activation of Jakl .
  • JK activation refers to activation of Jak2.
  • JK activation refers to activation of Jak3.
  • JAK activation refers to activation of TYK2.
  • treat refers to preventing, reducing, halting, or resolving a disease or condition in a subject. In one embodiment, the term “treat” refers to reducing, halting, or resolving a disease or condition in a subject. In one embodiment, the term “treat” refers to reducing, halting, or resolving at least one objectively measurable manifestation of a disease or condition in a subject.
  • an “effective amount” as used herein refers to an amount that is sufficient to bring about a desired biological result. In one embodiment, an “effective amount” is a therapeutically effective amount.
  • a “therapeutically effective amount” as used herein refers to an amount that is sufficient to bring about a desired therapeutic result, e.g., to treat a disease or condition in a subject.
  • An aspect of the invention is a method for suppressing an immune response in a mammal.
  • the method includes the step of administering to a mammal in need thereof an effective amount of a compound of the invention to suppress the immune response.
  • An immune response is suppressed if it is reduced by an objectively measurable amount compared to a relevant control.
  • the immune response is reduced by at least 5 percent.
  • the immune response is reduced by at least 10, 20, 30, 30, 40, 50, 60, 70, 80, or 90 percent.
  • the immune response is reduced by at least 95 percent.
  • the immune response is reduced by essentially 100 percent.
  • 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 or a base 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 composition.
  • 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, i.e., orally or parenterally, by intravenous,
  • 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.
  • the percentage of the 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.
  • the 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 polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • 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.
  • compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see U.S. Pat. No. 4,608,392 to Jacquet et al, U.S. Pat. No. 4,992,478 to Geria, U.S. Pat. No. 4,559,157 to Smith et al, and U.S. Pat. No. 4,820,508 to Wortzman, all of which are incorporated by reference.
  • 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 to Borch et al., incorporated herein by reference.
  • 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 and the treatment of cancer (e.g., a hematologic malignancy or other malignancy).
  • 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 the invention, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the invention or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to a mammal to treat a cancer in the mammal.
  • the mammal is a human.
  • the invention also provides a kit comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the invention or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to a mammal to suppress an immune response in the mammal.
  • the mammal is a human.
  • 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., Jakl, Jak2, Jak3 or TYK2) including the pathological activation of a kinase such as a Janus kinase (e.g., Jakl, Jak2, Jak3 or TYK2).
  • a kinase such as a Janus kinase (e.g., Jakl, Jak2, Jak3 or TYK2))- related disease, condition or disorder.
  • a compound of the invention to bind to Jak3 and other members of the JAK family (e.g., Jakl, Jak2 or TYK2) can be determined using pharmacological models which are well known to the art, or using Test A described below.
  • Inhibition constants can be determined against Jak3 (JH1 domain-catalytic) kinase and other members of the JAK family. Assays can be performed as described in Fabian et al. (2005) Nat. Biotechnol. 23:329-336; Karaman et al. (2008) Nat. Biotechnol. 26: 127-132; C. Tanego et al (2009): “Comparison of Bio luminescent Kinase Assay Using Substrate Depletion and Product Formation", Assay and Drug Development Technologies, 7: 606-615; H.
  • 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.
  • the ability of a compound ofthe 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.
  • the reaction was quenched by adding ice water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The ethyl acetate extracts were combined washed with hydrochloric acid (1 N, 30 mL), water (50 mL), saturated sodium bicarbonate (1 x 20 mL), water (50 mL), brine (20 mL) dried and concentrated. The crude residue was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexanes (0 to 5 %)) to furnish pure
  • the crude product was purified by flash column chromatography ((silica gel 12 g, eluting with hexane: ethyl acetate (0 to 100%)) to furnish 2-(pyrrolo[l,2-f][l,2,4]triazin-4- yl)aniline (22h) (0.584 g, 28 % yield) as a yellow solid.
  • reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f] azulen-3-yl)-3-fiuorophenol (22k) (0.015 g,
  • reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-3-chlorophenol (23c)
  • the reaction mixture was stirred at 80 °C for 2 h and diluted with H 2 0 (25 mL).
  • the product was extracted with ethyl acetate (3 x 25 mL).
  • the organic layers were combined, washed with water (2 x 25 mL), dried, filtered and concentrated in vacuo.
  • the crude product was purified by flash column chromatography ((silica gel 12 g, eluting with hexane: ethyl acetate (0 to 100%)) to furnish methyl 4-(2- aminophenyl)pyrrolo[l,2-f][l,2,4]triazin-2-ylcarbamate 17e (0.2 g, 71 % yield) as a yellow solid.
  • the reaction mixture was stirred at 80 °C for 2 h and diluted with H 2 0 (25 mL).
  • the product was extracted with ethyl acetate (3 x 25 mL).
  • the organic layers were combined, washed with water (2 x 25 mL), dried, filtered and concentrated in vacuo.
  • the crude product was purified by flash column chromatography ((silica gel 24 g, eluting with hexane: ethyl acetate (0 to 100%)) to furnish in the following order:
  • reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-methoxyphenol 34a
  • reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2 -methylphenol 34b (115 mg, 68.07 %) as a orange solid.
  • reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol 34c (116 mg, 84 %) as a orange solid.
  • reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-bromophenol 34d (52 mg, 68 %) as a orange solid.

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Abstract

The invention provides compounds of formula I: (I) or a salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for suppressing an immune response or treating cancer, including a hematologic malignancy, using compounds of formula I.

Description

HETEROCYCLIC COMPOUNDS AS JANUS
KINASE INHIBITORS
RELATED APPLICATIONS
This application claims benefit of priority from U.S. Provisional Patent Application No. 61/617,971, filed March 30, 2012; U.S. Provisional Patent Application No. 61/610,273, filed March 13, 2012; and U.S. Provisional Patent Application No. 61/528,547, filed August 29, 2011.
BACKGROUND OF THE INVENTION
Kinases have become one of the most intensively pursued classes of drug targets. Deregulation of kinase function has been implicated not only in cancer but also in disorders which include immunological, neurological, metabolic and infectious disease. Compounds having protein kinase, particularly Janus kinase (JAK) inhibitory activity may be beneficial in various diseases which include, autoimmune diseases, atopic diseases, cancer, and in prevention of transplant rejection. The mammalian JAK family has four members: Jakl, Jak2, Jak3, and tyrosine kinase (TYK2). Genetic knock out studies have shown that JAKs and STATs have highly specific function in the control of various immune responses.
Janus kinase 3 (Jak3) is a cytoplasmic protein tyrosine kinase associated with the common gamma chain (yc), which is an integral component of various cytokine receptors. Kudlacz, E. et al., Am. J. Transplant. (2004) 4:51-7. 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 JAK 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. JAK is a viable target for immunosuppression and transplant rejection. JAK inhibitors may also be useful for the treatment of cancer including hematologic and other malignancies that involve pathologic JAK activation.
Currently, there is a need for compounds, compositions and methods that are useful for treating diseases and conditions associated with pathologic JAK activation and for treating diseases and conditions that can be treated with JAK inhibitors. SUMMARY OF THE INVENTION
embodiment, the invention provides a compound represented by formula I
Figure imgf000004_0001
I
wherein:
A is a fused aryl or heteroaryl, wherein any aryl or heteroaryl of A is optionally substituted with one or more groups selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Cy)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, -
NRcRj, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd;
W is -N- or -CH2N-, Z is C, and the bond represented by— is a double bond; or W is -NRs-, -C(0)0- or -C(0)NRs-, Z is CRla, and the bond represented by— is a single bond; or W is -NReC(O)-, -C(O)-, -CH2- or -C(=NH)-, Z is CRla or N and the bond represented by— is a single bond;
X is N or CR3; Y is N or CR4 and V is N or CR5 provided that no more than two of
X, Y, or V is N;
Rla is H, or -C(0)ORf;
R1 is H, (Ci-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, -(Ci-Ce)alkylaryl, -(Ci-C6)alkylheteroaryl, (C3-Cy)cycloalkyl, heterocycle, aryl, heteroaryl, -C(0)(Ci-C6)alkyl, -C(0)0(Ci-C6)alkyl or -S(0)2(Ci-C6)alkyl wherein any aryl or heteroaryl of R1 is optionally substituted with one or more groups selected from the group consisting of Z1, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(Ci-C6)haloalkyl, -(Ci-C6)alkylNRiRj, -(Ci-C6)alkylORg, -(Ci-C6)alkylSRg, -(Ci-C6)alkylN
02, -(Ci-C6)alkylCN and -(Ci-C6)alkylOH, and wherein any
(C3-C7)cycloalkyl, -(Ci-C6)alkylaryl, -(Ci-C6)alkylheteroaryl or heterocycle of R1 is optionally substituted with one or more groups selected from the group consisting of Z1, oxo, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, -(Ci-C6)alkylNRiRj, -(Ci-C6)alkylORg, -(Ci-C6)alkylSRg, -(Ci-C6)alkylN 02, -(Ci-C6)alkylCN and -(Ci-C6)alkylOH, and wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -C(0)(Ci-C6)alkyl, -C(0)0(Ci-C6)alkyl or -S(0)2(Ci-C6)alkyl of R1 is optionally substituted with one or more Z1 groups;
R2 is H, halogen, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, aryl, heteroaryl, heterocycle, N02, CN, -OH, -ORk, -NRmRn, N3,
SH, -SRk, -C(0)Ro, -C(0)OR0, -C(0)NRmRn,
Figure imgf000005_0001
-NRoCORk, -NRoC(0)ORk, -NR0C(0)OH, -NRoS(0)2Rk, -NRoCONRmRn, -OC(0)NRmRn, -S(0)Rk, -S(0)NRmRn, -S( 0)2Rk, -S(0)2OH, or -S(0)2NRmRn, wherein any (C C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, aryl or heteroaryl of R2 is optionally substituted with one or more Z2 groups, and wherein any (C3-C8)cycloalkyl or heterocycle of R2 is optionally substituted with one or more groups selected from the group consisting of Z2, oxo and
Figure imgf000005_0002
R3 is H, OH, N02, C02H,
C02Rr, -C(0)NRpRq, -C(0)NHNRpRq, -C(0)NHNHC02Rr, -NHS(0)2Rr, -NHC02Rr, -NH CORs, -NRpRq or halogen;
R4 is H, OH, N02, C02H,
C02Rr, -C(0)NRpRq, -C(0)NHNRpRq, -C(0)NHNHC02Rr, -NHS(0)2Rr, -NHC02Rr, -NH CORs, -NRpRq or halogen;
R5 is H, halogen, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, heteroaryl, heterocycle, N02, CN, OH, -ORw, -NRURV,
N3, _SH, -SRW, -C(0)(Ci-C6)alkyl, -C(0)(C2-C6)alkenyl, -C(0)(C2-C6)alkynyl, -C(0)(C3-C6 )cycloalkyl, -C(0)aryl, -C(0)heteroaryl, -C(0)heterocycle, -C(0)ORw, -C(0)NRuRv, -C(=N RW)NRURV, -NRwCOR,, -NRwC(0)OR,, -NRwS(0)2R,, -NRwCONRuRv, -OC(0)NRuRv, -S( 0)R,, -S(0)NRuRv, -S(0)2R,, -S(0)2OH, -S(0)2NRuRv or -C(=0)C(=0)NH(Ci-C6)alkyl, wherein any aryl, -C(0)aryl, -C(0)heteroaryl, or heteroaryl of R5 is optionally substituted with one or more Z4 groups and wherein any (Ci-C6)alkyl, (C3-C6)cycloalkyl,
(C2-C6)alkenyl,
(C2-C6)alkynyl, -C(0)(Ci-C6)alkyl, -C(0)(C2-C6)alkenyl, -C(0)(C2-C6)alkynyl, -C(0)(C3-C 6)cycloalkyl, -C(0)heterocycle or heterocycle of R5 is optionally substituted with one or more groups selected from the group consisting of Z4, oxo and =NORw;
each Ra is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-Cv)cycloalkyl, heterocycle, heteroaryl or aryl; each Rb is independently (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-Cv)cycloalkyl, heterocycle, heteroaryl or aryl;
Rc and Rd are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, heterocycle, aryl and heteroaryl; or Rc and Rd together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino;
each Re is independently H, (Ci-C6)alkyl, -(Ci-Ce)alkylaryl or -C(0)ORsi;
each Rei is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, -(Ci-C6)alkylaryl, -(Ci-C6)alkylheteroaryl, (C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl;
each Rf is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, -(Ci-Ce)alkylaryl, -(Ci-C6)alkylheteroaryl, (C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl;
each Rg is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, -(Ci-Ce)alkylaryl, -(Ci-C6)alkylheteroaryl, (C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of Rg is optionally substituted with one or more groups selected from the group consisting of halogen, OH, CN and NRz5Rz6, and wherein any -(Ci-Ce)alkylaryl, -(Ci-C6)alkylheteroaryl, (C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl of Rg is optionally substituted with one or more groups selected from the group consisting of halogen, OH, CN, NRz5Rz6 and
(Ci-C6)alkyl;
each R is independently (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl;
Ri and Rj are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, heterocycle, aryl and heteroaryl; or Ri and Rj together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino;
Rk is (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, heterocycle, heteroaryl or aryl;
Rm and Rn are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, heterocycle and heteroaryl, wherein any (Ci-C6)alkyl of Rm or Rn is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of -C(0)OH and OH; or Rmand Rm together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino;
Ro is H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, heterocycle, heteroaryl or aryl;
Rp and Rq are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-C6)alkylaryl, heterocycle and heteroaryl, wherein any (Ci-C6)alkyl of Rp or Rq is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of -C(0)OH and OH; or Rp and Rq together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
each Rr is independently selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-Ce)alkylaryl, heterocycle and heteroaryl;
each Rs is independently selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-Ce)alkylaryl, heterocycle and heteroaryl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-C6)alkylaryl, heterocycle or heteroaryl of Rs is optionally substituted with one or more halogens;
each Rt is independently selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, -(C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-Ce)alkylaryl, heterocycle and heteroaryl;
Ru and Rv are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-C6)alkylaryl, heterocycle and heteroaryl, wherein any (Ci-C6)alkyl of Ru or Rv is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of -C(0)OH and OH; or Ru and Rv together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino ring;
each Rw is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-C6)alkylaryl, heterocycle and heteroaryl;
each Z1 is independently selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, (C3-Cy)cycloalkyl,
CN, -ORg, -OC(0)Rh, -OC(0)NRiRj, -SRg, -S(0)Rg, -S(0)2OH, -S(0)2Rh, -S(0)2ORh, -S(0 )2NRiRj, -NRiRj, -N(ORg)Rg, -NRgC(0)Rh, -NRgC(S)Rh, -NRgC02Rh, -NRgC(0)NRiRj, -NR gS(0)2NRiRj, -NRgC(S)NR1RJ, -NRgS(0)2Rh,
N02, -B(ORg)2, -CHO, -C(0)Rg, -C(S)Rg, -C(0)ORg, -C(0)NRiRj, -C(S)NRiRj, -C(=NRg)N
RiRj, -C(0)N(ORg)Rg, -C(=NORg)Rg, -NRgNRgC(0)Rh, -NRgNRgC (O)NRiRj , -NRgNRgCO
2Rh, -C(0)C(0)Rg and -C(0)CH2C(0)Rg, wherein any aryl, heteroaryl, heterocycle or
(C3-Cy)cycloalkyl of Z1 is optionally substituted with one or more groups selected from the group consisting of NH2, -NH(Ci-C4)alkyl, -N(Ci-C4)alkyl2, halogen,
(Ci-C4)alkyl, -0(Ci-C4)alkyl, N02, CN C02H, C(0)0(Ci-C4)alkyl, -0(Ci-C4)haloalkyl and
(Ci-C4)haloalkyl;
each Z2 is independently selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, Rz, OH, CN, -ORz, -Oaryl, -OC(0)Rz, -OC(0)NRziRz2,
SH, -SRZ, -Saryl, -Sheteroaryl, -S(0)Rz, -S(0)aryl, -S(0)heteroaryl, -S(0)2OH, -S(0)2Rz, - S(0)2aryl, _S(0)2heteroaryl, -S(0)2NRziRz2, -NRziRz2, -NHCORz, -NHCOaryl, -NHCOheter oaryl, -NHC02Rz, -NHCONRziRz2, -NHS(0)2Rz, -NHS(0)2aryl, -NHS(0)2NH2,
N02, -CHO, -C(0)Rz, -C(0)OH, -C(0)ORz, -C(0)NRziRz2 and -C(0)C(0)Rz, wherein any aryl, -Oaryl, -Saryl, -S(0)aryl, -S(0)2aryl, -NHCOaryl or -NHS(0)2aryl of Z2 is optionally substituted with one or more Z5 groups;
each Z4 is independently selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, Rz, OH, CN, -ORz, -Oaryl, -OC(0)Rz, -OC(0)NRziRz2,
SH, -SRZ, -Saryl, -Sheteroaryl, -S(0)Rz, -S(0)aryl, -S(0)heteroaryl, -S(0)2OH, -S(0)2Rz, - S(0)2aryl, _S(0)2heteroaryl, -S(0)2NRziRz2, -NRziRz2, -NHCORz, -NHCOaryl, -NHCOheter oaryl, -NHC02Rz, -NHCONRziRz2, -NHS(0)2Rz, -NHS(0)2aryl, -NHS(0)2NH2,
N02, -CHO, -C(0)Rz, -C(0)OH, -C(0)ORz, -C(0)NRziRz2 and -C(0)C(0)Rz, wherein any aryl, -Oaryl, -Saryl, -S(0)aryl, -S(0)2aryl, -NHCOaryl or -NHS(0)2aryl of Z4 is optionally substituted with one or more Z5 groups;
each Z5 is independently halogen, aryl, Rz, OH, CN,
ORz, -Oaryl, -Oheteroaryl, -OC(0)Rz, -OC(0)NRziRz2, SH,
SRZ, -Saryl, -Sheteroaryl, -S(0)Rz, -S(0)aryl, -S(0)heteroaryl, -S(0)2OH, -S(0)2Rz, -S(0)2 aryl, -S(0)2heteroaryl, -S(0)2NRziRz2, -NRziRz2, -NHCORz, -NHCOaryl, -NHCOheteroaryl , -NHC02Rz, -NHCONRziRz2, -NHS(0)2Rz, -NHS(0)2aryl, -NHS(0)2NH2, N02,
CHO, -C(0)Rz, -C(0)OH, -C(0)ORz, -C(0)NRziRz2, -C(0)C(0)Rz, heterocycle or heteroaryl; each Rz is independently (Ci-C6)alkyl or (C3-C6)cycloalkyl, wherein any
(Ci-C6)alkyl of Rz is optionally substituted with one or more Rz4 groups, and wherein any (C3-C6)cycloalkyl of Rz is optionally substituted with one or more groups selected from the group consisting of Rz4, (C1-C6)alkyl, -(C1-C6)alkylCN and -(Ci-C6)alkylOH;
Rzi and Rz2 are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-Ce)alkynyl, (C3-C6)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl or (C2-Ce)alkynyl of Rzi or Rz2 is optionally substituted with one or more Rz3 groups and wherein any aryl or heteroaryl of Rzi or Rz2 is optionally substituted with one or more (Ci-C6)alkyl or Rz3 groups, and wherein any heterocycle or (C3-C6)cycloalkyl of Rzi or Rz2 is optionally substituted with or more (Ci-C6)alkyl, oxo or Rz3 groups; or Rzi and Rz2 together with the nitrogen to which they are attached form a cyclic amino optionally substituted with one or more (Ci-C6)alkyl, oxo or Rz3 groups;
each Rz3 is independently selected from the group consisting of halogen, CN, CF3, NRz5Rz6, OH, -0(Ci-C6)alkyl, -C(0)NRz5Rz6, -C(0)(Ci-C6)alkyl, aryl, heterocycle and heteroaryl, wherein any heterocycle of Rz3 is substituted with one or more (Ci-C6)alkyl; each Rz4 is independently selected from the group consisting of halogen, CN, OH, -NRz5Rz6, -SCN, -0(Ci-C6)alkyl, -Sheteroaryl, -S(0)aryl, -S(0)2aryl, -Oaryl, -C(0)NR z5RZ6, (C3-C6)cycloalkyl, -CH2NHCOaryl, -CH2OCH2aryl, biphenyl, aryl, heterocycle and heteroaryl, wherein any aryl, heteroaryl,
Sheteroaryl, -S(0)aryl, -S(0)2aryl, -Oaryl, -CH2NHCOaryl, -CH2OCH2aryl, biphenyl or heterocycle of Rz4 may be optionally substituted with one or more halogen,
CN, -(Ci-C6)alkyl, -NH2, -NHheteroaryl, -NHS(0)2(Ci-C6)alkyl or -0(Ci-C6)alkyl; and RZ5 and Rz6 are each independently selected from the group consisting of H and (Ci-C6)alkyl, wherein (Ci-C6)alkyl is optionally substituted with NH2;
or a pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and 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 to a mammal in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to treat the disease or condition associated with pathologic JAK activation.
The invention also provides a method for treating a cancer (e.g., a hematologic malignancy or other malignancy) in a mammal (e.g., a human), comprising administering to a mammal in need thereof an effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof, to treat the cancer.
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 the prophylactic or therapeutic treatment of a cancer (e.g., 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).
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).
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 cancer (e.g., a hematologic malignancy or other malignancy) in 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 to a mammal in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to suppress the immune response.
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
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 1-55.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The term "alkyl" as used herein refers to alkyl groups having from 1 to 10 carbon atoms which are straight or branched groups. For example, the term "(Ci-C6)alkyl" as used herein refers to alkyl groups having from 1 to 6 carbon atoms which are straight or branched. The term "(Ci-Cg)alkyl" as used herein refers to alkyl groups having from 1 to 8 carbon atoms which are straight or branched.
The terms "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,
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, 2-methyl-2-propen-l-yl and
l-methyl-2-propen-l-yl and the like. For example, the term "(C2-C6)alkenyl" as used herein refers to alkenyl groups having from 2 to 6 carbon atoms which are straight or branched. The term "(C2-C8)alkenyl" as used herein refers to alkenyl groups having from 2 to 8 carbon atoms which are straight or branched.
The term "alkynyl" or "alkyne" as used herein refers to an alkynyl group having from 2-10 carbon atoms which are straight or branched groups and having at least one triple bond. Such groups are exemplified by, but not limited to ethyn-l-yl, propyn-l-yl, propyn-2-yl, l-methylprop-2-yn-l-yl, butyn-l-yl, butyn-2-yl, butyn-3-yl and the like. For example, the term "(C2-Ce)alkynyl" as used herein refers to alkynyl groups having from 2 to 6 carbon atoms which are straight or branched. The term "(C2-C8)alkynyl" as used herein refers to alkynyl groups having from 2 to 8 carbon atoms which are straight or branched.
The term "halogen" or "halo"as used herein refers to fluoro, chloro, bromo and iodo. The term "haloalkyl" as used herein referes to an alkyl as described above wherein one one or more of the hydrogens of the alkyl is replaced with a halogen. For example, the term "(Ci-C6)haloalkyl" as used herein 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 .
The term "cycloalkyl" as used herein 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, cyclooctadienyl, decahydronaphthalene and spiro[4.5]decane.
The term "aryl" as used herein 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 any non-aromatic portion (i.e., saturated or partially unsaturated) of the multiple condensed ring. It is to be understood that the point(s) of attachment of a bicyclic or multicyclic aryl can be at any position of the ring system including an aromatic or non-aromatic portion of the ring.
Exemplary aryls include, but are not limited to phenyl, indanyl, naphthyl,
1 ,2-dihydronaphthyl and 1 ,2,3,4-tetrahydronaphthyl.
The term "heteroaryl" as used herein 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. It is to be understood that the point(s) of attachment of a bicyclic or multicyclic heteroaryl can be at any position of the ring system including an aromatic or non-aromatic portion of the ring. Exemplary 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, benzoxazolyl, indazolyl, indolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinoline and the like.
The term "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. The term 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. It is to be understood that the point(s) of attachment of a bicyclic or multicyclic heterocycle can be at any position of the ring system including an aromatic or non-aromatic portion of the ring. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl and dihydrooxazolyl.
The term "cyclic amino" as used herein is a subgroup of heterocycles and refers to a 3-membered to 8-membered saturated or partially unsaturated, single ring which has at least one nitrogen atom, and may have one or more identical or different hetero atoms selected from the group consisting of nitrogen, oxygen, and sulfur wherein the nitrogen or sulfur atoms may be oxidized. Cyclic amino includes but is not limited to values such as aziridino, azetidino, pyrrolidino, piperidino, homopiperidino, morpholino, thiomorpholino, and piperazino.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I. Additionally, administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of 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. Pharmaceutically acceptable 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. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
Specific values listed below for 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 the other formulas depicted.
A specific compound of formula I is a compound of formula Ia3 :
Figure imgf000014_0001
or a pharmaceutically acceptable salt thereof.
Another specific compound of formula I is a compound of formula Ia4 - Ia9:
Figure imgf000015_0001
Figure imgf000015_0002
Ia7 Ia8 Ia9 wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa or -C(0)NRcRd;
or a pharmaceutically acceptable salt thereof.
Another specific compound of formula I is a compound of formula la 10 - Ial4:
Figure imgf000015_0003
IalO Ial l Ial2
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof.
Another specific compound of formula I is a compound of formula Ial5:
Figure imgf000016_0002
Ial 5
or a pharmaceutically acceptable salt thereof.
Another specific compound of formula I is a compound of formula Ia22 or Ia23:
Figure imgf000016_0003
or a pharmaceutically acceptable salt thereof.
Another specific compound of formula I is a compound of formula Ia24 - Ia29:
Figure imgf000017_0001
Figure imgf000017_0002
Ia27 Ia28 Ia29 wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa or -C(0)NRcRd;
or a pharmaceutically acceptable salt thereof.
A specific compound of formula I is a compound of formula Ia36 or Ia37:
Figure imgf000017_0003
la36 Ia37 or a pharmaceutically acceptable salt thereof.
Another specific compound of formula I is a compound of formula Ia38 - Ia43:
Figure imgf000018_0001
Figure imgf000018_0002
Ia41 Ia42 Ia43 wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd;
or a pharmaceutically acceptable salt thereof.
Another specific com ound of formula I is a compound of formula Ia50 or Ia51 :
Figure imgf000018_0003
or a pharmaceutically acceptable salt thereof. Another s ecific compound of formula I is a compound of formula Ia52 - Ia57:
Figure imgf000019_0001
Ia57 wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa or -C(0)NRcRd;
or a salt thereof.
Another spe ific compound of formula I is a compound of formula Ia64 or Ia65:
Figure imgf000019_0002
or a pharmaceutically acceptable salt thereof. Another specific compound of formula I is a compound of formula Ia66 - Ia71 :
Figure imgf000020_0001
Ia69 Ia70 Ia71 wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd;
or a pharmaceutically acceptable salt thereof.
Another spe ific compound of formula I is a compound of formula Ia78 or Ia79:
Ia78 Ia79 or a pharmaceutically acceptable salt thereof. Another specific compound of formula I is a compound of formula Ia80 - Ia85:
Figure imgf000021_0001
wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd;
or a pharmaceutically acceptable salt thereof.
Another specific com ound of formula I is a compound of formula Ia92 or Ia93:
Figure imgf000021_0002
Ia92 Ia93 or a pharmaceutically acceptable salt thereof.
