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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • 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
  • A61P35/02—Antineoplastic agents specific for leukemia
• • 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

Definitions

• the invention relates to novel substituted imidazopyridazines that are useful as anti-cancer agents.
• This invention also relates to a method of using the compounds in the treatment of proliferative and other types of diseases and to pharmaceutical compositions containing the compounds.
• the invention relates to fused heterocyclic compounds which inhibit protein kinase enzymes, compositions which contain protein kinase inhibiting compounds and methods of using inhibitors of protein kinase enzymes to treat diseases which are characterized by an overexpression or upregulation of protein kinases.
• Protein kinases mediate intracellular signal transduction. They do this by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway.
• An extracellular stimulus may effect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.
• Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
• Serine/threonine kinases are a class of protein kinases that are among the most promising drug targets for future small molecule inhibitors. Inhibition of serine/threonine kinases is likely to have relevance to the treatment of cancer, diabetes and a variety of inflammatory disorders.
• Gleevec as a Bcr/Abl protein kinase inhibitor has provided further evidence that protein kinases including protein kinase CK2 are valid drug targets for potential cancer therapies.
• Protein kinase CK2 (formerly known as casein kinase II) is a highly conserved serine/threonine kinase. In mammals, the enzyme exists in two isozymic forms, CK2 ⁇ (CK2A1) and CK2 ⁇ ' (CK2A2), due to variations in the catalytic subunits of the enzyme. Protein kinase CK2 is ubiquitously distributed and constitutively active in eukaryotes. It interacts with a variety of cellular proteins and has been implicated in cell replication such as cell proliferation and differentiation, cellular survival, and tumorigenesis.
• protein kinase CK2 has been implicated in kidney tumors (Stalter et al, "Asymmetric expression of protein kinase CK2 subunits in human kidney tumors", Biochem. Biophys. Res.
• mammary gland tumors Landesman-Bollag et al., "Protein kinase CK2 in mammary gland tumorigenesis", Oncology, 20:3247-3257 (2001)
• lung carcinoma Daya-Makin et al., "Activation of a tumor-associated protein kinase (p40TAK) and casein kinase II in human squamous cell carcinomas and adenocarcinomas of the lung", Cancer Res., 54:2262-2268 (1994)
• head and neck carcinoma Feaust et al., "Antisense oligonucleotides against protein kinase CK2- ⁇ inhibit growth of squamous cell carcinoma of the head and neck in vitro", Head Neck, 22:341-346 (2000)
• prostate cancer Wang et al., "Role of protein kinase CK2 in the regulation of tumor
• Inhibitors of protein kinases are widely sought and several publications report effective classes of compounds.
• pyrazolotriazines as CK2 kinase inhibitors were reported in Nie et al. (Bioorgainic & Medicinal Chemistry Letters, 17 (2007)) and imidazopyridazines as IRAK kinase modulators were reported in WO 2008/030579.
• certain imidazopyridazine compounds were disclosed in WO 2007/038314, published April 5, 2007, WO 2008/0045536, published February 21, 2008, both assigned to the present assignee.
• the present invention relates to a new class of imidazopyridazineamides found to be effective inhibitors of protein kinases, particularly the CK2 kinase. These novel compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index and toxicity values that are important to their drugability.
• the invention is directed to fused heterocyclic compounds of Formulae (I)-(If) that inhibit protein kinase enzymes, especially protein kinase CK2 for the treatment of cancer, or stereoisomers, tautomers, pharmaceutically acceptable slats, solvates or prodrugs thereof.
• the present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides a method for inhibiting the activity of protein kinase CK2 comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides a method for inhibiting angiogenesis or treating cancers comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy.
• the present invention also provides the use of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, in preparing a medicament for the treatment of cancer in a human patient, particularly a cancer receptive to treatment via inhibition of the CK2 enzyme.
• the invention provides for novel imidazopyridazine compounds useful as anti-cancer agents, pharmaceutical compositions employing such novel compounds and for methods of using such compounds. [0017] In accordance with the invention, there are disclosed compounds of formula I
• Ri and R 3 are each independently selected from hydrogen, halogen, cyano, and Ci_ 4 alkyl;
• R 2 is selected from cycloalkyl, substituted cycloalkyl, heterocyclo, substituted heterocyclo, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R 5 is selected from hydrogen and Ci_ 4 alkyl;
• Re is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclo, substituted heterocyclo, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and R 7 is selected from hydrogen and Ci_ 4 alkyl; or Re and R7 together with the nitrogen atom to which they are attached form an optionally substituted 5-, 6- or 7-membered monocyclic heteroaryl or heterocyclo ring, or an optionally substituted 7- to 11-membered bicyclic heteroaryl or heterocyclo ring; Rs is selected from hydrogen and Ci- 4 alkyl; and
• R 2 is then R 3 is not hydrogen.
• R 2 is selected from aryl, substituted aryl, C3-7cycloalkyl, substituted C3-7cycloalkyl, 5- or 6-membered heterocyclo and heteroaryl, and substituted 5- or ⁇ membered heterocyclo and heteroaryl.
• R 2 is selected from phenyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, benzothiazolyl, pyridazinyl pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thienyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, triazinyl, and triazolyl, wherein each R 2 is optionally substituted with halogen, cyano, hydroxy, Ci- 4 alkyl, substituted Ci- 4 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Ci- 4 alkoxy, haloalkyl, C 3 - 7 cycloalkyl, heterocyclo, heteroaryl, -NR 2a R 2b , -
• R 4 is selected from alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl, wherein each R 4 is optionally substituted by one to three groups, T 1 , T 2 , and/or T3; T 1 , T 2 , and T3 are each independently selected from halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, nitro, cyano, -(CHR) 1 -SO 3 H, -(CHR) 1 SR 9 , -(CHR) r S(O) p R ⁇ , -(CHR) 1 S(O) ⁇ NR 9 R 1 O, -(CHR) r NR 9 S(O) p R ⁇ , -(CHR) 1 OR 9 , -(CHR) 1 -NR 9 R 1 O, -(CHR) r NR 9
• R 6 is selected from Ci- 4 alkyl, aryl, C3-7cycloalkyl, 5- or 6-membered monocyclic heterocyclo and heteroaryl ring, wherein R 6 is optionally substituted by one to three groups, T 4 , T 5 , and/or T 6 ; T 4 , T 5 and T 6 are independently selected from halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, nitro, cyano, -(CHR) 1 SRi 5 , -(CHR) 1 S(O) 9 Ri 7 , -(CHR) 1 S(O) 9 NRi 5 Ri 6 , -(CHR) 1 NRi 5 S(O) 9 Ri 7 , -(CHR) 1 NR I5 S(O) 9 NR I5 R I6 , -(CHR) 1 OR I5 ,
• R 6 is selected from Ci_ 4 alkyl, aryl, C 3 _ 7 cycloalkyl, 5- or 6-membered monocyclic heterocyclo and heteroaryl ring, wherein R 6 is optionally substituted by one to three groups, T 4 , T 5 , and/or T 6 ; T 4 , T 5 and T 6 are independently selected from halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, nitro, cyano, -(CHR) 1 SR 15 , -(CHR) 1 S(O) 9 R 17 , -(CHR) 1 S(O) 9 NR 15 R 16 , -(CHR) 1 NR 15 S(O) 9 R 17 , -(CHR) 1 NR 15 S(O) 9 NR 15 R 16 , -(CHR) 1 OR 15 , -(CHR) 1 SR 15 , -(CHR)
• R 6 is Ci_ 4 alkyl optionally substituted by one to three groups, T 4 , T 5 , and/or T 6 ;
• R 15 and R 16 are each independently selected from hydrogen, alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, and substituted heterocyclo;
• R 7 is selected from hydrogen and C ⁇ alkyl; or
• R 6 and R 7 together with the nitrogen atom to which they are attached form an optionally substituted 5-, 6- or 7-membered monocyclic heteroaryl or heterocyclo ring, or an optionally substituted 7- to 11-membered bicyclic heteroaryl or heterocyclo ring.
