NZ517828A - Inhibitors having activity against mammalian factor Xa - Google Patents

Inhibitors having activity against mammalian factor Xa

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Publication number
NZ517828A
NZ517828A NZ517828A NZ51782800A NZ517828A NZ 517828 A NZ517828 A NZ 517828A NZ 517828 A NZ517828 A NZ 517828A NZ 51782800 A NZ51782800 A NZ 51782800A NZ 517828 A NZ517828 A NZ 517828A
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NZ
New Zealand
Prior art keywords
group
substituted
independently selected
pct
usoo
Prior art date
Application number
NZ517828A
Inventor
Bing-Yan Zhu
Wenrong Huang
Yonghong Song
James Kanter
Robert M Scarborough
Zhaozhong Jon Jia
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Millennium Pharm Inc
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Publication date
Application filed by Millennium Pharm Inc filed Critical Millennium Pharm Inc
Publication of NZ517828A publication Critical patent/NZ517828A/en

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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Abstract

Compounds of formula A-Q-D-E-G-J-X in which D is a direct link, a substituted or unsubsituted phenyl or naphtyl gourp or a heterocyclic ring system; G is substituted or unsubstituted phenyl or a heterocyclic ring system; X is a substituted or unsubstituted phenyl or naphtyl group or a heterocyclic ring system; and the other variables are as defined in the claims, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed, These compounds are useful in vitro or in vivo for preventing or treating coagulation disorders.

Description

517^2 WO 01/19798 PCT/US00/25195 INHIBITORS OF FACTOR Xa Cross Reference to Related Applications This application claims benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60/154,332 filed on September 17,1999, which is herein 5 incorporated in its entirety by reference.
Field nf the Invention This invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa or when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation (e.g. 10 thrombin, fVIIa, fIXa) or the fibrinolytic cascades (e.g. plasminogen activators, plasmin). In another aspect, the present invention relates to novel non-amidino-containing compounds, their pharmaceutically acceptable salts, and pharmaceutical^ acceptable compositions thereof which are useful as potent and specific inhibitors of blood coagulation in mammals. In yet another aspect, the.invention relates to methods for using 15 these inhibitors as therapeutic agents for disease states in mammals characterized by coagulation disorders.
Background of the Invention Hemostasis, the control of bleeding, occurs by surgical means, or by the physiological properties of vasoconstriction and coagulation. This invention is 20 particularly concerned with blood coagulation and ways in which it assists in maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfunction or other disruption. Although platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of the processes involved in 25 platelet aggregation and fibrin deposition.
Thrombin is a key enzyme in the coagulation cascade as well as in hemostasis. Thrombin plays a central role in thrombosis through its ability to catalyze the conversion of fibrinogen into fibrin and through its potent platelet activation activity. Direct or WO 01/19798 PCT/US00/25195 2 indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies as reviewed by Claeson, G., "Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System", Blood Coag. Fibrinol. 5,411-436 (1994). Several classes of 5 anticoagulants currently used in the clinic directly or indirectly affect thrombin (i.e. heparins, low-molecular weight heparins, heparin-Iike compounds and coumarins).
A prothrombinase complex, including Factor Xa (a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein 10 family), converts the zymogen prothrombin into the active procoagulant thrombin.
Unlike thrombin, which acts on a variety of protein substrates as well as at a specific receptor, factor Xa appears to have a single physiologic substrate, namely prothrombin. Since one molecule of factor Xa may be able to generate up to 138 molecules of thrombin (Elodi et al., Thromb. Res. IS, 617-619 (1979)), direct inhibition of factor Xa as a way of 1S indirectly inhibiting the formation of thrombin may be an efficient anticoagulant strategy. Therefore, it has been suggested that compounds which selectively inhibit factor Xa may be useful as in vitro diagnostic agents, or for therapeutic administration in certain thrombotic disorders, see e.g., WO 94/13693.
Polypeptides derived from hematophagous organisms have been reported which 20 are highly potent and specific inhibitors of factor Xa. United States Patent 4,588,587 describes anticoagulant activity in the saliva of the Mexican leech, Haementeria officinalis. A principal component of this saliva was shown to be the polypeptide factor Xa inhibitor, antistasin (ATS), by Nutt, E. et al., "The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals'a Repeated Internal Structure", J. Biol. 25 Chem.. 263.10162-10167(1988). Another potent and highly specific inhibitor of Factor Xa, called tick anticoagulant peptide (TAP), has been isolated from the whole body extract of the soft tick Ornithidoros moubata, as reported by Waxman, L., et al, "Tick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa" Science, 24S, 593-596 (1990).
Factor Xa inhibitory compounds which are not large polypeptide-type inhibitors have also been reported including: Tidwell, R.R. et al., "Strategies for Anticoagulation WO 01/19798 PCT/US00/25195 3 With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors", Thromb. Res., 12,339-349 (1980); Turner, A.D. et al., "p-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin", Biochemistry,'25,4929-4935 (1986); Hitomi, Y. et al., "Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation 5 System", Haemostasis, 15,164-168 (1985); Sturzebecher, J. et al., "Synthetic Inhibitors of Bovine Factor Xa and Thrombin. Comparison of Their Anticoagulant Efficiency", Thromb. Res., 54,245-252 (1989); Kam, C.M. et al., "Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants", Biochemistry, 22,2547-2557 (1988); Hauptmann, J. et al., "Comparison of the 10 Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors", Thromb. Haemost., £2,220-223 (1990); and the like.
Others have reported Factor Xa inhibitors which are small molecule organic compounds, such as nitrogen containing heterocyclic compounds which have amidino substituent groups, wherein two functional groups of the compounds can bind to Factor 15 Xa at two of its active sites. For example, WO 98/28269 describes pyrazole compounds having a terminal C(=NH)-NH2 group; WO 97/21437 describes benzimidazole compounds substituted by a basic radical which are connected to a naphthyl group via a straight or branched chain alkylene,-C(=0) or -S(=0)2 bridging group; WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino-piperidine and 4-phenoxy-N-20 alkylamidino-piperidine group connected to a 3-amidinophenyl group via a carboxamidealkyleneamino bridge; and EP 798295 describes compounds having a 4-phenoxy-N-alkylamidino-piperidine group connected to an amidinonaphthyl group via a substituted or unsubstituted sulfonamide or carboxamide bridging group.
There exists a need for effective therapeutic agents for the regulation of 25 hemostasis, and for the prevention and treatment of thrombus formation and other pathological processes in the vasculature induced by thrombin such as restenosis and inflammation. In particular, there continues to be a need for compounds which selectively inhibit factor Xa or its precursors. Compounds are needed which selectively or preferentially bind to Factor Xa. Compounds with a higher affinity for binding to 30 Factor Xa than to thrombin are desired, especially those compounds having good bioavailability or other pharmacologically desirable properties.
WO 01/19798 PCT/US00/25195 4 Summary of the Invention The present invention relates to novel compounds which inhibit factor Xa, their pharmaceutical^ acceptable isomers, salts, hydrates, solvates and prodrug derivatives, and phaimaceutically acceptable compositions thereof which have particular biological 5 properties and are useful as potent and specific inhibitors of blood coagulation in mammals. In another aspect, the invention relates to methods of using these inhibitors as diagnostic reagents or as therapeutic agents for disease states in mammals characterized by undesired thrombosis which have coagulation disorders, such as in the treatment or prevention of any thrombotically mediated acute coronary or cerebrovascular syndrome, 10 any thrombotic syndrome occurring in the venous system, any coagulopathy, and any thrombotic complications associated with extracorporeal circulation or instrumentation, and for the inhibition of coagulation in biological samples.
In certain embodiments, this invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa when assembled in the IS prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation cascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and are useful as diagnostic reagents as well as antithrombotic agents.
In one embodiment, the present invention provides compounds comprising a five-membered heterocyclic ring structure having from 1-4 hetero atoms selected from the 20 group consisting of N, O and S or a bicyclic ring system comprising the 5-membered heterocyclic ring structure wherein the bicyclic ring structure may have 1-5 hetero atoms selected from the group consisting of N, O and S, and wherein the overall compound has an essentially neutral pH. Preferably, a pH of about pH 5-8, more preferably, about pH 6-7.5 and most preferably, about pH 7.0. The compounds according to the invention are 23 potent and selective inhibitors of factor Xa versus other proteases of the coagulation cascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and are useful as diagnostic reagents as well as antithrombotic agents. Particular embodiments of the compounds of the present invention are set forth below as preferred embodiments and include all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives 30 thereof.
In certain aspects of this invention, compounds are provided which are useful as diagnostic reagents. In another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier. In yet another aspect, the present invention includes methods comprising using the above compounds and pharmaceutical compositions for preventing or treating disease states characterized by undesired thrombosis or disorders of the blood coagulation process in mammals, or for preventing coagulation in stored blood products and samples. Optionally, the methods of this invention comprise administering the pharmaceutical composition in combination with an additional therapeutic agent such as an antithrombotic and/or a thrombolytic agent and/or an anticoagulant.
Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising" and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of "including, but not limited to".
The preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives.
Detailed Description of the Invention Definitions In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term "alkenyl" refers to a trivalent straight chain or branched chain unsaturated aliphatic radical. The term "alkinyl" (or "alkynyl") refers to a straight or branched chain aliphatic radical that includes at least two carbons joined by a triple bond. If no number of carbons is specified alkenyl and alkinyl each refer to radicals having from 2-12 carbon atoms.
INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 AUG 2003 (followed by page 5a) RECEIVED 5a The term "alkyl" refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic groups having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. The term "cycloalkyl" as used herein refers to a mono-, bi-. or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms. (followed by page 6) INTELLECTUAL PROPERTY OFFICE OF N.Z. 12 AUG 2003 RECEIVED WO 01/19798 PCT/US00/25195 6 As used herein, the terms "carbocyclic ring structure " and" C3.16 carbocyclic mono, bicyclic or tricyclic ring structure" or the like are each intended to mean stable ring structures having only caibon atoms as ring atoms wherein the ring structure is a substituted or unsubstituted member selected from the group consisting of: a stable 5 monocyclic ring which is an aromatic ring Caryl") having six ring atoms; a stable monocyclic non-aromatic ring having from 3 to 7 ring atoms in die ring; a stable bicyclic ring structure having a total of from 7 to 12 ring atoms in the two rings wherein the bicyclic ring structure is selected from the group consisting of ring structures in which both of the rings are aromatic, ring structures in which one of the rings is aromatic and 10 ring structures in which both of the rings are non-aromatic; and a stable tricyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein the tricyclic ring structure is selected from the group consisting of: ring structures in which three of the rings are aromatic, ring structures in which two of the rings are aromatic and ring structures in which three of the rings are non-aromatic. In each case, the non-aromatic IS rings when present in the monocyclic, bicyclic or tricyclic ring structure may independently be saturated, partially saturated or fully saturated. Examples of such carbocyclic ring structures include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, 20 phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Moreover, the ring structures described herein may be attached to one .or more indicated pendant groups via any carbon atom which results in a stable structure. The term "substituted" as used in conjunction with carbocyclic ring structures means that hydrogen atoms attached to the ring caibon atoms of ring structures described herein .may be substituted by one or more 25 of the substituents indicated for that structure if such substitution^) would result in a stable compound.
The term "aryl" which is included with the term "carbocyclic ring structure" refers to an unsubstituted or substituted aromatic ring, substituted with one, two or three substituents selected from loweralkoxy, loweralkyl, loweralkylamino, hydroxy, 30 aminoloweralkyl, hydroxyloweralkyl, halogen, cyano, hydroxy], mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but not limited to carbocyclic aryl, heterocyclic aiyl, and biaiyl groups and the like, all of which WO 01/19798 PCT/US00/25195 7 may be optionally substituted. Preferred aryl groups include phenyl, halophenyl, loweialkylphenyl, napthyl, biphenyl, phenanthrenyl and naphthacenyl.
The term "arylalkyl" which is included with the term "carbocyclic aryl" refers to one, two, or three aryl groups having the number of carbon atoms designated, appended 5 to an alkyl group having the number of carbon atoms designated. Suitable arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all of which may be optionally substituted.
As used herein, the term "heterocyclic ring" or "heterocyclic ring system" is intended to mean a substituted or unsubstituted member selected from the group 10 consisting of stable monocyclic ring having from 5-7 members in the ring itself and having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S; a stable bicyclic ring structure having a total of from 7 to 12 atoms in the two rings wherein at least one of the two rings has from 1 to 4 hetero atoms selected from N, O and S, including bicyclic ring structures wherein any of the described stable monocyclic 1S heterocyclic rings is fused to a hexane or benzene ring; and a stable tricyclic heterocyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein at least one of the three rings has from 1 to 4 hetero atoms selected from the group consisting of N, O and S. Any nitrogen and sulfur atoms present in a heterocyclic ring of such a heterocyclic ring structure may be oxidized. Unless indicated otherwise the terms "heterocyclic ring" 20 or "heterocyclic ring system" include aromatic rings, as well as non-aromatic rings which can be saturated, partially saturated or fully saturated non-aromatic rings. Also, unless indicated otherwise the term "heterocyclic ring system" includes ring structures wherein all of the rings contain at least one hetero atom as well as structures having less than all of the rings in the ring structure containing at least one hetero atom, for example bicyclic 25 ring structures wherein one ring is a benzene ring and one of the rings has one or more hetero atoms are included within the term "heterocyclic ring systems" as well as bicyclic ring structures wherein each of the two rings has at least one hetero atom. Moreover, the ring structures described herein may be attached to one or more indicated pendant groups via any hetero atom or carbon atom which results in a stable structure. Further, the term 30 "substituted" means that one or more of the hydrogen atoms on the ring carbon atom(s) or nitrogen atom(s) of the each of the rings in the ring structures described herein may be WO 01/19798 PCT/US00/25195 8 replaced by one or more of the indicated substituents if such replacements) would result in a stable compound. Nitrogen atoms in a ring structure may be quaternized, but such compounds are specifically indicated or are included within the term "a pharmaceutically acceptable salt" for a particular compound. When the total number of O and S atoms in a 5 single heterocyclic ring is greater than 1, it is preferred that such atoms not be adjacent to one another. Preferably, there are no more that 1 O or S ring atoms in the same ring of a given heterocyclic ring structure.
Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, 10 benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-caibazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, IS isobenzofiiranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyI, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, 20 phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pynolyl, quinazolinyl, quinolinyl, 4H-'quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydioisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-25 thiadazinyl, 1,2,3-thiadiazoIyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structures include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 30 lH-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocylic ring structures.
WO 01/19798 PCT/US00/25195 9 As used herein the term "aromatic heterocyclic ring system" has essentially the same definition as for the monocyclic and bicyclic ring systems except that at least one ring of the ring system is an aromatic heterocyclic ring or the bicyclic ring has an aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring 5 structure.
The terms "halo" or "halogen" as used herein refer to CI, Br, F or I substituents. The term "haloalkyl", and the like, refer to an aliphatic carbon radicals having at least one hydrogen atom replaced by a CI, Br, F or I atom, including mixtures of different halo atoms. Trihaloalkyl includes trifluoromethyl and the like as preferred radicals, for 10 example.
The term "methylene" refers to -CH2-.
The term "pharmaceutically acceptable salts" includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in both free base and salt form. In practice, the use of the salt form amounts to IS use of the base form; both acid and base addition salts are within the scope of the present invention.
"Pharmaceutically acceptable acid addition salt" refers to salts retaining the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, 20 hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fiimaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
"Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, WO 01/19798 PCT/US00/25195 and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine,. 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, 5 hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like'. Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
"Biological property" for the purposes herein means an in vivo effector or 10 antigenic function or activity that is directly or indirectly performed by a compound of this invention that are often shown by in vitro assays. Effector functions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, or any structural role. Antigenic IS functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it.
In the compounds of this invention, carbon atoms bonded to four non-identical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof. The syntheses described herein may employ racemates, 20 enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art. Each of the asymmetric carbon atoms, when present in the compounds of this 25 invention, may be in one of two configurations (R or S) and both are within the scope of the present invention.