Another specific compound of formula I is a compound of formula Ia94 - Ia99
Figure imgf000022_0001
wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd;
or a pharmaceutically acceptable salt thereof.
Another specific compound of formula I is a compound of formula la 106 or la 107:
Figure imgf000023_0001
Ial06 Ial07 or a pharmaceutically acceptable salt thereof.
Another specific compound of formula I is a compound of formula Ial08 - Ial 13:
Figure imgf000023_0002
wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd;
or a pharmaceutically acceptable salt thereof. Another specific compound of formula I is a compound of formula la 120 or Ial21 :
Figure imgf000024_0001
Ial20 Ial21 or a pharmaceutically acceptable salt thereof.
Another specific compound of formula I is a compound of formula la 122 - la 127:
Figure imgf000024_0002
lal24
Figure imgf000024_0003
wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd;
or a pharmaceutically acceptable salt thereof. Another spe ific compound of formula I is a compound of formula Ial34 or Ial35:
Figure imgf000025_0001
Ial34 iai35 or a pharmaceutically acceptable salt thereof.
Another s ecific compound of formula I is a compound of formula la 136 - la 141 :
Figure imgf000025_0002
Ial39 40 M41 wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd;
or a pharmaceutically acceptable salt thereof. Another specific compound of formula I is a compound of formula Ial48 or Ial49:
Figure imgf000026_0001
lal48 ial49 or a pharmaceutically acceptable salt thereof.
Another s ecific compound of formula I is a compound of formula Ial50 - Ial55:
Figure imgf000026_0002
Ial53 Ial54 wherein:
each Y1, Y2, Y3 and Y4 is independently N, CH or CZ7; and
each Z7 is independently halogen, aryl, heteroaryl, heterocycle, (Ci-Ce)alkyl,
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRj, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd;
or a pharmaceutically acceptable salt thereof. A specific value for X is CR3.
A specific value for Y is CR4.
A specific value for R3 is H.
A specific value for R4 is H.
A specific group of compounds of formula I are compounds wherein W and Y are each CH.
A specific group of compounds of formula I are compounds of formula Ia3 :
Figure imgf000027_0001
and pharmaceutically acceptable salts thereof.
A specific value for A is a fused aryl, wherein any aryl of A is optionally substituted with one or more groups selected from halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd.
Another specific value for A is fused phenyl, wherein phenyl is optionally substituted with one or more groups selected from halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd.
Another specific group of compounds of formula I are compounds of formula:
Figure imgf000027_0002
harmaceutically acceptable salts thereof. Another specific group of compounds of formula I are compounds of formula Ial3:
Figure imgf000028_0001
pharmaceutically acceptable salts thereof.
Another specific group of compounds of formula I are compounds of formula:
Figure imgf000028_0002
and pharmaceutically acceptable salts thereof.
Another specific group of compounds of formula I are compounds wherein W is -N-, Z is C, and the bond represented by— is a double bond; or W is -NRe-, Z is CRla, and the bond represented by— is a single bond; or W is -NReC(O)- or -C(O)-, Z is CRla or N and the bond represented by— is a single bond.
Another specific group of compounds of formula I are compounds wherein W is -N-, Z is C and the bond represented by— is a double bond; or W is -NRe-, Z is CRla and the bond represented by— is a single bond; or W is -NReC(0)-, Z is CRla and the bond represented by— is a single bond.
A specific value for Re is H.
A specific value for Rla is H or -C(0)0(Ci-C6)alkyl.
Another specific value for Rla is H.
A specific value for R2 is H or -NRmRn.
Another specific value for R2 is H or -NH2.
A specific value for V is N or CC(0)NRuRv.
Another specific value for V is N, CC(0)NH2 or CC(0)NHCH2C02H.
Another specific value for V is N. A specific value for R1 is (C3-Cy)cycloalkyl, heterocycle, aryl or heteroaryl, wherein any aryl or heteroaryl of R1 is optionally substituted with one or more groups selected from Z1, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(Ci-C6)haloalkyl, -(Ci-C6)alkylNRiRj, -(C C6)alkylORg, -(Ci-C6)alkylSRg, -(Ci-C6)alkylN 02, -(Ci-C6)alkylCN and -(Ci-C6)alkylOH, and wherein any (C3-Cy)cycloalkyl or heterocycle of R1 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups selected from Z1, oxo, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(Ci-C6)haloalkyl, -(Ci-C6)alkylNRiRj, -(Ci-C6)alkylORg, -(Ci-C6)alkylSRg, -(Ci-C6)alkylN 02, -(C C6)alkylCN and -(Ci-C6)alkylOH.
Another specific value for R1 is phenyl, wherein phenyl is optionally substituted with one or more groups selected from Z1, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, -(Ci-C6)alkylNRiRj, -(Ci-C6)alkylORg, -(Ci-C6)alkylSRg, -(Ci-C6)alkylN 02, -(C C6)alkylCN and -(Ci-C6)alkylOH.
Another specific value for R1 is phenyl, wherein phenyl is optionally substituted with one or more groups selected from halogen, CN, -ORg, -NRiRj, N02, -B(ORg)2, (Ci-C6)alkyl and (C2-C6)alkenyl.
Another specific value for R1 is phenyl, wherein phenyl is optionally substituted with one or more groups selected from halogen, -ORg and N02.
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
-30-
Figure imgf000033_0001
-31 -
Figure imgf000034_0001
-32-
Figure imgf000035_0001
-33 -
Figure imgf000036_0001
-34-
Figure imgf000037_0001
-35 -
Figure imgf000038_0001
-36-
Figure imgf000039_0001
-37-
Figure imgf000040_0001
-38 -
Figure imgf000041_0001
-39-
Figure imgf000042_0001
Figure imgf000043_0001
-41 -
Figure imgf000044_0001
-42-
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
-45 -
Figure imgf000048_0001
-46-
Figure imgf000049_0001
Figure imgf000050_0001
-48 -
Figure imgf000051_0001
Figure imgf000052_0001
-50-
Figure imgf000053_0001
Figure imgf000054_0001
-52-
Figure imgf000055_0001
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof.
An aspect of the invention is a compound of formula I which is:
Figure imgf000056_0002
pharmaceutically acceptable salt thereof.
An aspect of the invention is a compound of formula I which is:
Figure imgf000057_0001
armaceutically acceptable salt thereof.
An aspect of the invention is a compound of formula I which
Figure imgf000057_0002
armaceutically acceptable salt thereof.
An aspect of the invention is a compound of formula I which
Figure imgf000058_0001
-56-
Figure imgf000059_0001
, or a pharmaceutically acceptable salt thereof. An aspect of the invention is
Figure imgf000059_0002
Figure imgf000059_0003
, or a pharmaceutically acceptable salt thereof.
An aspect of the invention is a compound of formula I which is:
Figure imgf000060_0001
pharmaceutically acceptable salt thereof.
An aspect of the invention is a compound of formula I which is:
Figure imgf000060_0002
pharmaceutically acceptable salt thereof.
An aspect of the invention is a compound of formula I which is:
Figure imgf000061_0001
-59-
Figure imgf000062_0001
An aspect of the invention is a compound selected from the group consisting of: 4-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol,
4-(4,9, 11 , 11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol,
3- Chloro-4-(3 ,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
4- (4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-3-chlorophenol,
4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol,
4-(l O-Amino-4,9, 11,11 a-tetraazadibenzo[cd,fJazulen-3-yl)-3-fluorophenol,
Methyl 3-(4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulene-3- carboxylate,
3-(4-Hydroxyphenyl)-3H-5,10,12,12a-tetraazabenzo[4,5]cycloocta[l,2,3-cd]inden-4(5H)-o ne,
3-(3-Nitrophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
and pharmaceutically acceptable salts thereof.
An aspect of the invention is a compound selected from the group consisting of:
3- (4-Nitrophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
2-(4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)benzene-l ,4-diol,
4- (3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
1 l-Amino-3-(2-fluoro-4-hydroxyphenyl)-3H-4,10,12,12a-tetraazabenzo[4,5]
cycloocta[l,2,3-cd]inden-5(4H)-one,
2-(3,4-Dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-5-methoxyphenol,
4-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)benzene- 1 ,2-diol,
2-Chloro-3-(3 ,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-6-methoxyphenol, 2-Bromo-4-(3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
2-Chloro-4-(3 ,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol, and pharmaceutically acceptable salts thereof.
An aspect of the invention is a compound selected from the group consisting of: 2-Chloro-4-(3 ,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-6-methoxyphenol,
2- (4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-5-methoxyphenol,
2,6-Dichloro-4-(3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol, 4-(3,4-Dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol,
4-(3,4-Dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-2-methylphenol,
4-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-fluorophenol,
4-(3,4-Dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-2-methoxyphenol,
4-(4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-N,N-dimethylaniline,
3- Phenyl-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulene,
and pharmaceutically acceptable salts thereof.
An aspect of the invention is a compound selected from the group consisting of: 3-(2,4-Dichlorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(4-Chlorophenyl)-3 ,4-dihydro-4,9, 11 , 11 a-tetraazadibenzo [cd,f]azulene,
3-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo [cd,f]azulen-3-yl)benzonitrile,
3-(3,5-Dichlorophenyl)-3,4-dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulene,
3-(4-Ethylphenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo [cd,f]azulene,
3-(4-(Methylthio)phenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(4-(Tert-butyl)phenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo [cd,f]azulene,
3-(4-Propoxyphenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(3-Fluoro-4-methoxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,fJ azulene, and pharmaceutically acceptable salts thereof.
An aspect of the invention is a compound selected from the group consisting of: 3-(2,3,6-Trifluorophenyl)-3,4-dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulene,
3-(4-Chloro-3-fluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo [cd,f] azulene,
3- (2,4,5-Trifluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
4- (3,4-Dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-2-methoxyphenol,
4-(4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-methylphenol,
4-(4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol,
4-(4,9, 11 , 11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-bromophenol,
Methyl (3-(4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-10- yl)carbamate, Methyl (3-(3,4-dihydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f] azulen-10- yl)carbamate,
and pharmaceutically acceptable salts thereof.
An aspect of the invention is a compound selected from the group consisting of: Methyl (3-(4-hydroxy-2-methylphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo
[cd,f]azulen- 10-yl)carbamate,
Methyl (3-(4-hydroxy-3-methylphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo [cd,f] azulen- 10-yl)carbamate,
Methyl (3-(4-hydroxy-3-methoxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo [cd,f] azulen- 10-yl)carbamate,
Methyl (3-(3,4-dihydroxy-5-methoxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f] azulen- 10-yl)carbamate,
Methyl (3-(3-chloro-4-hydroxy-5-methoxyphenyl)-3,4-dihydro-4, 9,11,1 la-tetraazadibenzo [cd,f]azulen- 10-yl)carbamate,
Methyl (3-(2,5-dihydroxyphenyl)-4,9,l 1,1 la-tetraazadibenzo[cd,fjazulen-10-yl)carbamate, Methyl (3-(3-bromo-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo
[cd,f]azulen- 10-yl)carbamate,
Methyl (3-(2-chloro-3-hydroxy-4-methoxyphenyl)-3,4-dihydro-4, 9,11,1 la-tetraazadibenzo [cd,f]azulen- 10-yl)carbamate,
Methyl (3-(3-chloro-4-hydroxyphenyl)-3,4-dihydro-4, 9,11,1 la-tetraazadibenzo
[cd,f]azulen- 10-yl)carbamate,
and pharmaceutically acceptable salts thereof.
An aspect of the invention is a compound selected from the group consisting of: 4-(4,9, 11 , 11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-fluorophenol,
4-(l O-Amino-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-bromophenol,
4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro-6- methoxyphenol,
3- (l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro-6- methoxyphenol,
4- Bromo-5-(3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-methoxyphenol,
2- (l O-Amino-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)benzene- 1 ,4-diol,
3- (4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro-6-methoxyphenol,
4- (4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro-6-methoxyphenol, 4-(4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-chlorophenol,
and pharmaceutically acceptable salts thereof.
An aspect of the invention is a compound selected from the group consisting of: 3-(2,3-Dihydrobenzofuran-5-yl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo [cd,f]azulene, 3-(2,6-Difluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(4-Isopropoxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulene,
3- (2,4-Difluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
4- (10-Amino-3,4-dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)benzene-l,2-diol, 4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-methylphenol, 4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2,6-dichlorophenol,
3- (2,5-Difluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
4- (l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol, and pharmaceutically acceptable salts thereof.
An aspect of the invention is a compound selected from the group consisting of: 4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-chlorophenol, 4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
4-(l O-Amino-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
3-(3-((2-Chlorobenzyl)oxy)phenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene, 3-(3-((2-Chlorobenzyl)oxy)phenyl)-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)aniline,
3- (4,9,l 1,1 la-Tetraazadibenzo[cd,f]azulen-3-yl)aniline,
4- (4,9,l 1,1 la-Tetraazadibenzo[cd,f]azulen-3-yl)phenol,
5- (4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-4-bromo-2-methoxyphenol,
Methyl (3 -(2-hydroxy-4-methoxyphenyl)-3,4-dihydro-4, 9,11,1 la- tetraazadibenzo [cd,f] azulen- 10-yl)carbamate,
Methyl (3-(3,5-dichloro-4-hydroxyphenyl)-4, 9,11,1 la-tetraazadibenzo [cd,f]azulen-10- yl)carbamate,
and pharmaceutically acceptable salts thereof.
An aspect of the invention is a compound selected from the group consisting of: 4-(9-Amino-3,4-dihydro-5-thia-4,8,10,10a-tetraazabenzo[cd]cyclopenta[fJazulen-3-yl)-3- fluorophenol,
4-(9-Amino-5-thia-4,8, 10, 10a-tetraazabenzo[cd]cyclopenta[fJazulen-3-yl)-3-fluorophenol, Methyl (3-(2-fluoro-4-hydroxyphenyl)-3,4-dihydro-5-oxa-4,8, 10, 10a- tetraazabenzo[cd]cyclo penta[f]azulen-9-yl)carbamate,
4-(9-Amino-3,4-dihydro-5-oxa-4,8,10,10a-tetraazabenzo[cd]cyclopenta[f]azulen-3-yl)-3- fluorophenol,
4-(9-Amino-3,4-dihydro-5-thia-4,8,10,10a-tetraazabenzo[cd]cyclopenta[f]azulen-3- yl)phenol,
4-(9-Amino-5-thia-4,8, 10, 10a-tetraazabenzo[cd]cyclopenta[fJazulen-3-yl)phenol, and pharmaceutically acceptable salts thereof.
General and specific processes which can be used to prepare compounds of formula I and intermediates useful for preparing compounds of formula I are shown in the Schemes below.
General methods of preparation of invention compounds:
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. In Comprehensive Heterocyclic Chemistry; Potts, K. T., Ed.;
Pergamon Press: Oxford, 1984. f. Eloy, F. A review of the chemistry of 1,2,4-oxadiazoles.
Fortschr.Chem. Forsch. 1965, 4, pp 807-876. g. Adv. Heterocycl. Chem. 1976. h.
Comprehensive Heterocyclic Chemistry; Potts, K. T., Ed.; Pergamon Press: Oxford, 1984. i. Chem. Rev. 1961 61, 87-127. j. 1,2,4-Triazoles; John Wiley & Sons: New York,1981; Vol 37). Some of the functional groups during the synthesis may need to be protected and subsequently deprotected. Examples of suitable protecting groups can be found in
"Protective Groups in Organic Synthesis" fourth edition edited by Greene and Wuts. Scheme 1
,
Figure imgf000067_0001
Lv = leaving group, P = protecting group
Sche
Figure imgf000068_0001
Scheme 3
Figure imgf000068_0002
3c 3d 3e
Scheme 4
Figure imgf000069_0001
la acylation
Figure imgf000069_0002
Lv = leaving group, P = protecting group
Scheme 5
Figure imgf000069_0003
Scheme 6
Scheme 7
Figure imgf000070_0002
la ac lation
Figure imgf000070_0003
Lv = leaving group
Scheme 8
Figure imgf000071_0001
8c 8d 8e
Figure imgf000071_0002
8g 8h 8i
Lv = leaving group
Scheme 9
Pd/Ligand B HUaCrhtWwaigM
Figure imgf000072_0001
9c Coupling
Lv = leaving group
Scheme 10
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000073_0003
Scheme 11
Figure imgf000074_0001
lib 2. DBU
Figure imgf000074_0002
Figure imgf000075_0001
-73 -
Figure imgf000076_0001
-74- Scheme 14
Figure imgf000077_0001
14e 14f
Scheme 15
Figure imgf000078_0001
Scheme 16
Figure imgf000079_0001
Reference: Tetrahedron, Vol-27, 1971, 245-253
Figure imgf000079_0002
Scheme 17
Figure imgf000080_0001
Figure imgf000080_0002
Scheme 18
Figure imgf000081_0001
Figure imgf000081_0002
Scheme 19
Figure imgf000082_0001
Figure imgf000083_0001
20a
Figure imgf000083_0002
20k Scheme 21
Figure imgf000084_0001
Figure imgf000085_0001
Scheme 23
Figure imgf000086_0001
chloranil
Figure imgf000086_0002
Scheme 25
Figure imgf000087_0001
25b 25c a
J. Med. Chem. 2002, 45, 3946-3952
Figure imgf000087_0002
Figure imgf000087_0003
Figure imgf000088_0001
Scheme 27
Figure imgf000089_0001
Figure imgf000089_0002
Figure imgf000089_0003
Figure imgf000089_0004
Scheme 29
Figure imgf000090_0001
22h 29ac Scheme 29 (continued)
Figure imgf000091_0001
22h 29am Scheme 29 (continued)
Figure imgf000092_0001
Scheme 29 (continued)
Figure imgf000093_0001
Scheme 29 (continued)
Figure imgf000094_0001
Scheme 29 (continued)
Figure imgf000095_0001
Scheme 29 continued)
Figure imgf000096_0001
Figure imgf000096_0002
Figure imgf000096_0003
Figure imgf000096_0004
Scheme 30
Figure imgf000097_0001
2. NaOMe MeOH
Figure imgf000097_0002
Figure imgf000098_0001
Scheme 33
Figure imgf000098_0002
Figure imgf000098_0003
Figure imgf000099_0001
-97- Scheme 34 (continued)
5
Figure imgf000100_0001
Scheme 34 (continued)
Figure imgf000101_0001
Scheme 35
Figure imgf000102_0001
17e AcOH
35b
Figure imgf000102_0002
17e AcOH 35c
Figure imgf000102_0003
17e AcOH 35d
Figure imgf000102_0004
Scheme 35 (continued)
5
Scheme 35 (continued)
Figure imgf000104_0001
Scheme 36
Figure imgf000105_0001
Figure imgf000105_0002
35g 36c
Figure imgf000105_0003
Figure imgf000106_0001
Figure imgf000106_0002
- 104- Scheme 38
Figure imgf000107_0001
Figure imgf000107_0002
Scheme 40
Figure imgf000108_0001
40g Scheme 41
Figure imgf000109_0001
41 g 41 h
Scheme 42
Figure imgf000110_0001
42g Scheme 43
Figure imgf000111_0001
Figure imgf000111_0002
Figure imgf000111_0003
Scheme 44
Figure imgf000112_0001
Scheme 45
Figure imgf000113_0001
- Ill -
Figure imgf000114_0001
Scheme 47
Figure imgf000115_0001
Scheme 48
Figure imgf000116_0001
Scheme 49
Figure imgf000117_0001
Scheme 50
Figure imgf000118_0001
Scheme 51
Figure imgf000119_0001
Scheme 52
Figure imgf000120_0001
Scheme 53
Figure imgf000121_0001
Scheme 54
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000123_0002
An aspect of the invention is a pharmaceutical composition, comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. The pharmaceutical composition can be prepared by combining a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. Pharmaceutical compositions of the invention can be prepared in any of various suitable formulations, such as are discussed below.
An aspect of the invention is a method of treating a disease or condition associated with Janus kinase (JAK) activation in a mammal. The method includes the step of administering to a mammal in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to treat the disease or condition associated with Janus kinase (JAK) activation. In one embodiment, the JAK activation is pathologic JAK activation. In one embodiment, the mammal is a human.
In one embodiment, the disease or condition associated with JAK activation is selected from the group consisting of cancer, leukemia, T-cell prolymphocytic leukemia, lymphoma, cutaneous T-cell lymphoma, lymphoproliferative disorders, multiple myeloma, myleoproliferative disorders, acute and chronic allograft transplant rejection, graft-versus- host disease (GvHD), Alzheimer's disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, autoimmune thyroid disorders, Type I diabetes mellitus and complications from diabetes, lupus erythematosus, multiple sclerosis, T-cell autoimmune disease, asthma, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), psoriasis, chronic obstructive pulmonary disease (COPD), allergy, other inflammatory diseases, and sepsis.
In one embodiment, the disease or condition associated with JAK activation is cancer.
In one embodiment, the cancer is a hematologic malignancy, e.g., leukemia, lymphoma.
In one embodiment, the disease or condition associated with JAK activation is an undesirable immune response. An undesirable immune response includes, without limitation, an autoimmune disease (e.g., rheumatoid arthritis, autoimmune thyroid disorders, Type I diabetes mellitus, lupus erythematosus, multiple sclerosis, and
inflammatory bowel disease), acute and chronic allograft transplant rejection, acute and chronic graft- versus-host disease (GvHD), acute and chronic inflammation, and sepsis.
In one embodiment, "JAK activation" refers to activation of any one or more of Jakl, Jak2, Jak3, and TYK2.
In one embodiment, "JAK activation" refers to activation of Jakl .
In one embodiment, "JAK activation" refers to activation of Jak2.
In one embodiment, "JAK activation" refers to activation of Jak3.
In one embodiment, "JAK activation" refers to activation of TYK2.
The term "treat" as used herein refers to preventing, reducing, halting, or resolving a disease or condition in a subject. In one embodiment, the term "treat" refers to reducing, halting, or resolving a disease or condition in a subject. In one embodiment, the term "treat" refers to reducing, halting, or resolving at least one objectively measurable manifestation of a disease or condition in a subject.
The term "effective amount" as used herein refers to an amount that is sufficient to bring about a desired biological result. In one embodiment, an "effective amount" is a therapeutically effective amount. A "therapeutically effective amount" as used herein refers to an amount that is sufficient to bring about a desired therapeutic result, e.g., to treat a disease or condition in a subject.
An aspect of the invention is a method for suppressing an immune response in a mammal. The method includes the step of administering to a mammal in need thereof an effective amount of a compound of the invention to suppress the immune response. An immune response is suppressed if it is reduced by an objectively measurable amount compared to a relevant control. In one embodiment the immune response is reduced by at least 5 percent. In various other embodiments, the immune response is reduced by at least 10, 20, 30, 30, 40, 50, 60, 70, 80, or 90 percent. In one embodiment, the immune response is reduced by at least 95 percent. In one embodiment, the immune response is reduced by essentially 100 percent.
In one embodiment, 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 or a base under conditions suitable to provide the salt.
In one embodiment, 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 composition.
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, i.e., orally or parenterally, by intravenous,
intramuscular, topical or subcutaneous routes.
Thus, 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. For oral therapeutic administration, 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. The percentage of the 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. The 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. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, 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. For instance, 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. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, 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. In all cases, 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 polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. 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. In the case of sterile powders for the preparation of sterile injectable solutions, 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.
For topical administration, 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 U.S. Pat. No. 4,608,392 to Jacquet et al, U.S. Pat. No. 4,992,478 to Geria, U.S. Pat. No. 4,559,157 to Smith et al, and U.S. Pat. No. 4,820,508 to Wortzman, all of which are incorporated by reference.
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 to Borch et al., incorporated herein by reference.
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.
In general, however, 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. In one embodiment, 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 and the treatment of cancer (e.g., a hematologic malignancy or other malignancy). Accordingly, in one embodiment 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 the invention, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the invention or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to a mammal to treat a cancer in the mammal. In one embodiment, the mammal is a human.
The invention also provides a kit comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the invention or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to a mammal to suppress an immune response in the mammal. In one embodiment, the mammal is a human.
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., Jakl, Jak2, Jak3 or TYK2) including the pathological activation of a kinase such as a Janus kinase (e.g., Jakl, Jak2, Jak3 or TYK2). Accordingly, in one embodiment the invention provides a compound of formula I for the treatment of a kinase (such as a Janus kinase (e.g., Jakl, Jak2, Jak3 or TYK2))- related disease, condition or disorder.
The ability of a compound of the invention to bind to Jak3 and other members of the JAK family (e.g., Jakl, Jak2 or TYK2) can be determined using pharmacological models which are well known to the art, or using Test A described below.
Test A.
Inhibition constants (IC50s) can be determined against Jak3 (JH1 domain-catalytic) kinase and other members of the JAK family. Assays can be performed as described in Fabian et al. (2005) Nat. Biotechnol. 23:329-336; Karaman et al. (2008) Nat. Biotechnol. 26: 127-132; C. Tanego et al (2009): "Comparison of Bio luminescent Kinase Assay Using Substrate Depletion and Product Formation", Assay and Drug Development Technologies, 7: 606-615; H. Li et al (2009): "Evaluation of an Antibody-Free ADP Detection Assay: ADP-Glo", Assay and Drug Development Technologies, 7: 598-605; and Promega (2009): "ADP-Glo™ Kinase Assay", Technical Manual, Revised 8/09.
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.
The ability of a compound ofthe 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.
EXAMPLES
The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.
Example 1
4-(3,4-Dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol (22j)
Figure imgf000130_0001
To a solution of 2-(pyrrolo[2,l-fJ[l,2,4]triazin-4-yl)aniline 22h (0.248 g, 1.18 mmol) in acetic acid (10 mL) was added 2-fluoro-4-hydroxybenzaldehyde 22i (Aldrich, 0.28 g, 1.3 mmol) and heated at reflux for 4 days. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel 4 g, eluting with chloroform and CMA-80 (0-100%)) to furnish 4-(3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol 22j (0.085 g, 21%) as an orange solid; 1H NMR (300 MHz, DMSO-d6) d 9.87 (bs, 1H, D20 exchangeable),
8.57 - 8.45 (m, 2H), 8.03 (d, J = 2.6 Hz, 1H), 7.29 (m, 1H), 7.05 (m, 1H), 6.99 - 6.89 (m, 1H), 6.65 - 6.50 (m, 4H), 6.39 (dd, J = 8.5, 2.3 Hz, 1H), 5.88 (d, J = 3.5 Hz, 1H); MS (ES+): 333.1 (M+l), (ES-) 663.5 (2M-1). Analysis: Calculated for C19H13FN4O: C, 68.67; H, 3.94; N, 16.86. Found: C, 68.72; H, 3.96; N, 16.98.
Preparation of 2-(pyrrolo[2,l-fJ[l,2,4]triazin-4-yl)aniline (22h).
