Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/433—Thidiazoles
• • 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
  • 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
  • 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
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to compounds useful as inhibitors of c-Met.
• the invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
• Hepatocyte growth-factor also known as scatter factor
• HGF is a multifunctional growth factor that enhances transformation and tumor development by inducing mitogenesis and cell motility. Further, HGF promotes metastasis by stimulating cell motility and invasion through various signaling pathways, hi order to produce cellular effects, HGF must bind to its receptor, c-Met, a receptor tyrosine kinase.
• c-Met a widely expressed heterodimeric protein comprising of a 50 kilpdarton (kDa) ⁇ -subunit and a 145 kDa ⁇ -subunit (Maggiora et al., J.
• c-Met is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis.
• the various cancers in which c-Met overexpression is implicated include, but are not limited to, gastric adenocarcinoma, renal cancer, small cell lung carcinoma, colorectal cancer, prostate cancer, brain cancer, liver cancer, pancreatic cancer, and breast cancer.
• c-Met is also implicated in atherosclerosis and lung fibrosis. [0003] Accordingly, there is a great need to develop compounds useful as inhibitors of c-Met protein kinase receptor.
• the invention also provides pharmaceutical compositions that include a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• the invention provides methods of treating or lessening the severity of a proliferative disease, condition, or disorder in a patient that includes the step of administering to the patient a therapeutically effective dose of a compound of formula I, or a pharmaceutical composition thereof.
• Figure 1 shows a general scheme for the preparation of triazolothiadiazoles of the invention (compounds of formulae I-a and I-d).
• Figure 2 shows the synthesis of compound 2.
• Figure 3 shows the synthesis of compound 5.
• Figure 4 shows a general scheme for the preparation of triazolopyridazines of the invention (compounds of formula I-b, formula I-f, and formula I-b).
• Compounds of formula I-e are compounds of formula I-b where R c is hydrogen.
• Figure 5 shows the synthesis of compound 175.
• Figure 6 shows the synthesis of compound 190.
• Figure 7 shows the synthesis of compound 206.
• Figure 8 shows a general scheme for the preparation of triazolothiadiazines of the invention (compounds of formula I-c and formula I-g).
• Compounds of formula I-g are compounds of formula I-c where R is hydrogen.
• compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
• substituents such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
• the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”
• substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
• an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
• substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
• stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, preferably, their recovery, purification, and use for one or more of the purposes disclosed herein.
• a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 4O 0 C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
• aliphatic or "aliphatic group,” as used herein, means a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. In some embodiments, aliphatic groups contain 1-10 carbon atoms. In other embodiments, aliphatic groups contain 1-8 carbon atoms. In still other embodiments, aliphatic groups contain 1-6 carbon atoms, and in yet other embodiments, aliphatic groups contain 1-4 carbon atoms.
• Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Further examples of aliphatic groups include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, and sec-butyl.
• alkyl and the prefix "alk-,” as used herein, are inclusive of both straight chain and branched saturated carbon chain.
• alkylene represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene and the like.
• alkenyl represents monovalent straight or branched chain hydrocarbon group containing one or more carbon-carbon double bonds.
• alkynyl represents a monovalent straight or branched chain hydrocarbon group containing one or more carbon-carbon triple bonds.
• alkylidene represents a divalent straight chain alkyl linking group.
• cycloaliphatic refers to a monocyclic C 3 -Cg hydrocarbon or bicyclic Cs-Ci 2 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, and wherein any individual ring in said bicyclic ring system has 3-7 members.
• Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
• aliphatic groups include cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cycloheptenyl.
• heterocycle refers to a monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are an independently selected heteroatom and that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
• the "heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 8 ring members.
• heterocyclic rings include, but are not limited to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3- thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-
• heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quatemized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N- substituted pyrrolidinyl).
• alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.
• haloalkyl means alkyl, alkenyl, or alkoxy, as the case may be, substituted with one or more halogen atoms.
• halogen means F, Cl, Br, or I.
• aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems having a total of six to fourteen ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has a single point of attachment to the rest of the molecule.
• aryl may be used interchangeably with the term “aryl ring.” Examples of aryl rings would include phenyl, naphthyl, and anthracene.
• heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl,” or “heteroarylalkoxy,” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members and that has a single point of attachment to the rest of the molecule.
• heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic.”