• R 6 and R 7 together with the nitrogen atom to which they are attached form an optionally substituted 5-, 6- or 7-membered monocyclic heteroaryl or heterocyclo ring, or an optionally substituted 7- to 11-membered bicyclic heteroaryl or heterocyclo ring.
• R 2 is selected from aryl, substituted aryl, C3_7cycloalkyl, substituted C3_7cycloalkyl, 5-or 6-membered heterocyclo and heteroaryl, and substituted 5- or 6- membered heterocyclo and heteroaryl optionally substituted with halogen, cyano, hydroxy, Ci- 4 alkyl, substituted Ci- 4 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Ci- 4 alkoxy, haloalkyl, C 3 _ 7 cycloalkyl, heterocyclo, heteroaryl, -NR 2a R 2b , -NR 2a C(O)R 2b , C(O)NR 2a R 2b -C(O)OR 2a , wherein R 2a and R 2b are each independently selected from hydrogen and Ci- 4 alkyl; R 4 is selected from hydrogen, Ci_ 4 alkyl, aryl, C 3 _ 7 cycloal
• R 9 and Rio are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, and substituted heterocyclo; or R 9 and Rio together with the nitrogen atom to which they are attached form a heteroaryl or heterocyclo, wherein said heteroaryl or heterocyclo is optionally substituted as valence allows from one to three groups, R 12 , R 1 3 and/or Ri 4 ; each Rn is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; R12, R13, and Ri 4 are each independently selected from Ci_ 4 alkyl, substituted Ci_ 4 alkyl, C 2 - 4 alkenyl, substituted C 2
• R 6 is selected from C 1-4 alkyl, aryl, C 3 _7cycloalkyl, 5- or 6- membered monocyclic heterocyclo and heteroaryl, wherein R 6 is optionally substituted by one to three groups, T 4 , T 5 , and/or T 6 ;
• T 4 , T 5 and T 6 are independently selected from halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, nitro, cyano, -(CH 2 ) r SRi 5 , -(CH 2 ) r S(O) ?
• R 2 is selected from phenyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl and benzothiazolyl, wherein each R 2 is optionally substituted with F, Cl, Br, cyano, Ci_ 4 alkyl, Ci- 4 alkoxy, haloalkyl, C3_7cycloalkyl, heterocyclo, heteroaryl, -OR 23 , -NR 2a R 2 b, -NHC(O)R 2a -C(O)NR 2a R 2 b wherein R 2a and R 2 b are each independently selected from hydrogen and Ci_ 4 alkyl; R 4 is selected from Ci- 4 alkyl, phenyl, C 3 _ 6 cycloalkyl, and 4-, 5-, or 6- membered monocyclic heteroaryl or heterocyclo, each optionally substituted by one to two groups, T 1 , and/or T
• -(CH 2 ) r pyrazolyl -(CH 2 ) r cyclopropyl, -(CH 2 ) r pyrrolidinyl, -(CH 2 ) r piperidinyl, -(CH 2 ) r furyl, -(CH 2 ) r imidazolyl, -(CH 2 ) r pyrimidinyl, -(CH 2 ) r piperazinyl, and -(CH 2 ) r pyradizinyl, -(CH 2 ) r imidazolyl, -(CH 2 ) r pyrazolyl, -(CH 2 ) r triazolyl, -(CH 2 ) r tetrazolyl, -(CH 2 ) r thiazolyl, each group optionally substituted as valence allows from one to three groups, Ri 2 , R 1 3 and/or R 14 ; each r is independently zero, 1, 2,
• R 9 and Rio are each independently selected from hydrogen, Ci_ 4 alkyl, haloCi_ 4 alkyl, -(CH 2 ) r OH, -(CH 2 ) r N(alkyl) 2 , C 3 - 6 cycloalkyl, phenyl, pyrrolidinyl, morpholinyl, and pyridyl, each ring optionally substituted with NH 2 , Ci_ 4 alkyl and aryl; each Rn is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; Ri 2 , R 13 , and Ri 4 , are each independently selected from hydroxy, Ci_ 4 alkyl optionally substituted with hydroxy and halogen and phenyl; R 6 is selected from Ci_ 4 alkyl, C3_7cycloalkyl, a 5- to
• each w is independently 1, 2, or 3; alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclo, substituted heterocyclo, wherein the substituent is selected from Ci_ 4 alkyl, F, Cl, Br, NH 2 , NO 2, CN, and OH; Ri 8 and R 19 are each independently selected from hydrogen, Ci_ 4 alkyl, C 2 _ 4 alkenyl, and C 2 _ 4 alkynyl, each optionally substituted with C 1 ⁇ alkyl -(CH 2 ) r -C 3 - 6 cycloalkyl, F, Cl, Br, CN, NO 2 , NH 2 , CO 2 H,
• Compounds of the invention include, without limitation, the following:
• Yet another embodiment is directed to use of a compound according to formula I, and/or use of a compound of formula I(a), in preparing a medicament for the treatment of cancer in a human patient, particularly a cancer receptive to treatment via inhibition of the CK2 enzyme.
• alkyl refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
• lower alkyl refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
• substituted alkyl refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylsulfon
• halogen refers to fluorine (flouro), chlorine (chloro), bromine (bromo) and iodine (iodo).
• aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
• aryloxy refers to an aryl or substituted aryl bonded to an oxygen; an amino; an alkylamino; a thio; an alkanoylamino; a sulfonyl; an alkoxy; a sulfinyl; a heteroaryl or substituted heteroaryl; an alkylthio; a carbonyl; an alkenyl; or an alkylsulfonyl, respectively.
• arylsulfonylaminocarbonyl refers to an
• aryloxyalkyl refers to an aryloxy bonded to an alkyl or substituted alkyl; a carbonyl; or an aryl or substituted aryl, respectively.
