WO2011020861A1 - Heterocyclic oxime compounds - Google Patents

Heterocyclic oxime compounds Download PDF

Info

Publication number
WO2011020861A1
WO2011020861A1 PCT/EP2010/062057 EP2010062057W WO2011020861A1 WO 2011020861 A1 WO2011020861 A1 WO 2011020861A1 EP 2010062057 W EP2010062057 W EP 2010062057W WO 2011020861 A1 WO2011020861 A1 WO 2011020861A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
alkyl
compound
methyl
optionally substituted
Prior art date
Application number
PCT/EP2010/062057
Other languages
French (fr)
Inventor
Miao Dai
Xingnian Fu
Feng He
Lei Jiang
Yue Li
Fang Liang
Lei Liu
Yuan Mi
Yao-Chang Xu
Guoliang Xun
Xiaoxia Yan
Zhengtian Yu
Ji Yue Zhang
Original Assignee
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to EP10762878A priority Critical patent/EP2467383A1/en
Priority to MX2012002179A priority patent/MX2012002179A/en
Priority to JP2012525167A priority patent/JP5775871B2/en
Priority to CA2771432A priority patent/CA2771432A1/en
Priority to BR112012008061A priority patent/BR112012008061A2/en
Priority to AU2010284972A priority patent/AU2010284972A1/en
Priority to CN201080047132.XA priority patent/CN102574853B/en
Priority to KR1020127007032A priority patent/KR20120089463A/en
Priority to EA201200318A priority patent/EA201200318A1/en
Priority to IN1453DEN2012 priority patent/IN2012DN01453A/en
Publication of WO2011020861A1 publication Critical patent/WO2011020861A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

Definitions

  • the invention relates to bicyclic compounds of formula (I) and salts thereof, the uses of such compounds to treat the human or animal body, in particular with regard to a proliferative disease, pharmaceutical compositions comprising such compounds, combinations comprising a compound of formula (I), and processes for the preparation of such
  • the Hepatocyte Growth Factor Receptor herein referred to as c-Met, is a receptor tyrosine kinase that has been shown to be over-expressed and/or genetically altered in a variety of malignancies, specifically, gene amplification and a number of c-Met mutations are found in various solid tumors, see e.g. WO2007/126799. Further, the receptor tyrosine kinase c-Met is involved in the processes of migration, invasion and morphogenesis that accompany embryogenesis and tissue regeneration. C-met is also involved in the process of metastasis. Several lines of evidence have indicated that c-Met plays a role in tumor pathogenesis.
  • Gain of function germ line mutations in c-Met is associated with development of hereditary papillary renal cell carcinoma (PRCC). Amplification or mutations in c-Met have also been reported in sporadic forms of PRCC, in head and neck squamous cell carcinoma, in gastric carcinoma, in pancreatic carcinoma and in lung cancer. Such alterations have been shown in selected instances to confer dependence of the tumor on c-Met and/or resistence to other targeted therapies. Elevated levels of c-Met, together with its unique ligand HGF/SF, are observed at high frequency in multiple clinically relevant tumors. A correlation between increased expression and disease progression, metastases and patient mortality has been reported in several cancers, including bladder, breast, squamous cell carcinoma and gastric carcinoma as well as leiomyosarcoma and glioblastoma.
  • PRCC hereditary papillary renal cell carcinoma
  • WO 2008/008539 discloses certain fused heterocyclic derivatives which are useful in the treatment of HGF mediated diseases.
  • WO 2007/013673 discloses fused heterocyclic derivatives as Lck inhibitors which are useful as immunosuppressive agents.
  • EP0490587 discloses certain pyrazolopyrimidines which are useful as angiotensin Il antagonists.
  • the disclosures of the publications cited in this specification are herein incorporated by reference. It is an aim of the present invention to provide further compounds that modulate, and in particular inhibit, c-Met.
  • the compounds of the formula (I) described herein are inhibitors of c-Met and have a number of therapeutic applications.
  • the compounds of formula (I) are suitable for use in the treatment of diseases dependent on c-Met activity, especially solid tumors or metastasis derived therefrom.
  • compounds of the invention also have utility as antiinflammatory agents, for example for the treatment of an inflammatory condition which is due to an infection.
  • the compounds of the invention are metabolically stable, are non-toxic and demonstrate few side-effects.
  • preferred compounds of the invention exist in a physical form that is stable, non-hygroscopic and easily formulated.
  • One aspect of the invention is directed to compounds of formula (I) having an activity that is superior to the activity of compounds of the prior art, or other similar compounds.
  • Another aspect of the invention is directed to compounds of formula (I) having have good kinase selectivity.
  • Preferred compounds of the invention posses favourable pharmacokinetic properties, such as good in-vivo exposure and/or solubility.
  • the present invention relates to a compound of the formula (I)
  • Y is C or N
  • X is CH or N
  • B is CH or N
  • A is a ring; such that when X is CH and B is N, ring A is ring Ai or ring Aii;
  • R 1 is a group selected from i, ii and iii: V - A - wherein R 5 is heteroaryl 1 ,
  • R 6 is hydrogen, deuterium, OH, methyl or halo
  • R 7 is hydrogen, deuterium, halo, or (d-C 3 )alkyl, wherein said (d-C 3 )alkyl is optionally substituted by one or more substituents independently selected from OH and halo; or R 6 and R 7 , together with the carbon to which they are attached, form cyclopropyl
  • n is O, 1 or 2;
  • R 2 is hydrogen, NH 2 , or (d-C 4 )alkyl, wherein said (d-C 4 )alkyl is optionally substituted by one or more substituents independently selected from OH, NH 3 and halo; and R 3 is
  • phenyl wherein said phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (d-C 3 )alkyl and (d-C 3 )alkoxy, wherein said (C r C 3 )alkyl and (C r C 3 )alkoxy are each optionally substituted by one or more halo substituents,
  • a “compound of the invention”, or “compounds of the invention”, or “a compound of the present invention” means a compound or compounds of formula (I) as described herein.
  • the terms “including”, “containing” and “comprising” are used herein in their open, non-limiting sense.
  • Treatment includes prophylactic (preventive) and therapeutic treatment as well as the delay of progression of a disease, disorder or condition. Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight- chain or branched.
  • Alkyl refers to a straight-chain or branched-chain alkyl group. For example, (d-C 4 )alkyl includes methyl, ethyl, n- or iso-propyl, and n-, iso-, sec- or tert-butyl.
  • heteroaryl 1 is a 9- or 10- membered, unsaturated or partially unsaturated bicyclic group comprising 1 , 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein the total number of ring S atoms does not exceed 1 , and the total number of ring O atoms does not exceed 1 , wherein heteroaryl 1 is optionally substituted by one or more substituents, preferably 1 , 2 or 3 substituents, independently selected from:
  • heteroaryl 1 is optionally substituted by one or more substituents, preferably 1 , 2 or 3 substituents, independently selected from:
  • heteroaryl 1 include, but are not limited to, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7- naphthyridinyl, 1 ,8-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2- d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[
  • benzimidazolyl benzoxazolyl, indazoyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3- c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5- c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, indazolyl, purinyl, indolizinyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,5-a]pyridinyl, pyrazolo[1
  • heteroaryl 3 means a 9- or 10- membered, unsaturated or partially unsaturated bicyclic group comprising 1 or 2 ring N heteroatoms. Heteroaryl 3 is optionally substituted by one or more substituents independently selected from:
  • heteroaryl 3 is optionally substituted by one or more substituents independently selected from:
  • heteroaryl 3 include, but are not limited to, quinolinyl, isoquinolinyl, cinnolinyl, azaquinazolinyl, quinoxalinyl, phthalazinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, indolyl, benzimidazolyl, indazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2- c]pyridinyl, pyrrolo[3,2-b]pyridinyl, isoindolyl, indazolyl, indolininyl,
  • heterocyclyl 1 means a 4, 5 or 6 membered saturated or partially unsaturated monocyclic group comprising 1 or 2 ring heteroatoms independently selected from N, O and S.
  • Heterocyclyl 1 is optionally substituted by CONH 2 or (d-C 3 )alkyl.
  • Specific examples of heterocyclyl 1 include, but are not limited to, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 1 ,2,3,4-tetrahydropyridinyl, 1 ,2,5,6-tetrahydropyridinyl, pyrrolidinyl, piperidinyl and piperazinyl.
  • heterocyclyl 2 means a 5 or 6 membered saturated, unsaturated or partially unsaturated monocyclic group comprising 1 , 2 or 3 ring heteroatoms independently selected from N, O and S, wherein the total number of ring S atoms does not exceed 1 , and the total number of ring O atoms does not exceed 1 .
  • Heterocyclyl 2 is optionally substituted by (d-C 3 )alkyl.
  • heterocyclyl 2 include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, 1 ,2,3,4-tetrahydropyridinyl, 1 ,2,5,6-tetrahydropyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,3-triazolyl, 1 ,3,4-triazolyl, 1 -oxa-2,3-diazolyl, 1 -oxa-2,4-diazolyl, 1 - oxa-2,5-diazolyl, 1 -oxa-3,4-diazolyl, 1 -thia-2,3-diazolyl, 1 -thia
  • halo means fluoro, chloro, bromo or iodo. In a particular embodiment of the invention, halo is fluoro or chloro. Preferably, halo is fluoro.
  • the compound of formula (I) is selected from any one of the following structures (Ia) to (Ie):
  • Y is C or N
  • X is CH or N
  • Such compounds have the structure (Ia), (Ib), (Ic) or (Ie) as disclosed herein.
  • B is N;
  • Y is C or N;
  • X is CH or N;
  • Such compounds have the structure (Ia), (Ib) or (Ic) as disclosed herein.
  • R 1 is i or ii:
  • R 1 is
  • R 1 is a group selected from i, ii and iii: and R 5 is heteroaryl 3 . In another embodiment of the invention, R 1 is
  • R 5 is heteroaryl 3 .
  • heteroaryl 1 and heteroaryl 3 are each optionally substituted by one or more substituents independently selected from halo, 4-methylpiperazin- 1 -yl, ethanone O-(2-hydroxyethyl)oxime and (CrC 2 )alkyl.
  • R 5 is indazolyl or quinolinyl, each optionally substituted by one or more substituents independently selected from halo, (d-C 3 )alkyl, 4- methylpiperazin-1 -yl and ethanone O-(2-hydroxyethyl)oxime.
  • R 5 is indazolyl or quinolinyl optionally substituted by one, two or three substituents independently selected from halo and (CrC 3 )alkyl.
  • R 5 is indazolyl optionally substituted by one, two or three substituents independently selected from methyl and fluoro, or R 5 is quinolinyl optionally substituted by one or two fluoro substituents.
  • R 5 is indazol-5-yl substituted at the 1 position by a methyl substituent and optionally further substituted by one or two fluoro substituents, or R 5 is quinolin-6-yl optionally substituted by one or two fluoro substituents.
  • said fluoro substituents are present at the 5 and/or 7 positions of the quinolinyl group.
  • R 5 is quinolin-6-yl substituted by
  • R 5 is quinolin-6-yl substituted by 3-(4-Methylpiperazin-1 -yl) or quinolin-6-yl substituted by 3-ethanone O-(2-hydroxy-ethyl)oxime.
  • R 5 is 7-fluoro-quinolin-6-yl, quinolin-6-yl, 5,7- difluoroquinolin-6-yl, 1 -methyl-1 H-indazol-5-yl, 6-fluoro-1 -methyl-1 H-indazol-5-yl, 4,6-difluoro- 1 -methyl-1 H-indazol-5-yl, 5-Fluoroquinolin-6-yl, 3-(4-Methylpiperazin-1 -yl)quinolin-6-yl or 6- quinolin-3-yl-ethanone O-(2-hydroxy-ethyl)oxime.
  • R 6 is hydrogen, deuterium, OH or halo, particularly hydrogen, deuterium or halo, and in a preferred embodiment, R 6 is hydrogen.
  • R 7 is hydrogen, deuterium, halo, or methyl, wherein said methyl is optionally substituted by one or more substituents independently selected from OH and halo.
  • R 7 is hydrogen, deuterium, halo, or methyl.
  • R 7 is hydrogen or methyl, more preferably hydrogen.
  • the compound of formula (I) contains an asymmetric carbon atom at R 1 .
  • R 1 is i, and R 6 and R 7 are not both hydrogen
  • the compound of formula (I) contains an asymmetric carbon atom at R 1 .
  • R 1 is i, and R 6 and R 7 are not both hydrogen
  • the compound of formula (I) contains an asymmetric carbon atom at R 1 .
  • n is O.
  • R 2 is hydrogen or methyl.
  • R 2 is methyl.
  • R 3 is selected from:
  • phenyl wherein said phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (d-C 3 )alkyl and (d-C 3 )alkoxy, wherein said (CrC 3 )alkyl and (d-C 3 )alkoxy are each optionally substituted by one or more halo substituents,
  • R 3 is selected from:
  • phenyl wherein said phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (d-C 3 )alkyl and (d-C 3 )alkoxy, wherein said (Ci-C 3 )alkyl and (d-C 3 )alkoxy are each optionally substituted by one or more halo substituents,
  • R 3 is ethyl, methyl, 2-hydroxyethyl, 1 ,3- dihydroxypropan-2-yl-, 2,3-dihydroxypropyl-, 2-hydroxy-1 ,1 -dimethyl-ethyl-, 2-hydroxy-2- methyl-propyl-, pyrrolidin-3-yl-, -3-pyrrolidine-1 -carboxamide, hydrogen, benzyl, A- methoxybenzyl-, piperidin-4-yl-, piperidin-4-ylmethyl-, -CH 2 CO 2 CH 3 , -CH 2 CONH 2 2- aminoethyl-, 1 -hydroxypropan-2-yl-, -CH 2 CH 2 NHCO 2 CH 3 , -CH 2 CH 2 NHCONH 2 ; 3- trifluoromethylphenyl-, phenyl, 2-fluoroethyl-, 3-hydroxypropyl, 2-methoxyethyl, A- hydroxybutyl
  • R 3 is hydroxyethyl, particularly 2- hydroxyethyl, or hydrogen.
  • Y is C or N
  • X is CH or N
  • B is CH or N
  • A is a ring; such that when X is CH and B is N, ring A is ring Ai or ring Aii;
  • R 1 is i:
  • R 5 is 7-fluoro-quinolin-6-yl, quinolin-6-yl, 5,7-difluoroquinolin-6-yl, 1 -methyl-1 H-indazol-5-yl, 6- fluoro-1 -methyl-1 H-indazol-5-yl, 4,6-difluoro-1 -methyl-1 H-indazol-5-yl, 5-Fluoroquinolin-6-yl, (4-Methylpiperazin-1 -yl)quinolin-6-yl or 6-quinolin-3-yl-ethanone O-(2-hydroxy-ethyl)oxime
  • R 6 is hydrogen, deuterium, OH, methyl or halo
  • R 7 is hydrogen, deuterium, halo, or (d-C 3 )alkyl, wherein said (d-C 3 )alkyl is optionally substituted by one or more substituents independently selected from OH and halo; or R 6 and R 7 , together with the carbon to which they are attached form cyclopropyl;
  • R 2 is hydrogen, NH 2 , or (CrC 4 )alkyl
  • R 3 is ethyl, methyl, 2-hydroxyethyl, 1 ,3-dihydroxypropan-2-yl-, 2,3-dihydroxypropyl-, 2- hydroxy-1 ,1 -dimethyl-ethyl-, 2-hydroxy-2-methyl-propyl-, pyrrolidin-3-yl-, -3-pyrrolidine-1 - carboxamide, hydrogen, benzyl, 4-methoxybenzyl-, piperidin-4-yl-, piperidin-4-ylmethyl-, - CH 2 CO 2 CH 3 , -CH 2 CONH 2 2-aminoethyl-, 1 -hydroxypropan-2-yl-, -CH 2 CH 2 NHCO 2 CH 3 , - CH 2 CH 2 NHCONH 2 ; 3-trifluoromethylphenyl-, phenyl, 2-fluoroethyl-, 3-hydroxypropy
  • the invention provides a compound of formula (I) having a structure selected from (Ia), (Ib) or (Ic) above, wherein
  • R 1 is i:
  • R 5 is quinolin-6-yl optionally substituted by one or two fluoro substituents, the fluoro substituents being preferably in the 5 and/or 7 positions;
  • R 6 is hydrogen
  • R 7 is hydrogen or methyl
  • R 2 is methyl
  • R 3 is hydroxyethyl, more particularly 2-hydroxyethyl, or R 3 is hydrogen;
  • the invention provides one or more compounds selected from the Example compounds disclosed herein, or a pharmaceutically acceptable salt thereof.
  • Figure 1 herein shows the X-ray diffractogram of Example 53S amorphous form.
  • Figure 2 shows the X-ray diffractogram of Example 53S crystalline form I.
  • Figure 3 shows the X-ray diffractogram of Example 53S crystalline form II.
  • isomers refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or "a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom.
  • the invention includes enantiomers, diastereomers or racemates of the compound.
  • Enantiomers are a pair of stereoisomers that are non- superimposable mirror images of each other.
  • a 1 :1 mixture of a pair of enantiomers is a "racemic” mixture.
  • the term is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration, such as for the asymmetric carbon atom which may be present within the R 1 group (i) defined herein.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration.
  • the (S) enantiomer is in excess, in amounts as described above.
  • Substituents at atoms with unsaturated bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
  • the hydrazones of the present invention have the trans-(£)- form.
  • a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral
  • isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, 125 I respectively.
  • isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 13 C, and 14 C are incorporated.
  • isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography
  • PET positron emission tomography
  • SPECT single photoelectron emission tomography
  • an 18 F or labeled compound may be particularly preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a. readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium, for example in the ranges given above.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent ⁇ in place of the non-labeled reagent previously employed.
  • the term "pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
  • the salt can be present alone or in mixture with free compound of the formula (I).
  • the compounds of the present invention are capable of forming acid salts by virtue of the presence of amino groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, , hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/di
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO. Any formula given herein is intended to represent hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.
  • Compounds of the invention i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
  • These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co-crystal formers include those described in WO 2004/078163.
  • the invention further provides co-crystals comprising a compound of formula (I).
  • the compounds of the invention therefore include compounds of formula I, polymorphs, and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labelled compounds of formula I, as defined herein.
  • the invention relates to a compound of the formula (I), in free base form or in acid addition salt form, wherein the substituents are as defined herein.
  • the compounds of the present invention may be administered as prodrugs.
  • certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage.
  • prodrugs Such derivatives are referred to as 'prodrugs'.
  • 'prodrugs' Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro- moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
  • prodrugs include:
  • Certain compounds of formula (I) may also themselves act as prodrugs of other compounds of formula (I).
  • C-Met tyrosine kinase mediated diseases are especially such disorders that respond in a beneficial way (e.g. amelioration of one or more symptoms, delay of the onset of a disease, up to temporary or complete cure from a disease) to the inhibition of a protein tyrosine kinase, especially inhibition of a c-Met kinase.
  • These disorders include proliferative diseases such as tumor diseases, in particular solid tumors and metastasis derived thereof, e.g.
  • PRCC hereditary papillary renal cell carcinoma
  • sporadic forms of PRCC head and neck cancer
  • squamous cell carcinoma gastric carcinoma
  • pancreatic carcinoma lung cancer, bladder cancer, breast cancer
  • leiomyosarcoma glioblastoma
  • melanoma alveolar soft part sarcoma.
  • inflammatory conditions such as inflammatory conditions due to an infection.
  • Combination refers to either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the formula (I) and a combination partner (e.g. an other drug as explained below, also referred to as “therapeutic agent” or “co- agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • a combination partner e.g. an other drug as explained below, also referred to as “therapeutic agent” or “co- agent”
  • administration or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of formula (I) and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound of formula (I) and a combination partner are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • the invention relates especially to a compound of the formula (I) as provided in the
  • the compounds of formula (I) have valuable pharmacological properties, as described hereinbefore and hereinafter.
  • a method for treating a c-Met related disorder or condition is preferably a proliferative disease such as a cancer or an inflammatory condition.
  • Compounds of formula (I) are further useful for treating diseases associated with a c-Met-related condition.
  • Compounds of formula (I) are useful in the treatment of cancer wherein the cancer is selected from the group consisting of brain cancer, stomach cancer, genital cancer, urinary cancer, prostate cancer, bladder cancer (superficial and muscle invasive), breast cancer, cervical cancer, colon cancer, colorectal cancer, glioma (including glioblastoma, anaplastic astrocytoma, oligoastrocytoma, oligodendroglioma), esophageal cancer, gastric cancer, gastrointestinal cancer, liver cancer, hepatocellular carcinoma (HCC) including childhood HCC, head and neck cancer (including head and neck squamous-cell carcinoma,
  • HCC hepatocellular carcinoma
  • nasopharyngeal carcinoma Hurthle cell carcinoma, epithelial cancer, skin cancer, melanoma (including malignant melanoma), mesothelioma, lymphoma, myeloma (including multiple myeloma), leukemias, lung cancer (including non-small cell lung cancer (including all histological subtypes: adenocarcinoma, squamous cell carcinoma, bronchoalveolar carcinoma, large-cell carcinoma, and adenosquamous mixed type), small-cell lung cancer), ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer (including but not limited to papillary renal cell carcinoma), intestine cancer, renal cell cancer (including hereditary and sporadic papillary renal cell cancer, Type I and Type II, and clear cell renal cell cancer); sarcomas, in particular osteosarcomas, clear cell sarcomas, and soft tissue sarcomas (including alveolar and embryonal r
  • Compounds of formula (I) are useful in the treatment of cancer wherein the cancer is stomach, colon, liver, genital, urinary, melanoma, or prostate.
  • the cancer is liver or esophageal.
  • Compounds of formula (I) are useful in the treatment of colon cancer, including metastases, e.g. in the liver, and of non-small-cell lung carcinoma.
  • Compounds of formula (I) may also be used in the treatment of hereditary papillary renal carcinoma (Schmidt, L. et al. Nat. Genet. 16, 68-73, 1997) and other proliferative diseases in which c-MET is overexpressed or constitutively activated by mutations (Jeffers and Vande Woude. Oncogene 18, 5120-5125, 1999; and reference cited therein) or chromosomal rearrange-ments (e.g. TPR-MET; Cooper et al. Nature 31 1 , 29-33, 1984; Park, et al. Cell 45, 895-904, 1986).
  • Compounds of formula (I) are further useful in the treatment of additional cancers and conditions as provided herein or known in the art.
  • the inflammatory condition is due to an infection.
  • the method of treatment would be to block pathogen infection.
  • the infection is a bacterial infection, e.g., a Listeria infection. See, e.g., Shen et al. Cell 103: 501 -10, (2000) whereby a bacterial surface protein activates c-Met kinase through binding to the extracellular domain of the receptor, thereby mimicking the effect of the cognate ligand HGF/SF.
  • any of the above methods involve further administering a chemotherapeutic agent.
  • the chemotherapeutic agent is an anti-cancer agent. Specific combinations are provided throughout the application.
  • any of the above methods involve further administering a pathway specific inhibitor.
  • the pathway specific inhibitor may be a chemotherapeutic agent or may be a biologic agent, e.g., such as antibodies.
  • Pathway specific inhibitors include, but are not limited to, inhibitors of EGFR, Her-2, Her-3, VEGFR, Ron, IGF-IR, PI-3K, mTOR,
  • the invention relates to a method of treating a c-Met related disorder or condition which involves administering to a subject in need thereof an effective amount of a compound of formula (I).
  • the invention relates to a compound of formula (I) or a
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of one or more C-Met tyrosine kinase mediated diseases.
  • the invention relates to a method for the treatment of a disease or disorder which responds to an inhibition of C-Met tyrosine kinase, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, especially in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as active ingredient in association with at least one pharmaceutical carrier or diluent.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: (a) an effective amount of compound of formula (I) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and/or pharmaceutically active metabolites thereof; and (b) one or more pharmaceutically acceptable excipients and / or diluents.
  • a pharmaceutical preparation comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt of such a compound, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier and / or diluents and optionally one or more further therapeutic agents.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives ⁇ e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • the term "a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1 ) at least partially alleviating, inhibiting, preventing and/or
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of cMet; or at least partially reducing or inhibiting the expression of cMet.
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates ⁇ e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, ⁇ e.g., stabilization of a discernible symptom), physiologically, ⁇ e.g., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is "in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • the pharmaceutical compositions of the present invention can be made up in a solid form
  • compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier.
  • Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
  • topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • the invention relates also to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount, especially an amount effective in the treatment of one of the above-mentioned diseases, disorders or conditions, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be inorganic or organic, solid or liquid.
  • the dosage of the active ingredient to be applied to a warm-blooded animal depends upon a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and he- patic function of the patient; and the particular compound employed.
  • a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a con- sideration of the distribution, equilibrium, and elimination of a drug.
  • the dose of a compound of the formula (I) or a pharmaceutically acceptable salt thereof to be administered to warmblooded animals, for example humans of approximately 70 kg body weight, is preferably from approximately 3 mg to approximately 5 g, more preferably from approximately 10 mg to approximately 1 .5 g per person per day, divided preferably into 1 to 3 single doses which may, for example, be of the same size. Usually, children receive half of the adult dose.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1 -1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1 -500 mg or about 1 -250 mg or about 1 -150 mg or about 0.5-100 mg, or about 1 -50 mg of active ingredients.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 3 molar and 10 9 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1 -500 mg/kg, or between about 1 -100 mg/kg.
  • a combination of a compound of formula (I) with one or more other therapeutically active agents in another embodiment, there is provided a combination of a compound of formula (I) with one or more other therapeutically active agents.
  • a compound of formula (I) can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.
  • a compound of formula (I) can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these.
  • Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above.
  • Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
  • a compound of the formula (I) may be used in combination with other antiproliferative compounds.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase Il inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibittors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity; anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti- androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies;com
  • tumor treatment approaches including surgery, ionizing radiation, photodynamic therapy, implants, e.g. with corticosteroids, hormones, or they may be used as radiosensitizers.
  • aromatase inhibitor as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane can be administered, e.g., in the form as it is marketed, e.g.
  • Form- estane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARON.
  • Fadrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark AFEMA.
  • Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEX.
  • Letrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.
  • Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g. breast tumors.
  • antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX.
  • Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA.
  • Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g. under the trademark FASLODEX.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g. breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g. as disclosed in US 4,636,505.
  • bicalutamide CASODEX
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, go- serelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX.
  • Abarelix can be formulated, e.g. as disclosed in US 5,843,901.
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO99/ 17804).
  • Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CAMPTOSAR.
  • Topotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark HYCAMTIN.
  • topoisomerase Il inhibitor includes, but is not limited to the an- thracyclines such as doxorubicin (including liposomal formulation, e.g. CAELYX), dauno- rubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and lo- soxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide can be ad- ministered, e.g. in the form as it is marketed, e.g. under the trademark ETOPOPHOS.
  • Teniposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark VM 26-BRISTOL.
  • Doxorubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN.
  • Epirubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark FARMORUBICIN.
  • Idarubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZAVEDOS.
  • Mitoxantrone can be administered, e.g. in the form as it is marketed, e.g. under the trademark NOVANTRON.
  • microtubule active compound relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides, cochicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivatives thereof.
  • taxanes e.g. paclitaxel and docetaxel
  • vinca alkaloids e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine
  • discodermolides cochicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivative
  • Paclitaxel may be administered e.g. in the form as it is marketed, e.g. TAXOL.
  • Docetaxel can be administered, e.g., in the form as it is marketed, e.g. under the trademark TAXOTERE.
  • Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark VINBLASTIN R. P..
  • Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTIN.
  • Discodermolide can be obtained, e.g., as disclosed in US 5,010,099.
  • Epothilone derivatives which are disclosed in WO 98/10121 , US 6,194,181 , WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Especially preferred are Epothilone A and/or B.
  • alkylating compound includes, but is not limited to, cyclophospha- mide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
  • Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTIN.
  • Ifosfamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark HOLOXAN.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity.
  • SAHA Suberoylanilide hydroxamic acid
  • HDAC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065, in particular, ⁇ /-hydroxy-3-[4-[[[2-(2-methyl-1 H-indol-3-yl)-ethyl]-amino]me- thyl]phenyl]-2£-2-propenamide, or a pharmaceutically acceptable salt thereof and ⁇ /-hydroxy- 3-[4-[(2-hydroxyethyl) ⁇ 2-(1 H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • antimetabolite includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark XELODA.
  • Gemcitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark GEMZAR.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis- platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CARBOPLAT.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN.
  • compounds targeting/decreasing a protein or lipid kinase activity includes, but is not limited to, c-Met tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.,
  • PDGFR platelet-derived growth factor-receptors
  • compounds which target, decrease or inhibit the activity of PDGFR especially compounds which inhibit the PDGF receptor, e.g. a N-phenyl-2- pyrimidine-amine derivative, e.g. imatinib, SU101 , SU6668 and GFB-1 1 1 ;
  • FGFR fibroblast growth factor- receptors
  • IGF-IR insulin-like growth factor receptor I
  • IR especially compounds which inhibit the kinase activity of IGF-I receptor, such as those compounds disclosed in WO 02/092599, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors;
  • Kit/SCFR receptor tyrosine kinase e.g. imatinib
  • gene-fusion products e.g. BCR-AbI kinase
  • mutants such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib (AMN107)
  • PD180970 AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825) j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1 , PKB/Akt, and Ras/MAPK family members, and/or members of the cyclin- dependent kinase family (CDK) and are especially those staurosporine derivatives disclosed in US 5,093,330, e.g. midostaurin; examples of further compounds include e.g.
  • UCN-01 safingol, BAY 43-9006, Bryostatin 1 , Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521 ; LY333531/LY379196; isochinoline compounds such as those disclosed in WO 00/09495; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin.
  • GLEEVEC imatinib mesylate
  • tyrphostin tyrphostin.
  • a tyrphostin is preferably a low molecular weight (Mr ⁇ 1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S- arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810; AG 99;
  • adaphostin (4- ⁇ [(2,5-dihydroxyphenyl)methyl]amino ⁇ -benzoic acid adamantyl ester; NSC 680410, adaphostin);
  • compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the compound of ex.
  • trastuzumab HerceptinTM
  • cetuximab ErbituxTM
  • Iressa Tarceva
  • OSI- 774 Tarceva
  • OSI- 774 OSI- 774
  • EKB-569 E1 .1 , E2.4, E2.5, E6.2, E6.4, E2.1 1 , E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO 03/013541 ; and m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF;
  • n) compounds targeting, decreasing or inhibiting the activity of the Ron receptor tyrosine kinase.
  • anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (THALOMID) and TNP-470.
  • TAALOMID thalidomide
  • TNP-470 TNP-470.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase includes, but is not limited to inhibitors of phosphatase 1 , phosphatase 2A, or CDC25, e.g. okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes includes, but is not limited to e.g. retinoic acid, ⁇ - ⁇ - or ⁇ -tocopherol or ⁇ - ⁇ - or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, e.g. 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark DIDRONEL.
  • Clodronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS.
  • Teiludronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELID.
  • Pamidronic acid can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIATM.
  • “Alendronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX.
  • “Ibandronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANAT.
  • “Risedronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTONEL.
  • “Zoledronic acid” can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZOMETA.
  • the term “mTOR inhibitors” relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation.
  • the term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons, e.g. interferon ⁇ .
  • inhibitor of Ras oncogenic isoforms e.g. H-Ras, K-Ras, or N-Ras
  • H-Ras, K-Ras, or N-Ras refers to compounds which target, decrease or inhibit the oncogenic activity of Ras e.g. a "farnesyl transferase inhibitor” e.g. L-744832, DK8G557 or R1 15777 (Zarnestra).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are e.g. bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include e.g. Bortezomid (VelcadeTM)and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g.
  • FMS-like tyrosine kinase inhibitors e.g. compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1 -b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors e.g. compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, e.g. PKC412, midostaurin, a staurosporine derivative, SU1 1248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG, 17-DMAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors;IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (TEMODAL®), AUY922 from Novartis.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HerceptinTM), Trastuzumab-DM1 ,erbitux, bevacizumab (AvastinTM), rituximab (Rituxan ® ), PRO64553 (anti-CD40) and 2C4 Antibody.
  • antibodies is meant e.g. intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • antigenemic compounds includes, for example, Ara-C, a pyrimidine analog, which is the 2 ' -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
  • Ara-C Ara-C
  • pyrimidine analog which is the 2 ' -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine.
  • purine analog of hypoxanthine 6-mercaptopurine (6-MP)
  • 6-MP 6-mercaptopurine
  • fludarabine phosphate fludarabine phosphate.
  • compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of formula (I) can be administered in combination with, e.g., farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide,
  • Somatostatin receptor antagonists refers to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • ionizing radiation means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1 , pp. 248-275 (1993).
  • EDG binders refers a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • kinesin spindle protein inhibitors is known in the field and includes SB715992 or SB743921 from GlaxoSmithKline, pentamidine/chlorpromazine from CombinatoRx;
  • MEK inhibitors is known in the field and includes ARRY142886 from Array PioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, leucovorin.
  • ribonucleotide reductase inhibitors includes, but is not limited to to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1 H-isoindole-1 ,3-dione derivatives, such as PL-1 , PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).
  • S-adenosylmethionine decarboxylase inhibitors includes, but is not limited to the compounds disclosed in US 5,461 ,076.
  • VEGF / VEGFR disclosed in WO 98/35958, e.g. 1 -(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g. the succinate, or in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/1 1223, WO 00/27819 and EP 0 769 947; those as described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci U S A, Vol.
  • Angiozyme RPI 4610
  • Bevacizumab AvastinTM
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of
  • photodynamic therapy includes treatment with compounds, such as e.g. VISUDYNE and porfimer sodium.
  • Angiostatic steroids refers to compounds which block or inhibit
  • angiogenesis such as, e.g., anecortave, triamcinolone, hydrocortisone, 1 1 - ⁇ -epihydrocotisol, cortexolone, 17 ⁇ -hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Corticosteroids as used herein includes, but is not limited to compounds, such as e.g.
  • fluocinolone, dexamethasone in particular in the form of implants.
  • “Other chemotherapeutic compounds” include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • a compound of formula (I) may also be used in combination with one or more further drug substances selected from the group of anti-inflammatory drug substances; antihistamine drug substances; bronchodilatatory drug substances, NSAID; antagonists of chemokine receptors.
  • the compounds of the invention are also useful as co-therapeutic compounds for use in combination with such further drug substances, particularly in the treatment of inflammatory diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • a compound of the invention may be mixed with such other drug substance in a fixed pharmaceutical composition or it may be administered separately (i.e. before, simultaneously with or after the other drug substance).
  • the invention includes a combination of a compound of formula (I) with one or more further drug substance selected from the group of anti-inflammatory drug substances; antihistamine drug substances;
  • bronchodilatatory drug substances NSAID antagonists of chemokine receptors
  • said compound of the formula(l) and said drug substance being in the same or different pharmaceutical composition.
  • Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in WO 01/041 18, WO 02/51841 , WO 02/53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021 , US 5171744, US 3714357, WO 03/33495 and WO 04/018422.
  • Suitable chemokine receptors include, e.g. CCR-1 , CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351 125, SCH-55700 and SCH- D, Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo- cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-amin- ium chloride (TAK-770), and CCR-5 antagonists described in US 6166037 (particularly claims 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9),
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofena- dine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine as well as those disclosed in WO 03/099807, WO 04/026841 and JP
  • Therapeutic agents for possible combination are especially one or more antiproliferative, cytostatic or cytotoxic compounds, for example one or several agents selected from the group which includes, but is not limited to, an inhibitor of polyamine biosynthesis, an inhibitor of a protein kinase, especially of a serine/threonine protein kinase, such as protein kinase C, or of a tyrosine protein kinase, such as the EGF receptor tyrosine kinase, e.g. Iressa®, the VEGF receptor tyrosine kinase, e.g.
  • PTK787 or Avastin® an antibody against the ligand VEGF, or the PDGF receptor tyrosine kinase, e.g. STI571 (Glivec®), PI3K (such as BEZ235 from Novartis) and mToR inhibitors, such as rapamycin, RAD001 , a cytokine, a negative growth regulator, such as TGF- ⁇ or IFN- ⁇ , an aromatase inhibitor, e.g.
  • letrozole (Femara®) or anastrozole, an inhibitor of the interaction of an SH2 domain with a phosphorylated protein, antiestrogens, topoisomerase I inhibitors, such as irinotecan, topoisomerase Il inhibitors, microtubule active agents, e.g. paclitaxel or an epothilone, alkylating agents, antiproliferative antimetabolites, such as gemcitabine or capecitabine, platin compounds, such as carboplatin or cis-platin, bisphosphonates, e.g. AREDIA® or ZOMET A®, and monoclonal antibodies, e.g. against HER2, such as trastuzumab.
  • a phosphorylated protein e.g. paclitaxel or an epothilone
  • alkylating agents e.g. paclitaxel or an epothilone
  • antiproliferative antimetabolites such as gemcitabine or cap
  • the structure of the active agents identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference.
  • the above-mentioned compounds, which can be used in combination with a compound of the formula (I), can be prepared and administered as described in the art, such as in the documents cited above.
  • the combination therapies of the invention the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers.
  • the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g.
  • kits comprising the compound of the invention and the other therapeutic agent
  • the physician themselves or under the guidance of the physician
  • shortly before administration or in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
  • the invention provides the use of a compound of formula (I) for treating a disease or condition mediated by cMet, wherein the medicament is prepared for
  • the invention also provides the use of another therapeutic agent for treating a disease or condition mediated cMet,, wherein the
  • the invention relates in a further embodiment to a combination, particularly a pharmaceutical composition) comprising a therapeutically effective amount of a compound of formula (I) in free form or in pharmaceutically acceptable salt form and a second
  • the additional therapeutic agent is preferably selected from the group consisting of an anti-cancer agent; an anti-inflammatory agent.
  • the invention further relates to a method for the treatment of a disease or disorder which responds to a C-Met tyrosine kinase, especially a proliferative disorder or disease, in particular a cancer, said method comprises administration of an effective amount of a combination of pharmaceutical agents which comprise: (a) a compound of formula (I); and (b) one or more pharmaceutically active agents, to a subject in need thereof, especially human.
  • a combination of pharmaceutical agents which comprise: (a) a compound of formula (I); and (b) one or more pharmaceutically active agents, to a subject in need thereof, especially human.
  • the invention further relates to the use of a combination of pharmaceutical agents which comprise: (a) a compound of formula (I); and (b) one or more pharmaceutically active agents for the treatment of a disease or disorder which responds to a C-Met tyrosine kinase, especially a proliferative disorder or disease, in particular a cancer.
  • a combination of pharmaceutical agents which comprise: (a) a compound of formula (I); and (b) one or more pharmaceutically active agents for the treatment of a disease or disorder which responds to a C-Met tyrosine kinase, especially a proliferative disorder or disease, in particular a cancer.
  • the invention further relates to the use of a combination of pharmaceutical agents which comprise: (a) a compound of formula (I); and (b) one or more pharmaceutically active agents for themanufacture of a medicament for the treatment of a disease or disorder which responds to a C-Met tyrosine kinase, especially a proliferative disorder or disease, in particular a cancer.
  • the invention further relates to pharmaceutical compositions comprising (a) a compound of formula (I) and (b) a pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier; wherein at least one pharmaceutically active agent is an anti-cancer therapeutic.
  • the present invention further relates to a commercial package or product comprising:
  • the invention also provides the use of a compound of formula (I) for treating a disease or condition mediated by cMet, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or condition mediated by cMet, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I).
  • delay of progression means administration of the combination to patients being in a pre-stage or in an early phase, of the first manifestation or a relapse of the disease to be treated, in which patients, e.g., a pre-form of the corresponding disease is diagnosed or which patients are in a condition, e.g., during a medical treatment or a condition resulting from an accident, under which it is likely that a corresponding disease will develop.
  • joint therapeutically active or “joint therapeutic effect” means that the compounds may be given separately (in a chronically staggered manner, especially a sequence-specific manner) in such time intervals that they preferably, in the warm-blooded animal, especially human, to be treated, still show a (preferably synergistic) interaction (joint therapeutic effect).
  • a joint therapeutic effect can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
  • the term "Pharmaceutically effective” preferably relates to an amount that is therapeutically or in a broader sense also prophylactically effective against the progression of a disease or disorder as disclosed herein.
  • a commercial package or "a product”, as used herein defines especially a "kit of parts” in the sense that the components (a) and (b) as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the components (a) and (b), i.e., simultaneously or at different time points.
  • these terms comprise a commercial package comprising (especially combining) as active ingredients components (a) and (b), together with instructions for simultaneous, sequential (chronically staggered, in time-specific sequence, preferentially) or (less preferably) separate use thereof in the delay of progression or treatment of a proliferative disease.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the combination partners (a) and (b) (as can be determined according to standard methods.
  • the ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied, e.g., in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to the particular disease, age, sex, body weight, etc. of the patients.
  • there is at least one beneficial effect e.g., a mutual enhancing of the effect of the combination partners (a) and (b), in particular a more than additive effect, which hence could be achieved with lower doses of each of the combined drugs, respectively, than tolerable in the case of treatment with the individual drugs only without combination, producing additional advantageous effects, e.g., less side effects or a combined therapeutic effect in a non-effective dosage of one or both of the combination partners (components) (a) and (b), and very preferably a strong synergism of the
  • any combination of simultaneous, sequential and separate use is also possible, meaning that the components (a) and (b) may be administered at one time point simultaneously, followed by administration of only one component with lower host toxicity either chronically, e.g., more than 3-4 weeks of daily dosing, at a later time point and subsequently the other component or the combination of both components at a still later time point (in subsequent drug combination treatment courses for an optimal effect) or the like.
  • a method of manufacturing a compound of formula (I) and intermediates thereof A compound of the formula (I) may be prepared by processes that, though not applied hitherto for the new compounds of the present invention where they thus form new processes, are known per se.
  • the schemes provide a general overview of synthetic strategies to obtain a compound of formula (I). All methods described can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language ⁇ e.g. "such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
  • the invention relates in a further aspect to a manufacturing process (a method for manufacturing) a compound of formula (I) comprising at least one reaction step as disclosed herein, and intermediates thereof.
  • Z 1 is selected from Cl, Br and I
  • Scheme 2 provides details for a synthetic strategy to obtain preferred compounds of formula (IA, IB, IC) through (NA, NB and NC)
  • Zi and Z 2 are independently selected from Cl, Br and I
  • Scheme 3 provides details for a synthetic strategy to obtain preferred compounds of formula (ID) through (ND).
  • MD Z 1 is selected from Cl, Br and I
  • Scheme 4 provides details for a synthetic strategy to obtain preferred compounds of formula (IE) through (NE).
  • Zi is selected from Cl, Br and I Scheme 5 provides details for a synthetic strategy to obtain preferred compounds of formula (IF) through (NF).
  • Z 1 and Z 2 are independently selected from Cl, Br and I
  • Scheme 6 provides details for a synthetic strategy to obtain preferred compounds of formula (IG) and (IH) through (NG) and (NH) respectively.
  • Z 1 is selected from Cl, Br and I Scheme 7 provides alternative details for a synthetic strategy to obtain preferred compounds of formula (IH) through (NH).
  • Scheme 8 provides details for a synthetic strategy to obtain preferred compounds of formula (IK) through (NK).
  • Z 1 is selected from Cl, Br and I
  • Scheme 9 provides details for a synthetic strategy to obtain preferred compounds of formula (IL).
  • the flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)
  • the flow is 1.2 mL/min of methanol and water (with 0.5% acetic acid)
  • the flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)
  • the flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)
  • the flow is 0.5 mL/min of methanol and water (with 0.5 % acetic acid)
  • the flow is 1 ml_/min of Hexane/Ethanol/Diethyleamine 80/20/0.1 , v/v/v
  • the flow is 1 ml_/min of Hexane/Ethanol/Diethyleamine 70/30/0.1 , v/v/v
  • the flow is 1 ml_/min of Hexane/lsopropanol/Diethylamine 70/30/0.1 , v/v/v Column: CHIRALPAK OD-H
  • the flow is 45 g/min of Methanol/CO 2 70/30
  • the flow is 1.2 mL/min of methanol and water (with 0.5% acetic acid) 0 - 3.0 min: 60% to 90% of methanol
  • the flow is 45 g/min of Methanol/CO 2 75/25
  • 6-chloroimidazo[1 ,2-b]pyridazine (1 .5 g, 9.8 mmol) in AcOH (50 ml_) was added NaOAc (1 .4 g, 17.1 mmol) and paraformaldehyde (1.5 g). The mixture was heated at reflux overnight and concentrated under reduced pressure. The residue was basified to pH 12. Then the mixture was filtered and the solid was washed with EtOH to afford (6-chloro- imidazo[1 ,2-b]pyridazin-3-yl)-methanol (1.3 g) in 72% yield. 6-Chloro-imidazo[1 ,2-b]pyridazine-3-carbaldehyde (intermediate N)
  • the title compound was prepared according to the procedure described in WO2006/10094. To a mixture of /-butyl hydroxycarbamate (1 1.27 g, 85 mmol) and DBU (12.8 ml_, 85 mmol) was added 2-bromoethanol (15 ml_, 212 mmol) slowly, and the reaction mixture was stirred 30 at 40 0 C for 2.5 days. After cooling, the reaction mixture was diluted with DCM, and washed successively with cold 1 N HCI aqueous solution, water, and brine. The organic layer was dried over anhydrous Na 2 SO 4 , purified by column chromatography (38% EtOAc in hexane) to afford 12.6 g (70%) of the title compound as a colorless syrup.
  • Example 7A To a mixture of 2-(2,3-dihydroxypropoxy)isoindoline-1 ,3-dione and 2-(1 ,3-dihydroxypropan-2- yloxy)isoindoline-1 ,3-dione (1 :1 mixture) (intermediate B) in MeOH was added hydrazine monohydrate. The reaction mixture was allowed to stir at reflux for two h and then the solvent was removed under reduced pressure. The residue was washed with EtOAc and filtered. The filtrate was collected, evaporated and redissolved in MeOH.
  • Example 11 (example 11 -R, example 11 -S)
  • Example 12 (example 12-R, example 12-S)
  • the title compound (390.0 mg, 91 %) was synthesized from 1 -(6-chloro-imidazo[1 ,2- b]pyridazin-3-yl)-1 -(1 -methyl-1 H-indazol-5-yl)-ethanol (430.0 mg, 1 .31 mmol), I 2 (832.0 mg, 3.28 mmol) and H 3 PO 2 (0.72 mL, 6.56 mmol) using the same procedure as described in the synthesis of compound 13.2.
  • the title compound (12.0 mg, 89%) was synthesized from 1 -[3-(7-fluoro-quinolin-6-ylmethyl)- 3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and 2-aminooxy- 2-methyl-propan-1 -ol hydrochloride (8.8 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15.
  • the title compound (12.0 mg, 89%) was synthesized from 1 -[3-(7-fluoro-quinolin-6-ylmethyl)- 3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and 1 -aminooxy- 2-methyl-propan-2-ol (6.5 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15.
  • the title compound (7.0 mg, 50%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)- 3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and [R)-O- pyrrolidin-3-yl-hydroxylamine hydrochloride (10.8 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15.
  • the title compound was prepared from 1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and 1 -(aminooxy)-2-methylpropan-2-ol in 85% yield using the same procedure as described in the synthesis of example 22.
  • Example 39 (example 39-R, example 39-S)
  • the title compound (12 mg, 28.6%) was synthesized from 2-(1 ,3-dihydroxypropan-2- yloxy)isoindoline-1 ,3-dione (intermediate B) (152 mg, 0.643 mmol, isomer mixture), hydrazine monohydrate (14 mg, 0.27 mmol) and 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3- b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.1 1 mmol) using the same procedure as described in the synthesis of example 44.
  • the title compound (6 mg, 14.3%) was synthesized from 2-(2,3-dihydroxypropoxy)iso- indoline-1 ,3-dione (intermediate B) (152 mg, 0.643 mmol, isomer mixture), hydrazine monohydrate (14 mg, 0.27 mmol) and 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3- b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.1 1 mmol) using the same procedure as described in the synthesis of example 44. After purification by HPLC (acidic with 0.05%TFA, then neutralized to basic), the title compound was obtained as a white solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to compounds of formula (I) and salts thereof wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I).