Preferred Embodiments The invention provides a compound of the formula (I): WO 01/19798 PCT/US00/25195 11 A-Q-D-E-G-J-X wherein: A is selected fiom: (a) CrCe-alkyl; (b) C3-Cg-cycloalkyl; (c) -N(R2,R3), -C(=NR2)-R3, -C(=NR2)N(R2,R3), -N(R3)-C(=NR2)N(R2, R3)-, and -N(R2)C(=NR3)-R2 (d) phenyl, which is independently substituted with 0-2 R1 substituents; (e) naphthyl, which is independently substituted with 0-2 R1 substituents; and (f) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to ring atoms, wherein 1-4 ring atoms of the ring system are selected fiom N, O and S, and wherein the ring system may be substituted with 0-2 Rl substituents; R1 is selected from: Halo, -CN, -C(=0)-N(R2, R3), -NCh, -S02N(R2, R3), -S02R2, -(CH2)mNR2R3, - (CH2)m-C(=NR3)-R2, -(CH2)m-C(=NR2)-N(R2,R3), -(CH2)m-N(R2)-C(=NR2)-N(R2,R3), -(CH2)mNR2-C3^heterocyclics, C^aUcyl, C2-6alkenyl, C^alkynyl, C3. gcycloalkyl, C(MalkylC3^cycloalkyl, -CFj, -OR2, and a 5-6 membered heterocyclic system containing fiom 1-4 heteroatoms selected fiom N, O and S, wherein from 20 1-4 hydrogen atoms on the heterocyclic system may be independently replaced with a member selected fiom the group consisting of halo, CMalkyl-CN, Ci-4alkyl, C2^alkenyl, C^alkynyl, C3.8Cycloalkyl, Co^alkylCj-scycloalkyl and -N02; R2 and R3 are independently selected fiom the group consisting of: WO 01/19798 PCT/US00/25195 12 -H, -OR", -N(-R\ -R1*), -Ci^alkyl, -C2-6alkenyl, -Cwalkynyl, -C3^cycloalkyl, -Co^alkylCj^cycloalkyl, -Co^alkylphenyl and -Co-«alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, 5 CMalkyl-CN, -Ci^alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3.8cycloalkyl, -Co-«alkylC3- gcycloalkyl, -CN, and -NO2; or R2 and R3 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have fiom 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain fiom 1-4 heteroatoms 10 selected fiom N, O and S, wherein fiom 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected fiom the group consisting of halo, CMalkyl-CN, -Ci^alkyl, -C2-«alkenyl, -C2-6aIkynyl, -C3. gcycloalkyl, -Co-4alkylC3.gcycloalkyl and -N02; Ra and Rb are independently selected fiom the group consisting of -Ci^alkyl, -C2-6alkenyl, 15 -C2-6alkynyl, -C3.gcycloalkyl, -Co4alkylC3^cycloalkyl, or R" and Rb can be taken together with a nitrogen atom to which they are attached to form a 3-8 heterocyclic ring sytem containing 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, 20 -CN, -Cualkyl, -C2^alkenyl, ' -C2^alkynyl, -Cj.gcycloalkyl, -Co^alkylC3.8cycloalkyl and -NO2; m is an integer of 0-2; Q is selected fiom the group consisting of: a direct link, divalent -C]-4alkyI, divalent -C2-4alkenyl, divalent -C2-4alkynyl, 25 -C(=0)-, -C(=NH)-, -C(=NMe)-, -N(-R4)-, -N(-R4)-CH2-, -C(=0)-N(-R4)-, -N(-R4)-C(=0)-, -S(=0)2-, -0-, -S(=0)2-N(-R4> and -N(-R4)-S(=0)2-, wherein one or more hydrogens on each of the divalent Ci^alkyL, divalent C2-4alkenyl and divalent C2^alkynyl moieties can be replaced with a -R4 group; R4 is selected fiom the group consisting of: WO 01/19798 PCT/US00/25195 13 -H, -CF3> -Ci^alkyl, -C2^alkenyl, -C2^alkynyl, -C3-gcycloalkyI, -C&4alkylC3. gcycloalkyl, -Co-4alkylphenyl and -Co^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected fiom the group consisting of halo, 5 -CMalkyl, -C2^alkenyl, -Q-6alkynyl, -C3.8cycloalkyl, -C(MalkylC3.gcycIoalkyl, - CN, -CF3, and -NO2; D is selected from the group consisting of: (a) a direct link; (b) phenyl, which is independently substituted with 0-2 Rla substituents; (c) naphthyl, which is independently substituted with 0-2 Rla substituents; ■ and (d) monocyclic or fused bicyclic heterocyclic ring system having fiom 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 Rla IS substituents; Rla is selected from the group consisting of: halo, Cualkyl, C2^alkenyl, C2^alkynyl, C3.gcycloalkyl, Co^alkylC3.gcycloalkyl, -CN, -N02, (CH2)»NR2sR38, S02NR2aR3a, SCfcR2*, CF3, OR24, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O 20 and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, CMalkyl, C2^alkenyl, C2-6alkynyl, Cj-gcycloalkyl, Co^alkylCs. gcycloalkyl, -CN and -NO2; R2* and R3a are independently selected fiom the group consisting of: -H, CMalkyl, C2^alkenyl, C2^alkynyl, C3-gcycloalkyl, Co-4alkylC3.8cycloalkyl, Ciwalkylphenyl and Co^alkylnaphthyl, wherein fiom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced WO 01/19798 PCT/US00/25195 14 with a member selected from the group consisting of halo, CMalkyl, C^alkenyl, C2-6alkynyl, C3-gcycloalkyl, C<MalkylC3-gcyclc>alkyl, -CN and -NO2; n is an integer of 0-2; E is selected fiom the group consisting of: a direct link, -(CH2)q-C(=0)-, -(CH2)q-N(-R5)-C(=0)-(CH2)I[-) -(CH2)q-C(=0)-N(-R5)-(CH2V, -(CH2)q-N(-R5)-(CH2)x-, , -(CH2)q-N(R5)CO-NR6(CH2)x and -S02-; q and x are independently an integer of 0-2; R5 and R6 are independently selected fiom the group consisting of: H, -CMalkyl, -Cj^alkyloxy, -C2-6alkeriyl, -C2^alkynyl, -C3.gcycIoalkyl, -Co^alkylC3-8cycloalkyl, -Ci^alkyl-C(=0)-0H, -C(walkyl-(caibocyclic aryl), -Co-4alkyl-(monocyclic heteroaryl) and -C1 ^alkyl-C(=0)-0-C 1 ^alkyl, wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety and the monocyclic heteroaryl moieties may be independently replaced with a member 15 selected from the group consisting of halo, -Ci^alkyl, -C^alkenyl, -Qz^alkynyl, - Cs-gcycloalkyl, -Co^alkylCs-gcycloalkyl, -S(=0)2-0H, -CN, -CF3 and -N02; G is selected from the group consisting of: phenyl, which is substituted with 0-2 Rlb groups; and a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 20 hetero atoms selected fiom N, O and S wherein the heterocyclic ring is substituted with 0-2 Rlb groups; Rlb is independently selected from the group consisting of: halo, -Ci.6alkyl, -C2<alkenyl, -C^alkynyl, -Cs-gcycloalkyl, -Co-6alkylC3.gcycloalkyl, -C,^lkyl-C(=0)-0H, -CN, -COOR2b, -CONR2bR3b, -25 NOz, -S(=O)2-0H, -N(-R2b, -R3h), -C(=0)-N(-R2b, -R3b), -S(=0)2-N(-R2b, -R3b), - S(=0)2-R2b, -CF3, -0-R2b, -0-CH2-CH2-0-R2b, -0-CH2-C(=0)-0-R2b, WO 01/19798 PCT/US00/25195 -N(-R2b)-CH2-CH2-0-R2b, -N(-CH2-CH2-0-R2b)2, -N(-R2b)-C(=0)-R3b, -N(-R2b)-S(=0)2-R3b, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S substituted with 0-4 Rlb< groups; alternatively, when two Rlb may be present on adjacent ring atoms of G and 5 combine to form a benzene ring substituted with 0-4 Rlb> groups or a 5-6 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected fiomN, O and S substituted with 0-4 Rlb' groups; in a second alternative, one of the Rlb groups of G can cylize with the -N-Rs group of E to form a 5-7 membered heterocyclic ring containing 1-4 heteroatoms 10 selected from N, O and S, which is subtituted with 0-4 R,v groups, wherein two of the R,b' groups attached to the same ring carbon may form a (=0) group; R2b and R3b are independently selected from the group consisting of: -H, -Ci^alkyl, -Ci^alkyloxy, -C2.6alkenyl, -C2^alkynyl, -C3.gcycloalkyl, -Co-«alkylC3-gcycloalkyl and -Co.6alkyl-(carbocyclic aryl), wherein from 0-4 15 hydrogen atoms on the ring atoms of the carbocyclic aiyl moiety may be independently replaced with a member selected from the group consisting of halo, -Ci^alkyl, -C2-6alkenyl, -C2^alkynyl, -C3.gcycloalkyl, -CcualkylCj-gcycloalkyl, -S(=0)2-0H, -CN, -CF3 and -N02; Rlb'is independently selected from the group consisting of: halo, -Ci^alkyl, -C2^alkenyl, -C2^alkynyl, -C3.gcycloalkyl, -Co^alkylCj-gcycloalkyl, -C,4alkyl-C(=0)-0H, -CN, -N02, -S(=0)2-0H, -N(-R2b', -R3b), -C(=0)-N(-R2b', -R3b), -S(=0)2-N(-R2b', -R3W), -S(=0)2-R2bf, -CF3, -O-R2", -0-CH2-CH2-0-R2y, -0-CH2-C(=0)-0-R2b", -Nt-R^-CHz-CHz-O-R21', -N(-CH2-CH2-0-R2b)2, -N(-R2b')-C(=0)-R3b' and -N(-R2bP)-S(=0)2-R3b"; R2b' and R3b' are independently selected from the group consisting of: -H, -CMalkyl, -Ci-6alkoxy, -C2.6alkenyl, -C2^alkynyl, -C3.gcycloalkyl, -Co^alkylC3^cycloalkyl and -Co^alkyl-Ccarbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be 16 PCT/USOO/25195 independently replaced with a member selected from the group consisting of halo, -Ci^alkyl, -Cz^alkenyl, -C2-6alkynyl, -C3-scycloakyl, -Co4alkylC3^cycloalkyl, -S(=0)2-0H, -CN, -CF3 and -N02; J is selected from the group consisting of: a direct link, -S(=0>2-, -C(=0)-, -N(-R7)-S(=0)2-, -C(=0)-N(-R7)-S(=0)2-, -C(=0)-N(-R7)-(CH2)y-, -S(=0)2-N(-R7) -(GHj)y-, and -N(-R7)-C(=0)-(CH2V; y is an integer of 0-2; R7 is selected from the group consisting of: -H, -C2^alkyl, -C2^alkenyl, -C2.6alkynyl, -Cs-gcycloalkyl, -Co^alkylC3^cycloalkyl, 10 -Cj^alkyl-C(=0)-0H, -Ci^alkyl-OH, rCi^alkyl-O-Cualkyl, -Co- 4alkyl-(caibocyclic aryl), -C<Malkyl-(monocyclic or bicyclic heterocyclic ring r system having from 0-4 heteroatoms selected from the group consisting of N, O and S), -CH2-C(=0)-0-Ci^alkyl and -CH2-C(=0)-0-CMalkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl IS moiety or the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, -CMalkyl, -C2^alkenyl, -C2. 6alkynyl, -C3^cycloalkyl, -Co^alkylC3^cycloalkyl, -S(=0)2-0H, -CN, -CF3 and -N02; X is selected from die group consisting of: phenyl, which is substituted with 0-3 R,c groups; naphthyl, which is substituted with 0-3 R,c groups; a 6-membered hetero aromatic ring containing from 1-2 nitrogen atoms, wherein the ring is substituted with 0-3 R,c groups; and a fused heterobicyclic ring system, wherein the ring system contains 1-3 25 heteroatoms selected from N, O and S and is substituted with 0-3 R,c groups; Rlc is independently selected fiom the group consisting of: WO 01/19798 PCT/US00/25195 17 halo, -CF3, -Cj^alkyl, -C^alkenyl, -C2.6alkynyl, -C3-8cycIoalkyl, -Co-salkylCj-gcycloalkyl, -Ci^alkyl-C(=O)-0H, -CF3, -CN, -NO2, -(CH2)z-N(-R2e, -R3c), -C(=0)-N(-R2c, -R3c), -C(=NH)-N(-R2eJ -R3®), -C(=NMe)-N(-R2c, -R3e), -S(=0)2-N(-R2c, -R3c), -S(=0)2-R2c, -S(=0)2-0H, -CF3s -O-R26, -0(-CH2)z-0-R2c, 5 -0(-CH2)z-C(=0)-0-R2c, -N(-R2c), -OC-CHz^O-R26, -N[(-CH2)z-0-R2c]2, -(CH2)z-N(-R2e)-C(=0)-R3e, -(CH2)z-N(-R2e)-S(=0)2-R3e, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected fiom N, O and S; z is an integer of 0-4; R2c and R3c are independently selected fiom the group consisting of: -H, -Ci^alkyl, -Ci^alkyloxy, -C2^alkenyl, -C2^alkynyl, -C3-8cycloalkyl, -C0-6alkylC3.gcycloalkyl and -C(«alkyl-(carbocyclic aryl), wherein fiom 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be independently replaced with a member selected fiom the group consisting of halo, -CMalkyl, -C2^alkenyl, -Cualkynyl, -C3.gcycloalkyl, -Co^alkylCs-scycloalkyl, -15 S(=0)2-0H, -CN, -CF3 and -N02; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
The invention also provides a compound of the formula (I): A-Q-D-E-G-J-X wherein: A is selected from the group consisting of: -CMalkyl and -Cs^cycloalkyl; -phenyl, which is substituted with 0-2 R1 groups; naphthyl, which is substituted with 0-2 R1 groups; and WO 01/19798 PCT/US00/25195 18 a 5-10 membered aromatic or non-aromatic heterocyclic ring system which may be a monocyclic ring system or a fused bicyclic ring system, wherein the heterocyclic ring system contains 1-4 heteroatoms selected from N, O and S and is substituted with 0-2 R1 groups; R1 is independently selected from the group consisting of: halo, -CMalkyl, -CN, -N02, -(CH2)m-N(-R2,-R3), -C(=0)-N(-R2,-R3), -S(=0)2-N(-R2,-R3), -S(=0)2-R2, -(CH2)m-C(=NR3)-R2, -(CH2)m-C(=NR2)-N(R2,R3), -(CH2)m-N(R2)-C(=NR2)-N(R2,R3), -CF3, -(CH2)m-0-R2 and a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected fiom N, O and S; R2 and R3 are independently selected fiom the group consisting of: -H, -Ci^lkyl, or R2 and R3 taken together can foim a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have fiom 3 to 10 ring atoms, with-1 to 2 rings being in the ring system and contain fiom 1-4 heteroatoms 15 selected from N, O and S, wherein fiom 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected fiom the group consisting of halo, Ci-CMalkyl-CN, -CMalkyl, -C2^alkenyl, -C^alkynyl, -C3-gcycloalkyl, -Co^alkylCj-gcycloalkyl and -N02; m is an integer of 0-2; Q is selected from die group consisting of: a direct link, -Cj^lkyl, -C2-4alkenyl, -C2^alkynyl, -C(=0)-, -C(=NH)-, -C(=NMe)-, -N(-R4)-, -N(-R4)-CH2-, -QOJ-NC-R4)-, -N(-R4)-C(=0)-, -S(=0)2-, -0-, -S(=0)2-N(-R4)- and -N(-R4>S(=0)2-; R4 is selected fiom the group consisting of: -H, -CF3, -Ci^alkyl, D is selected fiom the group consisting of: WO 01/19798 PCT/USOO/25195 19 a direct link; phenyl, which is substituted with 0-2 Rla groups; and a 5-10 membered aromatic or non-aromatic heterocyclic ring system which may be a monocyclic ring system or a fused bicyclic ring system, wherein the 5 heterocyclic ring system contains 1-4 heteroatoms selected from N, O and S and the ring system is substituted with 0-2 RIs groups; R,a is independently selected fiom the group consisting of: halo, -CMalkyl, -CN, -N02, -(CH2)„-N(-R2a, -R3a), -S(=0)2-N(-R2a, -R3a), -StrOh-R2*, -CF3, -(CHjJn-OR28, -C^-O-R28, -CK^NO-R2', -R3a) and a 5-6 10 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected fiom N, O and S; n is an integer of 0-2; R28 and R3a are independently selected fiom the group consisting of: -H, -CF3 and -CMalkyl, E is selected fiom the group consisting of: a direct link, -(CH2)q-C(=0)-, -(CH2)q-N(-Rs>C(=0)-(CH2)x-, -(CH2)q-C(=0)-N(-RsMCH2)x-, -(CH2)q-N(-R5)-(CH2)x-, -(CH2)q-N(R5)CO-NR6(CH2)x- and -S02-; Rs and R6 are each H, -Ci^alkyl, -C2^alkenyl, -C2^alkynyl, -C3-gcycloalkyl, or 20 -QMalkylC3.gcycloalkyl; q and x are independently an integer of 0-2; G is selected fiom the group consisting of: phenyl, which is substituted with 0-2 RIb groups; and WO 01/19798 PCT/US00/25195 a 5-6 membered aromatic and non-aromatic heterocyclic ring containing 1-4 hetero atoms selected from O, S and N, wherein the heterocyclic ring is substituted with 0-2 Rlb groups; RIb is independently selected fiom the group consisting of: halo, -CMaIkyl, -CN, -N02) -N(-R2b, -R3b), -C(=0)-N(-R2b, -R3b), -S(=0)2-N(-R2\ -R3b), -S(=0)2-R2b, -CF3, -0-R2b, -0-CH2-CH2-0-R2b, -0-CH2-C(=0)-0-R2b, -N(-R2b)-CH2-CH2-0-R2b, -NC-CHa-CHj-O-R^j, -N(-R2b)-C(=0)-R3b, -N(-R2b)-S(=0)2-R3b and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected fiom N, O and S; alternatively, when two Rlb may be present on adjacent ring atoms of G and combine to form a benzene ring substituted with 0-4 Rlb groups or a 5-6 membered aromatic or non-aromatic heterocyclic ring having 1-3 heteroatoms selected fiom N, O and S substituted with 0-4 Rlb' groups; in a second alternative, one of the Rlb groups of G can cylize with the -N-R5 15 group of E to form a 5-7 membered saturated, unsaturated or partially unsaturated heterocyclic ring containing 1-4 heteroatoms selected fiom N, O and S, which is substituted with 0-4 Rlb> groups, wherein two of the Rlb groups attached to the same ring carbon may form a (=0) group; R2b and R3b are independently selected fiom the group consisting of: -H, -CF3, -Ci^alkyl and -Ci^alkyl-(caibocyclic aryl); < Rlb< is independently selected fiom the group consisting of: halo, -CMalkyl, -CN, -N02, -N(-R2b', -R3b), -C(=0)-N(-R2b', -R3b), -S(=0)2-N(-R2b, -R3b), -S(=0)2-R2b', -CF3, -O-R2"', -0-CH2-CH2-0-R2b, -0-CH2-C(=0)-0-R2b, -N(-R2b")-CH2-CH2-0-R2b", -N(-CH2-CH2-0-R2b,)2, 25 -N(-R2b')-C(=0)-R3b', -N(-R2b')-S(=0)2-R3tf; R21*' and R3b' are independently selected from die group consisting of: WO 01/19798 PCT/US00/25195 21 -H, -CMalkyl and -C1 ^alkyl-(carbocyclic aiyl); J is selected fiom the group consisting of: a direct link, -S(=0)2-, -C(=0)-, -N(-R7)-S(=0)2-, -C(=0)-N(-R7)-S(=0)2-, -C(=0)-N(-R7)-(CH2V, -S(=0)2-N(-R7)-, -(CHjV and -N(-R7)-C(=0)-(CH2)y-; y is an integer of 0-2; R7 is selected fiom the group consisting of: -H, -Ci^alkyl, -C2.6alkenyl, -C2-6alkynyl, -Co-4alkyl-(carbocyclic aryl), -C<Malkyl-(heteiocyclic ring system), -CH2-C(=0)-0-C i ^alkyl and -CH2-C(=0)-0-C i .4alkyl-(carbocyclic aryl); X is selected fiom the group consisting of: phenyl, which is substituted with 0-3 Rlc groups; . naphthyl, which is substituted with 0-3 Rlc groups; a 6-membered heteroaromatic ring containing fiom 1-2 nitrogen atoms, wherein the ring is substituted with 0-3 Rlc groups; and a fused heteiobicyclic ring system, wherein the ring system contains 1-3 heteroatoms selected fiom N, O and S and is substituted with 0-3 Rlc groups; Rlc is independently selected fiom the group consisting of: halo, -CMalkyl, -CN, -N02, -(CH&-N(-R2c. -R3c), -C(=0)-N(-R2c, -R3c), -C(=NH>N(-R2c, -R3c), -C(=NMe)-N(-R2c, -R3*), -S(=0)2-N(-R2c, -R3c), -S(=0)2- R20, -S(=0)2-0-, -CF3, -0-R2c, -0-CH2-CH2-0-R2c, -0-CH2-C(=0)-0-R2c, -N(-R2c)-CH2-CH2-0-R2c, -N(-CH2-CH2-0-R2c)2, -(CH2)z-N(-R2c)-C(=0)-R3c, -{CH^N^R^-SC^D^-R3®, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, O and S; z is an integer of 0-2; WO 01/19798 PCT/US00/25195 22 R2c and R3c are independently selected from the group consisting of: -H, -CMalkyl and -Ci^alkyl-(carbocyclic aiyl); and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
The present invention also provides compounds of the formula (I): A-Q-D-E-G-J-X wherein: A is selected from the group consisting of: / N Me S02NH2 SOsNHMe SOjMe CHjNHj r-N f ^ ( Y F a Br F / / rNN T"nn NC H2NOC H2NH2C NC HjNOC p- p- to-1 Kto- o- to- to- CI Br H2NH2C MejNHjC Me2N HjN ,NH2 CH2NH2. .CN ^/NM®2 to- to- to- to- to- to- to- to- CH2NMe2 s02nh2 s02m® /CQNH2 h2N H2NH>gC to- to- to- to- o- &- o H2N NH2 CHjpNHJ __ NH2 CH2NH2 /CN n2w ""2 __ «n2 / p-<y<y <y SOjMe NH2 H2N Me2N . H2NH2C H2NOC Nc to- to- to- fa- fa- fa- fa- i> \=N ^=N V=N \=N \=N \=N WN ^ WO 01/19798 PCT/US00/25195 23 P- 0- ^V-m"Cy hO- O- 0-°0- nh2 h O -O "•-O- "O- "O- O O- O" O O- Q- O- <^n- >- » Me Mb me D- O- JD- D*- O- Me Me H Me Me „ Cr Cr 0-1>- cj- ty tv tj- tj- t> a^aaaajt s- -r- -• H Mq Et II U Me, Me^ Me, Me, H Me I Me,N^ H2N-CH2- N-CH2- N-CH2- Me-N-CH2- Me-^-N- Me-)-0- H Me Me Me Me Q is selected from the group consisting of: a direct link, -C(=NH), -C(=NMe)-, -C(=0)-, -CH2-, -NH-, -N(-CH3)-, -0-, -NH-CH2-, -CH2-NH-, -N(-CH3)-CH2-, and-CH2-N(-CH3)-; D is selected from the group consisting of: 24 -O- -Q- -0" -d- -($- -($- _(£ CH2NH2 Me F F Fv CI. Br -o- <y -Q- -o- -b- -o- -o- F F -•O- "O*- -|Oj_ -O- -0— -0— -0--CP- ^b- -<£ -CJ- 4j- Met Me ^ -tf*- -cf- E is selected fiom the group consisting of: a direct link, -NH-C(=0)-, -N(-CH3>C(=0)-, -N(-CH2C02H)-C(=0)-, C(=0)-NH-, -CX=0)-N(-CH3)-, -NH-CH2- and-CH2-NH-; G is selected from the group consisting of: WO 01/19798 PCT/US00/25195 Rlb is independently selected from the group.consisting of: -H, -Me, -CF3, -F, -CI, -Br, -S02Me, -CN, -CONH2, -CONMe2, -NH2, -N02, -NHCOMe, -NHS02Me, -CH2NH2 and -C02H; J is selected from the group consisting of: a direct link, -NH-, -0-, -S(=0)2-, -S(=0)2-NH, -NH-S(=0)2-, -C(=0)-, -NH-C(=0)- and -C(=0)-NH-; WO 01/19798 PCT/USOO/25195 HCr^^^CI HO^^^Br H1 I vyvBr HCr^^ mr^ MeCT^^^F UeCT^^CA MeO^^^^Br MeC^"^ MeCT^^^ Mer ^ H2N'^^-~F HZN^^^XI HzN^^^Br H2I I \^^Br s^W-F YYY01 HzN^^ MeOzS-^^^F MeOzS^^^F »^-T -^ctX .^ax „^XC 'F v^xs^-wCI ^fYyBT V^Y^VF MeOjS'^^^Br MeOaS^^^Br Me02S^^^Br HaNOaS^^^^F ^^ccc «ccC -Br N]f,!Y*!*T'F WYBr H2N02S^^^CI HaNOaS^^^Br H2N02S^^^Br H2m^Sr^^Br jccc jox jox „cce ^ccx <*£Ct ^ccC Br "VV/'X^CI 02N^^^Br nc^V^f NC^^^F NCT^^F PCT/USOO/25195 31 TYV TT^C01 Trf* NcrA^kJA.cl NCA^A^AC| Ncr^^ei N n h2no h2no h2NH2i :.
Br f h2noi f h2no< ^ci 01 Br Br H2NOC f ci h2no£t^^xi hanoct^^^ci Br yyyci Br H2NOCT^^Br H2NO Br Br H2NH2i Br f hznhaca^^f h^hac^^^ci h2nh2c^^^ci VVVfif h2nh2ct^^"ci h2nh2' CI Br HzNHzCT^^^Br H2NH2i Br Br Br jh HzM^OOCq ^ca, Cl YVY81" YYYf yyyci CI H2N«j^Asi!#>lN#ii^Q| H2N^Jsvi!siJ«Si#4s.gr H2N^^k^s^Lgr h,n. jh Br W* Br XXXp nh2 nh2 nh2 nh2 nh2 ?x6 ;aX ;eacl ;ca NH2 Br MH2 Br NHa N NH2 N 32 H2N02: NH2 N PCT/USOO/25195 Me02: VH2 N H2NOI nh2 N fjJH2 NH2 hoPX? VH2 N CI and all phaimaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, thereof.
The compounds listed in the following S3 tables are an embodiment of the present invention: WO 01/19798 PCT/USOO/25195 33 Table 1 wherein: Rlb is selected from the group consisting of-H, -CH3 and -CF3.
Table 2 wherein: Rlal and Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br; WO 01/19798 PCT/USOO/25195 34 Rlb is selected from the group consisting of-H, -CH3 and CF3; and Rlc2 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3 and -NH2.
Table 3 wherein: Rlb is selected fiom the group consisting of-H, -CH3 and -CF3; and Rlc2 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3 and -NH2.