• arylalkyl refers to an alkyl or substituted alkyl in which at least one of the hydrogen atoms bonded to at least one of the carbon atoms is replaced with an aryl or substituted aryl.
• Typical arylalkyls include, but are not limited to, for example, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2- naphthylethan-1-yl, 2-naphthylethen-l-yl, naphthobenzyl, and 2-naphthophenylethan- 1-yl.
• arylalkyloxy refers to an arylalkyl bonded through an oxygen linkage (-O-arylalkyl).
• substituted aryl refers to an aryl group substituted by, for example, one to four substituents such as alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carba
• the substituent may be further substituted by hydroxy, halo, alkyl, alkoxy, alkenyl, alkynyl, aryl or arylalkyl.
• heteroaryl refers to an optionally substituted, aromatic group for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom and at least one carbon atom-containing ring, for example, pyridine, tetrazole, indazole, thiophene, indole, pyrimidine.
• alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four double bonds.
• substituted alkenyl refers to an alkenyl group substituted by, for example, one to two substituents, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
• alkynyl refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2
• substituted alkynyl refers to an alkynyl group substituted by, for example, a substituent, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclyl, e.g.
• a substituent such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy
• heterocycle refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
• Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized.
• the heterocyclic group may be attached at any heteroatom or carbon atom.
• Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, homopiperazinyl, 2- oxohomopiperazinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyri
• Exemplary bicyclic heterocyclic groups include indolyl, 2,3-dihydro-2- oxo-lH-indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3- c]pyridinyl, furo[3,l-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl
• substituents include one or more alkyl or arylalkyl groups as described above or one or more groups described above as alkyl substituents.
• smaller heterocyclyls such as, epoxides and aziridines.
• carbocyclic ring or “carbocyclyl” refers to stable, saturated, partially saturated or unsaturated, mono or bicyclic hydrocarbon rings that contain 3- 12 atoms. Particularly, this includes a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.
• Suitable values include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, dihydroindenyl and tetrahydronaphthyl.
• the term "optionally substituted” as it refers to "carbocyclic ring" or “carbocyclyl” herein indicates that the carbocyclic ring may be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino), dialkylamino (preferably a di[lower]alkylamino), cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido
• alkoxyalkyl preferably a lower alkoxy[lower]alkyl
• alkoxycarbonyl preferably a lower alkoxycarbonyl
• alkylcarbonyloxy preferably a lower alkylcarbonyloxy
• aryl preferably phenyl
• heteroatoms shall include oxygen, sulfur and nitrogen.
• amide refers to the group -C(O)NH 2 .
• sulfonamide refers to the group -SO 2 NH 2 .
• substituted amide refers to an amide, sulfonamide, or carbamate, respectively, having at least one hydrogen replaced with a group chosen from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, and substituted cycloalkyl.
• a substituted sulfonamide refers to the group -SO 2 NR°R P wherein R° and R p are independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, and substituted cycloalkyl, provided at least one of R° or R p is a substituted moiety.
• cyano refers to the group -CN.
• cycloalkylalkyl or “cycloalkylalkoxy” refer to a cycloalkyl or substituted cycloalkyl bonded to an alkyl or substituted alkyl; or an alkoxy, respectively.
• nitro refers to the group -N(O) 2 .
• thio refers to the group -SH.
• alkylthio refers to the group -SR S where R s is an alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.
• thioalkyl refers to the group -R 1 S where R 1 is an alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.
• carboxyalkoxy or “alkoxycarbonylalkoxy” refer to a carboxy, or an alkoxycarbonyl, respectively, bonded to an alkoxy.
• arylalkoxycarbonyl refers to an aryl or substituted aryl bonded to an alkoxycarbonyl.
• alkylcarbonyloxy or arylcarbonyloxy refer to the group
• alkylcarbonyl refers to an alkyl or substituted alkyl; an amino; an alkylamino or substituted alkylamino; an aminoalkyl or substituted aminoalkyl; or an arylamino, respectively, bonded to a carbonyl.
• aminocarbonylaryl or “aminocarbonylalkyl” refer to an aminocarbonyl bonded to an aryl or substituted aryl; or an alkyl or substituted alkyl, respectively.
• carboxyalkyl refers to an alkyl or substituted alkyl bonded to a carboxy.
• hydroxy herein alone or as part of another group refers to -OH.
• the compounds of formula I may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
• the compounds of formula I may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like.
• alkali metals such as sodium, potassium and lithium
• alkaline earth metals such as calcium and magnesium
• organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like.
• amino acids such as arginine, lysine and the like.
• the compounds for formula I may form salts with a variety of organic and inorganic acids.
• Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like).
• Such salts can be formed as known to those skilled in the art.
• zwitterions in addition, zwitterions (“inner salts”) may be formed.
• All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
• the definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity.
• the racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
• the individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
• Compounds of the formula I may also have prodrug forms.
• prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form.
• the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same.
• Prodrugs are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
• Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxy, free amino, or free sulfhydryl group, respectively.
• Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
• Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 112, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krosgaard-
• the compounds of the invention modulate kinase activity.
• Types of kinase activity may be modulated by the compounds of the invention including, but not limited to, AAKl, ABL, ACK, ACTR2, ACTR2B, ADCK3, ADCK4, AKTl, AKT2, AKT3, ALK, ALKl, ALK2, ALK4, AMPKAl, AMPKA2, ARG, AURA, AURB, AURC, AXL, BCR-ABL, BIKE, BLK, BMPRlA, BMX, BRAF, BRSK2, BRK, BTK, CAMKlA, CAMK2A, CAMK2B, CAMKlD, CAMK2D, CAMKlG, CAMK2G, CAMKKl, CAMKK2, CDKl, CDK2, CDK5, CHK2, CK1A2, CKlD, CKlE, CKlGl, CK1G2, CK2A1, CK
• compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) have particular utility in treating proliferative conditions associated with the modulation of kinase activity, and particularly the inhibition of tyrosine and serine/threonine kinase activities.
• the compounds of the present invention can be used to treat proliferative disorders associated with abnormal kinase activity.
• treating and “treatment” encompass either or both responsive and prophylaxis measures, e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms.
• one aspect of the invention is the use of a compound of the Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an antiproliferative effect in a warm-blooded animal such as a human being.
• a method for producing an antiproliferative effect in a warm-blooded animal such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),or (If) or a pharmaceutically acceptable salt thereof as defined herein before.
• solvates e.g., hydrates
• Methods of solvation are generally known in the art.
• a compound of the formula I, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an antiproliferative effect in a warm-blooded animal such as a human being.
• a method for producing an antiproliferative effect in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined herein before.
• the anti-proliferative treatment defined herein before may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
• the compounds of this invention may also be useful in combination with known anti-cancer and cytotoxic agents and treatments, including radiation. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range.