• heteroaryl rings include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3- ⁇ yridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g.,
• an aryl (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl, heteroarylalkoxy, and the like) group may contain one or more substituents.
• Optional substituents on the aliphatic group of R° are selected from -NH 2 , -NH(Ci -4 aliphatic), -N(Ci -4 aliphatic) 2 , halogen, C ⁇ -4 aliphatic, -OH, -0(Ci -4 aliphatic), -NO 2 , -CN, -C(O)OH, -C(O)O(Ci -4 aliphatic), -O(haloCi -4 aliphatic), or haloCi 4 aliphatic, wherein each of the foregoing Ci -4 . aliphatic groups of R° is unsubstituted.
• Optional substituents on the aliphatic group of R * are selected from -NH 2 , -NH(Ci -4 aliphatic), -N(Ci -4 aliphatic) 2 , halogen, Ci -4 aliphatic, -OH, -0(Ci -4 aliphatic), -NO 2 , -CN, -C(O)OH, -C(O)O(Ci -4 aliphatic), -C(O)NH 2 , -C(O)NH(C !-4 aliphatic), -C(O)N(C 1-4 aliphatic) 2 , -O(halo-C] -4 aliphatic), and halo(C].
• Ci -4 aliphatic groups of R * is unsubstituted; or two R* on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Optional substituents on the aliphatic group or the phenyl ring of R + are selected from -NH 2 , -NH(Ci -4 aliphatic), -N(C 1-4 aliphatic) 2 , halogen, Ci -4 aliphatic, -OH, -0(C 1-4 aliphatic), -NO 2 , -CN, -C(O)OH, -C(O)O(Ci -4 aliphatic), -O(halo(Ci -4 aliphatic)), or halo(Ci 4 aliphatic), wherein each of the foregoing groups of R is unsubstituted.
• two independent occurrences of R° may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring.
• Exemplary rings that are formed when two independent occurrences of R° (or R , or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°) 2 , where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R° (or R + , or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two
• a methylene unit of the alkyl or aliphatic chain is optionally replaced with another atom or group.
• the optional replacements form a chemically stable compound.
• Optional atom or group replacements can occur both within the chain and at either end of the chain; i.e. both at the point of attachment and/or also at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound.
• the replacement atom is bound to an H on the terminal end. For example, if one methylene unit of -CH 2 CH 2 CH 3 was optionally replaced with -0-, the resulting compound could be -OCH 2 CH 3 , -CH 2 OCH 3 , or -CH 2 CH 2 OH.
• a bond drawn from a substituent to the center of one ring within a multiple-ring system represents substitution of the substituent at any substitutable position in any of the rings within the multiple ring system.
• Figure a represents possible substitution in any of the positions shown in Figure b.
• Figure a This also applies to multiple ring systems fused to optional ring systems (which would be represented by dotted lines).
• X is an optional substituent both for ring A and ring B.
• each substituent only represents substitution on the ring to which it is attached.
• Y is an optionally substituent for ring A only
• X is an optional substituent for ring B only.
• structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
• protecting group represent those groups intended to protect a functional group, such as, for example, an alcohol, amine, carboxyl, carbonyl, etc., against undesirable reactions during synthetic procedures. Commonly used protecting groups are disclosed in Greene and Wuts, Protective Groups In Organic Synthesis, 3 rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
• nitrogen protecting groups include acyl, aroyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ - chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine and the like; sulfonyl groups such as benzenesulfonyl, p- toluenesulfonyl and the like; carbamate groups such as benzyloxycarbonyl, p- chlorobenzyl
• Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
• prodrug represents a compound that is transformed in vivo into a compound of formula I, I-a, I-b, or I-c, or a compound listed in Tables 1, 2, or 3. Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue.
• Prodrugs of the compounds of the invention may be, for example, esters.
• Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (Ci-C 24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters.
• a compound of the invention that contains an OH group may be acylated at this position in its prodrug form.
• Other prodrug forms include phosphates, such as, for example those phosphates resulting from the phosphorylation of an OH group on the parent compound.