PCT/USOO/25195 Table 4 wherein: Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and -Br; Rlb is selected from the group consisting of-H, -CH3 and -CF3; and Rlcl is selected from the group consisting of -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -C02H, -COzMe, -S02Me, -S02NH2, -OH, -NH2, and -N02. 36 PCT/USOO/25195 Table 5 wherein: Rlal and RlaZ are independently selected from the group consisting of -H, -F, -CI and -Br; Rlb is selected from the group consisting of-H, -CH3 and -CF3; and 5 Rlc3 is selected fiom the group consisting of -H, -F, -CI, -Br, -OH, -OCH3 and -NH2. 37 PCT/USOO/25195 Table 6 wherein: RU1 and R,a2 are independently selected from the group consisting of -H, -F, -CI and -Br; R,b is selected from the group consisting of -H, -CH3, -CF3, -CH2CH3, -CF2CF3, -CH2NH2, -CONHj, -SO2CH3, -S02NH2> -NH2COCH3 and -NH2COCF3; R,cl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2> -CO2H, -C02Me, -S02Me, -S02NH2l -OH, -NH2, and -N02; RIc2 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and Rlc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, and -NH2. 38 PCT/USOO/25195 Table 7 wherein: R1 is selected from the group consisting of -H, -NHfe, -SO2NH2, -SO2CH3, -CN, -CONHz, -CONH(CH3), -CON(CH3)2.-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; R1' is selected from the group consisting of -H, -NH2, -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2i-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rlal and Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br; Rlb is selected from the group consisting of -H, -CH3, -CF3, -CH2CH3, -CF2CF3, -CH2NH2, -CONH2, -SO2CH3, -SO2NH2, -NH2COCH3 and -NH2COCF3; Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONHz, -C(=NH)NH2, -C02H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; R1<a is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and —NH2; and Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2.
PCT/USOO/25195 39 Table 8 ,R' wherein: R1 is selected fiom the group consisting of -SO2NH2, -S02CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2,-CH2NH2,-CH2NH(CH3), -CH2N(CH3)2; Rlb is selected fiom the group consisting of-H, -CH3 and -CF3; Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; R1<a is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and Rlc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, and -NH2. 40 PCT/USOO/25195 Table 9 wherein: A is selected fiom the group consisting of: V- "V- V- "V- "V- o- o*~ H H H Ma Ma B 0*~ cS~ O*- o C/~ r>0~ O o <vCr hO mb^O~ O O O O o-"t> WO 01/19798 PCT/USOO/25195 41 R,al and Rla2 are independently selected fiom the group consisting of-H, -F, -CI and -Br, Rlb is selected from the group consisting of -H, -CH3, -CF3, -CH2CH3, -CF2CF3, -CH2NH2, -CONH2, -SO2CH3, -SO2NH2, -NH2COCH3 and -NH2COCF3; Rlcl is selected fiom the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -5 CONH2, -C(=NH)NH2, -C02H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlc2 is selected fiom the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2.
Table 10 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 42 T Q- q- 0- [J- c5-Q-Q-q- Et Me B Me a*- Q^O^cF- c^cyj^ Me Me qjx&_ i^-ts- cyt«- Q-^- Q-1-5- R1"1 and R,a2 are independently selected fiom the group consisting of -H, -F, -CI and -Br; Rlb is selected from the group consisting of -H, -CH3, -CF3| -CH2CH3, -CF2CF3, -CH2NH2, -CONH2, -SO2CH3, -S02NH2> -NH2COCH3 and -NH2COCF3; Rlcl is selected fiom the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -5 CONHz, -C(=NH)NH2, -C02H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -NO2; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2.
PCT/USOO/25195 43 Table 11 R1 R1" r1 r1"1 r1 Q-P " R« Rfc' wherein: R1 is selected from the group consisting of -S02NH2> -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2,-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rlb is selected from the group consisting of -H, -CH3 and -CF3; Rlal and R,a2 are independently selected fiom die group consisting of-H, -F, -CI and -Br; R,cl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2j -C(=NH)NH2, -C02H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -NO2; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; R,c3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and G is selected from the group consisting of: wherein: Rlbl is selected fiom the group consisting of-H, -CH3 and -CF3; Rlb2 is selected fiom the group consisting of-H, -CH3 and -CF3; and 44 PCT/USOO/25195 Table 12 Rlb3 is selected from the group consisting of-CI, -NH2» -CH3 and -CF3. wherein: A is selected from the group consisting of: y~ y- y- y- y- y- o- <$• «~0- O- c5*~ C"~ o X> O- O- O O "-0~ OOOO- tO"X> PCT/USOO/25195 45 Rlb is selected from the group consisting of-H, -CH3 and -CFj; Rlal and R1"2 are independently selected from the group consisting of -H, -F, -CI and -Br; Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -C02H, -C02Me, -SOjMe, -S02NH2, -OH, -NH2, and -N02; R,c2 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, and -NH2; Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and G is selected from the group consisting of: wherein: Rlbl is selected fiom the group consisting of -H, -CH3 and -CF3; Rlb2 is selected fiom the group consisting of-H, -CH3 and -CF3; and RIU is selected from the group consisting of -CI, -NH2, -CH3 and -CF3.
Table 13 wherein: A-Q is selected from the group consisting of: 46 PCT/USOO/25195 q- q- q- q- o- o-Orq-Q- n® Et Ma Et o- o- o cyt- cy*.
Me Ma Me IV ■N—0— cy^ Q-^ Gr^ Q-^- O-1 Me CH~*~ "O" "-"O- x> hO~ -O- ^ ^ MeJ^JT"we/" CV C^~ /""\ f\_ f~~\ ,N— N^N— J' ^_ bNHj Rlb is selected fiom the group consisting of-H, -CH3 and -CF3; Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and -Br; Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; Rlc3 is selected fiom the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and WO 01/19798 PCT/USOO/25195 47 G is selected from the group consisting of: wherein: Rlbl is selected from the group consisting of-H, -CH3 and -CF3; RIW is selected from the group consisting of-H, -CH3 and -CF3; and Rlb3 is selected from the group consisting of -CI, -NHfe, -CH3 and -CF3.
Table 14 wherein: WO 01/19798 PCT/USOO/25195 48 R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2i -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rlb is selected from the group consisting of-H, -CH3, -CF3; R,cl is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -5 CONH2, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NHa, and -N02; Rlc2 is selected fiom the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and-NH2; and Rlc3 is selected fiom the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2.
PCT/USOO/25195 49 Table 15 wherein: 50 A is selected from die group consisting of: PCT/USOO/25195 y~ y- y- y- y- >- o- o- ex- o~ cP* """O- -XD1- O O O hO~ Rlb is selected from the group consisting of-H, -CH3 and -CF3; Rlel is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; R,c2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and R,c3 is selected fiom the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2. 51 PCT/USOO/25195 Table 16 wherein: A-Q is selected fiom the group consisting of: WO 01/19798 PCT/USOO/25195 52 Q-cht^o-o-o-o-Q-Q- "o Et Ma Et Q-O-O^^cK^O^ Mb CFQ^O^-O4 O-^C^-O-^ Ma Ma c>**- &**- cp- o Me /~X 1% r~\ r—\ j \ f \ H\_y Me_lW~ "W" M,r~\_yN— >0- JT J-Jrjr,wr O- ji- Th, N—0— / \ /=\ /""N /-\ n<Y"— ny-"— lf=y~~ Me CONH, CH2NH2 Rlb is selected fiom the group consisting of-H, -CH3 and -CF3; R,cl is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONHz, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2. 53 Table 17 PCT/USOO/25195 54 PCT/USOO/25195 Table 17 (continued) wherein: R1 is selected from the group consisting of -S02NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3),-CON(CH3)2i-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; R,al and Rla2 are independently selected from the group consisting of -H, -F, -CI and Br; Rlb is selected from the group consisting of-H, -CH3 and -CF3; Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONHz, -C(=NH)NHZ, -C02H, -COzMe, -S02Me, -S02NH2, -OH, -NH2, and -NOz; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and Rlc3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2. 55 Table 18 PCT/USOO/25195 PCT/USOO/25195 56 Table 18 (continued) wherein: A is selected fiom the group consisting of: y~ y~d- y~ d- >-"v- <i>^ C"- C"- C/"- 01- O- - o- o- o o —•o-O O O O "OX> RIal and Rla2 are independently selected fiom the group consisting of -H, -F, -CI and Br, Rib is selected fiom the group consisting of -H, -CH3 and -CF3; Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONHz, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and R,c3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2. 57 Table 19 PCT/USOO/25195 PCT/USOO/25195 58 Table 19 (continued) wherein: A-Q is selected fiom the group consisting of: WO 01/19798 PCT/USOO/25195 59 thchcyo-cyoQrQ-O M. 1 * * El Ms El O-Q-O-cp^cK^O^ Me Rlal and Rla2 are independently selected from the group consisting of-H, -F, -CI and Br; Rlb is selected from the group consisting of -H, -CH3 and -CF3; Rlcl is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -5 CONH2, -C(=NH)NH2, -C02H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlc2 is selected fiom the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and R,c3 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2.
PCT/USOO/25195 60 Table 20 wherein: R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2>-CH2NH2, -CH2NH(CH3), -CH2N(CHj)2; RlBl and R1a2 are independently selected from the group consisting of -H, -F, -CI and -Br; R,c' is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -COzH, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of -H, -F, -CI, -Br, and -OCH3; Rlc3 is selected from the group consisting of -H," -F, -CI, -Br, -OH, -OCH3, -NH2, -10 CONH2, -CH2NH2, -CH2NHCH3. -CH2N(CH3)2, -C(=NH)NH2; and G is selected fiom the group consisting of: wherein: Rlbl is selected from the group consisting of-H, -CH3 and -CF3; Rlb2 is selected from the group consisting of.-H, -CH3 and -CF3; IS Rlb3 is selected fiom the group consisting of-CI, -NH2, -CH3 and -CF3.
PCT/USOO/25195 61 Table 21 j*1 tf*1 yr, r1 o~9-*" " o-o r« r*" wherein: R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2,-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rlal and R1*2 are independently selected from the group consisting of -H, -F, -CI and -Br; Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, -COjMe, -SOzMe, -S02NH2, -OH, -NH2, and -N02; R,c2 is selected from the group consisting of -CH2-, -0-, -NH-, -N(CH3)-, -CH2CH2-, -O-CH2-, -NH-CH2-, and -N(CH3)-CH2-; Rlc3 is selected from the group consisting of -CH2-, -O-, -NH-, -N(CH3)-, and -CH(NH2)-; and G is selected from the group consisting of: wherein: R,bl is selected from the group consisting of-H, -CH3 and -CF3; RIb2 is selected from the group consisting of-H, -CH3 and -CF3; and WO 01/19798 PCT/USOO/25195 62 RIb3 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3.
Table 22 wherein: R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, 5 -CONH(CH3), -CON(CH3)2> -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rlal and RlaZ are independently selected fiom the group consisting of -H, -F, -CI and -Br; Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NHz, -CO2H, -C02Me, -S02Me, -SO2NH2, -OH, -NH2, and -N02; RIe2 is selected fiom the group consisting of-H, -F, -CI, -Br, and -OCH3; Rlc3 is selected fiom the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, -NH2, -CONH2, -CH2NH2, -CH2NHCH3,-CH2N(CH3)2, -C(=NH)NH2; and G is selected fiom the group consisting of: wherein: WO 01/19798 PCT/USOO/25195 63 Rlbl is selected fiom the group consisting of-H, -CH3 and -CF3; R1W is selected from the group consisting of-H, -CH3 and -CF3; and R,b3 is selected from the group consisting of-CI, -NH2, -CH3 and -CF3.
Table 23 S wherein: R1 is selected from the group consisting of -SO2NH2. -S02CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2,-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; RIal and RIa2 are independently selected from the group consisting of -H, -F, -CI and -Br; WO 01/19798 PCT/USOO/25195 64 Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -C02H, -CC>2Me, -S02Me, -S02NH2, -OH, -NH2, and -NO2; Rlc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and G is selected from the group consisting of: wherein: R,bl is selected from the group consisting of -H, -CH3 and -CF3; Rlb2 is selected from the group consisting of -H, -CH3 and -CF3; and Rlb3 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3.
Table 24 wherein: PCT/USOO/25195 65 R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2i-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rlal and Rla2 are independently selected fiom the group consisting of -H, -F, -CI and -Br; Rlcl is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -5 CONH2, -C(=NH)NH2, -C02H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlc2 is selected fiom the group consisting of-CH-, and -N-; Rlc3 is selected fiom the group consisting of -NH-, and -O-; and G is selected from the group consisting of: wherein: Rlbl is selected from the group consisting of-H, -CH3 and -CF3; Rlb2 is selected from the group consisting of -H, -CH3 and -CF3; and Rlb3 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3. 66 PCT/USOO/25195 Table 25 j*1 ft* ' r" O-0-* O-CK r« 101 .R1" p1 ■ r1 Q O-CK wherein: R1 is selected fiom the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CHj), -CON(CH3)2l-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rlal and Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br; Rlcl is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, -COzMe, -S02Me, -SO2NH2, -OH, -NH2> and -N02; Rle2 is selected fiom the group consisting of-CH2-, -0- and -NH-; R,c3 is selected fiom the group consisting of-CH-, -C(NH2)- and -N-; and G is selected fiom the group consisting of: wherein: PCT/USOO/25195 67 Rlbl is selected from the group consisting of-H, -CH3 and -CF3; R,b2 is selected from the group consisting of-H, -CH3 and -CF3; and RlbJ is selected from the group consisting of -CI, -NH2, -CH3 and -CF3.
Table 26 wherein: A is selected from the group consisting of: v- y- v~ y- V- v~ O1*- H H H Me Me Ef cy- 6- o*~ o Ca" u°~~Gr~ O O O hO~ K)" OOOO O-^O PCT/USOO/25195 68 R,al and R,a2 are independently selected from the group consisting of -H, -F, -CI and -Br; Rlel is selected fiom the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -COzH, -C02Me, -S02Me, -S02NH2j -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCHj; RlcJ is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCHj, -NH2, -CONH2, -CH2NH2, -CH2NHCH3.-CH2N(CH3)2, -C(=NH)NH2; and G is selected from the group consisting of: wherein: Rlbl is selected from the group consisting of -H, -CH3 and -CF3; Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and Rlb3 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3.
Table 27 a— wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 69 Q- Q- q- o- o- o- Or q- q- Et Site Et " Me qx. qx qz. qz. ox qs^ cp Rlal and Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br; R,cl is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONHz, -C(=NH)NH2, -COzH, -C02Me, -SOzMe, -S02NH2, -OH, -NH2, and -N02; R,c2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; Rlc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, -NH2, -CONHz, -CH2NH2, -CH2NHCH3.-CH2N(CHj)2, -C(=NH)NH2; and 70 PCT/USOO/25195 G is selected fiom the group consisting of: wherein: Rlbl is selected fiom the group consisting of -H, -CH} and -CF3; Rlb2 is selected fiom the group consisting of-H, -CH3 and -CF3; and 5 R,m is selected fiom the group consisting of -CI, -NH2, -CH3 and -CF3.
Table 28 wherein: WO 01/19798 PCT/USOO/25195 71 A is selected from the group consisting of: yy yy y y~ o- <>■ C*~ c£- O*- O- <^- K> IX> O- O- "O" "O- "-o- OOOO t>"X> RIal and Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br; R1cl is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -5 CONH2, -C(=NH)NH2, -C02H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; Rlc3 is selected fiom the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, -NH2, -CONH2, -CH2NH2, -CH2NHCH3,-CH2N(CH3)2, -C(=NH)NH2; G is selected fiom the group consisting of: pibl sibi Rih2 ff \ ^ JH wherein: Rlbl is selected fiom the group consisting of-H, -CH3 and -CF3; Rlb2 is selected fiom the group consisting of-H, -CH3 and -CF3; and R,b3 is selected fiom the group consisting of rCl, -NH2, -CH3 and -CF3. 72 PCT/USOO/25195 Table 29 wherein: A-Q is selected fiom the group consisting of: WO 01/19798 PCT/USOO/25195 73 Q-q-q-o-o-o-Q-q-Q- •*> Et Ma Et O-.O- O Q*- cp- cK cF- cy^ H Me Me Me CjJts. cyj^ 0^ Me ^ i^hj /"a / \ h\ / \ f^\ f^\ ^—N—C— H>^ Ji— Me—— J—V—/1— H\_/N— **—'\ /*— hT ^C-M:rjrQ*- O2NH2 SOjNH, SOjMe SCyVts CONH2 CONHj CH,NH2 CHjhIH, Jjr Q- Q~Sr •o1— no— "o— >(~y~ Me CONH2 CH,NH2 R * and R are independently selected from the group consisting of -H, -F, -CI and -Br; Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; RIc2 is selected from the group consisting of -CH2-, -0-, -NH-, -N(CH3)-, -CH2CH2-, -O-CH2-, -NH-CH2-, and -N(CH3)-CH2-; RIc3 is selected from the group consisting of -CH2-, -0-, -NH-, -N(CH3)-, and -CH(NH2)-; and WO 01/19798 PCT/USOO/25195 74 G is selected from the group consisting of: plbl plbl plU // \v jc^ JH wherein: Rlbl is selected from the group consisting of-H, -CH3 and -CF3; Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and Rlb3 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3. 75 PCT/USOO/25195 Table 30 wherein: WO 01/19798 PCT/USOO/25195 76 A is selected from the group consisting of: y y- y- y- y- o- <£- "-O- O"- Cy*- C*~ O dP" "-O ^O- O O- O "O- O O O "O 0"t> RlsI and R,a2 are independently selected from the group consisting of -H, -F, -CI and -Br; RlcI is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -5 CONH2, -C(=NH)NH2, -C02H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -0CH3; R,c3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, -NH2, -CONH2, -CH2NH2, -CHzNHCHj, -CH2N(CH3)2, -C(=NH)NH2, -C(=NH)NH(CH3), -C(=NH)NH(CH3)2; and G is selected from the group consisting of: wherein: RlbI is selected fiom the group consisting of -H, -CH3 and -CF3; Rlb2 is selected fiom the group consisting of-H, -CH3 and -CF3; and PCT/USOO/25195 77 Rlb3 is selected from the group consisting of-CI, -NH2, -CH3 and -CF3.
Table 31 A— wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 78 t}- cf- 0- o- 0- 0- q- q- q- M9 Et Mb Et O-O-O-cv^cpc^c^O^ Mb Th, Q*- Q1- o-*- cp- Mb Mb q-£*~ o-^- Qr^ (V^ q-^- Mb Ci iv / \ / \ f^\ f^\ y—N-Q— Hl^ yj— Me—^ y*— y*— Hh^ y*— Me—— Me >0- «3*~ «x"-t"-r"-«r 0- q- SOjNHj SOjNHi SOjMe SOjMe «MH2 CONHj pijNHj PH2NHa •O*- fO1— Me CONH, CHjNH, Rlal and R,aZ are independently selected from the group consisting of -H, -F, -CI and -Br; RIcI is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONHj, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; R,c2 is selected from the group consisting of-H, -F, -CI, -Br, -OH, -OCH3, and -NH2; Rlc3 is selected from the group consisting of -H, -F, -CI, -Br, -OH, -OCH3, and -NH2; and PCT/USOO/25195 79 G is selected from the group consisting of: ntt) nlbl p1D2 BID) // \ J\ wherein: Rlbl is selected from the group consisting of-H, -CH3 and -CF3; R,b2 is selected from the group consisting of-H, -CH3 and -CF3; and 5 Rlb3 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3. wherein: Table 32 80 A is selected fiom the group consisting of: PCT/USOO/25195 y y y- y~ y~ y-o- <$- "-0"- C*- O*- o*- o u">0^ .Q- .w0- »Q- »"Q»- o o o o Rlal and Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br; Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONHj, -C(=NH)NH2, -C02H, -C02Me, -S02Me, -SO2NH2, -OH, -NHZ, and -NO2; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and G is selected from the group consisting of: „ R_ - r\ J^, H wherein: R1bl is selected from the group consisting of -H, -CH3 and -CF3; RIbZ is selected fiom the group consisting of-H, -CH3 and -CF3; and R1M is selected fiom the group consisting of -CI, -NH2, -CH3 and -CF3.
PCT/USOO/25195 81 wherein: Table 33 A is selected fiom the group consisting of: y~ y- y- y- y- y- o- J>- Me We Me^0N- cy~ C/~ o- o C/~ Me~o~ IXD- O- <D~ oO hO O O O °o o-^o PCT/USOO/25195 82 Rlal and R,a2 are independently selected from the group consisting of -H, -F, -CI and -Br, Rlcl is selected fiom the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NHZ, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -NOz; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and G is selected fiom the group consisting of: wherein: Rlbl is selected fiom the group consisting of-H, -CH3 and -CF3; Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and Rlb3 is selected from the group consisting of-CI, -NH2, -CH3 and-CF3. 83 Table 34 PCT/USOO/25195 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 84 q- q- c- o- c-o q- q- Et Ms El OO-Ocy^CKcy^cKc^ H Ms cp <y- a*- cp*- Q**- Rlal and Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br; Rlcl is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH* -C(=NH)NH2, -CO2H, -C02Me, -SCWe, -S02NH2, -OH, -NH2j and -N02; Rlc2 is selected fiom the group consisting of-H, -F, -CI, -Br, and -OCH3; and 85 PCT/USOO/25195 G is selected from the group consisting of: wherein: Rlbl is selected fiom the group consisting of-H, -CH3 and -CF3; Rlb2 is selected from the group consisting of-H, -CH3 and -CF3; and 5 Rlb3 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3.