Description

Heterocyclic Oxime Compounds
The invention relates to bicyclic compounds of formula (I) and salts thereof, the uses of such compounds to treat the human or animal body, in particular with regard to a proliferative disease, pharmaceutical compositions comprising such compounds, combinations comprising a compound of formula (I), and processes for the preparation of such
compounds.
The Hepatocyte Growth Factor Receptor, herein referred to as c-Met, is a receptor tyrosine kinase that has been shown to be over-expressed and/or genetically altered in a variety of malignancies, specifically, gene amplification and a number of c-Met mutations are found in various solid tumors, see e.g. WO2007/126799. Further, the receptor tyrosine kinase c-Met is involved in the processes of migration, invasion and morphogenesis that accompany embryogenesis and tissue regeneration. C-met is also involved in the process of metastasis. Several lines of evidence have indicated that c-Met plays a role in tumor pathogenesis. Gain of function germ line mutations in c-Met is associated with development of hereditary papillary renal cell carcinoma (PRCC). Amplification or mutations in c-Met have also been reported in sporadic forms of PRCC, in head and neck squamous cell carcinoma, in gastric carcinoma, in pancreatic carcinoma and in lung cancer. Such alterations have been shown in selected instances to confer dependence of the tumor on c-Met and/or resistence to other targeted therapies. Elevated levels of c-Met, together with its unique ligand HGF/SF, are observed at high frequency in multiple clinically relevant tumors. A correlation between increased expression and disease progression, metastases and patient mortality has been reported in several cancers, including bladder, breast, squamous cell carcinoma and gastric carcinoma as well as leiomyosarcoma and glioblastoma.
WO 2008/008539 discloses certain fused heterocyclic derivatives which are useful in the treatment of HGF mediated diseases. WO 2007/013673 discloses fused heterocyclic derivatives as Lck inhibitors which are useful as immunosuppressive agents. EP0490587 discloses certain pyrazolopyrimidines which are useful as angiotensin Il antagonists. The disclosures of the publications cited in this specification are herein incorporated by reference. It is an aim of the present invention to provide further compounds that modulate, and in particular inhibit, c-Met. It has now been found that the compounds of the formula (I) described herein are inhibitors of c-Met and have a number of therapeutic applications. For example, the compounds of formula (I) are suitable for use in the treatment of diseases dependent on c-Met activity, especially solid tumors or metastasis derived therefrom.
Through the inhibition of c-Met, compounds of the invention also have utility as antiinflammatory agents, for example for the treatment of an inflammatory condition which is due to an infection. Preferably, the compounds of the invention are metabolically stable, are non-toxic and demonstrate few side-effects. In addition, preferred compounds of the invention exist in a physical form that is stable, non-hygroscopic and easily formulated. One aspect of the invention is directed to compounds of formula (I) having an activity that is superior to the activity of compounds of the prior art, or other similar compounds. Another aspect of the invention is directed to compounds of formula (I) having have good kinase selectivity.
Preferred compounds of the invention posses favourable pharmacokinetic properties, such as good in-vivo exposure and/or solubility.
The present invention relates to a compound of the formula (I)
Figure imgf000004_0001
wherein
Y is C or N;
X is CH or N;
B is CH or N;
A is a ring; such that when X is CH and B is N, ring A is ring Ai or ring Aii;
Ai Aii
Figure imgf000005_0001
when X is N and B is N, ring A is Aiii;
Aiii
Figure imgf000005_0002
and when X is N and B is N, or X is N and B is CH, ring A is Ai;
Ai
Figure imgf000005_0003
R1 is a group selected from i, ii and iii:
Figure imgf000005_0004
V - A - wherein R5 is heteroaryl1,
R6 is hydrogen, deuterium, OH, methyl or halo; R7 is hydrogen, deuterium, halo, or (d-C3)alkyl, wherein said (d-C3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo; or R6 and R7, together with the carbon to which they are attached, form cyclopropyl; n is O, 1 or 2;
R2 is hydrogen, NH2, or (d-C4)alkyl, wherein said (d-C4)alkyl is optionally substituted by one or more substituents independently selected from OH, NH3 and halo; and R3 is
• (Ci-C6)alkyl, wherein said (d-C6)alkyl is optionally substituted by one or more
substituents independently selected from halo, hydroxy and (CrC3)alkoxy,
• heterocyclyl1
• phenyl, wherein said phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (d-C3)alkyl and (d-C3)alkoxy, wherein said (CrC3)alkyl and (CrC3)alkoxy are each optionally substituted by one or more halo substituents,
• -CH2- heterocyclyl1
• -CH2-phenyl, wherein the phenyl of said -CH2-phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (CrC3)alkyl and (Ci-C3)alkoxy, wherein said (d-C3)alkyl and (d-C3)alkoxy are each optionally substituted by one or more halo substituents,
• (d-C4)alkylCO2(d-C2)alkyl,
• (C0-C4)alkylCONH2,
• (d-C4)alkylNH2,
• (d-C4)alkylNHCONH2,
• (CrC4)alkylCO2H,
• (d-C4)alkylNHCO2CH3,
• -(C0-C4)alkyl(C3-C6)cycloalkyl or -(Co-C4)alkyl(C4-C6)cycloalkenyl, or • Hydrogen, or a pharmaceutically acceptable salt thereof. The following general definitions shall apply in this specification, unless otherwise specified:
A "compound of the invention", or "compounds of the invention", or "a compound of the present invention" means a compound or compounds of formula (I) as described herein. As used herein, the terms "including", "containing" and "comprising" are used herein in their open, non-limiting sense.
Where the plural form (e.g. compounds, salts) is used, this includes the singular (e.g. a single compound, a single salt). "A compound" does not exclude that (e.g. in a pharmaceu- tical formulation) more than one compound of the formula (I) (or a salt thereof) is present.
"Treatment" includes prophylactic (preventive) and therapeutic treatment as well as the delay of progression of a disease, disorder or condition. Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight- chain or branched. "Alkyl" refers to a straight-chain or branched-chain alkyl group. For example, (d-C4)alkyl includes methyl, ethyl, n- or iso-propyl, and n-, iso-, sec- or tert-butyl. heteroaryl1 is a 9- or 10- membered, unsaturated or partially unsaturated bicyclic group comprising 1 , 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein the total number of ring S atoms does not exceed 1 , and the total number of ring O atoms does not exceed 1 , wherein heteroaryl1 is optionally substituted by one or more substituents, preferably 1 , 2 or 3 substituents, independently selected from:
• halo,
• OH,
• (CrC3)alkyl, said (CrC3)alkyl being optionally substituted by one or more substituents independently selected from OH and halo,
• heterocyclyl2, • -C(CH3)=NO(Ci-C3)alkyl, wherein the (Ci-C3)alkyl of said C(CH3)=NO(Ci-C3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo. In another embodiment, heteroaryl1 is optionally substituted by one or more substituents, preferably 1 , 2 or 3 substituents, independently selected from:
• halo,
• OH,
• (Ci-C3)alkyl, said (CrC3)alkyl being optionally substituted by one or more substituents independently selected from OH and halo, and
• -C(CH3)=NO(Ci-C3)alkyl, wherein the (Ci-C3)alkyl of said C(CH3)=NO(Ci-C3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo. Specific examples of heteroaryl1 include, but are not limited to, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7- naphthyridinyl, 1 ,8-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2- d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3- b]pyrazinyl, pyrimido[4,5-d]pyrimidinyl, benzofuranyl, benzothiophenyl, indolyl,
benzimidazolyl, benzoxazolyl, indazoyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3- c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5- c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, indazolyl, purinyl, indolizinyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,5-a]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, pyrrolo[1 ,2-b]pyridazinyl and imidazo[1 ,2- c]pyrimidinyl, and the partially saturated equivalents thereof.
"heteroaryl3" means a 9- or 10- membered, unsaturated or partially unsaturated bicyclic group comprising 1 or 2 ring N heteroatoms. Heteroaryl3 is optionally substituted by one or more substituents independently selected from:
• halo,
• OH,
• (Ci-C3)alkyl, wherein said (d-C3)alkyl is optionally substituted by one or more
substituents independently selected from OH and halo. • heterocyclyl2, and
• -C(CH3)=NO(Ci-C3)alkyl, wherein the (d-C3)alkyl of said C(CH3)=NO(Ci-C3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo,
In another embodiment, heteroaryl3 is optionally substituted by one or more substituents independently selected from:
• halo,
• OH,
• (CrC3)alkyl, wherein said (d-C3)alkyl is optionally substituted by one or more
substituents independently selected from OH and halo, and
• -C(CH3)=NO(Ci-C3)alkyl, wherein the (d-C3)alkyl of said C(CH3)=NO(d-C3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo.
Specific examples of heteroaryl3 include, but are not limited to, quinolinyl, isoquinolinyl, cinnolinyl, azaquinazolinyl, quinoxalinyl, phthalazinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, indolyl, benzimidazolyl, indazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2- c]pyridinyl, pyrrolo[3,2-b]pyridinyl, isoindolyl, indazolyl, indolininyl, imidazo[1 ,2-a]pyridinyl, imidazo[1 ,5-a]pyridinyl, pyrazolo[1 ,5-a]pyridinyl and pyrrolo[1 ,2-b]pyridazinyl.
"heterocyclyl1" means a 4, 5 or 6 membered saturated or partially unsaturated monocyclic group comprising 1 or 2 ring heteroatoms independently selected from N, O and S.
Heterocyclyl1 is optionally substituted by CONH2 or (d-C3)alkyl. Specific examples of heterocyclyl1 include, but are not limited to, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 1 ,2,3,4-tetrahydropyridinyl, 1 ,2,5,6-tetrahydropyridinyl, pyrrolidinyl, piperidinyl and piperazinyl. "heterocyclyl2" means a 5 or 6 membered saturated, unsaturated or partially unsaturated monocyclic group comprising 1 , 2 or 3 ring heteroatoms independently selected from N, O and S, wherein the total number of ring S atoms does not exceed 1 , and the total number of ring O atoms does not exceed 1 . Heterocyclyl2 is optionally substituted by (d-C3)alkyl. Specific examples of heterocyclyl2 include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, 1 ,2,3,4-tetrahydropyridinyl, 1 ,2,5,6-tetrahydropyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,3-triazolyl, 1 ,3,4-triazolyl, 1 -oxa-2,3-diazolyl, 1 -oxa-2,4-diazolyl, 1 - oxa-2,5-diazolyl, 1 -oxa-3,4-diazolyl, 1 -thia-2,3-diazolyl, 1 -thia-2,4-diazolyl, 1 -thia-2,5-diazolyl, 1 -thia-3,4-diazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 3,4-dihydro-2H-pyranyl, 5,6- dihydro-2H-pyranyl and 2H-pyranyl.
"disease" as used herein includes a disorder or condition. Halo means fluoro, chloro, bromo or iodo. In a particular embodiment of the invention, halo is fluoro or chloro. Preferably, halo is fluoro.
According to the disclosures herein, the compound of formula (I) is selected from any one of the following structures (Ia) to (Ie):
Figure imgf000010_0001
Figure imgf000010_0002
In an embodiment of the invention, there is provided a compound of formula (I) wherein B is N;
Y is C or N;
X is CH or N;
such that when X is CH, ring A is ring Ai or ring Aii
Ai Aii
Figure imgf000011_0001
when X is N, ring A is Aiii;
Aiii
Figure imgf000011_0002
and when X is N and B is CH, ring A is Ai.
Ai
Figure imgf000011_0003
Such compounds have the structure (Ia), (Ib), (Ic) or (Ie) as disclosed herein. In another embodiment of the invention, there is provided a compound of formula (I) wherein B is N;
Y is C or N; X is CH or N;
such that when X is CH, ring A is ring Ai or ring Aii
Ai Aii
Figure imgf000012_0001
and when X is N, ring A is Aiii;
Aiii
Figure imgf000012_0002
Such compounds have the structure (Ia), (Ib) or (Ic) as disclosed herein In a particular embodiment of the invention there is provided a compound having formula (Ib), wherein the substituents are as defined herein.
In another embodiment of the invention, R1 is i or ii:
Figure imgf000012_0003
In a preferred embodiment of the invention, R1 is
Figure imgf000012_0004
In another embodiment of the invention, R1 is a group selected from i, ii and iii:
Figure imgf000013_0001
and R5 is heteroaryl3. In another embodiment of the invention, R1 is
Figure imgf000013_0002
and R5 is heteroaryl3.
In another embodiment of the invention, heteroaryl1 and heteroaryl3 are each optionally substituted by one or more substituents independently selected from halo, 4-methylpiperazin- 1 -yl, ethanone O-(2-hydroxyethyl)oxime and (CrC2)alkyl.
In a preferred embodiment of the invention, R5 is indazolyl or quinolinyl, each optionally substituted by one or more substituents independently selected from halo, (d-C3)alkyl, 4- methylpiperazin-1 -yl and ethanone O-(2-hydroxyethyl)oxime. In particular, R5 is indazolyl or quinolinyl optionally substituted by one, two or three substituents independently selected from halo and (CrC3)alkyl.
In a further preferred embodiment of the invention, R5 is indazolyl optionally substituted by one, two or three substituents independently selected from methyl and fluoro, or R5 is quinolinyl optionally substituted by one or two fluoro substituents.
In a particular embodiment of the invention, R5 is indazol-5-yl substituted at the 1 position by a methyl substituent and optionally further substituted by one or two fluoro substituents, or R5 is quinolin-6-yl optionally substituted by one or two fluoro substituents. In an embodiment of the invention, said fluoro substituents are present at the 5 and/or 7 positions of the quinolinyl group.
In a particular embodiment of the invention, R5 is quinolin-6-yl substituted by
• heterocyclyl2, or • -C(CH3)=NO(Ci-C3)alkyl, wherein the (Ci-C3)alkyl of said C(CH3)=NO(Ci-C3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo wherein said heterocyclyl2 and -C(CH3)=NO(Ci-C3)alkyl substituents are present at the 3- position of the quinolinyl group.
In a further embodiment, R5 is quinolin-6-yl substituted by 3-(4-Methylpiperazin-1 -yl) or quinolin-6-yl substituted by 3-ethanone O-(2-hydroxy-ethyl)oxime.
In a particular embodiment of the invention, R5 is 7-fluoro-quinolin-6-yl, quinolin-6-yl, 5,7- difluoroquinolin-6-yl, 1 -methyl-1 H-indazol-5-yl, 6-fluoro-1 -methyl-1 H-indazol-5-yl, 4,6-difluoro- 1 -methyl-1 H-indazol-5-yl, 5-Fluoroquinolin-6-yl, 3-(4-Methylpiperazin-1 -yl)quinolin-6-yl or 6- quinolin-3-yl-ethanone O-(2-hydroxy-ethyl)oxime.
In another embodiment of the invention, R6 is hydrogen, deuterium, OH or halo, particularly hydrogen, deuterium or halo, and in a preferred embodiment, R6 is hydrogen.
In another embodiment of the invention, R7 is hydrogen, deuterium, halo, or methyl, wherein said methyl is optionally substituted by one or more substituents independently selected from OH and halo. In another embodiment of the invention R7 is hydrogen, deuterium, halo, or methyl. In a preferred embodiment, R7 is hydrogen or methyl, more preferably hydrogen.
Where R1 is i, and R6 and R7 are not both hydrogen, the compound of formula (I) contains an asymmetric carbon atom at R1. Included within the scope of the invention is a compound of formula (I) containing the (R), or the (S) enantiomer of R1i, or a mixture thereof. In a preferred embodiment of the invention there is provided a compound of formula (I) containing the (S) enantiomer of R1i, or a mixture including the (S) enantiomer as a major component.
Figure imgf000014_0001
In a preferred embodiment of the invention n is O. In another embodiment of the invention, R2 is hydrogen or methyl. Preferably, R2 is methyl.
In another embodiment of the invention, R3 is selected from:
• (Ci-C6)alkyl, wherein said (d-C6)alkyl is optionally substituted by one or more substituents independently selected from halo, hydroxy and (d-C3)alkoxy,
• heterocyclyl1
• phenyl, wherein said phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (d-C3)alkyl and (d-C3)alkoxy, wherein said (CrC3)alkyl and (d-C3)alkoxy are each optionally substituted by one or more halo substituents,
• -CH2- heterocyclyl1
• -CH2-phenyl, wherein the phenyl of said -CH2-phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (d-C3)alkyl and (Ci-C3)alkoxy, wherein said (d-C3)alkyl and (d-C3)alkoxy are each optionally substituted by one or more halo substituents,
• (d-C2)alkylCO2(d-C2)alkyl,
• (C0-C2)alkylCONH2,
• (d-C4)alkylNH2,
• (CrC2)alkylNHCONH2,
• (d-C2)alkylCO2H,
• (CrC2)alkylNHCO2CH3, or
• Hydrogen,
In another embodiment of the invention, R3 is selected from:
• (CrC4)alkyl, wherein said (d-C4)alkyl is optionally substituted by one or more substituents independently selected from halo, hydroxy and methoxy,
• pyrrolidinyl, optionally substituted by CONH2,
• piperidinyl,
• phenyl, wherein said phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (d-C3)alkyl and (d-C3)alkoxy, wherein said (Ci-C3)alkyl and (d-C3)alkoxy are each optionally substituted by one or more halo substituents,
• -CH2-pyrrolidinyl, wherein said pyrrolidinyl is optionally substituted by CONH2,
• -CH2-piperidinyl, • -CH2-phenyl, wherein the phenyl of said -CH2-phenyl is optionally substituted by one or more substituents independently selected from halo, methyl and methoxy, wherein said methyl is optionally substituted by one, two or three halo substituents,
• (C1-C2)alkylCθ2(C1-C2)alkyl,
• (C0-C2)alkylCONH2,
• (C2-C4)alkylNH2,
• (CrC2)alkylNHCONH2,
• (CrC2)alkylCO2H,
• oxetanyl
• (CrC2)alkylNHCO2CH3,
• -CH2-(C3-C6)cycloalkyl, and
• hydrogen
In a particular embodiment of the invention, R3 is ethyl, methyl, 2-hydroxyethyl, 1 ,3- dihydroxypropan-2-yl-, 2,3-dihydroxypropyl-, 2-hydroxy-1 ,1 -dimethyl-ethyl-, 2-hydroxy-2- methyl-propyl-, pyrrolidin-3-yl-, -3-pyrrolidine-1 -carboxamide, hydrogen, benzyl, A- methoxybenzyl-, piperidin-4-yl-, piperidin-4-ylmethyl-, -CH2CO2CH3, -CH2CONH2 2- aminoethyl-, 1 -hydroxypropan-2-yl-, -CH2CH2NHCO2CH3, -CH2CH2NHCONH2; 3- trifluoromethylphenyl-, phenyl, 2-fluoroethyl-, 3-hydroxypropyl, 2-methoxyethyl, A- hydroxybutyl, 4-fluorobutyl, CONH2, 1 -hydroxy-2-methylpropan-2-yl, oxetan-3-yl or - CH2CO2H, cyclopropylmethyl, or hydrogen;
In another particular embodiment of the invention, R3 is hydroxyethyl, particularly 2- hydroxyethyl, or hydrogen.
In another embodiment there is provided a compound of formula (I)
Figure imgf000016_0001
wherein
Y is C or N;
X is CH or N;
B is CH or N;
A is a ring; such that when X is CH and B is N, ring A is ring Ai or ring Aii;
Ai Aii
Figure imgf000017_0001
when X is N and B is N, ring A is Aiii;
Aiii
Figure imgf000017_0002
and when X is N and B is N, or X is N and B is CH, ring A is Ai;
Ai
Figure imgf000017_0003
R1 is i:
Figure imgf000018_0001
R5 is 7-fluoro-quinolin-6-yl, quinolin-6-yl, 5,7-difluoroquinolin-6-yl, 1 -methyl-1 H-indazol-5-yl, 6- fluoro-1 -methyl-1 H-indazol-5-yl, 4,6-difluoro-1 -methyl-1 H-indazol-5-yl, 5-Fluoroquinolin-6-yl, (4-Methylpiperazin-1 -yl)quinolin-6-yl or 6-quinolin-3-yl-ethanone O-(2-hydroxy-ethyl)oxime
R6 is hydrogen, deuterium, OH, methyl or halo;
R7 is hydrogen, deuterium, halo, or (d-C3)alkyl, wherein said (d-C3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo; or R6 and R7, together with the carbon to which they are attached form cyclopropyl;
R2 is hydrogen, NH2, or (CrC4)alkyl, and R3 is ethyl, methyl, 2-hydroxyethyl, 1 ,3-dihydroxypropan-2-yl-, 2,3-dihydroxypropyl-, 2- hydroxy-1 ,1 -dimethyl-ethyl-, 2-hydroxy-2-methyl-propyl-, pyrrolidin-3-yl-, -3-pyrrolidine-1 - carboxamide, hydrogen, benzyl, 4-methoxybenzyl-, piperidin-4-yl-, piperidin-4-ylmethyl-, - CH2CO2CH3, -CH2CONH2 2-aminoethyl-, 1 -hydroxypropan-2-yl-, -CH2CH2NHCO2CH3, - CH2CH2NHCONH2; 3-trifluoromethylphenyl-, phenyl, 2-fluoroethyl-, 3-hydroxypropyl, 2- methoxyethyl, 4-hydroxybutyl, 4-fluorobutyl, CONH2, 1 -hydroxy-2-methylpropan-2-yl, oxetan- 3-yl, hydrogen, cyclopropylmethyl, or -CH2CO2H; or a pharmaceutically acceptable salt thereof.
In a further embodiment the invention provides a compound of formula (I) having a structure selected from (Ia), (Ib) or (Ic) above, wherein
R1 is i:
Figure imgf000019_0001
R5 is quinolin-6-yl optionally substituted by one or two fluoro substituents, the fluoro substituents being preferably in the 5 and/or 7 positions;
R6 is hydrogen;
R7 is hydrogen or methyl;
R2 is methyl; and
R3 is hydroxyethyl, more particularly 2-hydroxyethyl, or R3 is hydrogen;
Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.
In a particular embodiment, the invention provides one or more compounds selected from the Example compounds disclosed herein, or a pharmaceutically acceptable salt thereof.
Figure 1 herein shows the X-ray diffractogram of Example 53S amorphous form. Figure 2 shows the X-ray diffractogram of Example 53S crystalline form I. Figure 3 shows the X-ray diffractogram of Example 53S crystalline form II. As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. Also as used herein, the term "an optical isomer" or "a stereoisomer" refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration, such as for the asymmetric carbon atom which may be present within the R1 group (i) defined herein. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Preferably for the asymmetric R1 group (i) defined herein, the (S) enantiomer is in excess, in amounts as described above.
Substituents at atoms with unsaturated bonds may, if possible, be present in cis- (Z)- or trans- (E)- form. Preferably, the hydrazones of the present invention have the trans-(£)- form. Accordingly, as used herein a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization. Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral
chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent. Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31P, 32P, 35S, 36CI, 125I respectively. Various isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 13C, and 14C are incorporated. Such isotopically labelled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography
(SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a. readily available isotopically labeled reagent for a non-isotopically labeled reagent.
Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this invention any atom specifically designated as a deuterium (D) is meant to represent deuterium, for example in the ranges given above.
Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagentβ in place of the non-labeled reagent previously employed.
As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. The salt can be present alone or in mixture with free compound of the formula (I). In many cases, the compounds of the present invention are capable of forming acid salts by virtue of the presence of amino groups or groups similar thereto.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, , hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). "Salts", or " salts thereof" or "or a salt thereof", can be present alone or in mixture with free compound of the formula (I).
For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred. In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO. Any formula given herein is intended to represent hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.
Compounds of the invention, i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of formula (I).
The compounds of the invention therefore include compounds of formula I, polymorphs, and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labelled compounds of formula I, as defined herein. In preferred embodiments, which are preferred independently, collectively or in any combination or sub-combination, the invention relates to a compound of the formula (I), in free base form or in acid addition salt form, wherein the substituents are as defined herein. The compounds of the present invention may be administered as prodrugs. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. [Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).]
Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro- moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
Some examples of such prodrugs include:
(i) where the compound of formula (I) contains a carboxylic acid functionality
(-COOH), an ester thereof, for example, replacement of the hydrogen with (d-C8)alkyl; (ii) where the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (Ci-C6)alkanoyloxymethyl; and (iii) where the compound of formula (I) contains a primary or secondary amino functionality (- NH2 or -NHR where R≠ H), an amide thereof, for example, replacement of one or both hydrogens with (d-Cio)alkanoyl.
Certain compounds of formula (I) may also themselves act as prodrugs of other compounds of formula (I).
The invention further relates to a pharmaceutically acceptable prodrug of a compound of formula (I). The invention further relates to a pharmaceutically acceptable metabolite of a compound of formula (I). "C-Met tyrosine kinase mediated diseases" are especially such disorders that respond in a beneficial way (e.g. amelioration of one or more symptoms, delay of the onset of a disease, up to temporary or complete cure from a disease) to the inhibition of a protein tyrosine kinase, especially inhibition of a c-Met kinase. These disorders include proliferative diseases such as tumor diseases, in particular solid tumors and metastasis derived thereof, e.g.
hereditary papillary renal cell carcinoma (PRCC), sporadic forms of PRCC, head and neck cancer, squamous cell carcinoma, gastric carcinoma, pancreatic carcinoma, lung cancer, bladder cancer, breast cancer, leiomyosarcoma, glioblastoma, melanoma, alveolar soft part sarcoma. These disorders further include inflammatory conditions, such as inflammatory conditions due to an infection.
"Combination" refers to either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the formula (I) and a combination partner (e.g. an other drug as explained below, also referred to as "therapeutic agent" or "co- agent") may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The terms "co-administration" or "combined
administration" or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of formula (I) and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of formula (I) and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.
The invention relates especially to a compound of the formula (I) as provided in the
Examples, as well as the methods of manufacture described therein. The compounds of formula (I) have valuable pharmacological properties, as described hereinbefore and hereinafter. In another embodiment of the invention, there is provided a method for treating a c-Met related disorder or condition. The disorder or condition to be treated is preferably a proliferative disease such as a cancer or an inflammatory condition. Compounds of formula (I) are further useful for treating diseases associated with a c-Met-related condition. A: Proliferative diseases: Compounds of formula (I) are particular useful for the treatment of one or more of the following proliferative diseases:
Compounds of formula (I) are useful in the treatment of cancer wherein the cancer is selected from the group consisting of brain cancer, stomach cancer, genital cancer, urinary cancer, prostate cancer, bladder cancer (superficial and muscle invasive), breast cancer, cervical cancer, colon cancer, colorectal cancer, glioma (including glioblastoma, anaplastic astrocytoma, oligoastrocytoma, oligodendroglioma), esophageal cancer, gastric cancer, gastrointestinal cancer, liver cancer, hepatocellular carcinoma (HCC) including childhood HCC, head and neck cancer (including head and neck squamous-cell carcinoma,
nasopharyngeal carcinoma), Hurthle cell carcinoma, epithelial cancer, skin cancer, melanoma (including malignant melanoma), mesothelioma, lymphoma, myeloma (including multiple myeloma), leukemias, lung cancer (including non-small cell lung cancer (including all histological subtypes: adenocarcinoma, squamous cell carcinoma, bronchoalveolar carcinoma, large-cell carcinoma, and adenosquamous mixed type), small-cell lung cancer), ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer (including but not limited to papillary renal cell carcinoma), intestine cancer, renal cell cancer (including hereditary and sporadic papillary renal cell cancer, Type I and Type II, and clear cell renal cell cancer); sarcomas, in particular osteosarcomas, clear cell sarcomas, and soft tissue sarcomas (including alveolar and embryonal rhabdomyosarcomas, alveolar soft part sarcomas); thyroid carcinoma (papillary and other subtypes).
Compounds of formula (I) are useful in the treatment of cancer wherein the cancer is stomach, colon, liver, genital, urinary, melanoma, or prostate. In a particular embodiment, the cancer is liver or esophageal.
Compounds of formula (I) are useful in the treatment of colon cancer, including metastases, e.g. in the liver, and of non-small-cell lung carcinoma. Compounds of formula (I) may also be used in the treatment of hereditary papillary renal carcinoma (Schmidt, L. et al. Nat. Genet. 16, 68-73, 1997) and other proliferative diseases in which c-MET is overexpressed or constitutively activated by mutations (Jeffers and Vande Woude. Oncogene 18, 5120-5125, 1999; and reference cited therein) or chromosomal rearrange-ments (e.g. TPR-MET; Cooper et al. Nature 31 1 , 29-33, 1984; Park, et al. Cell 45, 895-904, 1986).
Compounds of formula (I) are further useful in the treatment of additional cancers and conditions as provided herein or known in the art. B: Inflammatory conditions: Compounds of formula (I) are particular suitable for the treatment of one or more inflammatory conditions.
In a further embodiment, the inflammatory condition is due to an infection. In one
embodiment, the method of treatment would be to block pathogen infection. In a particular embodiment, the infection is a bacterial infection, e.g., a Listeria infection. See, e.g., Shen et al. Cell 103: 501 -10, (2000) whereby a bacterial surface protein activates c-Met kinase through binding to the extracellular domain of the receptor, thereby mimicking the effect of the cognate ligand HGF/SF.
Compounds of formula (I) are further useful in the treatment of additional inflammatory disorders and conditions as provided herein or known in the art.
C: Combination therapy: In certain embodiments, any of the above methods involve further administering a chemotherapeutic agent.
In a related embodiment, the chemotherapeutic agent is an anti-cancer agent. Specific combinations are provided throughout the application.
In a further related embodiment, any of the above methods involve further administering a pathway specific inhibitor. The pathway specific inhibitor may be a chemotherapeutic agent or may be a biologic agent, e.g., such as antibodies. Pathway specific inhibitors include, but are not limited to, inhibitors of EGFR, Her-2, Her-3, VEGFR, Ron, IGF-IR, PI-3K, mTOR,
Raf.
In a further related embodiment to several of the above methods, following administering to the subject or contacting the cell, these methods can further involve observing amelioration or retardation of development or metastasis of the cancer. Thus, in one embodiment, the invention relates to a method of treating a c-Met related disorder or condition which involves administering to a subject in need thereof an effective amount of a compound of formula (I). In a further embodiment, the invention relates to a compound of formula (I) or a
pharmaceutically acceptable salt thereof, for use as a medicament, in particular for the treatment of one or more C-Met tyrosine kinase mediated diseases.
In a further embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of one or more C-Met tyrosine kinase mediated diseases.
In a further embodiment, the invention relates to a method for the treatment of a disease or disorder which responds to an inhibition of C-Met tyrosine kinase, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, especially in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.
In a further embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) as active ingredient in association with at least one pharmaceutical carrier or diluent.
In a further embodiment, the invention relates to a pharmaceutical composition comprising: (a) an effective amount of compound of formula (I) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and/or pharmaceutically active metabolites thereof; and (b) one or more pharmaceutically acceptable excipients and / or diluents.
In a further embodiment, the invention relates to a pharmaceutical composition for treatment of a disease, e.g. of solid or liquid tumours in warm-blooded animals, including humans, comprising a dose effective in the treatment of said disease of a compound of the formula (I) as described above or a pharmaceutically acceptable salt of such a compound together with a pharmaceutically acceptable carrier (= carrier material). In another embodiment of the invention, there is provided a pharmaceutical preparation (composition), comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt of such a compound, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable carrier and / or diluents and optionally one or more further therapeutic agents.
As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives {e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1 ) at least partially alleviating, inhibiting, preventing and/or
ameliorating a condition, or a disorder or a disease (i) mediated by cMet or (ii) associated with cMet activity, or (iii) characterized by activity (normal or abnormal) of cMet; or (2) reducing or inhibiting the activity of cMet; or (3) reducing or inhibiting the expression of cMet. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of cMet; or at least partially reducing or inhibiting the expression of cMet.
As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates {e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically, {e.g., stabilization of a discernible symptom), physiologically, {e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form
(including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
Tablets may be either film coated or enteric coated according to methods known in the art.
Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.
Suitable compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
As used herein a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant. The invention relates also to a pharmaceutical composition comprising an effective amount, especially an amount effective in the treatment of one of the above-mentioned diseases, disorders or conditions, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be inorganic or organic, solid or liquid.
The dosage of the active ingredient to be applied to a warm-blooded animal depends upon a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and he- patic function of the patient; and the particular compound employed. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a con- sideration of the distribution, equilibrium, and elimination of a drug. The dose of a compound of the formula (I) or a pharmaceutically acceptable salt thereof to be administered to warmblooded animals, for example humans of approximately 70 kg body weight, is preferably from approximately 3 mg to approximately 5 g, more preferably from approximately 10 mg to approximately 1 .5 g per person per day, divided preferably into 1 to 3 single doses which may, for example, be of the same size. Usually, children receive half of the adult dose.
The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1 -1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1 -500 mg or about 1 -250 mg or about 1 -150 mg or about 0.5-100 mg, or about 1 -50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 103 molar and 109 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1 -500 mg/kg, or between about 1 -100 mg/kg. In another embodiment of the invention, there is provided a combination of a compound of formula (I) with one or more other therapeutically active agents. Thus, a compound of formula (I) can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.
A compound of formula (I) can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk. Thus, a compound of the formula (I) may be used in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase Il inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibittors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity; anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti- androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors; kinesin spindle protein inhibitors; MEK inhibitors; leucovorin; EDG binders; antileukemia compounds; ribonucleotide reductase inhibittors; S-adenosylmethionine decarboxylase inhibitors; angiostatic steroids; corticosteroids; other chemotherapeutic compounds (as defined below); photosensitizing compoounds.
Further, alternatively or in addition they may be used in combination with other tumor treatment approaches, including surgery, ionizing radiation, photodynamic therapy, implants, e.g. with corticosteroids, hormones, or they may be used as radiosensitizers.
The term "aromatase inhibitor" as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark AROMASIN. Form- estane can be administered, e.g., in the form as it is marketed, e.g. under the trademark LENTARON. Fadrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark AFEMA. Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR. Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g. under the trademark ORIMETEN. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g. breast tumors. The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX. Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTA. Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g. under the trademark FASLODEX. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g. breast tumors. The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g. as disclosed in US 4,636,505. The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, go- serelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX. Abarelix can be formulated, e.g. as disclosed in US 5,843,901.
The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO99/ 17804). Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark CAMPTOSAR. Topotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark HYCAMTIN.
The term "topoisomerase Il inhibitor" as used herein includes, but is not limited to the an- thracyclines such as doxorubicin (including liposomal formulation, e.g. CAELYX), dauno- rubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and lo- soxantrone, and the podophillotoxines etoposide and teniposide. Etoposide can be ad- ministered, e.g. in the form as it is marketed, e.g. under the trademark ETOPOPHOS.
Teniposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark VM 26-BRISTOL. Doxorubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark FARMORUBICIN. Idarubicin can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZAVEDOS.
Mitoxantrone can be administered, e.g. in the form as it is marketed, e.g. under the trademark NOVANTRON.
The term "microtubule active compound" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides, cochicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivatives thereof.
Paclitaxel may be administered e.g. in the form as it is marketed, e.g. TAXOL. Docetaxel can be administered, e.g., in the form as it is marketed, e.g. under the trademark TAXOTERE. Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark VINBLASTIN R. P.. Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTIN. Discodermolide can be obtained, e.g., as disclosed in US 5,010,099. Also included are Epothilone derivatives which are disclosed in WO 98/10121 , US 6,194,181 , WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Especially preferred are Epothilone A and/or B.
The term "alkylating compound" as used herein includes, but is not limited to, cyclophospha- mide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark HOLOXAN. The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes compounds disclosed in WO 02/22577, especially N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1 H- indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(2-methyl-1 H- indol-3-yl)-ethyl]-amino]methyl]phenyl]-2£-2-propenamide and pharmaceutically acceptable salts thereof. It further especially includes Suberoylanilide hydroxamic acid (SAHA).
Compounds which target, decrease or inhibit activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065, in particular, Λ/-hydroxy-3-[4-[[[2-(2-methyl-1 H-indol-3-yl)-ethyl]-amino]me- thyl]phenyl]-2£-2-propenamide, or a pharmaceutically acceptable salt thereof and Λ/-hydroxy- 3-[4-[(2-hydroxyethyl){2-(1 H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. The term "antineoplastic antimetabolite" includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark XELODA. Gemcitabine can be administered, e.g., in the form as it is marketed, e.g. under the trademark GEMZAR.
The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis- platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN.
The term "compounds targeting/decreasing a protein or lipid kinase activity"; or a "protein or lipid phosphatase activity"; or "further anti-angiogenic compounds" as used herein includes, but is not limited to, c-Met tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.,
a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, e.g. a N-phenyl-2- pyrimidine-amine derivative, e.g. imatinib, SU101 , SU6668 and GFB-1 1 1 ;
b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor- receptors (FGFR);
c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-
IR, especially compounds which inhibit the kinase activity of IGF-I receptor, such as those compounds disclosed in WO 02/092599, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors;
d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin kinase family inhibitors;
e) compounds targeting, decreasing or inhibiting the activity of the AxI receptor tyrosine kinase family;
f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase;
g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, e.g. imatinib;
h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases - (part of the PDGFR family), such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, e.g. imatinib;
i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-AbI kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib (AMN107);
PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825) j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1 , PKB/Akt, and Ras/MAPK family members, and/or members of the cyclin- dependent kinase family (CDK) and are especially those staurosporine derivatives disclosed in US 5,093,330, e.g. midostaurin; examples of further compounds include e.g. UCN-01 , safingol, BAY 43-9006, Bryostatin 1 , Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521 ; LY333531/LY379196; isochinoline compounds such as those disclosed in WO 00/09495; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin. A tyrphostin is preferably a low molecular weight (Mr < 1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S- arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810; AG 99;
Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and
adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin);
I) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the compound of ex. 39, or in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g. compound known as CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g. compound ZM105180); e.g. trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI- 774, CI-1033, EKB-569, GW-2016, E1 .1 , E2.4, E2.5, E6.2, E6.4, E2.1 1 , E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO 03/013541 ; and m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF;
n) compounds targeting, decreasing or inhibiting the activity of the Ron receptor tyrosine kinase.
Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (THALOMID) and TNP-470.
The term "Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase" includes, but is not limited to inhibitors of phosphatase 1 , phosphatase 2A, or CDC25, e.g. okadaic acid or a derivative thereof.
The term "Compounds which induce cell differentiation processes" includes, but is not limited to e.g. retinoic acid, α- γ- or δ-tocopherol or α- γ- or δ-tocotrienol. The term "cyclooxygenase inhibitor" as used herein includes, but is not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, e.g. 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. "Etridonic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark DIDRONEL. "Clodronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS. "Tiludronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELID. "Pamidronic acid" can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIA™.
"Alendronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX. "Ibandronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANAT. "Risedronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTONEL. "Zoledronic acid" can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZOMETA. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus
(Rapamune®), everolimus (Certican™), CCI-779 and ABT578.
The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88.
The term "biological response modifier" as used herein refers to a lymphokine or interferons, e.g. interferon γ.
The term "inhibitor of Ras oncogenic isoforms", e.g. H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras e.g. a "farnesyl transferase inhibitor" e.g. L-744832, DK8G557 or R1 15777 (Zarnestra).
The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g.
telomestatin.
The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are e.g. bengamide or a derivative thereof.
The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include e.g. Bortezomid (Velcade™)and MLN 341. The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551 ) BMS- 279251 , BAY 12-9566, TAA21 1 , MMI270B or AAJ996.
The term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors e.g. compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1 -b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors e.g. compounds which target, decrease or inhibit anaplastic lymphoma kinase.
The term "Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R)" are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, e.g. PKC412, midostaurin, a staurosporine derivative, SU1 1248 and MLN518.
The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG, 17-DMAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors;IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (TEMODAL®), AUY922 from Novartis.