• the present invention features compounds having the formula:
• R A is selected from:
• each of R ⁇ and R A6 is, independently, selected from hydrogen, halogen, -CN, -C(O)OR +4" , -C(O)R ++ , -C(O)N(R ++ ) 2 , -C(S)N(R ++ ) 2 , -C(NH)N(R ++ ) 2 , -OR ++ , -O(halo(C 1-4 aliphatic)), -OC(O)N(R +4 ),, -SR +" ", -NO 2 , -N(R ++ ) 2 , -N(R ++ )C(O)( R ++ ), -N(R ++ )C(O)N(R ++ ) 2 , -N(R ++ )C(0)0R ++ , -N(R ++ )N(R ++ )C(O)R ++ , -N(R ++ )N(R ++
• R ⁇ 3 is R ⁇ ; or R A3 , R A4 and the carbons to which they are bonded form a 6 membered aryl ring optionally substituted with up to 4 independent occurrences of R ⁇ , or a 5- 6 membered heterocyclyl or heteroaryl ring containing at least one O, N, or S, wherein said heterocyclyl or heteroaryl ring is optionally substituted with up to 3 independent occurrences of R ⁇ ;
• R M is -OH, -B(0R*) 2 , -SR*, -N(R*) 2 , -N(R*)C(0)R*, -N(R*)C(O)N(R*) 2 , -N(R*)C(O)OR*, -N(R*)N(R*)C(0)R * , -N(R*)N(R*)C(0)N(R*) 2 , -N(R*)N(R*)C(O)OR * , -N(R*)S(O) 2 N(R*) 2 , -N(R*)S(O) 2 R * , -C(O)OR*, -C(0)N(R*) 2 ;
• R A5 is hydrogen or R Ar ;
• L B is a covalent bond between R B and the carbon to which L B is bonded or is a saturated or unsaturated Ci -4 alkylene chain optionally substituted with up to 5 groups, independently selected from halogen, Ci -4 aliphatic, ImIo(Ci -4 aliphatic), -OR ++ , -O(halo(Ci -4 aliphatic)), -NO 2 , -CN, -C(O)OR ++ , -C(O)N(R ++ ) 2 , or -N(R +4 ⁇ ) 2 , wherein up to two saturated carbons of said alkylene chain are optionally replaced by -C(O)-, -C(O)N(R + *)-, -C(O)N(R ++ )N(R ++ )-, -C(O)O-, -N(R ++ )-, -N(R ++ )C(O)-, -N(R
• R is halogen, -R°, -OR°, -SR°, -OC(O)(Ci -8 aliphatic), Ph optionally substituted with R°, -O(Ph) optionally substituted with R°, -CH 2 (Ph) optionally substituted with R°, -CH 2 CH 2 (Ph) optionally substituted with R°, -NO 2 , -CN, -N(R°) 2 , -NR°C(O)R°, -NR°C(O)N(R°) 2j -NR°C(O)OR°, -NR°NR°C(O)R°, -NR°NR°C(O)N(R°) 2 , -NR°NR°C(O)OR°, -C(O)C(O)R°, -C(O)CH 2 C(O)R°, -C(O)OR°, -C(O)R°, -C(0)N(R°) 2 ,
• each substituent of said optionally substituted aliphatic of R° is, independently, -NH 2 , -NH(C] -4 aliphatic), -N(Ci -4 aliphatic) 2 , halogen, Ci -4 aliphatic, -OH, -0(Ci -4 aliphatic), -NO 2 , -CN, -C(O)OH, -C(O)O(C] -4 aliphatic), -C(O)NH 2 , -C(O)NH(C] -4 aliphatic), -C(O)N(CM aliphatic) 2 , -O(halo(C] A aliphatic)), or halo(Ci -4 aliphatic); or two R° on the same nitrogen are taken together with the nitrogen to form a
• the compound of formula I is a triazolothiadiazole having the formula:
• the compound of formula I is a triazolopyridazine having the formula:
• R c is hydrogen
• the compound of formula I is a triazolothiadiazine having the formula:
• R ++ is hydrogen.
• R is selected from:
• R is selected from:
• R A comprises a bicyclic system
• R ⁇ 3 R M
• R M optionally form a heterocyclyl or heteroaryl ring selected from:
• R A is
• R A is selected from:
• L B is a covalent bond, -CH 2 -, or -N(R*)-.
• R B is selected from the group consisting of:
• L B R B groups include the following:
• the invention features a compound selected from the group of compounds listed in Tables 1, 2, or 3.