Step 1:
To a stirred solution of tert-butyl hydrazinecarboxylate 22b (50 g, 412.37 mmol) and 2,5-dimethoxytetrahydrofuran 22a (54.5 g, 412.37 mmol) in dioxane (300 mL) was added aqueous hydrochloric acid (5 mL, 2N). The reaction was set up using a dean-stark apparatus and heated at 90 °C for 20 h. Reaction mixture was cooled to 20 °C, neutralized with saturated sodium bicarbonate (18 mL) and filtered to remove inorganics. The filtrate was concentrated in vacuum and triturated with ether. The solid obtained was collected by filtration to furnish on drying tert-butyl lH-pyrrol-l-ylcarbamate 22c (43 g, 57.2%) as a yellow brown solid. 1H NMR (300 MHz, CD3OD) δ 6.62 (t, J= 2.3, 2H), 6.02 (t, J= 2.3, 2H), 1.48 (s, 9H); MS (ES+): 181.1 (M _1). Analysis: Calculated for C9Hi4N202: C, 59.32; H, 7.74; N, 15.37. Found: C, 59.32; H, 7.65; N, 15.02.
Step 2:
To a stirred solution of tert-butyl lH-pyrrol-l-ylcarbamate 22c (40 g, 219.52 mmol), in acetonitrile (350 mL) was added chlorosulfonyl isocyanate (32.62 g, 230.50 mmol) slowly at 0 °C and continued stirring at 0 °C for 30 min. To the solution N, N-dimethyl formamide (40 mL) was added below 5 °C and continued stirring at 0 °C for 1 hr. The reaction mixture was poured into a mixture of crushed ice (1 L) and ethyl acetate (1 L). The layers were separated and the organic layer was washed with water (500 mL), brine (250 mL), dried and concentrated in vacuum to furnish crude (43 g) product. The crude was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexane
0-50%) to afford pure tert-butyl 2-cyano-lH-pyrrol-l-ylcarbamate 22d (30 g, 66 %>) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.80 (s, 1H, D20 exchangeable), 7.23 (dd, J= 1.7, 2.9, 1H), 6.94 (dd, J= 1.7, 4.3, 1H), 6.20 (dd, J= 2.9, 4.3, 1H), 1.45 (s, 9H). Analysis: Calculated for Ci0Hi3N3O2: C, 57.95; H, 6.32; N, 20.27. Found: C, 58.02; H, 6.45; N, 20.18. Step 3:
To a stirred solution of tert-butyl 2-cyano-lH-pyrrol-l-ylcarbamate 22d (5 g, 24.12 mmol) in ethyl alcohol (100 mL) was added concentrated aqueous ammonium hydroxide solution (50 mL) at 20 °C followed by hydrogen peroxide (7.4 mL, 72.38 mmol, 30 % in water) slowly at 20 °C and stirred at the same temperature for 16 h. Reaction mixture was concentrated in vacuum and diluted with ethyl acetate (150 mL), washed with water (2 x 50 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The combined ethyl acetate layers were washed with water (100 mL), brine (50 mL), dried, filtered, and concentrated in vacuum. The residue obtained was crystallized from diisopropyl ether and hexane to afford tert-butyl 2-carbamoyl-lH-pyrrol-l-ylcarbamate 22e (4.0 g, 73.6%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H, D20 exchangeable), 7.31 (d, J = 38.5, 1H), 6.84 (dd, J= 1.9, 2.8, 2H, lH is D20 exchangeable), 6.76 (dd, J = 1.9, 4.2, 1H), 5.97 (dd, J= 2.8, 4.2, 1H), 1.40 (s, 9H); Analysis: Calculated for Ci0Hi5N3O3: C, 53.32; H, 6.71 ; N, 18.65. Found: C, 53.40; H, 6.74; N, 18.55.
Step 4:
To a solution of tert-butyl 2-carbamoyl-lH-pyrrol-l-ylcarbamate 22e (2g, 8.87 mmol) in dichloromethane (15 mL) was added trifluoro acetic acid (15 mL) at 20 °C and stirred for 30 min. The reaction mixture was concentrated to dryness to remove excess trifluoroacetic acid and diluted with dichloromethane. Triethylorthoformate (30 mL) was added to the residue and was heated to 79 °C overnight. Reaction mixture was concentrated to dryness and triturated with hexanes, the solid obtained was collected by filtration dried in vacuum to give crude pyrrolo[l ,2-f][l ,2,4]triazin-4-ol 22f (1.1 g, 91%) as a dark brown solid. 1H NMR (300 MHz, DMSO-d6) δ 11.63 (s, 1H, D20 exchangeable), 7.83 (d, J= 4.0, 1H), 7.59 (dd, J= 1.7, 2.6, 1H), 6.89 (dd, J= 1.6, 4.3, 1H), 6.54 (dd, J = 2.7, 4.3, 1H); MS (ES+): 136.2 (M + l).
Step 5:
The stirred solution of pyrrolo[l ,2-f][l ,2,4]triazin-4-ol 22f (1 g, 7.40 mmol), benzyltriethylammonium chloride (3.29 g, 14.80 mmol), and N,N-dimethylaniline (1.35 g, 1 1.10 mmol) in acetonitrile (25 mL) was heated to 80 °C and at this temperature phosphorous oxy chloride (6.88 g, 44.40 mmol) was added and stirred at 80 °C for 16 h. The reaction was concentrated to remove acetonitrile and phosphorus oxy chloride. The reaction was quenched by adding ice water (20 mL) and extracted with ethyl acetate (2 x 100 mL). The ethyl acetate extracts were combined washed with hydrochloric acid (1 N, 30 mL), water (50 mL), saturated sodium bicarbonate (1 x 20 mL), water (50 mL), brine (20 mL) dried and concentrated. The crude residue was purified by flash chromatography (silica gel, eluting with ethyl acetate in hexanes (0 to 5 %)) to furnish pure
4-chloropyrrolo[l,2-fJ[l,2,4]triazine 22g (0.7 g, 61.6 %) as a colorless oil, which solidified on standing in refrigerator. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.27 (dd, J = 1.5, 2.5, 1H), 7.12 (qd, J= 2.0, 4.6, 2H). Step 6:
A solution of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (10m) (2.3 g, 9.8 mmol) and 4-chloropyrrolo[l,2-f][l,2,4]triazine (22g) (1.5 g, 9.8 mmol) in DMF (90 mL) was degassed with nitrogen for 15 min followed by addition of sodium carbonate (3.615 g, 34.2 mmol) in water (17 mL) under a continuous flow of nitrogen
palladium(II)bis(triphenyl phosphine) dichloride (0.69 g, 0.98 mmol) was added to the reaction mixture. The reaction mixture was stirred at 80 °C for 1 h and diluted with H20 (100 mL). The product was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with water (2 x 100 mL), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography ((silica gel 12 g, eluting with hexane: ethyl acetate (0 to 100%)) to furnish 2-(pyrrolo[l,2-f][l,2,4]triazin-4- yl)aniline (22h) (0.584 g, 28 % yield) as a yellow solid. ¾ NMR (300 MHz, DMSO- 6) δ 8.53 (s, 1H), 8.10 (dd, J = 2.2, 1.8 Hz, 1H), 7.81 (dd, J = 7.9, 1.5 Hz, 1H), 7.25 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.87 (dd, J = 8.3, 1.0 Hz, 1H), 6.69 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 6.62 (s, 2H, D20 exchangeable); MS (ES+) 233.1 (M+Na), (ES-) 208.9 (M-1). Analysis calculated for Ci2Hi0N4: C, 68.56; H, 4.79; N, 26.65. Found: C, 68.53; H, 4.83; N, 26.57.
Example 2
4-(4,9,ll,lla-Tetraazadibenzo[cd,f|azulen-3-yl)-3-fluorophenol (22k)
Figure imgf000134_0001
To a solution of 4-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,fJazulen-3-yl)-3- fiuorophenol (22j) (0.035 g, 0.1 mmol) in benzene (4 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.031 g, 0.12 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f] azulen-3-yl)-3-fiuorophenol (22k) (0.015 g,
22%) as a orange solid. H NMR (300 MHz, DMSO- 6) δ 10.27 (s, 1H, D20
exchangeable), 8.70 (dd, J = 8.1, 1.5 Hz, 1H), 8.33 (s, 1H), 8.08 (d, J = 2.9 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.60 (m, 1H), 7.55 - 7.47 (m, 1H), 7.42 (t, J = 8.5 Hz, 1H), 6.79 - 6.62 (m, 3H). 19F NMR (300 MHz, DMSO) δ -111.56 (s); MS (ES+) 331.0 (M+l), (ES-) 328.8 (M-l), 659.4 (2M-1).
Example 3
3-Chloro-4-(3,4-dihydro-4,9,ll, ,f|azulen-3-yl)phenol (23b)
Figure imgf000134_0002
23b
To a solution of 2-(pyrrolo[2,l-fJ[l,2,4]triazin-4-yl)aniline 22h (0.204 g, 1.0 mmol) in acetic acid (10 mL) was added 2-chloro-4-hydroxybenzaldehyde 23a (Aldrich, 0.188 g, 1.2 mmol) and heated at reflux for 4 days. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography
(silica gel 4 g, eluting with Chloroform and CMA-80 (0-100%)) to furnish 3-chloro-4-(3,4- dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)phenol 23b (0.055 g, 16%>) as a yellow solid. ¾ NMR (300 MHz, DMSO- 6) δ 9.88 (s, 1H, D20 exchangeable), 8.58 - 8.45 (m, 2H), 8.02 (d, J = 2.6 Hz, 1H), 7.36 - 7.25 (m, 1H), 7.08 (m, 1H), 6.98 (m, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.73 (m, 1H), 6.56 (m, 1H), 6.51 (d, J = 2.6 Hz, 1H), 6.47 (d, J
5.94 (d, J = 3.2 Hz, 1H); MS (ES-) 695.3 (2M-1).
Example 4
4-(4,9,l 1 ,1 la-Tetraazadibenzo [cd,f| azulen-3-yl)-3-chlorophenol (23c)
Figure imgf000135_0001
23c
To a solution of furnish 3-chloro-4-(3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)phenol 23b (0.037 g, 0.1 mmol) in benzene (4 mL) was added 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (0.031 g, 0.12 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-3-chlorophenol (23c)
(0.015 g, 22%) as a yellow solid. 1H NMR (300 MHz, DMSO- 6) δ 10.18 (s, 1H, D20 exchangeable), 8.71 (dd, J = 8.1, 1.6 Hz, 1H), 8.35 (s, 1H), 8.05 (d, J = 2.9 Hz, 1H), 7.78 - 7.67 (m, 1H), 7.65 - 7.48 (m, 2H), 7.35 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.4, 2.3 Hz, 1H), 6.46 (d, J = 2.9 Hz, 1H); MS (ES+) 346.91 (M+l), (ES-) 344.49 (M-l).
Example 5
4-(10-Amino-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol (24b) and 4-(10-amino-4,9,ll,lla-tetraazadibenzo[cd,f|azulen-3-yl)-3-fluorophenol (24c)
Figure imgf000135_0002
24b 24c
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate (17e) (0.5 g, 1.765 mmol) in acetic acid (10 mL) was added 2-fiuoro-4- hydroxybenzaldehyde 22i (0.371 g, 2.65 mmol) and heated at reflux for 16 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, 4 g, eluting with 0 to 100% chloroform in methanol) to furnish methyl (3-(2-fluoro-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate (24a) (0.077 g, 11%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 2H), 8.75 (dd, J = 8.1, 1.6 Hz, 1H), 7.95 (d, J = 2.9 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.63 (m, 1H), 7.52 (m, 1H), 7.41 (t, J = 8.6 Hz, 1H), 6.71 (ddd, J = 14.3, 10.3, 2.2 Hz, 2H), 6.58 (t, J = 2.8 Hz, 1H), 3.70 (s, 3H); MS (ES+) 403.96 (M+l), (ES-) 402.11 (M-l).
To the residue of methyl (3-(2-fluoro-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate (24a) was added methanol (3 mL) and 1 N NaOH (3.1 mL, 3.1 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 12 g, eluting with 0-100% CMA-80 in chloroform) to furnish: 4-(10-amino-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-3- fluorophenol (24c) (0.023g, 11%) as an orange solid; 1H NMR (300 MHz, DMSO- 6) δ 10.22 (s, 1H), 8.73 (dd, J = 8.1, 1.5 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.60 (dd, J = 8.1, 1.4 Hz, 1H), 7.53 - 7.46 (m, 1H), 7.38 (t, J = 8.6 Hz, 1H), 6.73 (dd, J = 8.3, 2.3 Hz, 1H), 6.70 - 6.65 (m, 1H), 6.50 (s, 2H), 6.37 (t, J = 2.7 Hz, 1H); 19F NMR (282 MHz, DMSO) δ -112.33; MS (ES+) 346.08 (M+l), 344.01 (M-l) and 4-(10-amino-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol (24b) (0.017 g, 7 %>) as an orange solid; 1H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.45 (dd, J = 8.1, 1.6 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.31 - 7.20 (m, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.65 (t, J = 8.8 Hz, 1H), 6.54 (dd, J = 12.2, 2.3 Hz, 1H), 6.40 (dd, J = 8.5, 2.3 Hz, 1H), 6.36 (d, J = 3.4 Hz, 1H), 6.16 (d, J = 2.3 Hz, 1H), 6.12 (s, 2H), 5.75 (d, J = 3.3 Hz, 1H); 19F NMR (300 MHz, DMSO) δ -116.71; MS (ES+) 348.06 (M+l); (ES-) 346.00 (M-l), 692.56 (2M-1).
Preparation of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate (17e).
Step 1:
To a solution of ethyl pyrrole-2-carboxylate 10b (5 g, 98%, 35.21 mmol) in DMF (300 mL) cooled to -10 °C was added dropwise LiHMDS (1 M in THF, 42.3 mL) and stirred at -10 °C for 15 min. To the cold reaction mixture was added O- (diphenylphosphoryl)hydroxylamine 10c (15 g, 64.32 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (800 mL) washed with water (2 x 400 mL), brine (200 mL), dried over MgS04 and filtered. The filtrate was concentrated in vacuo and the residue obtained was purified by column chromatography (silica gel 200 g, eluting with hexanes/ethyl acetate, 1 :0 to 4: 1 , product Rf = 0.46 in hexanes/ethyl acetate = 4: 1 ) to furnish ethyl l-amino-lH-pyrrole-2-carboxylate (lOd), (3.868 g, 71%) as a light yellow oil. 1H NMR (300 MHz, DMSC ¾): δ 7.01 (t, J= 2.3 Hz, 1H), 6.70 (dd, J= 2.0, 4.3 Hz, 1H), 6.26 (s, 2H), 5.97 (dd, J= 2.6, 4.3 Hz, 1H), 4.22 (q, J= 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).
Step 2:
To a solution of methyl 1 -amino- lH-pyrrole-2-carboxylate (lOd) (0.29 g, 2.1 mmol) in methanol/ AcOH (5 mL/0.6 mL) was added S-methyl bis(methoxycarbonyl)thiourea
(17a) (0.47 g, 2.28 mmol) and stirred at room temperature for 16 h. The reaction mixture was diluted with ether (5 mL) and hexane (15 mL). The solid obtained was collected by filtration, washed with hexane and dried under vacuum to furnish methyl l-(2,3- bis(methoxycarbonyl)guanidino)-lH-pyrrole-2-carboxylate (17b) (0.5 g, 81%) as a white solid; mp 160.3 °C. 1H NMR (300 MHz, OMSO-d6) δ 11.17-10.23 (m, 1H), 10.16-9.48 (m, 1H), 7.10-6.86 (m, 1H), 6.79 (s, 1H), 6.11 (s, 1H), 3.70 (s, 3H), 3.66 (s, 3H), 3.49 (s, 3H). MS ES(+) 299.1 (M+l); ES(-) 296.9 (M-l). Analysis: Calcd for CnHi4N406: C, 44.30; H, 4.73; N, 18.79. Found: C, 44.21; H, 4.76; N, 18.72.
Step 3:
To a solution of methyl l-(2,3-bis(methoxycarbonyl)guanidino)-lH-pyrrole-2- carboxylate (17b) (0.145 g, 0.5 mmol) in methanol (5 mL) was added NaOMe (25% wt, 1.08 mL, 5 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum and the residue obtained was triturated with water. The solid obtained was collected by filtration and dried under vacuum to furnish methyl
4-hydroxypyrrolo[l,2-/][l,2,4]triazin-2-ylcarbamate (17c) (0.087 g, 84%>) as an off-white solid; mp 232.4 °C. 1H NMR (300 MHz, DMSO-<¾) δ 11.00 (s, 2H), 7.50 (dd, J = 1.7, 2.6 Hz, 1H), 6.89 (dd, J= 1.7, 4.4 Hz, 1H), 6.50 (dd, J= 2.6, 4.4 Hz, 1H), 3.72 (s, 3H).
Analysis: Calculated for C8H8N403: C, 46.16; H, 3.87; N, 26.91. Found: C, 46.07; H, 3.85; N, 26.88. Step 4:
To a solution of methyl 4-hydroxypyrrolo[l,2: ][l,2,4]triazin-2-ylcarbamate (17c) (1.9 g, 9.12 mmol) in acetonitrile (75mL) was added benzyltriethylammonium chloride (4.15 g, 18.24 mmol) and N,N-diethylaniline (2.17 g, 14.6 mmol). The reaction mixture was heated to 80 °C, to the heat reaction mixture was added dropwise POCI3 (11.18 g, 72.96 mmol) and continued heating for 15 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The residue obtained was taken in ethyl acetate (400 mL), washed with aqueous NaHC03 (IN, 200 mL), water (200 mL), brine (100 mL), dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel, eluting with ethylacetate/hexanes) to afford methyl (4-chloropyrrolo[2,l-f][l,2,4]triazin-2-yl)carbamate (17d) (1.05 g, 50%) as a light yellow solid. 1H NMR (300 MHz, DMSC ¾) δ 10.55 (s, 1H), 8.10 (dd, J= 2.5, 1.5 Hz, 1H), 7.04 (dd, J= 4.7, 1.5 Hz, 1H), 6.98 (dd, J = 4.7, 2.5 Hz, 1H), 3.68 (s, 3H); MS (ES+) 227.1 (M+l).
Step 5:
A solution of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (10m) (0.329 g, 1.5 mmol) and methyl (4-chloropyrrolo[2,l-f][l,2,4]triazin-2-yl)carbamate (17d) (0.227 g, 1.0 mmol) in DMF (10 mL) was degassed with nitrogen for 15 min followed by addition of sodium carbonate (1.75 mL, 3.5 mmol) in water (1.6 mL) under a continuous flow of nitrogen palladium(II)bis(triphenyl phosphine) dichloride (0.070 g, 0.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at 80 °C for 2 h and diluted with H20 (25 mL). The product was extracted with ethyl acetate (3 x 25 mL). The organic layers were combined, washed with water (2 x 25 mL), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography ((silica gel 12 g, eluting with hexane: ethyl acetate (0 to 100%)) to furnish methyl 4-(2- aminophenyl)pyrrolo[l,2-f][l,2,4]triazin-2-ylcarbamate 17e (0.2 g, 71 % yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.47 (s, 1H), 7.95 - 7.89 (m, 2H), 7.30 - 7.20 (m, 1H), 7.14 (s, 2H), 7.07 (dd, J = 4.7, 1.4 Hz, 1H), 6.93 (dd, J = 4.6, 2.5 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.70 - 6.61 (m, 1H), 3.70 (s, 3H). Analysis: Calculated for Ci4Hi3N502: C, 59.36; H, 4.63; N, 24.72. Found: C, 59.08; H, 4.51; N, 24.34. Example 6
Methyl 3-(4-hydroxyphenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulene-3- carboxylate (25d)
Figure imgf000139_0001
To a solution of 2-(pyrrolo[2,l-fJ[l,2,4]triazin-4-yl)aniline 22h (0.275 g, 1.31 mmol) in acetic acid (5 mL) was added 2-(4-hydroxyphenyl)-2-oxoacetate 25c (0.035 g, 0.25 mmol) and heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 12 g, eluting with (9: 1) ethyl acetate / methanol in hexane (0-100%)) to furnish methyl 3-(4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulene-3-carboxylate 25d (0.124 g, 25%) as a yellow solid. 1H NMR (300 MHz, DMSO-de) δ 9.52 (s, 1H, D20 exchangeable), 8.54 (s, 1H), 8.48 - 8.34 (m, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.36 (m, 2H), 7.06 - 6.92 (m, 3H), 6.80 - 6.65 (m, 3H), 6.41 (d, J = 2.6 Hz, 1H), 3.62 (d, J = 8.9 Hz, 3H); MS (ES+) 395.1 (M+Na), (ES-) 743.4 (2M-1).
Preparation of methyl 4-hydroxyphenylglyoxylate 25c (Prepared according to the procedure reported in J. Med. Chem. 2002, 45, 3946-3952).
Step 1:
To a solution of (R)-2-amino-2-(4-hydroxyphenyl)acetic acid 25a
(D-4Hydroxyphenyl glycine, 10.0 g, 60.1 mmol) in methanol (200 mL) was added dropwise thionyl chloride (8 mL) and stirred at room temperature for 10 h. The reaction mixture was concentrated in vacuum and the residue was washed twice with ether to yield (Pv)-methyl 2-amino-2-(4-hydroxyphenyl)acetate (D-4-hydroxyphenylglycine methyl ester 25b (13.0 g, 60.0 mmol, 100%) as a white solid. 1H NMR (300 MHz, DMSO- 6) δ 3.68 (s, 3 H), 5.07 (s, 1 H), 6.85 (d, J= 8.5 Hz, 2 H), 7.29 (d, J= 8.6 Hz, 2 H), 9.03 (s, 3 H), 10.02 (s, 1 H).
Step 2:
(R)-methyl 2-amino-2-(4-hydroxyphenyl)acetate 25b (©-4-hydroxyphenylglycine methyl ester, 0.302 g, 1.39 mmol) was dissolved in a freshly prepared aqueous solution of glyoxylic acid (1.27 g, 13.8 mmol) and copper(II) sulfate pentahydrate (0.35 g, 1.40 mmol) in a buffer containing 2.5 M pyridine and 0.5 M acetic acid. The mixture was stirred for 10 h at room temperature and then extracted with three portions of methylene chloride (10 mL). The organic layers were combined, washed three times with 0.5 M HC1 (20 mL), dried, filtered and concentrated in vacuum to dryness. The residue was purified by flash column chromatography (silica gel, eluting with chloroform) to yield methyl
2- (4-hydroxyphenyl)-2-oxoacetate 25c (0.109 g, 6.06 mmol, 44%) as a clear oil. 1H NMR (300 MHz, CDCls) δ 3.99 (s, 3 H), 5.41 (br s, 1 H), 6.95 (d, J= 8.8 Hz, 2 H), 8.00 (d, J = 8.8 Hz, 2 H).
Example 7
3- (4-Hydroxyphenyl)-3H-5,10,12,12a-tetraazabenzo[4,5]cycloocta[l,2,3-cd]inden- 4(5H)-one (25f)
Figure imgf000140_0001
Method 1
A solution of methyl methyl 2-(4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-5-yl)- 2-(4-hydroxyphenyl)acetate 25e (0.068 g, 0.18 mmol) in aqueous HC1 (6N 2 mL) was heated at reflux for 48 h. The reaction mixture was concentrated in vacuo to furnish crude residue of 2-(4-(2-aminophenyl)pyrrolo[2, 1 -f][ 1 ,2,4]triazin-5-yl)-2-(4- hydroxyphenyl)acetic acid. The solid was taken as such for next step. MS (ES+) 361.0 (M+l); (ES-) 394.6 (M+Cl).
To a solution of 2-(4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-5-yl)-2-(4- hydroxyphenyl)acetic acid in DMF (2 mL) was added at room temperature triethylamine (0.075 mL, 0.54 mmol) followed by (2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate) (HATU, 0.102 g, 0.27 mmol). The reaction mixture was heated at 60 °C for 30 min, cooled to room temperature and concentrated in vacuum. The crude material was purified by flash column chromatography (silica gel 4g, eluting with 0-100% (9: 1) ethyl acetate/methanol in hexanes) to furnish 3-(4-hydroxyphenyl)-3H-5,10,12,12a- tetraazabenzo[4,5]cycloocta[l,2,3-cd]inden-4(5H)-one (25f). MS (ES+) 343.0 (M+l). Preparation of methyl 2-(4-(2-aminophenyl)pyrrolo[2,l-fJ[l,2,4]triazin-5-yl)-2-(4- hydroxyphenyl)acetate (25e).
To a solution of methyl 3-(4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulene-3-carboxylate 25d (100 mgs, 0.27 mmol) in methanol (20 mL) was added aqueous 6N 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. The residue obtained was purified by flash column chromatography (silica gel 12 g, eluting with CMA-80 in chloroform (0-100%)) to furnish methyl 2-(4-(2- aminophenyl)pyrrolo[2,l-fJ[l,2,4]triazin-5-yl)-2-(4-hydroxyphenyl)acetate 25e (0.081 g, 80 %) as a yellow solid. ¾ NMR (300 MHz, DMSO- 6) δ 9.35 (s, 1H, D20 exchangeable), 8.49 (s, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.28 - 7.15 (m, 1H), 6.96 (d, J = 6.3 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.80 - 6.74 (m, 3H), 6.63 (m, 3H), 5.25 (s, 2H, D20 exchangeable), 4.91 (s, 1H), 3.43 (s, 3H); MS (ES+) 375 (M+l), (ES-) 408.9 (M+Cl).
Method 2
To a solution of 2-(4-(2-aminophenyl)pyrrolo[l,2-fJ[l,2,4]triazin-5-yl)-2-(4- hydroxyphenyl)acetic acid (25g) (0.056 g, 0.155 mmol) in DMF (5 mL) was added triethylamine (0.108 mL, 0.777 mmol), (2-(7-Aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate) (HATU) (0.089 g, 0.233 mmol) and heated at 70 °C for 5 h. The reaction was cooled to room temperature and concentrated in vacuum to dryness. The crude residue was purified twice by flash column chromatography (silica gel 4g, eluting 0-100% CMA80 in chloroform) to furnish 3-(4-hydroxyphenyl)-3H- 5,10,12,12a-tetraazabenzo[4,5]cycloocta[l,2,3-cd]inden-4(5H)-one (25f) (0.003 g, 6 % yield) as an orange solid. 1H NMR (300 MHz, Methanol-^) δ 8.41 (s, 1H), 8.00 - 7.92 (m, 1H), 7.89 (d, J= 2.7 Hz, 1H), 7.66 (ddd, J= 12.4, 7.5, 1.7 Hz, 2H), 7.44 (d, J= 8.7 Hz, 2H), 7.41 - 7.36 (m, 1H), 6.80 (d, J= 8.6 Hz, 2H), 6.70 (dd, J= 2.7, 0.9 Hz, 1H), 5.24 (s, 1H); MS (ES+) 343.05 (M+l), (ES-) 341.23 (M-l). Preparation of 2-(4-(2-aminophenyl)pyrrolo[l,2-f][l,2,4]triazin-5-yl)-2-(4- hydroxyphenyl)acetic acid (25g)
To a solution of methyl 2-(4-(2-aminophenyl)pyrrolo[l,2-fJ[l,2,4]triazin-5-yl)-2-(4- hydroxyphenyl)acetate (25e) (0.103 g, 0.275 mmol) in methanol (10 mL) was added 2 N aqueous sodium hydroxide (1.376 mL, 2.75 mmol) and heated at reflux for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to remove methanol. The reaction mixture was acidified with 1 N HC1 and extracted with ethyl acetate. The ethyl acetate layer was dried, filtered and concentrated in vacuum to furnish 2- (4-(2-aminophenyl)pyrrolo[l,2-f][l,2,4]triazin-5-yl)-2-(4-hydroxyphenyl)acetic acid (25g) (0.056 g, 0.155 mmol, 57 % yield) as a yellow solid, which was used as such in the next step; MS (ES+) 361.06 (M+l), (ES-) 359.10 (M-l).