Table 35 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 86 qj-cj-rt-c>-o-o-Q-'q-q- Me a Me Et Me QJt. QX QX- QJL (>i QJs- Ma Me &**- Or^~ CJ~^~ Ma q_ts_ «-o~ d-0- o- yCy J-jr-o- t£-j£- SOjNH, SdjNH, SOgMe SOfeMe CONH, CONH, CHjNHj p^NHj SOjNH, SOjNHj SOgMe SOjMe CONH, CONH, CH,NHj »yih Cr- j-y Cr' 9-9-9-O- JflXjL Ms CONH, CHjNH, wherein: A is selected fiom the group consisting of: y "y y y- y y o- <S Me Me "-<>- O*- O1- O— o Q- "^O-X> O- O- "O*- O "-O- o o o o o-~t> PCT/USOO/25195 87 R,al and R,a2 are independently selected fiom the group consisting of-H, -F, -CI and -Br; Rlct is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -NO2; R,c2 and Rlc3 are independently selected fiom the group consisting of-H, -F, -CI, -Br, and 5 -OCH3; and G is selected fiom the group consisting of: wherein: . Rlbl is selected from the group consisting of-H, -CH3 and -CF3; Rlb2 is selected from the group consisting of -H, -CH3 and -CF3; and Rlb3 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3. 88 PCT/USOO/25195 Table 36 wherein: WO 01/19798 PCT/USOO/25195 89 A-Q is selected from the group consisting of: q-C^O-Q-Q-OQrq-Q- Me Et Me Et Ma Me N V® u. MB a-&- cjjte. tyt*. $x*.
Ma cy4-®- "O- "~o- ID-O- "O1- "-O- ^}-0- «2°~ -X" J0- «7~o~ NH, SO2NH3 SOgMa SOjMe CONH, CONH, OfeNH, CH,NH, jlXjl Me CONH, CH,NHj wherein: 90 PCT/USOO/25195 A is selected from the group consisting of: y y y y y y ^ V O Ma Ma •*-0- O c5- O*- o Q- u°~(D>~ r>0~ O O- O O ^O- c^oc^-o- O^O RlBl and RlaZ are independently selected fiom the group consisting of -H, -F, -CI and -Br; Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -5 CONHz, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2j -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of-CH2-, -O- and -NH-; Rlc3 is selected from the group consisting of-CH-, -C(NH2)- and -N-; and G is selected from the group consisting of: wherein: Rlbl is selected from the group consisting of-H, -CHj and -CF3; Rlb2 is selected fiom the group consisting of-fH, -CH3 and -CF3; and Rlb3 is selected from the group consisting of-CI, -NH2, -CH3 and -CF3. 91 PCT/USOO/25195 Table 37 wherein: R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, CONH(CH3), -CON(CH3)2,-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; RIa is selected from the group consisting of -H, -F, -CI and -Br; Rlbl is selected from the group consisting of -H, -CH3 and -CF3; Rlb2 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3; R1cl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, CONH2, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlcz is selected from the group consisting of -H, -F, -CI and -Br; and WO 01/19798 PCT/USOO/25195 92 Rlc3 is selected from the group consisting of-H, -F, -CI and -Br.
Table 38 wherein: R1 is selected from the group consisting of -so2nh2, -so2ch3, -CN, -CONH2, 5 CONH(CHj), -CON(CH3)2. -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rla is selected from the group consisting of -H, -F, -CI and -Br; RIbl is selected from the group consisting of -H, -CH3 and -CF3; R,w is selected from the group consisting of -CI, -NH2, -CH3 and -CF3; R,cl is selected fiom the group consisting of -H, -F, -CI, -Br, -CN, -ch2nh2, -ch2oh, 10 conh2, -C(=NH)NH2, -co2h, -COzMe, -S02Me, -S02NH2, -OH, -NH2, and -no2; Rlc2 is selected fiom the group consisting of-H, -F, -CI and -Br, and 93 Rlc3 is selected fiom the group consisting of-H and -NH2.
PCT/USOO/25195 Table 39 wherein: A-Q is selected fiom the group consisting of: WO 01/19798 PCT/USOO/25195 94 q-q-o-q-q-o-g-q-q- Mb et Me Et H Me Q_£. QJL QJL QX- or cp- b- ^ CH*- Q-^ CK*- a— N- Th, * Mi O"-^- o -o- "y-o- "O- —O k3°~»x" j0- «jr~»/- 0- SOjNHJ SOjNH, SOjMs SOjMe CONH, CONH, CHjNH, CHjNH, 'v- J3- 6-^>-x/x lite CONH, CHjNHj wherein: A is selected from the group consisting of: •v r~ ~)ry y- y- y- ^"V- o- <> «-o- o*- c5*~ o- o*- ■—o- O- O- O O "-O- O O O O "0"X> PCT/USOO/25195 95 Rla is selected from the group consisting of -H, -F, -CI and -Br, Rlbl is selected from the group consisting of-H, -CH3 and -CF3; Rlb2 is selected from the group consisting of -CI, -NH2, -CH3 and -CFj; Rlcl is selected from the group consisting of-H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -5 CONH2, -C(=NH)NH2, -CO2H, -C02Me, -S02Me, -SO2NH2, -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of-H, -F, -CI and -Br, and Rlc3 is selected from the group consisting of-H, -F, -CI and -Br.
Table 40 A— ,1l wherein: WO 01/19798 PCT/USOO/25195 96 A-Q is selected from the group consisting of: q-c^cvo-Q-o-arq-Q- Me et Me Et Me CH*- ojc* w w Me Me Me ClT h, /—\ y—N—C— ^N— Me—^ Jt— /~\ /*— H\__/N— l*>~\ /N— IvO1- jrjrjr Mjruj~ Q+- C/- wherein: A is selected fiom the group consisting of: vy V V V V is-V o- H ri H Me Me Et Me~CN_ o C/- c*- o~ mb-o*~ IXD1- O O O O- ^O- ot>oo Rla is selected from the group consisting of -H, -F, -CI and -Br; Rlbl is selected from the group consisting of-H, -CH3 and -CFj; Rlb2 is selected fiom the group consisting of-CI, -NH2, -CH3 and -CF3; R,cl is selected from the group consisting of -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -C02H, -C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; RlcZ is selected from the group consisting of-H, -F, -CI and -Br; and Rlc3 is selected from the group consisting of-H and -NH2.
WO 01/19798 PCT/USOO/25195 98 Table 41 wherein: R1 is selected from the group consisting of -S02NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2,-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rla is selected from the group consisting of -H, -F, -CI and -Br; Rlbl is selected from the group consisting of-H, -CH3 and -CF3; R,b2 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3; Rlcl is selected from the group consisting of -H, -F, -CN, -CH2NH2, -CONH2, -S02Me, -S02NH2 and -N02; Rlc2 is selected from the group consisting of-H, -F, -CI, -Br and -OCH3; and RIc3 is selected from the group consisting of -H, -F, -CI, Br, -OCH3, -CH2NH2, -CONH2 and -C(N=H)NH2. 99 Table 42 PCT/USOO/25195 wherein: R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, CONH(CH3), -CON(CH3)2,-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rla is selected from the group consisting of -H, -F, -CI and -Br; PCT/USOO/25195 100 R,bl is selected fiom the group consisting of-H, -CH3 and -CF3; Rlb2 is selected fiom the group consisting of-CI, -NH21-CH3 and -CF3; Rlcl is selected fiom the group consisting of -H, -F, -CN, -CH2NH2, -CONH2, -SC^Me, -SO2NH2 and -N02; Rlc2 is selected fiom the group consisting of -H, -F, -CI, -Br and -OCH3; and R,c3 is selected fiom the group consisting of -H, -F, -CI, Br, -OCH3, -CH2NH2, -CONH2 and-C(N=H)NH2.
Table 43 wherein: A-Q is selected fiom the group consisting of: WO 01/19798 PCT/USOO/25195 101 chq-cyQ-Q-o-Qrq-q- Ma et Ma Et Ma Ma Ma qj^ Q4± Ma wherein: A is selected fiom the group consisting of: 102 PCT/USOO/25195 y~ y~ y i/- <^~ <^~ <X- 0- S- O*- o CA" "-Q-X> O O- O O "-O- OOOt> 0-"X>- Rla is selected from the group consisting of -H, -F, -CI and -Br; R,bl is selected from the group consisting of-H, -CHj and -CF3; R,b2 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3; Rlcl is selected from the group consisting of -H, -F, -CN, -CH2NH2, -CONH2, -S02Me, -SO2NH2 and -N02; Rlc2 is selected fiom the group consisting of -H, -F, -CI, -Br and-OCH3; and R,c3 is selected from the group consisting of -H, -F, -CI, Br, -OCH3, -CH2NH2, -CONH2 and -C(N=H)NH2.
PCT/USOO/25195 103 Table 44 wherein: WO 01/19798 PCT/USOO/25195 104 A-Q is selected fiom the group consisting of: Q- Q- Q- Q- O- Or Q~ Q~ Me Et Ms El Ma Me r «. r» /-uis- rv«- o^- cy^ O^- Q Ma «\ r-\ r-\ r*~c- h\_v*~ „/ v7*~ va ^vy"- Ma Ma ^"O*- x" "x" «7"m/~ Q- C^"- POjNH, SOzNHj SOjMe SOjMe CONH, PONHj CHjNHj OljNHj* v-J^r 6- jir O ,xXJ_ Ms CONH, CHjNH, wherein: A is selected from the group consisting of: 105 PCT/USOO/25195 yy C"- d- o— o w— ""O— SO- O- O- "O- O ""O- O O OO 0~0 Rla is selected from the group consisting of -H, -F, -CI and -Br; Rlbl is selected fiom the group consisting of-H, -CH3 and -CF3; Rlb2 is selected fiom the group consisting of -CI, -NH2, -CH3 and -CF3; R,cl is selected fiom the group consisting of-H, -F, -CN, -CH2NH2, -CONH2, -SC^Me, -SO2NH2 and -N02; Rlc2 is selected fiom the group consisting of-H, -F, -CI, -Br and -OCH3; and R,c3 is selected fiom the group consisting of -H, -F, -CI, Br, -OCH3, -CH2NH2, -CONH2 and -C(N=H)NH2. 106 PCT/USOO/25195 Table 45 D1 Dlal „lcl RteJ R1®2 rm r1ca ,1 oil "UuL r r" r,t3 v* r1c3 r« wherein: R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rlal and Rla2 are independently selected fiom the group consisting of -H, -F, -CI and -Br, R]c2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and G is selected fiom the group consisting of: 107 PCT/USOO/25195 wherein: RlbI is selected fiom the group consisting of-H, -CH3 and -CF3; Rlb2 is selected fiom the group consisting of-H, -CH3 and -CF3; and R,b3 is selected fiom the group consisting of -CI, -NH2, -CH3 and -CF3. 108 PCT/USOO/25195 Table 46 bi di«i BIC3 \>*J rm ru .Id Y,le2 wherein: R1 is selected from the group consisting of -SQ2NH2, -SO2CHJ, -CN, -CONH2, -CONH(CH3), -CON(CH3)2,-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; R,al and R1®2 are independently selected from the group consisting of -H, -F, -CI and -Br; Rlc2 and R,c3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and G is selected from the group consisting of: 109 PCT/USOO/25195 -*v "y -y "v" wherein: R b is selected fiom the group consisting of -H, -CH3 and -CF3; Rlb2 is selected fiom the group consisting of-H, -CH3 and -CF3; and R,b3 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3.
Table 47 a— wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 110 q-q-ty-cytycyQrq-q- Me Et Me Et o O- O- c}-£- c^-£- cy-*- Me qjl qjc. Qt. qjl (yt- QU- q-U 9- 9- 9- o Jt- Xx He CONK, CmNH2 wherein: A is selected fiom the group consisting of: y~ y v y~ y~ y~ o- <!>- Me Me o*~ C/~ o*~ dy~ d/- "-o~ X> O 0~ O O "-O- O O O "O iO"X> WO 01/19798 PCT/USOO/25195 111 Rla1 and Rla2 are independently selected from the group consisting of -H, -F, -CI and -Br, RIc2 and R,c3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and G is selected fiom the group consisting of: wherein: RIbl is selected from the group consisting of-H, -CH3 and -CF3; Rlbz is selected from the group consisting of-H, -CH3 and -CF3; and Rlb3 is selected from the group consisting of -CI, -NH2, -CH3 and -CF3.
PCT/USOO/25195 Table 48 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 113 thO-a-O-O-O-QrO-Q- Me Et Ma Et o o- o cp cp cf- o*- Ms CV1 wherein: A is selected from the group consisting of: y y y y y y o&- *~o*- o*~ c*~ o ^y~ "*~0— x> o o- m)- o "-o~ O O O O t>"X> WO 01/19798 PCT/USOO/25195 114 Rlal and Rla2 are independently selected fiom the group consisting of -H, -F, -CI and -Br; R,c2 and RIc3are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and G is selected fiom die group consisting of: wherein: Rlbl is selected fiom the group consisting of-H, -CH3 and -CF3; Rlb2 is selected fiom the group consisting of-H, -CH3 and -CF3; and Rlb3 is selected fiom the group consisting of -CI, -NH2, -CH3 and -CF3. 115 PCT/USOO/25195 Table 49 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 116 chq-c^Q-o-o-arq-Q- M" Et Ms El Me CH1 Q-1- 0s- CF- O-t cp®- qa Mb Mb ^ ^ ojcs- Qt^ qj^ cp Ma qjl&_ hrq_ mer_q^_ "^q1" o- yC>- cy & jS- HJ SOjNHj SOjMe SOjMb CONH, CONHj CH,NH, pHsNH, jir Q~Jy J3- o^Sr o- o- o- Q_ jt Xj- Me CONH, CH2NH2 wherein: A is selected from the group consisting of: Me—0N_ cx— c£- O*- O- c£~ ""O-SO O O- *0- O "-O- OOOO hO"X> WO 01/19798 PCT/USOO/25195 117 Rlal and R,a2 are independently selected from the group consisting of-H, -F, -CI and -Br; Rlc2 and R,c3 are independently selected from the group consisting of-H, -F, -CI, -Br, and -OCH3; and G is selected from the group consisting of: wherein: R,bl is selected from the group consisting of-H, -CH3 and -CF3; R,b2 is selected from the group consisting of-H, -CH3 and -CF3; and Rlb3 is selected from the group consisting of-CI, -NH2, -CH3 and-CFj.
WO 01/19798 PCT/USOO/25195 118 Table 50 wherein: R1 is selected fiom the group consisting of -SO2NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2,-CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rla is selected fiom the group consisting of -H, -F, -CI and -Br, Rlbl is selected fiom die group consisting of -H, -CH3 and -CF3; and Rlc2 and R,c3 are independently selected fiom die group consisting of-H, -F, -CI, -Br, and -OCH3. 119 PCT/USOO/25195 Table 51 dkxr" d!<>Y wherein: R1 is selected from the group consisting of -SO2NH2, -SO2CH3, -CN, -CONHj, -5 CONH(CH3), -CON(CH3)2, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2; Rla is selected from the group consisting of -H, -F, -CI and -Br; Rlb1 is selected from the group consisting of-H, -CH3 and -CF3; and R,c2 and Rlc3 are independently selected fiom the group consisting of -H, -F, -CI, -Br, and -OCH3.
WO 01/19798 PCT/USOO/25195 120 Table 52 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 121 ChQ- Q- 0- 0- cJ-OQ-Q- Ms a MS Et " me Q-t- Q-t- QJL Q-t- Q-T- Cp-- Q-fe Q- 9- V- o- J- XJL Me CONH, CHjNHj wherein: A is selected from the group consisting of: 122 PCT/USOO/25195 v v y y v v t-V o- <5-, H H H Mb M* Et "—0"- cy d- cy cy cV "—cy r=o~ <y o- "O- "O*- —o-O O O 01>"X> R1' is selected from the group consisting of -H, -F, -CI and -Br; Rlbl is selected from the group consisting of-H, -CH3 and -CF3; and RIc2 and Rlc3 are independently selected fiom the group consisting of -H, -F, -CI, -Br and 5 -OCH3.
PCT/USOO/25195 123 Table 53 wherein: A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 124 Cf-.cj- [> o- Q- O-OrO-Q- Me *e, Me Et O-O-O-^^cKcylOl " Me QJL QX- QX a-*- Cp^ Cp wherein: A is selected from the group consisting of: 125 PCT/USOO/25195 y- y y y- y y o- Me Me ■—o- 0— C— O*- O O-O-X> O" O- O "-O" OOOO- 0~0 Rla is selected from the group consisting of -H, -F, -CI and -Br; RIbl is selected from the group consisting of -H, -CH3 and -CF3; and Rlc2 and Rlc3 are independently selected from the group consisting of-H, -F, -CI, -Br and 5 -OCH3.
The following compounds are an embodiment of the present invention: wherein: R1 is selected from the group consisting of: 10 -S02NH2> -S02Me, -CH2NH2 and -CH2NMe2; Rla is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 126 -H, -F, -CI and -Br; Rlb is selected from the group consisting of: -CH3, -CF3, -CH2CH3j -SOzMe, -CONH2 and -NHS02Me; Rlcl is selected from the group consisting of: -H, -F, -CI, -Br, -NH2, -OH, -S02Me, -S(>2Et, -S02NH2, -N02, -CH2NH2, -CN, - CONH2, -CH2OH; RlcZ is selected from the group consisting of: -H, -F, -CI and -Br; and Rlc3 is selected from the group consisting of: -H, -F, -CI and -Br.
The following compounds are an embodiment of the present invention: wherein: R1 is selected fiom the group consisting of: 15 -S02NH2, -S02Me, -CH2NH2 and -OfeNMej; Rla is selected fiom the group consisting of: -H, -F, -CI and -Br; WO 01/19798 PCT/USOO/25195 127 Rlb is selected from the group consisting of: -CHj, -CF3, -CH2CH3, -SOzMe, -CONH2 and -NHS02Me; RlcI is selected from the group consisting of: -H, -F, -CI, -Br, -NH2, -OH, -S02Me, -S02Et, -S02NH2, -N02, -CH2NH2, -CN, 5 CONH2, -CH2OH; Rlc2 is selected from the group consisting of: -H, -F, -CI, -Br and -OMe; and Rlc3 is selected from the group consisting of: -H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
The following compounds are an embodiment of the present invention: R1 is selected from the group consisting of: -SO2NH2, -SO2CH3, -CN, -CONHz, -CONH(CH3), -C0N(CH3)2i -CH2NH2, CH2NH(CH3), -CH2N(CH3)2; R1 a is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 128 -H, -F, -CI and -Br; Rlb is selected from the group consisting of: -CH3and-CF3: R,cI is selected from the group consisting of: -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -C02H, C02Me, -S02Me, -S02NH2l -OH, -NH2, and -N02; RlcZ is selected from the group consisting of: -H, -F, -CI, -Br, and -OCH3; and Rlc3 is selected from the group consisting of: -H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
The following compounds are an embodiment of the present invention: R1 is selected from the group consisting of: -S02NH2, -S02Me, -CH2NH2 and -CH2NMe2; WO 01/19798 PCT/USOO/25195 129 Rla is selected from the group consisting of: -H, -F, -CI and -Br; Rlb is selected from the group consisting of: -CH3, -CF3, -CH2CH3, -S02Me, -CONH2 and -NHSOzMe; and Rlc is selected from die group consisting of: -H, -F, -CI, -Br, -NH2, -OH, -S02Me, -S02Et, -S02NH2, -N02, -CH2NH2, -CN, CONH2, -CH2OH; 130 PCT/USOO/25195 The following compounds are an embodiment of the present invention: j.1c2 >mc2 wherein: R1 is selected from the group consisting of: -SO2NH2, -S02Me, -CH2NH2 and -CH2NMe2; RIa is selected from the group consisting of: -H, -F, -CI and -Br; RIb is selected from the group consisting of: PCT/USOO/25195 131 -CH3, -CF3, -CH2CH3, -S02Me, -CONH2 and -NHS02Me; Rlcl is selected fiom the group consisting of: -H, -F, -CI, -Br, -NH2, -OH, -S02Me, -S02Et, -S02NH2, -N02, -CH2NH2, -CN, -CONH2, -CH2OH; and R,c2 and Rlc3 are independently selected from the group consisting of: -H, -F, -CI and -Br.
The following compounds are an embodiment of the present invention: wherein: A-Q is selected fiom the group consisting of: WO 01/19798 PCT/USOO/25195 132 chO-cvcytyo-Orq-Q- Ms Et Me Et Ma QJC. Qt- QJC- QX- QX Cp- Cp N—C— Me Mb i "i -*•—c- cp- cp- o**- cp <y^ o Me Q-tS- „Q_ «rtQ- yo- "O- "-O- x> jrjrjrjrj- O- c£-ji- SOjNH, SQzNHj SOjMe SOjMa CONH, CONH2 CHjNHj OHjNH, Q~JJ- Q~Sf- Cr Js- Y" 9" Y" 0~ ^Xjl MB CONHj CHjNHj wherein: A is selected fiom the group consisting of: Ma Mb 0— O— t> O1- Ch O- "-O-20- O O- O O "~0- O O O O "O^O WO 01/19798 PCT/USOO/25195 133 Rla is selected froni the group consisting of -H, -F, -CI and -Br; Rlb is selected from the group consisting of: -Me, -CF3, -Et, -S02Me, -CONH2 and -NHS02Me; Rlcl is selected fiom the group consisting of: -H, -F, -CI, -Br, -NH2, -OH, -SOzMe, -S02Et, -S02NH2, -N02, -CH2NH2, -CN, - CONH2, -CH2OH; Rlc2 is selected fiom the group consisting of: -H, -F, -CI and -Br; and RIc3 is selected fiom the group consisting of: -H, -F, -CI and -Br.