• Compounds of formula I may be used sequentially with known anticancer or cytotoxic agents and treatment, including radiation when a combination formulation is inappropriate.
• anti-cancer agent includes any known agent that is useful for the treatment of cancer including the following: 17 ⁇ -ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, Zoladex; matrix metalloproteinase inhibitors; VEGF inhibitors, such as anti-VEGF antibodies (AVASTIN®) and small molecules such as ZD6474 and SU6668; Vatalanib, BAY-43-9006, SUl 1248, CP-547632, and CEP-7055; HER 1
• GLEEVEC® and dasatinib CASODEX® (bicalutamide, Astra Zeneca), Tamoxifen; MEK-I kinase inhibitors, MAPK kinase inhibitors, PI3 kinase inhibitors; PDGF inhibitors, such as imatinib; anti-angiogenic and antivascular agents which, by interrupting blood flow to solid tumors, render cancer cells quiescent by depriving them of nutrition; castration, which renders androgen dependent carcinomas non-proliferative; inhibitors of non-receptor and receptor tyrosine kinases; inhibitors of integrin signaling; tubulin acting agents such as vinblastine, vincristine, vinorelbine, vinflunine, paclitaxel , docetaxel, 7-O- methylthiomethylpaclitaxel, 4-desacetyl-4-methylcarbonatepaclitaxel, 3 '-tot-butyls' -N-tert-butyl
• 6-thioguanine and 6-mercaptopurine glutamine antagonists, e.g. DON (AT-125; d-oxo-norleucine); ribonucleotide reductase inhibitors; mTOR inhibitors; and haematopoietic growth factors.
• Additional cytotoxic agents include, cyclophosphamide, doxorubicin, daunorubicin, mitoxanthrone, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, bicalutamide, leuprolide, pyridobenzoindole derivatives, interferons, and interleukins.
• cytotoxic agents include, cyclophosphamide, doxorubicin, daunorubicin, mitoxanthrone, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, bicalutamide, leuprolide, pyridobenzoindole derivative
• the other component(s) of such treatment in addition to the antiproliferative treatment defined herein before may be surgery, radiotherapy or chemotherapy.
• chemotherapy may cover three main categories of therapeutic agent: (i) antiangiogenic agents that work by different mechanisms from those defined herein before (for example, linomide, inhibitors of integrin ⁇ v ⁇ 3 function, angiostatin, razoxane);
• cytostatic agents such as antiestrogens (for example, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene), progestogens (for example, megestrol acetate), aromatase inhibitors (for example, anastrozole, letrozole, borazole, exemestane), antihormones, antiprogestogens, antiandrogens (for example, flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example, gosereline acetate, leuprolide), inhibitors of testosterone 5 ⁇ -dihydroreductase (for example, finasteride), farnesyltransferase inhibitors, anti- invasion agents (for example, metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasmin
• the formula I compounds of the invention are of interest for their antiproliferative effects. Such compounds of the invention are expected to be useful in a wide range of disease states including cancer, psoriasis, and rheumatoid arthritis.
• the compounds of formula I are useful in the treatment of a variety of cancers, including (but not limited to) the following:
• - carcinoma including that of the prostate, pancreatic ductal adreno- carcinoma, breast, colon, lung, ovary, pancreas, and thyroid; - tumors of the central and peripheral nervous system, including neuroblastoma, glioblastoma, and medullobalstoma; and
• tumors including melanoma and multiple myeloma.
• inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation and inflammatory bowel disease.
• any disease process e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation and inflammatory bowel disease.
• the compounds of formula I are especially useful in treatment of tumors having a high incidence of protein kinase activity, such as prostate, colon, brain, thyroid and pancreatic tumors. Additionally, the compounds of the invention may be useful in treatment of sarcomas and pediatric sarcomas.
• a composition (or a combination) of the compounds of this invention By the administration of a composition (or a combination) of the compounds of this invention, development of tumors in a mammalian host is reduced.
• compositions of the invention containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may 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.
• Formulations for oral use may also 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 soluble carrier such as polyethyleneglycol 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 soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
• the pharmaceutical compositions may be in the form of sterile injectable aqueous solutions.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• the sterile injectable preparation may also be a sterile injectable oil-in- water microemulsion where the active ingredient is dissolved in the oily phase.
• the active ingredient may be first dissolved in a mixture of soybean oil and lecithin.
• the oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
• the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
• a continuous intravenous delivery device may be utilized.
• An example of such a device is the Deltec CADD-PLUS. TM. Model 5400 intravenous pump.
• compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
• This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.
• the combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent or treatment within its approved dosage range.
• Compounds of formula I may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of formula I may be administered either prior to or after administration of the known anticancer or cytotoxic agent(s).
• a combination product can, for example, utilize a dosage of the compound of formula I within the dosage range described above and the dosage of another anti-cancer agent/treatment within the approved dosage range for such known anti-cancer agent/treatment. If a combination product is inappropriate, the compound of formula I and the other anti-cancer agent/treatment can, for example, be administered simultaneously or sequentially. If administered sequentially, the present invention is not limited to any particular sequence of administration.
• compounds of formula I can be administered either prior to, or after, administration of the known anti-cancer agent or treatment.
• the compounds may be administered in a dosage range of about 0.05 to 200 mg/kg/day, preferably less than 100 mg/kg/day, in a single dose or in 2 to 4 divided doses.
• BIOLOGICAL ASSAYS A. CK2 Kinase Assay The effectiveness of compounds of the present invention as inhibitors of protein kinases can be readily tested by assays known to those skilled in the art. For example, in vitro protein kinase assays may be conducted with a relevant purified protein kinase and an appropriate synthetic substrate to determine the inhibitory activities of the compounds. Assays for inhibition of CK2 by the instant compounds were performed in 384-well plates with reaction mixtures containing 10 ⁇ M of peptide substrate (RRRADDSDDDDD-NH2), [ ⁇ - 33 P]ATP (10 ⁇ Ci) at 25 ⁇ M
• CK2A1 CK2A1
• CK2A2 5 ⁇ M
• CK2A2 20 mM Hepes (pH 7.4), 100 mM NaCl, 10 mM MgCl 2 , 0.25 mM dithiothreitol, Brij-35 at 0.015%
• recombinant CK2A1 10 nM, Invitrogen
• CK2A2 5 nM, Upstate Biotechnology
• Reaction mixtures were incubated at 30 0 C for 1 h, and reaction products were captured by binding to phosphocellulose (P81) filter plates. Incorporation of radioactive phosphate into the peptide substrate was determined by liquid scintillation counting.
• the potency of compounds in inhibiting CK2 is expressed as IC50, defined as the concentrations of compounds required to inhibit the enzymatic activity by 50%.
• Compounds of the present invention exhibit enhanced CK2 inhibitory activity.