Example 8
3-(3-Nitrophenyl)-3,4-dihydro-4, -tetr aazadibenzo [cd,f| azulene (29b)
Figure imgf000142_0001
To a solution of 2-(pyrrolo[2,l-fJ[l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 3-nitro benzaldehyde 29a (0.155 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(3-nitrophenyl)-3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f] azulene 29b (0.283 g, 87 %) as a yellow solid. 1H NMR (300 MHz, DMSO- e) δ 8.55 (s, 1H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 8.11 (s, 1H), 8.11 (s, 1H), 8.04 (dt, J= 7.6, 2.0 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.30 (ddd, J= 8.5, 7.0, 1.7 Hz, 1H), 7.19 (d, J= 4.4 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.97 - 6.90 (m, 1H), 6.82 (d, J= 2.6 Hz, 1H), 5.98 (d, J= 4.4 Hz, 1H); MS (ES+) 344.08 (M+l), 342.266 (M-l).
Example 9
3-(4-Nitrophenyl)-3,4-dihydro- -tetr aazadibenzo [cd,f| azulene (29d)
Figure imgf000142_0002
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.1 g, 0.48 mmol) in acetic acid (5 mL) was added 4-nitro benzaldehyde 29c (0.079 g, 0.52 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate in hexane (0-30%)) to furnish 3-(4-nitrophenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulene 29d (0.076 g, 47 %) as a yellow solid. 1H NMR (300 MHz, DMSO) 5 8.55 (s, 1H), 8.49 (dd, J= 8.1, 1.6 Hz, 1H), 8.13 - 8.07 (m, 3H), 7.39 (s, 1H), 7.37 (s, 1H), 7.29 (ddd, J= 8.5, 7.1, 1.7 Hz, 1H), 7.20 (d, J= 4.6 Hz, 1H), 7.01 (d, J= 7.4 Hz, 1H), 6.97 - 6.90 (m, 1H), 6.82 (d, J= 2.6 Hz, 1H), 5.96 (d, J= 4.5 Hz, 1H); MS (ES+) 344.1 (M+l), (ES-) 377.8 (M+Cl).
Example 10
2-(4,9,ll,lla-Tetraazadibenzo[cd f|azulen-3-yl)benzene-l,4-diol (29f)
Figure imgf000143_0001
29f
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.1 g, 0.48 mmol) in acetic acid (5 mL) was added 2,5-dihydroxy benzaldehyde 29e (0.072 g, 0.52 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate in hexane (0-30%)) to furnish 2-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3- yl)benzene-l,4-diol 29f (0.030 g, 19 %) as a dark brown solid;. 1H NMR (300 MHz,
DMSO) δ 9.49 (s, 1H), 8.95 (s, 1H), 8.70 (dd, J= 8.1, 1.4 Hz, 1H), 8.33 (s, 1H), 8.07 (d, J = 2.9 Hz, 1H), 7.75 - 7.67 (m, 1H), 7.58 (dd, J= 7.8, 0.9 Hz, 1H), 7.51 (t, J= 7.5 Hz, 1H), 6.84 - 6.68 (m, 4H); MS (ES+) 329.12 (M+l); (ES-) 362.90 (M+Cl), 691.5 (2M+C1).
Example 11
4-(3,4-Dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulen-3-yl)phenol (29h)
Figure imgf000144_0001
29h
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.1 g, 0.48 mmol) in acetic acid (5 mL) was added 4-hydroxy benzaldehyde 29g (0.072 g, 0.52 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate in hexane (0-40%)) to furnish 4-(3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)phenol 29h (0.103 g, 69 % yield) as yellow solid. 1H NMR (300 MHz, DMSO) δ 9.31 (s, 1H), 8.51 - 8.45 (m, 2H), 8.02 (d, J= 2.5 Hz, 1H), 7.28 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.05 (dd, J= 8.2, 0.9 Hz, 1H), 6.99 - 6.87 (m, 3H), 6.82 (d, J= 3.8 Hz, 1H), 6.66 - 6.58 (m, 3H), 5.64 (d, J= 3.6 Hz, 1H); MS (ES+) 315.1 (M+l), (ES-) 348.9 (M+Cl).
Example 12
ll-Amino-3-(2-fluoro-4-hydroxyphenyl)-3H-4,10,12,12a-tetraazabenzo[4,5] cycloocta[l,2,3-cd]inden-5(4 -one (30e)
Figure imgf000144_0002
To a solution of 2-(2-aminopyrrolo[2,l-f][l,2,4]triazin-4-yl)benzamide 30d (0.15 g, 0.59 mmol) in acetic acid (3.5 mL) was added 2-fluoro-4-hydroxybenzaldehyde 22i (0.083 g, 0.59 mmol) and heated at 80 °C for 5 h in a microwave. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, 4 g, eluting with 0 to 100% methanol in chloroform) to furnish 11 -amino-3-(2-f uoro-4-hydroxyphenyl)-3H-4, 10, 12, 12a-tetraazabenzo[4,5]
cycloocta[l,2,3-cd]inden-5(4H)-one (30e); MS (ES+) 377.10 (ES+), (ES-) 410.29 (M+Cl). Preparation of methyl (4-(2-cyanophenyl)pyrrolo[2,l-f][l,2,4]triazin-2-yl)carbamate (30b), 2-(2-aminopyrrolo[2,l-f][l,2,4]triazin-4-yl)benzonitrile (30c), and 2-(2- aminopyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-yl)benzamide (30d).
A solution of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (30a) (0.55 g, 2.4 mmol) and methyl (4-chloropyrrolo[2,l-f][l,2,4]triazin-2-yl)carbamate (17d) (0.45 g, 2.0 mmol) in DMF (10 mL) was degassed with nitrogen for 15 min followed by addition of sodium carbonate (3.5 mL, 3.5 mmol) in water (3.2 mL) under a continuous flow of nitrogen palladium(II)bis(triphenyl phosphine) dichloride (0.14 g, 0.2 mmol) was added to the reaction mixture. The reaction mixture was stirred at 80 °C for 2 h and diluted with H20 (25 mL). The product was extracted with ethyl acetate (3 x 25 mL). The organic layers were combined, washed with water (2 x 25 mL), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography ((silica gel 24 g, eluting with hexane: ethyl acetate (0 to 100%)) to furnish in the following order:
2-(2-Aminopyrrolo[2,l-f][l,2,4]triazin-4-yl)benzamide (30d) (0.16 g, 32%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.95 (bs, 1H), 7.72 - 7.65 (m, 1H),
7.63 - 7.54 (m, 4H), 7.31 (bs, 1H), 6.55 (m, 1H), 6.35 (dd, J = 4.5, 1.5 Hz, 1H), 6.17 (bs, 2H); MS (ES+) 254.1 (M+l), 529.0 (2M+Na), (ES-) 288 (M+Cl).
Methyl (4-(2-cyanophenyl)pyrrolo[2,l-f][l,2,4]triazin-2-yl)carbamate (30b) (0.11 g, 19%) as a yellow solid. 1H NMR (300 MHz, DMSO) δ 10.42 (bs, 1H, D20
exchangeable), 8.16 - 8.09 (m, 2H), 8.03 - 7.98 (m, 1H), 7.93 (m, 1H), 7.83 (m, 1H),
7.02 (m, 1H), 6.84 (dd, J = 4.7, 1.4 Hz, 1H), 3.69 (s, 3H); MS (ES+) 609.0
(2M+Na), (ES-) 292.0 (M-l).
2-(2-Aminopyrrolo[2,l-f][l,2,4]triazin-4-yl)benzonitrile (30c) (0.15 g, 32%) as a yellow solid. 'H NMR (300 MHz, DMSO) δ 8.11 - 8.05 (m, 1H), 7.98 - 7.86 (m, 2H), 7.80 (dd, J = 7.6, 1.6 Hz, 1H), 7.77 - 7.73 (m, 1H), 6.71 (dd, J = 4.6, 2.4 Hz, 1H), 6.57
(dd, J = 4.6, 1.4 Hz, 1H), 6.42 (s, 2H). MS (ES+) 258.0 (M+Na).
Example 13
2-(3,4-Dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulen-3-yl)-5-methoxyphenol (29k)
Figure imgf000145_0001
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.1 g, 0.48 mmol) in acetic acid (5 mL) was added 2-hydroxy-4-methoxy benzaldehyde 29i (0.079 g, 0.52 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate in hexane (0-30%)) to furnish 2-(3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)-5-methoxyphenol 29k (0.023 g, 14 %) as a yellow solid; MS (ES+) 345.2 (M+l).
Example 14
4-(3,4-Dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)benzene-l,2-diol (29m)
Figure imgf000146_0001
29m
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 3,4-dihydroxy benzaldehyde 291 (0.181 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)] to furnish 4-(3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)benzene-l,2-diol 29m (0.070 g, 18 %>) as a orange brown solid. 1H NMR (300 MHz, DMSO- 6) δ 8.67 (s, 1H), 8.51 - 8.46 (m, 2H), 8.02 (d, J= 2.5 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.04 (d, J= 7.4 Hz, 1H), 6.94 - 6.85 (m, 1H), 6.80 (d, J= 3.8 Hz, 1H), 6.61 (d, J= 2.5 Hz, 1H), 6.59 (d, J= 8.0 Hz, 1H), 6.51 - 6.43 (m, 2H), 5.56 (d, J = 3.7 Hz, 1H); 1H NMR (300 MHz, DMSO-d6/D20) δ 8.47 (s, 1H), 8.44 (dd, J= 8.4, 1.6 Hz, 1H), 8.03 (d, J= 2.5 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.02 - 6.94 (m, 2H), 6.73 (d, J= 2.5 Hz, 1H), 6.60 (d, J= 8.1 Hz, 1H), 6.49 - 6.40 (m, 2H), 5.62 (s, 1H); MS (ES+) 331.055 (M+l), 329.172 (M-l).
Example 15
2-Chloro-3-(3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-6- methoxyphenol (29o)
Figure imgf000147_0001
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 2-chloro-3-hydroxy-4-methoxy benzaldehyde 29n (0.2 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 2-chloro-3-(3,4- dihydro-4,9,l l,l la-tetraazadibenzo[cd,fJazulen-3-yl)-6-methoxyphenol 29o (0.125 g, 28 %) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.54 (s, 1H), 8.50 (dd, J= 8.1, 1.6 Hz, 1H), 8.03 (d, J= 2.6 Hz, 1H), 7.28 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.95 (ddd, J= 8.1, 7.1, 1.1 Hz, 1H), 6.71 (d, J= 8.7 Hz, 1H), 6.60 (d, J= 2.6 Hz, 1H), 6.49 (d, J= 3.8 Hz, 1H), 6.20 (d, J= 8.6 Hz, 1H), 5.99 (d, J= 3.8 Hz, 1H), 3.72 (s, 3H); MS(ES+) 379.012 (M+l), (ES-) 376.579 (M-l).
Example 16
2-br omo-4-(3,4-dihydro-4,9, 11,11 -tetraazadibenzo [cd,f| azulen-3-yl)phenol (29q)
Figure imgf000147_0002
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 3-bromo-4-hydroxy benzaldehyde 22p (0.263 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 2-bromo-4-(3,4- dihydro-4,9,11,1 la-tetraazadibenzo[cd,f]azulen-3-yl)phenol 22q (0.123 g, 26%>) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.51 (s, 1H), 8.48 (dd, J= 8.2, 1.6 Hz, 1H), 8.05 (d, J= 2.6 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.04 (d, J= 7.3 Hz, 1H), 6.96 - 6.75 (m, 4H), 6.68 (d, J= 2.5 Hz, 1H), 5.68 (d, J= 3.8 Hz, 1H); MS (ES+) 394.898 (M+l), 390.367, 392.297 (M-l). Example 17
2-chloro-4-(3,4-dihydro-4,9,ll,ll -tetraazadibenzo[cd,f|azulen-3-yl)phenol (29s)
Figure imgf000148_0001
29s
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 3-chloro-4-hydroxy benzaldehyde 29r (0.205 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 2-chloro-4-(3,4- dihydro-4,9,l l,l la-tetraazadibenzo[cd,fJazulen-3-yl)phenol 29s (0.093 g, 22 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.51 (s, 1H), 8.48 (dd, J = 8.1, 1.6 Hz, 1H), 8.05 (d, J= 2.5 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.16 (d, J= 1.6 Hz, 1H), 7.04 (d, J= 7.4 Hz, 1H), 6.96 - 6.87 (m, 2H), 6.85 - 6.76 (m, 2H), 6.68 (d, J= 2.5 Hz, 1H), 5.68 (d, J= 3.9 Hz, 1H); MS(ES+) 349.03 (M+l); (ES-) 346.624 (M-l). Example 18
2-Chloro-4-(3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-6- methoxyphenol (29u)
Figure imgf000148_0002
29u
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 3-chloro-4-hydroxy-5-methoxybenzaldehyde 29t (0.244 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 2-chloro-4-(3,4- dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-6-methoxyphenol 29u (0.125 g, 28 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.52 (s, 1H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 8.06 (d, J= 2.5 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.09 (d, J= 7.4 Hz, 1H), 6.96 - 6.87 (m, 3H), 6.71 (d, J= 2.6 Hz, 1H), 6.51 (d, J= 1.7 Hz, 1H), 5.67 (d, J= 3.8 1H), 3.68 (s, 3H); MS (ES+) 378.984 (M+l), 392.00 (M+Na), (ES-) 413.078 (M+Cl).
Example 19
2-(4,9,ll,lla-Tetraazadibenzo[cd,f|azulen-3-yl)-5-methoxyphenol (29w)
Figure imgf000149_0001
29w
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 2-hydroxy-4-methoxybenzaldehyde 29v (0.2 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 2-(4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)-5-methoxyphenol 29w (0.023 g, 6 %) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.67 (d, J= 7.8 Hz, 1H), 8.36 (s, 1H), 8.13 (d, J= 2.5 Hz, 1H), 7.69 (d, J= 6.8 Hz, 1H), 7.61 - 7.45 (m, 3H), 6.97 (s, 1H), 6.53 (s, 2H), 3.81 (s, 3H).; MS (ES+) 343.062 (M+l).
Example 20
2,6-Dichloro-4-(3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)phenol (29y)
Figure imgf000149_0002
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 3,5-dichloro-4-hydroxybenzaldehyde 29x (0.197 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 2,6-dichloro-4- (3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)phenol 29y (0.192 g, 53 %>) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.53 (s, 1H), 8.48 (dd, J = 8.2, 1.6 Hz, 1H), 8.07 (d, J= 2.6 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.08 - 7.03 (m, 3H), 6.98 6.91 (m, 2H), 6.75 (d, J= 2.6 Hz, 1H), 5.72 (d, J= 4.0 Hz, 1H); MS (ES+) 382.973, 384.006 (M+l), 382.4 (M-l).
Example 21
4-(3,4-dihydro-4,9, 11,11 a-tetraazadibenzo cd,f| azulen-3-yl)-3-methylphenol (29aa)
Figure imgf000150_0001
29aa
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-hydroxy-2-methylbenzaldehyde 29z (0.14 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 4-(3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol 29aa (0.185 g, 60 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.56 - 8.49 (m, 2H), 7.97 (d, J= 2.5 Hz, 1H), 7.35 - 7.24 (m, 1H), 7.15 (d, J= 7.4 Hz, 1H), 7.00 - 6.91 (m, 1H), 6.80 (d, J= 8.4 Hz, 1H), 6.64 (d, J= 2.4 Hz, 1H), 6.47 (dd, J= 8.4, 2.5 Hz, 1H), 6.33 (d, J= 1.9 Hz, 1H), 6.29 (d, J= 2.5 Hz, 1H), 5.73 (d, J= 1.7 Hz, 1H), 2.35 (s, 3H); MS (ES+) 329.117 (M+l), (ES-) 327.107 (M-l).
Example 22
4-(3,4-dihydro-4,9, 11,11 a-tetraazadibenzo [cd,f| azulen-3-yl)-2-methylphenol (29ac)
Figure imgf000150_0002
29ac
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-hydroxy-3-methylbenzaldehyde 29ab (0.14 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 4-(3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f azulen-3-yl)-2-methylphenol 29ac (0.234 g, 75 %) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.52 - 8.46 (m, 2H), 8.01 (d, J = 2.5 Hz, 1H), 7.28 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.07 (d, J= 7.3 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.74 (dd, J= 9.8, 2.8 Hz, 2H), 6.62 (d, J= 8.2 Hz, 1H), 6.54 (d, J= 2.5 Hz, 1H), 5.58 (d, J= 3.3 Hz, 1H), 2.02 (s, 3H).; MS (ES+) 329.1 (M+l), (ES-) 327.0 (M-l).
Example 23
4-(3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulen-3-yl)-2-fluorophenol (29ae)
Figure imgf000151_0001
29ae
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 3-fluoro-4-hydroxybenzaldehyde 29ad (0.144 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 4-(3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-fluorophenol 29ae (0.295 g, 94 %>) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.50 (s, 1H), 8.48 (dd, J= 8.2, 1.6 Hz, 1H), 8.05 (d, J= 2.5 Hz, 1H), 7.29 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.04 (d, J= 7.4 Hz, 1H), 6.93 (ddd, J= 8.9, 6.7, 1.6 Hz, 3H), 6.82 - 6.74 (m, 1H), 6.71 - 6.63 (m, 2H), 5.68 (d, J= 3.9 Hz, 1H); MS (ES+) 333.1 (M+l), (ES-) 331.0 (M-l).
Example 24
4-(3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulen-3-yl)-2-methoxyphenol (29ag)
Figure imgf000151_0002
29ag To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-hydroxy-3-methoxybenzaldehyde 29af (0.157 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 4-(3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-methoxyphenol 29ag (0.302 g, 92 %) as a yellow solid. 1H NMR (300 MHz, DMSO- 6) δ 8.89 (s, 1H), 8.51 - 8.45 (m, 2H), 8.02 (d, J= 2.5 Hz, 1H), 7.29 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.09 (d, J= 7.3 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.82 (d, J= 3.7 Hz, 1H), 6.63 (d, J= 2.5 Hz, 1H), 6.58 (d, J= 8.1 Hz, 1H), 6.36 (dd, J= 8.1, 1.9 Hz, 1H), 5.63 (d, J= 3.6 Hz, 1H), 3.65 (s, 3H); MS (ES+) 345.1 (M+l), (ES-) 342.9 (M-l).
Example 25
4-(4,9, 11 ,11 a-tetr aazadibenzo [cd,f] azulen-3-yl)-N,N-dimethylaniline (29ai)
Figure imgf000152_0001
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-(dimethylamino)benzaldehyde 29ah (0.154 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9 : 1 ) in hexane (0- 100%)) to furnish 4-(4,9, 11,11a- tetraazadibenzo[cd,f]azulen-3-yl)-N,N-dimethylaniline 29ai (0.101 g, 31 %>) as a red solid. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (dd, J= 8.1, 1.4 Hz, 1H), 8.31 (s, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.74 - 7.59 (m, 4H), 7.41 (ddd, J= 8.3, 6.7, 1.7 Hz, 1H), 7.02 (d, J= 2.9 Hz, 1H), 6.81 (d, J= 9.0 Hz, 2H), 3.02 (s, 6H); MS (ES+) 340.2 (M+l).
Example 26
3-phenyl-3,4-dihydro-4,9,l 1,11 a-tetraazadibenzo [cd,f| azulene (29ak)
Figure imgf000153_0001
29ak
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added (4-formylphenyl)boronic acid 29aj (0.154 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-phenyl-3,4-dihydro-
4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29ak (0.262 g, 93 %) as a yellow solid. 1H NMR (300 MHz, DMSO-de) δ 8.52 - 8.46 (m, 2H), 8.05 (d, J= 2.6 Hz, 1H), 7.31 - 7.13 (m, 6H), 7.05 (dd, J= 8.2, 1.0 Hz, 1H), 7.01 (d, J= 4.1 Hz, 1H), 6.90 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 6.67 (d, J= 2.5 Hz, 1H), 5.77 (d, J= 4.0 Hz, 1H); MS (ES+) 299.141 (M+l), (ES-) 297.102 (M-l).
Example 27
3-(2,4-dichlorophenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulene (29am)
Figure imgf000153_0002
29am
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 2,4-dichlorobenzaldehyde 29al (0.180 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(2,4-dichlorophenyl)-3,4- dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulene 29am (0.126 g, 36 %>) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.51 (dd, J= 8.1, 1.7 Hz, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.68 (d, J= 2.2 Hz, 1H), 7.32 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.23 (dd, J= 8.4, 2.2 Hz, 1H), 7.05 (d, J= 7.3 Hz, 1H), 7.02 - 6.96 (m, 1H), 6.87 (d, J= 8.4 Hz, 1H), 6.65 (d, J= 3.7 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 6.05 (d, J= 3.6 Hz, 1H); MS (ES+) 367.016 (M+l), (ES-) 364.531 (M-l).
Example 28
3-(4-chlorophenyl)-3,4-dihydro- -tetraazadibenzo [cd,f| azulene (29ao)
Figure imgf000154_0001
29ao
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-chlorobenzaldehyde 22an (0.144 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(4-chlorophenyl)-3,4- dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulene 29ao (0.128 g, 44 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.51 (dd, J= 8.1, 1.7 Hz, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.68 (d, J= 2.2 Hz, 1H), 7.32 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.23 (dd, J= 8.4, 2.2 Hz, 1H), 7.05 (d, J= 7.3 Hz, 1H), 7.02 - 6.96 (m, 1H), 6.87 (d, J= 8.4 Hz, 1H), 6.65 (d, J= 3.7 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 6.05 (d, J= 3.6 Hz, 1H); MS (ES+) 367.016 (M+l), (ES-) 364.531 (M-l).
Example 29
3-(3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulen-3-yl)benzonitrile (29aq)
Figure imgf000154_0002
29aq
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 3-formylbenzonitrile 29ap (0.135 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)benzonitrile 29aq (0.225 g, 73 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.49 (dd, J= 8.1, 1.7 Hz, 1H), 8.09 (d, J= 2.6 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.48 - 7.36 (m, 2H), 7.31 (ddd, J= 8.5, 7.0, 1.7 Hz, 1H), 7.07 (d, J= 4.4 Hz, 1H), 7.04 (dd, J = 8.2, 0.9 Hz, 1H), 6.94 (ddd, J= 8.1, 7.0, 1.1 Hz, 1H), 6.75 (d, J= 2.6 Hz, 1H), 5.88 (d, J= 4.2 Hz, 1H); MS (ES+) 324.031 (M+l), (ES-) 323.141 (M-
1).
Example 30
3-(3,5-dichlorophenyl)-3,4-dihyd -4,9,ll,lla-tetraazadibenzo[cd,f|azulene (29as)
Figure imgf000155_0001
29as
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 3,5-dichlorobenzaldehyde 22ar (0.180 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(3,5-dichlorophenyl)-3,4- dihydro-4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29as (0.223 g, 64 %>) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.49 (dd, J= 8.1, 1.7 Hz, 1H), 8.10 (d, J= 2.6 Hz, 1H), 7.44 (t, J= 1.9 Hz, 1H), 7.34 (ddd, J= 8.5,7.0, 1.7 Hz, 1H), 7.17 - 7.12 (m, 2H), 7.08 (d, J= 4.5 Hz, 1H), 7.05 (dd, J= 8.2, 0.9 Hz, 1H), 6.96 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 6.81 (d, J= 2.6 Hz, 1H), 5.85 (d, J= 4.3 Hz, 1H); MS (ES+) 368.965 (M+l), (ES-) 364.484 (M-l).
Example 31
3-(4-ethylphenyl)-3,4-dihydro-4 -tetr aazadibenzo [cd,f] azulene (29au)
Figure imgf000155_0002
29au To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-ethylbenzaldehyde 29at (0.144 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(4-ethylphenyl)-3,4-dihydro-
4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29au (0.193 g, 62 %) as a yellow solid. 1H NMR (300 MHz, DMSO-de) δ 8.49 (q, J= 2.0 Hz, 2H), 8.04 (d, J= 2.6 Hz, 1H), 7.28 (ddd, J = 8.4, 7.0, 1.7 Hz, 1H), 7.07 (s, 4H), 7.04 (s, 1H), 6.96 (d, J= 4.0 Hz, 1H), 6.90 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 6.64 (d, J= 2.5 Hz, 1H), 5.72 (d, J= 3.9 Hz, 1H), 2.57 - 2.51 (m, 2H), 1.10 (t, J= 7.6 Hz, 3H); MS (ES+) 349.1 (M+Na), (ES-) 325.5 (M-l).
Example 32
3-(4-(methylthio)phenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulene (29aw)
Figure imgf000156_0001
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-(methylthio)benzaldehyde 29av (0.157 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(4-(methylthio)phenyl)-3,4- dihydro-4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29aw (0.244 g, 75 %>) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.50 (d, J= 2.0 Hz, 1H), 8.48 (dd, J= 8.2, 1.7 Hz, 1H), 8.05 (d, J= 2.5 Hz, 1H), 7.28 (ddd, J= 8.5, 7.0, 1.7 Hz, 1H), 7.14 - 7.04 (m, 5H), 7.01 (dd, J= 6.3, 2.6 Hz, 1H), 6.91 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 6.70 (d, J= 2.6 Hz, 1H), 5.74 (d, J = 4.1 Hz, 1H), 2.39 (s, 3H); MS (ES+) 345.062 (M+l), (ES-) 342.742 (M-l).
Example 33
-(tert-butyl)phenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo [cd,f| azulene (29ay)
Figure imgf000157_0001
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-(tert-butyl)benzaldehyde 29ax (0.167 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(4-(tert-butyl)phenyl)-3,4- dihydro-4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29ay (0.189 g, 56 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.54 - 8.49 (m, 2H), 8.03 (d, J= 2.5 Hz, 1H), 7.33 - 7.25 (m, 3H), 7.09 (dd, J= 8.3, 2.0 Hz, 3H), 6.99 (d, J= 3.9 Hz, 1H), 6.94 - 6.87 (m, 1H), 6.62 (d, J= 2.5 Hz, 1H), 5.72 (d, J= 3.8 Hz, 1H), 1.21 (s, 9H); MS (ES+) 355.109 (M+l), (ES-) 352.867 (M-l).