The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DM1 ,erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant e.g. intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity. The term "antileukemic compounds" includes, for example, Ara-C, a pyrimidine analog, which is the 2'-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. For the treatment of acute myeloid leukemia (AML), compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of formula (I) can be administered in combination with, e.g., farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide,
Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
"Somatostatin receptor antagonists" as used herein refers to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
"Tumor cell damaging approaches" refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1 , pp. 248-275 (1993).
The term "EDG binders" as used herein refers a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
The term "kinesin spindle protein inhibitors" is known in the field and includes SB715992 or SB743921 from GlaxoSmithKline, pentamidine/chlorpromazine from CombinatoRx;
The term "MEK inhibitors" is known in the field and includes ARRY142886 from Array PioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, leucovorin. The term "ribonucleotide reductase inhibitors" includes, but is not limited to to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1 H-isoindole-1 ,3-dione derivatives, such as PL-1 , PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).
The term "S-adenosylmethionine decarboxylase inhibitors" as used herein includes, but is not limited to the compounds disclosed in US 5,461 ,076.
Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF / VEGFR disclosed in WO 98/35958, e.g. 1 -(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g. the succinate, or in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/1 1223, WO 00/27819 and EP 0 769 947; those as described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci U S A, Vol. 93, pp. 14765-14770 (1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209- 3214 (1998); and Mordenti et al., Toxicol Pathol, Vol. 27, No. 1 , pp. 14-21 (1999); in WO 00/37502 and WO 94/10202; ANGIOSTATIN, described by O'Reilly et al., Cell, Vol. 79, pp. 315-328 (1994); ENDOSTATIN, described by O'Reilly et al., Cell, Vol. 88, pp. 277-285
(1997); anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti- VEGF antibodies or anti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g. Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,
Angiozyme (RPI 4610) and Bevacizumab (Avastin™).
"Photodynamic therapy" as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of
photodynamic therapy includes treatment with compounds, such as e.g. VISUDYNE and porfimer sodium.
"Angiostatic steroids" as used herein refers to compounds which block or inhibit
angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 1 1 -α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
"Corticosteroids" as used herein includes, but is not limited to compounds, such as e.g.
fluocinolone, dexamethasone; in particular in the form of implants. "Other chemotherapeutic compounds" include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
A compound of formula (I) may also be used in combination with one or more further drug substances selected from the group of anti-inflammatory drug substances; antihistamine drug substances; bronchodilatatory drug substances, NSAID; antagonists of chemokine receptors.
The compounds of the invention are also useful as co-therapeutic compounds for use in combination with such further drug substances, particularly in the treatment of inflammatory diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. A compound of the invention may be mixed with such other drug substance in a fixed pharmaceutical composition or it may be administered separately (i.e. before, simultaneously with or after the other drug substance). Accordingly, the invention includes a combination of a compound of formula (I) with one or more further drug substance selected from the group of anti-inflammatory drug substances; antihistamine drug substances;
bronchodilatatory drug substances, NSAID antagonists of chemokine receptors; said compound of the formula(l) and said drug substance being in the same or different pharmaceutical composition.
Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or
mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 1 1 , 14, 17, 19, 26, 34, 37, 39, 51 , 60, 67, 72, 73, 90, 99 and 101 ), WO 03/035668, WO 03/048181 , WO 03/062259, WO 03/064445, WO 03/072592, non-steroidal glucocorticoid receptor agonists such as those described in WO 00/00531 , WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229; LTB4 antagonists such LY2931 1 1 , CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247 and those described in US 5451700; LTD4 antagonists such as montelu- kast and zafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden),V-1 1294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed in WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751 , WO 98/18796, WO 99/16766, WO 01 /13953, WO 03/104204, WO 03/104205, WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451 , WO 04/018457, WO 04/018465, WO 04/ 018431 , WO 04/018449, WO 04/018450, WO 04/018451 , WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805; A2a agonists such as those disclosed in EP 409595A2, EP 1052264, EP 1241 176, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451 , WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01/27131 , WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO 04/ 039762, WO 04/039766, WO 04/045618 and WO 04/046083; A2b antagonists such as those described in WO 02/42298; and beta-2 adrenoceptor agonists such as albuterol
(salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially, formoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula I of WO 00751 14, which document is incorporated herein by reference, preferably compounds of the Examples thereof, especially a compound of formula
Figure imgf000047_0001
OH
and pharmaceutically acceptable salts thereof, as well as compounds (in free or salt or solvate form) of formula I of WO 04/16601 , and also compounds of WO 04/033412.
Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in WO 01/041 18, WO 02/51841 , WO 02/53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021 , US 5171744, US 3714357, WO 03/33495 and WO 04/018422.
Suitable chemokine receptors include, e.g. CCR-1 , CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351 125, SCH-55700 and SCH- D, Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo- cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-amin- ium chloride (TAK-770), and CCR-5 antagonists described in US 6166037 (particularly claims 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO 04/026873.
Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofena- dine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine as well as those disclosed in WO 03/099807, WO 04/026841 and JP
2004107299.
Therapeutic agents for possible combination are especially one or more antiproliferative, cytostatic or cytotoxic compounds, for example one or several agents selected from the group which includes, but is not limited to, an inhibitor of polyamine biosynthesis, an inhibitor of a protein kinase, especially of a serine/threonine protein kinase, such as protein kinase C, or of a tyrosine protein kinase, such as the EGF receptor tyrosine kinase, e.g. Iressa®, the VEGF receptor tyrosine kinase, e.g. PTK787 or Avastin®, an antibody against the ligand VEGF, or the PDGF receptor tyrosine kinase, e.g. STI571 (Glivec®), PI3K (such as BEZ235 from Novartis) and mToR inhibitors, such as rapamycin, RAD001 , a cytokine, a negative growth regulator, such as TGF-β or IFN-β, an aromatase inhibitor, e.g. letrozole (Femara®) or anastrozole, an inhibitor of the interaction of an SH2 domain with a phosphorylated protein, antiestrogens, topoisomerase I inhibitors, such as irinotecan, topoisomerase Il inhibitors, microtubule active agents, e.g. paclitaxel or an epothilone, alkylating agents, antiproliferative antimetabolites, such as gemcitabine or capecitabine, platin compounds, such as carboplatin or cis-platin, bisphosphonates, e.g. AREDIA® or ZOMET A®, and monoclonal antibodies, e.g. against HER2, such as trastuzumab. The structure of the active agents identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. The above-mentioned compounds, which can be used in combination with a compound of the formula (I), can be prepared and administered as described in the art, such as in the documents cited above. In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
Accordingly, the invention provides the use of a compound of formula (I) for treating a disease or condition mediated by cMet, wherein the medicament is prepared for
administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition mediated cMet,, wherein the
medicament is administered with a compound of formula (I).
Thus, the invention relates in a further embodiment to a combination, particularly a pharmaceutical composition) comprising a therapeutically effective amount of a compound of formula (I) in free form or in pharmaceutically acceptable salt form and a second
therapeutically active agent, for simultaneous or sequential administration. The additional therapeutic agent is preferably selected from the group consisting of an anti-cancer agent; an anti-inflammatory agent.
The invention further relates to a method for the treatment of a disease or disorder which responds to a C-Met tyrosine kinase, especially a proliferative disorder or disease, in particular a cancer, said method comprises administration of an effective amount of a combination of pharmaceutical agents which comprise: (a) a compound of formula (I); and (b) one or more pharmaceutically active agents, to a subject in need thereof, especially human.
The invention further relates to the use of a combination of pharmaceutical agents which comprise: (a) a compound of formula (I); and (b) one or more pharmaceutically active agents for the treatment of a disease or disorder which responds to a C-Met tyrosine kinase, especially a proliferative disorder or disease, in particular a cancer.
The invention further relates to the use of a combination of pharmaceutical agents which comprise: (a) a compound of formula (I); and (b) one or more pharmaceutically active agents for themanufacture of a medicament for the treatment of a disease or disorder which responds to a C-Met tyrosine kinase, especially a proliferative disorder or disease, in particular a cancer. The invention further relates to pharmaceutical compositions comprising (a) a compound of formula (I) and (b) a pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier; wherein at least one pharmaceutically active agent is an anti-cancer therapeutic.
The present invention further relates to a commercial package or product comprising:
(a) a compound of formula (I) ; and (b) a pharmaceutical formulation of a pharmaceutically active agent for simultaneous, concurrent, separate or sequential use; wherein at least one pharmaceutically active agent is an anti-cancer therapeutic.
Also combinations of two or more of sequential, separate and simultaneous administration are possible, preferably such that the combination component-drugs show a joint therapeutic effect that exceeds the effect found when the combination component-drugs are used independently at time intervals so large that no mutual effect on their therapeutic efficiency can be found, a synergistic effect being especially preferred. The invention also provides the use of a compound of formula (I) for treating a disease or condition mediated by cMet, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition mediated by cMet, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I).
The term "delay of progression" as used herein means administration of the combination to patients being in a pre-stage or in an early phase, of the first manifestation or a relapse of the disease to be treated, in which patients, e.g., a pre-form of the corresponding disease is diagnosed or which patients are in a condition, e.g., during a medical treatment or a condition resulting from an accident, under which it is likely that a corresponding disease will develop.
The term "Jointly therapeutically active" or "joint therapeutic effect" means that the compounds may be given separately (in a chronically staggered manner, especially a sequence-specific manner) in such time intervals that they preferably, in the warm-blooded animal, especially human, to be treated, still show a (preferably synergistic) interaction (joint therapeutic effect). A joint therapeutic effect can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
The term "Pharmaceutically effective" preferably relates to an amount that is therapeutically or in a broader sense also prophylactically effective against the progression of a disease or disorder as disclosed herein.
The term "a commercial package" or "a product", as used herein defines especially a "kit of parts" in the sense that the components (a) and (b) as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the components (a) and (b), i.e., simultaneously or at different time points. Moreover, these terms comprise a commercial package comprising (especially combining) as active ingredients components (a) and (b), together with instructions for simultaneous, sequential (chronically staggered, in time-specific sequence, preferentially) or (less preferably) separate use thereof in the delay of progression or treatment of a proliferative disease. The parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. Very preferably, the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the combination partners (a) and (b) (as can be determined according to standard methods. The ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied, e.g., in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to the particular disease, age, sex, body weight, etc. of the patients. Preferably, there is at least one beneficial effect, e.g., a mutual enhancing of the effect of the combination partners (a) and (b), in particular a more than additive effect, which hence could be achieved with lower doses of each of the combined drugs, respectively, than tolerable in the case of treatment with the individual drugs only without combination, producing additional advantageous effects, e.g., less side effects or a combined therapeutic effect in a non-effective dosage of one or both of the combination partners (components) (a) and (b), and very preferably a strong synergism of the
combination partners (a) and (b).
Both in the case of the use of the combination of components (a) and (b) and of the commercial package, any combination of simultaneous, sequential and separate use is also possible, meaning that the components (a) and (b) may be administered at one time point simultaneously, followed by administration of only one component with lower host toxicity either chronically, e.g., more than 3-4 weeks of daily dosing, at a later time point and subsequently the other component or the combination of both components at a still later time point (in subsequent drug combination treatment courses for an optimal effect) or the like.
In another embodiment of the invention, there is provided a method of manufacturing a compound of formula (I) and intermediates thereof. A compound of the formula (I) may be prepared by processes that, though not applied hitherto for the new compounds of the present invention where they thus form new processes, are known per se. The schemes provide a general overview of synthetic strategies to obtain a compound of formula (I). All methods described can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language {e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. Thus, the invention relates in a further aspect to a manufacturing process (a method for manufacturing) a compound of formula (I) comprising at least one reaction step as disclosed herein, and intermediates thereof.
Scheme 1
Figure imgf000052_0001
Z1 is selected from Cl, Br and I
Scheme 2 provides details for a synthetic strategy to obtain preferred compounds of formula (IA, IB, IC) through (NA, NB and NC)
Scheme 2
Figure imgf000053_0001
Zi and Z2 are independently selected from Cl, Br and I
Scheme 3 provides details for a synthetic strategy to obtain preferred compounds of formula (ID) through (ND).
Scheme 3
Figure imgf000053_0002
Figure imgf000053_0003
MD Z1 is selected from Cl, Br and I
Scheme 4 provides details for a synthetic strategy to obtain preferred compounds of formula (IE) through (NE).
Scheme 4
Figure imgf000054_0001
Zi is selected from Cl, Br and I Scheme 5 provides details for a synthetic strategy to obtain preferred compounds of formula (IF) through (NF).
Scheme 5 'F
Figure imgf000054_0002
Z1 and Z2 are independently selected from Cl, Br and I
Oxidation using methods well known to the skilled person results in SO/SO2 linkers
Scheme 6 provides details for a synthetic strategy to obtain preferred compounds of formula (IG) and (IH) through (NG) and (NH) respectively.
Scheme 6
Figure imgf000054_0003
Z1 is selected from Cl, Br and I Scheme 7 provides alternative details for a synthetic strategy to obtain preferred compounds of formula (IH) through (NH).
Figure imgf000055_0001
Scheme 8 provides details for a synthetic strategy to obtain preferred compounds of formula (IK) through (NK).
Scheme 8
Figure imgf000055_0002
Z1 is selected from Cl, Br and I
Scheme 9 provides details for a synthetic strategy to obtain preferred compounds of formula (IL). Scheme 9
Figure imgf000055_0003
The following examples illustrate the invention without limiting the scope thereof. In the examples provided, temperatures are measured in degrees Celsius. Unless otherwise indicated, the reactions take place at room temperature (rt). Further, if not indicated otherwise, the analytical and preparative HPLC conditions are as follows:
Method A:
The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)
0 - 4.0 min: 10% to 90% of methanol
4.0 - 6.0 min: 90% of methanol
Column: GP C18 3 μm 4.6 x 30 mm from Sepax.
Oven temperature: 30 0C
Method B:
The flow is 1.2 mL/min of methanol and water (with 0.5% acetic acid)
0 - 2.0 min: 10% to 90% of methanol
2.0 - 3.0 min 90% of methanol
Column: GP C18 3 μm 4.6 x 30 mm from Sepax.
Oven temperature: 30 0C
Method C:
The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)
0 - 3.0 min: 60% to 90% of methanol
3.0 - 5.0 min: 90% of methanol
Column: GP C18 3 μm 4.6 x 30 mm from Sepax.
Oven temperature: 30 0C Method D:
The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)
0 - 3.0 min: 10% to 50% of methanol
3.0 - 4.0 min: 50% of methanol
Column: GP C18 3 μm 4.6 x 30 mm from Sepax.
Oven temperature: 30 0C
Method E:
The flow is 0.5 mL/min of methanol and water (with 0.5 % acetic acid)
0 - 4.0 min: 10 % to 90 % of methanol 4.0 - 8.0 min: 90 % of methanol
Column: GP C18 3 μm 4.6 x 30 mm from Sepax.
Oven temperature: 30 0C Method F:
The flow is 1 ml_/min of Hexane/Ethanol/Diethyleamine 80/20/0.1 , v/v/v
Column: AD-H
Oven temperature: 25 0C Method G:
The flow is 1 ml_/min of Hexane/Ethanol/Diethyleamine 70/30/0.1 , v/v/v
Column: AD-H
Oven temperature: 25 0C Method H:
The flow is 1 ml_/min of Hexane/lsopropanol/Diethylamine 70/30/0.1 , v/v/v Column: CHIRALPAK OD-H
Oven temperature: 25 0C Method I:
SFC equipment: Thar SFC Prep 80
The flow is 45 g/min of Methanol/CO2 70/30
Column: CHIRALPAK OD-H, 2.0 x 25 cm
Wave length: UV 254 nm
Oven temperature: 35 0C
Method J:
The flow is 1.2 mL/min of methanol and water (with 0.5% acetic acid) 0 - 3.0 min: 60% to 90% of methanol
Column: GP C18 3 μm 4.6 x 30 mm from Sepax.
Oven temperature: 30 0C
Method K
The flow is 1 ml_/min of Hexane/Ethanol/Diethyleamine 80/20/0.1 , v/v/v Column: OJ-H
Oven temperature: 250C
Method L
SFC equipment: Thar SFC Prep 80
The flow is 45 g/min of Methanol/CO2 75/25
Column: CHIRALPAK AD-H, 2.0 x 25 cm
Wave length: UV 254 nm
Oven temperature: 35 0C
In the following examples, the abbreviations given below are used:
AcOH acetic acid
aq. aqueous
atm. atmosphere
BINAP 2,2'-bis-diphenylphosphanyl-[1 ,1 ']binaphthalenyl
Bn benzyl
Boc tert-butoxycarbonyl
DCC dicyclohexylcarbodiimide
DCM dichloromethane
DME 1 ,2-dimethoxyethane
Et2O diethyl ether
EtOAc or EA ethyl acetate
EtOH ethanol
DME dimethyl ethylene glycol
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
eq. equivalent(s)
h hour(s)
HATU 2-(1 H-7-Azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
HPLC High Performance Liquid Chromatography
HV high vacuum
IBX 2-iodoxybenzoic acid
lsolute lsolute® HM-N by International Solvent Technology Ltd., U.K.
LAH lithium aluminium hydride LCMS liquid chromatography coupled with mass spectrometry
LDA lithium diisopropylamide
mL milliliter(s)
min minute(s)
MPLC Medium Pressure Liquid Chormatography
MS-ES electrospray mass spectrometry
MW microwave
NBS Λ/-bromosuccinimide
n-BuLi n-butyllithium
NMP Λ/-methylpyrrolidinone
PdCI2(dppf) 1 ,1 -bis(diphenylphosphino)ferrocenedichloropalladium (I
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium (0)
PdCI2(Ph3)2 dichlorobis(triphenylphosphine)palladium (II)
Rf ratio of fronts in TLC
rt room temperature
TBAF tetrabutylammonium fluoride
TBME methyl tert-butyl ether
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
tR retention time
UV Ultraviolet
Syntheses of intermediates:
Intermediate A
3-Bromo-6-chloroimidazo[1 ,2-b]pyridazine
Figure imgf000059_0001
intermediate A
To a solution of 6-chloroimidazo[1 ,2-b]pyridazine (5 g, 32.6 mmol) in acetonitrile (300 mL) was added NBS (6.37 g, 35.8 mmol) and TFA (0.75 mL). The resulting solution was allowed to stir at rt overnight. The solvents were removed under reduced pressure and the residue was dissolved in EtOAc, wahsed with NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo to afford 7.2 g (92%) of the title compound as a light yellow solid. 1H-NMR (400MHz, CDCI3) δ ppm 7.91 (d, 1 H), 7.79 (s, 1 H), 7.12 (d, 1 H). LCMS (method A): [MH]+ = 232/234, tR = 4.48 min.
Intermediate B
2-(2,3-Dihydroxypropoxy)isoindoline-1 ,3-dione and 2-(1 ,3-dihydroxypropan-2- yloxy)isoindoline-1 ,3-dione
0 To a solution of glycerol in THF containing phthalimide and PPh3 was added DIAD at O 0C.
After being stirred for 20 h at rt, the mixture was concentrated under reduced pressure. Then water was added and the aqueous solution was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (2% MeOH in DCM) to afford the title 5 compound (1 :1 mixture) as a white solid. LCMS (method A): [MH]+ = 238, tR = 3.39/3.46 min.
Intermediate C
1 -Methyl-1 H-indazole-5-carbaldehyde
I) MeONH2-HCI, K2CO3 NaH, MeI / THF
2) N2H4, reflux
Figure imgf000060_0002
Figure imgf000060_0004
Figure imgf000060_0003
n-BuLi, EtMgBr, DMF
Toluene/THF, -300C Q int
Figure imgf000060_0005
5-Bromo-1 H-indazole (i)
A suspension of 5-bromo-2-fluorobenzaldehyde (10.15 g, 50 mmol), MeONH2-HCI (4.07 g, 50 mmol) and K2CO3 (7.59 g, 55.0 mmol) in 100 mL of DMF was stirred at 40 QC for 5 h. The mixture was filtered. The filtrate containing the oxime intermediate was concentrated in vacuo to give approximately 50 ml_ of residue. To this concentrated oxime residue was added N2H4-H2O (50 ml_, 1 .03 mol) and the mixture was heated at reflux overnight. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (hexane:EtOAc = 10:1 ) to afford the title compound as a white solid (6.02 g, 61.2 %). 1H- NMR (400MHz, DMSO-Cf6) δppm 13.24 (bs, 1 H), 9.85 (s, 1 H), 8.05 (s, 1 H), 7.99 (s, 1 H), 7.52 (d, 1 H), 7.44 (dd, 1 H). LCMS (method A): [MH]+ = 197/199, tR = 4.94 min. 5-Bromo-1-methyl-1 H-indazole (ii) and 5-Bromo-2-methyl-2H-indazole (iii)
To a solution of 5-bromo-1 H-indazole (0.19 g, 0.94 mmol) in 3 ml_ of THF at 0 QC was added NaH (0.04 g, 1 .03 mmol). The reaction mixture was stirred at this temperature for 1 h before the addition of methyl iodide (0.09 ml_, 1 .41 mmol) at 0 QC. The reaction was allowed to warm to rt slowly and stirred for 2 h, quenched with water and concentrated in vacuo. The residue was diluted with water and extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude products were purified by flash chromatography (hexane:EtOAc = 10:1 ) to give the title compound ii (88.7 mg, 42.5 %) and iii (60.9 mg, 29 %) as white solid, ii: 1H-NMR (400MHz, DMSO-d6) Dppm 8.02 (d, 1 H), 7.99 (d, 1 H), 7.64 (d, 1 H), 7.50 (dd, 1 H), 4.04 (s, 3H). LCMS (method A): [MH]+ = 21 1/213, tR = 5.19 min. iii: 1H-NMR (400MHz, DMSO-Cf6) δppm 8.33 (s, 1 H), 7.95 (d, 1 H), 7.57 (d, 1 H),
7.30 (dd, 1 H), 4.16 (s, 3H). LCMS (method A): [MH]+ = 21 1/213, tR = 4.95 min. i-Methyl-I H-indazole-5-carbaldehyde (intermediate C)
A suspension of n-BuLi (7.33 mL, 1 1.73 mmol) and ethylmagnesium bromide (5.76 mL, 5.76 mmol) in toluene (30 mL) was stirred at -30 QC for 30 min, and then a solution of 5-bromo-1 - methyl-1 H-indazole (2.25 g, 10.66 mmol) in THF (5 mL) was added. After 1 h, anhydrous
DMF (4.95 mL, 64.0 mmol) was added at -10 QC. The reaction mixture was allowed to warm to rt and stirred for 2 h. The reaction was quenched with saturated aqueous NH4CI solution and concentrated in vacuo. The residue was diluted with water, extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (hexane:EtOAc = 10:1 ) to give the title compound as a white solid (1 .37 g, 76 %). 1H-NMR (400MHz, DMSO-Cf6) δppm 10.02 (s, 1 H), 8.41 (d, 1 H),
8.31 (d, 1 H), 7.86 (dd, 1 H), 7.78 (d, 1 H), 4.09 (s, 3H). LCMS (method A): [MH]+ = 161 , tR = 4.00 min. lntermediate D
Quinolin-6-ylmethanamine
Figure imgf000062_0001
intermediate D
Quinolin-6-ylmethanol (i)
To a slolution of methyl quinoline-6-carboxylate (14 g, 74.8 mmol) in THF (80 ml_) was added LiAIH4 (2.84 g, 74.8 mmol) in portions. The reaction was stirred at rt for 20 min. Then water (2.84 ml_) and aqueous NaOH (10%, 4.26 ml_) were added dropwise to quench the reaction. After stirring for additional 20 min, ether was added and the resulting mixture was filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by column chromatography with hexane/EtOAc to afford quinolin-6-ylmethanol (7.6 g, 64%).
2-(Quinolin-6-ylmethyl)isoindoline-1 ,3-dione (ii)
To a solution of isoindoline-1 ,3-dione (6.47 g, 44.0 mmol) and triphenylphosphine (1 1 .53 g, 44.0 mmol) in THF (70 ml_) at 0 0C was added a solution of quinolin-6-ylmethanol (7 g, 44.0 mmol) in THF (3OmL) and (£)-diisopropyl diazene-1 ,2-dicarboxylate (8.89 g, 44.0 mmol) dropwise over a period of 30 min. The mixture was heated at 30 0C and kept stirring for 20 h. After cooling and concentration, the resulting residue was purified by Analogix silica gel with gradient hexanes/EtOAc to provide 2-(quinolin-6-ylmethyl)isoindoline-1 ,3-dione (12.04 g, 95%). LCMS (method A): [MH]+ = 289, tR = 4.89 min.
Quinolin-6-ylmethanamine (intermediate D)
To a solution of 2-(quinolin-6-ylmethyl)isoindoline-1 ,3-dione (2Og, 69.4 mmol) in MeOH (100 mL) was added hydrazine monohydrate (3.47 g, 69.4 mmol). The solution was heated at reflux for 3 h, then cooled to rt and filtered through celite. The filtrate was concentrated in vacuo. EtOAc then was added to the residue and the resulting solution was filtered and concentrated in vacuo to afford 5 g (41 %) of the title compound. LCMS (method B): [MH]+ = 159, tR = 0.93 min.
Intermediate E and F 7-Fluoro-quinoline-6-carbaldehyde and 7-(7-fluoro-quinolin-6-yl)-methylamine
Figure imgf000063_0001
i intermadiate E intermadiate F
6-Bromo-7-fluoro quinoline (i)
To a suspension of 4-bromo-3-fluoro-phenylamine (100.0 g, 526 mmol) in concentrated sulfuric acid (290 ml_) was added glycerol (220.0 g, 2.39 mol, 4.5 eq.) followed by ferrous sulfate (30.0 g, 0.2 eq.). The reaction mixture was heated at 130 QC for 14 h, cooled to rt and poured onto ice-water. The solution was adjusted with saturated aqueous ammonium hydroxide to pH 8 and extracted with DCM (2 Lχ3). The combined organic layers were washed with brine (1 Lχ3), dried over Na2SO4 and concentrated under reduced pressure to afford a crude product, which was purified by column chromatography (petroleum:EtOAc =
10:1 ) to give the title compound as white solid (45 g, 39%). 1H-NMR (400MHz, DMSO-Cf6) δppm 8.86 (s, 1 H), 8.56 (m, 1 H), 8.45 (m, 1 H), 7.90 (d, 1 H), 7.71 (m, 1 H).
7-Fluoro-quinoline-6-carbaldehyde (intermediate E)
To a suspension of Pd(PPh3)4 (1.27 g, 1 .1 mmol) and sodium formate (13.8 g, 132 mmol, 6 eq.) in acetonitrile (30 ml_) was added a solution of 6-bromo-7-fluoro quinoline (5 g, 22 mmol) in DMSO (30 ml_). The reaction mixture was heated at 120 QC under a CO atmosphere (1 MPa) for 4 h, cooled to rt and concentrated under reduced pressure. The residue was partitioned between water (100 ml_) and EtOAc (150 ml_). The organic layer was separated, washed with brine (100 ml_), dried over Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by column choromatography with gradient petroleum :EtOAc from 10:1 to 3:1 to give the title compound as a white solid (400 mg, 10.4%). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.95 (s, 1 H), 8.46 (m, 1 H), 8.20 (m, 1 H), 7.75 (d, 1 H), 7.53 (m, 1 H).
7-(7-Fluoro-quinolin-6-yl)-methylamine (intermediate F)
7-Fluoro-quinoline-6-carbaldehyde ( 500 mg, 2.85 mmol ) was dissolved in an ammonia solution (2 M in methanol, 50 ml_). After stirring at rt for 3 h, NaBH4 (108.0 mg, 2.85 mmol) was added in portions. The reaction was stirred overnight, quenched by water in an ice-bath. After removal of methanol under reduced pressure, the residue was diluted with water, adjusted its pH to around 8 with 1 N HCI solution, and extracted with DCM three times. The combined organic layers were washed with water and dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (DCM:MeOH = 50:1 ) to give the title compound as a yellow solid (250.0 mg, 49 %). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.86 (dd, 1 H), 8.36 (d, 1 H), 8.07 (d, 1 H), 7.68 (d, 1 H), 7.49 (dd, 1 H), 3.93 (s, 2H), 1 .98 (s, 2H).
Intermediate G
O-(4-Methoxybenzyl)hydroxylamine
Figure imgf000064_0002
Figure imgf000064_0001
intermediate G
(i)
To a solution of 2-hydroxyisoindoline-1 ,3-dione (1 .0 g, 6.13 mmol) in DMSO (10 ml_) was added Cs2CO3 (1 .997 g, 6.13 mmol). The resulting mixture was stirred at rt for 30 min. 1 - bromomethyl 4-methoxy-benzene (0.88 ml_, 6.13 mmol) was then added dropwise. After stirring at 50 QC overnight, the reaction mixture was quenched with NH4CI (aq), extracted with EtOAc, washed with NH4CI (aq), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column with gradient hexanes:EtOAc to give 2-(benzyloxy)isoindoline-1 ,3-dione as a white solid (0.9 g, 49%). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 7.85 (s, 4H), 7.42 (d, 2H), 6.94 (d, 2H), 5.08 (s, 2H), 3.75 (s, 3H). O-(4-Methoxybenzyl)hydroxylamine (intermediate G)
To a solution of 2-(4-methoxybenzyloxy)isoindoline-1 ,3-dione (200 mg, 0.706 mmol) in MeOH (5 ml_) was added hydrazine monohydrate (35.3 mg, 0.706 mmol). The reaction mixture was stirred at 65 QC for 1 h. The solvent was removed in vacuo, and the resulting residue was diluted with EtOAc (5 ml_). After stirring for 20 min, the mixture was filtered. The filtrate was concentrated in vacuo to afford the title compound. 1H-NMR (400MHz, CDCI3) δ ppm 7.30 (m, 2H), 6.90 (m, 2H), 4.63 (m, 2H), 3.81 (s, 3H).
Intermediate H
O-Benzylhydroxylamine
Figure imgf000065_0001
i intermediate H
2-(Benzyloxy)isoindoline-1 ,3-dione (i)
The title compound was prepared from 2-hydroxyisoindoline-1 ,3-dione and (bromomethyl)benzene in 64% yield using the same procedure as described in the synthesis of intermediate G. LCMS (method A): [MH]+ = 254, tR = 5.19 min.
O-Benzylhydroxylamine (intermediate H)
The title compound was prepared from 2-(benzyloxy)isoindoline-1 ,3-dione and hydrazine monohydrate in 64% yield using the same procedure as described in the synthesis of intermediate G. 1H-NMR (400MHz, CDCI3) δ ppm 7.37 (m, 5H), 6.70 (s, 2H).
Intermediate I
f-Butyl 4-(aminooxy)piperidine-1 -carboxylate
Figure imgf000065_0002
Figure imgf000065_0003
intermediate I
f-Butyl 4-(1 ,3-dioxoisoindolin-2-yloxy)piperidine-1 -carboxylate (i)
To a solution of /-butyl 4-hydroxypiperidine-1 -carboxylate (250 mg, 1 .242 mmol) was added triphenylphosphine (326 mg, 1.242 mmol) and 2-hydroxyisoindoline-1 ,3-dione (203 mg, 1 .242 mmol). After stirring at rt for 10 min, (£)-diisopropyl diazene-1 ,2-dicarboxylate (251 mg, 1.242 mmol) was added. After stirring at 30 QC overnight, the reaction mixture was quenched with NH4CI (aq), extracted with EtOAc, washed with NH4CI (aq), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column with gradient hexanes:EtOAc to give the title compound as a colorless oil (252 mg, 59%). LCMS (method B): [MNa]+ = 369, tR = 2.59 min. f-Butyl 4-(aminooxy)piperidine-1 -carboxylate (intermediate I) The title compound was prepared from /e/t-butyl 4-(1 ,3-dioxoisoindolin-2-yloxy)piperidine-1 - carboxylate and hydrazine monohydrate in 85% yield using the same procedure as described in the synthesis of intermediate G
Intermediate J
f-Butyl 4-(aminooxymethyl)piperidine-1-carboxylate
Figure imgf000066_0001
Figure imgf000066_0002
intermediate J
f-Butyl 4-((1 ,3-dioxoisoindolin-2-yloxy)methyl)piperidine-1-carboxylate (i)
The title compound was prepared from /-butyl 4-(hydroxymethyl)piperidine-1 -carboxylate and 2-hydroxyisoindoline-1 ,3-dione in 80% yield using the same procedure as described in the synthesis of intermediate B. LCMS (method B): [MNa]+ = 383, tR = 2.64 min. f-Butyl 4-(aminooxymethyl)piperidine-1-carboxylate (intermediate J)
The title compound was prepared from /-butyl 4-((1 ,3-dioxoisoindolin-2-yloxy)methyl)- piperidine-1 -carboxylate and hydrazine monohydrate in 85% yield using the same procedure as described in the synthesis of intermediate B.
Intermediate K
Methyl 2-(aminooxy)acetate
Figure imgf000066_0003
' intermediate K
Methyl 2-(1 ,3-dioxoisoindolin-2-yloxy)acetate (i)
The title compound was prepared from 2-hydroxyisoindoline-1 ,3-dione and methyl 2- bromoacetate in 56% yield using the same procedure as described in the synthesis of intermediate G. LCMS (method B): [MH]+ = 236, tR = 1.82 min.
Methyl 2-(aminooxy)acetate (intermediate K) The title compound was prepared from methyl 2-(1 ,3-dioxoisoindolin-2-yloxy)acetate and hydrazine monohydrate in 67% yield using the same procedure as described in the synthesis of intermediate G.
Intermediate L
5-Bromo-6-fluoro-1-methyl-1 H-indazole
Figure imgf000067_0001
To a solution of 5-bromo-6-fluoro-1 H-indazole (4 g, 18.60 mmol) in DMF (20 ml_) was added potassium 2-methylpropan-2-olate (2.087 g, 18.60 mmol). The resulting mixture was stirred for 40 min. CH3I (3.17 g, 22.32 mmol) was added dropwise. After stirring overnight, the reaction mixture was quenched with NH4CI (aq), extracted with EtOAc, washed with NH4CI (aq), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified with silica gel column chromatography with gradient hexanes:EtOAc to give 5- bromo-6-fluoro-1 -methyl-1 H-indazole (1 .86g, 42%) as light yellow solid.
Intermediate M
1 -(6-Chloro-imidazo[1 ,2-b]pyridazin-3-yl)-ethanone DMF DMA chloroacetone
reflux NaI, DMF
Figure imgf000067_0003
Figure imgf000067_0002
Figure imgf000067_0004
N'-(6-Chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine (i)
A mixture of 3-amino-6-chloropyridazine (1 .3 g, 10 mmol) and dimethylformamide dimethylacetal (1 .35 ml_, 10.2 mmol) was heated at reflux for 2 h and concentrated in vacuo to afford a brown solid. After recrystallization with EtOAc, 1 .5 g of N'-(6-chloro-pyridazin-3- yl)-N,N-dimethyl-formamidine was obtained in 81% yield.
1 -(6-Chloro-imidazo[1 ,2-b]pyridazin-3-yl)-ethanone (intermediate M)
To a solution of N'-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine (1 .3 g, 7 mmol) in DMF (60 ml_) was added NaI (1 g, 6.7 mmol) and chloroacetone (1 ml_, 12.6 mmol). The mixture was heated at 80 0C overnight and concentrated under reduced pressure. The residue was purified by column chromatography to afford 1 -(6-chloro-imidazo[1 ,2- b]pyridazin-3-yl)-ethanone (0.7 g) in 51 % yield. 1H-NMR (400MHz, CDCI3) δ ppm 8.42 (s, 1 H), 8.05 (d, 1 H), 7.31 (d, 1 H), 2.77 (s, 3H).
Intermediate N
6-Chloro-imidazo[1 ,2-b]pyridazine-3-carbaldehyde
Figure imgf000068_0001
I intermediate N
(6-Chloro-imidazo[1 ,2-b]pyridazin-3-yl)-methanol (i)
To a solution of 6-chloroimidazo[1 ,2-b]pyridazine (1 .5 g, 9.8 mmol) in AcOH (50 ml_) was added NaOAc (1 .4 g, 17.1 mmol) and paraformaldehyde (1.5 g). The mixture was heated at reflux overnight and concentrated under reduced pressure. The residue was basified to pH 12. Then the mixture was filtered and the solid was washed with EtOH to afford (6-chloro- imidazo[1 ,2-b]pyridazin-3-yl)-methanol (1.3 g) in 72% yield. 6-Chloro-imidazo[1 ,2-b]pyridazine-3-carbaldehyde (intermediate N)
To a solution of (6-chloro-imidazo[1 ,2-b]pyridazin-3-yl)-methanol (1.3 g, 7.1 mmol) in DCM (50 ml_) was added active MnO2 (3 g, 34.5 mmol). The mixture was stirred at rt overnight and filtered. The filtrate was concentrated under vacuum and the residue was washed with EtOAc to affrode 6-chloro-imidazo[1 ,2-b]pyridazine-3-carbaldehyde (0.7 g) in 54% yield. 1H- NMR (400MHz, CDCI3) δ ppm 10.36 (s, 1 H), 8.42 (s, 1 H), 8.08 (d, 1 H), 7.38 (d, 1 H).
Intermediate O
6-((6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline
Figure imgf000068_0002
intermediate O 3-Chloro-6-hydrazinylpyridazine (i)
A solution of 3,6-dichloropyridazine (3g, 20.14 mmol) and hydrazine monohydrate (1 g, 20.14 mmol) in 20 ml_ THF in a sealed tube was heated at 80 0C for 5 h. Solvent was evaporated and the crude was used in the next step without purification (3.56 g, 100%). LCMS (method B): [MH]+ = 145.1 , tR = 0.574 min.
N'-(6-Chloropyridazin-3-yl)-2-(quinolin-6-yl)acetohydrazide (ii)
To a suspension of 3-chloro-6-hydrazinylpyridazine (3 g, 20.75 mmol) and 2-(quinolin-6- yl)acetic acid (4.27 g, 22.83 mmol) in DCM (200 ml_) was added DCC (5.14 g, 24.90 mmol). The solution was stirred at rt over weekend. The title compound as a white solid containing some dicyclohexyl urea was collected and used in the next step without further purificaiton (8 g, 100%). LCMS (method A): [MH]+ = 314.1 , tR = 2.851 min.
6-((6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (intermediate O)
A solution of N'-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)acetohydrazide (8 g crude, 25.5 mmol) in 250 mL of acetic acid was heated at 50 0C for 5 h. After the reaction was complete, the solvent was evaporated and the residue was taken up in EtOAc. The formed solid (mainly dicyclohexyl urea ) was filtered off and the filtrate was evaporated to afford the title compound as yellow solid (4 g, 53%). 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.82 (d, 1 H), 8.33 (d, 1 H), 8.25 (d, 1 H), 8.0 (d, 1 H), 7.93 (s, 1 H), 7.83 (d, 1 H), 7.53 (m, 1 H), 7.42 (d, 1 H), 4.79 (s, 2H). LCMS (method B): [MH]+ = 296.0, tR = 1.876 min.
Intermediate P
4,6-Difluoro-1-methyl-1 H-indazole
Figure imgf000069_0001
i intermediate P
N-Methyl-N'-[1-(2,4,6-trifluoro-phenyl)-meth-(£)-ylidene]-hydrazine (i)
A solution of 2,4,6-trifluorobenzaldehyde (3 g, 18.74 mmol) and methyl hydrazine (40% in water, 2.6 mL, 18.74mmol) in 20 mL of anhydrous ethanol was stirred at rt for 1 h. Solvent was evaporated to give the crude title compound as a white solid which was used in the next step without purification (3.95 g, 100%). LCMS (method B): [MH]+ = 189, tR = 2.16 min. 4,6-Difluoro-1-methyl-1 H-indazole (intermediate P)
N-Methyl-N'-[1 -(2,4,6-trifluoro-phenyl)-meth-(£)-ylidene]-hydrazine (3.85 g, 20.46 mmol) was heated in a seaed tube at 210 0C for 2 h. After cooling, the black residue was dissovled in DCM and purified by flash chromatography (EtOAc: hexane 10:90) to give the title compound as a light yellow crystal (1.926 g, 56%). 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.05 (s, 1 H), 7.16 (d, 1 H), 6.75 (t, 1 H), 3.32 (s, 3H). LCMS (method B): [MH]+ = 169, tR = 2.28 min.
Intermediate Q
2-(Aminooxy)propan-1-ol
Figure imgf000070_0001
LiAlH4
THF, 0°C
HO
Figure imgf000070_0002
"
Ethyl 2-(tert-butoxycarbonylaminooxy)propanoate (i)
To a solution of /-butyl hydroxycarbamate (530 mg, 3.98 mmol) and potassium hydroxide (223 mg, 3.98 mmol) in EtOH (10 ml_) was added ethyl 2-bromopropanoate (600 mg, 3.31 mmol) slowly at rt. The reaction mixture was heated at reflux overnight. White precipitate was filtered off and the filtrate was concentrated. The resulting residue was dissolved in ether, washed with water and brine, and dried over Na2SO4. Solvent was evaporated to afford the title compound as a clear oil which was used in the next step without further purificaiton (825 mg, 100%). 1H-NMR (400MHz, CDCI3) δ ppm 7.62 (s, 1 H), 4.46 (q, 1 H), 4.24 (q, 2H), 1.46 (d, 3H), 1.48 (s, 9H), 1.28 (t, 3H). f-Butyl 1-hydroxypropan-2-yloxycarbamate (ii)
A solution of LiAIH4 (213 mg, 5.62 mmol) in anhydrous THF (8 mL) was added slowly to a solution of ethyl 2-(/-butoxycarbonylaminooxy)propanoate (820 mg, 3.52 mmol) in THF (15 mL) at 0 0C. The mixture was stirred at 0 0C for 5 h and then at rt overnight. The solution was quenched with a mixture of Na2SO4 and water, and stirred for an additional 1.5 h. The mixture was filtered and concentrated. The crude was dissolved in EtOAc, washed with water and brine, and then dried over Na2SO4. Solvent was evaporated to afford the title compound as a clear oil (500 mg, 74.4%). 1H-NMR (400MHz, CDCI3) δ ppm 7.09 (s, 1 H), 3.95 (m, 1 H), 3.69(dd, 1 H), 3.47 (m, 1 H), 1 .51 (s, 9H), 1.21 (d, 3H).
2-(Aminooxy)propan-1-ol (intermediate Q)
To a solution of /-butyl i -hydroxypropan-2-yloxycarbamate (500 mg, 2.61 mmol) in DCM (15 ml_) was added 3 ml_ of HCI in dioxane. The solution was then stirred at rt overnight. Solvent was evaporated to provide the title compound as HCI salt (365 mg, 98%, purity 90%). 1H- NMR (400MHz, MeOH-Cf4) δ ppm 4.28 (m, 1 H), 3.80 (m, 1 H), 3.70 (m, 1 H), 1 .23 (d, 3H). Intermediate R
6-[(6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)-difluoro-methyl]-quinoline
Figure imgf000071_0001
N2H4
MeOH
Figure imgf000071_0002
intermediate R ii
Difluoro-quinolin-6-yl-acetic acid ethyl ester (i)
Sodium iodide (4.32 g, 28.8 mmol), copper (I) iodide (137 mg, 0.72 mmol), 6-bromo- quinoline (3 g, 14.4 mmol), N,N'-dimethyl-cyclohexane (0.227 ml_, 1 .44 mmol) and dioxane were charged in a microwave tube (25 ml_). The tube was purged with nitrogen for 10 min and sealed with a Teflon septum. The reaction mixture was stirred at 1 10 0C for 15 h. After cooling, the mixture was poured onto ice-water and extracted with DCM. The crude was purified by silica gel column to give 6-iodo-quinoline as light green solid (3.5 g, 92%).
To a suspension of 6-iodo-quinoline (1 .0 g, 4 mmol) and Cu(O) (559 mg, 8.8 mmol) in dry DMSO was added bromodifluoro-acetic acid ethyl ester (893 mg, 4.4 mmol). The reaction mixture was stirred under N2 at 55 0C for 15 h. The mixture was poured in a solution of K2CO3 and extracted with EtOAc. The organic layer was collected and dried over MgSO4. The crude was purified by silica gel column to give the title compound as a red oil (310 mg, 30%). 1H-NMR (400MHz, CDCI3) δ ppm 1.33 (t, 3H), 4.334 (q, 2H), 7.52 (m, 1 H), 7.93 (m, 1 H), 8.15 (s, 1 H), 8.20-8.23 (m, 2H), 9.03 (s, 1 H).
Difluoro-quinolin-6-yl-acetic acid hydrazide (ii)
5 Difluoro-quinolin-6-yl-acetic acid ethyl ester (836 mg, 3.33 mmol) was dissolved in MeOH (13 ml_). Hydrazine monohydrate (1 .5 ml_, 16.8 mmol) was added. The mixture was heated at 45 0C for 30 min, cooled to rt, concentrated, and taken up in DCM. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column to give the title compound as light orange solid (400 mg, 51 %). 10 1H-NMR (400MHz, CDCI3) πppm 3.99 (br s, 2H), 7.51 (m, 1 H), 7.92 (m, 1 H), 8.15 (s, 1 H), 8.20-8.26 (q, 2H), 9.02 (m, 1 H).
6-[(6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)-difluoro-methyl]-quinoline
(intermediate R)
15 3,6-Dichloropyridazine (160 mg, 1.07 mmol) and difluoro-quinolin-6-yl-acetic acid hydrazide (254 mg, 1 .07 mmol) were added in n-BuOH (20 ml_). The reaction mixture was heated at 130 0C for 12 h. The solvent was removed under reduced pressure. The crude was partitioned in aqueous solution of K2CO3 and EtOAc. The organic layers were combined and concentrated to give a solid, which was purified by silica gel column to give the title
20 compound as black solid (190 mg, 53%). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 7.62 (m, 2H), 7.90 (m, 1 H), 8.22 (m, 1 H), 8.35 (m, 1 H), 8.65 (m, 2H), 9.02 (m, 1 H).
Intermediate S
2-(Aminooxy)ethanol hydrochloride
Figure imgf000072_0001
pc i intermediate S
f-Butyl 2-hydroxyethoxycarbamate hydrochloride (i)
The title compound was prepared according to the procedure described in WO2006/10094. To a mixture of /-butyl hydroxycarbamate (1 1.27 g, 85 mmol) and DBU (12.8 ml_, 85 mmol) was added 2-bromoethanol (15 ml_, 212 mmol) slowly, and the reaction mixture was stirred 30 at 40 0C for 2.5 days. After cooling, the reaction mixture was diluted with DCM, and washed successively with cold 1 N HCI aqueous solution, water, and brine. The organic layer was dried over anhydrous Na2SO4, purified by column chromatography (38% EtOAc in hexane) to afford 12.6 g (70%) of the title compound as a colorless syrup. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.95 (s br, 1 H), 4.55 (t, 1 H), 3.70 (t, 2H), 3.45-3.55 (m, 2H), 1 .38 (s, 9H). 2-(Aminooxy)ethanol hydrochloride (intermediate S)
To a solution of /-butyl 2-hydroxyethoxycarbamate hydrochloride (5.82 g, 32.8 mmol) in dioxane (60 ml_) was added concentrated HCI (3.5 ml_) dropwise, and the reaction mixture was stirred at rt overnight. Solvent was removed to afford 3.78 g (100%) of the title compound as colorless syrup. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 10.93 (s br, 2H), 3.70- 4.80 (s br, 1 H), 4.02 (t, 2H), 3.60 (t, 2H).
Intermediate T
3-(Aminooxy)propan-1-ol hydrochloride
H0^^°^NH2.HCI
The title compound was prepared using the same procedure as described in the synthesis of intermediate S. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 10.89 (s br, 2H), 3.85-4.50 (s br, 1 H), 4.05 (t, 2H), 3.45 (t, 2H), 1 .68-1 .74 (m, 2H).
Intermediate U
O-(Oxetan-3-yl)hydroxylamine
Figure imgf000073_0001
j intermediate U
2-(Oxetan-3-yloxy)isoindoline-1 ,3-dione (i)
To a solution of oxetan-3-ol (1 .Og, 13.50mmol) were added triphenylphosphine (4.25g, 16.20mmol) and 2-hydroxyisoindoline-1 ,3-dione (2.42g, 14.85mmol). After stirring at rt for 10 min, (£)-diisopropyl diazene-1 ,2-dicarboxylate (3.28g, 16.20mmol) was added. After stirring at 30 0C overnight, the reaction mixture was quenched with NH4CI (aq), extracted with EtOAc, washed with NH4CI (aq), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified with column chromatography on silica gel (gradient hexanes:EtOAc) to give a colorless oil 2-(oxetan-3-yloxy)isoindoline-1 ,3-dione (400 mg, 6%). LCMS (method B): [MH]+ = 220, tR = 1 .67 min. O-(Oxetan-3-yl)hydroxylamine (intermediate U)
To a solution of 2-(oxetan-3-yloxy)isoindoline-1 ,3-dione (220mg, LOmmol) in MeOH (5 ml_) was added hydrazine hydrate (50.4mg, 1 .Ommol). The reaction was allowed to stir at 65 0C for 1 h. Solvent was removed in vacuo and the resulting residue was diluted with EtOAc (5 ml_). After the mixture was stirred for 20min, the formed precipitate was filtered off. The filtrate was concentrated in vacuo to afford the product.
Intermediate V
2-(1 ,3-Dioxoisoindolin-2-yloxy)acetamide
Figure imgf000074_0001
intermediate V