• compositions that include a compound of formula I, I-a, I-b, or I-c, or a compound listed in Tables 1-3, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• the amount of compound in the compositions of the invention is such that is effective to detectably inhibit a protein kinase, particularly c-Met in a biological sample or in a patient.
• c-Met is synonymous with "cMet", “MET", “Met” or other designations known to one skilled in the art.
• a composition of the present invention is formulated for administration to a patient in need of such composition.
• the composition of this invention is formulated for oral administration to a patient.
• patient means an animal, preferably a mammal, and most preferably a human.
• a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
• the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitory active metabolite or residue thereof.
• the term “inhibitory active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of c-Met.
• compositions of this invention include those derived from suitable inorganic and organic acids and bases.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and TSf + (Ci -4 alkyl) 4 salts.
• This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil- soluble or dispersable products may be obtained by such quaternization.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations fo ⁇ ned using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C ⁇ g sulfonate and aryl sulfonate.
• compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin
• compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
• parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques.
• the compositions are administered orally, intraperitoneally or intravenously.
• Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3- butanediol.
• a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3- butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
• Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
• compositions of this invention may be orally administered in any orally acceptable dosage fo ⁇ n including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
• carriers commonly used include lactose and corn starch.
• Lubricating agents such as magnesium stearate, are also typically added.
• useful diluents include lactose and dried cornstarch.
• aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
• the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
• a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
• Such materials include cocoa butter, beeswax and polyethylene glycols.
• the pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
• Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
• the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
• Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
• the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
• Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
• the pharmaceutically acceptable compositions may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride.
• the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
• the pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation.
• compositions are prepared according to techniques well-known in the art of pharmaceutical fo ⁇ nulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
• the pharmaceutically acceptable compositions of this invention are formulated for oral administration.
• Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tet ⁇ hydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art such as, for example, water or other solvents
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution, U. S.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• the rate of compound release can be controlled.
• biodegradable polymers include poly(orthoesters) and poly(anhydrides).
• Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
• compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, marmitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such, as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• Examples of embedding compositions that can be used include polymeric substances and waxes.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
• the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
• Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
• Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
• the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
• Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
• the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
• dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
• the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
• compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
• additional therapeutic agents which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention.
• additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated.”
• the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
• the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
• a compound or composition of the invention can be used as a monotheraphy to treat or lessen the severity of a proliferative disease, condition, or disorder in a patient by administering to the patient a compound or a composition of the invention in an effective amount.
• diseases, conditions, or disorders include cancer, particularly metastatic cancer, atherosclerosis, and lung fibrosis.
• cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation.
• examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
• cancers include adrenocortical cancer; bladder cancer; bone cancer; brain cancer; breast cancer; cancer of the peritoneum; cervical cancer; colon cancer; colorectal cancer; endometrial or uterine carcinoma; esophogeal cancer; eye cancer; gallbladder cancer; gastrointestinal cancer; glioblastoma; various types of head and neck cancer; hepatic carcinoma; hepatocellular cancer; kidney cancer; laryngeal cancer; liver cancer; lung cancer, such as, for example, adenocarcinoma of the lung, small-cell lung cancer, squamous carcinoma of the lung, non-small cell lung cancer; melanoma and nonmelanoma skin cancer; myeloproliferative disorders, such as, for example, polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia (CML),
• CML
• the treatment method that includes administering a c-Met inhibitor of the invention can further include administering to the patient an additional therapeutic agent (combination therapy) selected from: a chemotherapeutic or anti-proliferative agent, or an anti-inflammatory agent, wherein the additional therapeutic agent is appropriate for the disease being treated and the additional therapeutic agent is administered together with a compound or composition of the invention as a single dosage form or separately from the compound or composition as part of a multiple dosage form.
• the additional therapeutic agent may be administered at the same time as a compound of the invention or at a different time. In the latter case, administration may be staggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.
• Non-limiting examples of chemotherapeutic agents or other anti-proliferative agents that may be combined with the compounds of this invention include tamoxifen, raloxifene, anastrozole, exemestane, letrozole, herceptinTM (trastuzumab), GleevecTM (imatanib), TaxolTM (paclitaxel), cyclophosphamide, lovastatin, minosine, araC, 5-fluorouracil (5-FU), methotrexate (MTX), TaxotereTM (docetaxel), ZoladexTM (goserelin), vincristin, vinblastin, nocodazole, teniposide, etoposide, GemzarTM (gemcitabine), epothilone, navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin (adriamycin
• the additional chemotherapeutic agent can be a cytokine such as G-CSF (granulocyte colony stimulating factor).