The following compounds are an embodiment of file present invention: wherein: A-Q is selected fiom the group consisting of: WO 01/19798 PCT/USOO/25195 134 £}" q- 0- 0- 0- 0-OrQ-q- Ma Et Me Et Me <yc- q-t qx cH- o-t cp- Me Mb <y^ Q**- CV_KLa_ "'V. y—W-0— Hl^ J*— Me—J*— H\ yt— Me— ^N— yO*" hJ~ mo7~me/~ O1" C/~ POjNHJ SOJNHJ SOjMe S(Ve CONH, CONH, CHjNHj CHjNH, 9- 9- 9- o- jcl XJ_ Me CONH, CH,NH, wherein: A is selected fiom the group consisting of: y~ y~ y~ y- y~ y- o- ■•-C"- ex- c5*- C"- o "*~o— ro*- O" o- o o --o- O O O O 0~0 WO 01/19798 PCT/USOO/25195 135 Rla is selected fiom the group consisting of: -H, -F, -CI and -Br; Rlb is selected fiom the group consisting of: -CH3, -CF3, -CH2CH3, -SC^Me, -CONH2 and -NHS02Me; R1cl is selected fiom the group consisting of: -H, -F, -CI, -Br, -NH2, -OH, -S02Me, -S02Et, -S02NH2, -N02, -CH2NH2, -CN, CONH2, -CH2OH; RlcZ is selected fiom the group consisting of: -H, -F, -CI, -Br and -OMe; and Rlc3 is selected from the group consisting of: -H, -F, -CI, -Br, -OH, -OCH3j -NH2, -CONH2, -CH2NH2. 136 PCT/USOO/25195 The following compounds are an embodiment of the present invention: WO 01/19798 PCT/USOO/25195 137 wherein: R1 is selected from the group consisting of: -so2nh2, -so2ch3, -cn, -conh2) -conh(ch3), -con(ch3)2> -ch2nh2, CH2NH(CH3), -CH2N(CH3)2; Rla is selected from the group consisting of: -H, -F, -CI and Br, Rlb is selected from the group consisting of: —CH3 and -CF3; R,cl is selected from the group consisting of: -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -C02H, C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of: -H, -F, -CI and -Br, and IS Rlc3 is selected from the group consisting of: -H, -F, -CI and -Br.
The following compounds are an embodiment of the present invention: PCT/USOO/25195 138 WO 01/19798 PCT/USOO/25195 139 wherein: R1 is selected from the group consisting of: -CN, -CH2NH2, -CONH2, -C(=NH)NH2„ S02Me, -SO2NH2, and -NHZ; Rla is selected from the group consisting of: -H, -F, -CI and -Br; Rlb is selected from the group consisting of: -CH3, -CF3, -CH2CH3, -S02Me, -CONH2 and -NHS02Me; Rlcl is selected from the group consisting of: -H, -F, -CI, -Br, -NH2, -OH, -S02Me, -S02Et, -SO2NH2, -NOz, -CH2NH2, -CN, 10 CONH2) -CH2OH; Rlc2 is selected from the group consisting of: -H, -F, -CI, -Br and -OCH3; Rlc3 is selected from the group consisting of: -H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
The following compounds are an embodiment of the present invention: 140 PCT/USOO/25195 wherein: A-Q is selected from the group consisting of: cj-o-q-o-Q-o-Qrq-q- Me Et Me Et OOOC^^.C^O-11^ CK cp wherein: S A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 141 y~ y* y D*- y~ >- k*-1*^>- o*- o*~ c£- o— o o- "-o- £o~ O O- O O "-0~ OOOO 0~0 RU1 is selected from the group consisting of: -H, -F, -CI and -Br; RIb is selected from the group consisting of: -CH3 and -CF3; Rlcl is selected from the group consisting of: -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -C02H, C02Me, -SOjMe, -SC^NHz, -OH, -NH2, and -N02; Rlc2 is selected from the group consisting of: -H, -F, -CI, -Br, and -OCH3; and Rlc3 is selected from the group consisting of: -H, -F, -CI, -Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
IS The following compounds are an embodiment of the present invention: 142 PCT/USOO/25195 wherein: R1 is selected fiom the group consisting of: -SO2NH2, -S02CH3> -CN, -CONHz, -CONH(CH3), -CON(CH3)2, -CH2NH2, 5 CH2NH(CH3), -CH2N(CH3)2; RlB is selected from the group consisting of: -H, -F, -CI and -Br; Rlb is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 143 -H,-CH3and-CF3; R,cl is selected fiom the group consisting of: -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2, -C(=NH)NH2, -C02H, C02Me, -S02Me, -S02NH2> -OH, -NH2, and -N02; Rlc2 is selected fiom the group consisting of: -H, -F, -CI and -Br; and R,c3 is selected fiom the group consisting of: -H, -F,-CI and-Br.
The following compounds are an embodiment of the present invention: 144 PCT/USOO/25195 1=0 ckV c rm wherein: R1 is selected from the group consisting of: -S02NH2, -SO2CH3, -CN, -CONH2, -CONH(CH3), -CON(CH3)2, -CH2NHz, CH2NH(CH3), -CH2N(CH3>2; Rla is selected from the group consisting of: -H, -F, -CI and -Br; Rlb is selected from the group consisting of: -H, -CH3 and -CF3; R is selected from the group consisting of: PCT/USOO/25195 14S -H, -F, -CN, -CH2NH2, -CONH2, -S02Me, -S02NH2 and -N02; Rlc2 is selected from the group consisting of: -H, -F, -CI, -Br and -OCH3; and Rlc3 is selected from the group consisting of: -H, -F, -CI, -Br, -OCH3> -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe2.
The following compounds are an embodiment of the present invention: NH HjN.
WO 01/19798 PCT/USOO/25195 146 wherein: cj- p- o- cj- o- oQrq-C}- Me a Ma Et Me CP Q*- CP CP O41 cp*- cp Me Me r» rv£*_ (3-ts- <3-^ O-^ Cp- -n—c- **~tf \—NH N— Me Civ Vh, / v r~\ H»\ r~~\ f^\ y—N—C— Ji— Me—1^ p— /\ /— H\ /*— Me—— >0 Q-. cj- j$- PQjNHJ SOJNHJ SO^Me SC^Me CONH, CONH, CHjNH, a-feN^ Cr „Xr Cr jCr Cr Cr J5*- O- <j>- O- {> jt. X Me CONH, CHjNH, A-Q is selected from die group consisting of: wherein: A is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 147 y 7" y y y~ y o- <S- •»-o- o- c5*- o*- o cy "-o*- so- o cy o -cy --cy cy o cy "Cy o-^cy R,a is selected from the group consisting of: -H, -F, -CI and -Br; Rlb is selected from the group consisting of: -H, -CH3 and -CF3; Rlcl is selected from the group consisting of: -H, -F, -CI, -Br, -CN, -CH2NH2, -CH2OH, -CONH2j -C(=NH)NH2, "C02H, C02Me, -S02Me, -S02NH2, -OH, -NH2, and -N02; R,c2 is selected from the group consisting of: -H, -F, -CI and -Br, and Rlc3 is selected from the group consisting of: -H, -F, -CI and-Br. 148 PCT/USOO/25195 A-Q is selected from the group consisting of: WO 01/19798 PCT/USOO/25195 149 q-q-c^o-cj-o-Qrq-q- Mb Et Ms Et o- o o ^ cp- cy*- Ma QX QX QX OX O-t ^ Cp wherein: A is selected from die group consisting of: WO 01/19798 PCT/USOO/25195 150 t^V O- i- o- o*- c£- o— o o*-o~ X> O- O O O •*-o_ O O O O o~o- Rla is selected fiom the group consisting of: -H, -F, -CI and -Br, Rlb is selected fiom the group consisting of: -H, -CH3 and —CF3; Rlcl is selected from the group consisting of: -H, -F, -CN, -CH2NH2, -CONH2, -S02Me, -S02NH2 and -N02; Rlc2 is selected fiom the group consisting of: -H, -F, -CI, -Br and -OCH3; and 10 Rlc3 is selected from the group consisting of: -H, -F, -CI,-Br, -OCH3, -NH2, -CH2NH2, -CONH2, -CONHMe, -CONMe* 151 PCT/USOO/25195 The following compounds are an embodiment of the present invention: R*3 R R1C) Rlc2 wherein: R1 is selected from the group consisting of: -SO2NH2, -S02Me, -CH2NH2 and -CH2NMe2; Rla is selected from the group consisting of: -H, -F, -CI and -Br; Rlb is selected fiom the group consisting of: -CH3, -CF3j -CH2CH3> -S02Me, -CONH2 and -NHS02Me; RIc2 and Rlc3 are independently selected fiom the group consisting of: -H, -F, -CI and -Br.
PCT/USOO/25195 152 The following compounds are an embodiment of the present invention: wherein: R1 is selected from die group consisting of: -SO2NH2, -S02Me, -CH2NH2 and -CH2NMe2; RIa is selected from the group consisting of: -H, -F, -CI and -Br; Rlb is selected from the group consisting of: -CHj, -CF3, -CH2CH3, -SCbMe, -CONH2 and -NHS02Me; 10 R1c2 and Rlc3 are independently selected from the group consisting of: -H, -F, -CI and -Br. 153 PCT/USOO/25195 This invention also encompasses all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives of the compounds of the formula (I). In addition, the compounds of formula (I) can exist in various isomeric and tautomeric 5 forms, and all such forms are meant to be included in the invention, along with pharmaceutically acceptable salts, hydrates, solvates and prodrug derivatives of such isomers and tautomers.
The compounds of this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within 10 the scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification.
A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, the free acid or free base form of a 15 compound of one of the formulas above can be reacted with one or more molar equivalents of the desired acid or base in a solvent or. solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base foim of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the 20 product may be converted to another using the same general process.
Preparation of Compounds The compounds of the present invention may be synthesized by standard organic chemical synthetic methods as described and referenced in standard textbooks. These methods are well known in die ait See, e.g., March, "Advanced Organic Chemistry", 25 John Wiley & Sons, New York,, 1992; Joule, Mills and Smith, "Heterocyclic Chemistry", Chapman & Hall, London, 1995, et seq.
Starting materials used in any of these methods are commercially available from chemical vendors such as Aldrich, Fluka, Lancaster, TCI, Maybridge, Frontier, Fluorochem, Alfa Aesar, and the like, or may be readily synthesized by known WO 01/19798 PCT/USOO/25195 154 procedures.
Reactions are carried out in standard laboratory glassware and reaction vessels under reaction conditions of standard temperature and pressure, except where otherwise indicated.
During the syntheses of these compounds, the functional groups of the substitutents are optionally protected by blocking groups to prevent cross reaction. Examples of suitable protective groups and their use are described in Kocienski, "Protecting Groups", Thieme, Stuttgart, 1994; Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1999, and the disclosures of which 10 are incorporated herein by reference.
Non-limiting exemplary synthesis schemes are outlined directly below, and specific steps are described in the Examples. The reaction products are isolated and purified by conventional methods, typically by solvent extraction into a compatible solvent. The products may be further purified by any means known in the art such as, for 15 example, flash column chromatography, reverse-phase preparative high performance liquid chromatography (HPLC) with high purity water and acetonitrile, or other appropriate methods.
General Synthesis General synthesis for compounds with a N-linked G ring is outlined in Scheme 1 20 below. In Scheme 1, A', Q\ D', E\ J' and X' are protected functional structures which can be converted to A, Q, D, E, J and X respectively by methods known in the art (e.g. deprotection methods). For formation of the N-linked G ring, the appropriate aromatic amine precursor is treated under conditions described in Joule, Mills and Smith, "Heterocyclic Chemistry", Chapman & Hall, London, 1995, or the references cited 25 therein, or as described later in the preparation section to give the G ring.
PCT/USOO/25195 155 Scheme I For nitrogen-linked heterocycle G nii. heterocycle formation coupling deprotection x u WO 01/19798 PCT/USOO/25195 156 Scheme 2 For pyrazole-linked compounds H, 1)NaNOj NHNH, HCI, 0°C JL R,» v COjB xj 2) SnCfe LxJ HOAc. THF HCI, OX reflux i r° LiOH MeOH.THF, HO,I water R1b r' A^Qc^{}JLrf 1) NaNOj ■ A A HO. (re «nux I^ei Scheme 2 above shows the general synthesis of compounds with a N-linked pyiazole G ring. Appropriately protected aromatic amines are converted to aromatic WO 01/19798 PCT/USOO/25195 157 hydrazines by reduction of their diazonium salts. The hydrazines are condensed with 1,3-diketones to yield the pyrazole structures.
Scheme 3 shows the general synthesis of compounds with a N-linked triazole G 5 ring. An appropriately protected aromatic amine is converted to aromatic azide from its diazonium salt. The azide is condensed with an alkyne to yield the triazole structure. 158 PCT/USOO/25195 Scheme 3 For triazole-linked compounds NH, 1)nan02 TFA, 0°C 2)nan3 -COjEt EKV toluene, heat JT\ UOH XI MeOH.THF. HO^CY xl water 159 PCT/USOO/25195 Scheme 4 For tetrazole-linked compounds NH2 I a cojet x u efcn 1 wt^coiel PhaP, DEAD LiOH J~\ MeOH.THF. Hq^V" water ^ k-a-a-bj-l \ deprotecti? a—o—d- n g N—N j-ly- WO 01/19798 PCT/USOO/25195 160 Scheme 4 shows the general synthesis of compounds with a N-linked tetrazole G ring. An appropriately protected aromatic amine is acylated with ethyl chlorooxoacetate. The resulting amide can be converted to the tetrazole by methods known in the art. See e.g. Journal of Organic Chemistry, 2395 (1991); Synthesis, 767 (1993); Journal of 5 Organic Chemistry, 5S, 32 (1993); Bioorganic & Medicinal Chemistry Letters, £,1015 (1996)).
General synthesis for compounds with a C-linked G ring is outlined in Scheme S. A', Q\ D", E\ J' and X' are protected functional structures which can be converted to A, 10 Q, D, E, J and X respectively. For formation of the C-linked G ring, the appropriate aromatic aldehyde precursor is treated under conditions described in Joule, Mills and Smith, "Heterocyclic Chemistry", Chapman & Hall, London, 1995, or the references cited therein, or as described later in the preparation section to give the G ring. The C-linked G ring can also be connected to aromatic X or aromatic D using Suzuki cross-coupling 15 method (Chemical Reviews, 25,2457 (1995)).
PCT/USOO/25195 161 Scheme 5 For carbon-linked heterocycle G 1 Scheme 6 shows the general synthesis of compounds with a C-linked isoxazole G ring. A substituted aromatic aldehyde is reacted with hydroxylamine and then chlorinated 5 to yield the hydroximinoyl choride (Journal of Organic Chemistry, 45, 3916 (1980)). It is treated with triethylamine to generate nitrile oxide in situ, which is reacted with methyl /rans-3-mthoxyacrylate or methyl propiolate to give the isoxazole structure (Chemical Letters, 1, 85(1987)).
WO 01/19798 PCT/USOO/25195 162 Scheme 6 For isoxazole-Hnked hetereocycle compounds Scheme 7 shows the general synthesis of compounds with a C-linked thiozole G ring. A substituted aromatic aldehyde is reacted with ethyl diazoacetate in presence of tin(II) chloride to afford the beta-ketoester. It is then converted to thiazole.
WO 01/19798 PCT/USOO/25195 163 Scheme 7 Forthiazole-linked hetereocyde compounds Compositions and Formulations The compounds of this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within 5 tiie scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification.
WO 01/19798 PCT/USOO/25195 164 A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, reaction of the free acid or free base form of a compound of the structures recited above with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is S insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.
This invention also encompasses prodrug derivatives of the compounds contained 10 herein. The term "prodrug" refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. Prodrugs are variations or derivatives of the compounds of this invention which have groups cleavable under metabolic conditions. Prodrugs become the compounds of the invention which are pharmaceutically active in 15 vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds of this invention may be called single, double, triple etc., depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue 20 compatibility, or delayed release in the mammalian organism (see, Bundgaid, Design of Prodrugs, pp. 7-9,21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA, 1992). Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters'prepared by reaction of the parent 25 acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative. Moreover, the prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailability.
Diagnostic applications of the compounds of this invention will typically utilize 30 formulations such as solution or suspension. In the management of thrombotic disorders the compounds of this invention may be utilized in compositions such as tablets, capsules WO 01/19798 PCT/USOO/25195 165 or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated into shaped articles. Subjects in need of treatment (typically mammalian) using the compounds of this invention can be administered dosages that will provide optimal efficacy. The dose and method of 5 administration will vary fiom subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical aits will recognize. 0 Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for 5 example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit. 1985). Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, 0 gelatin, or immunoglobulins, hydrophilic polymers such as polyvinalpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as Tween, 5 Pluronics or polyethyleneglycol.
Dosage formulations of the compounds of this invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in lyophilized form or as an aqueous solution. The 0 pH of the preparations of this invention typically will be between about 3 and about 11, more preferably from about 5 to about 9 and most preferably from about 7 to about 8. It WO 01/19798 PCT/USOO/25195 166 will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by injection, other methods of administration are also anticipated such as intravenously (bolus and/or infusion), subcutaneoiisly, intramuscularly, colonically, 5 rectally, nasally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches. The compounds of this invention are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for 10 example, Silastic, silicone rubber or other polymers commercially available.
The compounds of this invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, steaiylamine or phosphatidylcholines., The compounds of this invention may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled. The compounds .of this invention may also be coupled with suitable polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, 20 polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the factor Xa inhibitors of this invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers ofpolylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, 25 polyacetals, polydihydropyrans, polycyanoaciylates and cross linked or amphipathic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle.
WO 01/19798 PCT/USOO/25195 167 Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will naturally be influenced by the route of 5 administration, the therapeutic objectives, and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absorption efficiency must be individually determined for each inhibitor by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of 10 administration as required to obtain the optimal therapeutic effect. The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
A typical dosage might range froni about 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compounds of this invention may be administered several times daily, and other dosage regimens may also be useful.
Typically, about 0.5 to about 500 mg of a compound or mixture of compounds of 20 this invention, as the free acid or base form or as a pharmaceutically acceptable salt, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
Typical adjuvants which may be incorporated into tablets, capsules and the like are a binder such as acacia, corn starch or gelatin, and excipient such as microcrystalline cellulose, a disintegrating agent like corn starch or alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose or lactose, or a flavoring agent. When a dosage form is a capsule, in addition to the above materials it may also contain a 30 liquid carrier such as water, saline, a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit Sterile WO 01/19798 PCT/USOO/25195 168 compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired. Buffers, preservatives, antioxidants and the like can be incorporated according to 5 accepted pharmaceutical practice.
In practicing the methods of this invention, the compounds of this invention may be used alone or in combination, or in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of this inventions may be coadministered along with other compounds typically prescribed for these conditions 10 according to generally accepted medical practice, such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of this invention can be utilized in vivo, ordinarily in mammals such as primates, such as humans, sheep, horses, cattle; pigs, dogs, cats, rats and mice, or 15 in vitro.
The preferred compounds of the present invention are characterized by their ability to inhibit thrombus formation with acceptable effects on classical measures of coagulation parameters, platelets and platelet function, and acceptable levels of bleeding complications associated with their use. Conditions characterized by undesired 20 thrombosis would include those involving the arterial and venous vasculature.
With respect to the coronary arterial vasculature, abnormal thrombus formation characterizes the rupture of an established atherosclerotic plaque which is the major cause of acute myocardial infarction and unstable angina,, as well as also characterizing the occlusive coronary thrombus formation resulting from either thrombolytic therapy or 25 percutaneous transluminal coronary angioplasty (PTCA).
With respect to the venous vasculature, .abnormal thrombus formation characterizes the condition observed iii patients undergoing major surgery in the lower extremities or the abdominal area who often suffer from thrombus formation in the venous vasculature resulting in reduced blood flow to the affected extremity and a 30 predisposition to pulmonary embolism. Abnormal thrombus, formation further WO 01/19798 PCT/USOO/25195 169 characterizes disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the S microvasculature leading to widespread organ failure.
The compounds of this present invention, selected and used as disclosed herein, are believed to be useful for preventing or treating a condition characterized by undesired thrombosis, such as (a) the treatment or prevention of any thrombotically mediated acute coronary syndrome including myocardial infarction, unstable angina, refractory angina, 10 occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, (b) the treatment or prevention of any thrombotically mediated cerebrovascular syndrome including embolic stroke, thrombotic stroke or transient ischemic attacks, (c) the treatment or prevention of any thrombotic syndrome occurring in i the venous system including deep venous thrombosis or pulmonary embolus occurring 15 either spontaneously or in the setting of malignancy, surgery or trauma, (d) the treatment or prevention of any coagulopathy including disseminated intravascular coagulation (including the setting of septic shock or other infection, surgery, pregnancy, trauma or malignancy and whether associated with multi-organ failure or not), thrombotic thrombocytopenic purpura, thromboangiitis obliterans, or thrombotic disease associated 20 with heparin induced thrombocytopenia, (e) the treatment or prevention of thrombotic complications associated with extracorporeal circulation (e.g. renal dialysis, cardiopulmonary bypass or other oxygenation procedure, plasmapheresis), (f) the treatment or prevention of thrombotic complications associated with instrumentation (e.g. cardiac or other intravascular catheterization, intra-aortic balloon pump, coronary stent or 25 cardiac valve), and (g) those involved with the fitting of prosthetic devices.
Anticoagulant therapy is also useful to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus the compounds of this invention can be added to or contacted with any medium containing or suspected to contain factor Xa and in which it is desired that blood coagulation be 30 inhibited, e.g., when contacting the mammal's blood'with material such as vascular PCT/USOO/25195 170 grafts, stents, orthopedic prostheses, cardiac stents, valves and prostheses, extra corporeal circulation systems and the like.
Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize 5 the compounds of the present invention and practice the claimed methods. The following working examples therefore, specifically point out preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.
Examples Example 1.