A solution of 2-hydroxyisoindoline-1 ,3-dione (2.4 g, 14.71 mmol), 2-chloroacetamide (1 .65 g, 17.65 mmol) and K2CO3 (2.44 g, 17.65 mmol) in 40 ml_ of DMF was stirred at 90 0C overnight. The solid was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, DMSO-Cf6) δ ppm 7.89 (dd, 1 H), 7.68-7.64 (m, 2H), 7.45-7.43 (m, 2H), 7.35 (s, 1 H), 4.23 (s, 2H). LCMS (method A): [MH]+ = 221 , tR = 2.665 min. Intermediate W
1 -(3-(Quinolin-6-ylmethyl)imidazo[1 ,2-a]pyrimidin-6-yl)ethanone (W)
Figure imgf000074_0002
intermediate W
6-((6-Bromoimidazo[1 ,2-a]pyrimidin-3-yl)methyl)quinoline (i)
A solution of 2-chloro-3-(quinolin-6-yl)propanal (1 .0 g, 2.54 mmol) and 5-bromopyrimidin-2- amine (0.53 g, 3.05 mmol) in 2-methyl-butan-2-ol (10 ml_) was stirred at 135 0C for 12 h. After cooling, the solvent was removed in vacuo and the residue was purified by flash chromatography in silica gel eluting with a CH2CI2/Me0H gradient to afford a mixture of the title compound and 6-(6-bromo-imidazo[1 ,2-a]pyrimidin-2-ylmethyl)quinoline (250 mg, 29%) as brown solid. LCMS (method E): [MH]+ = 339/341 , tR = 3.51 min.
1 -(3-(Quinolin-6-ylmethyl)imidazo[1 ,2-a]pyrimidin-6-yl)ethanone (W)
A solution of 6-((6-bromoimidazo[1 ,2-a]pyrimidin-3-yl)methyl)quinoline and 6-(6-bromo- imidazo[1 ,2-a]pyrimidin-2-ylmethyl)quinoline (mixture, 250 mg, 0.737 mmol), PdCI2(PPh3)2 (51 .7 mg, 0.074 mmol) and tributyl(1 -ethoxyvinyl)stannane (399 mg, 1 .106 mmol) in 5 mL of 1 ,4-dioxane was heated at 80 0C for 12 h under N2. The reaction mixture was diluted with EtOAc, washed with water. The organic layer was dried over Na2SO4, filtered and
concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCI and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in CH2CI2, washed with sat. aqeous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel eluting with a EtOAc/MeOH gradient to afford the title compound as a yellow solid. 1H-NMR (400MHz, CDCI3) δ ppm 8.97 (d, 1 H), 8.84 (d, 1 H), 8.67 (d, 1 H), 8.04-7.99 (m, 2H), 7.74 (s, 1 H), 7.53-7.51 (m, 1 H), 7.34 (dd, 1 H), 7.19 (s, 1 H), 4.44 (s, 2H), 2.49 (s, 3H).
Example 1
(£)-1-(3-((7-Fluoroquinolin-6-yl)methyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O-ethyl oxime
Figure imgf000075_0001
6-Chloro-imidazo[1 ,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol (1.1)
To a solution of 3-bromo-6-chloro-imidazo[1 ,2-b]pyridazine (13.27 g, 57.1 mmol) in 160 ml_ THF was added EtMgBr (1 M in THF, 68.5 ml_, 68.5 mmol) solution at rt. The reaction mixture was stirred for 30 min and a suspension of 7-fluoro-quinoline-6-carbaldehyde (10 g, 57.1 mmol) in 40 ml_ of THF was added. The resulting mixture was stirred at rt for 3 h and then quenched with 400 ml_ water and stirred for an additional 1 h. The precipitate was collected by filtration, washed with EtOAc and dried over vacuum oven overnight to afford 13 g (69%) of the title compound. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.91 (dd, 1 H), 8.49 (d, 1 H), 8.28 (d, 1 H), 8.24 (d, 1 H), 7.74 (d, 1 H), 7.54(q, 1 H), 7.51 (s, 1 H), 7.40 (d, 1 H), 6.54 (m, 2H).
6-(6-Chloro-imidazo[1 ,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (1.2)
To a solution of 6-chloro-imidazo[1 ,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol (9.48 g, 28.8 mmol) in acetic acid (80 ml_) was added phosphinic acid (50% aqueous solution, 15.73 ml_, 144 mmol) and iodine (18.3 g, 72.1 mmol). The resulting solution was heated at 1 10 0C overnight. The solvent was removed under reduced pressure. The residue was diluted with water and pH of the mixture was adjusted to 8-10 with 6N NaOH solution. The mixture then was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (5% to 10% MeOH in DCM) to afford 5.8 g (64.3%) of the title compound. 1H-NMR (400MHz, CDCI3) δ ppm 8.91 (dd, 1 H), 8.14 (d, 1 H), 7.93 (d, 1 H), 7.85 (d, 1 H), 7.75 (d, 1 H), 7.66(s, 1 H), 7.41 (q, 1 H), 7.09 (d, 1 H), 4.56 (s, 2H). LCMS (method B): [MH]+ = 313, tR = 2.48 min.
1 -[3-(7-Fluoro-quinolin-6-ylmethyl)-imidazo[1 ,2-b]pyridazin-6-yl]-ethanone (1.3)
To a flask loaded with tetrakis-(triphenylphosphine)-palladium (1 .7 g, 1 .48 mmol) under nitrogen was added a solution of 6-(6-chloro-imidazo[1 ,2-b]pyridazin-3-ylmethyl)-7-fluoro- quinoline (5.8 g, 18.55 mmol) in DMF (150 ml_). The system was purged with nitrogen three times and then tributyl-(1 -ethoxy-vinyl)-stannane (6.59 ml_, 19.47 mmol) was added. The temperature was increased to 100 0C and stirred overnight. After cooling, 20 ml_ of 3N HCI was added and the mixture was stirred for additional 2 h. Water was added and the product was then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4.8 g (79%) of the title compound as a dark yellow solid. 1H-NMR (400MHz, MeOH- Cf4) δ ppm 8.82 (dd, 1 H), 8.31 (d, 1 H), 8.10 (d, 1 H), 7.98 (d, 1 H), 7.85 (s, 1 H), 7.78 (d, 1 H), 7.72 (d, 1 H), 7.50 (q, 1 H), 4.72 (s, 2H), 2.68 (S, 3H). LCMS (method A): [MH]+ = 321 , tR = 5.07 min.
(£)-1 -(3-((7-f luoroquinolin-6-yl)methyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O-ethyl oxime (example 1)
To a solution of 1 -[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1 ,2-b]pyridazin-6-yl]-ethanone (50 mg, 0.16 mmol) in methanol (10 ml_) was added O-ethylhydroxylamine hydrochloride (46 mg, 0.47 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at rt overnight. The solution was concentrated under reduced pressure and the residue was purified by prep-HPLC to afford 30 mg (53%) of the title compound as a white solid. 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.82 (dd, 1 H), 8.30 (d, 1 H), 7.93 (m, 2H), 7.85 (d, 1 H), 7.70 (d, 1 H), 7.66 (s, 1 H), 7.49 (q, 1 H), 4.62 (s, 2H), 4.31 (q, 2H), 2.27 (s, 3H), 1 .36 (t, 3H). LCMS (method C): [MH]+ = 364, tR = 4.71 min. Example 2
(£)-1 -(3-((7-Fluoroquinolin-6-yl)methyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O-methyl oxime
Figure imgf000077_0001
The title compound was prepared in analogy to the synthesis of example 1. 1H-NMR (400MHz, CDCI3) δ ppm 8.88 (d, 1 H), 8.03 (d, 1 H), 7.87 (d, 1 H), 7.76 (m, 2H), 7.68 (d, 1 H), 7.67 (s, 1 H), 7.35 (q, 1 H), 4.58 (s, 2H), 4.06 (s, 3H), 2.31 (s, 3H). LCMS (method C): [MH]+ = 350, tR = 4.40 min.
Example 3
(£)-1-(3-((7-Fluoroquinolin-6-yl)methyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O-2- hydroxyethyl oxime
Figure imgf000077_0002
The title compound was prepared in analogy to the synthesis of example 1. 1H-NMR (400MHz, CDCI3) δ ppm 8.88 (d, 1 H), 8.03 (d, 1 H), 7.88 (d, 1 H), 7.77 (d, 1 H), 7.69 (m, 3H), 7.35 (q, 1 H), 4.58 (s, 2H), 4.39 (t, 2H), 3.96 (m, 2H), 2.36 (s, 3H). LCMS (method A): [MH]+ = 380, tR = 5.15 min.
Example 4
(£)-1 -(3-(Quinolin-6-ylmethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O-ethyl oxime
Figure imgf000078_0001
The title compound was prepared in analogy to the synthesis of example 1. 1H-NMR (400MHz, CDCI3) δ ppm 8.86 (dd, 1 H), 8.04 (m, 2H), 7.82 (d, 1 H), 7.70 (m, 3H), 7.59 (s, 1 H), 7.35 (q, 1 H), 4.51 (s, 2H), 4.28 (q, 2H), 2.28 (s, 3H), 1 .35 (t, 3H). LCMS (method C): [MH]+ = 346, tR = 4.54 min.
Example 5
(£)-1 -(3-(Quinolin-6-ylmethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O-methyl oxime
Figure imgf000078_0002
The title compound was prepared in analogy to the synthesis of example 1. 1H-NMR (400MHz, CDCI3) δ ppm 8.86 (dd, 1 H), 8.04 (m, 2H), 7.83 (d, 1 H), 7.71 (m, 3H), 7.60 (s, 1 H), 7.35 (q, 1 H), 4.51 (s, 2H), 4.04 (s, 3H), 2.28 (s, 3H). LCMS (method C): [MH]+ = 332, tR = 3.96 min.
Example 6
(£)-1 -(3-(Quinolin-6-ylmethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O-2-hydroxyethyl oxime
Figure imgf000079_0001
The title compound was prepared in analogy to the synthesis of example 1. 1H-NMR (400MHz, CDCI3) δ ppm 8.87 (dd, 1 H), 8.06 (m, 2H), 7.85 (d, 1 H), 7.69 (m, 4H), 7.37 (q, 1 H), 4.52 (s, 2H), 4.38 (m, 2H), 3.97 (t, 2H), 2.31 (s, 3H). LCMS (method A): [MH]+ = 362, tR = 4.80 min.
Example 7A and 7B
(£)-1-(3-(Quinolin-6-ylmethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone 0-1 ,3- dihydroxypropan-2-yl oxime and
(£)-1-(3-(quinolin-6-ylmethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone 0-2,3- dihydroxypropyl oxime
Figure imgf000079_0002
Example 7A
Figure imgf000079_0003
To a mixture of 2-(2,3-dihydroxypropoxy)isoindoline-1 ,3-dione and 2-(1 ,3-dihydroxypropan-2- yloxy)isoindoline-1 ,3-dione (1 :1 mixture) (intermediate B) in MeOH was added hydrazine monohydrate. The reaction mixture was allowed to stir at reflux for two h and then the solvent was removed under reduced pressure. The residue was washed with EtOAc and filtered. The filtrate was collected, evaporated and redissolved in MeOH. Then 1 -(3-(quinolin-6- ylmethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone (prepared in analog of compound 1.3) was added and the reaction mixture was allowed to stir at 30 0C for 5 h. After purifing by HPLC the title compounds were separated and obtained as a white solid. Data for example 7A: 1H- NMR (400MHz, CDCI3) δ ppm 8.85 (d, 1 H), 8.05 (m, 2H), 7.82 (d, 1 H), 7.65 (m, 4H), 7.36 (q, 1 H), 4.49 (m, 3H), 3.98 (d, 4H), 2.26 (s, 3H). LCMS (method A): [MH]+ = 392, tR = 3.98 min. Data for example 7B: 1H-NMR (400MHz, CDCI3) δ ppm 8.89 (dd, 1 H), 8.08 (m, 2H), 7.88 (d, 1 H), 7.69 (m, 4H), 7.39 (q, 1 H), 4.55 (s, 2H), 4.36 (d, 2H), 4.13 (m, 1 H), 3.81 (dd, 1 H), 3.69 (dd, 1 H), 2.34 (s, 3H). LCMS (method A): [MH]+ = 392, tR = 4.42 min.
Example 8
(£)-1 -(3-((5,7-Dif luoroquinolin-6-yl)methyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O- methyl oxime
Figure imgf000080_0001
The title compound was prepared in analogy to the synthesis of example 1. 1H-NMR (400MHz, CDCI3) δ ppm 8.96 (dd, 1 H), 8.47 (d, 1 H), 8.05 (d, 1 H), 7.68 (m, 2H), 7.59 (m, 2H), 4.58 (s, 2H), 3.99 (s, 3H), 2.23 (s, 3H). LCMS (method A): [MH]+ = 368, tR = 5.58 min.
Example 9
(£)-1 -(3-((5,7-Dif luoroquinolin-6-yl)methyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O-2- hydroxyethyl oxime
Figure imgf000080_0002
The title compound was prepared in analogy to the synthesis of compound of example 1.
1H-NMR (400MHz, CDCI3) δ ppm 8.96 (dd, 1 H), 8.47 (d, 1 H), 8.04 (d, 1 H), 7.69 (m, 4H), 4.58 (s, 2H), 4.22 (t, 2H), 3.67 (t, 2H), 2.24 (s, 3H). LCMS (method A): [MH]+ = 398, tR = 5.52 min.
Example 10
(E)-1-(3-((5,7-Difluoroquinolin-6-yl)(hydroxy)methyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone O-methyl oxime DMF
Figure imgf000081_0001
MeONH,, MeOH
Figure imgf000081_0003
Figure imgf000081_0002
example 10 10.2
(6-Chloroimidazo[1 ,2-b]pyridazin-3-yl)(5,7-dif luoroquinolin-6-yl)methanol (10.1 )
To a solution of 3-bromo-6-chloro-imidazo[1 ,2-b]pyridazine (2.40 g, 10.35 mmol) in 30 ml_ of THF was added EtMgBr (1 M in THF, 12.43 ml_, 12.42 mmol) solution at rt. The solution was stirred for 30 min and a solution of 5,7-difluoroquinoline-6-carbaldehyde (2.0 g, 10.35 mmol) in 1 O mL of THF was added. The resulting mixture was stirred at rt for additional 2 h and then quenched with 50 ml_ of NH4CI solution. The solution was extracted with EtOAc and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford 3.48 g (97%) of the title compound. LCMS (method B): [MH]+ = 347, tR = 1 .23 min.
1-(3-((5,7-Difluoroquinolin-6-yl)(hydroxy)methyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone (10.2)
To a flask charged with Pd(PPh3)4 (67 mg, 0.058 mmol) under nitrogen was added a solution of (6-chloroimidazo[1 ,2-b]pyridazin-3-yl)(5,7-difluoroquinolin-6-yl)methanol (200 mg, 0.56 mmol) in DMF (10 mL). The system was purged with nitrogen gas three times and then tributyl-(1 -ethoxy-vinyl)-stannane (0.21 mL, 0.61 mmol) was added. The temperature was increased to 100 0C and stirred overnight. Then the reaction mixture was cooled to rt, 3N HCI was added and the mixture was stirred for additional 4 h. Water was added and the product was extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography
(3% to 10% MeOH in DCM) to afford 132 mg (55%) of the title compound. 1H-NMR
(400MHz, CDCI3) Hppm 8.98 (dd, 1 H), 8.42 (d, 1 H), 8.05 (dd, 1 H), 8.00 (s, 1 H), 7.77 (dd,
1 H), 7.68 (d, 1 H), 7.48 (q, 1 H), 7.03 (s, 1 H), 2.72 (s, 3H). LCMS (method B): [MH]+ = 355, tR = 2.08 min. (£)-1-(3-((5,7-Difluoroquinolin-6-yl)(hydroxy)methyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone O-methyl oxime (example 10)
The title compound was prepared in analogy to the synthesis of example 1. 1H-NMR (400MHz, MeOH-Cf4) πppm 8.89 (d, 1 H), 8.52 (d, 1 H), 7.90 (m, 2H), 7.65 (m, 3H), 6.89 (s, 1 H), 3.98 (s, 3H), 2.09 (s, 3H). LCMS (method A): [MH]+ = 384, tR = 5.34 min.
Example 11 (example 11 -R, example 11 -S)
(£)-1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O-2- hydroxyethyl oxime
Figure imgf000082_0001
example 11 -R and 11 -S
(6-Chloroimidazo[1 ,2-b]pyridazin-3-yl)(7-f luoroquinolin-6-yl)methanone (11.1)
To a suspension of (6-chloro-imidazo[1 ,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol (1.8 g, 5.48 mmol) in acetone (200 ml_) was added IBX (8.52 g, 45%, 13.69 mmol). The reaction mixture was stirred at reflux for 1 day. Then the solvent was removed under reduced pressure and the residue was dissolved in 200 ml_ of water. The solution was basified by 3N
NaOH solution and the precipitate was collected, washed with water and dried over vacuum oven to afford 1 .7 g (95%) of the title compound as a gray solid. 1H-NMR (400MHz, DMSO- Cf6) δ ppm 9.04 (dd, 1 H), 8.56 (d, 1 H), 8.47 (m, 2H), 8.41 (s, 1 H), 7.92 (d, 1 H), 7.75 (d, 1 H),
7.64 (q, 1 H). LCMS (method B): [MH]+ = 327, tR = 2.03 min. 1-(6-Chloroimidazo[1 ,2-b]pyridazin-3-yl)-1-(7-fluoroquinolin-6-yl)ethanol (11.2)
To a solution of (6-chloroimidazo[1 ,2-b]pyridazin-3-yl)(7-fluoroquinolin-6-yl)methanone (2.93 g, 6.73 mmol) in THF (80 ml_) was added MeMgI solution (3 M in THF, 4.48 ml_, 13.45 mmol) and the resulting solution was stirred at reflux for 5 h. Then the reaction mixture was cooled to rt, quenched with water, washed with NH4CI solution and extracted by DCM. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 2.2 g (95%) of the title compound which was used to next step.
6-(1-(6-Chloroimidazo[1 ,2-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (11.3)
To a solution of 1 -(6-chloroimidazo[1 ,2-b]pyridazin-3-yl)-1 -(7-fluoroquinolin-6-yl)ethanol (420 mg, 1 .10 mmol) in acetic acid (20 ml_) was added phosphinic acid (50% aqueous solution, 0.60 ml_, 5.51 mmol) and iodine (700 mg, 2.76 mmol). The resulting solution was heated at 1 10 0C overnight. Solvents was then removed. The residue was diluted with water and pH was adjusted to 8-10 with 6N NaOH solution. The product was extracted by DCM and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (3% to 10% MeOH in DCM) to afford 260 mg (72%) of the title compound. LCMS (method B): [MH]+ = 327, tR = 2.52 min. 1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone (11.4)
To a flask charged with Pd(PPh3)4 (46 mg, 0.040 mmol) under nitrogen was added a solution of 6-(1 -(6-chloroimidazo[1 ,2-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (130 mg, 0.40 mmol) in DMF (5 ml_). The system was purged with nitrogen gas three times and then tributyl-(1 - ethoxy-vinyl)-stannane (0.14 ml_, 0.42 mmol) was added. The temperature was increased to 100 0C and stirred for 2 h. Then the reaction mixture was cooled to rt, 3N HCI was added and the mixture was stirred for additional 4 h. Water was added and the product was then extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (3% to 10% MeOH in DCM) to afford 120 mg (90%) of the title compound. LCMS (method B): [MH]+ = 335, tR = 2.41 min.
(£)-1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone 0-2- hydroxyethyl oxime (example 11 , example 11 -R, example 11 -S) The title compound was prepared in analogy to the synthesis of example 1. 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.79 (d, 1 H), 8.22 (d, 1 H), 7.89 (dd, 1 H), 7.80 (s, 1 H), 7.74 (m, 3H), 7.44 (q, 1 H), 5.12 (q, 1 H), 4.28 (t, 2H), 3.80 (t, 2H), 2.12 (s, 3H), 1 .91 (d, 3H). LCMS (method A): [MH]+ = 394, tR = 5.37 min. Chiral separation (method F) provided enantiomeric pure compounds example 11 -R and example 11 -S.
Example 12 (example 12-R, example 12-S)
(£)-1 -(3-(1 -(5,7-Dif luoroquinolin-6-yl)ethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone O-2- hydroxyethyl oxime
Figure imgf000084_0001
example 12-S example 12-R
The title compounds as a racemic mixture were prepared in analogy to the synthesis of example 11. 1H-NMR (400MHz, CDCI3) δ ppm 8.90 (dd, 1 H), 8.32 (d, 1 H), 7.87 (s, 1 H), 7.84 (d, 1 H), 7.61 (d, 1 H), 7.55 (d, 1 H), 7.40 (q, 1 H), 5.23 (q, 1 H), 4.34 (m, 2H), 3.93 (m, 2H), 2.19 (s, 3H), 2.01 (d, 3H). LCMS (method A): [MH]+ = 412, tR = 5.77 min. Chiral separation (method G) provided enantiomeric pure compounds example 12-R and 12-S.
Example 13
(£)-1 -[3-(1 -Methyl-1 H-indazol-5-ylmethyl)-imidazo[1 ,2-b]pyridazin-6-yl]-ethanone O-(2- hydroxy-ethyl)- oxime
Figure imgf000084_0002
(6-Chloroimidazo[1 ,2-b]pyridazin-3-yl)(1-methyl-1 H-indazol-5-yl)methanol (13.1)
To a solution of 3-bromo-6-chloroimidazo[1 ,2-b]pyridazine (232.0 mg, 1 .00 mmol) in THF (5 ml_) was added EtMaBr (1 M in THF, 1 .50 ml_, 1 .50 mmol) at -10 QC. After stirring at -10 QC for 1 h, i -methyl-I H-indazole-5-carbaldehyde (240.0 mg, 1.50 mmol) was added. The mixture was allowed to warm to rt slowly and stirred for 2 h. The reaction was quenched with saturated NH4CI solution and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was washed with DCM to give the title compound as a white solid (230 mg, 70 %). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.21 (d, 1 H), 8.02 (s, 1 H), 7.81 (s, 1 H), 7.59 (d, 1 H), 7.56 (s, 1 H), 7.49 (d, 1 H), 7.35 (d, 1 H), 6.29 (d, 1 H), 6.21 (d, 1 H), 4.02 (s, 3H). LCMS (method A): [MH]+ = 314, tR = 4.44 min.
6-Chloro-3-((1-methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazine (13.2)
A solution of (6-chloroimidazo[1 ,2-b]pyridazin-3-yl)(1 -methyl-1 H-indazol-5-yl)methanol (156.8 mg, 0.50 mmol), I2 (381 mg, 1 .50 mmol) and H3PO2 (0.273 ml_, 2.50 mmol) in AcOH (4 ml_) was heated at 1 10 QC for 7 h. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (DCM:MeOH=20:1 ) to give the title compound containing some iodine and used in the next step without further purification (180.0 mg, 36% purity, 44%). LCMS
(method A): [MH]+ = 298, tR = 5.37 min.
6-(1-Ethoxy-vinyl)-3-(1-methyl-1 H-indazol-5-ylmethyl)-imidazo[1 ,2-b]pyridazine (13.3)
A suspension of 6-chloro-3-((1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazine (180.0 mg, 36 % purity, 0.22 mmol), tributyl(1 -ethoxyvinyl)stannane (94 mg, 0.26 mmol) and
Pd(PPh3)4 (25.1 mg, 0.02 mmol) in 10 mL of DMF was flushed with nitrogen, then heated at
1 10 QC and stirred overnight. Solvent was removed under reduced pressure; the residue was diluted with DCM, washed sequentially with aqueous KF and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (DCM:MeOH=20:1 ) to give the title compound containing some triphenylphosphine oxide impurity but used in the next step without further purification (49 mg, 47 %, 70 % purity). LCMS (method A): [MH]+ = 334, tR = 5.71 min.
1-(3-((1-Methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone (13.4) A solution of 6-(1 -ethoxy-vinyl)-3-(1 -methyl-1 H-indazol-5-ylmethyl)-imidazo[1 ,2-b]pyridazine (50 mg, 0.15 mmol) and HCI (0.15 ml_, 0.15 mmol) in AcOH (10 ml_) was heated at 50 QC for 3 h. The solvent was removed under reduced pressure. The residue was diluted with water and pH of solution was adjusted to around 8 with saturated NaHCO3 solution, then was extracted with DCM three times. Organic layers were combined, dried over Na2SO4 and concentrated. The crude product was used in the next step without purification (45mg, 75 %, 76 % purity). LCMS (method A): [MH]+ = 306, tR = 5.03 min.
(£)-1 -[3-(1 -Methyl-1 H-indazol-5-ylmethyl)-imidazo[1 ,2-b]pyridazin-6-yl]-ethanone O-(2- hydroxy-ethyl)- oxime (example 13)
A solution of 1 -(3-((1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone (20.0 mg, 0.07 mmol) and 2-(aminooxy)ethanol hydrochloride (14.87 mg, 0.13 mmol) in 10 ml_ THF was stirred at 40 QC overnight. Solvent was removed in vacuo. The crude product was purified on flash chromatography (DCM:MeOH = 50:1 ) to give the title compound as a yellow solid (15.0 mg, 57 %). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.04 (d, 1 H), 7.94 (s, 1 H), 7.68-7.61 (m, 3H), 7.54 (d, 1 H), 7.39 (d, 1 H), 4.41 (s, 2H), 4.23 (s, 2H), 3.98 (s, 3H), 3.68 (s, 2H), 2.29 (s, 3H). LCMS (method A): [MH]+ = 365, tR = 4.70 min.
Example 14
(£)-1-{3-[1-(1 -Methyl-1 H-indazol-5-yl)-ethyl]-imidazo[1 ,2-b]pyridazin-6-yl}-ethanone O-
(2-hydroxy-ethyl)- oxime
Figure imgf000086_0001
(6-Chloroimidazo[1 ,2-b]pyridazin-3-yl)(1 -methyl-1 H-indazol-5-yl)methanone (14.1)
A suspension of (6-chloroimidazo[1 ,2-b]pyridazin-3-yl)(1 -methyl-1 H-indazol-5-yl)methanol (13.1) (500.0 mg, 1 .60 mmol) and 2-lodoxybenzoic acid (45%)(1488.0 mg, 2.39 mmol) in 10 mL acetone was heated at reflux for 3 h. Solvent was removed under reduced pressure. The residue was diluted with water; pH was adjusted to around 10 with 10 % NaOH aqueous solution. The precipitates were collected by filtration and washed with water three times. The solid was dissolved in DCM, dried over Na2SO4, filtered and concentrated to give the title compound as a white solid (410.0 mg, 78%). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.46 (s, 1 H), 8.42 (m, 1 H), 8.32 (m, 1 H), 8.27 (d, 1 H), 7.95 (dd, 1 H), 7.815 (d, 1 H), 7.66 (d, 1 H), 4.12 (s, 2H). LCMS (method A): [MH]+ = 312, tR = 4.64 min. i^θ-Chloro-imidazoII ^-blpyridazin-S-yO-i^i-methyl-I H-indazol-S-yO-ethanol (14.2)
To a solution of (6-chloroimidazo[1 ,2-b]pyridazin-3-yl)(1 -methyl-1 H-indazol-5-yl)methanone (410 mg, 1 .32 mmol) in 10 ml_ THF was added methylmagnesium iodide (0.88 ml_, 2.63 mmol) at 0 QC. After stirring at 0 QC for 3 h, the reaction was quenched with saturated NH4CI and concentrated under resdue pressure.The residue was extracted with DCM three times. The organic layers were combined, dried over Na2SO4 and concentrated to give the title compound as a white solid (430.0 mg, 95 %). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.17 (d, 1 H), 7.99 (s, 1 H), 7.50 (m, 1 H), 7.40 (d, 1 H), 7.25 (d, 1 H), 5.98 (s, 1 H), 3.99 (s, 3H), 2.05 (s, 3H). LCMS (method A): [MH]+ = 328, tR = 4.55 min.
6-Chloro-3-[1-(1-methyl-1 H-indazol-5-yl)-ethyl]-imidazo[1 ,2-b]pyridazine (14.3)
The title compound (390.0 mg, 91 %) was synthesized from 1 -(6-chloro-imidazo[1 ,2- b]pyridazin-3-yl)-1 -(1 -methyl-1 H-indazol-5-yl)-ethanol (430.0 mg, 1 .31 mmol), I2 (832.0 mg, 3.28 mmol) and H3PO2(0.72 mL, 6.56 mmol) using the same procedure as described in the synthesis of compound 13.2. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.18 (d, 1 H), 7.95 (s, 1 H), 7.83 (s, 1 H), 7.55 (m, 2H), 7.36 (d, 1 H), 7.28 (d, 1 H), 4.70 (q, 1 H), 3.99 (s, 3H), 1.74 (d, 3H). LCMS (method A): [MH]+ = 312, tR = 5.49 min. 6-(1-Ethoxy-vinyl)-3-[1-(1-methyl-1 H-indazol-5-yl)-ethyl]-imidazo[1 ,2-b]pyridazine (14.4)
The title compound (415.0 mg, 86 %, 90 % purity) was synthesized from 6-chloro-3-[1 -(1 - methyl-1 H-indazol-5-yl)-ethyl]-imidazo[1 ,2-b]pyridazine (390.0 mg, 1.25 mmol), tributyl(1 - ethoxyvinyl)stannane (497.0 mg, 1.38 mmol) and Pd(PPh3)4 (145 mg, 0.13 mmol) using the same procedure as described in the synthesis of compound 13.3. LCMS (method A): [MH]+ = 348, tR = 5.86 min.
1-(3-(1-(1-Methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone (14.5)
The title compound (325.0 mg, 75 %, 88 % purity) was synthesized from 6-(1 -ethoxy-vinyl)-3- [1 -(1 -methyl-1 H-indazol-5-yl)-ethyl]-imidazo[1 ,2-b]pyridazine (415.0 mg, 1.20 mmol) and HCI (1.20 ml_, 1.20 mmol) using the same procedure as described in the synthesis of compound 13.4. LCMS (method A): [MH]+ = 320, tR = 5.21 min.
(£)-1-{3-[1-(1-Methyl-1 H-indazol-5-yl)-ethyl]-imidazo[1 ,2-b]pyridazin-6-yl}-ethanone O- (2-hydroxy-ethyl)- oxime (example 14)
The title compound (9.0 mg, 17 %, 88 % purity) was synthesized from 1 -(3-(1 -(1 -methyl-1 H- indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone (40.0 mg, 0.13 mmol) and 2- (aminooxy)ethanol hydrochloride (19.31 mg, 0.25 mmol) using the same procedure as described in the synthesis of example 13. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 7.94 (d, 1 H), 7.85 (s, 1 H), 7.79 (s, 1 H), 7.66 (s, 1 H), 7.85 (d, 1 H), 7.52 (d, 1 H), 7.37 (dd, 1 H), 4.72 (t, 2H), 4.21 (t, 2H), 3.97 (s, 3H), 3.66 (q, 1 H), 2.20 (s, 3H), 1.78 (d, 3H). LCMS (method A): [MH]+ = 379, tR = 5.25 min.
Example 15
(£)-1 -[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone O-(2-hydroxy-ethyl)-oxime
Figure imgf000088_0001
5-Bromo-N*3*-(7-fluoro-quinolin-6-ylmethyl)-pyrazine-2,3-diamine (15.1)
A mixture of C-(7-fluoro-quinolin-6-yl)-methylamine (1.69 g, 9.63 mmol ), 3,5-dibromopyrazin- 2-amine (2.43 g, 9.63 mmol ) and DIPEA (2.96 g, 22.90 mmol ) was heated with microwave irradiation at 120 0C for 10 h. The reaction mixture was diluted with DCM and water. The organic layer was separated and washed with saturated NH4CI solution, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (DCM:MeOH) to give the title compound as a yellow solid (2.60 g, 69%). LCMS (method E): [MH]+ = 348/350, tR = 5.21 min. 6-(6-Bromo-[1 ,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-7-fluoro-quinoline (15.2)
To a solution of 5-bromo-N*3*-(7-fluoro-quinolin-6-ylmethyl)-pyrazine-2,3-diamine (90 mg,
0.26 mmol ) in acetic acid (4 ml_) was added a solution of sodium nitrite (1 1.4 mg, 0.26 mmol) in water (1 ml_). After stirring at rt for 3 h, the solvent was removed in vacuo. The residue was diluted with NaHCO3 (aq.), extracted with DCM. The organic layer was separated and washed with water, dried over Na2SO4, filtered and concentrated in vacuo.
The crude product was purified by silica gel chromatography with DCM:MeOH = 50:1 to give the title compound as a yellow solid (57.0 mg, 61 %). 1H-NMR (400MHz, DMSO-Cf6) δ ppm
9.03 (s, 1 H), 8.94 (d, 1 H), 8.40 (d, 1 H), 8.08 (d, 1 H), 7.84 (d, 1 H), 7.55 (dd, 1 H), 7.53 (dd, 1 H), 6.21 (s, 2H). LCMS (method A): [MH]+ = 359/361 , tR = 2.23 min.
6-[6-(1-Ethoxy-vinyl)-[1 ,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl]-7-fluoro-quinoline (15.3)
A mixture of 6-(6-bromo-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -ylmethyl)-7-fluoro-quinoline (2.0 g, 5.57 mmol ), Pd(Ph3P)4 (0.64 g, 0.56 mmol ) and tributyl(1 -ethoxyvinyl)stannane (4.02 g, 1 1.14 mmol) in DMF (50 ml_) was purged with nitrogen and then heated at 100 0C for 7 h. After removal of the solvent under reduced pressure, the residue was diluted with DCM, washed sequentially with aqueous KF and water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with gradient (DCM:MeOH = 50:1 ) to give the title compound as a white solid. 1H-NMR (400MHz, DMSO- Cf6) δ ppm 9.1 1 (s, 1 H), 8.93 (d, 1 H), 8.40 (d, 1 H), 8.15 (d, 1 H), 7.83 (d, 1 H), 7.54 (m, 1 H), 6.22 (s, 2H), 5.50 (d, 1 H), 4.73 (d, 1 H), 4.02 (q, 2H), 1.40 (t, 3H). LCMS (method E): [MH]+ = 351 , tR = 5.42 min.
1-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4)
A solution of 6-[6-(1 -ethoxy-vinyl)-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -ylmethyl]-7-fluoro-quinoline (600.0 mg, 0.89 mmol) and 3 N HCI (0.1 mL) in acetic acid was stirred at 50 0C for 2 h. The solvent was removed under reduced pressure. The residue was diluted with water; the pH of solution was adjusted to around 8 with aqueous NaHCO3; extracted with DCM twice. The combined organic layers were washed sequentially with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as white solid (630 mg, 96%). 1H-NMR (400MHz, CDCI3) δ ppm 9.46 (s, 1 H), 8.94 (d, 1 H), 8.1 1 (d, 2H), 7.85 (dd, 1 H), 7.41 (dd, 1 H), 6.23 (s, 2H), 2.79 (s, 3H). LCMS (method A): [MH]+ = 323, tR = 2.23 min. 1 -[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone O-(2- hydroxy-ethyl)-oxime (example 15)
To a solution of 1 -[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]- ethanone (190.0 mg, 0.59 mmol) in MeOH (40 ml_) was added 2-(aminooxy)ethanol hydrochloride (134.0mg, 1.18 mol). The mixture was heated at 45 0C overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography with gradient (DCM:MeOH =10:1 ) to give the title compound as a white solid (168.0 mg,
71%). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.30 (s, 1 H), 8.93 (d, 1 H), 8.41 (d, 1 H), 8.19 (d,
1 H), 7.83 (d, 1 H), 7.54 (dd, 1 H), 6.24 (s, 2H), 4.78 (t, 1 H), 4.31 (t, 2H), 3.72 (m, 2H), 2.29 (s, 3H). LCMS (method A): [MH]+ = 382, tR = 4.99 min.
Example 16
(£)-1-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone
O-methyl-oxime
Figure imgf000090_0001
The title compound (22.2 mg, 64%) was synthesized from 1 -[3-(7-fluoro-quinolin-6-ylmethyl)-
3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (30.0 mg, 0.09 mmol) and O-methyl- hydroxylamine hydrochloride (78.0 mg, 0.93 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400MHz, CDCI3) δ ppm 9.45 (s, 1 H), 8.92 (d, 1 H), 8.08 (d, 1 H), 7.81 (d, 1 H), 7.78 (s, 1 H), 7.39 (dd, 1 H), 6.16 (s, 2H), 4.13 (s, 3H), 2.33 (s, 3H). LCMS (method E): [MH]+ = 352, tR = 5.43 min.
Example 17
(£)-1-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone O-(2-hydroxy-1 ,1 -dimethyl-ethyl)-oxime
Figure imgf000090_0002
The title compound (12.0 mg, 89%) was synthesized from 1 -[3-(7-fluoro-quinolin-6-ylmethyl)- 3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and 2-aminooxy- 2-methyl-propan-1 -ol hydrochloride (8.8 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400MHz, CDCI3) δ ppm 9.41 (s, 1 H), 8.94 (d, 1 H), 8.18(d, 1 H), 7.94 (d, 1 H), 7.83 (s, 1 H), 7.46 (dd, 1 H), 6.17 (s, 2H), 3.75 (d, 2H), 2.36 (s, 3H), 1 .95 (t, 1 H), 1 .41 (s, 6H). LCMS (method A): [MH]+ = 410, tR = 5.39 min.
Example 18
(£)-1-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone O-(2-hydroxy-2-methyl-propyl)-oxime
Figure imgf000091_0001
The title compound (12.0 mg, 89%) was synthesized from 1 -[3-(7-fluoro-quinolin-6-ylmethyl)- 3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and 1 -aminooxy- 2-methyl-propan-2-ol (6.5 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.29 (s, 1 H), 8.93 (dd, 1 H), 8.41 (dd, 1 H), 8.19(d, 1 H), 7.83 (d, 1 H), 7.54 (dd, 1 H), 6.23 (s, 2H), 4.60 (s, 1 H), 4.12 (d, 2H), 2.30 (s, 3H), 1 .17 (s, 6H). LCMS (method A): [MH]+ = 410, tR = 5.40 min.
Example 19
(S,£)-1-(1-((7-Fluoroquinolin-6-yl)methyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-pyrrolidin-3-yl oxime
Figure imgf000091_0002
The title compound (37.0 mg, 70%) was synthesized from 1 -[3-(7-fluoro-quinolin-6-ylmethyl)-
3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (40.0 mg, 0.12 mmol) and (S)-O- pyrrolidin-3-yl-hydroxylamine hydrochloride (30.0 mg, 0.17 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.30 (s, 1H), 8.92 (dd, 1H), 8.41 (dd, 1H), 8.18(d, 1H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.23 (s, 2H), 4.95 (m, 1H), 3.16-2.87 (m, 3H), 2.77-2.71 (m, 1H), 2.25 (s, 3H), 2.01-1.87 (m, 2H). LCMS (method A): [MH]+ = 407, tR = 3.09 min.
Example 20
(ff,£)-1-(1-((7-Fluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-pyrrolidin-3-yl oxime
Figure imgf000092_0001
The title compound (7.0 mg, 50%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)- 3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and [R)-O- pyrrolidin-3-yl-hydroxylamine hydrochloride (10.8 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400MHz, DMSO-Cf6) δppm 9.31 (s, 1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.16 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.24 (s, 2H), 4.95 (m, 1H), 3.01-2.87 (m, 3H), 2.74-2.67 (m, 1H), 2.27 (s, 3H), 2.15-1.90 (m, 2H). LCMS (method A): [MH]+ = 407, tR = 3.98 min.
Example 21
(S,£)-3-(1-(1-((7-Fluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6- yl)ethylideneaminooxy)pyrrolidine-1-carboxamide
Figure imgf000092_0002
To a solution of (S,£)-1-(1-((7-fluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6- yl)ethanone O-pyrrolidin-3-yl oxime (example 19) (20.0 mg, 0.05 mmol) in EtOH (5 mL) was added isocyanatotrimethylsilane (7.9 mg, 0.07 mmol). The mixture was stirred overnight. The solvent was removed under reduced pressure. The residue was diluted with MeOH (3 ml_) and filtered. The filtrate was purified on HPLC (basic with 0.05% NH4OH) to give the title compound as a white solid (15.0 mg, 64%). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.31 (s, 1 H), 8.92 (dd, 1 H), 8.40 (d, 1 H), 8.17 (d, 1 H), 7.82 (d, 1 H), 7.53 (dd, 1 H), 6.23 (s, 2H), 5.77 (s, 2H), 4.99 (m, 1 H), 3.59 (d, 1 H), 3.51 -3.47 (m, 1 H), 3.44-3.38 (m, 1 H), 3.28-3.23 (m, 1 H), 2.26 (s, 3H), 2.18-2.17 (m, 2H). LCMS (method A): [MH]+ = 450, tR = 4.38 min.
Example 22
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-methyl oxime
Figure imgf000093_0001
example 22
6-Bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (22.1 )
A mixture of quinolin-6-ylmethanamine (3.6g, 22.76mmol), 3,5-dibromopyrazin-2-amine (5.75 g, 22.76 mmol) and triethyl amine (4.61 g, 45.5 mmol) was heated with microwave irradiation at 130 0C for 5 h. The reaction mixture was diluted with CH2CI2 and water and the organic layer was separated, washed with aqueous NH4CI, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with
EtOAc:hexanes to provide 6.93 g (92%) of the title compound. LCMS (method A): [MH]+ = 330, tR = 4.89 min.
6-((6-Bromo-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)quinoline (22.2)
To a solution of 6-bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (6.55 g, 19.84 mmol) in acetic acid (15 mL) was added a solution of sodium nitrite (2.74 g, 39.7 mmol) in water (3 mL). After stirring at rt for 3 h, the solution was concentrated. The residue was taken with NaHCO3 (aq) and extracted with DCM. The organic layer was washed with NH4CI (aq), dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography with EtOAc:hexane to provide 3.35 g (47%) of the title compound. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.05 (s, 1 H), 8.89 (d, 1 H), 8.34 (d, 1 H), 8.02 (d, 1 H), 7.9 3(s, 1 H), 7.76 (dd, 1 H), 7.53 (dd, 1 H), 6.19 (s, 2H). LCMS (method B): [MH]+ = 343, tR = 2.1 1 min. 6-((6-(1-Ethoxyvinyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (22.3)
To a degassed solution of 6-((6-bromo-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)quinoline (2.50 g, 5.86 mmol) in DMF (20 ml_) was added Pd(Ph3P)4 (0.542 g, 0.469 mmol). The solution was stirred for 20 min at rt, and then tributyl(1 -ethoxyvinyl)stannane (2.1 17 g, 5.86 mmol) was added. The mixture was heated at 100 0C until LC-MS showed the reaction was complete. The reaction mixture was filtered through celite and the filtrate was washed with water, dried over Na2SO4, and concentrated. The resulting crude product was purified by column chromatography with gradient hexanes:EtOAc to give 1.2 g (62%) of the title compound. 1H-NMR (400MHz, CDCI3) δ ppm 9.19 (s, 1 H), 8.94 (m, 1 H), 8.20 (m, 1 H), 7.99 (s, 1 H), 7.89 (d, 1 H), 7.55 (m, 1 H), 6.12 (s, 2H), 5.61 (d, 1 H), 4.61 (d, 1 H), 4.05(q, 2H), 1 .51 (t, 3H). LCMS (method B): [MH]+ = 360, tR = 2.40 min.
1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4)
To a solution of the 6-((6-(1 -ethoxyvinyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 - yl)methyl)quinoline (150 mg, 0.451 mmol) in acetic acid was added 3N HCI (0.1 mL). After stirring at rt for 2 h, solvent was removed under reduced pressure. The residue was diluted with water and its pH was adjusted to basic with aqeous NaHCO3, and extracted with DCM. The combined organic layers were washed with NaHCO3 (aq) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 131 mg (91%) of the title compound as a yellow solid. 1H-NMR (400MHz, CDCI3) δ ppm 9.45 (s, 1 H), 8.95 (d, 1 H), 8.14 (m, 2H), 7.95 (s, 1 H), 7.84 (d, 1 H), 7.45 (m, 1 H), 6.19 (s, 2H), 2.75 (s, 3H). LCMS (method B): [MH]+ = 305, tR = 2.95 min.
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-methyl oxime (example 22)
To a solution of 1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (6.3 mg, 0.021 mmol) in methanol (3 mL) was added O-methylhydroxylamine hydrochloride (16.7 mg, 0.20 mmol), followed by addition of triethyl amine to adjust the pH to 5-6. The reaction mixture was stirred at 30 0C for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The resulting solution was washed with NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 5.3 mg (69%) of the title compound. 1H-NMR (400MHz, CD3CI) δ ppm 9.67 (s, 1 H), 8.94 (m, 1 H), 8.16 (t, 2H), 7.93 (d, 1 H), 7.86 (dd, 1 H), 7.53 (dd, 1 H), 6.1 1 (s, 2H), 4.14 (s, 3H), 2.38 (s, 3H). LCMS (method A): [MH]+ = 334, tR = 5.02 min.
Example 23
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone 0-2- hydroxyethyl oxime
Figure imgf000095_0001
The title compound was prepared from 1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and 2-(aminooxy)ethanol in 21 % yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400MHz, CD2CI2) δ ppm 9.40 (s, 1 H), 8.91 (m, 1 H), 8.18 (d, 2H), 7.95(d, 1 H), 7.85 (dd, 1 H), 7.45 (dd, 1 H), 6.13 (s, 2H), 4.46 (t, 2H), 3.97 (t, 2H), 2.39 (s, 3H). LCMS (method A): [MH]+ = 364, tR = 4.28 min.
Example 24
1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone oxime
Figure imgf000095_0002
The title compound was prepared from 1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and hydroxylamine hydrochloride in 72% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400MHz, DMSO-Cf6), δ ppm 9.31 (s, 1 H), 8.89 (d, 1 H), 8.35 (d, 1 H), 8.01 (m, 2H), 7.82 (d, 1 H), 7.53 (dd, 1 H), 6.20 (s, 2H), 2.27 (s, 3H). Example 25
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-ethyl oxime
Figure imgf000096_0001
The title compound was prepared from 1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and O-ethylhydroxylamine hydrochloride in 61 % yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400MHz, DMSO-Cf6), δ ppm 9.31 (s, 1 H), 8.89 (m, 1 H), 8.35 (d, 1 H), 8.01 (m, 2H), 7.82 (d, 1 H), 7.53 (dd, 1 H), 6.20 (s, 2H), 4.34 (q, 2H), 2.32 (s, 3H), 1.24 (t, 3H). LCMS (method B): [MH]+ = 348, tR = 2.59 min.
Example 26A
(£)-1 -(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone 0-1 ,3- dihydroxypropan-2-yl oxime
Figure imgf000096_0002
The title compound was prepared from 1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and 2-(aminooxy)propane-1 ,3-diol (intermediate B) in 54% yield using the same procedure as described in the synthesis of example 22 and example 7A. 1H-NMR (400MHz, CD3OD), δ ppm 9.40 (s, 1 H), 8.86 (dd, 1 H), 8.38 (d, 1 H), 8.05 (m, 2H), 7.90 (dd, 1 H), 7.56 (dd, 1 H), 6.22 (s, 2H), 4.46 (t, 1 H), 3.87 (d, 4H), 2.42 (s, 3H). LCMS (method B): [MH]+ = 394, tR = 1.86 min. Example 26B
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone 0-2,3- dihydroxypropyl oxime
Figure imgf000097_0001
The title compound was prepared from 1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and (3-(aminooxy)propane-1 ,2-diol) (intermediate B) in 40% yield using the same procedure as described in the synthesis of example 22 and example 7B. 1H-NMR (400MHz, CD3OD) δ ppm 9.40 (s, 1 H), 8.86 (m, 1 H), 8.38 (d, 1 H), 8.05 (m, 2H), 7.90 (dd, 1 H), 7.57 (dd, 1 H), 6.23 (s, 2H), 4.45 (m, 1 H), 4.34 (m, 1 H), 4.01 (m, 1 H), 3.63 (m, 2H), 2.41 (s, 3H). LCMS (method B): [MH]+ = 394, tR = 1.96 min.
Example 27
(£)-1 -(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-benzyl
Figure imgf000097_0002
The title compound was prepared from1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and O-benzylhydroxylamine (intermediate H) in 43% yield using the same procedure as described in the synthesis of example 22 1H-NMR (400MHz, CDCI3), δ ppm 9.43 (s, 1 H), 8.93 (d, 1 H), 8.13 (m, 2H), 7.91 (s, 1 H), 7.83 (d, 1 H), 7.42 (m, 6H), 6.10 (s, 2H), 5.36 (s, 2H), 2.40 (s, 3H). LCMS (method A): [MH]+ = 410, tR = 5.94 min.
Example 28
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone 0-4- methoxybenzyl oxime
Figure imgf000098_0001
The title compound was prepared from1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and 0-(4-methoxybenzyl)hydroxylamine (intermediate G) in 37% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400MHz, CDCI3), δ ppm 9.44 (s, 1 H), 8.93 (s, 1 H), 8.13 (m, 2H), 7.91 (s, 1 H), 7.84 (d, 1 H), 7.47 (dd, 1 H), 7.44 (d, 2H), 6.92 (d, 2H), 6.10 (s, 2H), 5.28 (s, 2H), 3.82 (s, 3H), 2.37 (s, 3H). LCMS (method A): [MH]+ = 440, tR = 5.94 min.
Example 29
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O- piperidin-4-yl oxime
Figure imgf000098_0002
To a solution of 1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) (40 mg, 0.131 mmol) in methanol (10 ml_) was added /-butyl 4-(aminooxymethyl) piperidine-1 -carboxylate (intermediate I) (19.7 mg, 0.329 mmol). Acetic acid was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at 30 0C for 20 h. The solvent was removed in vacuo and the residue was dissolved in DCM (5ml_), followed by addition of TFA (0.2ml_). The reaction mixture was stirred at rt for 2 h, and then concentrated in vacuo to give crude product which was purified by column chromatography to afford 1 1 mg (16%) of the title compound. 1H-NMR (400MHz, CDCI3), δ ppm 9.45 (s, 1 H), 8.93 (m, 1 H), 8.15 (d, 1 H), 8.10 (d, 1 H), 7.93 (d, 1 H), 7.84 (d, 1 H), 7.44 (dd, 1 H), 6.1 1 (s, 2H), 4.46 (m, 1 H), 3.15 (m, 2H), 2.81 (m, 2H), 2.49 (s, 3H), 2.12 (m, 2H), 1.72 (m, 2H). LCMS (method B): [MH]+ = 403, tR = 1 .59 min. Example 30 (£)-1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone o- piperidin-4-ylmethyl oxime
Figure imgf000099_0001
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and /-butyl 4-(aminooxymethyl)piperidine-1-carboxylate (intermediate J) in 15% yield using the same procedure as described in the synthesis of example 29. 1H-NMR (400MHz, CDCI3), δ ppm 9.43 (s, 1H), 8.93 (m, 1H), 8.13 (m, 2H), 7.92 (s, 1H), 7.83 (dd, 1H), 7.43 (dd, 1H), 6.10 (s, 2H), 4.20 (d, 2H), 3.18 (d, 2H), 2.68 (t, 2H), 2.37(s, 3H), 1.98 (brs, 1H), 1.80 (d, 2H), 1.37 (q, 2H). LCMS (method A): [MH]+ = 417, tR= 1.66 min.
Example 31
(£)-Methyl2-(1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6- yl)ethylideneaminooxy)acetate
Figure imgf000099_0002
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and methyl 2-(aminooxy) acetate (intermediate K) in 31% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400MHz, CD3OD), δ ppm 9.32 (s, 1H), 8.86 (m, 1H), 8.38 (d, 1H), 8.06 (m, 2H), 7.90 (dd, 1H), 7.56 (dd, 1H), 6.24 (s, 2H), 4.87 (s, 2H), 3.79 (s, 3H), 2.45 (s, 3H). LCMS (method B): [MH]+ = 392, tR = 2.16 min.
Example 32
(£)-2-(1-(1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6- yl)ethylideneaminooxy)acetamide
Figure imgf000100_0001
To a solution of (£)-methyl 2-(1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6- yl)ethylideneaminooxy)acetate (example 31) (70 mg, 0.179 mmol) was added ammonia (2 N, 0.268 ml_, 0.537 mmol). The reaction was heated at reflux for 12 h. The reaction mixture was concentrated in vacuo to give a crude product which was purified by prep-HPLC to afford 9 mg (16%) of the title compound. 1H-NMR (400MHz, DMSO-C^D2O) δ ppm 9.32 (s, 1 H), 8.88 (d, 1 H), 8.34 (d, 1 H), 8.01 (m, 2H), 7.81 (d, 1 H), 7.52 (dd, 1 H), 7.33 (br, 2H), 6.20 (s, 2H), 4.67 (s, 2H), 2.27 (s, 3H). LCMS (method B): [MH]+ = 377, tR = 1 .06 min.
Example 33
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2- hydroxy-2-methylpropyl oxime
Figure imgf000100_0002
The title compound was prepared from 1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and 1 -(aminooxy)-2-methylpropan-2-ol in 85% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.29 (s, 1 H), 8.89 (d, 1 H), 8.35 (d, 1 H), 8.01 (m, 2H), 7.82 (dd, 1 H), 7.53 (dd, 1 H), 6.21 (s, 2H), 4.60 (s, 1 H), 4.13 (s, 2H), 2.34 (s, 3H), 1 .17 (s, 6H). LCMS (method B): [MH]+ = 392, tR = 2.38 min.
Example 34
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2- aminoethyl oxime
Figure imgf000101_0001
Figure imgf000101_0002
example 23 example 34
Figure imgf000101_0003
(£)-2-(2-(1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylidene- aminooxy)ethyl)isoindoline-1 ,3-dione (34.1 )
To a solution of (£)-1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone 0-2-hydroxyethyl oxime (example 23) (200 mg, 0.55 mmol) in THF (1 OmL) were added triphenylphosphine (144 mg, 0.55 mmol), isoindoline-1 ,3-dione (81 mg, 0.55 mmol) and [E)- diisopropyl diazene-1 ,2-dicarboxylate (1 1 1 mg, 0.55 mmol) sequentially. The mixture was stirred at rt for 48 h and concentrated in vacuo. The residue was purified by column chromatography to afford 120 mg (42%) of the title compound. 1H-NMR (400MHz, DMSO- Cf6) δ ppm 8.90 (s, 1 H), 8.89 (m, 1 H), 8.35 (d, 1 H), 8.02 (m, 2H), 7.81 (d, 1 H), 7.71 (m, 2H), 7.63 (m, 2H), 7.52 (dd, 1 H), 6.19 (s, 2H), 4.53 (t, 2H), 3.97 (t, 2H), 2.20 (s, 3H). LCMS (method B): [MH]+ = 493, tR = 2.52 min.
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2- aminoethyl oxime (example 34)
To a solution of (£)-2-(2-(1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6- yl)ethylideneaminooxy)ethyl)isoindoline-1 ,3-dione (70 mg, 0.142 mmol) in MeOH (1 OmL) was added hydrazine monohydrate (35.6 mg, 0.71 1 mmol). The solution was heated at reflux for 30 h and concentrated in vacuo. The crude was purified by column chromatography to afford 19 mg (37%) of the title compound. 1H-NMR (400MHz, DMSO-c/6+D2O) δ ppm 9.35 (s, 1 H), 8.98 (s, 1 H), 8.35 (d, 1 H), 8.02 (s, 1 H), 8.01 (d, 1 H), 7.81 (d, 1 H), 7.53 (m, 1 H), 6.20 (s, 2H), 4.47 (s, 2H), 3.22 (s, 2H), 2.34 (s, 3H). LCMS (method B): [MH]+ = 363, tR = 1.57 min.
Example 35
(ff,£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O- pyrrolidin-3-yl oxime
Figure imgf000102_0001
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) (25 mg, 0.082 mmol) and (/:?)-0-(pyrrolidin-3-yl)hydroxylamine dihydrochloride in 60% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400MHz, CDCI3) δ ppm 9.41 (s, 1H), 8.92 (d, 1H), 8.13 (d, 1H), 8.09 (d, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.41 (dd, 1H), 6.10 (s, 2H), 5.30 (s, 1H), 5.09 (s, 1H), 3.31 (m, 3H), 2.38 (s, 3H), 2.25 (m, 2H). LCMS (method B): [MH]+ = 389, tR = 1.17 min.
Example 36
(£)-1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-1- hydroxypropan-2-yl oxime
Figure imgf000102_0002
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and 2-(aminooxy)propan-1-ol hydrochloride (intermediate Q) in 90% yield using the same procedure as described in the synthesis of example 22. 1H- NMR (400MHz, DMSO-Cf6) δ ppm 9.41 (s, 1H), 8.93 (m, 1H), 8.15 (m, 2H), 7.92 (s, 1H), 7.84 (dd, 1H), 7.43 (dd, 1H), 6.12 (s, 2H), 4.61 (m, 1H), 3.85 (m, 2H), 2.41 (s, 3H), 2.00 (s, 1H), 1.38 (d, 3H). LCMS (method B): [MH]+ = 378, tR = 1.96 min. Example 37A
(£)-Methyl2-(1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6- yl)ethylideneaminooxy)ethyl carbamate
Figure imgf000103_0001
To a solution of (£)-1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-aminoethyl oxime (example 34) (6 mg, 0.017 mmol) in DCM (5 ml_) were added methyl chloroformate (2.66 mg, 0.028 mmol) and triethyl amine (3.35 mg, 0.033 mmol). The mixture was stirred at rt for 10 h. After concentration, the crude was purified by chromatography on silica gel to afford 3.4 mg (46%) of the title compound. 1H-NMR (400MHz, CDCI3) δ ppm 9.41 (s, 1 H), 8.93 (s, 1 H), 8.14 (dd, 2H), 7.92 (s, 1 H), 7.84 (dd, 1 H), 7.44 (m, 1 H), 6.12 (s, 2H), 4.42 (t, 2H), 3.69 (s, 3H), 3.60 (m, 2H), 2.39 (s, 3H). LCMS (method B): [MH]+ = 421 , tR = 1 .95 min.
Example 37B
(£)-1-(2-(1-(1-(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6- yl)ethylideneaminooxy)ethyl)urea
Figure imgf000103_0002