Example 34
3-(4-propoxyphenyl)-3,4-dihydro-4,9, 11,11 a-tetr aazadibenzo [cd,f| azulene (29ba)
Figure imgf000157_0002
29ba
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-propoxybenzaldehyde 29az (0.169 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(4-propoxyphenyl)-3,4- dihydro-4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29ba (0.19 g, 56 %>) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.52 - 8.45 (m, 2H), 8.04 (d, J= 2.6 Hz, 1H), 7.28 (ddd, J = 8.4, 7.0, 1.7 Hz, 1H), 7.04 (d, J= 8.7 Hz, 3H), 6.90 (ddd, J = 8.0, 6.1, 1.1 Hz, 2H), 6.78 (d, J= 8.8 Hz, 2H), 6.64 (d, J= 2.6 Hz, 1H), 5.70 (d, J= 3.9 Hz, 1H), 3.83 (t, J= 6.5 Hz, 2H), 1.76 - 1.58 (m, 2H), 0.92 (t, J= 7.4 Hz, 3H); MS (ES+) 357.106 (M+l), (ES-) 354.961 (M-
1). Example 35
3-(3-fluoro-4-methoxyphenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f| azulene (29bc)
Figure imgf000158_0001
29bc
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 3-fluoro-4-methoxybenzaldehyde 29bb (0.159 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(3-fluoro-4- methoxyphenyl)-3,4-dihydro-4,9,l l,l la-tetraazadibenzo[cd,f azulene 29bc (0.231 g, 70 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 8.06 (d, J= 2.6 Hz, 1H), 7.30 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.05 (dt, J= 3.7, 2.2 Hz, 2H), 6.97 (dd, J= 6.5, 2.1 Hz, 2H), 6.92 (ddd, J= 8.1, 7.0, 1.2 Hz, 1H), 6.76 (d, J= 8.5 Hz, 1H), 6.72 (d, J= 2.6 Hz, 1H), 5.73 (d, J= 4.1 Hz, 1H), 3.74 (s, 3H); 19F NMR (300 MHz, DMSO-de) δ -135.42; MS (ES+) 347.069 (M+l), (ES-) 344.555 (M-l).
Example 36
3-(2,3,6-trifluorophenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulene (29be)
Figure imgf000158_0002
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 2,3,6-trifluorobenzaldehyde 22bd (0.165 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(2,3,6-trifluorophenyl)-3,4- dihydro-4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29be (0.111 g, 33 %>) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 - 8.56 (m, 2H), 8.02 (d, J= 2.6 Hz, 1H), 7.53 (ddd, J= 19.1, 9.3, 4.9 Hz, 1H), 7.35 (ddd, J = 8.5, 7.0, 1.7 Hz, 1H), 7.17 (tdd, J= 9.5, 3.8, 2.2 Hz, 1H), 7.12 - 7.08 (m, 1H), 7.02 (ddd, J= 8.1, 7.0, 1.1 Hz, 1H), 6.78 (d, J= 2.1 Hz, 1H), 6.59 (d, J= 2.6 Hz, 1H), 6.11 (s, 1H); 19F NMR (300 MHz, DMSO-d6) δ -116.55, -135.92, - 142.16; MS (ES+) 353.033 (M+l), (ES-) 350.742 (M-l).
Example 37
3-(4-chloro-3-fluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo [cd,f| azulene (29bg)
Figure imgf000159_0001
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 4-chloro-3-fluorobenzaldehyde 29bf (0.163 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(4-chloro-3-fluorophenyl)- 3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulene 29bg (0.22 g, 66 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.43 (t, J= 8.1 Hz, 1H), 7.31 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.21 (dd, J = 10.6, 1.9 Hz, 1H), 7.07 (d, J= 4.5 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.98 - 6.86 (m, 2H), 6.79 (d, J= 2.6 Hz, 1H), 5.83 (d, J= 4.3 Hz, 1H); 19F NMR (282 MHz, DMSO-d6) δ -116.38; MS (ES+) 351.014 (M+l), (ES-) 348.555 (M-l).
Example 38
3-(2,4,5-trifluorophenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulene (29bi)
Figure imgf000159_0002
29bi To a solution of 2-(pyrrolo[2,l-fJ[l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added 2,4,5-trifluorobenzaldehyde 29bh (0.163 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(2,4,5-trifluorophenyl)-3,4- dihydro-4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29bi (0.155 g, 46 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.52 (dd, J= 8.1, 1.7 Hz, 1H), 8.06 (d, J= 2.6 Hz, 1H), 7.61 (td, J= 10.4, 6.7 Hz, 1H), 7.33 (ddd, J= 8.3, 7.0, 1.7 Hz, 1H), 7.05 (dd, J = 8.2, 0.9 Hz, 1H), 7.00 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 6.89 (ddd, J= 11.1, 9.1, 6.8 Hz, 1H), 6.76 (d, J= 3.8 Hz, 1H), 6.67 (d, J= 2.6 Hz, 1H), 5.99 (d, J= 3.5 Hz, 1H); 19F NMR (300 MHz, DMSO-de) δ -117.50, -135.22, -135.35 (m), -143.02 (m); MS (ES+) 353.042 (M+1), (ES-) 351.312 (M-l).
Example 39
4-(3,4-dihydro-4,9, 11,11 a-tetraazadibenzo [cd,f| azulen-3-yl)-2-methoxyphenol (34a)
Figure imgf000160_0001
34a
To a solution of 4-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2- methoxyphenol 29ag (0.1 g, 0.3 mmol) in benzene (5 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.090 g, 0.36 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-methoxyphenol 34a
(0.086 g, 86 %) as a orange solid. 1H NMR (300 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.65 (dd, J= 8.1, 1.2 Hz, 1H), 8.32 (s, 1H), 8.11 (d, J= 2.9 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.45 (ddd, J= 8.3, 6.5, 2.1 Hz, 1H), 7.35 (d, J= 1.9 Hz, 1H), 7.25 (dd, J = 8.1, 2.0 Hz, 1H), 7.02 (d, J = 2.9 Hz, 1H), 6.89 (d, J= 8.2 Hz, 1H), 3.84 (s, 3H); MS (ES+) 343.07 (M+1), (ES-) 341.195 (M-l). Example 40
4-(4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-2-methylphenol (34b)
Figure imgf000161_0001
34b
To a solution of 4-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,fJazulen-3-yl)-2- methylphenol 29ac (0.169 g, 0.52 mmol) in benzene (5 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.14 g, 0.572 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2 -methylphenol 34b (115 mg, 68.07 %) as a orange solid. 1H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.64 (dd, J = 8.1, 1.4 Hz, 1H), 8.32 (s, 1H), 8.11 (d, J= 2.9 Hz, 1H), 7.71 - 7.60 (m, 2H), 7.52 (s, 1H), 7.49 - 7.40 (m, 2H), 6.96 (d, J= 2.9 Hz, 1H), 6.89 (d, J= 8.3 Hz, 1H), 2.21 (s, 3H); MS (ES+) 327.093 (M+l), (ES-) 325.317 (M-l). Example 41
4-(4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol (34c)
Figure imgf000161_0002
34c
To a solution of 4-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-3- methylphenol 29aa (0.138 g, 0.42 mmol) in benzene (5 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.113 g, 0.462 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol 34c (116 mg, 84 %) as a orange solid. 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.70 (dd, J= 8.1, 1.6 Hz, 1H), 8.34 (s, 1H), 8.04 (d, J= 2.8 Hz, 1H), 7.74 - 7.65 (m, 1H), 7.58 (d, J= 7.1 Hz, 1H), 7.50 (t, J= 7.5 Hz, 1H), 7.19 (d, J= 8.2 Hz, 1H), 6.74 (d, J= 2.1 Hz, 1H), 6.70 (dd, J = 8.2, 2.3 Hz, 1H), 6.48 (d, J= 2.6 Hz, 1H), 2.19 (s, 3H); MS (ES+) 327.103 (M+l), (ES-) 324.788 (M-l). Example 42
4-(4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-2-bromophenol (34d)
Figure imgf000162_0001
34d
To a solution of 2-bromo-4-(3,4-dihydro-4,9,l 1,11 a-tetraazadibenzo [cd,f]azulen-3- yl)phenol 29q (0.077 g, 0.2 mmol) in benzene (5 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.054 g, 0.22 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-bromophenol 34d (52 mg, 68 %) as a orange solid. 1H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.65 (dd, J= 8.1, 1.4 Hz, 1H), 8.33 (s, 1H), 8.12 (d, J= 2.9 Hz, 1H), 7.88 (d, J= 2.1 Hz, 1H), 7.72 - 7.60 (m, 3H), 7.46 (ddd, J= 8.3, 6.7, 1.8 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.94 (d, J= 3.0 Hz, 1H); MS (ES+) 392.926 (M+l), (ES-) 390.359 (M-l).
Example 43
Methyl (3-(4-hydroxyphenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-10- yl)carbamate (35a)
Figure imgf000162_0002
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 4- hydroxybenzaldehyde 29g (0.134 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35a (0.051 g, 13 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.30 (s, 1H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 7.89 (d, J= 2.5 Hz, 1H), 7.28 (ddd, J= 8.5, 7.0, 1.7 Hz, 1H), 7.04 (d, J= 7.5 Hz, 1H), 6.97 (s, 1H), 6.94 (s, 1H), 6.92 - 6.86 (m, 1H), 6.83 (d, J= 3.8 Hz, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 6.49 (d, J= 2.4 Hz, 1H), 5.61 (d, J= 3.6 Hz, 1H), 3.69 (s, 3H); MS (ES+) 388.078 (M+l), (ES-) 385.547 (M-l). Example 44
Methyl (3-(3,4-dihydroxyphenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f] azulen- 10-yl)carbamate (35b)
Figure imgf000163_0001
35b
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 3,4- dihydroxybenzaldehyde 291 (0.152 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(3,4-dihydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35b (0.095 g, 22 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.74 (s, 2H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 7.89 (d, J= 2.5 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.03 (d, J= 7.5 Hz, 1H), 6.89 (t, J= 7.1 Hz, 1H), 6.81 (d, J= 3.9 Hz, 1H), 6.58 (d, J= 8.6 Hz, 1H), 6.51 (d, J= 2.4 Hz, 1H), 6.49 - 6.45 (m, 2H), 5.54 (d, J= 3.7 Hz, 1H), 3.69 (s, 3H); MS (ES+) 404.078 (M+l), (ES-) 401.531 (M-l).
Example 45
Methyl (3-(4-hydroxy-2-methylphenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo
[cd,f| azulen- 10-yl)carbamate (35c)
Figure imgf000164_0001
35c
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-fJ[l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 4-hydroxy-2- methylbenzaldehyde 29z (0.15 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(4-hydroxy-2-methylphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35c (0.215 g, 50 %) as a orange brown solid. 1H NMR (300 MHz, DMSO- 6) δ 10.16 (s, 1H), 9.28 (s, 1H), 8.52 (dd, J= 8.1, 1.6 Hz, 1H), 7.84 (d, J= 2.5 Hz, 1H), 7.29 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.13 (dd, J= 8.1, 0.7 Hz, 1H), 6.94 (dd, J= 8.1, 6.9 Hz, 1H), 6.80 (d, J= 8.4 Hz, 1H), 6.63 (d, J= 2.4 Hz, 1H), 6.47 (dd, J= 8.3, 2.4 Hz, 1H), 6.33 (d, J= 2.1 Hz, 1H), 6.18 (d, J= 2.3 Hz, 1H), 5.71 (s, 1H), 3.69 (s, 3H), 2.35 (s, 3H); MS (ES+) 402.107 (M+l), (ES-) 399.484 (M-l). Example 46
Methyl (3-(4-hydroxy-3-methylphenyl)-3,4-dihydro-4,9,l 1,11a- tetraazadibenzo[cd,f]azul -10-yl)carbamate (35d)
Figure imgf000164_0002
35d
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 4-hydroxy-3- methylbenzaldehyde 29ab (0.15 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(4-hydroxy-3-methylphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35d (0.085 g, 20 %>) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.21 (s, 1H), 8.49 (dd, J= 8.1, 1.7 Hz, 1H), 7.87 (d, J= 2.5 Hz, 1H), 7.32 - 7.25 (m, 1H), 7.06 (dd, J= 8.1, 0.7 Hz, 1H), 6.95 - 6.86 (m, 2H), 6.77 - 6.71 (m, 2H), 6.62 (d, J= 8.3 Hz, 1H), 6.44 (d, J= 2.4 Hz, 1H), 5.56 (d, J = 3.3 Hz, 1H), 3.69 (s, 3H), 2.02 (s, 3H); MS (ES+) 402.091 (M+l), (ES-) 400.188 (M-l).
Example 47
Methyl (3-(4-hydroxy-3-methoxyphenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f] azulen-10-yl)carbamate (35e)
Figure imgf000165_0001
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 4-hydroxy-3- methoxybenzaldehyde 29af (0.15 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(4-hydroxy-3-methoxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f] azulen-10-yl)carbamate 35e (0.13 g, 30 %) as a orange yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.88 (s, 1H), 8.47 (dd, J= 8.1, 1.6 Hz, 1H), 7.89 (d, J= 2.5 Hz, 1H), 7.29 (ddd, J= 8.5, 7.0, 1.7 Hz, 1H), 7.08 (d, J= 7.5 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.83 (d, J= 3.7 Hz, 1H), 6.57 (d, J= 8.1 Hz, 1H), 6.52 (d, J= 2.5 Hz, 1H), 6.36 (dd, J= 8.2, 1.8 Hz, 1H), 5.61 (d, J= 3.6 Hz, 1H), 3.69 (s, 3H), 3.65 (s, 3H); MS (ES+) 418.084 (M+l), (ES-) 416.188 (M-l).
Example 48
Methyl (3-(3,4-dihydroxy-5-methoxyphenyl)-3,4-dihydro-4,9,l 1,11a- tetraazadibenzo[cd,f] azulen-10-yl)carbamate (35f)
Figure imgf000166_0001
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 3,4-dihydroxy-5- methoxybenzaldehyde 29bj (0.185 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(3,4-dihydroxy-5-methoxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f azulen-10-yl)carbamate 35f (0.095 g, 21 %) as a yellow solid. 1H NMR (300 MHz, DMSO- 6) δ 10.15 (s, 1H), 8.48 (dd, J= 8.2, 1.6 Hz, 1H), 7.90 (d, J= 2.5 Hz, 1H), 7.28 (ddd, J= 8.5, 7.0, 1.7 Hz, 1H), 7.06 (d, J= 7.5 Hz, 1H), 6.93 - 6.86 (m, 1H), 6.82 (d, J= 3.8 Hz, 1H), 6.56 (d, J= 2.5 Hz, 1H), 6.52 (d, J= 1.9 Hz, 1H), 5.99 (d, J= 1.8 Hz, 1H), 5.54 (d, J= 3.7 Hz, 1H), 3.69 (s, 3H), 3.65 (s, 3H); MS (ES+) 433.997 (M+l), (ES-) 432.031 (M-l). Example 49
Methyl (3-(3-chloro-4-hydroxy-5-methoxyphenyl)-3,4-dihydro-4,9,l 1,11a- tetraazadibenzo [cd,f]azulen-10-yl)carbamate (35g)
Figure imgf000166_0002
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 3-chloro-4-hydroxy- 5 -methoxybenzaldehyde 29t (0.205 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(3-chloro-4-hydroxy-5-methoxyphenyl)-3,4-dihydro- 4,9,11,1 la-tetraazadibenzo [cd,f]azulen-10-yl)carbamate 35g (0.1 g, 21 %) as a yellow solid. 1H NMR (300 MHz, OMSO-de) δ 10.17 (s, 1H), 9.33 (s, 1H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 7.92 (d, J= 2.5 Hz, 1H), 7.31 (ddd, J= 8.4, 7.1, 1.7 Hz, 1H), 7.08 (d, J= 7.6 Hz, 1H), 6.97 - 6.87 (m, 3H), 6.60 (d, J= 2.5 Hz, 1H), 6.51 (d, J= 1.7 Hz, 1H), 5.65 (d, J= 3.7 Hz, 1H), 3.69 (s, 3H), 3.69 (s, 3H); MS (ES+) 452.086 (M+1), (ES-) 449.430 (M-1).
Example 50
Methyl (3-(2,5-dihydroxyphenyl)-4,9, 11,11 a-tetr aazadibenzo [cd,f] azulen-10- yl)carbamate (35h)
Figure imgf000167_0001
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 2,5- dihydroxybenzaldehyde 29e (0.152 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(2,5-dihydroxyphenyl)-4,9, 11,11a- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35h (0.058 g, 14 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.61 (s, 1H), 8.95 (s, 1H), 8.75 (dd, J= 8.1, 1.6 Hz, 1H), 7.96 (d, J= 2.9 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.60 (dd, J= 8.1, 1.2 Hz, 1H), 7.56 - 7.50 (m, 1H), 6.84 (d, J= 2.6 Hz, 1H), 6.78 (dd, J= 10.6, 5.7 Hz, 2H), 6.66 (d, J = 2.9 Hz, 1H), 3.70 (s, 3H); MS (ES+) 402.012 (M+1), (ES-) 400.258 (M-1).
Example 51
Methyl (3-(3-bromo-4-hydroxyphenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo
[cd,f] azulen- 10-yl)carbama
Figure imgf000167_0002
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-fJ[l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 3-bromo-4- hydroxybenzaldehyde 29p (0.221 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(3-bromo-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35i (0.136 g, 27.5 %) as a yellow solid. 1H NMR (300 MHz, DMSO- 6) δ 10.16 (s, 2H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 7.91 (d, J= 2.5 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.03 (d, J= 7.4 Hz, 1H), 6.95 - 6.88 (m, 2H), 6.84 (dd, J = 8.4, 2.0 Hz, 1H), 6.77 (d, J= 8.4 Hz, 1H), 6.57 (d, J= 2.5 Hz, 1H), 5.65 (d, J= 3.9 Hz, 1H), 3.69 (s, 3H); MS (ES+) 467.922 (M+l), (ES-) 464.188 (M-l).
Example 52
Methyl (3-(2-chloro-3-hydroxy-4-methoxyphenyl)-3,4-dihydro-4,9,l 1,11a- tetraazadibenzo [cd,f]azule -10-yl)carbamate (35j)
Figure imgf000168_0001
35j
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 2-chloro-3-hydroxy- 4-methoxybenzaldehyde 29n (0.205 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(2-chloro-3-hydroxy-4-methoxyphenyl)-3,4-dihydro- 4,9,11,1 la-tetraazadibenzo [cd,f]azulen-10-yl)carbamate 35j (0.118 g, 24.6 %>) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.41 (s, 1H), 8.50 (dd, J= 8.1, 1.6 Hz, 1H), 7.90 (d, J= 2.5 Hz, 1H), 7.28 (ddd, J= 8.4, 7.1, 1.7 Hz, 1H), 7.01 (d, J= 7.6 Hz, 1H), 6.98 - 6.91 (m, 1H), 6.71 (d, J= 8.7 Hz, 1H), 6.53 - 6.47 (m, 2H), 6.22 (d, J= 8.6 Hz, 1H), 5.97 (d, J= 3.8 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H); MS (ES+) 451.995 (M+l), (ES-) 449.395 (M-l). Example 53
Methyl (3-(3-chloro-4-hydroxyphenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo
[cd,f] azulen- 10-yl)carbamate (35k)
Figure imgf000169_0001
35k
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-fJ[l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 3-chloro-4- hydroxybenzaldehyde 29r (0.172 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(3-chloro-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35k (0.111 g, 24.8 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 10.08 (s, 1H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 7.91 (d, J= 2.5 Hz, 1H), 7.30 (ddd, J= 8.4, 7.1, 1.7 Hz, 1H), 7.16 (d, J= 1.6 Hz, 1H), 7.03 (d, J= 7.5 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.84 - 6.76 (m, 2H), 6.57 (d, J= 2.5 Hz, 1H), 5.65 (d, J= 3.9 Hz, 1H), 5.65 (d, J= 3.9 Hz, 1H), 3.69 (s, 3H); MS (ES+) 422.031 (M+l), (ES-) 420.141 (M-l).
Example 54
4-(4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-2-fluorophenol (34e)
Figure imgf000169_0002
34e
To a solution of 4-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2- fiuorophenol 29ae (0.1 g, 0.3 mmol) in benzene (5 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.090 g, 0.36 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish impure 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-fluorophenol 34e (0.093 g, 92%) as an orange solid. This was repurified by flash column chromatography to furnish pure 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-fluorophenol 34e (silica gel 4 g, eluting with methanol in CMA 0-100%) as an orange solid. ¾ NMR (300 MHz, DMSO- d6) δ 10.38 (s, 1H, D20 exchangeable), 8.65 (dd, J = 8.1, 1.3 Hz, 1H), 8.34 (s, 1H), 8.12 (d,
J = 3.0 Hz, 1H), 7.73 - 7.61 (m, 2H), 7.55 (dd, J = 12.2, 2.1 Hz, 1H), 7.46 (m, 2H), 7.07 (t, J = 8.7 Hz, 1H), 6.99 (d, J = 3.0 Hz, 1H); 19F NMR (300 MHz, DMSO-d6) δ -136.29 (s); MS (ES+) 331.00 (M+l), (ES-) 328.89 (M-l).
Example 55
4-(10-amino-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-2-bromophenol (36a)
Figure imgf000170_0001
To a solution of methyl (3-(3-bromo-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35i (0.0695 g, 0.149 mmol) in MeOH (1.5 mL) was added aqueous NaOH (2 N, 0.745 mL, 1.490 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temperature and neutralized with 1 N HC1 to pH = 6. The reaction mixture was heated to solubilize and decanted to remove insoluble orange residue. The filtrate was cooled overnight at room temperature to furnish 4-(10-amino- 4,9,11,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-bromophenol 36a (0.03 g, 0.074 mmol, 49.5 % yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.32 - 7.23 (m, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.93 - 6.86 (m, 2H), 6.80 - 6.71 (m, 2H), 6.26 (d, J = 2.3 Hz, 1H), 5.55 (d, J = 3.6 Hz, 1H); MS (ES+) 407.892; (ES-) 405.256 (M-l).
Example 56
4-(l 0-amino-3,4-dihydro-4,9,l 1,11 a-tetraazadibenzo [cd,f| azulen-3-yl)-2-chloro-6- methoxyphenol (36b)
Figure imgf000171_0001
36b
To a solution of methyl (3-(3-chloro-4-hydroxy-5-methoxyphenyl)-3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35g (0.021 g, 0.046 mmol) in MeOH (0.5 mL) was added aqueous NaOH (2 N, 0.232 mL, 0.465 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temperature and pH was adjusted to 6 using 1 N HC1. The solid obtained was collected by filtration dried in vacuum to furnish 4-(10-amino-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro-6- methoxyphenol 36b (0.014 g, 0.036 mmol, 76 % yield) as a yellow solid. 1H NMR (300 MHz, DMSO-de) δ 9.29 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.27 (t, J = 6.8 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.94 - 6.85 (m, 2H), 6.70 (d, J = 4.0 Hz, 1H), 6.52 (s, 1H), 6.29 (d, J = 2.1 Hz, 1H), 6.13 (s, 2H), 5.54 (d, J = 3.4 Hz, 1H), 3.69 (s, 3H); MS (ES+) 394.00 (M+l); (ES-) 392.133 (M-l).
Example 57
3-(l 0-amino-3,4-dihydro-4,9,l 1,11 a-tetraazadibenzo [cd,f| azulen-3-yl)-2-chloro-6- methoxyphenol (36c)
Figure imgf000171_0002
36c
To a solution of methyl (3-(2-chloro-3-hydroxy-4-methoxyphenyl)-3,4-dihydro- 4,9,11,11 a-tetraazadibenzo [cd,f]azulen-10-yl)carbamate 35g (0.0666 g, 0.147 mmol) in MeOH (1.5 mL) was added aqueous NaOH (2 N, 0.737 mL, 1.474 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The reaction mixture was cooled to room temperature and pH was adjusted to 6 using 1 N HC1. The solid obtained was collected by filtration dried in vacuum to furnish 3-(10-amino-3,4-dihydro-4,9,l 1 ,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro- 6-methoxyphenol 36c (0.056 g, 0.142 mmol, 96 % yield) as a yellow solid. 1H NMR (300 MHz, DMSO-de) δ 9.37 (s, 1H), 8.44 (d, J = 8.1 Hz, 1H), 7.53 (s, 1H), 7.24 (t, J = 6.8 Hz, 1H), 7.03 - 6.88 (m, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.34-6.06 (m, 5H), 5.87 (s, 1H), 3.72 (s, 3H); MS (ES+) 394.017 (M+l); (ES-) 392.25 (M-l). Example 58
4-Bromo-5-(3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-2- methoxyphenol (29bk)
Figure imgf000172_0001
29bk
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 2-bromo-5-hydroxy-4-methoxybenzaldehyde 29bj (0.3 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 4-bromo-5-(3,4- dihydro-4,9,l l,l la-tetraazadibenzo[cd,fJazulen-3-yl)-2-methoxyphenol 29bk (0.335 g, 67 %) as an orange brown solid. 1H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.56 (s, 1H), 8.54 (dd, J= 8.2, 1.7 Hz, 1H), 8.03 (d, J= 2.6 Hz, 1H), 7.33 (ddd, J= 8.5, 7.0, 1.7 Hz, 1H), 7.16 (s, 1H), 7.13 (d, J= 7.3 Hz, 1H), 7.00 (ddd, J= 8.1, 7.0, 1.2 Hz, 1H), 6.46 (s, 1H), 6.45 (d, J= 2.6 Hz, 1H), 6.42 (d, J= 2.8 Hz, 1H), 5.85 (d, J= 2.7 Hz, 1H), 3.77 (s, 3H); MS (ES+) 423.954 (M+l), 422.333 (M-l).
Example 59
2-(10-amino-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)benzene-l,4-diol (36d)
Figure imgf000172_0002
To a solution of methyl (3-(2,5-dihydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35h (0.0273 g, 0.068 mmol) in MeOH (0.6 mL) was added aqueous NaOH (2 N, 0.338 mL, 0.677 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 4 g, eluting with 0-100% CMA-80 in chloroform) to furnish 2-(10-amino-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)benzene-l,4-diol 36d (0.008 g, 0.023 mmol, 34.4 % yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.92 (s, 1H), 8.73 (dd, J = 8.2, 1.6 Hz, 1H), 7.71 (dd, J= 7.0, 1.7 Hz, 1H), 7.67 (d, J= 2.8 Hz, 1H), 7.56 (dd, J= 8.0, 1.1 Hz, 1H), 7.49 (ddd, J= 8.3, 7.1, 1.4 Hz, 1H), 6.86 (d, J= 2.6 Hz, 1H), 6.78 (d, J= 8.5 Hz, 1H), 6.73 (dd, J= 8.7, 2.7 Hz, 1H), 6.54 - 6.48 (m, 3H); MS (ES+) 344.016 (M+l); (ES-) 342.159 (M-l), 377.399 (M+Cl).
Example 60
3-(4,9,ll,ll a-tetr aazadibenzo [cd,f] azulen-3-yl)-2-chloro-6-methoxyphenol (34f)
Figure imgf000173_0001
34f
To a solution of 2-chloro-3-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3- yl)-6-methoxyphenol 29o (0.084 g, 0.22 mmol) in benzene (5 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.060 g, 0.24 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to 3- (4,9, 11,11 a-tetraazadibenzo[cd,f azulen-3-yl)-2-chloro-6-methoxyphenol 34f (63 mg, 75.45 % yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.72 (dd, J = 8.1, 1.5 Hz, 1H), 8.35 (s, 1H), 8.04 (d, J= 2.9 Hz, 1H), 7.75 - 7.66 (m, 1H), 7.62 - 7.48 (m, 2H), 7.08 (d, J= 8.5 Hz, 1H), 6.94 (d, J= 8.4 Hz, 1H), 6.43 (d, J= 2.9 Hz, 1H), 3.90 (s, 3H); MS (ES+) 376.949 (M+l), (ES-) 374.598 (M-l).