• a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, may be administered in combination with radiation therapy.
• a compound of the present invention may be administered in combination with standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, and paclitaxel), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).
• CMF cyclophosphamide, methotrexate and 5-fluorouracil
• CAF cyclophosphamide, adriamycin and 5-fluorouracil
• AC adriamycin and cyclophosphamide
• FEC 5-
• the invention also features a method of inhibiting the growth of a cell that expresses c-Met or hepatocyte growth factor, or both, that includes contacting the cell with a compound or composition of the invention, thereby causing inhibition of growth of the cell.
• Examples of a cell whose growth can be inhibited include: a breast cancer cell, a colorectal cancer cell, a lung cancer cell, a papillary carcinoma cell, a prostate cancer cell, a lymphoma cell, a colon cancer cell, a pancreatic cancer cell, an ovarian cancer cell, a cervical cancer cell, a central nervous system cancer cell, an osteogenic sarcoma cell, a renal carcinoma cell, a hepatocellular carcinoma cell, a bladder cancer cell, a gastric carcinoma cell, a head and neck squamous carcinoma cell, a melanoma cell, or a leukemia cell.
• the invention provides a method of inhibiting c-Met kinase activity in a biological sample that includes contacting the biological sample with a compound or composition of the invention.
• biological sample means a sample outside a living organism and includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
• Inhibition of kinase activity, particularly c-Met kinase activity, in a biological sample is useful for a variety of purposes known to one of skill in the art and is limited to non-therapeutic methods. Examples of such purposes include, but are not limited to, biological specimen storage and biological assays.
• the invention also provides a method of inhibiting c-Met kinase activity in a patient, comprising administering to the patient a compound or composition of the invention.
• the invention comprises a method of treating or lessening the severity of a c-Met-mediated condition or disease in a patient.
• c-Met- mediated disease or "c-MET-mediated condition”
• u c- Met-mediated disease or "c-Met-mediated condition” also mean those diseases or conditions that are alleviated by treatment with a c-Met inhibitor.
• Such conditions include, without limitation, cancers, such as, for example, gastric adenocarcinoma, gliobastoma, renal cancer, small cell lung carcinoma, colorectal cancer, prostate cancer, brain cancer, liver cancer, pancreatic cancer, and breast cancer, and other proliferative diseases, such as, for example, atherosclerosis and lung fibrosis.
• cancers such as, for example, gastric adenocarcinoma, gliobastoma, renal cancer, small cell lung carcinoma, colorectal cancer, prostate cancer, brain cancer, liver cancer, pancreatic cancer, and breast cancer
• other proliferative diseases such as, for example, atherosclerosis and lung fibrosis.
• an "effective amount” or “effective dose” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of the aforementioned disorders.
• the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening
• the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
• a compound or composition can also be administered with one or more other therapeutic agents, as discussed above.
• the compounds of this invention or pharmaceutical compositions thereof may also be used for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
• vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
• patients using stents or other implantable devices risk clot formation or platelet activation.
• Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562; 5,886,026; and 5,304,121, the contents of each of which are incorporated by reference herein.
• the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
• the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics into the composition.
• Implantable devices coated with a compound of this invention are another embodiment of the present invention.
• the compounds may also be coated on implantable medical devices, such as beads, or co- formulated with a polymer or other molecule, to provide a "drug depot," thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug.
• a carboxylic acid of formula II is reacted neat with thiocarbonohydrazide with heating (about 17O 0 C) in a condensation reaction to produce a 4-amino-l,2,4-triazole-3 -thiol of formula III.
• the compound of formula III is reacted with a carboxylic acid of formula IV in refiuxing phosphorus oxychloride to produce a compound of formula I-a, where R A , L B , and R B are as defined herein for compounds of formula I.
• Triazolothiadiazole compounds of the invention prepared by these methods include those compounds listed in Table 1. Analytical characterization data of representative compounds are provided in Table 4.
• a compound of formula VI containing leaving groups Z and Z' (e.g., halogen, phosphonate, tosylate, or triflate), which can be the same or different, is reacted with hydrazine in a suitable solvent, such as, for example, isopropanol at an elevated temperature under microwave irradiation to produce a compound of formula VII.