• the compounds of the invention herein e.g., compounds of Formula (I) (including Formulae (Ia), (Ib), (Ic), (Id), (Ie), and (If) are surprisingly advantageous for their CK2 enzyme inhibition activity and/or other drugability properties, e.g., having desirable stability, bioavailability, therapeutic index and/or toxicity values that are important to their use as pharmaceutical agents.
• the compounds of the present invention may be prepared by methods such as those illustrated in the following schemes. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture compounds disclosed herein. Different methods may be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound(s). All documents cited herein are incorporated herein by reference in their entirety.
• the time taken to complete a reaction procedure will be judged by the person performing the procedure, preferably with the aid of information obtained by monitoring the reaction by methods such as HPLC or TLC.
• a reaction does not have to go to completion to be useful to this invention.
• the methods for the preparation of various heterocycles used to this invention can be found in standard organic reference books, for example, Comprehensive Heterocyclic Chemistry, The Structure, Reactions, Synthesis and Uses, of Heterocyclic Compounds, Katritzky, A.R., Rees, C. W., eds.
• A C 1-4 lower alkyl
• HaIi-HaI 4 Cl, Br, I, F
• a formate ester such as ethyl formate
• a base such as sodium ethoxide
• suitable solvent such as ethanol
• Step 2 Halogenation of a suitably substituted pyridazine-3 -amine such as 6- chloropyridazine-3 -amine using a reagent such as bromine in an appropriate solvent such as ethanol provides compounds of formula ii.
• Step 5 Activation of the carboxylic acid of compound v through, for example, formation of the acid chloride with thionyl chloride in a suitable solvent such as dichloromethane affords compounds of formula vi.
• Step 6 Reaction of vi with an amine in a solvent such as dichloromethane or dimethylformamide in the presence of a tertiary amine base such as triethyl amine affords amides of formula vii.
• steps 5-6 may be accomplished in a single step through use of a coupling reagent such as BOP or DCC.
• Step 8 Compound viii may be treated with a suitable amine either neat or in an appropriate solvent such as dimethylformamide or N-methylpyrrolidine at elevated temperature or in a microwave to afford compounds of formula ix.
• P protecting group
• a base such as diisopropylethyamine or potassium tert-butoxide
• Step 2 Treatment of compound x with with a suitable amine either neat or in an appropriate solvent such as dimethylformamide or N-methylpyrrolidine at elevated temperature or in a microwave to afford compounds of formula xi.
• acylation may be effected by treatment with a reagent such as an acid chloride in a solvent such as dichloromethane in the presence of a base such as triethylamine.
• Sulfonamides may be prepared by treatment of xiii with a sulfonylchloride in an appropriate solvent such as dichloromethane or THF in the presence of a base such as triethylamine or diisopropylamine to afford compounds of general formula xv.
• Step 3 Ureas may be prepared by treatment of xiii with an appropriately substituted isocyanate in a solvent such as dimethylformamide or THF to afford compounds of general formula xvi.
• Step 4 Treatment of compounds of general formula xiii with a sulfamoyl chloride in the presence of a base such as diisopropylethylamine in a suitable solvent such as dichloromethane affords sulfonyl ureas of general formula xvii.
• a base such as diisopropylethylamine
• a suitable solvent such as dichloromethane
• Step 5 Treatment of xiii with an appropriate alkyl bromide such as methyl 2- bromoacetate in the presence of a base such as diisopropylethyl amine in an aprotic solvent such as dichloromethane or THF affords alkyl substituted amines of formula xviii.
• an appropriate alkyl bromide such as methyl 2- bromoacetate
• a base such as diisopropylethyl amine
• an aprotic solvent such as dichloromethane or THF
• Step 6 Treatment of xiii with a chlorocarbonate in the presence of a base such as diisopropylethylamine in an appropriate solvent such as dichloromethane affords carbamates of general formula xix.
• a base such as diisopropylethylamine
• an appropriate solvent such as dichloromethane
• the final removal of the protecting group (P) from xiv-xix may be effected by a variety of known conditions.
• P is equivalent to a p- methoxybenzyl group
• treatment with trifluoroacetic acid in a solvent such as dichloromethane at ambient or elevated temperatures affords compounds of general formula xx-xxv.
• compounds of formula xxvi may be reacted with an acylating reagent such as an acid chloride or sulfonyl chloride in the presence of a base such as sodium hydride in a solvent such as dimethylformamide to afford compounds of general formula xxvii (Step 1).
• an acylating reagent such as an acid chloride or sulfonyl chloride in the presence of a base such as sodium hydride in a solvent such as dimethylformamide
• ethyl 2-chloro-3-oxopropanoate (4.5 g, 29.9 mmol, 15.44 % yield).
• Solvent B (90% MeOH, 10 % H 2 O, 0.1% TFA).
• Solvent A (10% MeOH, 90 % H 2 O, 0.1% TFA).
• aqueous layer was acidified with HCl (IN) to pH 4 and then extracted with ethyl acetate (3x).
• the ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a mixture of 8-bromo-6-chloroimidazo[l,2-b] pyridazine-3-carboxylic acid and 6,8- dichloroimidazo[l,2-b]pyridazine -3-carboxylic acid (150 mg, 0.543 mmol, 55%).
• Solvent B (90% MeOH, 10 % H 2 O, 0.1% TFA).
• Solvent A (10% MeOH, 90 % H 2 O, 0.1% TFA).
• Solvent B (90% MeOH, 10 % H 2 O, 0.1% TFA).
• Solvent A (10% MeOH, 90 % H 2 O, 0.1% TFA).
• Solvent B (90% MeOH, 10% H 2 O, 0.2% H 3 PO 4 ).
• Solvent A (10% MeOH, 90% H 2 O, 0.2% H 3 PO 4 ).
• reaction mixture was fitted with a reflux condenser and heated to 65 0 C for Ih, whereupon it slowly became a light yellow, homogeneous solution.
• the mixture was cooled to room temperature, toluene was added, and the solution was concentrated in vacuo. (This process was repeated two more times to remove excess oxalyl chloride.)
• the resulting solid was dried in vacuo.
• the light yellow solid was then suspended in 1 ,2-dichloroethane (33.2 mL) and charged with 3-fluoropyridin-4-amine (1.160 g, 10.34 mmol) and DIEA (4.52 mL, 25.9 mmol). The resulting light tan suspension stirred overnight at room temperature.
• a -1 1 mixture 6,8-dichloroimidazo[l,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[l,2-b]pyridazine-3-carboxylic acid ID (4.7 g, 18.6 mmol) was suspended in DCE (140 mL), and treated with neat oxalyl chloride (2.65 mL 30.4 mmol) followed by N,N-dimethylformamide (0.08 mL, 1.034 mmol). The reaction mixture was heated at 65 0 C for 5 hours, concentrated and dried under high vacuum for lhr and taken into the next step without further purification.
• reaction mixture was filtered through Buchner funnel, washed with DCE (2x25 mL) to isolate a 1 : 1 mixture of 6, 8-dichloro-N-(3 -fluoropyridin-4-yl)imidazo [ 1 ,2-b]pyridazine-3 - carboxamide and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[l,2- b]pyridazine-3-carboxamide (5.2 g, 15.0 mmol, 80 % yield) as light brown solid.