Example 61
4-(4,9, 11 ,11 a-tetr aazadibenzo [cd,f] azulen-3-yl)-2-chloro-6-methoxyphenol (34g)
Figure imgf000174_0001
34g
To a solution of 2-chloro-4-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,fJazulen-3- yl)-6-methoxyphenol 29u (0.042 g, 0.11 mmol) in benzene (5 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.030 g, 0.121 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro-6-methoxyphenol 34g (29 mg, 69.46 % yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 9.91 (d, J= 12.6 Hz, 1H), 8.66 (d, J= 8.1 Hz, 1H), 8.34 (s, 1H), 8.12 (d, J= 2.8 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.53 - 7.44 (m, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 7.04 (d, J= 2.7 Hz, 1H), 3.90 (s, 3H); MS (ES+) 376.965 (M+l), (ES-) 374.436 (M-l).
Example 62
4-(4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-2-chlorophenol (34h)
Figure imgf000174_0002
34h
To a solution of 2-chloro-4-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3- yl)-6-methylphenol 29s (0.042 g, 0.11 mmol) in benzene (5 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.030 g, 0.121 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2-chlorophenol 34h (29 mg, 69.46 % yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 9.91 (d, J= 12.6 Hz, 1H), 8.66 (d, J= 8.1 Hz, 1H), 8.34 (s, 1H), 8.12 (d, J= 2.8 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.53 - 7.44 (m, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 7.04 (d, J= 2.7 Hz, 1H), 3.90 (s, 3H); MS (ES+) 346.989 (M+l), (ES-) 344.704 (M-l).
Example 63
3-(2,3-dihydrobenzofuran-5-yl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo [cd,f|azulene
(29bm)
Figure imgf000175_0001
29bm
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 2,3-dihydrobenzofuran-5-carbaldehyde 29bl (0.194 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(2,3- dihydrobenzofuran-5-yl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulene 29bm (0.179 g, 44 %) as an orange brown solid. 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.51 - 8.46 (m, 2H), 8.02 (d, J= 2.5 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.04 (d, J= 7.4 Hz, 1H), 6.94 - 6.85 (m, 1H), 6.80 (d, J= 3.8 Hz, 1H), 6.61 (d, J= 2.5 Hz, 1H), 6.59 (d, J= 8.0 Hz, 1H), 6.51 - 6.43 (m, 2H), 5.56 (d, J= 3.7 Hz, 1H); 1H NMR (300 MHz, DMSO-d6/D20) δ 8.47 (s, 1H), 8.44 (dd, J= 8.4, 1.6 Hz, 1H), 8.03 (d, J= 2.5 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.02 - 6.94 (m, 2H), 6.73 (d, J= 2.5 Hz, 1H), 6.60 (d, J= 8.1 Hz, 1H), 6.49 - 6.40 (m, 2H), 5.62 (s, 1H); MS (ES+) 341.047 (M+l), 338.898 (M-l).
Example 64
3-(2,6-difluorophenyl)-3,4-dihydr -4,9,ll,lla-tetraazadibenzo[cd,f|azulene (29bo)
Figure imgf000175_0002
29bo To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 2,6-difluorobenzaldehyde 29bn (0.186 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(2,6-difluorophenyl)-3,4- dihydro-4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29bo (0.124 g, 31 %) as an orange brown solid. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (dd, J= 8.2, 1.6 Hz, 1H), 8.55 (s, 1H), 7.99 (d, J= 2.6 Hz, 1H), 7.46 (tt, J= 8.1, 6.5 Hz, 1H), 7.33 (ddd, J= 8.5, 7.0, 1.7 Hz, 1H), 7.16 - 7.07 (m, 3H), 7.00 (ddd, J= 8.1, 7.1, 1.1 Hz, 1H), 6.73 (d, J= 1.9 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 6.09 (s, 1H); MS (ES+) 335.039 (M+l), 332.664 (M-l).
Example 65
3-(4-isopropoxyphenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulene (29bq)
Figure imgf000176_0001
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 4-isopropoxybenzaldehyde 29bp (0.215 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(4-isopropoxyphenyl)-3,4- dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene 29bq (0.171 g, 40 %>) as an orange brown solid. 1H NMR (300 MHz, DMSO-d6) δ 8.52 - 8.46 (m, 2H), 8.03 (d, J= 2.5 Hz, 1H), 7.28 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.08 - 7.00 (m, 3H), 6.94 - 6.87 (m, 2H), 6.77 (d, J= 8.7 Hz, 2H), 6.63 (d, J= 2.5 Hz, 1H), 5.68 (d, J= 3.7 Hz, 1H), 4.51 (dt, J= 12.1, 6.0 Hz, 1H), 1.20 (d, J= 6.0 Hz, 6H); MS (ES+) 357.094 (M+l), 354.844 (M-l).
Example 66
3-(2,4-difluorophenyl)-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulene (29bs)
Figure imgf000177_0001
29bs
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 2,4-difluorobenzaldehyde 29br (0.186 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(2,4-difluorophenyl)-3,4- dihydro-4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29bs (0.216 g, 54 %) as an orange brown solid. 1H NMR (300 MHz, DMSO-d6) δ 8.52 - 8.46 (m, 2H), 8.03 (d, J= 2.5 Hz, 1H), 7.28 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.08 - 7.00 (m, 3H), 6.94 - 6.87 (m, 2H), 6.77 (d, J= 8.7 Hz, 2H), 6.63 (d, J= 2.5 Hz, 1H), 5.68 (d, J= 3.7 Hz, 1H), 4.51 (dt, J= 12.1, 6.0 Hz, 1H), 1.20 (d, J= 6.0 Hz, 6H); MS (ES+) 335.06 (M+l), 333.228 (M-l).
Example 67
4-(l 0-amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo [cd,f] azulen-3-yl)benzene- 1 ,2-diol (36e)
Figure imgf000177_0002
To a solution of methyl (3-(3,4-dihydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35b (0.06 g, 0.149 mmol) in MeOH (1.5 mL) was added aqueous NaOH (2 N, 0.744 mL, 1.487 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 8 g, eluting with 0-100% CMA-80 in chloroform) to furnish 4-(10-amino-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)benzene-l,2-diol 36e (0.025 g, 0.072 mmol, 48.7 %> yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J= 1.5 Hz, 2H), 8.44 (dd, J = 8.1, 1.6 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.23 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.90 - 6.83 (m, 1H), 6.53 (dt, J= 10.3, 4.8 Hz, 4H), 6.18 (d, J= 2.3 Hz, 1H), 6.08 (s, 2H), 5.43 (d, J= 3.6 Hz, 1H); MS (ES+) 346.039; (ES-) 345.461 (M-l).
Example 68
4-(l 0-Amino-3,4-dihydr 0-4,9,11,11 a-tetraazadibenzo [cd,f] azulen-3-yl)-2-methylphenol
(36f)
Figure imgf000178_0001
To a solution of methyl (3-(4-hydroxy-3-methylphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35d (0.32 g, 0.797 mmol) in MeOH (0.8 mL) was added aqueous NaOH (2 N, 3.99 mL, 7.97 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temeprature and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 4 g, eluting with 0-100% CMA-80 in chloroform) to furnish 4-(10-amino-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)-2-methylphenol 36f (0.01 g, 0.029 mmol, 3.65 % yield). 1H NMR (300 MHz, DMSO-d6) 6 9.18 (s, 1H), 8.44 (dd, J= 8.1, 1.6 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.24 (ddd, J= 8.4, 7.0, 1.6 Hz, 1H), 7.04 (d, J= 7.4 Hz, 1H), 6.93 (s, 1H), 6.88 (t, J= 7.5 Hz, 1H), 6.77 (dd, J= 8.2, 2.1 Hz, 1H), 6.62 (d, J= 8.2 Hz, 1H), 6.50 (d, J= 3.2 Hz, 1H), 6.11 (d, J= 2.3 Hz, 1H), 6.08 (s, 2H), 5.45 (d, J= 3.1 Hz, 1H), 2.02 (s, 3H); MS (ES+) 344.0 (ES+); (ES-) 378.0 (M+Cl).
Example 69
4-(l 0-amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo [cd,f| azulen-3-yl)-2,6- dichlorophenol (36g)
Figure imgf000178_0002
To a solution of methyl (3-(3,5-dichloro-4-hydroxyphenyl)-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 351 (0.0718 g, 0.157 mmol) in MeOH (1.6 mL) was added aqueous NaOH (2 N, 0.787 mL, 1.574 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 8 g, eluting with 0-100% CMA-80 in chloroform) to furnish 4-(10-amino-3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-2,6-dichlorophenol 36g (0.024 g, 0.060 mmol, 38.3 % yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.42 (d, J = 6.6 Hz, 1H), 7.58 (d, J= 2.4 Hz, 1H), 7.28 (t, J= 6.8 Hz, 1H), 7.08 (s, 2H), 7.01 (d, J = 7.5 Hz, 1H), 6.91 (t, J= 7.5 Hz, 1H), 6.79 (d, J= 4.2 Hz, 1H), 6.33 (d, J= 2.4 Hz, 1H), 6.16 (s, 2H), 5.59 (d, J= 3.9 Hz, 1H); MS (ES+) 397.969 (M+l); (ES-) 395.375 (M-l).
Example 70
3-(2,5-difluorophenyl)-3,4-dihyd -4,9,ll,lla-tetraazadibenzo[cd,f|azulene (29bv)
Figure imgf000179_0001
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.25 g, 1.19 mmol) in acetic acid (5 mL) was added 2,4-difluorobenzaldehyde 29bu (0.186 g, 1.31 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(2,5-difluorophenyl)-3,4- dihydro-4,9,11,1 la-tetraazadibenzo[cd,f]azulene 29bv (0.143 g, 36 %>) as an orange brown solid. 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.52 (dd, J= 8.1, 1.7 Hz, 1H), 8.06 (d, J= 2.6 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.18 - 7.08 (m, 1H), 7.05 (d, J= 8.2 Hz, 1H), 6.98 (ddd, J= 8.1, 7.0, 1.2 Hz, 1H), 6.79 (d, J= 3.9 Hz, 1H), 6.68 (d, J= 2.6 Hz, 1H), 6.58 (ddd, J= 9.0, 5.7, 3.2 Hz, 1H), 6.02 (d, J= 3.8 Hz, 1H); MS (ES+) 335.065 (M+l), 332.623 (M- 1).
Example 71
4-(10-amino-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol (36h)
Figure imgf000180_0001
To a solution of methyl (3-(4-hydroxy-2-methylphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35c (0.0786 g, 0.196 mmol) in MeOH (2.0 mL) was added aqueous NaOH (2 N, 0.979 mL, 1.958 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 12 g, eluting with 0-100% CMA-80 in chloroform) to furnish 4-(10-amino-3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol 36h (0.014 g, 0.041 mmol, 20.82 % yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.47 (dd, J= 8.1, 1.6 Hz, 1H), 7.47 (d, J= 2.3 Hz, 1H), 7.26 (ddd, J= 8.5, 7.0, 1.7 Hz, 1H), 7.14 (dd, J= 11.0, 7.9 Hz, 1H), 7.13 (t, J= 9.5 Hz, 1H), 6.93 (t, J= 7.5 Hz, 1H), 6.85 (d, J= 8.4 Hz, 1H), 6.62 (d, J= 2.4 Hz, 1H), 6.48 (dd, J= 8.2, 2.6 Hz, 1H), 6.10 (s, 2H), 6.08 (d, J= 1.7 Hz, 1H), 5.86 (d, J= 2.2 Hz, 1H), 5.61 (s, 1H), 2.32 (s, 3H); MS (ES+) (ES-) 377.8 (M+Cl), 685.4 (2M-1).
Example 72
4-(l 0-amino-3,4-dihydro-4,9, 11 ,11 a-tetraazadibenzo [cd,f| azulen-3-yl)-2-chlor ophenol (36i)
Figure imgf000180_0002
36i
To a solution of methyl (3-(3-chloro-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 35k (0.0766 g, 0.182 mmol) in MeOH (1.8 mL) was added aqueous NaOH (2 N, 0.908 mL, 1.816 mmol) and heated at reflux for 5 h. The residue obtained was purified by flash column chromatography (silica gel 8 g, eluting with 0-100% CMA-80 in chloroform) to furnish 4-(10-amino-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)-2-chlorophenol 36i (0.046 g, 0.126 mmol, 69.6 %> yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.42 (dd, J= 8.1, 1.6 Hz, 1H), 7.55 (d, J= 2.4 Hz, 1H), 7.25 (dd, J= 10.9, 4.2 Hz, 1H), 7.14 (d, J= 2.0 Hz, 1H), 7.01 (d, J= 7.3 Hz, 1H), 6.92 - 6.83 (m, 2H), 6.79 (d, J= 8.4 Hz, 1H), 6.70 (d, J= 4.0 Hz, 1H), 6.25 (d, J= 2.3 Hz, 1H), 6.12 (s, 2H), 5.54 (d, J= 3.7 Hz, 1H); MS (ES-) 362.20 (M-
1).
Example 73
4-(10-Amino-3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)phenol (36j)
36j
To a solution of methyl (3-(4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate (35a) (0.039 g, 0.101 mmol) in methanol (0.6 mL) was added aqueous 2 N sodium hydroxide (0.503 mL, 1.0 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 4 g, eluting with 0-100% CMA-80 in chloroform) to furnish 4-(10-Amino-3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f]azulen-3-yl)phenol (36j) (0.021 g, 0.064 mmol, 63.3 % yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H, D20
exchangeable), 8.69 (d, J = 8.0 Hz, 1H), 7.78-7.55 (m, 5H), 7.50-7.38 (m, 1H), 6.92-6.82 (m, 2H), 6.68 (d, J = 2.9 Hz, 1H), 6.52 (s, 2H, D20 exchangeable); MS (ES+) 328.05 (M+l); (ES-) 326.24 (M-l).
Example 74
4-(10-amino-4,9,ll,l -tetraazadibenzo[cd,f|azulen-3-yl)phenol (36k)
Figure imgf000181_0002
To a solution of furnish 4-(10-Amino-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)phenol (36j) in benzene (4 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.014 g, 0.058 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(10-amino-4,9,l 1 ,1 la-tetraazadibenzo[cd,f]azulen-3-yl)phenol (36k) (0.08 g, 0.244 mmol, 50 % yield) as a orange solid; 1H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H, D20 exchangeable), 8.69 (d, J = 8.0 Hz, 1H), 7.78-7.55 (m, 5H), 7.50-7.38 (m, 1H), 6.92- 6.82 (m, 2H), 6.68 (d, J = 2.9 Hz, 1H), 6.52 (s, 2H, D20 exchangeable).MS (ES+): MS (ES+) 328.05 (M+l), (ES-) 326.24 (M-l).
Example 75
Methyl (3-(2-fluor o-4-hydr oxyphenyl)-4,9, 11,11 a-tetr aazadibenzo [cd,f] azulen- 10- yl)carbamate (35i)
Figure imgf000182_0001
Methyl (3-(2-fluoro-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen- 10-yl)carbamate (24a)
Figure imgf000182_0002
24a
Method A:
To a solution of methyl 4-(2-aminophenyl)pyrrolo[l,2-fJ[l,2,4]triazin-2- ylcarbamate (17e) (0.283 g, 1 mmol) in MeOH (20 mL) was added 2-fluoro-4- hydroxybenzaldehyde (0.280 g, 2.0 mmol), HC1 (4 M solution in dioxane, 2 mL, 8.00 mmol) and stirred at reflux for 1.5 h. Evaporate to dryness and purify the residue obtained by column (12 g, eluting 0-100% CHC13 in CMA-80) to furnish methyl (3-(2-fiuoro-4- hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-10-yl)carbamate (24a) (0.03 g, 0.074 mmol, 7.40 % yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.84 (s, 1H), 8.50 (dd, J= 8.1, 1.7 Hz, 1H), 7.89 (d, J= 2.5 Hz, 1H), 7.29 (ddd, J= 8.5, 7.0, 1.7 Hz, 1H), 7.04 (dd, J= 8.3, 1.2 Hz, 1H), 6.94 (ddd, J= 8.2, 7.0, 1.2 Hz, 1H), 6.67 - 6.52 (m, 3H), 6.49 (d, J= 2.5 Hz, 1H), 6.39 (dd, J= 8.5, 2.4 Hz, 1H), 5.86 (d, J= 3.5 Hz, 1H), 3.69 (s, 3H); 19F NMR (282 MHz, DMSO-d6) δ -116.43; MS (ES+) 407.0 (M+1); (ES-) 403.9 (M-l).
Method B:
To a solution of methyl 4-(2-aminophenyl)pyrrolo[l,2-f][l,2,4]triazin-2- ylcarbamate (17e) (1.133 g, 4 mmol) in MeOH (40 mL) was added 2-fluoro-4- hydroxybenzaldehyde (0.701 g, 5.00 mmol), molecular sieves (0.3 g), sulfuric acid (0.278 mL, 10.00 mmol) and stirred at reflux for 2 h. Evaporate to dryness and purify residue obtained by column (40 g, eluting 0-100% CHC13 in CMA-80) to furnish methyl (3-(2- fluoro-4-hydroxyphenyl)-3,4-dihydro-4,9,l l,l la-tetraazadibenzo[cd,fJazulen-10- yl)carbamate (24a) (0.843 g, 2.080 mmol, 52 % yield) as a yellow solid confirmed by NMR analysis.
To a solution of methyl (3-(2-fluoro-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate (24a) (0.972 g, 2.398 mmol) in benzene (30 mL) was added 2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione (0.707 g, 2.88 mmol) and heated at reflux for 60 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 40 g, eluting with ethyl acetate in hexanes from 0-100%) to furnish methyl (3-(2-fluoro-4-hydroxyphenyl)-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate (35i) (0.438 g, 1.086 mmol, 45.3 % yield) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 2H), 8.75 (dd, J = 8.1, 1.6 Hz, 1H), 7.95 (d, J = 2.9 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.63 (m, 1H), 7.52 (m, 1H), 7.41 (t, J = 8.6 Hz, 1H), 6.71 (ddd, J = 14.3, 10.3, 2.2 Hz, 2H), 6.58 (t, J = 2.8 Hz, 1H), 3.70 (s, 3H); MS (ES+) 403.96 (M+l), (ES-) 402.11 (M-l).
Example 76
4-(l 0- Amino-4,9, 11,11 a-tetraazadibenzo [cd,f| azulen-3-yl)-3-fluorophenol (24c)
Figure imgf000184_0001
24c
To a solution of methyl (3-(2-fluoro-4-hydroxyphenyl)-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate (35i) (0.433 g, 1.073 mmol) in methanol (6 mL) was added 2 N aqueous sodium hydroxide (5.37 mL, 10.73 mmol) and stirred at room temperature for 13 h. The reaction mixture was cooled to room temperature and
concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 24 g, eluting with 0-100% CMA-80 in chloroform) to furnish 4- (10-amino-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol (24c) (0.215 g, 0.623 mmol, 58.0 % yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.73 (dd, J= 8.1, 1.7 Hz, 1H), 7.73 - 7.56 (m, 3H), 7.49 (ddd, J = 8.4, 6.9, 1.6 Hz,
1H), 7.38 (t, J= 8.5 Hz, 1H), 6.73 (dd, J= 8.3, 2.3 Hz, 1H), 6.68 (dd, J= 12.0, 2.2 Hz, 1H), 6.52 (s, 2H), 6.37 (t, J= 2.7 Hz, 1H).
Example 77
3-(3-((2-chlorobenzyl)oxy)phenyl)-3,4-dihydro-4,9,l 1,11a- tetraazadibenzo[cd,f|azulene (29bx) and 3-(3-((2-chlorobenzyl)oxy)phenyl)-4,9,l 1,11a- tetraazadibenzo [cd,f] azulene (34i)
Figure imgf000184_0002
29bx 34i
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.22 g, 1.05 mmol) in acetic acid (5 mL) was added 3-((2-chlorobenzyl)oxy)benzaldehyde 29bw (0.285 g, 1.155 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish: 3-(3-((2-chlorobenzyl)oxy)phenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulene 29bx (0.17 g, 37 %) as an orange semisolid. 1H NMR (300 MHz, DMSO-de) δ 8.50 (s, 1H), 8.47 (dd, J= 8.1, 1.6 Hz, 1H), 8.04 (d, J= 2.5 Hz, 1H), 7.47 (ddd, J= 6.8, 5.0, 2.0 Hz, 2H), 7.35 (td, J= 7.1, 1.8 Hz, 2H), 7.31 - 7.25 (m, 1H), 7.16 (t, J= 7.8 Hz, 1H), 7.07 - 7.01 (m, 2H), 6.90 (ddd, J= 8.1, 7.0, 1.1 Hz, 1H), 6.86 - 6.79 (m, 2H), 6.74 - 6.69 (m, 2H), 5.76 (s, 2H), 5.02 (s, 2H); MS (ES+) 438.973 (M+l), 436.93 (M-l); and
3-(3-((2-chlorobenzyl)oxy)phenyl)-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulene 34i (0.07 g, 15 %) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (dd, J = 8.1, 1.5 Hz, 1H), 8.35 (s, 1H), 8.10 (d, J= 2.9 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.67 - 7.61 (m, 2H), 7.56 - 7.39 (m, 5H), 7.36 - 7.31 (m, 2H), 7.24 - 7.18 (m, 1H), 6.80 (d, J= 2.9 Hz, 1H), 5.26 (s, 2H); MS (ES+) 436.844.
Example 78
3-(3,4-dihydro-4,9,ll,lla-tetraazadibenzo[cd,f|azulen-3-yl)aniline (29bz)
Figure imgf000185_0001
To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.22 g, 1.05 mmol) in acetic acid (5 mL) was added 3-aminobenzaldehyde 29by (0.14 g, 1.155 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)aniline 29bz (0.111 g, 34 %) as a yellow solid. 1H NMR (300 MHz, DMSO-de) δ 8.53 - 8.45 (m, 2H), 8.02 (d, J= 2.5 Hz, 1H), 7.28 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.07 (d, J= 7.4 Hz, 1H), 6.90 (td, J= 8.0, 1.9 Hz, 2H), 6.83 (d, J= 3.7 Hz, 1H), 6.60 (d, J= 2.5 Hz, 1H), 6.46 (d, J= 7.6 Hz, 1H), 6.37 (dd, J= 7.9, 1.3 Hz, 1H), 6.25 (s, 1H), 5.56 (d, J= 3.6 Hz, 1H), 5.01 (s, 2H); MS (ES+) 314.091 (M+l), 311.672 (M-l).
Example 79
3-(4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)aniline (34j)
Figure imgf000186_0001
To a solution of 3-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)aniline 29bz (0.08 g, 0.25 mmol) in benzene (5 mL) was added 2,3,5,6-tetrachlorocyclohexa-2,5- diene-l,4-dione (0.068 g, 0.275 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 3-(4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)aniline 34j (0.06 g, 77 % yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 8.67 (dd, J= 8.1, 1.5 Hz, 1H), 8.33 (s, 1H), 8.09 (d, J= 2.9 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.62 (dd, J= 8.1, 1.4 Hz, 1H), 7.48 (ddd, J= 8.3, 6.9, 1.6 Hz, 1H), 7.14 (t, J= 7.8 Hz, 1H), 6.94 - 6.90 (m, 1H), 6.88 (d, J= 2.9 Hz, 1H), 6.83 (d, J= 7.6 Hz, 1H), 6.74 - 6.68 (m, 1H), 5.27 (s, 2H); ); MS (ES+) 312.086 (M+l), (ES-) 620.57 (2M- 1).
Example 80
4-(4,9,ll,lla-tetraazadibenzo[cd,f]azulen-3-yl)phenol (34k)
Figure imgf000186_0002
To a solution of 4-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)phenol 29h (0.092 g, 0.29 mmol) in benzene (5 mL) was added 2,3,5,6-tetrachlorocyclohexa-2,5- diene-l,4-dione (0.079 g, 0.32 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 4-(4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-3-yl)phenol 34k (0.042 g, 46 %> yield) as an orange brown solid. 1H NMR (300 MHz, DMSO) δ 9.92 (s, 1H), 8.65 (dd, J= 8.1, 1.4 Hz, 1H), 8.32 (s, 1H), 8.11 (d, J= 2.9 Hz, 1H), 7.72 - 7.59 (m, 4H), 7.44 (ddd, J= 8.3, 6.9, 1.7 Hz, 1H), 6.95 (d, J= 2.9 Hz, 1H), 6.89 (d, J= 8.6 Hz, 2H); MS (ES+) 313.062 (M+l), (ES-) 310.922 (M- 1).
Example 81
5-(4,9, 11 ,11 a-tetr aazadibenzo [cd,f] azulen-3-yl)-4-bromo-2-methoxyphenol (341)
Figure imgf000187_0001
341
To a solution of 4-bromo-5-(3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3- yl)-2-methoxyphenol 29bk (0.22 g, 0.52 mmol) in benzene (10 mL) was added 2,3,5,6- tetrachlorocyclohexa-2,5-diene-l,4-dione (0.141 g, 0.57 mmol) and heated at reflux for 48 h. The reaction mixture was concentrated in vacuum to dryness and purified by flash column chromatography (silica gel 4 g, eluting with methanol in chloroform 0-50%) to furnish 5-(4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-3-yl)-4-bromo-2-methoxyphenol 341 (0.172 g, 79 % yield) as an orange brown solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.71 (dd, J= 8.1, 1.5 Hz, 1H), 8.35 (s, 1H), 8.05 (d, J= 2.9 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.60 (dd, J= 8.1, 1.3 Hz, 1H), 7.53 (ddd, J= 8.4, 7.1, 1.5 Hz, 1H), 7.23 (s, 1H), 6.90 (s, 1H), 6.46 (d, J= 2.9 Hz, 1H), 3.86 (s, 3H); MS (ES+) 422.922 (M+l), (ES-) 420.609 (M-l).
Example 82
Methyl (3-(2-hydroxy-4-methoxyphenyl)-3,4-dihydro
tetraazadibenzo[cd,f]azule -10-yl)carbamate (351)
Figure imgf000187_0002
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate 17e (0.275 g, 0.97 mmol) in acetic acid (5 mL) was added 2-hydroxy-4- methoxybenzaldehyde 29by (0.162 g, 1.07 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish methyl (3-(2-hydroxy-4-methoxyphenyl)-3,4-dihydro- 4,9,11,11 a-tetraazadibenzo [cd,f] azulen- 10-yl)carbamate 351 (0.028 g, 6.9 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 12.37 (s, 1H), 10.65 (s, 1H), 10.36 (s, 1H), 8.73 (d, J= 6.5 Hz, 1H), 8.02 (d, J= 2.9 Hz, 1H), 7.73 (t, J= 7.6 Hz, 1H), 7.63 - 7.48 (m, 4H), 6.93 (d, J= 2.9 Hz, 1H), 6.58 - 6.51 (m, 2H), 3.81 (s, 3H), 3.71 (s, 3H).