To a solution of (£)-1 -(1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-aminoethyl oxime (example 34) (15 mg, 0.041 mmol) in DCM (5 ml_) was added trimethylsilyl isocyanate (19.07 mg, 0.166 mmol). The mixture was stirred for 24 h. After concentration, the crude product was purified by chromatography on silica gel to afford 1 1.6 mg (69%) of the title compound. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.32 (s, 1 H), 8.89 (dd, 1 H), 8.35 (d, 1 H), 8.01 (m, 2H), 7.82 (d, 1 H), 7.53 (dd, 1 H), 6.21 (s, 2H), 6.05 (t, 1 H), 5.50 (s, 2H), 4.27 (t, 2H), 3.35 (m, 2H), 2.32 (s, 3H). LCMS (method B): [MH]+ = 406, tR = 1 .91 min.
Example 38 (£)-1 -(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazine-6-carbaldehyde 0-2- hydroxyethyl oxime
Figure imgf000104_0001
example 38
Figure imgf000104_0002
6-((6-Vinyl-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (38.1)
To a degassed solution 6-((6-bromo-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)quinoline (22.2) (1 .2g, 3.52 mmol) in DMF (10 mL) was added Pd(PPh3)4 (610 mg, 0.528 mmol). The solution was stirred for 20 min, then tributyl(vinyl)stannane (1 .227 g, 3.87 mmol) was added. The reaction mixture was heated at 120 0C for 5 h. Aqueous NH4CI solution was added to quench the reaction, followed by addition of EtOAc. The mixture was filtered through celite and the filtrate was washed with saturated NaHCO3 and NH4CI solutions. The organic layer was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified with Analogix system on silica gel (hexanes:EtOAc) to afford 210 mg (20%) of the title compound. LCMS (method B): [MH]+ = 288, tR = 2.05 min.
1 -(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazine-6-carbaldehyde (38.2)
To a mixture of 6-((6-vinyl-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)quinoline (100 mg, 0.347 mmol) and 2,6-dimethylpyridine (74.3 mg, 0.694 mmol) was added a solution of osmium(VIII) oxide (297 mg, 1 .387 mmol) in water (1.333 mL), followed by addition of a solution of sodium periodate (88 mg, 6.94 μmol) in 1 ,4-dioxane (4 mL). The reaction mixture was stirred at rt for 10 h. The solvent was removed in vacuo and DCM was added to dilute the residue. The resulting solution was washed with saturated NaHCO3 solution, NH4CI and brine. The organic layer was separated, dried over Na2SO4, and concentrated to give the crude product which was purified with Analogix system on silca gel (hexanes:EtOAc) to afford 45 mg (43%) of the title compound. LCMS (method B): [MH]+ = 291 , tR = 1 .00 min.
(£)-1 -(Quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazine-6-carbaldehyde 0-2- hydroxyethyl oxime (example 38) The title compound was prepared from 1 -(quinolin-6-ylmethyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazine-6-carbaldehyde and 2-(aminooxy)ethanol hydrochloride in 45% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400MHz, CD3OD), δ ppm 9.27 (s, 1 H), 8.84 (m, 1 H), 8.36 (s, 1 H), 8.34 (d, 1 H), 8.01 (d, 1 H), 8.00 (s, 1 H), 7.85 (d, 1 H), 7.53 (dd, 1 H), 6.20 (s, 2H), 4.39 (t, 2H), 3.87 (t, 2H). LCMS (method B): [MH]+ = 350, tR = 1.94 min.
Example 39 (example 39-R, example 39-S)
(£)-1 -(3-(1 -(6-Fluoro-1 -methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone O-2-hydroxyethyl oxime
Figure imgf000105_0001
1-(6-Chloroimidazo[1 ,2-b]pyridazin-3-yl)-1-(6-fluoro-1 -methyl-1 H-indazol-5-yl)ethanol (39.1)
To a solution of 5-bromo-6-fluoro-1 -methyl-1 H-indazole (intermediate L) (1.800 g, 7.86 mmol) in THF (79 mL) at -100 0C was added n-BuLi (5.40 mL, 8.64 mmol) dropwise. After stirring for 1 h at -100 0C, a solution of 1 -(6-chloroimidazo[1 ,2-b]pyridazin-3-yl)ethanone (intermediate M) (1 .691 g, 8.64 mmol) in THF (20 mL) was added dropwise. The reaction solution was stirred for additional 2 h and quenched with NH4CI (aq). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NH4CI (aq), dried over Na2SO4 and concentrated in vacuo to afford the crude product which was purified by column chromatography (hexanes:EtOAc) to give the title compound in 34% yield. LCMS (method B): [MH]+ = 346, tR = 2.14 min. 6-Chloro-3-(1-(6-fluoro-1 -methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazine (39.2) A mixture of 1 -(6-chloroimidazo[1 ,2-b]pyridazin-3-yl)-1 -(6-fluoro-1 -methyl-1 H-indazol-5- yl)ethanol (1.1 g, 3.18 mmol), diiodine (2.019 g, 7.95 mmol) and phosphinic acid (0.840 g, 12.73 mmol) in acetic acid (10 ml_) was heated at 120 0C for 5 h. After cooling, the reaction mixture was concentrated in vacuo. The residue was taken with water and adjusted to pH 8 with aqueous NaOH. Then the mixture was extracted with DCM, dried over Na2SO4 and concentrated. The residue was purified with column chromatography (MeOH :EtOAc) to give 900 mg (60%) of the title compound. LCMS (method B): [MH]+ = 330, tR = 2.59 min.
6-(1-Ethoxyvinyl)-3-(1-(6-fluoro-1-methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazine (39.3)
To a solution of 6-chloro-3-(1 -(6-fluoro-1 -methyl-1 H-indazol-5-yl)ethyl)imidazo[1 , 2- b]pyridazine (900 mg, 1.910 mmol) in DMF (8 ml_) was added Pd(Ph3P)4 (221 mg, 0.191 mmol). The mixture was stirred for 20 min, and tributyl(1 -ethoxyvinyl)stannane (784 mg, 2.102 mmol) was added. The resulting mixture was heated at 100 0C until LC-MS showed the reaction was complete. The reaction mixture was filtered through celite and the solid was washed with ether. The combined filtrate was washed with water, dried over Na2SO4, and concentrated. The residue was purified by column chromatography with gradient hexane:EtOAc to give 450mg (52%) of the title compound. 1 -(3-(1 -(6-Fluoro-1 -methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone (39.4)
To a solution of the 6-(1 -ethoxyvinyl)-3-(1 -(6-fluoro-1 -methyl-1 H-indazol-5-yl)ethyl)- imidazo[1 ,2-b]pyridazine (450 mg, 0.985 mmol) in acetic acid (8 mL) was added 3N HCI (0.5 mL). The solution was stirred at rt for 2 h and the solvent was removed under reduced pressure. The residue was diluted with water and its pH was adjusted to basic with aqeous NaHCO3 solution and extracted with DCM. The organic layer was washed with NaHCO3 (aq) and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography to give 300mg (81%) of the title compound as a yellow solid. LCMS (method B): [MH]+ = 338, tR = 2.49 min.
(£)-1 -(3-(1 -(6-Fluoro-1 -methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone 0-2-hydroxyethyl oxime (example 39, example 39-R, example 39-S)
To a solution of 1 -(3-(1 -(6-fluoro-1 -methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone (100 mg, 0.267 mmol) in methanol (10 mL) was added 2-(aminooxy)ethanol hydrochloride (30.3 mg, 0.267 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at 30 0C for 20 h. The solvent was removed in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (aq) and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product which was purified by chromatography on silica gel to afford 19 mg (17%) of the title compound. 1H-NMR (400MHz, DMSO-d6) δ ppm 8.01 (d, 1 H), 7.91 (s, 1 H), 7.77 (s, 1 H), 7.58 (d, 1 H), 7.50 (s, 1 H), 7.49 (d, 1 H), 4.91 (q, 1 H), 4.76 (t, 1 H), 4.20 (t, 2H), 3.95 (s, 3H), 3.65 (m, 2H), 2.13 (s, 3H), 1.76 (d, 3H). LCMS (method B): [MH]+ = 397, tR = 2.50 min. Chiral separation (method K) provided enantiomeric pure compounds example 39-ff and example 39-S.
Example 40
(£)-1 -(3-((6-Fluoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone O-2-hydroxyethyl oxime
Figure imgf000107_0001
6-Chloroimidazo[1 ,2-b]pyridazin-3-yl)(6-f luoro-1 -methyl-1 H-indazol-5-yl)methanol (40.1 )
The title compound was prepared as a yellow solid in analogy to the synthesis of compound 39.1 from 6-chloroimidazo[1 ,2-b]pyridazine-3-carbaldehyde. LCMS (method B): [MH]+ = 332, tR = 2.09 min. 6-Chloro-3-((6-f luoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazine (40.2)
The title compound was prepared as a yellow solid in analogy to the synthesis of compound 39.2 from (6-chloroimidazo[1 ,2-b]pyridazin-3-yl)(6-fluoro-1 -methyl-1 H-indazol-5-yl)methanol. LCMS (method B): [MH]+ = 316, tR = 2.56 min. 6-(1-Ethoxyvinyl)-3-((6-fluoro-1-methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazine (40.3)
The title compound was prepared in analogy to the synthesis of compound 39.3 from 6- chloro-3-((6-fluoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazine.
1 -(3-((6-Fluoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazin-6-yl)ethanone (40.4)
The title compound was prepared as a white solid in analogy to the synthesis of compound 39.4 from 6-(1 -ethoxyvinyl)-3-((6-fluoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2- b]pyridazine. LCMS (method B): [MH]+ = 324, tR = 2.41 min.
(£)-1 -(3-((6-Fluoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone O-2-hydroxyethyl oxime (example 40)
To a solution of 1 -(3-((6-fluoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 , 2-b]pyridazin-6- yl)ethanone (50 mg, 0.155 mmol) in methanol (7 ml_) was added 2-(aminooxy)ethanol hydrochloride (17.6 mg, 0.155 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at 30 0C for 20 h. The solvent was removed in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (aq) and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product which was purified by column chromatography to afford 43 mg (70%) of the title compound. 1H- NMR (400MHz, DMSO-Cf6) δ ppm 8.05 (d, 1 H), 7.97 (s, 1 H), 7.70 (d, 1 H), 7.63 (d, 1 H), 7.62 (s, 1 H), 7.53 (d, 1 H), 4.75 (t, 1 H), 4.43 (s, 1 H), 4.23 (t, 2H), 3.97 (s, 3H), 3.68 (q, 2H), 2.28 (s, 3H). LCMS (method B): [MH]+ = 383, tR = 2.45 min. Example 41
(£)-1 -(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-methyl oxime
Figure imgf000109_0001
intermediate O
Figure imgf000109_0002
example 41
6-((6-(1-Ethoxyvinyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline(41.1)
A solution of 6-((6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (intermediate O) (50 mg, 0.169 mmol) and tributyl(1 -ethoxyvinyl)stannane(0.06 ml_, 0.178 mmol) in DMF (6 mL) was purged with N2 for 30 min and then Pd(PPh3)4 (9.77 mg, 0.0085 mmol) was added. The resulting solution was heated at 1000C for 3 h. The reaction mixture was quenched with water, extracted with EtOAc three times. The organic layers were combined, washed with KF solution and brine, dried over Na2SO4. After concentration, the crude was used in the next step without further purification. LCMS (method A): [MH]+ = 332.1 , tR = 4.969 min.
1 -(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone(41.2)
To a solution of 6-((6-(1 -ethoxyvinyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline in MeOH (30 mL) was added excess 3N HCI solution. The solution was stirred at rt overnight and neutralized with saturated NaHCO3 solution. Organic solvent was evaporated and the residue was extracted wtih EtOAc three times. Organic layers were combined, washed with brine and dried over Na2SO4. Solvent was evaporated and the crude was purified by colulmn chromatography (DCM:MeOH = 95:5) to give the title compound as yellow solid (51.3%). LCMS (method B): [MH]+ = 304.1 , tR = 1 .708 min. (£)-1 -(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-methyl oxime(Example 41)
A solution of 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (60 mg, 0.198 mmol) and 0-methylhydroxylamine(49.6 mg, 0.593 mmol) in MeOH (10 mL) was stirred at rt overnight. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA and then neutralized to free base) to give 40mg (60.8%) of the title compound as a white solid. 1H-NMR(400MHz, MeOH-Cf4 δ ppm 8.82 (s, 1 H), 8.32 (d, 1 H), 8.12 (d, 1 H), 7.98 (m, 3H), 7.84(d, 1 H), 7.54 (m, 1 H), 4.83 (s, 2H), 4.09 (s, 3H), 2.28 (s, 3H). LC-MS(method B): [MH]+ =333.1 , tR = 2.34 min.
Example 42
(£)-1 -(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-ethyl oxime
Figure imgf000110_0001
A solution of 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2)
(30 mg, 0.099 mmol) and O-ethylhydroxylamine (18.12 mg, 0.297 mmol) in 5 ml_ of MeOH was stirred at rt overnight. Solvent was evaporated and the crude was purified by HPLC
(acidic with 0.05% TFA) to give 15.8 mg (46.1%) of the title compound as a white TFA salt.
1H-NMR (400MHz, MeOH-d4δ ppm 9.05 (s,1 H), 8.85 (d,1 H), 8.23 (s, 1 H), 8.12 (m,3H), 7.98
(d,1 H), 7.89 (m, 1 H), 4.91 (s, 2H), 4.36 (q, 2H), 2.30 (s, 3H), 1.36 (t, 3H). LC-MS (method B):
[MH]+ =347.1 .1 , tR = 2.50 min.
Example 43
(£)-1-(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-1- hydroxypropan-2-yl oxime
Figure imgf000110_0002
A solution of 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2)
(40 mg, 0.132 mmol) and 2-(aminooxy)propan-1 -ol (intermediate Q) (33.6 mg, 0.264 mmol) in 15 mL of MeOH was stirred at rt overnight. Solvent was evaporated and the crude was purified by HPLC (basic with 0.05% NH4OH) to give 22 mg (44%) of the title compound as a white solid. 1H-NMR (400MHz, MeOH-Cf4 δ ppm 8.82 (s, 1 H), 8.33 (d, 1 H), 8.12 (d, 1 H), 7.98 (t, 3H), 7.84 (d, 1 H), 7.55 (m, 1 H), 4.84 (s, 2H), 4.50 (m, 1 H), 3.72 (d, 2H), 2.32 (s, 3H), 1 .33 (d, 3H). LC-MS (method B): [MH]+ =377.0, tR = 1.867 min. Example 44
(£)-1-(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-2- hydroxyethyl oxime
Figure imgf000111_0001
Hydrazine monohydrate (3.96 mg, 0.124 mmol) was added to a solution of 2-(2- hydroxyethoxy)isoindoline-1 ,3-dione (produced with a similar procedure for intermediate B) (25.6 mg, 0.124 mmol) in 5 ml_ of MeOH. The solution was heated at reflux for 2 h and then cooled to rt. White precipitate was filtered off and 1 -(3-(quinolin-6-ylmethyl)- [1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (15 mg, 0.049 mmol) was added. The pH value of the solution was adjusted to 5-6 with 1 N HCI solution. The reaction solution was then stirred at rt for 2 h. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA) to give 8 mg (44.5%) of the title compound as a white TFA salt. 1H-NMR (400MHz, MeOH-Cf4) δ ppm 9.09 (s, 1 H), 8.93 (d, 1 H), 8.27 (s, 1 H), 8.16 (m, 3H), 7.98 (d, 1 H), 7.93 (m, 1 H), 4.92 (s, 2H), 4.38 (t, 2H), 3.86 (t, 2H), 2.34 (s, 3H). LC-MS (method B): [MH]+ =363.1 , tR = 2.31 min.
Example 45
(£)-1-(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-1 ,3- dihydroxypropan-2-yl oxime
Figure imgf000111_0002
The title compound (12 mg, 28.6%) was synthesized from 2-(1 ,3-dihydroxypropan-2- yloxy)isoindoline-1 ,3-dione (intermediate B) (152 mg, 0.643 mmol, isomer mixture), hydrazine monohydrate (14 mg, 0.27 mmol) and 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3- b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.1 1 mmol) using the same procedure as described in the synthesis of example 44. After purification by HPLC (acidic with 0.05%TFA, then neutralized to basic), the title compound was obtained as a white solid. 1H-NMR (400MHz, CDCI3) δ ppm 8.89 (d, 1 H), 8.12 (d, 1 H), 8.08 (d, 1 H), 7.97 (d, 1 H), 7.86 (s, 1 H), 7.82 (d, 1 H), 7.73 (d, 1 H), 7.42 (m, 1 H), 4.77 (s, 2H), 4.49 (m, 1 H), 4.00 (dd, 4H), 2.33 (s, 3H). LC-MS (method B): [MH]+ =393.2, tR = 1.708 min.
Example 46
(£)-1-(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-2,3- dihydroxypropyl oxime
Figure imgf000112_0001
The title compound (6 mg, 14.3%) was synthesized from 2-(2,3-dihydroxypropoxy)iso- indoline-1 ,3-dione (intermediate B) (152 mg, 0.643 mmol, isomer mixture), hydrazine monohydrate (14 mg, 0.27 mmol) and 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3- b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.1 1 mmol) using the same procedure as described in the synthesis of example 44. After purification by HPLC (acidic with 0.05%TFA, then neutralized to basic), the title compound was obtained as a white solid. 1H-NMR (400MHz, CDCI3) δ ppm 8.89 (d, 1 H), 8.12 (d, 1 H), 8.08 (d, 1 H), 7.98 (d, 1 H), 7.86 (s, 1 H), 7.83 (d, 1 H), 7.74 (d, 1 H), 7.42 (m, 1 H), 4.78 (s, 2H), 4.37 (d, 2H), 4.15 (m, 1 H), 3.75 (m, 2H), 2.32 (s, 3H). LC-MS (method B): [MH]+ =393.2, tR = 1.841 min.
Example 47
(£)-1-(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-3- (trifluoromethyl)phenyl oxime
Figure imgf000112_0002
Hydrazine monohydrate (2.6 mg, 0.052 mmol) was added to a solution of 2-(3- (trifluoromethyl)phenoxy)isoindoline-1 ,3-dione (Organic Lett., 2001 , 31, 139) (19.75 mg, 0.064 mmol) in 5 mL of MeOH. The solution was heated at reflux for 2 h and then cooled to rt. White precipitate was filtered off and 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3- b]pyridazin-6-yl)ethanone (41.2) (15 mg, 0.049 mmol) was added. The pH value of solution was adjusted to 5-6 with 1 N HCI solution. The reaction solution was stirred at rt overnight. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA) to give the title compound as a white solid (TFA salt, 15 mg, 65.6%). 1H-NMR (400MHz, MeOH-Cf4) δ ppm 9.07 (s, 1 H), 8.90 (d, 1 H), 8.26 (m, 2H), 8.16 (m, 3H), 7.91 (m, 1 H), 7.60 (m, 3H), 7.43 (d,1 H), 4.96 (s, 2H), 2.59 (s, 3H). LC-MS (method E): [MH]+ =463.1 , tR = 6.03 min.
Example 48
(£)-1-(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-phenyl oxime
Hydrazine monohydrate (5.45 mg, 0.109 mmol) was added to a solution of 2- phenoxyisoindoline-1 ,3-dione (Organic Lett., 2001 , 31, 139) (30.8 mg, 0.129 mmol) in 10 mL of MeOH. The solution was heated at reflux for 2 h and then cooled to rt. White precipitate was filtered off and 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.1 mmol) was added. The pH value of solution was adjusted to 5-6 with 1 N HCI solution. The reaction solution was then stirred at rt overnight. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA) to give 23 mg (59%) of the title compound as a white solid (TFA salt). 1H-NMR (400MHz, CDCI3) δ ppm 9.23 (d, 1 H), 8.68 (d, 1 H), 8.53 (d, 1 H), 8.15 (m, 3H), 8.04 d, 1 H), 7.83 (m, 1 H), 7.40 (t, 2H), 7.29 (m, 2H), 7.15 (t, 1 H), 4.92 (s, 2H), 2.56 (s, 3H). LC-MS (method H): [MH]+ =395.2, tR = 2.42 min.
Example 49
(£)-1 -(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-benzyl oxime
Figure imgf000114_0001
The title compound was prepared from 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3- b]pyridazin-6-yl)ethanone (41.2) and O-benzylhydroxylamine (intermediate H) using the same procedure described in the synthesis of example 41. 1H-NMR(400MHz, CHCI3-C/,) δ ppm 8.87(d, 1 H), 8.06(m, 2H), 7.95(d, 1 H), 7.84(s, 1 H), 7.80(m, 2H), 7.38(m, 6H), 5.30(s, 2H), 4.77(s, 2H), 2.32(s, 3H). LC-MS (method J): [MH]+ =409.1 , tR = 2.42 min.
Example 50
(£)-1 -(3-(Dif luoro(quinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-
2-hydroxyethyl oxime
Figure imgf000114_0002
1 -(3-(Dif luoro(quinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (50.1 )
The title compound as a light yellow oil (180 mg, 30%, 80% purity) was synthesized from 6- ((6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)difluoromethyl)quinoline (intermediate R) (500 mg, 1.507 mmol), tributyl(1 -ethoxyvinyl)stannane (2.55 ml_, 7.54 mmol) and PdCI2(PPh3)2 (106 mg, 0.151 mmol) in 1 , 4-dioxane using the similar procedure as described in the synthesis of compound 41.2. 1H-NMR (400MHz, MeOH-Cf4) δ ppm 9.17 (s, 1 H), 8.91 (d, 1 H), 8.65 (s, 1 H), 8.43 (d, 1 H), 8.28 (q, 2H), 7.96 (d, 1 H), 7.92 (m, 1 H), 2.61 (s, 3H). LCMS (method B): [MH]+ = 340.1 , tR = 2.16 min.
(£)-1 -(3-(Dif luoro(quinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O- 2-hydroxyethyl oxime (example 50)
A solution of 1 -(3-(difluoro(quinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (54 mg, 0.159 mmol) and 2-(aminooxy)ethanol (intermediate S) (36.1 mg, 0.318 mmol) in 8 mL of MeOH was stirred at rt overnight. Solvent was evaporated and the residue was partitioned between water and EtOAc. Aqueous layer was extracted with EtOAc twice. Organic layers were combined, washed with brine and dried over Na2SO4. Solvent was evaporated and the crude was purified by HPLC (basic with 0.05% NH4OH) to give 35 mg (55%) of the title compound as a white solid. 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.98 (d, 1 H), 8.52 (d, 1 H), 8.43 (s, 1 H), 8.23 (d, 1 H), 8.19 (d, 1 H), 8.06 (d, 1 H), 8.04 (d, 1 H), 7.66(m, 1 H), 4.36 (m, 2H), 3.84 (m, 2H), 2.18 (s, 3H). LCMS (method B): [MH]+ = 398.9, tR = 2.29 min.
Example 51 (example 51 -R, example 51 -S)
(£)-1 -(3-(1 -(4,6-Dif luoro-1 -methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone O-2-hydroxyethyl oxime
Figure imgf000115_0001
1 -(6-Chloro-imidazo[1 ,2-b]pyridazin-3-yl)-1 -(4,6-dif luoro-1 -methyl-1 H-indazol-5-yl)- ethanol (51.1)
To a solution of 4, 6-difluoro-1 -methyl-1 H-indazole (intermediate P) (600 mg, 3.57 mmol) in anhydrous THF (20 mL) at -780C was added n-Buϋ (1.6M solution in hexane, 2.56 mL, 4.1 mmol). The solution was stirred at this temperature for 1 h and then a solution of 1 -(6-chloro- imidazo[1 ,2-b]pyridazin-3-yl)-ethanone (intermediate M) (698mg, 3.57 mmol) in anhydrous THF (10 mL) was added dropwise. The resulting solution was stirred at this temperature for 3 h and allowed to warm to rt slowly and stirred overnight. The reaction mixture was quenched with water, extracted with EtOAc three times. The organic layers were combined and washed with brine, dried over Na2SO4. The crude was purified by flash chromatography (DCM: MeOH = 95:5) to give 530 mg (41%) of the title compound as yellow oil. 1H-NMR (400MHz, CDCI3) δ ppm 8.05 (d, 1 H), 8.0 (s, 1 H), 7.85 (s, 1 H), 7.1 (d, 1 H), 6.85 (d, 1 H), 4.0(s, 3H), 2.3(s, 3H). LCMS (method B): [MH]+ = 363.9, tR = 2.15 min. 6-Chloro-3-[1 -(4,6-dif luoro-1 -methyl-1 H-indazol-5-yl)-ethyl]-imidazo[1 ,2-b]pyridazine (51.2)
A solution of 1 -(6-chloro-imidazo[1 ,2-b]pyridazin-3-yl)-1 -(4, 6-difluoro-1 -methyl-1 H-indazol-5- yl)-ethanol (530 mg, 1 .457 mmol), Iodine (925 mg, 3.64 mmol) and phosphinic acid (50%, 0.556 ml_) in 20 ml_ of acetic acid was heated at 1 1 O0C for 2 h. Solvent was evaporated and the residue was dissolved in water, neutralized with saturated NaHCO3 solution and extracted with DCM three times. Organic layers were combined and washed with brine, dried over Na2SO4. Solvent was then evaporated and the crude was purified by flash chromatography (hexane: EtOAc = 1 :2) to give the title compound as light yellow solid (320mg, 63.2%). 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.03 (s, 1 H), 8.0 (d, 1 H), 7.8 (s, 1 H), 7.23 (d, 1 H), 7.19 (d, 1 H), 5.1 (q, 1 H), 4.0(s, 3H), 1 .92 (d, 3H). LCMS (method B): [MH]+ = 347.9, tR = 2.69 min.
3-[1-(4,6-Dif luoro-1 -methyl-1 H-indazol-5-yl)-ethyl]-6-(1-ethoxy-vinyl)-imidazo[1 ,2- b]pyridazine (51.3)
A solution of 6-chloro-3-[1 -(4, 6-difluoro-1 -methyl-1 H-indazol-5-yl)-ethyl]-imidazo[1 , 2- b]pyridazine (80 mg, 0.23 mmol) and tributyl(1 -ethoxyvinyl)stannane (0.234 ml_, 0.69 mmol) in 15 ml_ of DMF was purged with N2 for 30min and then Pd(PPh3)4 (80 mg, 0.069 mmol) was added and the solution was heated at 950C overnight. After the reaction was complete, it was quenched with water, extracted with EtOAc three times. The organic layers were combined, washed with KF solution then brine, dried over Na2SO4. Solvent was evaporated and the crude (80mg, 90%) was used in the next step without further purification. LCMS (method C): [MH]+ = 384.0, tR = 4.67 min 1 -(3-(1 -(4,6-Dif luoro-1 -methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone (51.4)
2 mL of 3N HCI solution was added to a solution of 3-[1 -(4, 6-difluoro-1 -methyl-1 H-indazol-5- yl)-ethyl]-6-(1 -ethoxy-vinyl)-imidazo[1 ,2-b]pyridazine in 10 mL of MeOH. The reaction solution was stirred at rt for 3 h and then neutralized with saturated NaHCO3 solution. Solvent was evaporated and the residue was purified by chromatography (DCM: MeOH = 10:1 ) to give the title compound as yellow solid (30mg, 41%). LCMS (method C): [MH]+ = 355.9, tR = 3.75 min (£)-1 -(3-(1 -(4,6-Dif luoro-1 -methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone O-2-hydroxyethyl oxime (example 51 , example 51 -R, example 51 -S)
A solution of 1 -(3-(1 -(4, 6-difluoro-1 -methyl-1 H-indazol-5-yl)ethyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone (1 10 mg, 0.31 mmol) and 2-(aminooxy)ethanol (intermediate S) (35.1 mg, 0.31 mmol) in 1 OmL of MeOH was stirred at rt overnight. Solvent was evaporated and the residue was partitioned between water and EtOAc. Aqueous layer was extracted with EtOAc twice. Organic layers were combined, washed with brine and dried over Na2SO4. Solvent was evaporated and the crude was purified by HPLC (basic with 0.05% NH4OH) to give 55 mg (43%) of the title compound as white solid. 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.01 (s, 1 H), 7.88 (d, 1 H), 7.78 (s, 1 H), 7.76 (s, 1 H), 7.16 (d, 1 H), 5.16 (m, 1 H), 4.29 (m, 2H), 3.99 (s, 3H), 3.82 (m, 2H), 2.17 (s, 3H), 1 .95 (d, 3H). LCMS (method B): [MH]+ = 415.0, tR = 2.64 min. Chiral separation (method G) provided enantiomeric pure compounds example 51 -R and example 51 -S.
Example 52
(£)-1 -(3-((4,6-Dif luoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone O-2-hydroxyethyl oxime
Figure imgf000117_0001
(6-Chloroimidazo[1 ,2-b]pyridazin-3-yl)(4,6-dif luoro-1 -methyl-1 H-indazol-5-yl)methanol (52.1)
The title compound as a yellow solid (60 mg, 41%) was synthesized from (intermediate P) (70 mg, 0.416 mmol) and 6-chloroimidazo[1 ,2-b]pyridazine-3-carbaldehyde (intermediate N) (76 mg, 0.416 mmol) using the same procedure as described in the synthesis of compound 51.1. 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.08 (s, 1 H), 8.03 (d, 1 H), 7.85(s, 1 H), 7.26 (q, 2H), 6.76 (s, 1 H), 4.03 (s, 3H). LCMS (method B): [MH]+ = 349.9, tR = 2.12 min. 6-Chloro-3-((4,6-dif luoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazine (52.2)
The title compound as a light yellow solid (370 mg, 78%) was synthesized from (6- chloroimidazo[1 ,2-b]pyridazin-3-yl)(4,6-difluoro-1 -methyl-1 H-indazol-5-yl)methanol (500 mg, 1 .43 mmol), iodine (907 mg, 3.57 mmol) and phosphinic acid (50%, 0.55 ml_) using the same procedure as described in the synthesis of compound 51.2. 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.07(s, 1 H), 8.01 (d, 1 H), 7.44 (s, 1 H), 7.29 (d, 1 H), 7.27 (d, 1 H), 4.46 (s, 2H), 4.04 (s, 3H). LCMS (method B): [MH]+ = 333.9, tR = 2.68 min.
1 -(3-((4,6-Dif luoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone (52.3)
The title compound as a light yellow solid (350 mg, 71.3%) was synthesized from 6-chloro-3- ((4,6-difluoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazine (360 mg, 1.079 mmol), tributyl(1 -ethoxyvinyl)stannane (1 .095 ml_, 3.24 mmol) and Pd(PPh3)4 (374 mg, 0.324 mmol) using the same procedure as described in the synthesis of compound 51.3 and 51.4. 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.09 (s, 1 H), 8.07 (s, 1 H), 7.78 (d, 1 H), 7.71 (s, 1 H), 7.26 (d, 1 H), 4.59 (s, 2H), 4.02 (s, 3H), 2.74 (s, 3H). LCMS (method B): [MH]+ = 342.0, tR = 2.39 min.
(£)-1 -(3-((4,6-Dif luoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone 0-2-hydroxyethyl oxime (example 52)
A solution of 1 -(3-((4,6-difluoro-1 -methyl-1 H-indazol-5-yl)methyl)imidazo[1 ,2-b]pyridazin-6- yl)ethanone (62 mg, 0.136 mmol) and 2-(aminooxy)ethanol (intermediate S) (77 mg, 0.681 mmol) in 3 mL of MeOH and 2 mL of DCM was stirred at rt for 2 days. Solvent was evaporated to give a residue, which was purified by chromatography (DCM:MeOH 10:1 ) and recrystalized from MeOH to give the title compound as a white solid (32mg, 59%). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.16 (s, 1 H), 8.04 (d, 1 H), 7.62 (t, 2H), 7.48 (d, 1 H), 4.44 (s, 2H), 4.24 (t, 2H), 4.00 (s, 3H), 3.68 (m, 2H), 2.29 (s, 3H). LCMS (method E): [MH]+ = 401 .1 , tR = 5.591 min.
Example 53 (example 53-S and example 53- R)
(£)-1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-2-hydroxyethyl oxime
Figure imgf000119_0001
2-(5,7-Difluoro-quinolin-6-yl)-propionic acid methyl ester (53.1)
To a solution of LDA (1 .2 M in THF, 9.5 ml_, 1 1.4 mmol) in dry THF (30 ml_) at -78 0C was added a solution of (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester (2.12 g, 9.5 mmol) in THF (20 ml_) dropwise. After 30 min, MeI (0.9 ml_, 14.2 mmol) was added dropwise, and the reaction mixture was allowed to rise to O 0C naturally. After 1 h, the reaction was quenched by saturated aqueous NaHCO3 solution, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to afford 2.272 g (95%) of the title compound as a pale yellow solid. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.93 (d, 1 H), 8.39 (dd, 1 H), 7.61 (dd, 1 H), 7.41 -7.46 (m, 1 H), 4.29 (q, 1 H), 3.73 (s, 3H), 1 .62 (d, 3H). LCMS (method A): [MH]+ = 252, tR = 5.09 min. (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester was synthesized using the method described in WO2008/144767 p108 (intermediate 2), followed by the method described for Intermediate 12, step 1 WO2008/144767 p1 14.
2-(5,7-Difluoro-quinolin-6-yl)-propionic acid hydrazide (53.2)
2-(5,7-Difluoro-quinolin-6-yl)-propionic acid methyl ester (2.270 g, 9.57 mmol) in ethanol (25 mL) was added hydrazine monohydrate (3 mL, 96 mmol), and the reaction mixture was stirred at 25 0C overnight. Solvent was removed under reduced pressure, and the residue was used without further purification. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.06 (s, 1 H), 8.97 (dd, 1 H), 8.45 (d, 1 H), 7.58-7.67 (m, 2H), 4.23 (br s, 2H), 4.08 (q, 1 H), 1 .51 (d, 3H). LCMS (method A): [MH]+ = 252, tR = 3.82 min.
6-[1-(6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (53.3) A solution of 2-(5,7-difluoro-quinolin-6-yl)-propionic acid hydrazide (2.404 g, 9.404 mmol) and 3,6-dichloropyridazine (2.138 g, 14.35 mmol) in butan-1 -ol (60 ml_) was stirred at 135 0C in a sealed tube overnight. Solvent was removed under reduced pressure, and the residue was purified by column chromatography to afford 1 .476 g (45% for two steps) of the title compound as a pale yellow solid. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.93 (dd, 1 H), 8.36 (dd, 1 H), 8.07 (d, 1 H), 7.62 (dd, 1 H), 7.43 (dd, 1 H), 7.05 (d, 1 H), 5.26 (q, 1 H), 2,13 (d, 1 H). LCMS (method A): [MH]+ = 346, tR = 5.00 min.
6-{1-[6-(1-Ethoxy-vinyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]-ethyl}-5,7-difluoro-quinoline (53.4)
A solution of 6-[1 -(6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (1.500 g, 4.34 mmol) in dioxane (60 mL) was purged with argon for 3 min, followed by addition of tributyl-(1 -ethoxy-vinyl)-stannane (2.2 mL, 6.51 mmol) and PdCI2(PPh3)2 (150 mg, 0.21 mmol) sequentially. The mixture was purged with argon for another half min. The reaction mixture was stirred at 80-85 0C for 6 h under argon. LC/MS showed the reaction was complete. The reaction mixture was diluted with EtOAc, washed successively with aqueous KF solution (2x25 mL), water, and brine. The organic phase was dried over anhydrous Na2SO4, concentrated to give the crude title compound, which was used without further purification. LCMS (method A): [MH]+ = 382, tR = 5.05 min. 1-{3-[1-(5,7-Difluoro-quinolin-6-yl)-ethyl]-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl}-ethanone (53.5)
The crude 6-{1 -[6-(1 -ethoxy-vinyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]-ethyl}-5,7-difluoro- quinoline obtained from the previous step was dissolved in HOAc (50 mL), 3N HCI aqueous solution (5 mL) was added. The reaction mixture was stirred at rt overnight. LC/MS showed the reaction was complete. Solvent was removed under reduced pressure. EtOAc was added, and cold 1 N NaOH aqueous solution was added slowly until pH 8-9. The mixture was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to afford 1.0 g (65% for two steps) of the title compound as a white solid. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.92 (dd, 1 H), 8.32 (d, 1 H), 8.14 (d, 1 H), 7.68 (d, 1 H), 7.61 (d, 1 H), 7.42 (dd, 1 H), 5.32 (q, 1 H), 2.43 (s, 3H), 2.21 (d, 3H). LCMS (method A): [MH]+ = 354, tR = 4.42 min.
(£)-1 -(3-(1 -(5,7-Dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-2-hydroxyethyl oxime (example 53)
To a suspension of 1 -{3-[1 -(5,7-difluoro-quinolin-6-yl)-ethyl]-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl}-ethanone (4.2 g, 1 1.9 mmol) in methanol (250 ml_) was added 2-(aminooxy)ethanol hydrochloride (intermediate S) (2.70 g, 23.8 mmol). The mixture was stirred at rt overnight. LC-MS showed the reaction was complete. An aqueous 1 N NaOH solution was added slowly until pH 8-9. The mixture was concentrated, extracted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by gradient column chromatography (EtOAc:hexane = 2:1 , then 100% EtOAc, and then MeOH:EtOAc = 1 :12 as eluent) to afford 4.8 g (98%) of the title compound as a white solid. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.97 (dd, 1 H), 8.44 (m, 1 H), 8.25 (d, 1 H), 7.64- 7.70 (m, 2H), 7.59 (dd, 1 H), 5.25 (q, 1 H), 4.70 (t, 1 H), 4.19 (t, 2H), 3.62 (dd, 2H), 2.02 (d, 3H), 1 .88 (s, 3H). LCMS (method A): [MH]+ = 413, tR = 5.09 min.
(£)-1 -(3-(1 -(5,7-Dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-2-hydroxyethyl oxime (example 53-S and example 53-R)
The title compounds were obtained by separation of racemic mixture (£)-1 -(3-(1 -(5,7- difluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-2-hydroxyethyl oxime (4.2 g) with Method I. Data for example 53-S (1 .5 g): 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.96 (d, 1 H), 8.44 (d, 1 H), 8.25 (d, 1 H), 7.64-7.71 (m, 2H), 7.59 (dd, 1 H), 5.25 (q, 1 H), 4.70 (t, 1 H), 4.19 (t, 2H), 3.62 (dd, 2H), 2.02 (d, 3H), 1.88 (s, 3H). LCMS (method A): [MH]+ = 413, tR=5.09 min. Data for example 53-R (1 .6 g): 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.96 (d, 1 H), 8.44 (d, 1 H), 8.25 (d, 1 H), 7.64-7.71 (m, 2H), 7.59 (dd, 1 H), 5.25 (q, 1 H), 4.70 (t, 1 H), 4.19 (t, 2H), 3.62 (dd, 2H), 2.02 (d, 3H), 1 .88 (s, 3H). LCMS (method A): [MH]+ = 413, tR = 5.09 min. Example 54
(£)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-2-hydroxyethyl oxime
Figure imgf000122_0001
The title compound was prepared using the same procedure as described in the synthesis of example 53. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.00 (d, 1 H), 8.50 (d, 1 H), 8.27 (d, 1 H), 7.72-7.76 (m, 2H), 7.63 (dd, 1 H), 4.78 (s, 3H), 4.27 (t, 2H), 3.69 (t, 2H), 2.20 (s, 3H). LCMS (method A): [MH]+ = 399, tR = 4.86 min.
Example 55
(£)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-2-fluoroethyl oxime
-j Q
Figure imgf000122_0002
To a solution of (£)-1 -(3-((5,7-difluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethanone 0-2-hydroxyethyl oxime (example 54) (20 mg, 0.05 mmol) in dry DCM (4 ml_) was added bis-(2-methoxyethyl)aminosulfur trifluoride (a 3.2 M solution in toluene, 0.13 ml_, 0.4 mmol) at 0 0C. The reaction mixture was stirred at 0 0C for 1 h, and then at 35 0C
15 overnight. LC-MS showed the reaction was complete, and 5 mL of saturated NaHCO3 solution was added. The mixture was extracted with DCM; the organic phase was dried over Na2SO4, filtered, concentrated, and purified by column chromatography to afford 6.8 mg (34%) of the title compound as a white solid. 1H-NMR (400MHz, CDCI3) δ ppm 8.95 (dd, 1 H), 8.41 (dd, 1 H), 8.00 (d, 1 H), 7.81 (d, 1 H), 7.66 (d, 1 H), 7.46 (dd, 1 H), 4.83 (s, 2H), 4.78 (dd,
20 1 H), 4.67 (dd, 1 H), 4.56 (dd, 1 H), 4.49 (dd, 1 H), 2.33 (s, 3H). LCMS (method A): [MH]+ = 401 , tR = 5.44 min.
Example 56
(£)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone
25 O-3-hydroxypropyl oxime
Figure imgf000123_0001
The title compound was prepared using the same procedure as described in the synthesis of example 53. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.99 (dd, 1 H), 8.49 (dd, 1 H), 8.26 (d, 1 H), 7.72-7.75 (m, 2H), 7.62 (dd, 1 H), 4.76 (s, 2H), 4.52 (t, 1 H), 4.32 (t, 2H), 3.48-3.53 (m, 2H), 2.18 (s, 3H), 1 .80-1 .88 (m, 2H). LCMS (method A): [MH]+ = 413, tR = 5.21 min.
Example 57
(£)-1-(3-((7-Fluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O- 2-hydroxyethyl oxime
Figure imgf000123_0002
The title compound was prepared using the same procedure as described in the synthesis of example 53. 1H-NMR (400MHz, DMSO-c/6) δ ppm 8.89 (d, 1 H), 8.36 (d, 1 H), 8.29 (d, 1 H), 8.06 (d, 1 H), 7.74-7.81 (m, 2H), 7.51 (dd, 1 H), 4.77 (s, 3H), 3.68-3.70 (m, 2H), 2.23 (s, 3H). LCMS (method A): [MH]+ = 381 , tR = 4.66 min.
Example 58
(£)-1-(3-((5-Fluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O- 2-hydroxyethyl oxime
Figure imgf000123_0003
The title compound was prepared using the same procedure as described in the synthesis of example 53. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.95 (d, 1 H), 8.50 (d, 1 H), 8.27 (d, 1 H), 7.85 (d, 1 H), 7.70-7.81 (m, 2H), 7.63 (dd, 1 H), 4.78 (s, 2H), 4.26 (t, 2H), 4.09 (s br, 1 H), 3.68-3.69 (m, 2H), 2.23 (s, 3H). LCMS (method A): [MH]+ = 381 , tR = 5.05 min.
Example 59
(£)-1 -(3-(1 -(Quinolin-6-yl)cyclopropyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O- ethyl oxime
Figure imgf000124_0001
examplθ 59 59.4 59.3
Methyl i-tquinolin-θ-yOcyclopropanecarboxylate (59.1)
LDA (1.8 M solution in toluene, 14.8 mL, 26.6 mmol) was added dropwise to a solution of quinolin-6-yl-acetic acid methyl ester (2.14 g, 10.64 mmol) in dry THF (40 mL) under nitrogen at -78 0C. After 30 min, 1 ,2-dibromoethane (2.40 g, 12.76 mmol) was added dropwise over 3 min. The resulting mixture was stirred for 1 h at rt, then quenched with saturated aqueous NH4CI, extracted with DCM, washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane gradient to afford the title compound as a yellow solid (463 mg, 20%). 1H- NMR (400 MHz, CDCI3) δ ppm 8.91 (dd, 1 H), 8.12 (d, 1 H), 8.07 (d, 1 H), 7.77-7.74 (m, 2H), 7.40 (dd, 1 H), 3.65 (s, 3H), 1.73-1 .71 (m, 2H), 1.33-1 .30 (m, 2H). LCMS (method A): [MH]+ = 228, tR = 4.37 min.
1 -(Quinolin-6-yl)cyclopropanecarbohydrazide (59.2)
A solution of methyl 1 -(quinolin-6-yl)cyclopropanecarboxylate (513 mg, 2.26 mmol) and hydrazine monohydrate (3.39 g, 67.7 mmol) in 5 mL of methanol was heated at reflux overnight. After cooling, solvent was removed in vacuo to afford the title compound (513 mg, 100%). LCMS (method A): [MH]+ = 228, tR = 2.88 min.
6-(1-(6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)cyclopropyl)quinoline (59.3) A sealed tube was charged with i -tøuinolin-θ-yOcyclopropanecarbohydrazide (513 mg, 2.26 mmol), 3,6-dichloro-pyridazine (437 mg, 2.93 mmol) and 5 ml_ of n-butanol. The mixture was heated at 140 0C for 12 h. After cooling, solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound (196 mg, 41 %). LCMS (method A): [MH]+ = 322, tR = 4.38 min.
1 -(3-(1 -(Quinolin-θ-yOcyclopropylHI ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (59.4)
A mixture of 6-[1 -(6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)-cyclopropyl]-quinoline (30 mg, 0.093 mmol), PdCI2(PPh3)2 (6.5 mg, 0.0093 mmol) and tributyl(1 -ethoxyvinyl)stannane (67 mg, 0.186 mmol) in 3 ml_ of 1 ,4-dioxane was heated at 90 0C for 3 h under nitrogen. The reaction mixture was diluted with EtOAc, washed with aqueous KF. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCI, and the solution was stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/MeOH gradient to afford the title compound as a yellow solid. 1H-NMR (400 MHz, CDCI3) δ ppm 8.89 (dd, 1 H), 8.13-8.04 (m, 3H), 7.93 (d, 1 H), 7.87 (dd, 1 H), 7.70 (d, 1 H), 7.40 (dd, 1 H), 2.51 (s, 3H), 1.92-1 .89 (m, 2H), 1.73-1 .69 (m, 2H). LCMS (method A): [MH]+ = 330, tR = 4.18 min.
(£)-1 -(3-(1 -(Quinolin-θ-yOcyclopropylHI ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O- ethyl oxime (example 59)
A solution of 1 -(3-(1 -(quinolin-6-yl)cyclopropyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (30 mg, 0.09 mmol) and O-ethyl-hydroxylamine hydrochloride (18 mg, 0.18 mmol) in 2 mL of
DCM was stirred at 40 0C overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, CDCI3) δ ppm 8.84 (d, 1 H), 8.29 (d,
1 H), 8.25 (d, 1 H), 7.92-7.91 (m, 2H), 7.72-7.68 (m, 2H), 7.49 (dd, 1 H), 4.26 (q, 2H), 2.01 (s, 3H), 1 .76 (s, 2H), 1.66 (s, 2H), 1 .27 (t, 3H). LCMS (method A): [MH]+ = 373, tR = 5.56 min.
Example 60
(£)-1 -(3-(1 -(Quinolin-θ-yOcyclopropylHI ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-2- hydroxyethyl oxime
Figure imgf000126_0001
A solution of 1 -(3-(1 -(quinolin-θ-yOcyclopropylHI ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone
(30 mg, 0.09 mmol) (59.4) and 2-aminooxy-ethanol hydrochloride (intermediate S) (14 mg,
0.18 mmol) in 4 ml_ of DCM and 0.5 ml_ of acetic acid was stirred at 40 0C overnight. The
5 solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with a EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, DMSO-Cf6) δ ppm 8.84 (t, 1 H), 8.30 (d, 1 H), 8.25 (d, 1 H),
7.93-7.91 (m, 2H), 7.71 -7.68 (m, 2H), 7.51 (dd, 1 H), 4.73 (t, 1 H), 4.23 (t, 2H), 3.65 (q, 2H),
2.02 (s, 3H), 1.78-1 .75 (m, 2H), 1 .68-1.64 (m, 2H). LCMS (method A): [MH]+ = 389, tR = 4.55
10 min.
Example 61
(£)-2-(1-(3-(Quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylidene- aminooxy)acetamide
-| 5
Figure imgf000126_0002
A microwave tube was charged with 2-(1 ,3-dioxoisoindolin-2-yloxy)acetamide (intermediate V) (166 mg, 0.76 mmol), hydrazine monohydrate (34.4 mg, 0.69 mmol) and 2 ml_ of methanol. It was heated at 95 0C for 12 h under microwave irradiation. After cooling, solid was removed by filtration and the solution was concentrated under reduced pressure.
20 The residue was diluted with methanol, then 1 -(3-(quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3- b]pyridazin-6-yl)ethanone (41.2) (32 mg, 0.105 mmol) and 0.3 ml_ of acetic acid were added and the mixture was stirred at 40 0C overnight. After concentration, the residue was purified by prep-HPLC to afford the title compound. 1H-NMR (400 MHz, DMSO-Cf6) δ ppm 8.86 (dd, 1 H), 8.33-8.27 (m, 2H), 7.98-7.95 (m, 2H), 7.78 (dd, 1 H), 7.69 (d, 1 H), 7.50 (dd, 1 H), 7.31 (d,
25 2H), 4.77 (s, 2H), 4.63 (s, 2H), 2.32 (s, 3H). LCMS (method A): [MH]+ = 376, tR = 4.02 min.
Example 62 (example 62-S and example 62-R) (£)-1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O- 2-hydroxyethyl oxime
Figure imgf000127_0001
2-(7-Fluoroquinolin-6-yl)propanehydrazide (62.1)
A solution of methyl 2-(7-fluoroquinolin-6-yl)propanoate (756 mg, 3.24 mmol) and hydrazine monohydrate (1 .5 ml_) in methanol (5 ml_) was heated at 50 0C overnight. After cooling, the solvent was removed in vacuo to afford the title compound (756 mg, 100%) which was used without further purification. LCMS (method A): [MH]+ = 234, tR = 3.14 min.
6-(1-(6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (62.2)
A sealed tube was charged with 2-(7-fluoroquinolin-6-yl)propanehydrazide (1 1.4 g, 48.9 mmol), 3,6-dichloro-pyridazine (8.01 g, 53.8 mmol) and 190 ml_ of n-butanol. The mixture was heated at 140 0C for 12 h. After cooling, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound (7.1 g, 44%). 1H-NMR (400 MHz, DMSO-Cf6) δ ppm 8.95 (d, 1 H), 8.49-8.46 (m, 2H), 7.96 (d, 1 H), 7.84 (d, 1 H), 7.58 (dd, 1 H), 7.48 (dd, 1 H), 5.17 (q, 1 H), 1 .88 (d, 3H). LCMS (method A): [MH]+ = 328, tR = 5.00 min. 1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (62.3)
A mixture of 6-(1 -(6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (100 mg, 0.305 mmol), PdCI2(PPh3)2 (21 .4 mg, 0.031 mmol) and tributyl(1 -ethoxyvinyl)stannane (220 mg, 0.61 mmol) in 5 mL of 1 ,4-dioxane was heated at 90 0C for 5 h under nitrogen. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCI, and stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/MeOH gradient to afford the title compound as a yellow solid. 1H-NMR (400 MHz, CDCI3) δ ppm 8.87 (d, 1 H), 8.16 (d, 1 H), 8.03 (d, 1 H), 7.80 (d, 1 H), 7.73 (d, 2H), 34 (dd, 1 H), 5.39 (q, 1 H), 2.62 (s, 3H), 2.09 (d, 3H). LCMS (method A): [MH]+ = 336, tR = 4.95 min.
(£)-1-(3-(1-(7-Fluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O- 2-hydroxyethyl oxime (example 63, example 62-S, example 62-R)
The title compounds as a racemic mixture were prepared using the same procedure as described in the synthesis of example 53. Data for the racemic mixture example 63: 1H- NMR (400 MHz, CDCI3) δ ppm 8.88 (d, 1 H), 8.1 1 (d, 1 H), 8.00 (d, 1 H), 7.86 (d, 1 H), 7.75 (d, 2H), 7.38 (dd, 1 H), 5.36 (q, 1 H), 4.38 (t, 2H), 3.93 (s, 3H), 2.24 (s, 3H), 2.06 (d, 3H). LCMS (method A): [MH]+ = 395, tR = 4.89 min.
The enantiomeric components of this racemic mixture were separated with method H: example 62-S, tR = 9.293 min and example 62-R, tR = 1 1.519 min.
Example 63
(£)-1-(3-((3-(4-Methylpiperazin-1-yl)quinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin- 6-yl)ethanone O-2-hydroxyethyl oxime
Figure imgf000128_0001
Methyl 2-(3-(4-methylpiperazin-1-yl)quinolin-6-yl)acetate (63.1)
A solution of methyl 2-(3-bromoquinolin-6-yl)acetate (1 .0 g, 3.57 mmol), 1 -methylpiperazine
(0.429 g, 4.28 mmol), Pd2(dba)3 (65 mg, 0.071 mmol), BINAP (133 mg, 0.214 mmol) and Cs2CO3 (1 .628 g, 5.00 mmol) in 10 mL of toluene was heated at 100 0C for 18 h. After cooling, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography in silica gel eluting with a EtOAC/hexane gradient to afford 599 mg (56%) of the title compound as a yellow solid. 1H- NMR (400MHz, CDCI3) δ ppm 8.77 (s, 1 H), 7.94 (d, 1 H), 7.57 (s, 1 H), 7.42 (d, 1 H), 7.30 (s, 1 H), 3.78 (s, 2H), 3.72 (s, 3H), 3.41 -3.33 (m, 4H), 2.65-2.63 (m, 4H), 2.39 (s, 3H). LCMS (method A): [MH]+ = 300, tR = 2.06 min.
2-(3-(4-Methylpiperazin-1-yl)quinolin-6-yl)acetohydrazide (63.2)
The title compound was prepared using the same procedure as described in the synthesis of
53.2. LCMS (method A): [MH]+ =300, tR = 1 .30 min.
6-((6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-3-(4-methylpiperazin-1- yl)quinoline (63.3)
The title compound was prepared using the same procedure as described in the synthesis of
53.3. 1H-NMR (400MHz, CDCI3) δ ppm 8.75 (d, 1 H), 8.05 (d, 1 H), 7.92 (d, 1 H), 7.68 (d, 1 H), 7.56 (dd, 1 H), 7.28 (s, 1 H), 7.10 (d, 1 H), 4.70 (s, 2H), 3.33-3.30 (m, 4H), 2.65-2.63 (m, 4H),
2.39 (s, 3H). LCMS (method A): [MH]+ = 394, tR = 2.679 min.
1-(3-((3-(4-Methylpiperazin-1-yl)quinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethanone (63.4)
The title compound was prepared using the same procedure as described in the synthesis of 53.4 and 53.5. LCMS (method A): [MH]+ = 402, tR = 2.506 min.
(£)-1-(3-((3-(4-Methylpiperazin-1-yl)quinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin- 6-yl)ethanone O-2-hydroxyethyl oxime (example 63)
The title compound was prepared using the same procedure as described in the synthesis of example 53. 1H-NMR (400MHz, CDCI3) δ ppm 8.74 (d, 1 H), 7.96 (d, 1 H), 7.90 (d, 1 H), 7.74 (d, 1 H), 7.66 (s, 1 H), 7.56 (dd, 1 H), 7.23 (d, 1 H), 4.72 (s, 2H), 4.40 (t, 2H), 3.95 (t, 2H), 3.30 (t, 4H), 2.63 (t, 4H), 2.38 (s, 3H), 2.32 (s, 3H). LCMS (method A): [MH]+ = 461 , tR = 2.965 min.
Example 64
(£)-1 -(3-(1 -(5,7-Dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone
O-2-methoxyethyl oxime
Figure imgf000130_0001
A solution of (£)-1 -(3-((5,7-difluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethanone 0-2-hydroxyethyl oxime (31 .0 mg, 0.078 mmol) (example 54), sodilum hydride (6.85 mg, 0171 mmol) and iodomethane (221 mg, 1 .556 mmol) in 5 ml_ of THF and 0.5 ml_ of DMF was stirred at rt for 3 h. The reaction was quenched by addition of 3 ml_ of methanol slowly. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, DMSO-Cf6) δ ppm 8.97 (dd, 1 H), 8.45 (dd, 1 H), 8.26 (d, 1 H), 7.70-7.65 (m, 2H), 7.60 (dd, 1 H), 5.26 (q, 1 H), 4.30 (dd, 2H), 3.58 (dd, 2H), 3.23 (s, 3H), 2.02 (d, 3H), 1 .88 (s, 3H). LCMS (method A): [MH]+ = 427, tR = 5.50 min.
Example 65
(£)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-4-hydroxybutyl oxime
Figure imgf000130_0002