• a —1 1 mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[l,2- b]pyridazine-3 -carboxamide and 8-bromo-6-chloro-N-(3 -fluoropyridin-4- yl)imidazo[l,2-b]pyridazine-3-carboxamide 8A (3g, 8.6mmol), N-(4-methoxybenzyl) cyclopropanamine (1.79 g, 10.12 mmol) and N,N-diisopropylethylamine (2.41 mL, 13.80 mmol) were suspended in DMF (30 mL) and heated at 80 0 C for 1 hr.
• the reaction mixture was concentrated, dried under reduced pressure for 16 hrs, suspended in methanol (20 mL) and an off-white solid collected via Buchner filtration (2x10 mL methanol rinse) and taken to the next step without further purification.
• the reaction mixture was combined with trans- 1 ,4-diaminocyclohexane (16.28 g, 143 mmol) and heated at 160 0 C for 2.5 hours.
• the reaction was cooled to room temperature, and water (40 mL) was added, and the solid collected via Buchner filtration.
• the crude product was purified with silica gel chromatography using a stepwise gradient of 10% methanol / chloroform to 25% methanol / chloroform / 1% triethylamine to isolated a foamy solid.
• the solid was suspended in water (50 mL) and collected with Buchner filtration (2X25mL water wash) and dried for 16 hrs under reduced pressure to isolate 6-((trans)-4-aminocyclohexylamino)-8- (cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[l,2- b]pyridazine-3 -carboxamide (3.2 g, 5.58 mmol, 63 % yield) as a off white solid.
• BOP (62.5 mg, 0.141 mmol) was added to a solution of 6-((trans)-4- aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3- fluoropyridin-4-yl)imidazo[l,2-b]pyridazine-3-carboxamide 8B (20 mg, 0.047 mmol), DIEA (0.0062 mL, 0.035 mmol) and (S)-2-(tert- butoxycarbonylamino)propanoic acid (17.83 mg, 0.094 mmol) in DMF (1 mL). The clear reaction mixture was stirred at room temperature for 30 min.
• reaction mixture was concentrated down, dissolved in CH 2 CI 2 (0.50 mL) and TFA (0.545 mL, 7.07 mmol) and stirred at rt for 30 min.
• the reaction mixture was concentrated and purified with HPLC (Phenomenex Axia Luna 5 micron 30 x 100 mm) 20% B
• reaction mixture was stirred at room temperature for 2 hrs, concentrated, re-dissolved in TFA (0.849 mL, 11.02 mmol) and heated at 70 0 C for lhr.
• reaction mixture was concentrated, treated with TFA (0.424 mL, 5.51 mmol) and heated at 65 0 C for lhr.
• a -1 1 mixture of 6,8-dichloroimidazo[l,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[l,2-b]pyridazine-3-carboxylic acid ID (2.0 g, 8.62 mmol) was suspended in DCE (20 mL), and treated with neat oxalyl dichloride (4.37g, 34.5 mmol) followed by N,N-Dimethylformamide (0.534 mL, 6.90 mmol). The reaction mixture was heated at 70 0 C for 6 hours, concentrated and dried under high vaccum for lhr and taken to the next step without further purification.
• reaction mixture was filtered through a Buchner funnel, and washed with water (2x25 mL) to isolate 1: 1 mixture of 6,8-dichloro-N-(2-fluoropyridin-4-yl)imidazo[l,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[l,2-b]pyridazine-3-carboxamide (1.18 g, 8.92 mmol, 40.5 % yield) as yellow solid.
• reaction mixture was concentrated, dissolved in NMP (5 mL), and trans-4- aminocyclohexanol (4238 mg, 36.8 mmol) was added.
• the reaction mixture was heated at 100 0 C for 24hrs, and purified using preparative HPLC ( Phenomenex Axia Luna 5 micron 30X100mm) with 40% to 100% MeOH (0.1% TFA) in water (0.1% TFA)) to isolate the title compound, 8-(cyclopropylamino)-N-(2-fluoro-4-pyridinyl)- 6-((trans-4-hydroxycyclohexyl)amino)imidazo[l,2-b]pyridazine-3 -carboxamide (179 mg, 0.421 mmol, 22.87 % yield), as a white solid.
• N-(4-methoxybenzl)cyclyopropanamine (381 mg, 2.148 mmol) was added to ⁇ 1 : 1 mixture of 6,8-dichloro-N-(pyrimidin-4-yl)imidazo[l,2-b]pyridazine-3- carboxamide and 8-bromo-6-chloro-N-(pyrimidin-4-yl)imidazo[l,2-b]pyridazine-3- carboxamide (467 mg, 1.432 mmol) and DIEA (0.500 mL, 2.86 mmol) in DMF (10 mL). The reaction mixture was heated at 80 0 C for 1.5 hrs.
• 6-Chloropyrimidin-4-amine 500 mg, 3.86 mmol
• sodium phenylmethanolate (1 M solution in benzyl alcohol, 4.67 mL, 4.67 mmol) were heated at 120 0 C for 16hrs.
• 6-(Benzyloxy)pyrimidin-4-amine 210 mg, 27% yield
• the purified material (a TFA salt) was converted to its free base by dissolving in ethyl acetate (20 mL) and washing with saturated NaHC ⁇ 3 (20 mL) for use in the next step.
• 6-(Benzyloxy)pyrimidin-4-amine (56.2 mg, 0.279 mmol) was added to a ⁇ 1 : 1 mixture of 6,8-dichloroimidazo[l,2-b]pyridazine-3-carbonyl chloride and 8- bromo-6-chloroimidazo[l,2-b]pyridazine-3-carbonyl chloride (prepared as shown in Example 1, 70 mg, 0.28 mmol) and TEA (0.33 mL, 2.4 mmol) in DCM (3 mL) and heated at 40 0 C for 3 hrs.
• reaction mixture was purified with ISCO chromatography (stepwise gradient 0 to 5% methanol in DCM) to isolate a ⁇ 1 : 1 mixture of N-(6-(benzyloxy)pyrimidin-4-yl)-6, 8-dichloroimidazo [ 1 ,2-b]pyridazine-3 - carboxamide and N-(6-(benzyloxy)pyrimidin-4-yl)-8-bromo-6-chloroimidazo[ 1 ,2- b]pyridazine-3 -carboxamide (51 mg, 43.9%) as a light yellow solid.
• a ⁇ 1 1 mixture of N-(6-(benzyloxy)pyrimidin-4-yl)-6,8- dichloroimidazo[l,2-b]pyridazine-3 -carboxamide and N-(6-(benzyloxy)pyrimidin-4- yl)-8-bromo-6-chloroimidazo[l,2-b]pyridazine-3 -carboxamide (279 mg, 0.672 mmol), cyclopropanamine (57.5 mg, 1.008 mmol) and DIEA (0.319 mL, 1.826 mmol) in THF (5 mL) were heated in sealed tube apparatus at 80 0 C for 2 hrs.