Example 83
Methyl (3-(3,5-dichloro-4-hydroxyphenyl)-4,9,ll,lla-tetraazadibenzo [cd,f| azulen- 10- yl)carbamate (35m)
Figure imgf000188_0001
To a solution of methyl (4-(2-aminophenyl)pyrrolo[2,l-f][l,2,4]triazin-2- yl)carbamate 17e (0.3 g, 1.06 mmol) in acetic acid (5 mL) was added 3,5-dichloro-4- hydroxybenzaldehyde 29bt (0.21 g, 1.1 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0- 100%)) to furnish methyl (3-(3,5-dichloro-4-hydroxyphenyl)-4,9,l 1,1 la- tetraazadibenzo[cd,f]azulen-10-yl)carbamate 351 (0.118 g, 24 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 10.09 (s, 1H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 7.94 (d, J= 2.5 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.08 (s, 2H), 7.04 (d, J= 8.1 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.64 (d, J= 2.5 Hz, 1H), 5.70 (d, J= 3.9 Hz, 1H), 3.69 (s, 3H); MS (ES+) 455.916 (M+l); (ES-) 453.312 (M-l). Example 84
4-(9-Amino-3,4-dihydro-5-thia-4,8,10,10a-tetraazabenzo[cd]cyclopenta[f|azulen-3-yl)- 3-fluorophenol (39e) and 4-(9-amino-5-thia-4,8,10,10a- tetraazabenzo[cd]cyclopenta[f]azulen-3-yl)-3-fluorophenol (39f)
Figure imgf000189_0001
39e
39f
To a solution of 2-tertbutoxycarbonylamino-3-(2- ((methoxycarbonyl)amino)pyrrolo[2,l-f][l,2,4]triazin-4-yl)Thiophene (39d) (0.057 g, 0.15 mmol) and 2-fluoro-4-hydroxybenzaldehyde (22i) (0.026 g, 0.18 mmol) in dioxane (4 mL) was added hydrogen chloride (4M in dioxane) (2.05 mL, 8.20 mmol) and stirred at room temperature for 14 h. The reaction mixture was concentrated under vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 12g, eluting with 0-100%, CMA in chloroform) to furnish product containing mixtures of 4-(9-amino- 3,4-dihydro-5-thia-4,8,10,10a-tetraazabenzo[cd]cyclopenta[f]azulen-3-yl)-3-fluorophenol (39e) and 4-(9-amino-5-thia-4,8,10,10a-tetraazabenzo[cd]cyclopenta[fJazulen-3-yl)-3- f uorophenol (39f); MS (ES+) 354.10 (M+l) for 39e and 352.11 (M+l) for 39f.
Preparation of 2-tertbutoxycarbonylamino-3-(2- ((methoxycarbonyl)amino)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-yl)Thiophene (39d)
Step 1:
To a solution of methyl 4-chloropyrrolo[l,2-f][l,2,4]triazin-2-ylcarbamate (17d)
(0.52 g, 2.295 mmol) and 2-formylthiophen-3-ylboronic acid (39a) (0.537 g, 3.44 mmol) in DMF (20 mL) was degassed with nitrogen gas for 15 min followed by addition of sodium carbonate (2 M in water, 4.02 mL, 8.03 mmol) under continuous follow of nitrogen.
Palladium(II)bis(triphenylphosphine) dichloride (322 mg, 0.459 mmol) was added to the reaction mixture under nitrogen atmosphere. The reaction was stirred at 80 °C overnight, cooled to room temperature and quenched with water (40 mL). The reaction mixture was extracted with ethyl acetate (2 x 25 mL). The organic layers were combined washed with water (25 mL), brine (25 mL), dried, filtered and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel, 12 g eluting with 0-100% ethyl acetate in hexane) to afford methyl 4-(2-formylthiophen-3-yl)pyrrolo[l,2- f][l,2,4]triazin-2-ylcarbamate (39b) (0.15 g, 22 % yield) as light yellow solid. 1H NMR (300 MHz, DMSO-de) δ 10.51 - 10.42 (m, 2H), 8.27 (dd, J = 5.1, 1.2 Hz, 1H), 8.11 (dd, J = 2.5, 1.4 Hz, 1H), 7.94 (d, J = 5.1 Hz, 1H), 7.11 (dd, J = 4.7, 1.4 Hz, 1H), 7.04 (dd, J = 4.7, 2.5 Hz, 1H), 3.70 (s, 3H); MS (ES+) 303.0 (M+l); (ES-) 336.8 (M+Cl). Step 2:
To a solution of methyl 4-(2-formylthiophen-3-yl)pyrrolo[l,2-f][l,2,4]triazin-2- ylcarbamate (39b) (1.5 g, 4.96 mmol) in acetonitrile (12 mL), t-BuOH (84 mL) was added sodium dihydrogenphosphate (1.191 g, 9.92 mmol) in water (6 mL) over a period of 5 min followed by 2-methylbut-2-ene (5.26 mL, 49.6 mmol). The reaction was cooled in an ice- water bath and then a solution of sodium chlorite (2.244 g, 24.81 mmol) in water (6 mL) was added dropwise over a period of 5 min. After stirring for 1.5 h, the reaction mixture diluted with water and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over MgSC^, filtered and concentrated in vacuum to dryness. The residue obtained was triturated with water and the solid obtained was collected by filtration, dried under vacuo to give 3-(2-(methoxycarbonylamino)pyrrolo[l,2-f][l,2,4]triazin-4- yl)thiophene-2-carboxylic acid (39c) (825 mg, 52 % yield) as light yellow solid, which was used as such for the next step. 1H NMR (300 MHz, DMSO-d6) δ 13.26 (s, 1H), 10.39 (s, 1H), 8.08 - 7.98 (m, 2H), 7.41 (d, J= 5.1 Hz, 1H), 6.90 (dd, J= 4.6, 2.5 Hz, 1H), 6.57 (dd, J= 4.6, 1.4 Hz, 1H), 3.67 (s, 3H); MS (ES+) 319.0 (M+l), 340.9 (M+Na).
Step 3:
Diphenyl phosphorazidate (0.982 mL, 4.56 mmol) was added to a solution of 3-(2- (methoxycarbonylamino)pyrrolo[l,2-f][l,2,4]triazin-4-yl)thiophene-2-carboxylic acid (39c) (0.725 g, 2.278 mmol) and triethylamine (0.813 mL, 5.83 mmol) in tert-BuOH (25 mL). The mixture was stirred at 100 °C for 4 h and concentrated in vacuum to remove tert- butanol. To the residue was added water and ethylacetate. (1 : 1, 50 mL). The ethylacetate layer was separated, dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel 25 g, eluting with 0-100% ethyl acetate in hexane) to furnish 2-tertbutoxycarbonylamino-3-(2-
((methoxycarbonyl)amino)pyrrolo[2,l-f][l,2,4]triazin-4-yl)Thiophene (39d) (0.16 g, 18 %> yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.58 (s, 1H), 7.93 (dd, J= 2.5, 1.3 Hz, 1H), 7.83 (d, J= 6.0 Hz, 1H), 7.35 (dd, J= 4.9, 1.4 Hz, 1H), 7.14 (dd, J= 6.0, 0.8 Hz, 1H), 6.95 (dd, J= 4.7, 2.5 Hz, 1H), 3.73 (s, 3H), 1.53 (s, 9H); MS (ES+) 390.3 (M+l); (ES-) 388.1 (M-l). Example 85
Methyl (3-(2-fluoro-4-hydroxyphenyl)-3,4-dihydro-5-oxa-4,8,10,
tetraazabenzo[cd]cyclo penta[f]azulen-9-yl)carbamate (40e)
Figure imgf000191_0001
40e
To a solution of 2-tert-butoxycarbonylamino-3-(2-(methoxycarbonylamino)pyrrolo
[l,2f][l,2,4]triazine-4-yl)furan (40d) (0.025 g, 0.067 mmol) and 2-fluoro-4- hydroxybenzaldehyde (22i) (0.012 g, 0.084 mmol) in dioxane (4 mL) was added hydrogen chloride (4M in dioxane, 0.937 mL, 3.75 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuum to dryness to furnish crude product containing methyl (3-(2-fluoro-4-hydroxyphenyl)-3,4-dihydro-5-oxa-4,8,10,10a- tetraazabenzo[cd]cyclo penta[f]azulen-9-yl)carbamate (40e), MS (ES+) 395.984 (M+1).
Preparation of 2-tert-butoxycarbonylamino-3 -(2-(methoxycarbonylamino)pyrrolo [ 1 ,2f] [ 1 ,2,4]triazine-4-yl)furan (40d)
Step 1:
A mixture of methyl 4-chloropyrrolo[l,2-f][l,2,4]triazin-2-ylcarbamate (17d) (0.9 g, 3.97 mmol), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)furan-2-carbaldehyde (40a) (1.01 g, 4.57 mmol), potassium bicarbonate (1.392 g, 13.90 mmol) in ethylene glycol dimethyl ether (15 mL) and water (0.3 mL) was degassed with nitrogen gas for 15 min followed by addition of Palladium(II)bis(triphenylphosphine) dichloride (558 mg, 0.794 mmol). The reaction mixture was heated at 90 °C for 3 h and cooled to room temperature. The solid obtained was diluted with ether (20 mL), collected by filtration washed with ethyl acetate (5 mL), water (5 mL) and dried in vacuum to furnish methyl 4-(2-formylfuran-3- yl)pyrrolo[l,2-f][l,2,4]triazin-2-ylcarbamate (40b) (0.725 g, 64 % yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.50 (s, 1H), 10.45(s, 1H), 8.31 (dd, J= 1.9, 0.8 Hz, 1H), 8.11 (dd, J= 2.5, 1.3 Hz, 1H), 7.59 (d, J= 1.9 Hz, 1H), 7.31 (dd, J= 4.7, 1.3 Hz, 1H), 7.05 (dd, J= 4.7, 2.5 Hz, 1H), 3.70 (s, 3H); MS (ES+) 325.0 (M+K), (ES-) 285.1 (M-
1). Step 2:
To a solution of methyl 4-(2-formylfuran-3-yl)pyrrolo[l,2-f][l,2,4]triazin-2- ylcarbamate (40b) (0.725 g, 2.53 mmol) in acetonitrile (12 mL), t-BuOH (50 mL) was added a solution of sodium dihydrogenphosphate (0.61 g, 5.07 mmol) in water (3 mL) over a period of 5 min followed by 2-methylbut-2-ene (2.68 mL, 25.3 mmol). The reaction was cooled in an ice-water bath and then a solution of sodium chlorite (1.145 g, 12.66 mmol) in water (3 mL) was added dropwise over a period of 5 min. After stirring for 4 h, the reaction mixture was concentrated in vacuum to dryness, the residue obtained was purified by flash column chromatography (silica gel 25 g, eluting with 0-50% methanol in chloroform) to afford 3-(2-(methoxycarbonylamino)pyrrolo[l,2-f][l,2,4]triazin-4-yl)furan-
2- carboxylic acid (40c) (0.83 mg, 108 % yield) as a light yellow solid. Analytical sample was obtained from the fractions collected during column purification as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 13.99 (s, 1H), 10.47 (s, 1H), 8.14 (d, J= 1.8 Hz, 1H), 8.07 (dd, J= 2.5, 1.4 Hz, 1H), 7.13 (d, J= 1.8 Hz, 1H), 6.97 (dd, J= 4.7, 2.5 Hz, 1H), 6.85 (dd, J= 4.7, 1.4 Hz, 1H), 3.68 (s, 3H); MS (ES+) 325.0 (M+Na).
Step 3:
Diphenyl phosphorazidate (1.092 mL, 5.07 mmol) was added to a solution of 3-(2- (methoxycarbonylamino)pyrrolo[l,2-f][l,2,4]triazin-4-yl)furan-2-carboxylic acid (40c) (0.766 g, 2.53 mmol) and triethylamine (0.904 mL, 6.49 mmol) in tert-BuOH (50 mL). The mixture was stirred at 100 °C for 4 h, cooled to room temperature and quenched with water and ethyl acetate (1 : 1, 50 mL). The organic layer was separated, dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column
chromatography (silica gel 25 g, eluting with 0-100% ethyl acetate in hexane) to afford 2- tert-Butoxycarbonylamino-3-(2-(methoxycarbonylamino)pyrrolo[ 1 ,2f] [ 1 ,2,4]triazine-4- yl)furan (40d) (0.23 g, 24 % yield) as light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.51 (s, 1H), 7.88 (dd, J= 2.5, 1.3 Hz, 1H), 7.62 (d, J= 2.3 Hz, 1H), 7.39 (d, J= 2.3 Hz, 1H), 7.34 (dd, J= 4.7, 1.4 Hz, 1H), 6.91 (dd, J= 4.7, 2.5 Hz, 1H), 3.71 (s, 3H), 1.49 (s, 9H); MS (ES+) 374.1 (M+l).
Example 86
4-(9-amino-3,4-dihydro-5-oxa-4,8,10,10a-tetraazabenzo[cd]cyclopenta[f]azulen-3-yl)-
3- fluorophenol (40g)
Figure imgf000193_0001
40g
To a solution of methyl (3-(2-fluoro-4-hydroxyphenyl)-3,4-dihydro-5-oxa- 4,8,10,10a-tetraazabenzo[cd]cyclo penta[f]azulen-9-yl)carbamate (40e) (0.029 g, 0.073 mmol) in methanol (10 mL) was added aqueous 2 N sodium hydroxide (0.367 mL, 0.734 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuum to remove methanol. The reaction mixture was acidified with 1 N HC1 and extracted with ethyl acetate. The ethyl acetate layer was dried, filtered and concentrated in vacuum to furnish product containing 4-(9-amino-3,4-dihydro-5-oxa-4,8,10,10a- tetraazabenzo[cd]cyclopenta[f]azulen-3-yl)-3-fluorophenol (40g); MS (ES+) 360.211 (M+Na), (Es-) 336.068 (M-l).
Example 87
3-tert-Butoxycarbonyl-2-(2-(methoxycarbonylamino)pyrrolo [l,2f] triazin-4-yl)furan (41d)
Figure imgf000193_0002
Diphenyl phosphorazidate (0.114 mL, 0.529 mmol) was added to 2-(2- (methoxycarbonyl amino)pyrrolo[l,2-f][l,2,4]triazin-4-yl)furan-3-carboxylic acid (41c) (80 mg, 0.27 mmol) and triethylamine (0.094 mL, 0.68 mmol) in t-BuOH (5 mL) and the mixture was stirred at 100 °C for 4 h. The reaction mixture was quenched with water (5 mL), and extracted with ethyl acetate (10 mL). The organic layer was dried, filtered and concentrated in vacuum. The residue obtained was purified by flash column
chromatography (silica gel 4 g, eluting with 0-100% ethyl acetate in hexane) to give 3-tert- butoxycarbonyl-2-(2-(methoxycarbonylamino)pyrrolo[l,2f]triazin-4-yl)furan (4 Id) (76 mg 77 % yield) as light yellow solid. 1H NMR (300 MHz, Chloroform-d) δ 7.65 (d, J= 2.1 Hz, 1H), 7.34 (dd, J= 4.7, 1.5 Hz, 1H), 7.15 (s, 1H), 7.12 (s, 1H), 6.98 (t, J= 7.7 Hz, 2H), 6.85 (dd, J= 4.6, 2.5 Hz, 1H), 3.46 (s, 3H), 0.88 (s, 9H). Preparation of 3-tert-butoxycarbonyl-2-(2- (methoxycarbonylamino)pyrrolo [ 1 ,2f]triazin-4-yl)furan (41 d)
Step :1
A mixture of methyl 4-chloropyrrolo[l,2-f][l,2,4]triazin-2-ylcarbamate (17d) (1.0 g, 4.41 mmol), 3-formylfuran-2-ylboronic acid (41a) (0.772 g, 5.52 mmol), potassium bicarbonate (1.55 g, 15.44 mmol) in ethylene glycol dimethyl ether (15 mL) and water (0.3 mL) was degassed with nitrogen gas for 15 min followed by addition followed by addition of Palladium(II)bis(triphenylphosphine) dichloride (0.62 g, 0.883 mmol). The reaction mixture was heated at 90 °C for 3 h and cooled to room temperature and quenched with water (30 mL). The reaction mixture was extracted with ethyl acetate (25 mL). The ethyl acetate layer was washed with brine, dried, filtered and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 12 g, eluting with 0-100% ethyl acetate in hexane) to furnish methyl 4-(3-formylfuran-2-yl)pyrrolo[l,2- f][l,2,4]triazin-2-ylcarbamate (41b) (0.16 g, 13 % yield) as light yellow solid. 1H NMR (300 MHz, DMSO-de) δ 11.06 (s, 1H), 10.55 (s, 1H), 8.23 (dd, J= 1.9, 0.6 Hz, 1H), 8.10 (dd, J= 2.5, 1.4 Hz, 1H), 7.40 (dd, J= 4.7, 1.4 Hz, 1H), 7.19 - 6.99 (m, 2H), 3.71 (s, 3H); MS (ES+) 287.1 (M+l), 309.0 (M+Na).
Step 2:
To a solution of methyl 4-(3-formylfuran-2-yl)pyrrolo[l,2-f][l,2,4]triazin-2- ylcarbamate (41b) (159 mg, 0.555 mmol) in acetonitrile (2 mL), t-BuOH (14 mL) was added a solution of sodium dihydrogenphosphate (133 mg, 1.111 mmol) in water (1 mL) over a period of 5 min followed by 2-methylbut-2-ene (0.588 mL, 5.55 mmol). The reaction was cooled in an ice-water bath and then a solution of sodium chlorite (251 mg, 2.78 mmol) in water (1 mL) was added dropwise over a period of 5 min. After stirring for 1.5 h, the reaction mixture was extracted with ethyl acetate (3x 20 mL). The organic layers were combined dried over MgS04, filtered and concentrated in vacuum to dryness. The residue was triturated with water, and the solid obtained was collected by filtration washed with water, dried in vacuum to give 2-(2-(methoxycarbonylamino)pyrrolo[l,2- f [l,2,4]triazin-4-yl)furan-3-carboxylic acid (41c) (80 mg, 48 % yield) as a light yellow solid which was used as such for the next step. 1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.28 (s, 1H), 8.24 (d, J= 2.1 Hz, 1H), 7.20 (s, 1H), 7.18 (s, 2H), 3.72 (s, 3H); MS (ES+) 303.3 (M+l), 325.0 (M+Na), 626.9 (2M+Na). Example 88
4-(9-amino-3,4-dihydro-5-thia-4,8,10,10a-tetraazabenzo[cd]cyclopenta[f|azulen-3- yl)phenol (56a) and 4-(9-amino-5-thia-4,8,10,10a- tetraazabenzo [cd] cyclopenta [f| azulen-3-yl)phenol (56b)
Figure imgf000195_0001
To a solution of 2-tertbutoxycarbonylamino-3-(2- ((methoxycarbonyl)amino)pyrrolo[2,l-f][l,2,4]triazin-4-yl)Thiophene (39d) (0.170 g, 0.437 mmol) and 4-hydroxybenzaldehyde (29g) (0.067 g, 0.546 mmol) in dioxane (4 mL) was added hydrogen chloride (4M in dioxane, 6.11 mL, 24.45 mmol) and stirred at room temperature 14 h. The reaction mixture was concentrated in vacuum to furnish product containing mixtures of 4-(9-amino-3,4-dihydro-5-thia-4,8,10,10a- tetraazabenzo[cd]cyclopenta[f]azulen-3-yl)phenol (56a) and 4-(9-amino-5-thia-4,8,l 0,10a- tetraazabenzo[cd]cyclopenta[f]azulen-3-yl)phenol (56b); MS (ES+) 332.67 (M+l) for compound 56a, MS (ES+) 330.756 (M+l) for compound 56b.
Example 89
ll-amino-3-(4-hydroxyphenyl)-3H-5,10,12,12a-tetraazabenzo[4,5]cycloocta[l,2,3- cd]inden-4(5H)-one (27c)
Figure imgf000195_0002
To a solution of 2-(2-amino-4-(2-aminophenyl)pyrrolo[l,2-fJ[l,2,4]triazin-5-yl)-2- (4-hydroxyphenyl)acetic acid (27d) (0.15 g, 0.4 mmol) in DMF (5 mL) was added triethylamine (0.278 mL, 2 mmol), 2-(7-Aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HATU) (0.228 g, 0.6 mmol) and heated at 70 °C for 4 h. The reaction was cooled to room temperature and concentrated in vacuum to dryness. The crude residue was purified by flash column chromatography (silica gel 4 g, eluting 0-100% CMA80 in chloroform) to furnish 1 l-amino-3-(4-hydroxyphenyl)-3H- 5,10,12,12a-tetraazabenzo[4,5]cycloocta[l,2,3-cd]inden-4(5H)-one (27c) (0.001 g, 1 % yield) as light green solid. 1H NMR (300 MHz, Methanol-^) δ 7.96 (dd, J= 7.7, 1.8 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.46 (d, J = 2.5 Hz, 1H), 7.36 (d, J= 1.5 Hz, 1H), 7.34 (d, J= 8.6 Hz, 2H), 6.73 (d, J= 8.6 Hz, 2H), 6.37 (dd, J= 2.5, 1.0 Hz, 1H), 5.04 (s, 1H); MS (ES+) 380.0 (M+Na), 737.0 (2M+Na), (ES-) 355.83 (M-l).
Preparation of 2-(2-amino-4-(2-aminophenyl)pyrrolo[l,2-f][l,2,4]triazin-5-yl)-2-(4- hydroxyphenyl)acetic acid (27d)
Step 1:
To a solution of methyl 4-(2-aminophenyl)pyrrolo[l,2-f][l,2,4]triazin-2-ylcarbamate (17e) (0.503 g, 1.78 mmol) and methyl 2-(4-hydroxyphenyl)-2-oxoacetate (25c) (0.384 g, 2.13 mmol) in Methanol (15 mL) was added HC1 (4 M solution in dioxane 3.55 mL, 14.20 mmol). The reaction vessel was sealed and heated at 100 °C for 48 h. The reaction was cooled to room temperature and concentrated in vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel 25 g, eluting with ethyl acetate in hexanes from 0 to 100%) to furnish methyl 3-(4-hydroxyphenyl)-10-((methoxycarbonyl)amino)-3,4-dihydro- 4,9,11,1 la-tetraazadibenzo[cd,f]azulene-3-carboxylate (27a) (0.233 g, 30 % yield) as a yellow solid, which was pure enough to be taken for next step; MS (ES+) 446.0 (M+l), (ES-) 480.8 (M-Cl).
Step 2:
To a solution of methyl 3-(4-hydroxyphenyl)-10-((methoxycarbonyl)amino)-3,4- dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulene-3-carboxylate (27a) (0.230 g, 0.516 mmol) in methanol (20 mL) was added 6 N aqueous HC1 (1.150 mL, 6.90 mmol) and palladium (10%> on carbon) (0.055 g, 0.52 mmol). The slurry was hydrogenated for 82 h at 55 psi. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel 12 g, eluting with ethyl acetate :methanol (9: 1) to 1 : 1 hexanes) from 0-100%) to furnish methyl 2-(4-(2-aminophenyl)-2-(methoxycarbonylamino)pyrrolo[ 1 ,2-fJ [ 1 ,2,4]triazin-5-yl)-2-(4- hydroxyphenyl)acetate (27b) (0.105 g, 0.235 mmol, 45 %> yield) as a yellow-orange solid. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.36 (s, 1H), 7.91 (d, J= 2.7 Hz, 1H), 7.30 - 7.16 (m, 1H), 7.01 (d, J= 7.5 Hz, 1H), 6.87 - 6.75 (m, 3H), 6.69 - 6.54 (m, 4H), 5.61 (t, J = 5.5 Hz, 2H), 4.93 (s, 1H), 3.66 (s, 3H), 3.44 (s, 3H); MS (ES+) 470.0 (M+Na), 917.1 (2M+Na).
Step 3:
To a solution of methyl 2-(4-(2-aminophenyl)-2-
(methoxycarbonylamino)pyrrolo [ 1 ,2-f] [ 1 ,2,4]triazin-5 -yl)-2-(4-hydroxyphenyl)acetate (27b) (0.050 g, 0.112 mmol) in methanol (10 mL) was added aqueous 2 N sodium hydroxide (0.559 mL, 1.117 mmol) and heated at reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to remove methanol. The reaction mixture was acidified with 1 N HC1 and extracted with ethyl acetate. The ethyl acetate layer was dried, filtered and concentrated in vacuum to furnish 2-(2-amino-4-(2- aminophenyl)pyrrolo[l,2-fJ[l,2,4]triazin-5-yl)-2-(4-hydroxyphenyl)acetic acid (27d) (0.150 g, 36 % yield) as a yellow solid, which was used as such in next step; MS (ES-) 374.184. Example 90
Inhibition constants (ICsos) 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 23:329-336; Karaman et al. (2008) Nature Biotechnology 26: 127-132; C. Tanego et al (2009): "Comparison of Bio luminescent Kinase Assay Using Substrate Depletion and Product Formation", Assay and Drug Development Technologies, 7: 606-615; H. Li et al (2009): "Evaluation of an Antibody-Free ADP Detection Assay: ADP-Glo", Assay and Drug Development Technologies, 7: 598-605; and Promega (2009): "ADP-Glo™ Kinase Assay", Technical Manual, Revised 8/09.
Inhibition constants were determined using 11 -point dose response curves which were performed in triplicate. Table 1 shown below lists compounds of the invention and their respective IC50 values.
Table 1. Activity for representative compounds of the invention for one or more memebers of the JAK family of enzymes
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Example 91
The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans. (i) Tablet 1 mg/tablet
Compound X 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0
300.0 (ii) Tablet 2 mg/tablet
Compound X 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0
500.0
Cm ) Capsule mg/capsule
Compound X 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5
Pregelatinized starch 120.0 Magnesium stearate _M
600.0
(iv Injection 1 (Ί mg/mL) mg/mL
Compound X (free acid form) 1.0
Dibasic sodium phosphate 12.0
Monobasic sodium phosphate 0.7
Sodium chloride 4.5 1.0 N Sodium hydroxide solution
(pH adjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL (V) Injection 2 (10 mg/mL) mg/mL
Compound X (free acid form) 10.0
Monobasic sodium phosphate 0.3
Dibasic sodium phosphate 1.1
Polyethylene glycol 400 200.0
01 N Sodium hydroxide solution
(pH adjustment to 7.0-7.5) q.s.