Step 1. To the solution of 2-naphthylboronic acid (5.00 g, 29.1 mmol) and ethyl 3-methylpyrazole-5-carboxylate (4.48 g, 29.1 mmol) in 100 mL dry dichloromethane (DCM) were added pyridine (4.7 mL, S8.2 mmol) and anhydrous powder of copper(II) acetate (7.94 g, 43.7 mmol). Some activated molecular sieve powder was added IS afterwards. The resulting slurry was stirred for 2 days under argon. The mixture was diluted with DCM. It was filtered through a celite bed. The blue filtrate was washed with water (X2), dried over MgS04, concentrated, purified by silica column to yield ethyl 3-methyl-l-(2-naphthyl)-lH-pyrazole-5-carboxylate and its regioisomer in a 1:1 ratio in 70% yield. Rf 0.59 (1:2 EtOAc: hexane), M+H 281; regioisomer, ethyl 5-methyl-l-(2-20 naphthyl)-lH-pyrazole-3-caiboxylate, Rf 0.44 (1:2 EtOAc: hexane). ES-MS: (M+H)+ 281.
Step 2. To a solution of 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine (50 mg, 0.16 mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.41 mL, 0.82 mmol) under argon at room temperature. After being stirred for 30 minutes, to the 25 mixture was added the above-prepared ester (46 mg, 0.16 mmol) in 1 mL DCM. The WO 01/19798 PCT/USOO/25195 171 resulting mixture was stirred overnight. The reaction was quenched using 5 mL saturated Rochelle salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, rotovaped and subjected on flash column to give the coupled product in 52% yield (46 mg). Rf 0.46 (1:1. EtOAc: hexane). ES-MS: (M+H)+ 5 539.
Step 3. The above-prepared compound (42 mg, 0.078 mmol) was placed in 3 mL trifluoroacetic acid (TFA). The solution was stirred in 60°C bath for 30 minutes. TFA was removed on rotovap. The residue was dissolved in methanol and purified by preparative HPLC to afford the title compound in 95% yield. ES-MS: (M+H)+ 483.
Example 2.
Stepl. A mixture of tin(II) chloride (2.08 g, 10.96 mmol) and ethyl diazoacetate (2.76 mL, 26.28 mmol) in 50 mL DCM was stirred for- 2 hours. Naphthalene-2-carbaldehyde was added. After stirred at room temperature for 18 hours, the mixture was concentrated, IS dissolved in EtOAc, washed with water (X3), dried and evaporated. The cmde material was purified to give product ethyl 3-(2-naphthyl)-3-oxoprppionate. Rf 0.61 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 243.
Step 2. To a solution of the above-prepared ester (240 mg, 1 mmol) in 15 mL MeCN at 65°C was added hydroxy(tosyloxy)iodobenzene (430 mg, 1.1 mmol). After stirred for 1 20 hour, to the mixture was added thiourea (83 mg, 1.1 mmol). The resulting mixture was stiiied overnight at 65°C. The solution was cooled and concentrated. The residue was dissolved in EtOAc, washed with brine, dried over MgS04, and evaporated to give crude 2-methyl-4-(2-naphthyl)-5-(caiboethoxy)thiazole. Rf 0.64 (1:3 EtOAc: hexane). ES-MS: (M+H)+ 298.
PCT/USOO/25195 172 Step 3. To a solution of the above-prepared product (148 mg, 0.S0 mmol) and 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine (152 mg, 0.50 mmol) in 3 mL DCM was added trimethylaluminum (2.0M in hexane, 0.75 mL, 1.5 mmol), and the mixture was stirred at room temperature for 20 hours. The reaction was neutralized with 4 mL IN 5 HCI and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, and concentrated to give the coupling product (170 mg, 61%). Rf 0.25 (1:3 EtOAc: hexane). ES-MS: (M+H)+ 556.
Step 4. The above-prepared product (100 mg) was placed in 3 mL TFA. The solution was stirred in 80°C bath for 60 minutes. TFA was removed on rotovap. The residue was 10 dissolved in methanol and purified by preparative HPLC to afford the title compound in over 90% yield. ES-MS: (M+H)+ 500.
IS Step 1. 3-Amino-2-naphthoic acid (40.4 g, 216 mmol) was placed in 200 mL concentrated HCI. At 0°C, the slurry was stirred vigorously using a mechanical stirring blade. To it was added a cold solution of sodium nitrite (29.8 g, 432 mmol) in 70 mL water. After completion, the cold sluny was stirred for 30 minutes at 0°C. To it was added cold tetrafluoroboric acid (48 wt. % in water, 56 mL; 432 mmol). After stirred at 0°C for 30 20 minutes, the solid was filtered using a Buchner funnel. The soild cake was carefully rinsed with cold water (10 mL X2), cold tetrafluoroboric acid (10 mL X2) and cold ethanol (5 mL X2). The solid was dried in vacuuo. It was then placed in 300 mL xylene and refluxed overnight. Xylene was removed on rotovap. The residue was acidified to Example 3 WO 01/19798 PCT/USOO/25195 173 pHl with aq HCI and taken into EtOAc. It was washed with brine (X2), dried, evaporated to give 3-fluoro-2-naphthoic acid (32.6 g, 78%). ES-MS: (M+H)+ 191.
Step 2. The above-prepared acid (14.7 g, 77 mmol) was dissolved in 200 mL CHCI3. To it was added 0.5 mL dry DMF. Then at room temperature, oxalyl chloride (20 mL, 232 5 mmol) was added dropwise. The reaction solution was stirred for overnight. All solvent was removed in vacuuo. The residue was pumped till dryness. It was dissolved in 150 mL dry dioxane, chilled to 0°C and vigorously stirred. To it, at the cold tempareture, was added the cold solution of sodium azide (10 g, 155 mmol, in 30 mL water and 15 mL dioxane) in small portions. The reaction was allowed for 2 hours at 0°C. Hie solvent was 10 removed in vacuuo. The residue was taken into EtOAc and washed with brine (X3). The organic phase was dried and evaporated to dryness in vacuuo to give 3-fluoro-2-naphthoyl azide. Rf 0.83 (1:1 EtOAc: hexane). It was dissolved in 80 mL DMF. To it was added 40 mL water. The milky mixture was refluxed overnight. The solvent was removed in vacuuo. The residue was taken into EtOAc, and washed with brine (X2). The organic IS phase was dried, concentrated and purified with flash silica column to yield 3-fluoro-2-naphthylamine (8.1 g, 65%). Rf 0.40 (1:3 EtOAc: hexane). ES-MS: (M+H)+ 162.
Step 3. The above-prepared compound (7.5 g, 46 mmol) was placed in 50 mL concentrate HCI. The mixture was vigorously stirred in ice bath. To it was dropwise added cold sodium nitrite (3.8 g, 55 mmol) solution in 10 mL water. After completion, the mixture 20 was stirred at 0°C for half an hour. At 0°C, to it was dropwise added cold SnCl2.2H20 (26.3 g, 116 mmol) solution in 20 mL concentrate HCI. The shiny was stirred for half an hour at 0°C, chilled, and filtered through a Buchner funnel to isolate the solid hydrazine. It was dried in vacuuo. The solid hydrazine was dissolved in 100 mL glacial acetic acid.. To it were added ethyl 2-N-(methoxy)imino-4-oxopentanoate (10.4 g, 56 mmol, prepared 2S from ethyl 2,4-dioxovalerate and methoxylamine hydrogen chloride in ethanol) and 50 mL THF. The mixture was refluxed for 2 hours. The solvent was removed in vacuuo. The residue was taken into EtOAc, washed with brine and water. The organic phase was dried, concentrated and purified with flash column to yield ethyl 3-methyl-1 -{3-fluoro-2-naphthyl)-lH-pyrazole-5-carboxylate (9.0 g, 65%). Rf 0.52 (1:2 EtOAc: hexane). ES-MS: 30 (M+H)+ 299.
WO 01/19798 PCT/USOO/25195 174 Step 4. To a solution of 2*-N-teit-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine (77mg, 0.2S mmol) in 1 mL dry DCM was added trimethylaluminum (2.0M in hexane, 0.51 mL, 1.0 mmol). The mixture was stirred for 20 minutes. The above-prepared ester (50 mg, 0.17 mmol) was dissolved in 3 mL dry DCM and added info the aluminum mixture. The 5 reaction was stirred at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHCI3 (X3). The organic phases were combined, dried, concentrated and purified with flash column to yield the coupling product (85 mg, 90%). Rf 0.45 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 557.
Step 5. The above-prepared product was placed into 3 mL TFA. The mixture was stirred 10 overnight at room temperature. It was evaporated, dissolved in methanol, purified with prep HPLC to afford the title compound in over 90% yield.). ES-MS: (M+H)+ 501.
Example 4.
Step 1. The preparation of ethyl 3-methyl-l-(3-fluoro-2-naphthyl)-lH-pyrazole-5-15 carboxylate was the same as that in Step 3 for Example 3. This ester (13.2 g, 44 mmol) was dissolved in 80 mL methanol. To it were added Li0H.H20 (3.7 g, 49 mmol) and 40 mL water. The mixture was stirred for overnight at room temperature. It was evaporated in vacuuo to remove methanol. The residue was acidified with IN HCI till pH 1. The mixture was extracted with EtOAc (X4). The organic extracts were combined, dried, 20 evaporated and pumped to dryness to afford 3-methyl-1 -(3-fluoro-2-naphthyl)- 1H-pyrazolecarboxylic acid in over 90% yield. ES-MS: (M+H)+ 271.
Step 2. The above-prepared acid (33 mg, 0.12 mmol), 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine (77 mg, 0.24 mmol) and catalytic amount of DMAP (5 mg) were dissolved in 2 mL pyridine. The solution was stirred at 0°C. To it was added PCT/USOO/25195 175 POCI3 (45 jiL, 0.48 mmol). The mixture was stirred for 1 hour and quenched with ice chips. To it was added EtOAc. It was washed with brine (X2), dried, and concentrated. To the residue was added 3 mL TFA. The mixture was stirred at 60°C for 1 hour, concentrated, dissolved in methanol and subjected on prep HPLC to afford the title 5 compound in 50% yield (31 mg). ES-MS: (M+H)+ 519.
This compound was prepared by the same methodology described for Example 4 with 2' N-tert-butylaminosulfonyl-3-chloro-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N-tert-10 butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 535.
This compound was prepared by the same methodology described for Example 4 with 2' N-tert-butylaminosuIfonyl-3-bromo-[l,r]-bipheriyl-4-ylamine substituted for 2'-N-tert-15 butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 579, 581 (Br pattern).
Example 5.
Example 6.
F 176 PCT/USOO/25195 Example 7.
This compound was prepared by the same methodology described for Example 4 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phcnyl)pyridine substituted for 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 502.
Example 8 This compound was prepared by die same methodology described for Example 4 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substituted for 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 503. 177 PCT/USOO/25195 Example 9.
This compound was prepared by die same methodology described for Example 4 with 2'-cyano-[l,r]-biphenyl-4-ylamine substituted 2'-N-tert-butylaminosulfbnyl-3-fluoro-[l,rj-biphenyl-4-ylamine, without the TFA treatment. ES-MS: (M+H)+ 447.
Example 10.
The title compound (40 mg, 0.09 mmol) of Example 9 was dissolved in 2 mL dry DMF. At 0°C, to it were added sodium borohydride (27 mg, 0.72 mmol) and anhydrous Co(II) chloride (23 mg, 0.18 mmol). The mixture was stirred for 2 hours and quenched with 1 10 mL acetic acid. The mixture was evaporated, dissolved in methanol, filtered, loaded on prep HPLC to afford the title compound in 60% yield. ES-MS: (M+H)+ 4S1. 178 PCT/USOO/25195 Example 11 The title compound (40 mg, 0.09 mmol) of Example 9 was dissolved in 2 mL dry DMF. At 0°C, to it were added sodium borohydride (27 mg, 0.72 mmol) and anhydrous Co(II) chloride (23 mg, 0.18 mmol). The mixture was stirred for 2 hours. To it was added 10 mL 5 acetone. The mixture was stirred for 1 hour at room temperature. The reaction was quenched with 1 mL acetic acid. The mixture was evaporated, dissolved in methanol, filtered, loaded on prep HPLC to afford the title compound in 50% yield. ES-MS: (M+H)+ 493.
Example 12.
This compound was prepared by the same methodology described for Example 4 with 2'-(N-dimethylamino)methyl-[l,r]-biphenyl-4-ylamine substituted for 2*-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine, without the TFA treatment. ES-MS: (M+H)+479.
WO 01/19798 Example 13 179 PCT/USOO/25195 Step 1. The preparation of 3-methyl-l-(3-fluoro-2-naphthyl)-lH-pyrazolecaiboxylic acid was the same as that in Step 1 of Example 4.
Step2. This acid (65 mg, 0.24 mmol), 4-aminobenzonitrile (57 mg, 0.48 mmol) and S DMAP (5 mg) were dissolved in 3 mL pyridine. The solution was stirred at 0°C. To it was added POCU (90 |iL, 0.96 mmol). The mixture was stirred for 1 hour. The reaction was then quenched with ice chips. It was diluted with EtOAc. The organic phase was washed with brine (X2). It was dried, concentrated and purified with flash column to afford the coupling product (60 mg, 68%). Rf 0.40 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 10 371.
Step 3. The above-prepared nitrile was dissolved in 10 mL dry methanol. It was chilled and stirred in an ice bath. To this solution was bubbled dry HCI gas via a long needle till saturation reached (indicated by a blown-up balloon attached on the top of the reaction flask). The resulting solution was stirred overnight. ES-MS: (M+H)+ 403. The solvent IS was removed in vacuuo. The residue was pumped to dryness. The solid was dissolved in 5 mL dry methanol. To it was added anhydrous N-methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour, concentrated and loaded on prep HPLC to afford the title compound in 80% yield. ES-MS: (M+H)+ 428. 180 PCT/USOO/25195 Example 14.
This compound was prepared by the same methodology described for Example 13 with pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 442.
Example IS.
This compound was prepared by the same methodology described for Example 13 with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 456.
Example 16.
This compound was prepared by die same methodology described for Example 13 with dimethylamine (commercial 2M solution in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 416. 181 PCT/USOO/25195 Example 17 This compound was prepared by the same methodology described for Example 13 with thiomorpholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 474.
Example 18.
This compound was prepared by die same methodology described for Example 13 with moipholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 458.
Example 19.
This compound was prepared by die same methodology described for Example 13 with piperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+457. 182 PCT/USOO/25195 Example 20 N-methylpiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 471.
Example 21 This compound was prepared by the same methodology described for Example 13 with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 388.
Example 22.
Step 1.2-Fluoro-4-iodoaniline (5.0 g, 21 mmol) was dissolved in 20 mL dry DMF. To it were added CuCN (3.8 g, 42 mmol) and catalytic amount of Cul (200 mg). The slurry was refluxed for 1 hour Diluted with EtOAc. Filtered through celite. Concentrated in vacuuo to yield solid 4-amino-3-f]uorobenzonitrile (2.9 g, 100%). ES-MS: (M+H)+ 137.
PCT/USOO/25195 183 Step 2. The preparation of 3-methyl-l-(3-fluoro-2-naphthyl)-lH-pyrazolecarboxylic acid was the same as that in Step 1 of Example 4. This acid (270 mg, 1.0 mmol), 4-amino-3-fluorobenzonitrile (272 mg, 2.0 mmol) and DMAP (10 mg) were dissolved in 15 mL pyridine. The solution was stirred at 0°C. To it was added POCI3 (380 |iL, 4.0 mmol). 5 The mixture was stirred for 1 hour. The reaction was then quenched with ice chips. It was diluted with EtOAc. The organic phase was washed with brine (X2). It was dried, concentrated and purified with flash column to afford the coupling product (350 mg, 97%). Rf 0.77 (7:3 EtOAc: hexane). ES-MS: (M+H)+ 389. .
Step 3. The above-prepared nitrile (30 mg, 0.077 mmol) was dissolved in 10 mL dry 10 methanol. It was chilled and stirred in an ice bath. To this solution was bubbled dry HCI gas via a long needle till saturation reached (indicated by a blown-up balloon attached on the top of the reaction flask). The resulting solution was stirred overnight. ES-MS: (M+H)+ 421. The solvent was removed in vacuuo. The residue was pumped to dryness. The solid was dissolved in 5 mL dry methanol. To it was added anhydrous N-15 methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour, concentrated and loaded on prep HPLC to afford the title compound in 80% yield. ES-MS: (M+H)+ 446.
Example 23 This compound was prepared by the same methodology described for Example 22 with 20 pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 460.
Example 24.
F 184 PCT/USOO/25195 This compound was prepared by the same methodology described for Example 22 with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+474.
Example 25.
This compound was prepared by the same methodology described for Example 22 with hexamethyleneimine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 488.
Example 26.
This compound was prepared by the same methodology described for Example 22 with morpholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 476.
Example 27.
WO 01/19798 PCT/USOO/25195 185 This compound was prepared by die same methodology described for Example 22 with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 406.
Example 28 Step 1. The preparation of 3-methyl-l-(3rfluoro-2-naphthyl)-lH-pyrazolecarboxylic acid was the same as that in Step 1 of Example 4. This acid (SO mg, 0.18 mmol), 4-amino-2,5-difluorobenzonitrile (57 mg, 0.36 mmol) and DMAP (5 mg) were dissolved in 8 mL pyridine. The solution was stirred at 0°C. To it was added POCI3 (70 |iL, 0.74 mmol). The mixture was stirred for 1 hour. The reaction was then quenched with ice chips. It was 10 diluted with EtOAc. The organic phase was washed with brine (X2). It was dried, concentrated and purified with flash column to afford the coupling product (70 mg, 93%). Rf 0.69 (7:3 EtOAc: hexane). ES-MS: (M+H)+ 407.
Step 2. The above-prepared nitrile (30 mg, 0.074 mmol) was dissolved in 10 mL dry methanol. It was chilled and stirred in an ice bath. To this solution was bubbled dry HCI 15 gas via a long needle till saturation reached (indicated by a blown-up balloon attached on the top of the reaction flask). The resulting solution was stirred overnight. ES-MS: (M+H)+ 439. The solvent was removed in vacuuo. The residue was pumped to dryness. The solid was dissolved in 5 mL dry methanol. To it was added anhydrous N-methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour, concentrated and 20 loaded on prep HPLC to afford the title compound in 80%' yield. ES-MS: (M+H)+ 464. 186 PCT/USOO/25195 Example 29 This compound was prepared by the same methodology described for Example 28 with pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 478.
Example 30.
This compound was prepared by the same methodology described for Example 28 with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 424.
Example 31.
This compound was prepared by the same methodology from Step 3 to Step S described for Example 3 with 3-chloro-2-naphthylamine substituted for 3-fluoro-2-naphthylamine. ES-MS: (M+H)+ 517.
WO 01/19798 Example 32 187 PCT/USOO/25195 This compound was prepared by die same methodology from Step 3 to Step 5 described for Example 3 with 3-bromo-2-naphthylamine substituted for 3-fluoro-2-naphthylamine. 5 ES-MS: (M+H)+ 561,563 (Brpattern).
Example 33.
This compound was prepared by the same methodology from Step 3 to Step 5 described for Example 3 with 3-hydroxy-2-naphthylamine substituted for 3-fluoro-2-10 naphthylamine. ES-MS: (M+H)+ 499.
Example 34.
/OjNHJ / WO 01/19798 PCT/USOO/25195 188 Step 1. The synthesis of ethyl 3-methyl-l-(3-bromo-2-naphthyl)-lH-pyrazole-carboxylate followed the same methodology described for Step 3 of Example 3 with commercial with 3-bromo-2-naphthylamine substituted for 3-fluoro-2-naphthylamine. Yield 60%. Rf 0.42 (1:3 EtOAc: hexane). ES-MS: (M+H)+ 359,361 (Br pattern).
Step 2. The above-prepaxed bromide (370 mg, 1.0 mmol) was dissolved in 3 mL dry DMF. To it were added CuCN (180 mg, 2.0 mmol) and Cul (20 mg). The slurry mixture was refluxed for 2 hours. It was diluted with EtOAc. Filtered through celite. Concentrated and purified by flash column to yield of ethyl 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-carboxylate (220 mg, 70%). Rf 0.48 (1:2 EtOAc: hexane).). ES-MS: (M+H)+ 10 306.
Step 3. To a solution of 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine (164 mg, 0.54 mmol) in 2 mL dry DCM was added trimethylaluminum (2.0M in hexane, 1.1 mL, 2.2 mmol). The mixture was stirred for 20 minutes.. The above-prepared ester (137 mg, 0.45 mmol) was dissolved in 6 mL dry DCM and added into the aluminum mixture. The IS reaction was stirred at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHCI3 (X3). The organic phases were combined, dried, concentrated and purified with flash column to yield 3-methyl-l-(3-cyano-2-naphthyl)-1 H-pyrazole-5-(N-(2,-N-tert-butylaminosulfonyl-[ 1,1 ']-biphen-4-yl))carboxyamide (170 mg, 67%). Rf0.40 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 564.
Step 4. The above-prepared compound (30 mg, 0.05 mmol) was dissolved in 5 mL dry DCM. At 0°C, to it was added BFj.OEt2 (62 jiL, 0.5 mmol) dropwise. The mixture was stirred overnight. Extra 1.0 mmol BFa.OEtz was added in small portions at room temperature the next day. After another overnight, deprotection was about 70% complete. The mixture was loaded on a short flash column for separation. The title product was 25 purified using prep HPLC (55% yield). ES-MS: (M+H)+ 508. 189 PCT/USOO/25195 Example 35 o-o^ JSOjNHJ Step 1. The synthesis of 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert-butylaminosulfonyl-[l,r]-biphen-4-yl))carboxyamide followed the same procedure of Step 3 for Example 34.