• N-(6-(benzyloxy)pyrimidin-4-yl)-6-chloro-8- (cyclopropylamino)imidazo[l,2-b]pyridazine-3-carboxamide 70 mg, 0.161 mmol
• trans- 1,4-diaminocyclohexane 367 mg, 3.21 mmol
• the mixture was then heated to 100 0 C for 24 h.
• the suspension was cooled to room temperature and then triturated with water.
• the resulting olive green suspension was carefully filtered through a medium-porosity frit.
• the solid was collected, suspended in THF, and azeotroped with PhMe to remove residual water and MeOH.
• the crude solid was suspended in NMP (0.767 mL) and (trans)- cyclohexane-l,4-diamine (0.210 g, 1.840 mmol) was added.
• the resulting brown suspension was irradiated in a CEM Discover 300W microwave at 110 0 C for 20 min.
• a -1 1 mixture 6,8-dichloroimidazo[l,2-b]pyridazine-3-carboxylic acid and 8-bromo-6-chloroimidazo[l,2-b]pyridazine-3-carboxylic acid (6.57 g, 28.3) was suspended in DCE (140 mL), and treated with neat oxalyl chloride (5.52 g, 42.5 mmol) followed by N,N-dimethylformamide (0.207 g, 2.83 mmol). The reaction mixture was heated at 65 0 C for 5 hours, concentrated and dried under high vacuum for lhr and taken into the next step without further purification.
• reaction mixture was filtered through a Buchner funnel, and washed with DCE (2x25mL) to isolate a 1: 1 mixture of 6,8- dichloro-N-(2-chloropyridin-4-yl)imidazo[ 1 ,2-b]pyridazine-3-carboxamide and 8- bromo-6-chloro-N-(2-chloropyridin-4-yl)imidazo[l,2-b]pyridazine-3-carboxamide (7.7 g, 22.5 mmol, 79 % yield) as a light brown solid.
• a ⁇ 1 1 mixture 6,8-dichloro-N-(2-chloropyridin-4-yl)imidazo[l,2- b]pyridazine-3 -carboxamide and 8-bromo-6-chloro-N-(2-chloropyridin-4- yl)imidazo[l,2-b]pyridazine-3-carboxamide (3 g, 8.6mmol), N-(4-methoxybenzyl) cyclopropanamine (8.16 g, 23.82 mmol) and N,N-diisopropylethylamine (3.08 g, 23.82 mmol) was suspended in DMF (100 mL) and heated at 80 0 C for 1.5 hrs.
• reaction mixture was concentrated and dried under reduced pressure for 16 hrs.
• the residue was suspended in methanol (75 mL) and an off-white solid was collected via Buchner filtration (2X25 mL methanol rinse) to isolate 6-chloro-N-(2-chloropyridin- 4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[l,2-b]pyridazine-3- carboxamide (10.2 g, 21.1 mmol, 89%) as a tan solid.
• the crude product was purified with silica gel chromatography using a stepwise gradient of 10%methanol / chloroform to 25% methanol / chloroform / 1% triethylamine to isolated foamy solid.
• the solid was suspended in water (400 mL) and collected with Buchner filtration (2x50 mL water wash) and dried for 16 hrs under reduced pressure to afford 6-((trans)-4- aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4- methoxybenzyl)amino)imidazo[l,2-b]pyridazine-3-carboxamide (10.2 g, 18.18 mmol, 98 % yield) as a off white solid.
• N-(4-methoxybenzyl)cyclopropanamine (381 mg, 2.148 mmol) was added to -1: 1 mixture of 6,8-dichloro-N-(2-fluoropyridin-4-yl)imidazo[l,2-b]pyridazine-3- carboxamide and 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[l,2- b]pyridazine-3-carboxamide 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[l,2- b]pyridazine-3-carboxamide (467 mg, 1.432 mmol, example 13A) and DIEA (0.500 mL, 2.86 mmol) in DMF (10 mL).
• reaction solution was stirred at room temperature for 30 min, concentrated and then treated with TFA (1.132 mL, 14.69 mmol) at 70 0 C for lhr.
• BOP (60.2 mg, 0.136 mmol) was added to a solution of 6-((trans)-4- aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)imidazo[l,2- b]pyridazine-3-carboxamide (20.00 mg, 0.045 mmol), DIEA (0.032 mL, 0.181 mmol) and 2-cyanoacetic acid (7.72 mg, 0.091 mmol) in DCM (1 mL).
• a 20 mL microwave vial was charged with, a stir bar, 3,6-dichloro-4- methylpyridazine (4.0 g, 24.54 mmol) and 14 mL of a new, freshly opened bottle of ammonium hydroxide.
• the vial was quickly sealed.
• the solution was heated in a microwave (Personal Chemistry, Emrys Optimizer) to 100 0 C for 3 h.
• the vial was cooled, opened, and a stream of nitrogen was used to remove excess ammonium hydroxide.
• the mixture was adjusted to pH 7 with IN NaOH, transferred to a separatory funnel, extracted with ethyl acetate (3x), washed with brine (3x), dried over anhydrous sodium sulfate and concentrated in vacuo to give ⁇ 4 g of a very dark semi-solid.
• the solid was purified on an ISCO 16X chromatography system (12O g silica cartridge, 0-100% Ethyl Acetate/Dichloromethane gradient, 70 mL/min).
• Oxalyl dichloride (4 mL, 8 mmol, 2M in dichloromethane) was added to a 100 mL round bottom flask charged with a mixture of 8-bromo-6-chloro-7- methylimidazo[l,2-b]pyridazine-3-carboxylic acid and 6,8-dichloro-7- methylimidazo[l,2-b]pyridazine-3-carboxylic acid 35D (0.256 g, 0.881 mmol), a stir bar and a septum which was wired on. Catalytic DMF was added and the suspension was stirred overnight at room temperature. The mixture was concentrated in vacuo.
• Solvent A (10% MeOH, 90% water, 0.1% TFA)
• Solvent B (90% MeOH, 10% water, 0.1% TFA) 10-60% solvent B gradient, 20 mL/min, 220 nM UV detection to provide 6-((trans)-4- aminocyclohexylamino)-7-methyl-8-(5-methylpyridin-2-ylamino)-N-(pyridin-4- yl)imidazo[l,2-b]pyridazine-3-carboxamide (0.0063 g, 6.83 ⁇ mol, 2.320 % yield).
• Example 36 may be prepared in a similar manner to that described for Example 35.
• HPLC Rt 2.04 min., Waters Sunfire C-18 column 4.65 X 50 mm, 5 urn: 0-100% Solvent B, 4 min gradient, 4 mL/min, 220 UV detection.