Water for injection q.s. ad 1 mL
(vi) Aerosol mg/can
Compound X 20.0
Oleic acid 10.0
Trichloromonofluoromethane 5,000.0
Dichlorodifluoromethane 10,000.0
Dichlorotetrafluoroethane 5,000.0
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
INCORPORATION BY REFERENCE
All publications, patents, and patent documents cited above are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

hat is claimed is:
Figure imgf000202_0001
I
wherein:
A is a fused aryl or heteroaryl, wherein any aryl or heteroaryl of A is optionally substituted with one or more groups selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Cy)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd;
W is -N- or -CH2N-, Z is C, and the bond represented by— is a double bond; or W is -NRs-, -C(0)0- or -C(0)NRs-, Z is CRla, and the bond represented by— is a single bond; or W is -NReC(O)-, -C(O)-, -CH2- or -C(=NH)-, Z is CRla or N and the bond represented by— is a single bond;
X is N or CR3; Y is N or CR4 and V is N or CR5 provided that no more than two of X, Y, or V is N;
Rla is H, or -C(0)ORf;
R1 is H, (Ci-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, -(Ci-Ce)alkylaryl, -(Ci-C6)alkylheteroaryl, (C3-Cy)cycloalkyl, heterocycle, aryl, heteroaryl, -C(0)(Ci-C6)alkyl, -C(0)0(Ci-C6)alkyl or -S(0)2(Ci-C6)alkyl wherein any aryl or heteroaryl of R1 is optionally substituted with one or more groups selected from the group consisting of Z1, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(Ci-C6)haloalkyl, -(Ci-C6)alkylNRiRj, -(Ci-C6)alkylORg, -(Ci-C6)alkylSRg, -(Ci-C6)alkylN 02, -(Ci-C6)alkylCN and -(Ci-C6)alkylOH, and wherein any
(C3-Cy)cycloalkyl, -(Ci-Ce)alkylaryl, -(Ci-C6)alkylheteroaryl or heterocycle of R1 is optionally substituted with one or more groups selected from the group consisting of Z1, oxo, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(Ci-C6)haloalkyl, -(Ci-C6)alkylNRiRj, -(Ci-C6)alkylORg, -(Ci-C6)alkylSRg, -(Ci-C6)alkylN 02, -(Ci-C6)alkylCN and -(Ci-C6)alkylOH, and wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -C(0)(Ci-C6)alkyl, -C(0)0(Ci-C6)alkyl or -S(0)2(Ci-C6)alkyl of R1 is optionally substituted with one or more Z1 groups;
R2 is H, halogen, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, aryl, heteroaryl, heterocycle, N02, CN, -OH, -ORk, -NRmRn, N3,
SH, -SRk, -C(0)Ro, -C(0)OR0, -C(0)NRmRn,
Figure imgf000203_0001
-NRoCORk, -NRoC(0)ORk, -NR0C(0)OH, -NR0S(0)2Rk, -NRoCONRmRn, -OC(0)NRmRn, -S(0)Rk, -S(0)NRmRn, -S( 0)2Rk, -S(0)2OH, or -S(0)2NRmR„, wherein any (Ci-C8)alkyl, (C2-C8)alkenyl,
(C2-C8)alkynyl, aryl or heteroaryl of R2 is optionally substituted with one or more Z2 groups, and wherein any (C3-C8)cycloalkyl or heterocycle of R2 is optionally substituted with one or more groups selected from the group consisting of Z2, oxo and
Figure imgf000203_0002
R3 is H, OH, N02, C02H,
C02Rr, -C(0)NRpRq, -C(0)NHNRpRq, -C(0)NHNHC02Rr, -NHS(0)2Rr, -NHC02Rr, -NH CORs, -NRpRq or halogen;
R4 is H, OH, N02, C02H,
C02Rr, -C(0)NRpRq, -C(0)NHNRpRq, -C(0)NHNHC02Rr, -NHS(0)2Rr, -NHC02Rr, -NH CORs, -NRpRq or halogen;
R5 is H, halogen, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, heteroaryl, heterocycle, N02, CN, OH, -ORw, -NRURV,
N3, _SH, -SRW, -C(0)(Ci-C6)alkyl, -C(0)(C2-C6)alkenyl, -C(0)(C2-C6)alkynyl, -C(0)(C3-C6 )cycloalkyl, -C(0)aryl, -C(0)heteroaryl, -C(0)heterocycle, -C(0)ORw, -C(0)NRuRv, -C(=N RW)NRURV, -NRwCOR,, -NRwC(0)OR,, -NRwS(0)2R,, -NRwCONRuRv, -OC(0)NRuRv, -S( 0)Rt, -S(0)NRuRv, -S(0)2R,, -S(0)2OH, -S(0)2NRuRv or -C(=0)C(=0)NH(Ci-C6)alkyl, wherein any aryl, -C(0)aryl, -C(0)heteroaryl, or heteroaryl of R5 is optionally substituted with one or more Z4 groups and wherein any (Ci-C6)alkyl, (C3-C6)cycloalkyl,
(C2-C6)alkenyl,
(C2-C6)alkynyl, -C(0)(Ci-C6)alkyl, -C(0)(C2-C6)alkenyl, -C(0)(C2-C6)alkynyl, -C(0)(C3-C 6)cycloalkyl, -C(0)heterocycle or heterocycle of R5 is optionally substituted with one or more groups selected from the group consisting of Z4, oxo and =NORw;
each Ra is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl; each Rb is independently (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-Cv)cycloalkyl, heterocycle, heteroaryl or aryl;
Rc and Rd are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, heterocycle, aryl and heteroaryl; or Rc and Rd together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino;
each Re is independently H, (Ci-C6)alkyl, -(Ci-Ce)alkylaryl or -C(0)ORsi;
each Rei is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, -(Ci-C6)alkylaryl, -(Ci-C6)alkylheteroaryl, (C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl;
each Rf is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, -(Ci-Ce)alkylaryl, -(Ci-C6)alkylheteroaryl, (C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl;
each Rg is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, -(Ci-Ce)alkylaryl, -(Ci-C6)alkylheteroaryl, (C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of Rg is optionally substituted with one or more groups selected from the group consisting of halogen, OH, CN and NRz5Rz6, and wherein any -(Ci-Ce)alkylaryl, -(Ci-C6)alkylheteroaryl, (C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl of Rg is optionally substituted with one or more groups selected from the group consisting of halogen, OH, CN, NRz5Rz6 and
(Ci-C6)alkyl;
each R is independently (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C7)cycloalkyl, heterocycle, heteroaryl or aryl;
Ri and Rj are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, heterocycle, aryl and heteroaryl; or Ri and Rj together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino;
Rk is (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, heterocycle, heteroaryl or aryl;
Rm and Rn are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, heterocycle and heteroaryl, wherein any (Ci-C6)alkyl of Rm or Rn is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of -C(0)OH and OH; or Rmand Rm together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino;
Ro is H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, heterocycle, heteroaryl or aryl;
Rp and Rq are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-C6)alkylaryl, heterocycle and heteroaryl, wherein any (Ci-C6)alkyl of Rp or Rq is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of -C(0)OH and OH; or Rp and Rq together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
each Rr is independently selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-Ce)alkylaryl, heterocycle and heteroaryl;
each Rs is independently selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-Ce)alkylaryl, heterocycle and heteroaryl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-C6)alkylaryl, heterocycle or heteroaryl of Rs is optionally substituted with one or more halogens;
each Rt is independently selected from the group consisting of (Ci-C6)alkyl, (C2-C6)alkenyl, -(C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-Ce)alkylaryl, heterocycle and heteroaryl;
Ru and Rv are each independently selected from the group consisting of H,
(Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-C6)alkylaryl, heterocycle and heteroaryl, wherein any (Ci-C6)alkyl of Ru or Rv is optionally substituted with one or more (e.g., 1, 2 or 3) groups selected from the group consisting of -C(0)OH and OH; or Ru and Rv together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino ring;
each Rw is independently selected from the group consisting of H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, -(Ci-C6)alkylaryl, heterocycle and heteroaryl;
each Z1 is independently selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, (C3-Cy)cycloalkyl,
CN, -ORg, -OC(0)Rh, -OC(0)NRiRj, -SRg, -S(0)Rg, -S(0)2OH, -S(0)2Rh, -S(0)2ORh, -S(0 )2NRiRj, -NRiRj, -N(ORg)Rg, -NRgC(0)Rh, -NRgC(S)Rh, -NRgC02Rh, -NRgC(0)NRiRj, -NR gS(0)2NRiRj, -NRgC(S)NR1RJ, -NRgS(0)2Rh,
N02, -B(ORg)2, -CHO, -C(0)Rg, -C(S)Rg, -C(0)ORg, -C(0)NRiRj, -C(S)NRiRj, -C(=NRg)N
RiRj, -C(0)N(ORg)Rg, -C(=NORg)Rg, -NRgNRgC(0)Rh, -NRgNRgC (O)NRiRj , -NRgNRgCO
2Rh, -C(0)C(0)Rg and -C(0)CH2C(0)Rg, wherein any aryl, heteroaryl, heterocycle or
(C3-Cy)cycloalkyl of Z1 is optionally substituted with one or more groups selected from the group consisting of NH2, -NH(Ci-C4)alkyl, -N(Ci-C4)alkyl2, halogen,
(Ci-C4)alkyl, -0(Ci-C4)alkyl, N02, CN C02H, C(0)0(Ci-C4)alkyl, -0(Ci-C4)haloalkyl and
(Ci-C4)haloalkyl;
each Z2 is independently selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, Rz, OH, CN, -ORz, -Oaryl, -OC(0)Rz, -OC(0)NRziRz2,
SH, -SRZ, -Saryl, -Sheteroaryl, -S(0)Rz, -S(0)aryl, -S(0)heteroaryl, -S(0)2OH, -S(0)2Rz, - S(0)2aryl, _S(0)2heteroaryl, -S(0)2NRziRz2, -NRziRz2, -NHCORz, -NHCOaryl, -NHCOheter oaryl, -NHC02Rz, -NHCONRziRz2, -NHS(0)2Rz, -NHS(0)2aryl, -NHS(0)2NH2,
N02, -CHO, -C(0)Rz, -C(0)OH, -C(0)ORz, -C(0)NRziRz2 and -C(0)C(0)Rz, wherein any aryl, -Oaryl, -Saryl, -S(0)aryl, -S(0)2aryl, -NHCOaryl or -NHS(0)2aryl of Z2 is optionally substituted with one or more Z5 groups;
each Z4 is independently selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, Rz, OH, CN, -ORz, -Oaryl, -OC(0)Rz, -OC(0)NRziRz2,
SH, -SRZ, -Saryl, -Sheteroaryl, -S(0)Rz, -S(0)aryl, -S(0)heteroaryl, -S(0)2OH, -S(0)2Rz, - S(0)2aryl, _S(0)2heteroaryl, -S(0)2NRziRz2, -NRziRz2, -NHCORz, -NHCOaryl, -NHCOheter oaryl, -NHC02Rz, -NHCONRziRz2, -NHS(0)2Rz, -NHS(0)2aryl, -NHS(0)2NH2,
N02, -CHO, -C(0)Rz, -C(0)OH, -C(0)ORz, -C(0)NRziRz2 and -C(0)C(0)Rz, wherein any aryl, -Oaryl, -Saryl, -S(0)aryl, -S(0)2aryl, -NHCOaryl or -NHS(0)2aryl of Z4 is optionally substituted with one or more Z5 groups;
each Z5 is independently halogen, aryl, Rz, OH, CN,
ORz, -Oaryl, -Oheteroaryl, -OC(0)Rz, -OC(0)NRziRz2, SH,
SRZ, -Saryl, -Sheteroaryl, -S(0)Rz, -S(0)aryl, -S(0)heteroaryl, -S(0)2OH, -S(0)2Rz, -S(0)2 aryl, -S(0)2heteroaryl, -S(0)2NRziRz2, -NRziRz2, -NHCORz, -NHCOaryl, -NHCOheteroaryl , -NHC02Rz, -NHCONRziRz2, -NHS(0)2Rz, -NHS(0)2aryl, -NHS(0)2NH2, N02,
CHO, -C(0)Rz, -C(0)OH, -C(0)ORz, -C(0)NRziRz2, -C(0)C(0)Rz, heterocycle or heteroaryl; each Rz is independently (Ci-C6)alkyl or (C3-C6)cycloalkyl, wherein any
(Ci-C6)alkyl of Rz is optionally substituted with one or more Rz4 groups, and wherein any (C3-C6)cycloalkyl of Rz is optionally substituted with one or more groups selected from the group consisting of Rz4, (C1-C6)alkyl, -(C1-C6)alkylCN and -(Ci-C6)alkylOH;
Rzi and Rz2 are each independently selected from the group consisting of H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-Ce)alkynyl, (C3-C6)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl or (C2-Ce)alkynyl of Rzi or Rz2 is optionally substituted with one or more Rz3 groups and wherein any aryl or heteroaryl of Rzi or Rz2 is optionally substituted with one or more (Ci-C6)alkyl or Rz3 groups, and wherein any heterocycle or (C3-C6)cycloalkyl of Rzi or Rz2 is optionally substituted with or more (Ci-C6)alkyl, oxo or Rz3 groups; or Rzi and Rz2 together with the nitrogen to which they are attached form a cyclic amino optionally substituted with one or more (Ci-C6)alkyl, oxo or Rz3 groups;
each Rz3 is independently selected from the group consisting of halogen, CN, CF3, NRz5Rz6, OH, -0(Ci-C6)alkyl, -C(0)NRz5Rz6, -C(0)(Ci-C6)alkyl, aryl, heterocycle and heteroaryl, wherein any heterocycle of Rz3 is substituted with one or more (Ci-C6)alkyl; each Rz4 is independently selected from the group consisting of halogen, CN, OH, -NRz5Rz6, -SCN, -0(Ci-C6)alkyl, -Sheteroaryl, -S(0)aryl, -S(0)2aryl, -Oaryl, -C(0)NR z5RZ6, (C3-C6)cycloalkyl, -CH2NHCOaryl, -CH2OCH2aryl, biphenyl, aryl, heterocycle and heteroaryl, wherein any aryl, heteroaryl,
Sheteroaryl, -S(0)aryl, -S(0)2aryl, -Oaryl, -CH2NHCOaryl, -CH2OCH2aryl, biphenyl or heterocycle of Rz4 may be optionally substituted with one or more halogen,
CN, -(Ci-C6)alkyl, -NH2, -NHheteroaryl, -NHS(0)2(Ci-C6)alkyl or -0(Ci-C6)alkyl; and
RZ5 and Rz6 are each independently selected from the group consisting of H and (Ci-C6)alkyl, wherein (Ci-C6)alkyl is optionally substituted with NH2;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein X is CR3.
3. The compound of claim 1 or 2, wherein Y is CR4.
4. The compound claim 1, wherein the compound of formula I is a compound of formula Ia3 :
Figure imgf000208_0001
Ia3 or a pharmaceutically acceptable salt thereof.
5. The compound of any one of claims 1-4, wherein A is aryl, wherein any aryl of A is optionally substituted with one or more groups selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd.
6. The compound of any one of claims 1-4, wherein A is phenyl, wherein phenyl is optionally substituted with one or more groups selected from the group consisting of halogen, aryl, heteroaryl, heterocycle, (Ci-C6)alkyl, (Ci-Ce)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl,
CN, -ORa, -OC(0)Rb, -OC(0)NRcRd, -SRa, -S(0)Rb, -S(0)2OH, -S(0)2Rb, -S(0)2NRcRd, - NRcRd, -NRaCORb, -NRaC02Rb, -NRaCONRcRd, -NRaS(0)2Rb,
N02, -CHO, -C(0)Ra, -C(0)ORa and -C(0)NRcRd.
7. The compound of claim 1, wherein the compound of formula I is a compound of formula Ial3:
Figure imgf000208_0002
Ial3 or a pharmaceutically acceptable salt thereof.
8. The compound of any one of claims 1-7, wherein W is -N-, Z is C, and the bond represented by— is a double bond; or W is -NRe- or -C(0)NRe-, Z is CRla, and the bond represented by— is a single bond; or W is -NRsC(O)- or -C(O)-, Z is CRla or N and the bond represented by— is a single bond.
9. The compound of any one of claims 1-7, wherein W is -N-, Z is C and the bond represented by— is a double bond; or W is -NRe- or -C(0)NRe-, Z is CRla and the bond represented by— is a single bond; or W is -NRsC(O)-, Z is CRla and the bond represented by— is a single bond.
10. The compound of any one of claim 1-9, wherein Rg is H.
1 1. The compound of any one of claim 1-10, wherein Rla is H or -C(0)0(Ci-C6)alkyl.
12. The compound of any one of claim 1-10, wherein Rla is H.
13. The compound of any one of claim 1-12, wherein R2 is H or -NRmRn.
14. The compound of any one of claim 1-12, wherein R2 is H or -NH2.
15. The compound of any one of claims 1-14, wherein V is N or CC(0)NRuRv.
16. The compound of any one of claims 1-14, wherein V is N.
17. The compound of any one of claims 1-16, wherein R1 is (C3-Cy)cycloalkyl, heterocycle, aryl or heteroaryl, wherein any aryl or heteroaryl of R1 is optionally substituted with one or more groups selected from the group consisting of Z1, (Ci-C6)alkyl,
(C2-C6)alkenyl, (C2-C6)alkynyl,
(Ci-C6)haloalkyl, -(Ci-C6)alkylNRiRj, -(Ci-C6)alkylORg, -(Ci-C6)alkylSRg, -(Ci-C6)alkylN 02, -(Ci-C6)alkylCN and -(Ci-C6)alkylOH, and wherein any (C3-Cy)cycloalkyl or heterocycle of R1 is optionally substituted with one or more groups selected from the group consisting of Z1, oxo, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(Ci-C6)haloalkyl, -(Ci-C6)alkylNRiRj, -(Ci-C6)alkylORg, -(Ci-C6)alkylSRg, -(Ci-C6)alkylN 02, -(Ci-C6)alkylCN and -(Ci-C6)alkylOH.
18. The compound of any one of claims 1-16, wherein R1 is phenyl, wherein phenyl is optionally substituted with one or more groups selected from the group consisting of Z1, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(Ci-C6)haloalkyl, -(Ci-C6)alkylNRiRj, -(Ci-C6)alkylORg, -(Ci-C6)alkylSRg, -(Ci-C6)alkylN 02, -(Ci-C6)alkylCN and -(Ci-C6)alkylOH.
19. The compound of any one of claims 1-16, wherein R1 is phenyl, wherein phenyl is optionally substituted with one or more groups selected from the group consisting of halogen, CN, -ORg, -NRiRj, N02, -B(ORg)2, (Ci-C6)alkyl and (C2-C6)alkenyl.
20. The compound of any one of claims 1-16, wherein R1 is phenyl, wherein phenyl is optionally substituted with one or more groups selected from the group consisting of halogen, -ORg and N02.
21. The compound of any one of claims 1-16, wherein R1 is selected from the group consisting of:
Figure imgf000210_0001
Figure imgf000211_0001
22. The compound of any one of claims 1-16, wherein R1 is selected from the group consisting of:
Figure imgf000211_0002
23. The compound of any one of claims 1-16, wherein R1 is selected from the group consisting of:
Figure imgf000212_0001
24. The com ound of claim 1, which is:
Figure imgf000212_0002
Figure imgf000212_0003
Figure imgf000213_0001
pharmaceutically acceptable salt thereof. 26. The compound of claim 1, which is:
Figure imgf000213_0002
Figure imgf000214_0001
Figure imgf000214_0002
29. The compound of claim 1, which is:
Figure imgf000215_0001
The compound of claim 1 , which
Figure imgf000215_0002
Figure imgf000216_0001
pharmaceutically acceptable salt thereof. 31. The compound of claim 1 , which is:
Figure imgf000216_0002
pharmaceutically acceptable salt thereof. 32. The compound of claim 1, which is:
Figure imgf000217_0001
Figure imgf000217_0002
-215 -
Figure imgf000218_0001
, or a pharmaceutically acceptable salt thereof.
34. The compound of claim 1, selected from the group consisting of:
4-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol,
4-(4,9, 11 , 11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol,
3- Chloro-4-(3 ,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
4- (4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-3-chlorophenol,
4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-3-fluorophenol,
4-(l O-Amino-4,9, 11,11 a-tetraazadibenzo[cd,fJazulen-3-yl)-3-fluorophenol,
Methyl 3-(4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulene-3- carboxylate,
3-(4-Hydroxyphenyl)-3H-5,10,12,12a-tetraazabenzo[4,5]cycloocta[l,2,3-cd]inden-4(5H)-o ne,
3-(3-Nitrophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
and pharmaceutically acceptable salts thereof.
35. The compound of claim 1, selected from the group consisting of:
3- (4-Nitrophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
2-(4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)benzene-l ,4-diol,
4- (3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
1 l-Amino-3-(2-fluoro-4-hydroxyphenyl)-3H-4,10,12,12a-tetraazabenzo[4,5]
cycloocta[l,2,3-cd]inden-5(4H)-one,
2-(3,4-Dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-5-methoxyphenol,
4-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)benzene- 1 ,2-diol,
2-Chloro-3-(3 ,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-6-methoxyphenol, 2-Bromo-4-(3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
2-Chloro-4-(3 ,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol, and pharmaceutically acceptable salts thereof.
36. The compound of claim 1, selected from the group consisting of:
2-Chloro-4-(3 ,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-6-methoxyphenol,
2- (4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-5-methoxyphenol,
2,6-Dichloro-4-(3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol, 4-(3,4-Dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol,
4-(3,4-Dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-2-methylphenol,
4-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-fluorophenol,
4-(3,4-Dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-2-methoxyphenol,
4-(4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-N,N-dimethylaniline,
3- Phenyl-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulene,
and pharmaceutically acceptable salts thereof.
37. The compound of claim 1, selected from the group consisting of:
3-(2,4-Dichlorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(4-Chlorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)benzonitrile,
3-(3,5-Dichlorophenyl)-3,4-dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulene,
3-(4-Ethylphenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(4-(Methylthio)phenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(4-(Tert-butyl)phenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(4-Propoxyphenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(3-Fluoro-4-methoxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,fJ azulene, and pharmaceutically acceptable salts thereof.
38. The compound of claim 1, selected from the group consisting of:
3-(2,3,6-Trifluorophenyl)-3,4-dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulene,
3-(4-Chloro-3-fluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f] azulene,
3- (2,4,5-Trifluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
4- (3,4-Dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)-2-methoxyphenol,
4-(4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-methylphenol,
4-(4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol,
4-(4,9, 11 , 11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-bromophenol,
Methyl (3-(4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulen-10- yl)carbamate, Methyl (3-(3,4-dihydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f] azulen-10- yl)carbamate,
and pharmaceutically acceptable salts thereof.
39. The compound of claim 1, selected from the group consisting of:
Methyl (3-(4-hydroxy-2-methylphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo
[cd,f]azulen- 10-yl)carbamate,
Methyl (3-(4-hydroxy-3-methylphenyl)-3,4-dihydro-4,9,l 1,1 la- tetraazadibenzo [cd,f] azulen- 10-yl)carbamate,
Methyl (3-(4-hydroxy-3-methoxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo [cd,f] azulen- 10-yl)carbamate,
Methyl (3-(3,4-dihydroxy-5-methoxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f] azulen- 10-yl)carbamate,
Methyl (3-(3-chloro-4-hydroxy-5-methoxyphenyl)-3,4-dihydro-4, 9,11,1 la-tetraazadibenzo [cd,f]azulen- 10-yl)carbamate,
Methyl (3-(2,5-dihydroxyphenyl)-4,9,l 1,1 la-tetraazadibenzo[cd,fjazulen-10-yl)carbamate, Methyl (3-(3-bromo-4-hydroxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo
[cd,f]azulen- 10-yl)carbamate,
Methyl (3-(2-chloro-3-hydroxy-4-methoxyphenyl)-3,4-dihydro-4, 9,11,1 la-tetraazadibenzo [cd,f]azulen- 10-yl)carbamate,
Methyl (3-(3-chloro-4-hydroxyphenyl)-3,4-dihydro-4, 9,11,1 la-tetraazadibenzo
[cd,f]azulen- 10-yl)carbamate,
and pharmaceutically acceptable salts thereof.
40. The compound of claim 1, selected from the group consisting of:
4-(4,9, 11 , 11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-fluorophenol,
4-(l O-Amino-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-bromophenol,
4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro-6- methoxyphenol,
3- (l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro-6- methoxyphenol,
4- Bromo-5-(3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-methoxyphenol,
2- (l O-Amino-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)benzene- 1 ,4-diol,
3- (4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro-6-methoxyphenol,
4- (4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-chloro-6-methoxyphenol, 4-(4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-2-chlorophenol,
and pharmaceutically acceptable salts thereof.
41. The compound of claim 1, selected from the group consisting of:
3-(2,3-Dihydrobenzofuran-5-yl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo [cd,f]azulene, 3-(2,6-Difluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(4-Isopropoxyphenyl)-3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulene,
3- (2,4-Difluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
4- (10-Amino-3,4-dihydro-4,9,l l,l la-tetraazadibenzo[cd,f]azulen-3-yl)benzene-l,2-diol, 4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-methylphenol, 4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2,6-dichlorophenol,
3- (2,5-Difluorophenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
4- (l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-3-methylphenol, and pharmaceutically acceptable salts thereof.
42. The compound of claim 1, selected from the group consisting of:
4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)-2-chlorophenol, 4-(l 0-Amino-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
4-(l O-Amino-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)phenol,
3-(3-((2-Chlorobenzyl)oxy)phenyl)-3,4-dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene, 3-(3-((2-Chlorobenzyl)oxy)phenyl)-4,9, 11,11 a-tetraazadibenzo[cd,f]azulene,
3-(3,4-Dihydro-4,9, 11,11 a-tetraazadibenzo[cd,f]azulen-3-yl)aniline,
3- (4,9,l 1,1 la-Tetraazadibenzo[cd,f]azulen-3-yl)aniline,
4- (4,9,l 1,1 la-Tetraazadibenzo[cd,f]azulen-3-yl)phenol,
5- (4,9, 11,11 a-Tetraazadibenzo[cd,f]azulen-3-yl)-4-bromo-2-methoxyphenol,
Methyl (3 -(2-hydroxy-4-methoxyphenyl)-3,4-dihydro-4, 9,11,1 la- tetraazadibenzo [cd,f] azulen- 10-yl)carbamate,
Methyl (3-(3,5-dichloro-4-hydroxyphenyl)-4, 9,11,1 la-tetraazadibenzo [cd,f]azulen-10- yl)carbamate,
and pharmaceutically acceptable salts thereof.
43. The compound of claim 1, selected from the group consisting of:
4-(9-Amino-3,4-dihydro-5-thia-4,8,10,10a-tetraazabenzo[cd]cyclopenta[fJazulen-3-yl)-3- fluorophenol,
4-(9-Amino-5-thia-4,8, 10, 10a-tetraazabenzo[cd]cyclopenta[fJazulen-3-yl)-3-fluorophenol, Methyl (3-(2-fluoro-4-hydroxyphenyl)-3,4-dihydro-5-oxa-4,8, 10, 10a- tetraazabenzo[cd]cyclo penta[f]azulen-9-yl)carbamate,
4-(9-Amino-3,4-dihydro-5-oxa-4,8,10,10a-tetraazabenzo[cd]cyclopenta[f]azulen-3-yl)-3- fluorophenol,
4-(9-Amino-3,4-dihydro-5-thia-4,8,10,10a-tetraazabenzo[cd]cyclopenta[f]azulen-3- yl)phenol,
4-(9-Amino-5-thia-4,8, 10, 10a-tetraazabenzo[cd]cyclopenta[fJazulen-3-yl)phenol, and pharmaceutically acceptable salts thereof.
44. A pharmaceutical composition comprising a compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
45. A compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, for use in medical therapy.
46. A compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of a disease or condition associated with pathologic Janus kinase (JAK) activation.
47. The compound of claim 46, wherein the disease or condition associated with pathologic JAK activation is cancer.
48. The compound of claim 47, wherein the cancer is a hematologic malignancy.
49. The use of a compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or condition associated with pathologic Janus kinase (JAK) activation in a mammal.
50. The use of claim 49, wherein the disease or condition associated with pathologic JAK activation is cancer.
51. The use of claim 50, wherein the cancer is a hematologic malignancy.
52. A compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic suppression of an immune response.
53. The use of a compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for suppressing an immune response in a mammal.
54. A method for treating a disease or condition associated with pathologic Janus kinase (JAK) activation in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof.
55. The method of claim 54, wherein the disease or condition associated with pathologic JAK activation is cancer.
56. The method of claim 55, wherein the cancer is a hematologic malignancy.
57. A method for suppressing an immune response in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof.
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