The title compound was prepared using the same procedure as described in the synthesis of example 53. 1H-NMR (400 MHz, CDCI3) δ ppm 8.93 (dd, 1 H), 8.39-8.36 (m, 1 H), 7.98 (d, 1 H), 7.82 (d, 1 H), 7.62 (d, 1 H), 7.43 (dd, 1 H), 4.81 (s, 2H), 4.32 (t, 2H), 3.73-3.69 (m, 2H), 2.26 (s, 3H), 1 .88-1.81 (m, 2H), 1.73-1 .66 (m, 2H). LCMS (method A): [MH]+ = 427, tR = 4.839 min.
Example 66
(£)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone 0-4-fluorobutyl oxime
Figure imgf000131_0001
To a solution of (£)-1 -(3-((5,7-difluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethanone 0-4-hydroxybutyl oxime (30 mg, 0.070 mmol) (example 65) in 4 ml_ of DCM at - 78 0C was added bis(2-methoxyethyl)aminosulfur trifluoride (180 mg, 0.813 mmol). The mixture was stirred at this temperature for 1 h, and stirred at rt overnight. The mixture was poured into saturated aqueous NaHCO3, extracted with DCM, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with DCM/methanol afforded the title compound. 1H-NMR (400 MHz, CDCI3) δ ppm 8.94 (s, 1 H), 8.37 (d, 1 H), 7.98 (d, 1 H), 7.81 (d, 1 H), 7.63 (d, 1 H), 7.44 (dd, 1 H), 4.81 (s, 2H), 4.58-4.57 (m, 1 H), 4.45 (t, 1 H), 4.32 (t, 2H), 2.26 (s, 3H), 1.90-1.78 (m, 4H). LCMS (method A): [MH]+ = 429, tR = 5.239 min.
Example 67
(£)-1 -(6-((6-((E)-I -(2-Hydroxyethoxyimino)ethyl)-1 W-[1 ,2,3]triazolo[4,5-b]pyrazin-1 - yl)methyl)quinolin-3-yl)ethanone 0-2-hydroxyethyl oxime
Figure imgf000131_0002
(3-Bromo-quinolin-6-yl)-methanol (67.1 )
To a stirred solution of methyl 3-bromo-quinoline-6-carboxylate (1 .09 g, 4 mmol) in THF (50 ml_) at 0 0C was added LiAIH4 (0.155 g, 4 mmol) in small portions. The resulting mixture was stirred at 0 0C for 0.5 h. Water (0.2 ml_) was added dropwise, followed by 0.2 ml_ of 10% aq. NaOH and 0.2 ml_ of water. The solid was removed and the solvent was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane gradient to afford the title compound (413 mg, 42%). LCMS (method A): [MH]+ = 238/240, tR = 4.453 min. 2-(3-Bromo-quinolin-6-ylmethyl)-isoindole-1 ,3-dione (67.2)
To a solution of phthalimide (281 mg, 1 .9 mmol), triphenyl phosphine (500 mg, 1 .9 mmol) in 10 mL of THF was added DIAD (386 mg, 1 .9 mmol) dropwise at 0 0C and the mixture was stirred at this temperature for 10 min. (3-Bromo-quinolin-6-yl)-methanol (413 mg, 1 .7 mmol) was added to the above solution in one portion and the resulting solution was stirred at rt for 30 min, then heated at 40 0C for 5 h. After cooling, the reaction mixture was taken up with EtOAc, washed with water, extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane gradient to afford the title compound. 1H-NMR (400 MHz, CDCI3) δ ppm 8.89 (d, 1 H), 8.31 (d, 1 H), 8.06 (d, 1 H), 7.90-7.86 (m, 3H), 7.82-7.73 (m, 3H), 5.04 (s, 2H). LCMS (method A): [MH]+ = 368/370, tR = 5.54 min.
(3-Bromoquinolin-6-yl)methanamine (67.3)
A solution of 2-(3-Bromo-quinolin-6-ylmethyl)-isoindole-1 ,3-dione (635 g, 1.73 mmol) in 15 mL of methanol and 1 mL of hydrazine monohydrate was heated at 80 0C for 2 h. After cooling, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. LCMS (method A): [MH]+ = 237/239, tR = 2.795 min.
6-Bromo-N2-((3-bromoquinolin-6-yl)methyl)pyrazine-2,3-diamine (67.4)
A microwave tube was charged with (3-bromoquinolin-6-yl)methanamine (237 mg, 1.0 mmol), 3,5-dibromopyrazin-2-amine (253 mg, 1 .0 mmol), DIPEA (0.6 mL) and 5 mL of ethanol. The tube was heated at 120 0C under microwave irradiation for 15 h. After cooling, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with DCM/methanol gradient to afford the title compound. LCMS (method E): [MH]+ = 406/408/410, tR = 5.803 min.
3-Bromo-6-((6-bromo-1 W-[1 ,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (67.5)
To a solution of 6-bromo-N2-((3-bromoquinolin-6-yl)methyl)pyrazine-2,3-diamine (300 mg, 0.73 mmol) in 5 ml_ of acetic acid was added dropwise a solution of NaNO2 (150 mg, 2.17 mmol) in 0.5 ml_ of water at 20 0C. The mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with DCM/methanol gradient to afford the title compound (130 mg, 42%). 1H- NMR (400MHz, CDCI3) δ ppm 8.84 (s, 1 H), 8.71 (s, 1 H), 8.24 (s, 1 H), 8.01 (d, 1 H), 7.74 (s, 2H), 5.99 (s, 2H). LCMS (method E): [MH]+ = 421 , tR = 5.50 min.
1 -(6-((6-Acetyl-1 H-[Λ ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)quinolin-3-yl)ethanone (67.6)
A solution of 3-bromo-6-((6-bromo-1 /-/-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)quinoline (128 mg, 0.305 mmol), Pd(PPh3)4 (51 .5 mg, 0.045 mmol) and tributyl(1 -ethoxyvinyl)stannane (253 mg, 0.701 mmol) in 5 mL of DMF was heated at 95 0C for 1 h under nitrogen. The reaction mixture was diluted with EtOAc, washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3
N HCI, and stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with DCM/MeOH gradient to afford the title compound (74 mg, 45%) as a yellow solid. 1H-NMR (400MHz, CDCI3) δ ppm 9.47-9.45
(m, 2H), 8.70 (d, 1 H), 8.19 (d, 1 H), 8.05 (d, 1 H), 7.97 (dd, 1 H), 6.21 (s, 2H), 2.82 (s, 3H), 2.74 (s, 3H). LCMS (method E): [MH]+ = 347, tR = 4.503 min.
(£)-1 -(6-((6-((E)-I -(2-Hydroxyethoxyimino)ethyl)-1 W-[1 ,2,3]triazolo[4,5-b]pyrazin-1 - yl)methyl)quinolin-3-yl)ethanone O-2-hydroxyethyl oxime (example 67)
A solution of 1 -(6-((6-acetyl-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)quinolin-3- yl)ethanone (74 mg, 0.213 mmol) and 2-aminooxy-ethanol (35 mg, 0.45 mmol) in 5 mL of methanol and 0.1 mL of acetic acid was stirred at 40 0C overnight. The solvent was removed under reduced pressure and the residue was diluted with DCM and methanol. The precipitate was collected, washed with DCM, dried to afford the title compound (16 mg, 15%) as a white solid. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.31 (s, 1 H), 9.23 (d, 1 H), 8.52 (d, 1 H), 8.03 (d, 1 H), 7.98 (s, 1 H), 7.86 (dd, 1 H), 6.22 (s, 2H), 4.76 (d, 2H), 4.31 (t, 2H), 4.22 (t, 2H), 3.72-3.69 (m, 4H), 2.32 (s, 3H), 2.29 (s, 3H). LCMS (method E): [MH]+ = 465, tR = 4.85 min.
Example 68 (example 68-R, example 68-S)
(£)-2-(1-(3-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethylideneaminooxy)acetic acid
Figure imgf000134_0001
intermidiate K(i)
Methyl 2-(1 ,3-dioxoisoindolin-2-yloxy)acetate (237 mg, 1 .01 mmol) and hydrazine monohydrate (50 mg, 1.0 mmol) were dissolved in methanol (3 ml_) and heated at 70 QC for 2 h. After filtration, the solid was washed with EtOAc. The combined solution was concentrated and the residue was diluted with methanol. A solution of NaOH (6 N, 3 ml_) was added and the mixture was stirred at 70 QC for 2 h. The solution was concentrated, acidified with 3 N HCI to pH 1 and filtered. The solid was washed with water, and the combined solution was concentrated. The residue was diluted with DCM, then ketone 53.5 (40 mg, 0.1 13 mmol) and HCI (4 N HCI in dioxane, 0.7 ml_) were added. It was stirred at rt for 24 h. After concentration, the residue was purified by prep-HPLC to give 21 mg (34%) of the title compound as white solid. 1H-NMR (400 MHz, DMSO-Cf6) δ ppm 12.90 (s, 1 H), 8.97 (d, 1 H), 8.45 (d, 1 H), 8.26 (d, 1 H), 7.70 (d, 1 H), 7.60 (d, 1 H), 5.27 (q, 1 H), 4.76 (s, 2H), 2.03 (d, 3H), 1.94 (s, 3H). LCMS (method B): [MH]+ = 427, tR = 2.259 min. Chiral separation (method L) provided enantiomeric pure compounds example 68-R (tR = 7.71 min) and example 68-S (tR = 9.99 min).
Example 69
(£)-1-(1-((5,7-Difluoroquinolin-6-yl)methyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6- yl)ethanone O-2-hydroxyethyl oxime
Figure imgf000135_0001
(5,7-Difluoroquinolin-6-yl)methanol (69.1)
To a slolution of δj-difluoroquinoline-θ-carbaldehyde (4.00 g, 20.71 mmol) in MeOH (120 ml_), was added NaBH4 (0.79 g, 20.71 mmol) in portions. After stirring for 15 min, saturated aqueous solution of NH4CI was added. The aqueous phase was extracted with CH2CI2 (4 x 25 ml_). The organic layers were combined and dried over NaSO4. The product was purified by silica gel with hexane:EtOAc to afford (5,7-difluoroquinolin-6-yl)methanol (3.80 g, 94 %). 1H-NMR (400MHz, CDCI3) δ ppm 8.97 (m, 1 H), 8.42 (m, 1 H), 7.63 (d, 1 H), 7.46 (m, 1 H), 4.99 (d, 2H), 2.07 (t, 1 H). LCMS (method B): [MH]+ = 196.0, tR = 1.67 min
2-(5,7-Difluoroquinolin-6-ylmethyl)isoindoline-1 ,3-dione (69.2)
A mixture of (£)-diisopropyl diazene-1 ,2-dicarboxylate (4.72 g, 23.36 mmol) and triphenylphosphine (6.13 g, 23.36 mmol) in THF (100 ml_) was stirred for 15 min, and a solution of (5,7-difluoroquinolin-6-yl)methanol (3.80 g, 19.47 mmol) and isoindoline-1 ,3-dione (3.15 g, 21 .42 mmol) in THF (200 ml_) was added dropwise. The reaction mixture was heated at 40 0C for 24 h. After cooling and evaporating, the residue was purified by silica gel with hexane:EtOAc to provide 2-(5,7-difluoroquinolin-6-ylmethyl)isoindoline-1 ,3-dione (5.10 g, 81 %). 1H-NMR (400MHz, CDCI3) δ ppm 8.93 (m, 1 H), 8.39 (m, 1 H), 7.85 (m, 2H), 7.72 (m, 2H), 7.59 (d, 1 H), 7.43 (m, 1 H), 5.15 (s, 2H).
(5,7-Difluoroquinolin-6-yl)methanamine (69.3)
To a solution of 2-(5,7-difluoroquinolin-6-ylmethyl)isoindoline-1 ,3-dione (5.10 g, 15.73 mmol) in CH3OH (150 ml_) was added hydrazine monohydrate (0.50 g, 15.73 mmol). The solution was heated at reflux for 3 h. After cooling, the mixture was filtered through celite. The filtrate was concentrated in vacuo. EtOAc was added to dilute the residue, filtered and concentrated in vacuo to afford (5,7-difluoroquinolin-6-yl)methanamine (2.70 g, 88 %). 1H- NMR (400MHz, CDCI3) δ ppm 8.93 (d, 1 H), 8.38 (d, 1 H), 7.59 (d, 1 H), 7.43 (m, 1 H), 4.12 (s, 2H). LCMS (method B): [MH]+ = 195.0, tR = 0.17 min.
6-Bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (69.4)
A mixture of (5,7-difluoroquinolin-6-yl)methanamine (2.7 g, 13.9 mmol), 3,5-dibromopyrazin- 2-amine (2.4 mg, 9.49 mmol) and triethyl amine (4.8 g, 47.5 mmol) in CH3CN (6 ml_) was heated under microwave irradiation at 180 0C for 40 min. The reaction mixture was concentrated in vacuo and purified by column chromatography (hexane:EtOAc) to provide 6- bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (1 .50 g, 43 %). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.00 (d, 1 H), 8.52 (d, 1 H), 7.73 (d, 1 H), 7.64 (m, 1 H), 7.21 (s, 1 H), 7.00 (s, 1 H), 6.21 (s, 2H), 4.69 (d, 2H). LCMS (method B): [MH]+ = 367.9, tR = 2.36 min
6-((6-Bromo-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)-5,7-dif luoroquinoline (69.5)
To a solution of 6-bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (1 .5 g, 4.10 mmol) in actic acid (50 mL) and water (10 mL) was added a solution of sodium nitrite (283 mg, 4.10 mmol) in water (3 mL). After stirring at rt for 3 h, the solvent was removed in vacuo, the residue was taken with NaHCO3 (aq.), extracted with CH2CI2. The organic layer was washed with NH4CI (aq.), dried over Na2SO4, filtered and concentrated in vacuo and purified by silica gel chromatography with hexanes:EtOAc to provide 6-((6-bromo-1 H- [1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)-5,7-difluoroquinoline (1.02 g, 65 %). 1H-NMR (400MHz, CDCI3) δ ppm 8.99 (d, 1 H), 8.79 (s, 1 H), 8.43 (d, 1 H), 7.65 (d, 1 H), 7.49 (m, 1 H), 6.13 (s, 2H). LCMS (method B): [MH]+ = 376.8, tR = 2.23 min.
6-((6-(1-Ethoxyvinyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-dif luoroquinoline (69.6)
To a degassed solution of 6-((6-bromo-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)-5,7- difluoroquinoline (10 mg, 0.03 mmol) in DMF (1 mL) was added Pd(Ph3P)4 (3.1 mg, 2.65 μmol). After stirring for 20 min, tributyl(1 -ethoxyvinyl)stannane(14.4 mg, 0.04 mmol) was added. The reaction was heated at 100 0C until the LC-MS showed its completetion. The reaction mixture was filtered through celite and washed with ether. The filtration was washed with water, dried over Na2SO4, and concentrated The crude product was purified by column chromatography with hexane:EtOAc to give 6-((6-(1 -ethoxyvinyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-1 -yl)methyl)-5,7-difluoroquinoline (6.0 mg, 61 %). 1H-NMR (400MHz, CDCI3) δ ppm 9.16 (s, 1 H), 8.98 (d, 1 H), 8.43 (d, 1 H), 7.65 (d, 1 H), 7.48 (m, 1 H), 6.17 (s, 2H), 5.60 (s, 1 H), 4.57 (s, 1 H), 4.04 (q, 2H), 1 .49 (t, 3H). LCMS (method B): [MH]+ = 369.0, tR = 2.45 min.
1-(1-((5,7-Difluoroquinolin-6-yl)methyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (69.7)
To a solution of the 6-((6-(1 -ethoxyvinyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)methyl)-5,7- difluoroquinoline (6.0 mg, 0.45 mmol) in acetic acid, 3N HCI (0.1 ml_) was added. The solution stirred at rt for 2 h. Solvents were removed under reduced pressure. The residue was diluted with water, treated with aqeous NaHCO3 solution, extracted with DCM. The organic layer was washed sequencially with NaHCO3 (aq.) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography with Hexane:ethyl acetate to give yellow solid 1 -(1 -((5,7-difluoroquinolin-6- yl)methyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (3.5 mg), yield 63 %. LCMS (method B): [MH]+ = 340.9, tR = 2.09 min. (£)-1-(1-((5,7-Difluoroquinolin-6-yl)methyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6- yl)ethanone O-2-hydroxyethyl oxime (example 69)
To a solution of 1 -(1 -((5,7-difluoroquinolin-6-yl)methyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6- yl)ethanone (3.5 mg, 0.01 mmol) in MeOH (1 mL), 2-(aminooxy)ethanol hydrochloride (intermediate S) (1 .6 mg, 0.02 mmol) was added, the solution was heated to 50 0C for overnight. The solvent was removed in vacuo. The residue was diluted with water, treated with aqeous NaHCO3 solution, extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prepared HPLC to give white solid (£)-1 -(1 -((5,7-difluoroquinolin-6-yl)methyl)-1 H-[1 ,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone O-2-hydroxyethyl oxime (2.4 mg, 56 %). 1H-NMR (400MHz, CDCI3) δ ppm 9.38 (s, 1 H), 8.98 (d, 1 H), 8.42 (d, 1 H), 7.64 (d, 1 H), 7.48 (m, 1 H), 6.18 (s, 2H), 4.45 (m, 2H), 3.98 (m, 2H), 2.36 (s, 3H), 1.96 (m, 1 H). LCMS (method B): [MH]+ = 399.9, tR = 2.19 min.
Example 70 (£)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanoneO-1- hydroxy-2-methylpropan-2-yl oxime
Figure imgf000138_0001
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4 )and 2-(aminooxy)-2-methylpropan-1-ol hydrochloride in 94% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.35 (s, 1H), 8.89 (m, 1H), 8.35 (dd, 1H), 8.01 (m, 2H), 7.82 (m, 1H), 7.52 (dd, 1H), 6.20 (s, 2H), 4.73 (t, 1H), 3.51 (d, 2H), 2.29 (s, 3H), 1.13 (s, 6H). LCMS (method B): [MH]+ = 392, tR = 2.40min.
Example 71
(£)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-oxetan-3- yl oxime
Figure imgf000138_0002
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5- b]pyrazin-6-yl)ethanone (22.4) and 0-(oxetan-3-yl)hydroxylamine (intermediate U) in 23% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.27 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (m, 1H), 7.52 (dd, 1H), 6.22 (s, 2H), 5.45 (t, 1H), 4.86 (t, 2H), 4.66 (m, 2H), 2.40 (s, 3H). LCMS (method B): [MH]+ = 376, tR = 2.26min.
Example 72
(£)-1-(1-((7-Fluoroquinolin-6-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone oxime
Figure imgf000139_0001
The title compound (68.0 mg, 62%) was synthesized from 1 -[3-(7-fluoro-quinolin-6-ylmethyl)- 3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (100.0 mg, 0.31 mmol) and hydroxylamine hydrochloride (43.1 mg, 0.62 mmol) using the same procedure as described in the synthesis of example 15. 1 H-NMR (400MHz, DMSO-Cf6) δ ppm 12.49 (bs, 1 H), 9.31 (s, 1 H), 8.92 (d, 1 H), 8.40 (d, 1 H), 8.18 (d, 1 H), 7.82 (d, 1 H), 7.54 (d, 1 H), 6.22 (s, 2H), 2.23 (s, 3H). LCMS (method A): [MH]+ = 338, tR = 5.15 min.
Example 73
(£)-1-(1-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6- yl)ethanone 0-2-hydroxyethyl oxime
Figure imgf000139_0002
1 -(5,7-Dif luoroquinolin-6-yl)ethanol (73.1 )
To a solution of 5,7-difluoroquinoline-6-carbaldehyde (5.0 g, 25.9 mmol) in THF (80 ml_) was added ethylmagnesium iodide (3 M, 9.5 ml_, 28.5 mmol) at -78 QC. After stirring at -78 QC for 1 hour, the reaction was quenched with saturated NH4CI and concentrated under reduced pressure. The residue was diluted with water, extracted with DCM three times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (haxane/EtOAc) to give the title compound as a white solid (3.3 g, 58 %). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.97 (dd, 1 H), 8.47 (d, 1 H), 7.66-7.58 (m, 2H), 5.54 (d, 1 H), 5.29 (m, 1 H), 1 .56 (d, 3H). LCMS (method A): [MH]+ = 210, tR = 4.71 min.
2-(1-(5,7-Difluoroquinolin-6-yl)ethyl)isoindoline-1 ,3-dione (73.2)
A mixture of (£)-diisopropyl diazene-1 ,2-dicarboxylate (3.8 g, 18.9 mmol) and triphenylphosphine (5.4 g, 20.5 mmol) in THF (50 ml_) was stirred for 30 min, and a solution of 1 -(5,7-difluoroquinolin-6-yl)ethanol (3.3 g, 15.8 mmol) and isoindoline-1 ,3-dione (2.7 g, 17.4 mmol) in THF (50 ml_) was added dropwise. The reaction mixture was heated at 50 0C overnight. After cooling and evaporating, the residue was purified by silica gel and eluted with hexane/EtOAc to give the title compound as a white solid (2.6 g, 49 %). LCMS (method A): [MH]+ = 339, tR = 5.81 min.
1 -(5,7-Dif luoroquinolin-6-yl)ethanamine (73.3)
To a solution of 2-(1 -(5,7-difluoroquinolin-6-yl)ethyl)isoindoline-1 ,3-dione (2.6 g, 7.7 mmol) in CH3OH (50 mL) was added hydrazine monohydrate (0.38 g, 7.7 mmol). The solution was heated at 50 0C and stirred overnight. After cooling and evaporating, the residue was purified by silica gel and eluted with hexane/EtOAc to give the title compound (1.0 g, 60 %). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.95 (d, 1 H), 8.45 (d, 1 H), 7.65 (d, 1 H), 7.60 (dd, 1 H), 4.49 (q, 1 H), 2.20 (bs, 2H), 1.48 (d, 3H).
6-Bromo-N2-(1-(5,7-difluoroquinolin-6-yl)ethyl)pyrazine-2,3-diamine (73.4)
A mixture of 1 -(5,7-difluoroquinolin-6-yl)ethanamine (800 mg, 3.8 mmol ), 3,5- dibromopyrazin-2-amine (972.0 mg, 3.8 mmol ) and DIPEA (2.0 g, 15.4 mmol ) in acetonitrile (50 mL) was heated with microwave irradiation at 180 0C for 45 min. The reaction mixture was concentrated under reduced pressure, diluted with water, extracted with DCM three times. The combined organic layers were separated and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (DCM/MeOH) to give the title compound as a yellow solid (508 mg, 35%). 1H-NMR (400MHz, DMSO-d6) δ ppm 8.95 (d, 1 H), 8.46 (dd, 1 H), 7.63 (d, 1 H), 7.60 (dd, 1 H), 7.1 1 (s, 1 H), 7.08 (dd, 1 H), 6.36 (bs, 2H), 5.45 (m, 1 H), 1 .70 (d, 3H). LCMS (method A): [MH]+ = 380/382, tR = 5.03 min.
6-(1-(6-Bromo-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-5,7-difluoroquinoline (73.5) To a solution of 6-bromo-N2-(1 -(5,7-difluoroquinolin-6-yl)ethyl)pyrazine-2,3-diamine (450 mg, 1 .2 mmol ) in acetic acid (12 ml_) was added a solution of sodium nitrite (82.0 mg, 1.2 mmol) in water (2 ml_). After stirring at rt for 2 hours, the solvent was removed in vacuo. The residue was diluted with NaHCO3 (aq.), extracted with DCM. The organic layer was separated and washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellow solid (423 mg, 91%). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.01 (dd, 1 H), 8.95 (s, 1 H), 8.52 (d, 1 H), 7.75 (d, 1 H), 7.64 (dd, 1 H), 6.77 (q, 1 H), 2.30 (d, 3H). LCMS (method A): [MH]+ = 391/393, tR = 5.59 min. 6-(1-(6-(1-Ethoxyvinyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-5,7-difluoroquinoline (73.6)
A mixture of 6-(1 -(6-bromo-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)ethyl)-5,7-difluoroquinoline (423.0 mg, 1 .2 mmol ), Pd(Ph3P)4 (125.0 mg, 0.12 mmol ) and tributyl(1 -ethoxyvinyl)stannane (781.0 mg, 2.2 mmol) in DMF (5 ml_) was purged with nitrogen and then heated at 100 0C for 12 hours. After removal of the solvent under reduced pressure, the residue was diluted with DCM, washed sequentially with aqueous KF and water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with gradient (DCM/MeOH = 50:1 ) to give the title compound as a yellow solid (370 mg, 91%). LCMS (method E): [MH]+ = 383, tR = 4.24 min.
1-(1-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone
(73.7)
A solution of 6-(1 -(6-(1 -ethoxyvinyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-1 -yl)ethyl)-5,7- difluoroquinoline (100.0 mg, 0.24 mmol) and 3 N HCI (0.1 mL) in CH3OH (10 mL) was stirred at 50 0C for 2 hours. The solvent was removed under reduced pressure. The reaction mixture was concentrated in vacuo to give the title compound as yellow solid (80.0 mg, 96%). 1H-NMR (400MHz, DMSO-d6) δ ppm 9.23 (s, 1 H), 9.01 (dd, 1 H), 8.53 (d, 2H), 7.76 (d, 1 H), 7.64 (dd, 1 H), 6.87 (q, 1 H), 2.49 (s, 3H), 2.40 (d, 3H). LCMS (method A): [MH]+ = 355, tR = 5.36 min.
(E)-1-(1-(1-(5,7-Difluoroquinolin-6-yl)ethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6- yl)ethanone O-2-hydroxyethyl oxime (example 73)
To a solution of 1 -(1 -(1 -(5,7-difluoroquinolin-6-yl)ethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6- yl)ethanone (76.5 mg, 0.22 mmol) in MeOH (50 mL) was added 2-(aminooxy)ethanol hydrochloride (49.0mg, 0.43 mol). The mixture was heated at 45 0C overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography with gradient (DCIWMeOH =10:1 ) to give the title compound as a white solid (58.0 mg, 62%). 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.23 (s, 1 H), 9.01 (dd, 1 H), 8.52 (d, 1 H), 7.74 (d, 1 H), 7.63 (dd, 1 H), 6.80 (q, 1 H), 4.74 (t, 1 H), 4.27 (t, 2H), 3.68 (m, 2H), 2.36 (d, 3H), 2.10 (s, 3H). LCMS (method A): [MH]+ = 414, tR = 5.44 min.
Example 74
inolin-6-yl)ethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-
Figure imgf000142_0001
The title compound (26.4 mg, 63%) was synthesized from 1 -(1 -(1 -(5,7-difluoroquinolin-6- yl)ethyl)-1 H-[1 ,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (73.7) (40.0 mg, 0.1 1 mmol) and hydroxylamine hydrochloride(15.7 mg, 0.23 mmol) using the same procedure as described in the synthesis of example 73. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 12.28 (bs, 1 H), 9.23 (s, 1 H), 9.01 (d, 1 H), 8.52 (d, 1 H), 7.73 (d, 1 H), 7.63 (dd, 1 H), 6.80 (q, 1 H), 2.36 (d, 3H), 2.05 (s, 3H). LCMS (method A): [MH]+ = 370, tR = 5.53 min.
Example 75-S and 75-ff
(S5E)- and (ff,E)-1 -(3-(1 -(5,7-dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethanone oxime
Figure imgf000142_0002
75- R (£)-1 -(3-(1 -(5,7-Dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone oxime (example 75)
1 -(3-(1 -(5,7-difluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (53.5, 491 mg, 1.390 mmol) in methanol (30 ml_) was added hydroxylamine hydrochloride (140 mg, 2.015 mmol), followed by hydrochloride dropwise to give a pale yellow clear solution. The reaction mixture was stirred at rt overnight. LCMS showed the reaction was complete.
Aqueous NaOH (1 N) solution was added at 0 0C until pH 8-9. Solvent was evaporated, and the residue was purified by column chromatography to afford 410 mg (88% yield) of the title compound as a white solid. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 12.21 (s, 1 H), 8.97 (dd, 1 H), 8.45 (d, 1 H), 8.22 (d, 1 H), 7.57-7.71 (m, 3H), 5.25 (q, 1 H), 2.01 (d, 3H), 1.84 (s, 3H). LCMS
(method A): [MH]+ = 369, tR = 5.45 min.
(S,£)- and (ff,E)-1 -(3-(1 -(5,7-Dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethanone oxime (example 75-S and 75-ff)
The title compounds were obtained by separation of racemic mixture (£)-1 -(3-(1 -(5,7- difluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone oxime (75, 12.0 g) with SFC (Method L). Data for example 75-S (4.98 g): 1H-NMR (400MHz, DMSO-Cf6) δ ppm 12.20 (s, 1 H), 8.96 (d, 1 H), 8.44 (d, 1 H), 8.22 (d, 1 H), 7.56-7.70 (m, 3H), 5.25 (q, 1 H), 2.01 (d, 3H), 1.84 (s, 3H). LCMS (method B): [MH]+ = 369, tR=2.35 min. Data for example 75-ff (5.08 g): 1H-NMR (400MHz, DMSO-Cf6) δ ppm 12.20 (s, 1 H), 8.96 (d, 1 H), 8.44 (d, 1 H), 8.22 (d, 1 H), 7.56-7.70 (m, 3H), 5.25 (q, 1 H), 2.01 (d, 3H), 1 .84 (s, 3H). LCMS (method B): [MH]+ = 369, tR = 2.35 min.
Example 76-S and 76-ff
(S,£)- and (ff,E)-1 -(3-(1 -(5,7-Dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethanone O-cyclopropylmethyl oxime
Figure imgf000144_0001
76- R
(£)-1 -(3-(1 -(5,7-Dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-cyclopropylmethyl oxime (example 76)
2-(cyclopropylmethoxy)isoindoline-1 ,3-dione (300 mg, 1.42 mmol), and hydrazine monohydrate (35 μl_, 0.71 mmol) in methanol (5 ml_) was heated at 75 0C for 3 hr. The reaction mixture was cooled, and the precipitate was filtered off, and washed twice with minimum methanol. To the combined methanol solution was added 1 -(3-(1 -(5,7- difluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (53.6, 100 mg, 0.28 mmol), followed by hydrochloride (1 N in dioxane) dropwise to give a clear solution. The reaction mixture was stirred at rt overnight, LCMS showed the reaction was complete. 1 N NaOH aqueous solution was added until pH 8-9. The mixture was concentrated, and purified by column chromatography to afford 109 mg (91 % yield) of the title compound as a white solid. 1H-NMR (400MHz, CDCI3) δ ppm 8.93 (dd, 1 H), 8.33 (d, 1 H), 7.96 (d, 1 H), 7.75 (d, 1 H), 7.59 (d, 1 H), 7.41 (dd, 1 H), 5.28 (q, 1 H), 4.03 (d, 2H), 2.19 (d, 3H), 2.02 (s, 3H), 1.13-1 .22 (m, 1 H), 0.52-0.62 (m, 2H), 0.22-0.31 (m, 2H). LCMS (method A): [MH]+ = 423, tR = 5.49 min.
(S,£)- and (ff,E)-1 -(3-(1 -(5,7-Dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethanone O-cyclopropylmethyl oxime (example 76-S and 76-R)
The title compounds were obtained by separation of racemic mixture (E)-1 -(3-(1 -(5,7- difluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone O-cyclopropylmethyl oxime (76, 102 mg) with SFC (Method I). Data for example 76-S (32 mg): 1H-NMR
(400MHz, DMSO-Cf6) δ ppm 8.96 (dd, 1 H), 8.44 (d, 1 H), 8.24 (d, 1 H), 7.66 (dd, 2H), 7.9 (dd, 1 H), 5.25 (q, 1 H), 4.01 (d, 2H), 2.02 (d, 3H), 1 .89 (s, 3H), 1.04-1 .18 (m, 1 H), 0.45-0.56 (m, 2H), 0.26-0.31 (m, 2H). Data for example 76-ff (42 mg): 1H-NMR (400MHz, DMSO-d6) δ ppm 8.96 (dd, 1 H), 8.44 (d, 1 H), 8.24 (d, 1 H), 7.66 (dd, 2H), 7.9 (dd, 1 H), 5.25 (q, 1 H), 4.01 (d, 2H), 2.02 (d, 3H), 1 .89 (s, 3H), 1.04-1.18 (m, 1 H), 0.45-0.56 (m, 2H), 0.26-0.31 (m, 2H).
Example 77-ff
(ff,E)-1 -(3-(1 -(5,7-dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethanone O-carbamoyl oxime
Figure imgf000145_0001
75-R H-R
Previously prepared (£)-1 -(3-(1 -(5,7-difluoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin- 6-yl)ethanone oxime (75-R, 100 mg, 0.271 mmol) in anhydrous THF (8 ml_) was added diphosgene (0.1 ml_, 0.829 mmol) dropwise at 0 0C, and the reaction mixture was heated at 50 0C for 4 hr. Oil bath was removed, and the reaction mixture was cooled in an ice-water bath. An ammonia solution (0.5 N in dioxane, 8.0 ml_, 4.0 mmol) was added dropwise. The temperature was allowed to rise to rt naturally, and the reaction mixture was stirred at rt overnight. Solvent was evaporated, and the residue was purified by column chromatography (8% methanol in ethyl acetate as eluent) to afford 64 mg (45.8% yield) of title compound as white solid, which was unstable at nucleophiles such as methanol, and was pro to degrade into starting material 75-R 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.96 (d, 1 H), 8.44 (d, 1 H), 8.34 (d, 1 H), 8.10 (d, 1 H), 7.56-7.74 (m, 2H), 7.34 (s br, 2H), 5.27 (q, 1 H), 2.02 (d, 3H), 2.03 (s, 3H). LCMS (method B): [MH]+ = 412, tR = 2.25 min.
Example 77-S
(S,£)-1-(3-(1 -(5,7-dif luoroquinolin-6-yl)ethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethanone O-carbamoyl oxime
Figure imgf000145_0002
75-R 77-ff
The title compounds were obtained from (£)-1 -(3-(1 -(5,7-difluoroquinolin-6-yl)ethyl)- [1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone oxime (75-S) with similar procedure as example 77-R 1H-NMR (400MHz, DMSO-d6) δ ppm 8.96 (d, 1 H), 8.44 (d, 1 H), 8.34 (d, 1 H), 8.10 (d, 1 H), 7.56-7.74 (m, 2H), 7.34 (s br, 2H), 5.27 (q, 1 H), 2.02 (d, 3H), 2.03 (s, 3H). LCMS (method B): [MH]+ = 412, tR = 2.20 min.
Example 78
(£)-1-(3-((5,7-Difluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone oxime
Figure imgf000146_0001
example 78
(5,7-Difluoro-quinolin-6-yl)-acetic acid hydrazide (78.1)
To a solution of (5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester (1 .023 g, 4.32 mmol) in ethanol (15 ml_) was added hydrazine monohydrate (2 ml_) and the mixture was stirred at 30 0C for 24 h. The solvent was removed in vacuo to afford 1.024 g of the title compound as white solid, which was used without further purification. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 9.33 (s, 1 H), 8.97 (d, 1 H), 8.46 (d, 1 H), 7.67 (d, 1 H), 7.61 (dd, 1 H), 4.27 (s, 2H). LCMS (method A): [MH]+ = 238, tR = 3.24 min. (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester was synthesized using the method described in WO2008/144767 p108 (intermediate 2), followed by the method described for Intermediate 12, step 1 WO2008/144767 p1 14.
6-(6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline (78.2)
A solution of (5,7-difluoro-quinolin-6-yl)-acetic acid hydrazide (1.024 g, 4.32 mmol) and 3,6- dichloropyridazine (0.772 g, 5.18 mmol) in 60 mL of butan-1 -ol was heated at 135 0C in a sealed tube for 16 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography to afford 842 mg of the title compound as a gray solid. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 8.96 (dd, 1 H), 8.26 (d, 1 H), 7.60-7.66 (m, 2H), 7.45 (d, 1 H), 4.81 (s, 2H). LCMS (method A): [MH]+ = 332, tR = 4.88 min. 6-[6-(1-Ethoxy-vinyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-5,7-difluoro-quinoline (78.3)
A solution of 6-(6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline (58 mg, 0.175 mmol) in dioxane (5 ml_) was purged with argon for 1 min. Tributyl-(1 -ethoxy- vinyl)stannane (0.2 ml_, 0.53 mmol) was then added, followed by addition of PdCI2(PPh3)2 (14.4 mg, 0.021 mmol). The reaction mixture was purged with argon for another half min. The reaction mixture was stirred at 80-85 0C for 4 h; LC/MS showed the reaction was complete. The reaction mixture was diluted with EtOAc, and 15 mL of aqueous KF solution was added. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, concentrated to give the crude title compound, which was used without further purification. LCMS (method A): [MH]+ = 368, tR = 5.39 min.
1-[3-(5,7-Difluoro-quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]ethanone (78.4)
Aqueous 3N HCI (0.2 mL, 0.6 mmol) was added to a solution of 6-[6-(1 -ethoxy-vinyl)- [1 ,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-5,7-difluoro-quinoline (87 mg, 0.237 mmol) in HOAc (2 mL). The reaction mixture was stirred at 40 0C for 6 h. LC/MS showed reaction was complete. The solvent was removed in vacuo, and the residue dissolved in EtOAc was neutralized, and extracted with EtOAc. The organic layer was dried, concentrated and purified by flash chromatography to afford 40 mg of the title compound as a pale yellow solid. 1H-NMR (400MHz, MeOH-Cf4) δ ppm 8.95 (dd, 1 H), 8.56 (d, 1 H), 8.29 (d, 1 H), 7.85 (d, 1 H), 7.60-7.67 (m, 2H), 4.94 (s, 2H), 2.67 (s, 3H). LCMS (method A): [MH]+ = 339, tR = 4.88 min.
(E)-1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone oxime (example 78)
1 -[3-(5,7-Difluoro-quinolin-6-ylmethyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]ethanone (78.4, 320 mg, 0.943 mmol) and hydroxylamine hydrochloride (131 mg, 1 .886 mmol) in methanol (30 mL) was stirred at rt overnight. LCMS showed the reaction was complete. The reaction solution was tuned with 1 N NaOH aqueous solution until pH 8-9, solvent was evaporated, and the residue was purified by column chromatography to afford 310 mg (93% yield) of the title compound as a yellow solid. 1H-NMR (400MHz, DMSO-Cf6) δ ppm 12.29 (s, 1 H), 8.99 (dd, 1 H), 8.49 (d, 1 H), 8.24 (d, 1 H), 7.74 (d, 2H), 7.63 (dd, 1 H), 4.76 (s, 2H), 2.15 (s, 3H).
LCMS (method A): [MH]+ = 355, tR = 5.32 min.
Example 79 (£)-1 -(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)ethanone 0-2- hydroxyethyl oxime
Figure imgf000148_0001
79.1 79.2
Figure imgf000148_0003
example 79 79.4
Figure imgf000148_0002
6-bromo-1 ,2,4-triazin-3-amine (79.1)
A mixture of 3-amino-1 ,2,4-triazine (50.0 g, 521 mmol) in water (6000 ml_) was cooled to 0-5 0C. The bromine (70 ml_, 1 .30 mmol) was added dropwise to the reaction mixture for 1 h. Then the mixture was stirred overnight at 0-10 0C. A satured aqueous Na2SO3 solution was added to the reaction and the mixture was neutralized to pH = 12 with a 6 N aqueous NaOH solution. The mixture was extracted with dichloromethane, dried over Na2SO4. The solvent was removed in vacuo to afford 50.0 g (54%) of the title compound as a yellow solid. 1H- NMR (400 MHz, CZ6-DMSO) δ ppm 8.40 (s, 1 H), 7.47 (s, 2H). LCMS (method B): [MH]+ = 175/177, tR = 0.328 min.
6-(1-ethoxyvinyl)-1 ,2,4-triazin-3-amine (79.2)
A solution of 6-bromo-1 ,2,4-triazin-3-amine (780 mg, 4.46 mmol) in N, N- dimethylformamide (50 ml_) was treated with tetrakis(triphenylphosphine) palladium (0) (258 mg, 0.22 mmol), Λ/,Λ/-diisopropylethyl amine (2284 mg, 1 1 .14 mmol), lithium chloride (661 mg, 15.6 mmol), and vinyltri-n-butyltin (2093 mg, 5.79 mmol), and the reaction was heated at 120 0C for 2 h. The reaction mixture was cooled to room temperature and concentrated the solvent in vacuo. The residue was diluted with dichloromethane and washed with aqueous KF solution. The crude product was purified by flash chromatography in silica gel eluting with a ethyl acetate/hexane gradient to afford 380 mg (51%) of the title compound as a yellow solid. 1H- NMR (400 MHz, CDCI3) δ ppm 8.48 (s, 1 H), 5.41 -5.39 (m, 3H), 4.36 (s, 1 H), 3.98 (q, 2H),
1 .43 (t, 2H).
6-((2-(2-methyl-1 ,3-dioxolan-2-yl)imidazo[1 ,2-b][1 ,2,4]triazin-7-yl)methyl)quinoline
(79.3)
A solution of 6-(1 -ethoxyvinyl)-1 ,2,4-triazin-3-amine (120 mg, 0.72 mmol), 2-chloro-3- (quinolin-3-yl)propanal (317 mg, 1.44 mmol) in ethylene glycol (8 ml_) was stirred at 140 0C for 2 h. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous Na2CO3 solution and diluted with water, extracted with ethyl acetate, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography in silica gel eluting with a ethyl acetate/hexane gradient to afford 135 mg (54%) of the title compound as yellow solid. LCMS (method B): [MH]+ = 348, tR = 2.03 min.
1 -(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)ethanone (79.4)
A solution of 6-((2-(2-methyl-1 ,3-dioxolan-2-yl)imidazo[1 ,2-b][1 ,2,4]triazin-7- yl)methyl)quinoline (130 mg, 0.37 mmol) in 3 N HCI (5 ml_) was stirred at 90 0C for 0.5 h.
The reaction mixture was cooled to room temperature, neutralized with saturated aqueous
Na2CO3 solution, extracted with ethyl acetate, dried over Na2SO4. The solvent was removed in vacuo to afford 85 mg (75%) of the title compound as yellow solid. 1H-NMR (400 MHz,
CDCI3) δ ppm 9.06 (s, 1 H), 8.91 (d, 1 H), 8.12 (t, 2H), 8.04 (s, 1 H), 7.74-7.71 (m, 2H), 7.48- 7.39 (m, 1 H), 4.60 (s, 2H), 2.70 (s, 3H). LCMS (method B): [MH]+ = 304, tR = 1 .81 min.
(£)-1 -(7-(quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)ethanone 0-2- hydroxyethyl oxime (Example 79)
A solution of 1 -(7-(quinolin-6-ylmethyl)imidazo[1 ,2-ιb][1 ,2,4]triazin-2-yl)ethanone (40 mg, 0.13 mmol), 2-(aminooxy)ethanol hydrochloride (30 mg, 0.26 mmol) and HCI (4 Λ/ in 1 ,4-dioxane, 0.1 mL) in methanol (5 mL) was stirred at room temperature for 48 h. The reaction mixture was neutralized with saturated aqueous NaHCO3 solution and diluted with water, extracted with dichloromethane, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography in silica gel eluting with a ethyl acetate/methanol gradient to afford 35 mg (74%) of the title compound as yellow solid. 1H- NMR (400 MHz, Cf6-DMSO) δ ppm 8.94 (s, 1 H), 8.84 (d, 1 H), 8.28 (d, 1 H), 7.97-7.91 (m, 3H), 7.77 (d, 1 H), 7.49 (dd, 1 H), 4.77 (t, 1 H), 4.56 (s, 2H), 4.30-4.27 (m, 2H), 3.71 -3.70 (m, 2H), 2.25 (s, 3H). LCMS (method B): [MH]+ = 363, tR = 2.08 min. Example 80
(£)-1-(7-(Quinolin-6-ylmethyl)imidazo[1 ,2-b][1 ,2,4]triazin-2-yl)ethanone oxime The title compound was prepared using the same procedure as described in the synthesis of example 79. 1H-NMR (400 MHz, Cf6-DMSO) δ ppm 12.27 (s, 1 H), 8.93 (s, 1 H), 8.85 (s, 1 H), 8.29 (d, 1 H), 7.95 (d, 1 H), 7.90 (d, 2H), 7.77 (d, 1 H), 7.50 (s, 1 H), 4.56 (s, 2H), 2.21 (s, 3H). LCMS (method B): [MH]+ = 319, tR = 2.065 min.
Example 81
1-(3-Quinolin-6-ylmethyl-imidazo[1 ,2-a]pyrimidin-6-yl)-ethanone oxime
Figure imgf000150_0001
1 -(3-Quinolin-6-ylmethyl-imidazo[1 ,2-a]pyrimidin-6-yl)-ethanone oxime can be generated from 1 -(3-quinolin-6-ylmethyl-imidazo[1 ,2-a]pyrimidin-6-yl)-ethanone (intermediate W) and hydroxyamine. Example 82
Figure imgf000150_0002
1 -(3-Quinolin-6-ylmethyl-imidazo[1 ,2-a]pyrimidin-6-yl)-ethanone O-(2-hydroxy-ethyl)-oxime can be generated from 1 -(3-quinolin-6-ylmethyl-imidazo[1 ,2-a]pyrimidin-6-yl)-ethanone
(intermediate W) and 2-Aminooxy-ethanol.
In another embodiment of the invention, there is provided a crystalline form of the compound of Example 53S. Such forms provide a significant improvement in processing properties compared to the amorphous form, and provide improvements in thermodynamic stability and and hygroscopicity. Furthermore, the crystallization process provided aids in removing impurities.
Example 1 : Amorphous form of the compound of Example 53S
The amorphous form of Ex 53S was obtained using the following methods: 1A. Room temperature slow evaporation crystallization method
Solvents: Acetone, isopentyl alcohol, methylene chloride, methylethyl ketone, n-propanol, tetrahydrofuran, Pentanol, EtOH/Water 1 :1 .
Procedure:
(1 ) About 2 mg of drug substance was dissolved in 0.2ml solvent.
(2) Solvent was allowed to evaporate slowly at room temperature
(3) The solid product was dried in vacuum oven at 400C overnight and analysed by XRPD.
IB. Anti-solvent method:
(1 ) About 2 mg of drug substance was dissolved in 0.2 ml solvent.
(2) Anti-solvent was added to precipitate the compound.
(3) The vial was refrigerated overnight.
(4) Solvent was allowed to evaporate slowly
(5) The solid product was dried in vacuum oven at 400C overnight and analysed by XRPD.
Figure imgf000151_0001
IC. Slurry method:
Solvent: ethyl acetate
(1 ) About 2 mg of drug substance was suspended in 0.2 ml solvent.
(2) Solvent was allowed to evaporate slowly at room temperature
(3) The solid product was dried in vacuum oven at 4O0C overnight and analysed by XRPD.
Example 2: Crystalline form I of the Compound of Example 53S
A crystalline form I of the compound of Example 53S was obtained using different crystallisation methods:
2A. Room temperature slow evaporation crystallization method Solvents: Acetonotrile, ethanol, ether, ethyl acetate, methanol, methyl tert-butyl ether, butyl acetate, 2-methyl-1 -propanol, toluene, water, 95% EtOH.
(1 ) About 2 mg of drug substance was dissolved in 0.2 ml solvent.
(2) Solvent was allowed to evaporate slowly at room temperature
(3) The solid product was dried in the vacuum oven at 40 <€ overnight and analysed by XRPD. Scale-up samples were further characterised using XRPD, DSC and TGA.
Ex 53S crystalline form I was obtained.
2B. Anti-solvent method:
(1 ) About 2 mg of drug substance was dissolved in 0.2 ml solvent.
(2) Anti-solvent was added to precipitate the compound.
(3) The vial was refrigeratated overnight.
(4) Solvent was allowed to evaporate slowly
(5) The solid product was dried in the vacuum oven at 40^ overnight and analysed by XRPD. Scale-up samples were characterized using XRPD, DSC and TGA.
Figure imgf000152_0001
Example 53S crystalline form I was obtained. 2C. Slurry method
Solvents: ether, hexane, methyl tert-butyl ether, Butyl acetate, toluene, Water, Pentane.
(1 ) About 2 mg of drug substance was suspended in 0.2 ml solvent and equilibrated for 24 hours.
(2) Solvent was allowed to evaporate slowly at room temperature
(3) The solid product was dried in the vacuum oven at 40^ overnight and investigated by XRPD. Scale-up samples were further characterized using XRPD, DSC and TGA.
Example 53S crystalline form I was obtained. Table 1 : XRPD data of Example 53S crystalline form I
Intensity
Angle d value %
2-Theta ° Angstrom %
10.6 8.34 86
14.2 6.24 100
15.6 5.66 27.5
17.1 5.20 59
17.5 5.05 73.1
19.3 4.60 53.3
20.9 4.25 56.1
21 .6 4.10 17.2
22.6 3.93 46.2
23.5 3.79 43
23.9 3.72 71 .9
24.8 3.59 43.5
25.3 3.51 46
26.2 3.40 25.5
26.7 3.34 32.4
27.3 3.27 26.6
28.7 3.1 1 29.6
30.9 2.89 29.8
31 .8 2.81 29.8
33.0 2.71 21 .3
37.0 2.43 18.1
In a particular embodiment of the invention, there is provided a crystalline form of the compound of Example 53S comprising the following peaks:
Angle d value
2-Theta ° Angstrom
ΪO6 8^34
14.2 6.24 17.1 5.20
17. 5 5 .05
23. 9 3 .72
Example 3: Crystalline form Il of the Compound of Example 53S
A crystalline form Il of the compound of Example 53S was obtained using different crystallization methods
3A. Room temperature slow evaporation crystallization method:
Solvents: cyclohexane, hexane, methanol, n-butanol, pentane.
(1 ) About 2 mg of drug substance was dissolved in 0.2 ml solvent.
(2) Solvent was allowed to evaporate slowly at room temperature
(3) The solid product was dried in the vacuum oven at 4O0C overnight and analysed by XRPD. Scale-up samples were further characterized using XRPD, DSC and TGA. Example 53S crystalline form Il was obtained. 3B. Anti-solvent method:
(1 ) About 2 mg of drug substance was dissolved in 0.2 ml methylene chloride.
(2) Anti-solvent hexane was added to precipitate compound.
(3) The vial was refrigerated overnight
(4) Solvent was allowed to evaporate slowly
(5) The solid product was dried in the vacuum oven at 400C overnight and analysed by XRPD. Scale-up samples were further characterized using XRPD, DSC and TGA. Example 53S crystalline form Il was obtained.
3C. Slurry method
Solvents: cyclohexane.
(1 ) About 2 mg of drug substance was suspended in 0.2 ml solvent.
(2) Solvent was allowed to evaporate slowly at room temperature
(3) The solid product was dried in the vacuum oven at 400C overnight and analysed by XRPD. Scale-up samples were further characterized using XRPD, DSC and TGA. Ex 53S crystalline form Il was obtained. Table 2. XRPD data of Exampe 53S crystalline form Il
Intensity
Angle d value %
2-Theta ° Angstrom %
8.7 10.16 19.9
9.0 9.80 40.3
10.0 8.83 49.1
10.7 8.29 28.3
1 1 .4 7.73 27
13.2 6.70 73.3
14.2 6.21 39.2
15.2 5.82 84.7
15.7 5.63 17.9
17.1 5.19 100
17.7 5.02 93.5
18.6 4.78 27.8
19.8 4.49 35.9
20.3 4.37 55.6
20.9 4.24 32.7
22.4 3.97 26.4
22.8 3.90 27.1
23.5 3.78 28.9
24.5 3.63 30.4
24.8 3.59 33.3
25.4 3.51 36.2
26.1 3.41 51 .4
27.0 3.30 32.3
28.7 3.1 1 28.7
29.9 2.99 21 .5
32.3 2.77 20.2
34.4 2.60 27.8
35.8 2.51 22.3
37.2 2.42 17.4 38.8 2.32 14.5
41 .2 2.19 13.6
43.3 2.09 16.2
In a particular embodiment of the invention, there is provided a crystalline form of the compound of Example 53S comprising the following peaks:
Angle d value
2-Theta ° Angstrom
13. 2 6. 70
15. 2 5. 82
17. 1 5. 19
17. 7 5. 02
20. 3 4. 37
Instrument name: X-ray Diffractometer
Model: D8 Discover
Manufacturer: Bruker AXS GMBH
Wavelength: 1 .54184A (Cu)
Generator setting: 40.00KV, 40.00mA
Monochromator
Detector: HI-STAR
Frame Size: 1024 pixels, 107.79mm Experiment method:
2-Theta start: 5.0 degree
2-Theta end: 45.0 degree
Pixel overlap: 20%
Integration stepsize: 0.02 degree
Scan time: 120 seconds
Temperature: Room Temperature
C-Met enzyme assay A number of compounds of the present invention were assayed in an antibody based kinase phosphorylation assay as follows.
EPK cMET Profiling Assay:
The EPK kinase assay for cMET receptor tyrosine kinase was developed, using the purified recombinant GST-fusion protein, containing the cytoplasmic domain of the enzyme. GST- cMET(969-1390) was purified by affinity chromatography.
The kinase assay is based on the LanthaScreen™ technology. LanthaScreen™ is the detection of Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) using lanthanide chelates to measure interactions between various binding partners. In a TR-FRET kinase assay, a long-lifetime lanthanide donor species is conjugated to an antibody that specifically binds to a phosphorylated product of a kinase reaction that is labeled with a suitable acceptor fluorophore. This antibody-mediated interaction brings the lanthanide donor and the acceptor into proximity such that resonance energy transfer can take place, resulting in a detectible increase in the FRET signal.
The kinase reactions were performed in 384 well microtiter plates in a total reaction volume of 10.05 μl_. The assay plates were prepared with 0.05 μl_ per well of test compound in the appropriate test concentration, as described under "preparation of compound dilutions". The reactions were started by combining 5 μl_ of ATP solution with 5 μl_ of enzyme-substrate mix (consisting of kinase and substrate). The final concentrations in the kinase reactions were 25 mM Tris/HCI, 1 mM DTT, 0.025% Tween20, 10 μM sodium orthovanadate, 0.25% BSA, 0.5 % DMSO, 10 mM MgCI2, 3 mM MnCI2, 2 μM ATP, 50 nM Fluorescein-PolyEAY, and 0.3 nM enzyme.
The reactions were incubated for 60 minutes at room temperature and stopped by adding 5 μl_ of stop buffer (50 mM EDTA, 0.04 % NP40, 20 mM Tris/HCI).
Subsequently 5 μl_ of detection mix (50 mM Tris/HCI, 2 mM DTT, 0.05% Tween20, 20 μM sodium orthovanadate, 1% BSA, 1 nM Tb-PY20 antibody) were added to the stopped reactions. After 45 minutes incubation in dark at room temperature, the plates were measured in a Perkinelmer Envision fluorescence reader. The effect of compound on the enzymatic activity was in all assays obtained from the linear progress curves and determined from one reading (end point measurement). Results are summarized in the Table below. "Active" compounds of the invention have an IC50 in this enzyme assay of less than 500OnM, preferably less than 100OnM, more preferably less than 20OnM and most preferably less than 1 OnM. GTL16 Cell Viability Assay:
GTL16 cell line is derived from a gastric cancer patient. GTL16 expresses high level of cMet receptor tyrosine kinase due to the gene amplification. The growth of GTL16 is highly dependent on cMet kinase activity; hence it is used as a cell base assay to monitor the cellular activity of the cMet kinase inhibitors.
GTL16 cells were seeded in DMEM medium with 10% FBS and 1% Pene. & Strep, at 5000 cells/well/90μl_ in 96 well plate and incubated overnight for attachment at 37°C in 5% CO2 incubator. 10-fold serials dilutions of compounds were added to the cell as 10μl_/well. The final assay volume was 100μl/well. The assay plates were incubated at 37°C in 5% CO2 incubator for 24 hours. The viability of cells was measured using the CellTiter GIo (Cat# G7573 Promega) according to the protocol suggested by the vender. Briefly, the plates were cooled at room temperature for 10 mins and 100 μl of CellTiter GIo reagent was added into each well. Plates were shaken for 10 mins. The chemiluminescent light unit was read in Envision from Perkin Elmer. All the tests were run at triplicates. The IC50 was calculated using Spotfire software.
Table 1 Inhibitory Activity of Compounds
Example cMet biochem Example cMet biochem number (IC50 nM) number (IC50 nM)
1 36 41 10
2 10 42 7
3 8 43 29
4 73 44 13
5 27 45 34
6 5.5 46 120
7A 59 47 3600 B 59 48 380
1.8 49 440
6.7 50 1.50 24 51-S 2.81-S 6 51-R 4601-R 117 52 112-S 2.5 53-S 3.52-R 100 53-R 3683 51 54 34 55 55 3.85 2.8 56 2.56 7.3 57 287 46 58 148 29 59 1539 5.4 60 1560 29 61 831 5.1 62-S 212 2.4 62-R 1373 2.2 63 64 3 64 185 34 65 156A 20 66 426B 9 67 87 440 68-S 138 590 68-R 2239 360 69 4.70 160 70 1271 28 71 72 32.5 72 113 70 73 124 12 74 175 60 75-S 1.26 35 75-R 19 A 16.5 76-S 24B 3.9 76-R 1064
3.6 77-S 0.48-R 444 77-R 20-S 19 78 0.4
68 79 7.1
80 3.8