Step 2. The above-prepared compound (30 mg, 0.05 mmol) was placed in 3 mL TFA and refluxed for 1 hour. After concentration, it was purified with prep HPLC to yield die title compound (85%). ES-MS: (M+H)+ 526. i Example 36 This compound was prepared by the same methodology described for Example 34 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine substituted for 2'-N- tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 526.
PCT/USOO/25195 190 Example 37, 80jNH2 r o-o This compound was prepared by the same methodology described for Example 35 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,l ']-biphenyl-4-ylamine substituted for 2'-N-5 tert-butylaminosulfonyl-[ 1,1 ']-biphenyl-4-ylamine. ES-MS: (M+H)+ 544.
Example 38 Step 1. The synthesis of ethyl 3-methyl-1 -(3-cyano-2-naphthyl)-1 H-pyrazole-carboxylate followed the same procedure of Step 2 for Example 34.
Step 2. The above-prepared ester (930 mg, 3.0 mmol) was dissolved in 20 mL methanol. To it were added Li0H.H20 (256 mg, 6.0 mmol) and 10 mL water. The mixture was stirred for 3 hours at room temperature. Methanol was removed in vacuuo. The residue was carefully acidified with IN HCI till pH 1. It was extracted with EtOAc (X4). The organic phases were combined, dried and evaporated in vacuuo till dryness to give 3- methyl-1 -(3-cyano-2-naphthyl)-1 H-pyrazole-5-carboxylic acid (720 mg, 85%). ES-MS: (M+H)+ 278.
PCT/USOO/25195 191 Step 3. The mixture of the above-prepared acid (110 mg, 0.40 mmol), 2'-N-tert-butylaminosulfonyl-3-chloro-[l,r]-biphenyl-4-ylamine (0.21 g, 0.60 mmol), DMAP (5 mg) were dissolved in 5 mL pyridine and stirred at 0°C. To it was added POCl3 (120 nL, 1.2 mmol). The mixture was stirred for 2.S hours and quenched with ice chips. It was 5 diluted with EtOAc, washed with brine (X2), dried, concentrated and purified with flash column to give 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert-butylaminosulfonyl-3-chloro-[l,r]-biphen-4-yl))carboxyamide (240 mg, 95%). Rf 0.65 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 598.
Step 4. The above-prepared compound (30 mg, 0.05 mmol) was dissolved in 5 mL dry 10 DCM. At 0°C, to it was added BF3.0Et2 (62 jiL, 0.5 mmol) dropwise. The mixture was stirred overnight. Extra 1.0 mmol BFj.OEta was added in small portions at room temperature the next day. After another overnight, deprotection was about 70% complete. The mixture was loaded on a short flash column for separation. The title product was purified using prep HPLC (52% yield). ES-MS: (M+H)+ 542.
Step 1. The synthesis of 3-methyl-1 -(3-cyano-2-naphthyl)-1 H-pyrazole-5-(N-(2'-N-tert-butylaminosulfonyl-3-chloro-[l,r]-biphen-4-yl))carboxyamide followed the same procedure of Step 3 for Example 38.
Step 2. The above-prepared compound (30 mg, 0.05 mmol) was placed in 3 mL TFA and refluxed for 1 hour. After concentration, it was purified with prep HPLC to yield the title compound (85%). ES-MS: (M+H)+ 560. is Example 39.
WO 01/19798 Example 40 192 PCT/USOO/25195 This compound was prepared by the same methodology described for Example 38 with 2'-N-tert-butylaminosulfonyl-3-bromo-[l,r]-biphenyl-4-ylamine substituted for 2'-N-5 tert-butylaminosulfonyl-3-chloro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 586, 588 (Br pattern).
Example 41 This compound was prepared by the same methodology described for Example 39 with 10 2'-N-tert-butylaminosulfonyl-3-bromo-[l,l ']-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-3-chloro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 604,606 (Br pattern). 193 PCT/USOO/25195 Example 42 This compound was prepared by the same methodology described for Example 38 with 2-amino-S-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine substituted for 2'-N-tert-5 butylaminosulfonyl-3-chloro-[ 1,1 ']-biphenyl-4-ylamine. ES-MS: (M+H)+ 509.
Example 43 This compound was prepared by the same methodology described for Example 39 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine substituted for 2'-N-tert-10 butylaminosulfonyl-3-chloro-[l, 1 ']-biphenyl-4-ylamine. ES-MS: (M+H)+ 527.
WO 01/19798 Example 44 194 PCT/USOO/25195 This compound was prepared by the same methodology described for Example 38 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substituted for 2'-N-tert-5 butylaminosulfonyl-3-chloro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 510.
Example 45 This compound was prepared by the same methodology described for Example 39 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substituted for 2'-N-teit-10 butylaminosulfonyl-3-chloro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 528.
Example 46.
PCT/USOO/25195 195 Step 1. To a solution of 4-nitroaniline (1.0 g, 6.7 mmol) in 50 mL anhydrous ethanol at 0°C was bubbled dry HCI gas via a long needle till saturation reached. The resulting solution was stirred overnight. The solvent was removed in vacuuo. The residue was pumped to dryness. It was dissolved in 50 mL anhydrous ethanol. To it was added 2 mL 5 N-methylethylenediamine. The mixture was refluxed for 1 hour and evaporated in vacuuo to give the l-methyl-2-(4-nitrophenyl)-2-imidazoline HCI salt in 90% yield. ES-MS: (M+H)+ 206.
Step 2. To a solution of the above-prepared nitro compound (500 mg, 2.4 mmol) in 4 mL 4N HCI and 50 mL methanol was added 10% Pd/C (50 mg). The mixture was stirred for 2 10 hours under a hydrogen balloon. It was filtered through celite and concentrated in vacuuo to give the 4-(l-methyl-2-imidazolin-2-yl)aniline HCI salt in 90% yield. ES-MS: (M+H)+ 176.
Step 3. To a solution of the above-prepared amine (40 mg, 0.22 mmol), 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-carboxylic acid (15 mg, 0.054 mmol, see Step 2, 15 Example 38), DMAP (2 mg) in 2 mL pyridine at 0°.C was added POCI3 (20 nL, 0.22 mmol). The mixture was stirred for 2 hours. It was concentrated in vacuuo and loaded on prep HPLC to afford the title compound in 60% yield. ES-MS: (M+H)+ 435.
The title compound in Example 46 (10 mg) was placed in TFA. It was refluxed for 1 hour and subjected on prep HPLC purification to afford the title compound in 85% yield. ES- Example 47 MS: (M+H)+ 453.
PCT/USOO/25195 196 Example 48 i^4ir( .CN Step 1. To a solution of 2-fluoro-4-nitroaniline (300 mg, 2.2 mmol) in 20 mL anhydrous methanol at 0°C was bubbled diy HCI gas via a long needle till saturation reached. The resulting solution was stirred overnight. The solvent was removed in vacuuo. The residue 5 was pumped to dryness. It was dissolved in 10 mL anhydrous methanol. To it was added 1 mL N-methylethylenediamine. The mixture was refluxed for 1 hour and evaporated in vacuuo to give the l-methyl-2-(2-fluoro-4-nitrophenyl)-2-imidazoline HCI salt in 90% yield. ES-MS: (M+H)+ 224.
Step 2. To a solution of the above-prepared nitro compound in 2 mL 4N HCI and 25 mL 10 methanol was added 10% Pd/C (20 mg). The mixture was stirred for 2 hours under a hydrogen balloon. It was filtered through celite and concentrated in vacuuo to give the 2-fluoro-4-(l-methyl-2-imidazolin-2-yl)aniline HCI salt in 90% yield. ES-MS: (M+H)+ 194.
Step 3. To a solution of the above-prepared amine (100 mg, 0.51 mmol) in 2 mL DCM was added trimethylaluminum (2.0M in hexane, 2 mL, 4.0 mmol). The mixture was 15 stirred for 20 minutes. Ethyl 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-carboxylate (76 mg, 0.25 mmol, see Step 2 of Example 34) was dissolved in 2 mL DCM and added into the reaction flask. The mixture was stirred for 2 days at room temperature. It was quenched with saturated Rochelle's salt aq solution and extracted with CHCI3 (X4). The organic phases were combined, dried, concentrated and purifed with prep HPLC to yield 20 the title compound (55%). ES-MS: (M+H)+ 453.
Example 49, 197 PCT/USOO/25195 \ The title compound in Example 48 (10 mg) was placed in TFA. It was refluxed for 1 hour and subjected on prep HPLC purification to afford the title compound in 85% yield. ES-MS: (M+H)+ 471.
Step 1. Compound 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert-butylaminosulfonyl-[l,r]-biphen-4-yl))carboxyamide was prepared by the same 10 procedure shown in Step 3 of Example 34.
Step 2. The above-prepared compound (70 mg, 0.12 mmol) was dissolved in 2 mL dry DMF. At 0°C, to it were added sodium borohydride (36 mg, 0.96 mmol) and C0CI2 (32 mg, 0.24 mmol). It was stirred for 2 days. Diluted with EtOAc and stirred for 1 hour. The mixture was filtered through celite. The filtrate was evaporated to give crude 3-methyl-1-15 (3-aminomethyl-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert-butylaminosulfonyl-[ 1,1']-biphen-4-yl))carboxyamide. ES-MS: (M+H)+ 568.
Example 50.
PCT/USOO/25195 198 Step 3. The above-prepared crude compound was taken into 3 mL TFA. The mixture was stirred for 1 hour at 60°C. The mixture was evaporated and subjected on prep HPLC to isolate the title compound (35% yield). ES-MS: (M+H)+ 512.
Example 51.
Step 1. Compound 3-methyl-1 -(3-cyano-2-naphthyl)-1 H-pyrazole-5-(N-(2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphen-4-yl))carboxyamide was prepared by the same methodology shown in Step 3 of Example 34, with 2.'-N-tert-butylaminosulfonyl-3-10 fluoro-[l,r]-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 582.
Step 2. To a solution of the above-prepared compound (77 mg, 0.13 mmol) in 3 mL anhydrous methanol and 3 mL anhydrous EtOAc at -20°C was bubbled dry HCI gas via a long needle till saturation reached. The mixture was stirred for overnight. The solvent was 15 removed in vacuuo. The dry residue was dissolved in 5 mL anhydrous methanol. To it was added 50 mg ammonium acetate. The mixture was refluxed for 2.5 hours. It was subjected on prep HPLC to isolate the title compound (55% yield). ES-MS: (M+H)* 543.
NH 199 PCT/USOO/25195 Example 52 Step 1. 3-Amino-2-naphthoic acid (5.8 g, 31 mmol) was placed in 50 mL concentrate HCI. The slurry was vigorously stirred at 0°C. To it was added dropwise a cold solution of sodium nitrite (2.35 g, 34 mmol, in 14 mL water). After completion, the mixture was 5 stirred for 40 minutes at 0°C. Under vigorously stirring, a cold solution of SnCl2.2HzO (21 g, 93 mmol, in 30 mL concentrate HCI) was added dropwise. The mixture was stirred for 30 minutes and chilled in ice bath. The crude 3-carboxyl-2-naphthylhydrazine was collected with a Buchner funnel and pumped to dryness in vacuuo.
Step 2. The crude hydrazine prepared above was taken into 60 mL glacial acetic acid and 10 30 mL THF. To it was added ethyl 2-N-(methoxy)imino-4-oxopentanoate (2.6 g, 14 mmol). The mixture was refluxed for overnight. The solvent was removed in vacuuo. The residue was dissolved in EtOAc and washed with brine (X2). The organic phase was dried, concentrated and purified with flash column to yield ethyl 3-methyl-1 -(3 -carboxyl-2-naphthyl)-lH-pyrazole-5-carboxylate (4.1 g, 90%). Rf 0.15 (1:1 EtOAc: hexane). ES-15 MS: (M+H)+ 325.
Step 3. To a solution of 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine (36 mg, 0.12 mmol) in 1 mL dry DCM was added trimethylaluminum (2.0M in hexane, 0.5 mL, 1.0 mmol). The mixture was stirred for 20 minutes. The above-prepared ester (38 mg, 0.12 mmol) was dissolved in 3 mL dry DCM and added into the aluminum mixture. The 20 reaction was stirred at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHCU (X3). The organic phases were combined, dried, concentrated and purified with flash column to yield the coupling product (60%). ES-MS: (M+H)+ 583.
WO 01/19798 PCT/USOO/25195 200 Step 4. The above-prepared compound (IS mg) was placed in 3 mL TFA and stirred overnight. It was concentrated and purified with prep HPLC to afford the title compound in 90% yield. ES-MS: (M+H)+ 527.
S Example 53 This compound was prepared by the same methodology described for Example 52 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 545.
Step 1. The above-prepared crude acid was dissolved in 150 mL anhydrous ethanol. To it 10 was added pTSA (3.3 g). The mixture was refluxed for 4 days till the esterification was over 95% complete. The solvent was removed in vacuuo. The residue was dissolved in EtOAc, washed with brine (X3), dried and purified by a short silica column to afford ethyl 3-methyl-l-(3-methylthio-2-naphthyI)-lH-pyrazole-5-caiboxyIate in over 80% yield. ES-MS: (M+H)+ 327.
IS Step 2. The above-prepared ester (4.95 g, 15 mmol) was dissolved in 150 mL DCM. At 0°C, to the vigorously stirred solution was added MCPBA (11 g, 38 mmol) in small portions over 20 minutes. The reaction was allowed for 1 hour and diluted with CHCI3. It was washed with NaHCOa saturated aq solution (X3), dried, concentrated and purified with flash column to give ethyl 3 -methyl-1 -(3 -methylsulfonyl-2-naphthyl)-1 H-pyrazole-20 5-carboxylate (3.49 g, 65%). Rf 0.52 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 359.
Step 3. To a solution of 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine (21 mg, 0.068 mmol) in 1 mL dry DCM was added trimethylaluminum (2.0M in hexane, 0.14 mL, 0.28 mmol). The mixture was stirred for 20 minutes:-The above-prepared ester (16 mg, 0.045 mmol) in Step 4 was dissolved in 4 mL dry DCM and added into the aluminum PCT/USOO/25195 201 mixture. The reaction was stirred at room temperature for overnight and quenched using saturated Rochelle's salt aq solution. It was extracted with CHCI3 (X3). The organic phases were combined, dried, concentrated and purified with flash column to yield the coupling product (52%). Rf 0.17 (1:1 EtOAc: Hexane). ES-MS: (M+H)+ 617.
Step 4. The above-prepared compound was dissolved in 2 mL acetonitrile and 2 mL TFA. The mixture was stirred for 1 hour at 70°C. The mixture was evaporated and purified with prep HPLC to afford the title compound in 90% yield. ES-MS: (M+H)+ 561.
Example 54, Step 1. The synthesis of ethyl 3-methyl-l-(3-methylsulfonyl-2-naphthyl)-lH-pyrazole-5-carboxylate was the same as that described in Step 4 of Example 53.
Step 2. The above-prepared ester (3.4 g, 9.7 mmol) was dissolved in 20 mL methanol. To it were added Li0H.H20 (0.82 g, 19.5 mmol) and 10 mL water. The mixture was stirred 15 at room temperature for overnight. The solvent was evaporated. The residue was acidified with IN HCI till pH 1. The mixture was extracted with EtOAc (X4). The organic phases were combined, dried, evaporated to dryness to afford 3-methyl-l-(3-methylsulfonyl-2-naphthyl)-lH-pyrazoIe-5-carboxylic acid (3.24 g, 99%). ES-MS: (M+H)+ 331.
Step 3. The above-prepared acid (102 mg, 0.31 mmol), 2'-N-tert-butylaminosulfonyl-3-20 fluoro-[l,l']-biphenyI-4-ylamine (150 mg, 0.46 mmol), DMAP (10 mg) were dissolved in 3 mL pyridine. To this stined solution at 0°C was added POCI3 (87 fiL, 0.93 mmol). The mixture was stirred for 2 hours and quenched with ice chips. It was diluted with EtOAc, PCT/USOO/25195 202 washed with brine (X2), dried, concentrated and purified with flash column to give the coupling product (130 mg, 66%); Rf 0.29 (1:1 EtOAc: hexane). MS: (M+H)+ 635.
Step 4. The above-prepared compound (100 mg) was taken into 5 mL TFA and stirred at room temperature for overnight After evaporation, the mixture was subjected on prep 5 HPLC to isolate the title compound (90%). MS: (M+H)+ 579.
Example 55.
This compound was prepared by the same methodology described for Example 54 with 2'-N-tert-butylarninosulfbnyl-3-chloro-[l,rj-biphenyl-4-ylamine substituted for 2'-N-10 tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 595.
Example 56 This compound was prepared by the same methodology described for Example 54 with 15 2'-N-tert-butylaminosulfonyl-3-bromo-[l,r]-biphenyl-4-ylamine substituted for 2'-N- WO 01/19798 PCT/USOO/25195 203 tert-butylaminosuIfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 639,641 (Br pattern).
Example 57.
This compound was prepared by the same methodology described for Example 54 with 2-amino-5-(2-(N-tert-butylarmnosulfbnyl)phenyl)pyridine substituted for 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 562.
Example 58 This compound was prepared by (he same methodology described for Example 54 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substituted for 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 563.
PCT/USOO/25195 204 Example 59.
SOjMe / 6-O^Q This compound was prepared by the same methodology described for Example 54 with for 2'-methylsulfonyl-[l,r]-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine, without the final TFA treatment. 5 ES-MS: (M+H)+ 560.
Example 60 This compound was prepared by the same methodology described for Example 54 with for 2' -cyano-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-3-10 fluoro-[l,l']-biphenyl-4-ylamine, without the final TFA treatment ES-MS: (M+H)+ 507.
PCT/USOO/25195 205 Example 61 <Sh ^sojme The title compound of Example 60 (55 mg, 0.11 mmol) was dissolved in 2 mL anhydrous DMF. To this stirred solution at 0°C were added sodium borohydride (33 mg, 0.88 mmol) 5 and c0ci2 (30 mg, 0.22 mmol). The reaction was allowed for 2 hours and quenched with acetic acid. The mixture was evaporated, diluted with EtOAc, and washed with NaHC03 aq solution. The organic phase was dried, evaporated and purified with prep HPLC to afford the title compound in 55% yield. ES-MS: (M+H)+ 511.
Example 62.
This compound was prepared by the same methodology described for Example 54 with for 2'-(N-dimethylaminomethyl)-[ 1,1 ']-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 539. / 206 PCT/USOO/25195 Example 63 This compound was prepared by the same methodology described for Example 54 with for 3'-(N-tert-Boc-aminomethyl)-[l,r]-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 511.
Example 64.
This compound was prepared by the same methodology described for Example 54 with for l-(4-Aminophenyl)-4-methylpiperazine hydrochloride substituted for 2'-N-tert-10 butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 504.
WO 01/19798 PCT/USOO/25195 207 F.xample 65.
This compound was prepared by the same methodology described for Example 54 with for l-(N-methylpiperidin-4-yl)-piperazine substituted for 2'-N-tert-butylaminosulfonyl-3-5 fluoro-[ 1,1 ']-biphenyl-4-ylamine, withoutthe final TFA treatment ES-MS: (M+H)+ 496.
Example 66 This compound was prepared by the same methodology described for Example 54 with for l-(4-pyridyl)-piperazine substituted for2,-N-tert-butylaminosulfonyl-3-fluoro-[ljr]-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 476.
PCT/USOO/25195 208 This compound was prepared by the same methodology described for Example 54 with for 4-(N-pyrrolidinylcarbonyl)-aniline substituted for 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine, without the final TFA treatment. ES-MS: (M+H)+ 503. s Example 68.
Step 1. The synthesis of 3-methyl-l-(3-methylsulfonyl-2-naphthyl)-lH-pyrazole-5-carboxylic acid was the same as that described in Step 2 of Example 54.
Step 2. The above-prepared acid (200 mg, 0.61 mmol), 4-aminobenzonitrile (108 mg, 0.91 mmol) and DMAP (10 mg) were dissolved in 6 mL pyridine. The solution was stirred at 0°C. To it was added POCU (170 jiL, 1.8 mmol). The mixture was stirred for 1 hour. The reaction was then quenched with ice chips. It was diluted with EtOAc. The organic phase was washed with brine (X2). It was dried, concentrated and purified with IS flash column to afford the coupling product (250 mg, 95%). Rf 0.20 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 431.
Step 3. The above-prepared nitrile (70 mg, 0.16 mmol) was dissolved in 6 mL dry methanol. It was chilled and stirred in an ice bath. To this solution was bubbled dry HCI gas via a long needle till saturation reached (indicated by a blown-up balloon attached on the top of the reaction flask). The resulting solution was stirred overnight. ES-MS: (M+H)+ 463. The solvent was removed in vacuuo. The residue was pumped to dryness. The solid was dissolved in 6 mL dry methanol. To it was added anhydrous N-methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour, concentrated and loaded on prep HPLC to afford the title compound in 80% yield. ES-MS: (M+H)+ 488.
Example 69. 209 PCT/USOO/25195 This compound was prepared by the same methodology described for Example 68 with pyrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 502.
Example 70.
This compound was prepared by the same methodology described for Example 68 with morpholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 518.
Example 71.
N-methylpiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 531. 210 PCT/USOO/25195 Example 72 This compound was prepared by the same methodology described for Example 68 with 4-5 amino-3-fluorobenzonitrile (preparation described in Step 1 of Example 22) substituted for 4-aminobenzonitrile. ES-MS: (M+H)+ 506.
Example 73.
This compound was prepared by the same methodology described for Example 68 with 4-amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with N-methyl-1,3-propanediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 520.
WO 01/19798 PCT/USOO/25195 211 Example 74.
This compound was prepared by the same methodology described for Example 68 with 4-amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with pyrrolidine 5 substituted for N-methylethylenediamine. ES-MS: (M+H)+ 520.
Example 75 This compound was prepared by the same methodology described for Example 68 with 4-10 amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 534.