• Solvent A 10% MeOH/90% Water/0.1% TFA, Solvent B 90% MeOH/10% Water/0.1% TFA.
• Solvent A (10% MeOH, 90% water, 0.1% TFA)
• Solvent B (90% MeOH, 10% water, 0.1% TFA) 20-100% solvent B gradient, 20 mL/min, 220 nM UV dectection to provide (S)-6-(piperidin-3-ylamino)- 8-(pyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[l,2-b]pyridazine-3-carboxamide (0.0169 g, 0.022 mmol, 20.69 % yield).
• the dichloromethane was removed and concentrated under a stream of nitrogen to provide 6-((trans)-4-aminocyclohexylamino)-8-(4- methoxybenzylamino)-N-(pyridin-4-yl)imidazo[ 1 ,2-b]pyridazine-3 -carboxamide (0.103 g).
• TFA (1 mL) was added to a 2 dram vial containing 6-((trans)-4- aminocyclohexylamino)-8-(4-methoxybenzylamino)-N-(pyridin-4-yl)imidazo[l,2- b]pyridazine-3 -carboxamide 39A and the mixture was heated at 40 0 C. After 40 min, the mixture was concentrated to dryness under a stream of nitrogen. The residue was dissolved in 3 mL of methanol and 3 mL of Solvent B (90% MeOH, 10% water, 0.1% TFA).
• Compound 45A was prepared from 6-bromopyridin-2-amine in a similar way as Example 4OA.
• Compound 5OA was prepared from 6,8-dichloro-N-(3-fluoropyridin-4- yl)imidazo[l,2-b]pyridazine-3-carboxamide and l-(2-(tert- butyldimethylsilyloxy)ethyl)-lH-pyrazol-3 -amine in a similar way as 48A.
• the suspension was cooled to room temperature and then triturated with water resulting in an olive green suspension, which was carefully filtered through a medium-porosity frit.
• the solid contains impure desired product, while the filtrate appears to contain only SM.
• the solid was collected, suspended in THF, and azeotroped with PhMe to remove residual water and MeOH.
• the crude solid was suspended in NMP (0.767 mL) and (trans)- cyclohexane-l,4-diamine (0.210 g, 1.840 mmol) was added.
• the resulting brown suspension was irradiated in a CEM Discover 300W microwave at 110 0 C for 20 min.
• Solvent B (90% MeOH, 10% H 2 O, 0.2% H 3 PO 4 ).
• Solvent A (10% MeOH, 90% H 2 O, 0.2% H 3 PO 4 ).
• MS: [M+H] 487.1.
• reaction mixture was then concentrated in vacuo and the residue mixed with trans- 1 ,4-diaminocyclohexane (0.5g, 4.39 mmol) and heated to 160 0 C for 5h. After cooling to room temperature, the reaction mixture was diluted with DCM/water and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (1 mL) at room temperature and charged with TFA (1 mL).
• reaction mixture was then concentrated in vacuo and the residue mixed with trans- 1 ,4-diaminocyclohexane (0.5g, 4.39 mmol) and heated to 160 0 C for 5h. After cooling to room temperature, the reaction mixture was diluted with DCM/water and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (1 mL) at room temperature and charged with TFA (1 mL).
• reaction mixture was then concentrated in vacuo and the residue mixed with trans- 1 ,4-diaminocyclohexane (0.5g, 4.39 mmol) and heated to 160 0 C for 5h. After cooling to room temperature, the reaction mixture was diluted with DCM/water and the layers separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (1 mL) at room temperature and charged with TFA (1 mL).
• reaction mixture was then concentrated in vacuo and the residue mixed with trans- 1,4-diaminocyclohexane (0.5g, 4.39 mmol) and heated to 160 0 C for 5h. After cooling to room temperature, the reaction mixture was diluted with DCM/water and the layers separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (1 mL) at room temperature and charged with TFA (1 mL).
• a 1 dram vial was charged with 8A (25 mg, 0.077 mmol) and THF (1 mL). Cyclobutylamine (8.54 ⁇ L, 0.100 mmol) was added and the reaction was heated to 80 0 C. After 4 hours at 80 0 C, the reaction was cooled to room temprature and the solvent was removed under a stream of nitrogen. Cyclohexylamine (500 ⁇ L, 4.37 mmol) was added and the reaction was heated to 140 0 C for 12 hours.
• the crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30 x 250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 50 min gradient, monitored at 220 nm).
• the crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 urn 30 x 250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm).
• a suspension of 23A (50.0 mg, 0.146 mmol) in THF (2 mL) was treated with 5-methylpyridin-2-amine (31.6 mg, 0.292 mmol).
• a solution of potassium tert- butoxide (0.292 mL, 0.292 mmol) in THF was added and the reaction was stirred at room temperature. The reaction was complete after two hours. The solvent was removed under a stream of nitrogen. The residue was taken up in MeOH and filtered. The solid material was dried under vacuum.
• a -1 1 mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[l,2- b]pyridazine-3 -carboxamide) and 8-bromo-6-chloro-N-(3 -fluoropyridin-4- yl)imidazo[l,2-b]pyridazine-3 -carboxamide (850 mg, 2.61 mmol, 5A), N-(4- methoxybenzyl)cyclopropanamine (508 mg, 2.87 mmol) and N,N- diisopropylethylamine (0.683 mL, 3.91 mmol) were heated in DMF (10 mL) at 80 0 C.
• reaction mixture was concentrated to dryness under reduced pressure, suspended in methanol (20 mL), and the solid was isolated via Buchner filtration. The solid was combined with 4.8g of trans-cyclohexanel-l,4-diamine and heated at 160 0 C. After 2.5 hrs, the reaction was cooled to room temperature, suspended in water (20 mL), and the isolated solid was purified with silica gel chromatography (10% methanol to 20% methanol/chloroform).
• reaction mixture was concentrated, and purified using silica gel chromatography (50% ethyl acetate/hexanes to ethyl acetate) to isolate tert-butyl (trans)-4-(8-(cyclopropyl(4-methoxybenzyl)amino)-3-(3- fluoropyridin-4-ylcarbamoyl)imidazo[l,2-b]pyridazin-6- ylamino)cyclohexylcarbamate (34 mg, 0.053 mmol, 93 % yield) as a glassy white solid.
• reaction mixture was concentrated under reduced pressure and purified using preparative HPLC containing TFA to isolate N-(3-acetamidophenyl)-6-((trans)-4- aminocyclohexylamino)-8-(cyclopropylamino)imidazo[l,2-b]pyridazine-3- carboxamide (4 mg, 5.02 ⁇ mol, 27.6 % yield) as a white solid.
• Example 86A was prepared in the same manner as detailed in Example 48A using the appropriate starting materials.
• Example 86B was prepared from 86A using the procedures described in Example 40.
• HPLC Rt 2.413 minutes (Chromolith SpeedROD 4.6 x 50 mm, 10- 90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm).
• [M+H] 479.0

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