Claims

1 . A compound of formula (I):
Figure imgf000161_0001
or a pharmaceutically acceptable salt thereof, wherein
Y is C or N;
X is CH or N;
B is CH or N;
A is a ring; such that when X is CH and B is N, ring A is ring Ai or ring Aii;
Ai Aii
Figure imgf000161_0002
when X is N and B is N, ring A is Aiii; Aiii
Figure imgf000162_0001
and when X is N and B is N, or X is N and B is CH, ring A is Ai;
Ai
Figure imgf000162_0002
wherein R5 is heteroaryl1,
R is hydrogen, deuterium, OH, methyl or halo;
R7 is hydrogen, deuterium, halo, or (d-C3)alkyl, wherein said (CrC3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo; or R6 and R7, together with the carbon to which they are attached, form cyclopropyl;
R2 is hydrogen, NH2, or (CrC4)alkyl, wherein said (CrC4)alkyl is optionally substituted by one or more substituents independently selected from OH, NH3 and halo; and R is • (CrC6)alkyl, wherein said (d-C6)alkyl is optionally substituted by one or more substituents independently selected from halo, hydroxy and (CrC3)alkoxy,
• heterocyclyl1
• phenyl, wherein said phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (d-C3)alkyl and (d-C3)alkoxy, wherein said (Ci-C3)alkyl and (d-C3)alkoxy are each optionally substituted by one or more halo substituents,
• -CH2- heterocyclyl1
• -CH2-phenyl, wherein the phenyl of said -CH2-phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (d-C3)alkyl and (CrC3)alkoxy, wherein said (CrC3)alkyl and (CrC3)alkoxy are each optionally substituted by one or more halo substituents,
• (Ci-C4)alkylCO2(Ci-C2)alkyl,
• (C0-C4)alkylCONH2,
• (Ci-C4)alkylNH2>
• (Ci-C4)alkylNHCONH2>
• (Ci-C4)alkylCO2H,
• (Ci-C4)alkylNHCO2CH3>
• -(C0-C4)alkyl(C3-C6)cycloalkyl or -(C0-C4)alkyl(C4-C6)cycloalkenyl, or
• hydrogen; heteroaryl1 is a 9- or 10- membered, unsaturated or partially unsaturated bicyclic group comprising 1 , 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein the total number of ring S atoms does not exceed 1 , and the total number of ring O atoms does not exceed 1 , and wherein heteroaryl1 is optionally substituted by one or more substituents independently selected from:
• halo,
• OH,
• (CrC3)alkyl, said (CrC3)alkyl being optionally substituted by one or more substituents independently selected from OH and halo,
• heterocyclyl2, and
• -C(CH3)=NO(CrC3)alkyl, wherein the (d-C3)alkyl of said C(CH3)=NO(d-C3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo; heterocyclyl1 is a 4, 5 or 6 membered saturated or partially unsaturated monocyclic group comprising 1 or 2 ring heteroatoms independently selected from N, O and S, and wherein heterocyclyl1 is optionally substituted by CONH2 or (d-C3)alkyl; and heterocyclyl2 is a 5 or 6 membered saturated, unsaturated or partially unsaturated monocyclic group comprising 1 , 2 or 3 ring heteroatoms independently selected from N, O and S, wherein the total number of ring S atoms does not exceed 1 , and the total number of ring O atoms does not exceed 1 , and heterocyclyl2 is optionally substituted by (CrC3)alkyl.
2. A compound or pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein B is N;
Y is C or N;
X is CH or N;
such that when X is CH, ring A is ring Ai or ring Aii
Ai Aii
Figure imgf000164_0001
and when X is N, ring A is Aiii;
Aiii
Figure imgf000164_0002
and the remaining substituents are as described in claim 1 .
3. A compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 or 2 wherein R5 is heteroaryl3, and heteroaryl3 is a 9- or 10- membered, unsaturated or partially unsaturated bicyclic group comprising 1 or 2 ring N heteroatoms, said heteroaryl3 being optionally substituted by one or more substituents independently selected from:
• halo,
• OH,
• (CrC3)alkyl, wherein said (CrC3)alkyl is optionally substituted by one or more
substituents independently selected from OH and halo.
• heterocyclyl2, and
• -C(CH3)=NO(CrC3)alkyl, wherein the (d-C3)alkyl of said C(CH3)=NO(CrC3)alkyl is optionally substituted by one or more substituents independently selected from OH and halo.
4. A compound or pharmaceutically acceptable salt thereof as claimed in claim 3, wherein R5 is indazolyl or quinolinyl, each optionally substituted by one or more substituents independently selected from halo, (Ci-C3)alkyl, 4-methylpiperazin-1 -yl and ethanone 0-(2- hydroxyethyl)oxime.
5. A compound or pharmaceutically acceptable salt thereof as claimed in claim 4, wherein R5 is indazolyl optionally substituted by one, two or three substituents independently selected from methyl and fluoro, or R5 is quinolinyl optionally substituted by one or two fluoro substituents.
6. A compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, wherein R6 is hydrogen.
7. A compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein R7 is hydrogen or methyl.
8. A compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, wherein R2 is methyl.
9. A compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, wherein R3 is selected from:
• (Ci-C4)alkyl, wherein said (d-C4)alkyl is optionally substituted by one or more substituents independently selected from halo, hydroxy and methoxy, • pyrrolidinyl, optionally substituted by CONH2,
• piperidinyl,
• phenyl, wherein said phenyl is optionally substituted by one or more substituents independently selected from halo, hydroxy, (d-C3)alkyl and (d-C3)alkoxy, wherein said (CrC3)alkyl and (CrC3)alkoxy are each optionally substituted by one or more halo substituents,
• -CH2-pyrrolidinyl, wherein said pyrrolidinyl is optionally substituted by CONH2,
• -CH2-piperidinyl,
• -CH2-phenyl, wherein the phenyl of said -CH2-phenyl is optionally substituted by one or more substituents independently selected from halo, methyl and methoxy, wherein said methyl is optionally substituted by one, two or three halo substituents,
• (CrC2)alkylCO2(CrC2)alkyl,
• (C0-C2)alkylCONH2,
• (C2-C4)alkylNH2,
• (Ci-C2)alkylNHCONH2>
• (CrC2)alkylCO2H,
• oxetanyl
• (CrC2)alkylNHCO2CH3,
• -CH2-(C3-C6)cycloalkyl, and
• hydrogen.
10. A compound or pharmaceutically acceptable salt thereof as claimed in claim 9, wherein R3 is ethyl, methyl, 2-hydroxyethyl, 1 ,3-dihydroxypropan-2-yl-, 2,3-dihydroxypropyl-, 2- hydroxy-1 ,1 -dimethyl-ethyl-, 2-hydroxy-2-methyl-propyl-, pyrrolidin-3-yl-, -3-pyrrolidine-1 - carboxamide, hydrogen, benzyl, 4-methoxybenzyl-, piperidin-4-yl-, piperidin-4-ylmethyl-, - CH2CO2CH3, -CH2CONH2 2-aminoethyl-, 1 -hydroxypropan-2-yl-, -CH2CH2NHCO2CH3, - CH2CH2NHCONH2; 3-trifluoromethylphenyl-, phenyl, 2-fluoroethyl-, 3-hydroxypropyl, 2- methoxyethyl, 4-hydroxybutyl, 4-fluorobutyl, CONH2, 1 -hydroxy-2-methylpropan-2-yl, oxetan- 3-yl, -CH2CO2H, cyclopropylmethyl, or hydrogen.
1 1. A compound or pharmaceutically acceptable salt thereof as claimed in claim 10, wherein R3 is hydroxyethyl or hydrogen.
12. A compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 1 1 , wherein when R1 is i and R6 and R7 are not both hydrogen, the compound of formula (I) is the (S) enantiomer.
13. A compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, for use in medicine.
14. A compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, for use in the treatment of one or more c-Met tyrosine kinase mediated diseases.
15. A compound or pharmaceutically acceptable salt thereof as claimed in claim 14, for use in the treatment of a proliferative disease or an inflammatory condition.
16. Use of a compound or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, in the manufacture of a medicament for the treatment of one or more C-Met tyrosine kinase mediated diseases.
17. A method of treating a c-Met related disorder or condition which involves administering to a subject in need thereof an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or diluents and optionally one or more further therapeutic agents.
19. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 12, in combination with one or more additional therapeutically active agents.
PCT/EP2010/062057 2009-08-20 2010-08-18 Heterocyclic oxime compounds WO2011020861A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EP10762878A EP2467383A1 (en) 2009-08-20 2010-08-18 Heterocyclic oxime compounds
MX2012002179A MX2012002179A (en) 2009-08-20 2010-08-18 Heterocyclic oxime compounds.
JP2012525167A JP5775871B2 (en) 2009-08-20 2010-08-18 Heterocyclic oxime compounds
CA2771432A CA2771432A1 (en) 2009-08-20 2010-08-18 Heterocyclic oxime compounds
BR112012008061A BR112012008061A2 (en) 2009-08-20 2010-08-18 heterocyclic oxime compounds
AU2010284972A AU2010284972A1 (en) 2009-08-20 2010-08-18 Heterocyclic oxime compounds
CN201080047132.XA CN102574853B (en) 2009-08-20 2010-08-18 Heterocyclic oxime compounds
KR1020127007032A KR20120089463A (en) 2009-08-20 2010-08-18 Heterocyclic oxime compounds
EA201200318A EA201200318A1 (en) 2009-08-20 2010-08-18 Heterocyclic oximes
IN1453DEN2012 IN2012DN01453A (en) 2009-08-20 2010-08-18

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US23544009P 2009-08-20 2009-08-20
US61/235,440 2009-08-20
CNPCT/CN2010/071978 2010-04-21
CN2010071978 2010-04-21
CN2010074089 2010-06-18
CNPCT/CN2010/074089 2010-06-18

Publications (1)

Publication Number Publication Date
WO2011020861A1 true WO2011020861A1 (en) 2011-02-24

Family

ID=43243152

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/062057 WO2011020861A1 (en) 2009-08-20 2010-08-18 Heterocyclic oxime compounds

Country Status (14)

Country Link
US (2) US8410264B2 (en)
EP (1) EP2467383A1 (en)
JP (1) JP5775871B2 (en)
KR (1) KR20120089463A (en)
AR (1) AR079486A1 (en)
AU (1) AU2010284972A1 (en)
BR (1) BR112012008061A2 (en)
CA (1) CA2771432A1 (en)
EA (1) EA201200318A1 (en)
IN (1) IN2012DN01453A (en)
MX (1) MX2012002179A (en)
TW (1) TW201113284A (en)
UY (1) UY32848A (en)
WO (1) WO2011020861A1 (en)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011145035A1 (en) * 2010-05-17 2011-11-24 Indian Incozen Therapeutics Pvt. Ltd. Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases
WO2012107500A1 (en) * 2011-02-10 2012-08-16 Novartis Ag [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of the c-met tyrosine kinase
WO2013038362A1 (en) 2011-09-15 2013-03-21 Novartis Ag 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase
WO2013098229A2 (en) 2011-12-27 2013-07-04 Bayer Intellectual Property Gmbh Heteroarylpiperidine and piperazine derivatives as fungicides
CN103459396A (en) * 2011-02-10 2013-12-18 诺瓦提斯公司 [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of c-met tyrosine kinase
EP2719699A1 (en) * 2009-12-31 2014-04-16 Hutchison Medipharma Limited Certain triazolopyrazines, compositions thereof and methods of use therefor
CN103958509A (en) * 2011-09-15 2014-07-30 诺华股份有限公司 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase
US9206166B2 (en) 2012-11-06 2015-12-08 SHANGHAI iNSTITUTE OF MATERIA MEDICA ACADEMY OF SCIENCES Certain protein kinase inhibitors
US9221804B2 (en) 2013-10-15 2015-12-29 Janssen Pharmaceutica Nv Secondary alcohol quinolinyl modulators of RORγt
US9284308B2 (en) 2013-10-15 2016-03-15 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
US9290476B2 (en) 2012-10-16 2016-03-22 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
US9303015B2 (en) 2012-10-16 2016-04-05 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORγt
US9309222B2 (en) 2012-10-16 2016-04-12 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US9328095B2 (en) 2013-10-15 2016-05-03 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORgammat
US9346782B2 (en) 2013-10-15 2016-05-24 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
US9403816B2 (en) 2013-10-15 2016-08-02 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US9624225B2 (en) 2013-10-15 2017-04-18 Janssen Pharmaceutica Nv Quinolinyl modulators of RORγt
EP3241830A1 (en) 2016-05-04 2017-11-08 Bayer CropScience Aktiengesellschaft Condensed bicyclic heterocyclic derivatives as pesticides
US10555941B2 (en) 2013-10-15 2020-02-11 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
WO2020260857A1 (en) 2019-06-13 2020-12-30 AdoRx Therapeutics Limited Hydroxamate compounds as antagonists of the adenosine a2a receptor

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2010283806A1 (en) 2009-08-12 2012-03-01 Novartis Ag Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation
GB201321736D0 (en) * 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
IL266955B2 (en) * 2016-11-29 2023-09-01 Ptc Therapeutics Mp Inc Polymorphs of sepiapterin and salts thereof
JP2020532535A (en) 2017-09-01 2020-11-12 ピーティーシー セラピューティクス エムピー，インコーポレイテッド Pharmaceutical composition containing sepiapterin and its use