• a suitable solvent such as, for example, isopropanol
• the reaction temperature is above 6O 0 C.
• R c is not hydrogen, the regiochemistry of substitution may be governed by the ease of leaving group displacement and/or the steric bulk of R c .
• the catalyst used in the cross coupling reaction can be, for example, a palladium catalyst/ligand system (such as, for example, Pd(PPh 3 ) 4 , Pd(PtBu 3 ) 4 , Pd[P(MeXtBu 3 )J 4 , PdCl 2 (PPh 3 ) 2 , PdCl 2 (dppf) 2 , Pd 2 (dba) 3 BINAP, or Pd 2 (dba) 3 P(o-tol) 3 (see Fu and Littke, Angew. Chem. Int. Ed. 41:4176-4211, 2002; Nicolaou et al, Angew. Chem. Int. Ed.
• the reaction is usually performed in the presence of a base.
• the M group of the compound of formula X can be, for example, -B(OAlkyl) 2 or -B(O ⁇ ) 2 (Suzuki reaction), -Mg-HaI (Kumada reaction), -Zn- HaI (Negishi reaction), -Sn(Alkyl) 3 (Stille reaction), -Si(Alkyl) 3 (Hiyama reaction), -Cu- HaI, -ZrCp 2 Cl, or -AlMe 2 .
• these groups can be introduced using those methods known to one skilled in the art or by methods described in U.S. Patent Nos. 6,939,985 and 6,559,310, and in U.S. Patent Application No. 20040133028. If so desired, the order of the functionalization of pyrimidine ring may be changed such that the cross- coupling reaction is performed first, followed by reaction with hydrazine.
• Triazolopyridazine compounds of the invention prepared by these methods include those compounds listed in Table 2. Analytical characterization data of representative compounds are provided in Table 4.
• the compound of formula III is reacted with a compound of formula XII under basic conditions, where LG is a leaving group such as, for example, chloro, bromo, iodo, tosyl, or trifyl, to produce a compound of formula I-c, where R A , L A , R B , L B , and R ++ are as defined herein for a compound of formula I.
• a compound of formula I-g is a compound of formula I-c where each R + * is hydrogen.
• Suitable bases for this reaction include hindered amine bases such as, for example, triethylamine, N,N-diisopropylethylamine, 2,6- lutidine, 2,6-di-fert-butylpyridine, or 2,6-di-tert-butyl-4-methyl-pyridine.
• the reaction mixture is heated to drive the reaction to completion.
• any of the functional groups residing on substituents L A , R ⁇ , L B , or R B may be suitably protected with a protecting group by methods known to those skilled in the art.
• Triazolothiadiazine compounds of the invention prepared by this method include those compounds listed in Table 3. Analytical characterization data of representative compounds are provided in Table 4.
• compound 1002 can be prepared as described above in Example 2. To compound 1002 (50 mg, 0.224 mmol) in tetrahydrofuran (2.5 mL) was added triethylamine (69 ⁇ L, 0.50 mmol), followed by 2-chloro-l-(thiophen-3-yl)ethanone (80 mg, 0.50 mmol). The reaction mixture was stirred at 65°C overnight, at which point LC-MS analysis indicated the disappearance of starting material and the presence of the desired product. The reaction mixture was concentrated in vacuo to give a dark oil, which was purified by reversed phase HPLC to give compound 541 (40 mg, 75 %) as a white solid.
• An assay stock buffer solution was prepared containing all of the reagents listed above with the exception of ATP and a test compound of the present invention.
• the assay stock buffer solution (175 ⁇ L) was incubated in a 96 well plate with 5 ⁇ L of the test compound of the present invention at final concentrations spanning 0.006 ⁇ M to 12.5 ⁇ M at 3O 0 C for 10 minutes.
• a 12-point titration was conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds of the present invention in daughter plates. The reaction was initiated by the addition of 20 ⁇ L of ATP (final concentration 200 ⁇ M).
• Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 minutes at 3O 0 C.
• the JQ values were determined from the rate data as a function of inhibitor concentration.
• Selected K; values are provided in Table 4 as a range, where "A” represents a Kj of less than 0.10 ⁇ M, "B” represents a K; of 0.10 ⁇ M to 2.0 ⁇ M, and "C” represents a Kj of greater than 2.0 ⁇ M.

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