Citations (145)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3714357A (en) 1968-07-15 1973-01-30 Rech D Applic Scient Sogeras S Pharmaceutical compositions comprising quinuclidinol derivatives
US4100274A (en) 1976-05-11 1978-07-11 Imperial Chemical Industries Limited Polypeptide
US4636505A (en) 1982-07-23 1987-01-13 Imperial Chemical Industries Plc Amide derivatives
US4659516A (en) 1983-10-12 1987-04-21 Imperial Chemical Industries Plc Steroid derivatives
EP0409595A2 (en) 1989-07-19 1991-01-23 Glaxo Group Limited Process for the preparation of a carbocyclic nucleoside analogue
US5010099A (en) 1989-08-11 1991-04-23 Harbor Branch Oceanographic Institution, Inc. Discodermolide compounds, compositions containing same and method of preparation and use
EP0424021A1 (en) 1989-10-19 1991-04-24 Pfizer Limited Antimuscarinic bronchodilators
US5093330A (en) 1987-06-15 1992-03-03 Ciba-Geigy Corporation Staurosporine derivatives substituted at methylamino nitrogen
EP0490587A1 (en) 1990-12-07 1992-06-17 Merck & Co. Inc. Substituted pyrazolopyrimidines and imidazopyridazines as angiotensin II antagonists
WO1992019594A1 (en) 1991-05-02 1992-11-12 Smithkline Beecham Corporation Pyrrolidinones
EP0520722A1 (en) 1991-06-28 1992-12-30 Zeneca Limited Therapeutic preparations containing quinazoline derivatives
EP0564409A1 (en) 1992-04-03 1993-10-06 Ciba-Geigy Ag Pyrimidin derivatives and process for their preparation
WO1993019750A1 (en) 1992-04-02 1993-10-14 Smithkline Beecham Corporation Compounds useful for treating allergic or inflammatory diseases
WO1993019749A1 (en) 1992-04-02 1993-10-14 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases
WO1993019751A1 (en) 1992-04-02 1993-10-14 Smithkline Beecham Corporation Compounds useful for treating inflammatory diseases and inhibiting production of tumor necrosis factor
EP0566226A1 (en) 1992-01-20 1993-10-20 Zeneca Limited Quinazoline derivatives
WO1994010202A1 (en) 1992-10-28 1994-05-11 Genentech, Inc. Vascular endothelial cell growth factor antagonists
WO1994017090A1 (en) 1993-01-20 1994-08-04 Glaxo Group Limited 2,6-diaminopurine derivatives
WO1995003283A1 (en) 1993-07-19 1995-02-02 Zeneca Limited Quinazoline derivatives and their use as anti-cancer agents
US5451700A (en) 1991-06-11 1995-09-19 Ciba-Geigy Corporation Amidino compounds, their manufacture and methods of treatment
US5461076A (en) 1990-05-07 1995-10-24 Stanek; Jaroslav Hydrazones
WO1996002553A2 (en) 1994-07-14 1996-02-01 Glaxo Group Limited AMINO PURINE-β-D-RIBOFURANURONAMIDE DERIVATIVES
WO1996002543A1 (en) 1994-07-14 1996-02-01 Glaxo Group Limited 2,3-dihydroxy cyclopentane derivatives of purines
WO1996030347A1 (en) 1995-03-30 1996-10-03 Pfizer Inc. Quinazoline derivatives
WO1996033980A1 (en) 1995-04-27 1996-10-31 Zeneca Limited Quinazoline derivatives
WO1997002266A1 (en) 1995-07-06 1997-01-23 Novartis Ag Pyrrolopyrimidines and processes for the preparation thereof
EP0769947A1 (en) 1995-06-07 1997-05-02 Sugen, Inc. Indolinone compounds for the treatment of disease
EP0787722A1 (en) 1996-02-05 1997-08-06 American Cyanamid Company Substituted quinazoline derivatives
WO1997030034A1 (en) 1996-02-14 1997-08-21 Zeneca Limited Quinazoline derivatives as antitumor agents
WO1997038983A1 (en) 1996-04-12 1997-10-23 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
WO1997049688A1 (en) 1996-06-24 1997-12-31 Pfizer Inc. Phenylamino-substituted tricyclic derivatives for treatment of hyperproliferative diseases
WO1998008849A1 (en) 1996-08-30 1998-03-05 Novartis Aktiengesellschaft Method for producing epothilones, and intermediate products obtained during the production process
WO1998010121A1 (en) 1996-09-06 1998-03-12 Obducat Ab Method for anisotropic etching of structures in conducting materials
WO1998010767A2 (en) 1996-09-13 1998-03-19 Sugen, Inc. Use of quinazoline derivatives for the manufacture of a medicament in the treatment of hyperproliferative skin disorders
WO1998011223A1 (en) 1996-09-11 1998-03-19 Schering Aktiengesellschaft Monoclonal antibodies against the extracellular domain of human vegf-receptor protein (kdr)
EP0837063A1 (en) 1996-10-17 1998-04-22 Pfizer Inc. 4-Aminoquinazoline derivatives
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
WO1998018796A1 (en) 1996-10-28 1998-05-07 Novartis Ag Naphthyridine derivatives
WO1998022461A1 (en) 1996-11-18 1998-05-28 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone c, d, e and f, production process, and their use as cytostatic as well as phytosanitary agents
WO1998025929A1 (en) 1996-12-13 1998-06-18 Novartis Ag Epothilone analogs
WO1998028319A1 (en) 1996-12-24 1998-07-02 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO1998035958A1 (en) 1997-02-13 1998-08-20 Novartis Ag Phthalazines with angiogenesis inhibiting activity
US5843901A (en) 1995-06-07 1998-12-01 Advanced Research & Technology Institute LHRH antagonist peptides
WO1999003854A1 (en) 1997-07-18 1999-01-28 Novartis Ag Crystal modification of a n-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use
WO1999016766A1 (en) 1997-10-01 1999-04-08 Kyowa Hakko Kogyo Co., Ltd. Benzodioxole derivatives
WO1999017804A1 (en) 1997-10-03 1999-04-15 Pharmacia & Upjohn S.P.A. Polymeric derivatives of camptothecins
WO1999024451A2 (en) 1997-11-08 1999-05-20 Glaxo Group Limited Adenosine a1 receptor agonists
WO1999024449A2 (en) 1997-11-08 1999-05-20 Glaxo Group Limited Adenosine a1 receptor agonists
WO1999024450A2 (en) 1997-11-08 1999-05-20 Glaxo Group Limited Adensine a1 receptor agonists
WO1999038877A2 (en) 1998-01-31 1999-08-05 Glaxo Group Limited 2-(PURIN-9-yl)-TETRAHYDROFURAN-3,4-DIOL DERIVATIVES
WO1999041267A1 (en) 1998-02-14 1999-08-19 Glaxo Group Limited 2-(purin-9-yl) -tetrahydrofuran-3, 4-diol derivatives
WO1999043653A1 (en) 1998-02-25 1999-09-02 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues therof
WO1999067263A1 (en) 1998-06-23 1999-12-29 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO1999067266A1 (en) 1998-06-23 1999-12-29 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO1999067264A1 (en) 1998-06-23 1999-12-29 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO1999067265A1 (en) 1998-06-23 1999-12-29 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO2000000531A1 (en) 1998-06-30 2000-01-06 The Dow Chemical Company Polymer polyols and a process for the production thereof
WO2000009495A1 (en) 1998-08-11 2000-02-24 Novartis Ag Isoquinoline derivatives with angiogenesis inhibiting activity
WO2000023457A1 (en) 1998-10-16 2000-04-27 Pfizer Limited Adenine derivatives
WO2000027819A2 (en) 1998-11-10 2000-05-18 Schering Aktiengesellschaft Antrhranilic acid amides and the use thereof as medicaments
WO2000027820A1 (en) 1998-11-10 2000-05-18 Novartis Ag N-aryl(thio)anthranilic acid amide derivatives, their preparation and their use as vegf receptor tyrosine kinase inhibitors
WO2000031247A2 (en) 1998-11-20 2000-06-02 Kosan Biosciences, Inc. Recombinant methods and materials for producing epothilone and epothilone derivatives
WO2000037502A2 (en) 1998-12-22 2000-06-29 Genentech, Inc. Vascular endothelial cell growth factor antagonists and uses thereof
WO2000059509A1 (en) 1999-03-30 2000-10-12 Novartis Ag Phthalazine derivatives for treating inflammatory diseases
WO2000066559A1 (en) 1999-05-04 2000-11-09 Schering Corporation Piperidine derivatives useful as ccr5 antagonists
WO2000066558A1 (en) 1999-05-04 2000-11-09 Schering Corporation Piperazine derivatives useful as ccr5 antagonists
EP1052264A2 (en) 1999-05-11 2000-11-15 Pfizer Products Inc. Process for the synthesis of nucleoside analogs
WO2000075114A1 (en) 1999-06-04 2000-12-14 Novartis Ag Beta2-adrenoceptor agonists
WO2000077018A2 (en) 1999-06-15 2000-12-21 Pfizer Limited Purine derivatives
US6166037A (en) 1997-08-28 2000-12-26 Merck & Co., Inc. Pyrrolidine and piperidine modulators of chemokine receptor activity
WO2000078774A2 (en) 1999-06-18 2000-12-28 University Of Virginia Patent Foundation Induction of pharmacological stress with adenosine receptor agonists
WO2001004118A2 (en) 1999-07-14 2001-01-18 Almirall Prodesfarma S.A. Quinuclidine derivatives and their use as muscarinic m3 receptor ligands
US6194181B1 (en) 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
WO2001013953A2 (en) 1999-08-21 2001-03-01 Byk Gulden Lomberg Chemische Fabrik Gmbh Synergistic combination of pde inhibitors and beta 2 adrenoceptor agonist
WO2001023399A1 (en) 1999-09-30 2001-04-05 Pfizer Products Inc. Compounds for the treatment of ischemia
WO2001027131A1 (en) 1999-10-14 2001-04-19 Pfizer Limited Purine derivatives
WO2001027130A1 (en) 1999-10-14 2001-04-19 Pfizer Limited Purine derivatives
WO2001060835A1 (en) 2000-02-18 2001-08-23 Pfizer Limited Purine derivatives
WO2001094368A1 (en) 2000-06-06 2001-12-13 Pfizer Limited 2-aminocarbonyl-9h-purine derivatives
WO2002000652A1 (en) 2000-06-27 2002-01-03 Laboratorios S.A.L.V.A.T., S.A. Carbamates derived from arylalkylamines
WO2002000679A2 (en) 2000-06-28 2002-01-03 Novartis Ag 9.alpha.-chloro-6.alpha.-fluoro-17.alpha.-hydroxy-16-methyl-17-beta-methoxycarbonyl-androst-1,4-dienes esterified in position 17.alpha. by a cyclic acyl group
WO2002010143A1 (en) 2000-07-28 2002-02-07 Schering Aktiengesellschaft Non-steroidal inflammation inhibitors
WO2002012266A1 (en) 2000-08-05 2002-02-14 Glaxo Group Limited 17.beta.-carbothioate 17.alpha.-arylcarbonyloxyloxy androstane derivative as anti-inflammatory agents
WO2002022630A1 (en) 2000-09-15 2002-03-21 Pfizer Limited Purine derivatives
WO2002022577A2 (en) 2000-09-01 2002-03-21 Novartis Ag Hydroxamate derivatives useful as deacetylase inhibitors
WO2002042298A1 (en) 2000-11-21 2002-05-30 Novartis Ag Aminothiazoles and their use as adenosine receptor antagonists
WO2002051841A1 (en) 2000-12-22 2002-07-04 Almirall Prodesfarma Ag Quinuclidine carbamate derivatives and their use as m3 antagonists
WO2002053564A2 (en) 2000-12-28 2002-07-11 Almirall Prodesfarma Ag Quinuclidine derivatives and their use as m3 antagonists
EP1241176A1 (en) 2001-03-16 2002-09-18 Pfizer Products Inc. Purine derivatives for the treatment of ischemia
WO2002088167A1 (en) 2001-04-30 2002-11-07 Glaxo Group Limited Anti-inflammatory 17.beta.-carbothioate ester derivatives of androstane with a cyclic ester group in position 17.alpha
WO2002092599A1 (en) 2001-05-14 2002-11-21 Novartis Ag 4-amino-5-phenyl-7-cyclobutyl-pyrrolo (2,3-d) pyrimidine derivatives
WO2002096462A1 (en) 2001-05-25 2002-12-05 Pfizer Inc. An adenosine a2a receptor agonist and an anticholinergic agent in combination for treating obstructive airways diseases
WO2002100676A1 (en) 2001-06-11 2002-12-19 Ts Tech Co., Ltd. Operating lever, and seat having the same
WO2002100879A1 (en) 2001-06-12 2002-12-19 Glaxo Group Limited Novel anti-inflammatory 17.alpha.-heterocyclic-esters of 17.beta.carbothioate androstane derivatives
WO2003000840A2 (en) 2001-06-21 2003-01-03 Diversa Corporation Nitrilases
WO2003013541A1 (en) 2001-08-07 2003-02-20 Novartis Ag 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
WO2003033495A1 (en) 2001-10-17 2003-04-24 Ucb, S.A. Quinuclidine derivatives, processes for preparing them and their uses as m2 and/or m3 muscarinic receptor inhibitors
WO2003035668A2 (en) 2001-10-20 2003-05-01 Glaxo Group Limited Novel anti-inflammatory androstane derivatives -17-carboxy-lactone substituted steroids with an aryl-carboxylic ester in position 17.alpha
WO2003039544A1 (en) 2001-11-05 2003-05-15 Novartis Ag Naphtyridine derivatives, their preparation and their use as phosphodiesterase isoenzyme 4 (pde4) inhibitors
WO2003048181A1 (en) 2001-12-01 2003-06-12 Glaxo Group Limited 17.alpha. -cyclic esters of 16-methylpregnan-3,20-dione as anti-inflammatory agents
WO2003053966A2 (en) 2001-12-20 2003-07-03 Laboratorios S.A.L.V.A.T., S.A. 1-alkyl-1-azoniabicyclo [2.2.2] octane carbamate derivatives and their use as muscarinic receptor antagonists
WO2003062259A2 (en) 2002-01-21 2003-07-31 Glaxo Group Limited Non-aromatic 17.alpha.-esters of androstane-17.beta.-carboxylate esters as anti-inflammatory agents
WO2003072592A1 (en) 2002-01-15 2003-09-04 Glaxo Group Limited 17.alpha-cycloalkyl/cycloylkenyl esters of alkyl-or haloalkyl-androst-4-en-3-on-11.beta.,17.alpha.-diol 17.beta.-carboxylates as anti-inflammatory agents
WO2003082280A1 (en) 2002-03-26 2003-10-09 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2003082787A1 (en) 2002-03-26 2003-10-09 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2003087094A2 (en) 2002-04-16 2003-10-23 Almirall Prodesfarma Ag Pyrrolidinium derivatives as antagonists of m3 muscarinic receptors
WO2003086408A1 (en) 2002-04-10 2003-10-23 University Of Virginia Patent Foundation Use of a2a adenosine receptor agonists for the treatment of inflammatory diseases
WO2003099807A1 (en) 2002-05-29 2003-12-04 Almirall Prodesfarma S.A. New indolylpiperidine derivatives as potent antihistaminic and antiallergic agents
WO2003104204A1 (en) 2002-06-05 2003-12-18 Merck Patent Gmbh Pyridazine derivatives
WO2003104195A1 (en) 2002-06-06 2003-12-18 Boehringer Ingelheim Pharmaceuticals, Inc. 4-(aryl or heteroaryl) -2-butylamine derivatives and their use as glucocorticoid ligans
WO2003104205A1 (en) 2002-06-10 2003-12-18 Merck Patent Gmbh Aryloximes
WO2003106444A1 (en) 2002-06-14 2003-12-24 Recordati S.A. N,n-disubstituted diazocycloalkanes useful for the treatment of cns disorders due to serotonergic dysfunction
WO2004000839A1 (en) 2002-06-19 2003-12-31 Merck Patent Gmbh Thiazole derivatives as phosphodiesterase iv inhibitors
WO2004000814A1 (en) 2002-06-25 2003-12-31 Merck Frosst Canada & Co. 8-(biaryl) quinoline pde4 inhibitors
WO2004005258A1 (en) 2002-07-02 2004-01-15 Merck Frosst Canada & Co. Di-aryl-substituted-ethane pyridone pde4 inhibitors
WO2004005229A1 (en) 2002-07-08 2004-01-15 Pfizer Products Inc. Modulators of the glucocorticoid receptor
WO2004005285A1 (en) 2002-07-02 2004-01-15 Almirall Prodesfarma Ag New quinuclidine amide derivatives
WO2004016601A1 (en) 2002-08-09 2004-02-26 Novartis Ag Benzothiazole derivatives having beta-2-adrenoreceptor agonist activity
WO2004018449A1 (en) 2002-08-10 2004-03-04 Altana Pharma Ag Piperidine-derivatives as pde4 inhibitors
WO2004018457A1 (en) 2002-08-10 2004-03-04 Altana Pharma Ag Pyrrolidinedione substituted piperidine-phthalazones as pde4 inhibitors
WO2004018422A1 (en) 2002-08-23 2004-03-04 Ranbaxy Laboratories Limited Fluoro and sulphonylamino containing 3,6-disubstituted azabicyclo (3.1.0) hexane derivatives as muscarinic receptor antagonists
WO2004018465A2 (en) 2002-08-17 2004-03-04 Altana Pharma Ag Benzonaphthyridines with pde 3/4 inhibiting activity
WO2004018451A1 (en) 2002-08-10 2004-03-04 Altana Pharma Ag Pyridazinone-derivatives as pde4 inhibitors
WO2004018425A1 (en) 2002-08-21 2004-03-04 Astrazeneca Ab N-4-piperidinyl compounds as ccr5 modulators
WO2004018450A1 (en) 2002-08-10 2004-03-04 Altana Pharma Ag Piperidine-n-oxide-derivatives
WO2004019944A1 (en) 2002-08-29 2004-03-11 Altana Pharma Ag 2-hydroxy-6-phenylphenanthridines as pde-4 inhibitors
WO2004026841A1 (en) 2002-09-18 2004-04-01 Sumitomo Pharmaceuticals Co., Ltd. Novel 6-substituted uracil derivative and therapeutic agent for allergic disease
WO2004026873A1 (en) 2002-09-18 2004-04-01 Ono Pharmaceutical Co., Ltd. Triazaspiro[5.5]undecane derivatives and drugs comprising the same as the active ingredient
JP2004107299A (en) 2002-09-20 2004-04-08 Japan Energy Corp New 1-substituted urasil derivative and therapeutic agent for allergic disease
WO2004033412A1 (en) 2002-10-04 2004-04-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel beta mimetics with extended duration of action, method for production and use thereof as medicaments
WO2004037805A1 (en) 2002-10-23 2004-05-06 Glenmark Pharmaceuticals Ltd. Novel tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
WO2004039766A1 (en) 2002-11-01 2004-05-13 Glaxo Group Limited Phenylethanolamine derivatives for the treatment of respiratory diseases
WO2004039762A1 (en) 2002-11-01 2004-05-13 Glaxo Group Limited Phenethanolamine derivatives for the treatment of respiratory diseases
WO2004045607A1 (en) 2002-11-15 2004-06-03 Elbion Ag Novel hydroxyindoles, use as inhibitors of phosphodiesterase 4 and method for production thereof
WO2004046083A1 (en) 2002-11-15 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel dihydroxy-methylphenyl derivatives, method for the production and use thereof as medicaments
WO2004078163A2 (en) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
WO2004101994A1 (en) 2003-05-19 2004-11-25 Federalnoe Gosudarstvennoe Unitarnoe Predpriiatie 'rossiiskii Federalnyi Iadernyi Centr - Vserossiiskii Nauchno-Issledovatelskii Institut Tehnicheskoi Fisiki Imeni Akademika E.I.Zababahina' Ultrahigh pressure plunger pump
WO2004101846A1 (en) 2003-05-16 2004-11-25 Sandvik Intellectual Property Ab Cutting tool for metalworking as well as method in the production of cutting tools
WO2004104561A1 (en) 2003-05-21 2004-12-02 Bayer Technology Services Gmbh Method and device for measuring the content of ferromagnetic particles in liquid suspensions, aerosol dispensers or solid mixtures
WO2006110094A1 (en) 2005-04-14 2006-10-19 Gyros Patent Ab Upward microconduits
WO2007013673A1 (en) 2005-07-29 2007-02-01 Astellas Pharma Inc. Fused heterocycles as lck inhibitors
WO2007126799A2 (en) 2006-03-30 2007-11-08 Novartis Ag Compositions and methods of use for antibodies of c-met
WO2008008539A2 (en) * 2006-07-14 2008-01-17 Amgen Inc. Fused heterocyclic derivatives useful as inhibitors of the hepatocyte growth factor receptor
WO2008100853A1 (en) 2007-02-12 2008-08-21 Wm. Wrigley Jr. Company Confectionery products comprising polyols
WO2008144767A1 (en) 2007-05-21 2008-11-27 Sgx Pharmaceuticals, Inc. Heterocyclic kinase modulators

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6031898A (en) 1997-01-22 1998-08-07 Eli Lilly And Company Anti-viral compounds
US6346534B1 (en) 1998-09-23 2002-02-12 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
ES2244613T3 (en) 2000-04-27 2005-12-16 Astellas Pharma Inc. IMIDAZOPIRIDINE DERIVATIVES
CA2530589A1 (en) 2003-07-02 2005-01-20 Sugen Inc. Arylmethyl triazolo and imidazopyrazines as c-met inhibitors
US7122548B2 (en) 2003-07-02 2006-10-17 Sugen, Inc. Triazolotriazine compounds and uses thereof
CA2537916A1 (en) 2003-09-03 2005-03-31 Neurogen Corporation 5-aryl-pyrazolo[4,3-d]pyrimidines, pyridines, and pyrazines and related compounds
WO2006101456A1 (en) 2005-03-21 2006-09-28 S*Bio Pte Ltd Bicyclic heterocycles hydroxamate compounds useful as histone deacetylase (hdac) inhibitors
US7572807B2 (en) 2005-06-09 2009-08-11 Bristol-Myers Squibb Company Heteroaryl 11-beta-hydroxysteroid dehydrogenase type I inhibitors
EP1904501A2 (en) 2005-07-11 2008-04-02 Smithkline Beecham Corporation Chemical compounds
WO2007064797A2 (en) 2005-11-30 2007-06-07 Vertex Pharmaceuticals Incorporated Inhibitors of c-met and uses thereof
US8030305B2 (en) 2005-12-21 2011-10-04 Janssen Pharmaceutica N.V. Triazolopyridazines as kinase modulators
NL2000613C2 (en) 2006-05-11 2007-11-20 Pfizer Prod Inc Triazole pyrazine derivatives.
WO2007138472A2 (en) 2006-05-30 2007-12-06 Pfizer Products Inc. Triazolopyridazine derivatives
WO2008003753A1 (en) 2006-07-07 2008-01-10 Biovitrum Ab (Publ) Pyrazolo [1,5-a] pyrimidine analogs for use as inhibitors of stearoyl-coa desaturase (scd) activity
JP5378222B2 (en) 2006-10-23 2013-12-25 エスジーエックス ファーマシューティカルズ、インコーポレイテッド Bicyclic triazoles as protein kinase modulators
ES2393132T3 (en) 2006-10-23 2012-12-18 Sgx Pharmaceuticals, Inc. Triazolopyridazine protein kinase modules
HUE026659T2 (en) 2006-11-22 2016-07-28 Incyte Holdings Corp Imidazotriazines and imidazopyrimidines as kinase inhibitors
WO2008116898A1 (en) 2007-03-28 2008-10-02 Biovitrum Ab (Publ) Pyrazolo [1,5-a]pyrimidines as inhibitors of stearoyl-coa desaturase
JP5488778B2 (en) 2007-07-02 2014-05-14 日産化学工業株式会社 Controlled release particulates and solid agrochemical formulations containing the granules
MX2010009414A (en) 2008-02-28 2010-09-24 Novartis Ag Imidazo [1,2-b] pyridazine derivatives for the treatment of c-met tyrosine kinase mediated disease.
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
AU2010283806A1 (en) 2009-08-12 2012-03-01 Novartis Ag Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation

Patent Citations (147)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3714357A (en) 1968-07-15 1973-01-30 Rech D Applic Scient Sogeras S Pharmaceutical compositions comprising quinuclidinol derivatives
US4100274A (en) 1976-05-11 1978-07-11 Imperial Chemical Industries Limited Polypeptide
US4636505A (en) 1982-07-23 1987-01-13 Imperial Chemical Industries Plc Amide derivatives
US4659516A (en) 1983-10-12 1987-04-21 Imperial Chemical Industries Plc Steroid derivatives
US5093330A (en) 1987-06-15 1992-03-03 Ciba-Geigy Corporation Staurosporine derivatives substituted at methylamino nitrogen
EP0409595A2 (en) 1989-07-19 1991-01-23 Glaxo Group Limited Process for the preparation of a carbocyclic nucleoside analogue
US5010099A (en) 1989-08-11 1991-04-23 Harbor Branch Oceanographic Institution, Inc. Discodermolide compounds, compositions containing same and method of preparation and use
US5171744A (en) 1989-10-19 1992-12-15 Pfizer Inc. Antimuscarinic bronchodilators
EP0424021A1 (en) 1989-10-19 1991-04-24 Pfizer Limited Antimuscarinic bronchodilators
US5461076A (en) 1990-05-07 1995-10-24 Stanek; Jaroslav Hydrazones
EP0490587A1 (en) 1990-12-07 1992-06-17 Merck & Co. Inc. Substituted pyrazolopyrimidines and imidazopyridazines as angiotensin II antagonists
WO1992019594A1 (en) 1991-05-02 1992-11-12 Smithkline Beecham Corporation Pyrrolidinones
US5451700A (en) 1991-06-11 1995-09-19 Ciba-Geigy Corporation Amidino compounds, their manufacture and methods of treatment
EP0520722A1 (en) 1991-06-28 1992-12-30 Zeneca Limited Therapeutic preparations containing quinazoline derivatives
EP0566226A1 (en) 1992-01-20 1993-10-20 Zeneca Limited Quinazoline derivatives
WO1993019750A1 (en) 1992-04-02 1993-10-14 Smithkline Beecham Corporation Compounds useful for treating allergic or inflammatory diseases
WO1993019749A1 (en) 1992-04-02 1993-10-14 Smithkline Beecham Corporation Compounds useful for treating allergic and inflammatory diseases
WO1993019751A1 (en) 1992-04-02 1993-10-14 Smithkline Beecham Corporation Compounds useful for treating inflammatory diseases and inhibiting production of tumor necrosis factor
EP0564409A1 (en) 1992-04-03 1993-10-06 Ciba-Geigy Ag Pyrimidin derivatives and process for their preparation
WO1994010202A1 (en) 1992-10-28 1994-05-11 Genentech, Inc. Vascular endothelial cell growth factor antagonists
WO1994017090A1 (en) 1993-01-20 1994-08-04 Glaxo Group Limited 2,6-diaminopurine derivatives
WO1995003283A1 (en) 1993-07-19 1995-02-02 Zeneca Limited Quinazoline derivatives and their use as anti-cancer agents
WO1996002553A2 (en) 1994-07-14 1996-02-01 Glaxo Group Limited AMINO PURINE-β-D-RIBOFURANURONAMIDE DERIVATIVES
WO1996002543A1 (en) 1994-07-14 1996-02-01 Glaxo Group Limited 2,3-dihydroxy cyclopentane derivatives of purines
WO1996030347A1 (en) 1995-03-30 1996-10-03 Pfizer Inc. Quinazoline derivatives
WO1996033980A1 (en) 1995-04-27 1996-10-31 Zeneca Limited Quinazoline derivatives
EP0769947A1 (en) 1995-06-07 1997-05-02 Sugen, Inc. Indolinone compounds for the treatment of disease
US5843901A (en) 1995-06-07 1998-12-01 Advanced Research & Technology Institute LHRH antagonist peptides
WO1997002266A1 (en) 1995-07-06 1997-01-23 Novartis Ag Pyrrolopyrimidines and processes for the preparation thereof
EP0787722A1 (en) 1996-02-05 1997-08-06 American Cyanamid Company Substituted quinazoline derivatives
WO1997030034A1 (en) 1996-02-14 1997-08-21 Zeneca Limited Quinazoline derivatives as antitumor agents
WO1997038983A1 (en) 1996-04-12 1997-10-23 Warner-Lambert Company Irreversible inhibitors of tyrosine kinases
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
WO1997049688A1 (en) 1996-06-24 1997-12-31 Pfizer Inc. Phenylamino-substituted tricyclic derivatives for treatment of hyperproliferative diseases
WO1998008849A1 (en) 1996-08-30 1998-03-05 Novartis Aktiengesellschaft Method for producing epothilones, and intermediate products obtained during the production process
WO1998010121A1 (en) 1996-09-06 1998-03-12 Obducat Ab Method for anisotropic etching of structures in conducting materials
WO1998011223A1 (en) 1996-09-11 1998-03-19 Schering Aktiengesellschaft Monoclonal antibodies against the extracellular domain of human vegf-receptor protein (kdr)
WO1998010767A2 (en) 1996-09-13 1998-03-19 Sugen, Inc. Use of quinazoline derivatives for the manufacture of a medicament in the treatment of hyperproliferative skin disorders
EP0837063A1 (en) 1996-10-17 1998-04-22 Pfizer Inc. 4-Aminoquinazoline derivatives
WO1998018796A1 (en) 1996-10-28 1998-05-07 Novartis Ag Naphthyridine derivatives
WO1998022461A1 (en) 1996-11-18 1998-05-28 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone c, d, e and f, production process, and their use as cytostatic as well as phytosanitary agents
WO1998025929A1 (en) 1996-12-13 1998-06-18 Novartis Ag Epothilone analogs
WO1998028319A1 (en) 1996-12-24 1998-07-02 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO1998035958A1 (en) 1997-02-13 1998-08-20 Novartis Ag Phthalazines with angiogenesis inhibiting activity
WO1999003854A1 (en) 1997-07-18 1999-01-28 Novartis Ag Crystal modification of a n-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use
US6166037A (en) 1997-08-28 2000-12-26 Merck & Co., Inc. Pyrrolidine and piperidine modulators of chemokine receptor activity
WO1999016766A1 (en) 1997-10-01 1999-04-08 Kyowa Hakko Kogyo Co., Ltd. Benzodioxole derivatives
WO1999017804A1 (en) 1997-10-03 1999-04-15 Pharmacia & Upjohn S.P.A. Polymeric derivatives of camptothecins
WO1999024451A2 (en) 1997-11-08 1999-05-20 Glaxo Group Limited Adenosine a1 receptor agonists
WO1999024449A2 (en) 1997-11-08 1999-05-20 Glaxo Group Limited Adenosine a1 receptor agonists
WO1999024450A2 (en) 1997-11-08 1999-05-20 Glaxo Group Limited Adensine a1 receptor agonists
WO1999038877A2 (en) 1998-01-31 1999-08-05 Glaxo Group Limited 2-(PURIN-9-yl)-TETRAHYDROFURAN-3,4-DIOL DERIVATIVES
WO1999041267A1 (en) 1998-02-14 1999-08-19 Glaxo Group Limited 2-(purin-9-yl) -tetrahydrofuran-3, 4-diol derivatives
US6194181B1 (en) 1998-02-19 2001-02-27 Novartis Ag Fermentative preparation process for and crystal forms of cytostatics
WO1999043653A1 (en) 1998-02-25 1999-09-02 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues therof
WO1999067263A1 (en) 1998-06-23 1999-12-29 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO1999067264A1 (en) 1998-06-23 1999-12-29 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO1999067265A1 (en) 1998-06-23 1999-12-29 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO1999067266A1 (en) 1998-06-23 1999-12-29 Glaxo Group Limited 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
WO2000000531A1 (en) 1998-06-30 2000-01-06 The Dow Chemical Company Polymer polyols and a process for the production thereof
WO2000009495A1 (en) 1998-08-11 2000-02-24 Novartis Ag Isoquinoline derivatives with angiogenesis inhibiting activity
WO2000023457A1 (en) 1998-10-16 2000-04-27 Pfizer Limited Adenine derivatives
WO2000027819A2 (en) 1998-11-10 2000-05-18 Schering Aktiengesellschaft Antrhranilic acid amides and the use thereof as medicaments
WO2000027820A1 (en) 1998-11-10 2000-05-18 Novartis Ag N-aryl(thio)anthranilic acid amide derivatives, their preparation and their use as vegf receptor tyrosine kinase inhibitors
WO2000031247A2 (en) 1998-11-20 2000-06-02 Kosan Biosciences, Inc. Recombinant methods and materials for producing epothilone and epothilone derivatives
WO2000037502A2 (en) 1998-12-22 2000-06-29 Genentech, Inc. Vascular endothelial cell growth factor antagonists and uses thereof
WO2000059509A1 (en) 1999-03-30 2000-10-12 Novartis Ag Phthalazine derivatives for treating inflammatory diseases
WO2000066558A1 (en) 1999-05-04 2000-11-09 Schering Corporation Piperazine derivatives useful as ccr5 antagonists
WO2000066559A1 (en) 1999-05-04 2000-11-09 Schering Corporation Piperidine derivatives useful as ccr5 antagonists
EP1052264A2 (en) 1999-05-11 2000-11-15 Pfizer Products Inc. Process for the synthesis of nucleoside analogs
WO2000075114A1 (en) 1999-06-04 2000-12-14 Novartis Ag Beta2-adrenoceptor agonists
WO2000077018A2 (en) 1999-06-15 2000-12-21 Pfizer Limited Purine derivatives
WO2000078774A2 (en) 1999-06-18 2000-12-28 University Of Virginia Patent Foundation Induction of pharmacological stress with adenosine receptor agonists
WO2001004118A2 (en) 1999-07-14 2001-01-18 Almirall Prodesfarma S.A. Quinuclidine derivatives and their use as muscarinic m3 receptor ligands
WO2001013953A2 (en) 1999-08-21 2001-03-01 Byk Gulden Lomberg Chemische Fabrik Gmbh Synergistic combination of pde inhibitors and beta 2 adrenoceptor agonist
WO2001023399A1 (en) 1999-09-30 2001-04-05 Pfizer Products Inc. Compounds for the treatment of ischemia
WO2001027131A1 (en) 1999-10-14 2001-04-19 Pfizer Limited Purine derivatives
WO2001027130A1 (en) 1999-10-14 2001-04-19 Pfizer Limited Purine derivatives
WO2001060835A1 (en) 2000-02-18 2001-08-23 Pfizer Limited Purine derivatives
WO2001094368A1 (en) 2000-06-06 2001-12-13 Pfizer Limited 2-aminocarbonyl-9h-purine derivatives
WO2002000652A1 (en) 2000-06-27 2002-01-03 Laboratorios S.A.L.V.A.T., S.A. Carbamates derived from arylalkylamines
WO2002000679A2 (en) 2000-06-28 2002-01-03 Novartis Ag 9.alpha.-chloro-6.alpha.-fluoro-17.alpha.-hydroxy-16-methyl-17-beta-methoxycarbonyl-androst-1,4-dienes esterified in position 17.alpha. by a cyclic acyl group
WO2002010143A1 (en) 2000-07-28 2002-02-07 Schering Aktiengesellschaft Non-steroidal inflammation inhibitors
WO2002012266A1 (en) 2000-08-05 2002-02-14 Glaxo Group Limited 17.beta.-carbothioate 17.alpha.-arylcarbonyloxyloxy androstane derivative as anti-inflammatory agents
WO2002022577A2 (en) 2000-09-01 2002-03-21 Novartis Ag Hydroxamate derivatives useful as deacetylase inhibitors
US6552065B2 (en) 2000-09-01 2003-04-22 Novartis Ag Deacetylase inhibitors
WO2002022630A1 (en) 2000-09-15 2002-03-21 Pfizer Limited Purine derivatives
WO2002042298A1 (en) 2000-11-21 2002-05-30 Novartis Ag Aminothiazoles and their use as adenosine receptor antagonists
WO2002051841A1 (en) 2000-12-22 2002-07-04 Almirall Prodesfarma Ag Quinuclidine carbamate derivatives and their use as m3 antagonists
WO2002053564A2 (en) 2000-12-28 2002-07-11 Almirall Prodesfarma Ag Quinuclidine derivatives and their use as m3 antagonists
EP1241176A1 (en) 2001-03-16 2002-09-18 Pfizer Products Inc. Purine derivatives for the treatment of ischemia
WO2002088167A1 (en) 2001-04-30 2002-11-07 Glaxo Group Limited Anti-inflammatory 17.beta.-carbothioate ester derivatives of androstane with a cyclic ester group in position 17.alpha
WO2002092599A1 (en) 2001-05-14 2002-11-21 Novartis Ag 4-amino-5-phenyl-7-cyclobutyl-pyrrolo (2,3-d) pyrimidine derivatives
WO2002096462A1 (en) 2001-05-25 2002-12-05 Pfizer Inc. An adenosine a2a receptor agonist and an anticholinergic agent in combination for treating obstructive airways diseases
WO2002100676A1 (en) 2001-06-11 2002-12-19 Ts Tech Co., Ltd. Operating lever, and seat having the same
WO2002100879A1 (en) 2001-06-12 2002-12-19 Glaxo Group Limited Novel anti-inflammatory 17.alpha.-heterocyclic-esters of 17.beta.carbothioate androstane derivatives
WO2003000840A2 (en) 2001-06-21 2003-01-03 Diversa Corporation Nitrilases
WO2003013541A1 (en) 2001-08-07 2003-02-20 Novartis Ag 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine derivatives
WO2003033495A1 (en) 2001-10-17 2003-04-24 Ucb, S.A. Quinuclidine derivatives, processes for preparing them and their uses as m2 and/or m3 muscarinic receptor inhibitors
WO2003035668A2 (en) 2001-10-20 2003-05-01 Glaxo Group Limited Novel anti-inflammatory androstane derivatives -17-carboxy-lactone substituted steroids with an aryl-carboxylic ester in position 17.alpha
WO2003039544A1 (en) 2001-11-05 2003-05-15 Novartis Ag Naphtyridine derivatives, their preparation and their use as phosphodiesterase isoenzyme 4 (pde4) inhibitors
WO2003048181A1 (en) 2001-12-01 2003-06-12 Glaxo Group Limited 17.alpha. -cyclic esters of 16-methylpregnan-3,20-dione as anti-inflammatory agents
WO2003053966A2 (en) 2001-12-20 2003-07-03 Laboratorios S.A.L.V.A.T., S.A. 1-alkyl-1-azoniabicyclo [2.2.2] octane carbamate derivatives and their use as muscarinic receptor antagonists
WO2003072592A1 (en) 2002-01-15 2003-09-04 Glaxo Group Limited 17.alpha-cycloalkyl/cycloylkenyl esters of alkyl-or haloalkyl-androst-4-en-3-on-11.beta.,17.alpha.-diol 17.beta.-carboxylates as anti-inflammatory agents
WO2003062259A2 (en) 2002-01-21 2003-07-31 Glaxo Group Limited Non-aromatic 17.alpha.-esters of androstane-17.beta.-carboxylate esters as anti-inflammatory agents
WO2003082280A1 (en) 2002-03-26 2003-10-09 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2003082787A1 (en) 2002-03-26 2003-10-09 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2003086408A1 (en) 2002-04-10 2003-10-23 University Of Virginia Patent Foundation Use of a2a adenosine receptor agonists for the treatment of inflammatory diseases
WO2003087094A2 (en) 2002-04-16 2003-10-23 Almirall Prodesfarma Ag Pyrrolidinium derivatives as antagonists of m3 muscarinic receptors
WO2003099807A1 (en) 2002-05-29 2003-12-04 Almirall Prodesfarma S.A. New indolylpiperidine derivatives as potent antihistaminic and antiallergic agents
WO2003104204A1 (en) 2002-06-05 2003-12-18 Merck Patent Gmbh Pyridazine derivatives
WO2003104195A1 (en) 2002-06-06 2003-12-18 Boehringer Ingelheim Pharmaceuticals, Inc. 4-(aryl or heteroaryl) -2-butylamine derivatives and their use as glucocorticoid ligans
WO2003104205A1 (en) 2002-06-10 2003-12-18 Merck Patent Gmbh Aryloximes
WO2003106444A1 (en) 2002-06-14 2003-12-24 Recordati S.A. N,n-disubstituted diazocycloalkanes useful for the treatment of cns disorders due to serotonergic dysfunction
WO2004000839A1 (en) 2002-06-19 2003-12-31 Merck Patent Gmbh Thiazole derivatives as phosphodiesterase iv inhibitors
WO2004000814A1 (en) 2002-06-25 2003-12-31 Merck Frosst Canada & Co. 8-(biaryl) quinoline pde4 inhibitors
WO2004005285A1 (en) 2002-07-02 2004-01-15 Almirall Prodesfarma Ag New quinuclidine amide derivatives
WO2004005258A1 (en) 2002-07-02 2004-01-15 Merck Frosst Canada & Co. Di-aryl-substituted-ethane pyridone pde4 inhibitors
WO2004005229A1 (en) 2002-07-08 2004-01-15 Pfizer Products Inc. Modulators of the glucocorticoid receptor
WO2004016601A1 (en) 2002-08-09 2004-02-26 Novartis Ag Benzothiazole derivatives having beta-2-adrenoreceptor agonist activity
WO2004018449A1 (en) 2002-08-10 2004-03-04 Altana Pharma Ag Piperidine-derivatives as pde4 inhibitors
WO2004018457A1 (en) 2002-08-10 2004-03-04 Altana Pharma Ag Pyrrolidinedione substituted piperidine-phthalazones as pde4 inhibitors
WO2004018451A1 (en) 2002-08-10 2004-03-04 Altana Pharma Ag Pyridazinone-derivatives as pde4 inhibitors
WO2004018450A1 (en) 2002-08-10 2004-03-04 Altana Pharma Ag Piperidine-n-oxide-derivatives
WO2004018465A2 (en) 2002-08-17 2004-03-04 Altana Pharma Ag Benzonaphthyridines with pde 3/4 inhibiting activity
WO2004018425A1 (en) 2002-08-21 2004-03-04 Astrazeneca Ab N-4-piperidinyl compounds as ccr5 modulators
WO2004018422A1 (en) 2002-08-23 2004-03-04 Ranbaxy Laboratories Limited Fluoro and sulphonylamino containing 3,6-disubstituted azabicyclo (3.1.0) hexane derivatives as muscarinic receptor antagonists
WO2004019944A1 (en) 2002-08-29 2004-03-11 Altana Pharma Ag 2-hydroxy-6-phenylphenanthridines as pde-4 inhibitors
WO2004026841A1 (en) 2002-09-18 2004-04-01 Sumitomo Pharmaceuticals Co., Ltd. Novel 6-substituted uracil derivative and therapeutic agent for allergic disease
WO2004026873A1 (en) 2002-09-18 2004-04-01 Ono Pharmaceutical Co., Ltd. Triazaspiro[5.5]undecane derivatives and drugs comprising the same as the active ingredient
JP2004107299A (en) 2002-09-20 2004-04-08 Japan Energy Corp New 1-substituted urasil derivative and therapeutic agent for allergic disease
WO2004033412A1 (en) 2002-10-04 2004-04-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel beta mimetics with extended duration of action, method for production and use thereof as medicaments
WO2004037805A1 (en) 2002-10-23 2004-05-06 Glenmark Pharmaceuticals Ltd. Novel tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
WO2004039766A1 (en) 2002-11-01 2004-05-13 Glaxo Group Limited Phenylethanolamine derivatives for the treatment of respiratory diseases
WO2004039762A1 (en) 2002-11-01 2004-05-13 Glaxo Group Limited Phenethanolamine derivatives for the treatment of respiratory diseases
WO2004045607A1 (en) 2002-11-15 2004-06-03 Elbion Ag Novel hydroxyindoles, use as inhibitors of phosphodiesterase 4 and method for production thereof
WO2004046083A1 (en) 2002-11-15 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel dihydroxy-methylphenyl derivatives, method for the production and use thereof as medicaments
WO2004078163A2 (en) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
WO2004101846A1 (en) 2003-05-16 2004-11-25 Sandvik Intellectual Property Ab Cutting tool for metalworking as well as method in the production of cutting tools
WO2004101994A1 (en) 2003-05-19 2004-11-25 Federalnoe Gosudarstvennoe Unitarnoe Predpriiatie 'rossiiskii Federalnyi Iadernyi Centr - Vserossiiskii Nauchno-Issledovatelskii Institut Tehnicheskoi Fisiki Imeni Akademika E.I.Zababahina' Ultrahigh pressure plunger pump
WO2004104561A1 (en) 2003-05-21 2004-12-02 Bayer Technology Services Gmbh Method and device for measuring the content of ferromagnetic particles in liquid suspensions, aerosol dispensers or solid mixtures
WO2006110094A1 (en) 2005-04-14 2006-10-19 Gyros Patent Ab Upward microconduits
WO2007013673A1 (en) 2005-07-29 2007-02-01 Astellas Pharma Inc. Fused heterocycles as lck inhibitors
WO2007126799A2 (en) 2006-03-30 2007-11-08 Novartis Ag Compositions and methods of use for antibodies of c-met
WO2008008539A2 (en) * 2006-07-14 2008-01-17 Amgen Inc. Fused heterocyclic derivatives useful as inhibitors of the hepatocyte growth factor receptor
WO2008100853A1 (en) 2007-02-12 2008-08-21 Wm. Wrigley Jr. Company Confectionery products comprising polyols
WO2008144767A1 (en) 2007-05-21 2008-11-27 Sgx Pharmaceuticals, Inc. Heterocyclic kinase modulators

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences, 18th Ed.", 1990, MACK PRINTING COMPANY, pages: 1289 - 1329
"Remington's Pharmaceutical Sciences, 20th ed.,", 1985, MACK PUBLISHING COMPANY
COOPER ET AL., NATURE, vol. 311, 1984, pages 29 - 33
HELLMAN ET AL.: "Principles and Practice of Oncology., 4th Edition", vol. 1, 1993, article "Principles of Radiation Therapy, Cancer", pages: 248 - 275
JEFFERS; VANDE WOUDE, ONCOGENE, vol. 18, 1999, pages 5120 - 5125
MORDENTI ET AL., TOXICOL PATHOL, vol. 27, no. 1, 1999, pages 14 - 21
NANDY ET AL., ACTA ONCOLOGICA, vol. 33, no. 8, 1994, pages 953 - 961
O'REILLY ET AL., CELL, vol. 79, 1994, pages 315 - 328
O'REILLY ET AL., CELL, vol. 88, 1997, pages 277 - 285
ORGANIC LETT., vol. 31, 2001, pages 139
PARK. ET AL., CELL, vol. 45, 1986, pages 895 - 904
PREWETT ET AL., CANCER RES, vol. 59, 1999, pages 5209 - 5218
SCHMIDT, L. ET AL., NAT. GENET., vol. 16, 1997, pages 68 - 73
SHEN ET AL., CELL, vol. 103, 2000, pages 501 - 10
STAHL AND WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
YUAN ET AL., PROC NATL ACAD SCI U S A, vol. 93, 1996, pages 14765 - 14770
ZHU ET AL., CANCER RES, vol. 58, 1998, pages 3209 - 3214

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2719699A1 (en) * 2009-12-31 2014-04-16 Hutchison Medipharma Limited Certain triazolopyrazines, compositions thereof and methods of use therefor
US9956218B2 (en) 2009-12-31 2018-05-01 Hutchison Medipharma Limited Certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor
US11896592B2 (en) 2009-12-31 2024-02-13 Hutchison Medipharma Limited Certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor
US8987269B2 (en) 2009-12-31 2015-03-24 Hutchison Medipharma Limited Certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor
US10946014B2 (en) 2009-12-31 2021-03-16 Hutchison Medipharma Limited Certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor
US10512645B2 (en) 2009-12-31 2019-12-24 Hutchinson Medipharma Limited Certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor
US10590129B2 (en) 2010-05-17 2020-03-17 Rhizen Pharmaceuticals Sa 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases
EA025281B1 (en) * 2010-05-17 2016-12-30 Инкозен Терапьютикс Пвт. Лтд. 3,5-DISUBSTITUED-3H-IMIDAZO[4,5-b]PYRIDINE AND 3,5-DISUBSTITUED-3H-[1,2,3]TRIAZOLO[4,5-b]PYRIDINE COMPOUNDS AS MODULATORS OF PROTEIN KINASES
US8481739B2 (en) 2010-05-17 2013-07-09 Incozen Therapeutics Pvt. Ltd. 3,5-Disubstituted-3H-imidazo[4,5-b]pyridine and 3,5-disubstituted-3H[1,2,3]triazolo [4,5-b] Pyridine Compounds as Modulators of protein kinases
US8912331B2 (en) 2010-05-17 2014-12-16 Rhizen Pharmaceuticals Sa 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases
CN103068824A (en) * 2010-05-17 2013-04-24 印蔻真治疗公司 Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases
WO2011145035A1 (en) * 2010-05-17 2011-11-24 Indian Incozen Therapeutics Pvt. Ltd. Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases
US10087182B2 (en) 2010-05-17 2018-10-02 Incozen Therapeutics Pvt. Ltd. 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases
CN103068824B (en) * 2010-05-17 2017-09-08 印蔻真治疗公司 It is used as new 3,5 2 substitution 3H imidazos [4,5 B] pyridine and 3,5 2 substitution 3H [1,2,3] triazol [4,5 B] pyridine compounds of protein kinase modulators
EA025281B9 (en) * 2010-05-17 2017-08-31 Инкозен Терапьютикс Пвт. Лтд. 3,5-DISUBSTITUED-3H-IMIDAZO[4,5-b]PYRIDINE AND 3,5-DISUBSTITUED-3H-[1,2,3]TRIAZOLO[4,5-b]PYRIDINE COMPOUNDS AS MODULATORS OF PROTEIN KINASES
CN103459396A (en) * 2011-02-10 2013-12-18 诺瓦提斯公司 [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of c-met tyrosine kinase
CN103459396B (en) * 2011-02-10 2015-08-19 诺瓦提斯公司 As [1,2,4] triazolo [4,3-b] pyridazine compound of c-Met tyrosine kinase inhibitor
WO2012107500A1 (en) * 2011-02-10 2012-08-16 Novartis Ag [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of the c-met tyrosine kinase
US9062045B2 (en) 2011-09-15 2015-06-23 Novartis Ag Triazolopyridine compounds
JP2014526499A (en) * 2011-09-15 2014-10-06 ノバルティス アーゲー 6-Substituted 3- (quinolin-6-ylthio)-[1,2,4] triazolo [4,3-A] pyrazine as tyrosine kinase
US9474762B2 (en) 2011-09-15 2016-10-25 Novartis Ag Triazolopyridine compounds
EA026655B1 (en) * 2011-09-15 2017-05-31 Новартис Аг 6-SUBSTITUTED 3-(QUINOLIN-6-YLTHIO)[1,2,4]TRIAZOLO[4,3-a]PYRIDINES AS c-Met TYROSINE KINASE INHIBITORS
WO2013038362A1 (en) 2011-09-15 2013-03-21 Novartis Ag 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase
CN103958509A (en) * 2011-09-15 2014-07-30 诺华股份有限公司 6 - substituted 3 - (quinolin- 6 - ylthio) - [1,2,4] triazolo [4, 3 -a] pyradines as tyrosine kinase
WO2013098229A2 (en) 2011-12-27 2013-07-04 Bayer Intellectual Property Gmbh Heteroarylpiperidine and piperazine derivatives as fungicides
EP2921494A1 (en) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Heteroarylpiperidine and heteroarylpiperazine derivatives
EP2921485A1 (en) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Isoxazole derivatives
EP2921492A1 (en) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Heteroarylpiperidine and heteroarylpiperazine derivatives
EP2921484A1 (en) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Oxazole derivatives
EP2921493A1 (en) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Heteroarylpiperidine and heteroarylpiperazine derivatives
EP2921481A1 (en) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH 4-piperidine carboxylic acid derivatives
EP2921491A1 (en) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Intermediates for the production of heteroarylpiperidine and heteroarylpiperazine derivatives as fungicides
EP2921495A1 (en) 2011-12-27 2015-09-23 Bayer Intellectual Property GmbH Heteroarylpiperidine and heteroarylpiperazine derivatives as fungicides
US9303015B2 (en) 2012-10-16 2016-04-05 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORγt
US9290476B2 (en) 2012-10-16 2016-03-22 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
US9309222B2 (en) 2012-10-16 2016-04-12 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US9567342B2 (en) 2012-11-06 2017-02-14 Shanghai Fochon Pharmaceutical Co., Ltd. Certain protein kinase inhibitors
US9206166B2 (en) 2012-11-06 2015-12-08 SHANGHAI iNSTITUTE OF MATERIA MEDICA ACADEMY OF SCIENCES Certain protein kinase inhibitors
US10369146B2 (en) 2013-10-15 2019-08-06 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US9328095B2 (en) 2013-10-15 2016-05-03 Janssen Pharmaceutica Nv Heteroaryl linked quinolinyl modulators of RORgammat
US10201546B2 (en) 2013-10-15 2019-02-12 Janssen Pharmaceutica Nv Quinolinyl modulators of RORγt
US9403816B2 (en) 2013-10-15 2016-08-02 Janssen Pharmaceutica Nv Phenyl linked quinolinyl modulators of RORγt
US9624225B2 (en) 2013-10-15 2017-04-18 Janssen Pharmaceutica Nv Quinolinyl modulators of RORγt
US10555941B2 (en) 2013-10-15 2020-02-11 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
US9284308B2 (en) 2013-10-15 2016-03-15 Janssen Pharmaceutica Nv Methylene linked quinolinyl modulators of RORγt
US9221804B2 (en) 2013-10-15 2015-12-29 Janssen Pharmaceutica Nv Secondary alcohol quinolinyl modulators of RORγt
US9346782B2 (en) 2013-10-15 2016-05-24 Janssen Pharmaceutica Nv Alkyl linked quinolinyl modulators of RORγt
EP3241830A1 (en) 2016-05-04 2017-11-08 Bayer CropScience Aktiengesellschaft Condensed bicyclic heterocyclic derivatives as pesticides
WO2020260857A1 (en) 2019-06-13 2020-12-30 AdoRx Therapeutics Limited Hydroxamate compounds as antagonists of the adenosine a2a receptor

Also Published As

Publication number Publication date
US8410264B2 (en) 2013-04-02
BR112012008061A2 (en) 2016-03-01
TW201113284A (en) 2011-04-16
IN2012DN01453A (en) 2015-06-05
JP5775871B2 (en) 2015-09-09
US20110065708A1 (en) 2011-03-17
KR20120089463A (en) 2012-08-10
AU2010284972A1 (en) 2012-03-08
US20120302570A1 (en) 2012-11-29
AR079486A1 (en) 2012-02-01
EP2467383A1 (en) 2012-06-27
EA201200318A1 (en) 2012-09-28
CA2771432A1 (en) 2011-02-24
UY32848A (en) 2011-03-31
JP2013502396A (en) 2013-01-24
MX2012002179A (en) 2012-03-16
US8507676B2 (en) 2013-08-13

Similar Documents

Publication Publication Date Title
US8507676B2 (en) Heterocyclic oxime compounds
US8497368B2 (en) Heterocyclic hydrazone compounds
TWI383982B (en) Imidazoquinolines as lipid kinase inhibitors
US9474762B2 (en) Triazolopyridine compounds
US20100305113A1 (en) Substituted Imidazopyridazines as Lipid Kinase Inhibitors
JP2010504933A (en) Pyrazolopyrimidines as PI3K lipid kinase inhibitors
EP2462143B1 (en) 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives as c-met tyrosine kinase modulators
US20130324526A1 (en) [1,2,4] triazolo [4,3-b] pyridazine compounds as inhibitors of the c-met tyrosine kinase
CN102548995B (en) Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation
CN102574853B (en) Heterocyclic oxime compounds

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080047132.X

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10762878

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2010284972

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1453/DELNP/2012

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2771432

Country of ref document: CA

Ref document number: 2012525167

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: MX/A/2012/002179

Country of ref document: MX

REEP Request for entry into the european phase

Ref document number: 2010762878

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2010762878

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2010284972

Country of ref document: AU

Date of ref document: 20100818

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 201200318

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 20127007032

Country of ref document: KR

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112012008061

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112012008061

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20120217