WO 01/19798 PCT/USOO/25195 212 Example 76.
This compound was prepared by the same methodology described for Example 68 with 4-amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with dimethylamine 5 (2M solution in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 494.
Example 77.
This compound was prepared by the same methodology described for Example 68 with 4-10 amino-3-fluorobenzonitriIe substituted for 4-aminobenzonitrile, and with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 466.
Example 78 01/19798 PCT/USOO/25195 213 Step 1. To a solution of 2-bromo-6-methoxynaphthalene (2.0 g, 8.4 mmol) in 20 mL anhydrous THF at -78°C was added BuLi (1.6M, 7.9 mL, 12.6 mmol) dropwise with a syringe. The mixture was stirred for 30 minutes, then to it was added triisopropyl borane (2.34 mL, 10.1 mmol) dropwise. The dry ice bath was removed. The reaction mixture was allowed to warm up to room temperature. After 15 hours, THF was mostly removed in vacuuo. To the residue was added 40 mL 3M HCI. The mixture was stirred at room temperature for 8 hours. Ether was used to extract the product (X3). The organic phases were combined, dried, concentrated in vacuuo and pumped to dryness to afford 6-methoxy-2-naphthylboronic acid (75% yield) as a white solid. Rf 0.34 (1:1 EtOAc: hexane).
Step 2. To a solution of the above-prepared boronic acid (0.84 g, 3.2 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.49 g, 3.2 mmol) in 20 mL dry DCM were added pyridine (0.77 mL, 9.5 mmol) and anhydrous powder of copper(II) acetate (1.15 g, 6.3 mmol). Some activated molecular sieve powder was added afterwards. The resulting IS slurry was stirred for 4 days under argon. The mixture was diluted with DCM. It was filtered through celite. The blue filtrate was washed with water (X2), dried, concentrated and purified by flash column to separately afford ethyl 3-methyl-l-(6-methoxy-2-naphthyl)-lH-pyrazole-5-carboxylate [37% yield. Rf 0.80 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 311] and ethyl 5-methyl-l-(6-methoxy-2-naphthyl)-lH-pyrazole-3-carboxylate 20 [25% yield. Rf 0.69 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 311] in a 1.5:1 ratio. , Step 3. To a solution of 2'-N-tert-butyIaminosulfonyl-[l,r]-biphenyl-4-ylamine (44 mg, 0.14 mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.35 mL, 0.70 mmol) at room temperature. The mixture was stirred for 30 minutes, and to it was added the above-prepared ethyl 3-methyl-l-(6-methoxy-2-naphthyl)-lH-pyrazole-5-caiboxylate 25 (44 mg, 0.14 mmol) in 2 mL DCM. The resulting mixture was stirred overnight. The reaction was quenched using 5 mL saturated Rochelle salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, concentrated and subjected on flash column to afford the coupling product in 84% yield (67 mg). Rf 0.41 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 569.
WO PCT/USOO/25195 214 Step 4. The above-prepared compound was placed in 3 mL TFA and stirred at 65°C for 30 minutes. After evaporation, the residue was dissolved in methanol and purified with prep HPLC to afford the title compound in 95% yield. ES-MS: (M+H)+ 513. °h Step 1. The preparation of ethyl 3-methyl-1 -(6-methoxy-2-naphthyl)-1 H-pyrazole-5 -carboxylate was the same as described in Step 2 of Example 83.
Step 2. The above-prepared compound (150 mg, 0.48 mmol) was dissolved in 2 mL DCM. At 0°C, to the stirred solution was added boron tribromide (l.OM in DCM, 0.72 10 mL, 0.72 mmol). The mixture was stirred overnight at room temperature. It was directly subjected to flash column to afford ethyl 3-methyl-l-(6-hydroxy-2-naphthyl)-lH-pyrazole-5-carboxylate (78 mg, 55%). Rf 0.73 (2:1 EtOAc: hexane). ES-MS: (M+H)+ 297.
Step 3. To a stirred solution of 2'-N-tert-butylaminosulfonyl-[1,1']-biphenyl-4-ylamine IS (80 mg, 0.26 mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.65 mL, 1.3 mmol) at room temperature. After 30 minutes, to die mixture was added ethyl 3-methyl-l-(6-hydroxy-2-naphthyl)-lH-pyrazole-5-carboxylate (78 mg, 0.26 mmol) in 3 mL DCM. The resulting mixture was stirred 4 hours. The reaction was quenched using 5 mL saturated Rochelle salt aq solution. The mixture was extracted using DCM (X3). The 20 organic phases were combined, dried, concentrated and purified with flash column to afford the coupling product in 65% yield. Rf 0.32 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 555.
Example 79.
WO 01/19798 PCT/USOO/25195 215 Step 4. The above-prepared compound was placed in 3 mL TFA and stirred at 70°C for 30 minutes. After evaporation, the residue was dissolved in methanol and purified with prep HPLC to afford the title compound in 95% yield. ES-MS: (M+H)+ 499.
Example 80.
Br Step 1. A mixture of 6-bromo-2-naphthoic acid (1.11 g, 4.4 mmol) and 2 mL thionyl chloride was refluxed for overnight. Thionyl chloride was removed in vacuuo. The dry acid chloride was dissolved in 5 mL dioxane. At 0°C to it was added a solution of sodium azide (0.52 g, 8.0 mmol) in 2.5 mL water and 2.5 mL dioxane dropwise. The mixture was 10 stirred for 2 hours. After evaporation in vacuuo to remove the solvent, the residue was dissolved in EtOAc, washed with brine, dried, concentrated in vacuuo to give the azidoketone (1.22 g, 99%). Rf 0.88 (1:1 EtOAc: hexane).
Step 2. The above-prepared compound was dissolved in 20 mL DMF. To it was added 10 mL water. The mixture was refluxed overnight It was diluted with 500 mL EtOAc, 15 washed with brine (X2), dried, concentrated in vacuuo to afford 6-bromo-2- naphthylamine (1.2 g, 99%). Rf 0.73 (1:1 EtOAc: hexane), ES-MS: (M+H)+ 222,224 (Br pattern).
Step 3. The above-prepared compound (1.2 g, 5.4 mmol) was placed in 6 mL concentrate HCI. At 0°C to it was added a solution of sodium nitrite (0.37 g, 5.4 mmol) in 2 mL water 20 dropwise. The mixture was stirred for 30 minutes. At 0°C to the mixture was added a solution ofSnCl2.2H20 (3.66 g, 16.2 mmol) in 6 mL concentrate HCI dropwise. After stirring for 10 minutes, the mixture was placed in a freezer for overnight. The solid was collected on a cold Buchner funnel. It was washed by ice-cold brine (7 mL) and ice-cold hexane (7 mL). The solid cake was transferred into a flask and pumped to dryness. To it WO 01/19798 PCT/USOO/25195 216 were added 30 mL acetic acid, IS mL THF, and ethyl 2-N-(methoxy)imino-4-oxopentanoate (1.3 g, 7.0 mmol). The resulting mixture was refluxed for overnight. The solvent was removed in vacuuo. The residue was dissolved in EtOAc, washed with brine (X2), dried, concentrated and purified by flash column to yield ethyl 3-methyl-1-(6-5 bromo-2-naphthyl)-1 H-pyrazole-5-carboxylate (0.64 g, 33%). Rf 0.71 (1:2 EtOAc: hexane). ES-MS: (M+H)+ 359,361 (Br pattern).
Step 4. To a stirred solution of 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine (93 mg, 0.31 mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.70 mL, 1.4 mmol) at room temperature. After 30 minutes, to the mixture was added the 10 above-prepared ethyl ester (100 mg, 0.28 mmol) in 3 mL DCM. The resulting mixture was stirred overnight. The reaction was quenched using 5 mL saturated Rochelle's salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, evaporated and purified with flash column to yield the coupling product (146 mg, 85%). Rf 0.44 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 617, 619 (Br pattern).
IS Step 5. The above-prepared compound was placed in 3 mL TFA and stirred at 65°C for 40 minutes. After evaporation, the residue was dissolved in methanol and purified with prep HPLC to afford the title compound in 95% yield. ES-MS: (M+H)+ 561, 563 (Br pattern).
PCT/USOO/25195 217 Example 81.
This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 579,581 (Br 5 pattern).
Example 82 Br This compound was prepared by the same methodology described for Example 80 with 2,-N-tert-butylaminosulfonyl-3-chloro-[l,r]-biphenyl-4-ylamine substituted for 2'-N-10 tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 595, 597 (BrCl pattern). 218 PCT/USOO/25195 Example 83 Br / 0-0-"-°^ This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-3-bromo-[l,l']-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 640,642,644 (Br2 5 pattern).
Example 84.
This compound was prepared by the same methodology described for Example 80 with 2'-N-tert-butylaminosulfonyl-5'-chloro-[l,r]-biphenyl-4-ylamine substituted for 2'-N-10 tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 595,597 (BiCl pattern).
Br 219 PCT/USOO/25195 Example 85 Br This compound was prepared by the same methodology described for Example 80 with 5-(2-N-tert-butylaminosulfonyl-1 -phenyl)-2,3-dihydroindole substituted for 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine. ES-MS: (M+H)+ 587, 589 (Br pattern).
Step 1. The synthesis of ethyl 3-methyl-1 -(6-bromo-2-naphthyl)-1 H-pyrazole-5-carboxylate was the same as Step 3 of Example 80.
Step 2. The above-prepared ethyl ester (1.0 g, 2.8 mmol) was dissolved in 20 mL 10 methanol. To the solution were added Li0H.H20 (350 mg, 8.3 mmol) and 10 mL water. The mixture was stirred for overnight and evaporated in vacuuo. The residue was acidified with IN HCI. It was extracted with EtOAc (X4). The organic phases were combined, dried and concentrated in vacuuo to give 3-methyl-l-(6-bromo-2-naphthyl)-lH-pyrazole-5-caiboxylic acid (0.97 g, 100%). ES-MS: (M+H)+ 331,333 (Br pattern).
Step 3. A mixture of the above-prepared acid (33 mg, 0.10 mmol), 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine (61 mg, 0.20 mmol), DMAP (5 mg) were dissolved in 3 mL pyridine and stirred at 0°C. To it was added POCh(55 jiL, 0.6 mmol). The mixture was stirred for 2 hours and quenched with ice chips. It was diluted with EtOAc, Example 86 PCT/USOO/25195 220 washed with brine (X2), dried, concentrated and purified with flash column to give the coupling product (34 mg, 55%). Rf 0.35 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 618,620 (Br pattern).
Step 4.. The above-prepared compound was placed in 3 mL TFA and stirred at 65°C for 5 40 minutes. After evaporation, the residue was dissolved in methanol and purified with prep HPLC to afford the title compound in 95% yield. ES-MS: (M+H)+ 562,564 (Br pattern).
Example 87.
This compound was prepared by the same methodology described for Example 86 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substituted for 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridme. ES-MS: (M+H)+ 563, 565 (Br pattern).
Br 221 PCT/USOO/25195 Example 88.
Step 1. The synthesis of 3-methyl-l-(6-bromo-2-naphthyl)-lH-pyrazole-5-carboxylic acid was the same as Step 2 of Example 86.
Step 2. A mixture of the above-prepared acid (970 mg, 2.9 mmol), 4-aminobenzonitrile 5 (700 mg, S.8 mmol), DMAP (40 mg) were dissolved in IS mL pyridine and stirred at 0°C. To it was added POCI3 (1.1 mL, 12 mmol). The mixture was stirred for 1 hour and quenched with ice chips. It was diluted with EtOAc, washed with brine (X2), dried, concentrated and purified with flash column to give the coupling product (720 mg, 58%). Rf 0.30(1:1 EtOAc: hexane). ES-MS: (M+H)+ 431,433 (Br pattern).
Step 3. The above-prepared nitrile (40 mg, 0.09 mmol) was dissolved in 6 mL dry methanol. It was chilled and stirred in an ice bath. To this solution was bubbled dry HCI gas via a long needle till saturation reached. The resulting solution was stirred overnight. ES-MS: (M+H)+ 463,465 (Br pattern). The solvent was removed in vacuuo. The residue was pumped to dryness. The solid was dissolved in 6 mL dry methanol. To it was added IS anhydrous N-methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour, concentrated and loaded on prep HPLC to afford the title compound in 85% yield. ES-MS: (M+H)+ 488,490 (Br pattern). 222 PCT/USOO/25195 Example 89.
Br This compound was prepared by the same methodology described for Example 88 with pyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ S02, 504 (Br pattern).
Example 90.
This compound was prepared by the same methodology described for Example 88 with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 516, 518 (Br pattern).
Example 91. oJLoMJS WO 01/19798 PCT/USOO/25195 223 This compound was prepared by the same methodology described for Example 88 with morpholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ SI8, S20 (Br pattern).
Example 92.
Br This compound was prepared by the same methodology described for Example 88 with N-methylpiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 531, 533 (Br pattern).
Example 93.
This compound was prepared by the same methodology described for Example 88 with 4-amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile. ES-MS: (M+H)+ 506, 508 (Br pattern). 224 PCT/USOO/25195 Example 94.
This compound was prepared by the same methodology described for Example 88 with 4-amino-2,S-difiuorobenzonitrile substituted for 4-aminobenzonitrile. ES-MS: (M+H)* 524, 526 (Br pattern).
Example 95.
This compound was prepared by die same methodology described for Example 88 with 4-amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile. ES-MS: (M+H)+ 522, 10 524 (BrCl pattern). 225 PCT/USOO/25195 Example 96.
This compound was prepared by the same methodology described for Example 88 with 4-amino-2-chlorobenzonitrile substituted for 4-aminobenzonitrile. ES-MS: (M+H)+ 522, 524 (BrCl pattern).
Example 97 This compound was prepared by the same methodology described for Example 88 with 4-amino-2-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with N-ethyl 10 ethylenediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 536,538 (BrCl pattern). 226 PCT/USOO/25195 Example 98.
This compound was prepared by the same methodology described for Example 88 with 4-amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with ethylenediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ S08, S10 5 (BrCl pattern).
Example 99.
This compound was prepared by the same methodology described for Example 88 with 4-amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with N-methyl-1,3-10 propanediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ S36,538 (BrCl pattern).
PCT/USOO/25195 227 Example 100 This compound was prepared by the same methodology described for Example 88 with 4-amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with 1,3-propanediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 522, 524 5 (BrCl pattern).
Example 101.
This compound was prepared by the same methodology described for Example 88 with 4-amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with pyrrolidine 10 substituted for N-methylethylenediamine. ES-MS: (M+H)+ 520, 522 (Br pattern).
PCT/USOO/25195 228 Example 102, Br This compound was prepared by the same methodology described for Example 88 with 4-amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with 2-5 methylpyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 534,536 (Br pattern).
Example 103.
This compound was prepared by the same methodology described for Example 88 with 4-amino-2,5-difluorobenzonitrile substituted for 4-aminobenzonitrile, and with pyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 538, 540 (Br pattern). 229 PCT/USOO/25195 Example 104.
This compound was prepared by the same methodology described for Example 88 with 4-amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with pyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 536, 538 (BrCl pattern).
Example 105.
This compound was prepared by the same methodology described for Example 88 with 4-amino-2-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with pyrrolidine 10 substituted for N-methylethylenediamine. ES-MS: (M+H)+ 536, 538 (BrCl pattern).
PCT/USOO/25195 230 Example 106.
This compound was prepared by the same methodology described for Example 88 with 4-amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with thiomoipholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 552, 554 (Br pattern).
Example 1Q7.
This compound was prepared by the same methodology described for Example 88 with 4-amino-3-fluorobenzonitrile substituted for 4-aminobenzonitrile, and with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 466,468 (Br pattern).
PCT/USOO/25195 231 Example 108 This compound was prepared by the same methodology described for Example 88 with 4-amino-2,5-difluorobenzonitrile substituted for 4-aminobenzonitrile, and with methylamine (2M in methanol) substituted for N-methylethylenediamine. ES-MS: 5 (M+H)+ 498, 500 (Br pattern).
Example 109.
This compound was prepared by the same methodology described for Example 88 with 4-amino-3-chlorobenzonitrile substituted for 4-aminobenzonitrile, and with dimethylamine 10 (2M in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 510, 512 (BrCl pattern).
Br 232 PCT/USOO/25195 Example 110 Step 1. To a solution of 6-bromo-2-naphthoic acid (4.4 g, 17.5 mmol) in 50 mL anhydrous DMF were added CuCI (8.7 g, 87.5 mmol) and Cul (0.2 g). The sluny was 5 refluxed for 1 hour. At room temperature it was diluted with 300 mL EtOAc and stirred for 2 hours. It was filtered through celite. The filtrate was evaporated in vacuuo to afford 6-chloro-2-naphthoic acid (2.7 g, 75%). ES-MS: (M+H)+ 207.
Step 2. The title compound was prepared using the same methodology shown for Example 80, with 6-chloro-2-naphthoic acid substituted for 6-bromo-2-naph1hoic acid. 10 ES-MS: (M+H)+517.
Example 111.
The title compound was prepared using the same methodology shown for Example 110, with 2'-N-tert-butylaminosulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine substituted for 2'-15 N-tert-butylaminosulfonyl- [1,1 ']-biphenyl-4-ylamine. ES-MS: (M+H)+ 535.
Example 112. 233 PCT/USOO/25195 The title compound was prepared using the same methodology shown for Example 110, with 2'-methylsulfonyl-3-fluoro-[l,r]-biphenyl-4-ylamine substituted for 2'-N-tert-butylaminosulfonyl-[ 1,1 ']-biphenyl-4-ylamine. ES-MS: (M+H)+ 534.
Example 113 The title compound was prepared using the same methodology shown for Example 93, with 6-chloro-2-naphthoic acid substituted for 6-bromo-2-naphthoic acid. ES-MS: (M+H)+ 462.
Example 114.
NH WO 01/19798 PCT/USOO/25195 234 The title compound was prepared using the same methodology shown for Example 101, with 6-chloro-2-naphthoic acid substituted for 6-bromo-2-naphthoic acid. ES-MS: (M+H)+ 476.
Example 115 The title compound was prepared using the same methodology shown for Example 114, with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 490.
Example 116. ci The title compound was prepared using the same methodology shown for Example 114, with dimethylamine (2M in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 450.
Example 117 235 PCT/USOO/25195 Step 1. The synthesis of 3-methyl-l-(3-cyano-2-naphthyl)-lH-pyrazole-5-(N-(2'-N-tert-butylaminosulfonyl-[l,r]-biphen-4-yl))carboxyamide followed the same procedure shown in Step 3 of Example 34.
Step 2. To a solution of the above-prepared compound (30 mg) in 10 mL anhydrous ethanol at 0°C was bubbled dry HCI gas via a long needle till saturation reached. The mixture was stirred for overnight. The solvent was removed in vacuuo. The dry residue was dissolved in 5 mL anhydrous methanol. To it was added 0.5 mL N-methylethylenediamine. The mixture was refluxed for 2 hours. ES-MS: (M+H)+ 621. It 10 was concentrated in vacuuo. To the residue was added 3 mL TFA and the mixture was stirred at 70°C for 1 hour. After evaporation, the reaction mixture was subjected on prep HPLC to isolate the title compound (20% yield). ES-MS: (M+H)+ 565.
Example 118.
The title compound was prepared using the same methodology shown for Example 117, with dimethylamine (2M in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 553.
Example 119. 236 PCT/USOO/25195 The title compound was prepared using the same methodology shown for Example 117, with pyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 579.
Example 120.
The title compound was prepared using the same methodology shown for Example 1, with 2-N-tert-butyIaminosulfonylphenylboronic acid substituted for 2-naphthylboronic 10 acid. ES-MS: (M+H)+ 512.
Example 121 PCT/USOO/25195 237 The title compound was prepared using the same methodology shown for Example 1, with 2-methylsulfonyIphenylboronic acid substituted for 2-naphthylboronic acid. ES-MS: (M+H)+ 511.
Example 122.
The title compound was prepared using the same methodology shown for Example 52, with commercial 2-nitrophenylhydrazine substituted for 3-caiboxyl-2-naphthylhydrazine. ES-MS: (M+H)+ 478.
Example 123.
Step 1.4-methylsulfonyl-3-nitrobenzoic acid (0.90 g, 3.7 mmol) was dissolved in 10 mL ethanol. To it were added hydrazine monohydrate (0.46 mL, 15 mmol) and catalytic amount of 10% Pd/C. The mixture was refluxed for 1.5 hour, diluted with methanol, filtered through celite and concentrated in vacuuo to afford 3-amino-4-15 methylsulfonylbenzoic acid (>70%). ES-MS: (M+H)+ 216.
Step 2. The above-prepared aniline (2.2 g, 10 mmol) was stirred in 16 mL concentrate HCI in ice bath. To it was dropwise added a cold solution of sodium nitrite (1.1 g, 15 mmol, in 7 mL water). After completion, the mixture was stirred for 30 minutes at 0°C. To it was added dropwise a cold solution of SnCl2-2H20 (9.2 g, 40 mmol, in 14 mL WO 01/19798 PCT/USOO/25195 238 concentrate HCI). The mixture was stirred for 30 minutes and filtered through a Buchner funnel. The solid crude hydrazine was collected and dried.
Step 3. The crude hydrazine was dissolved in 40 mL acetic acid. To it were added 20 mL THF and ethyl 2-N-(methoxy)imino-4-oxopentanoate (2.8 g, 15 mmol). The mixture was 5 refluxed for overnight. After removal of the solvent in vacuuo, the reaction mixture residue was dissolved in 800 mL ether. The organic solution was washed with brine (X2), dried, concentrated and purified with flash column to afford ethyl 3-methyl-1-(5-carboxyl-2-methylsulfonylphenyI)-lH-pyrazole-5-carboxylate (2.1 g, 60%). Rf 0.17 (pure EtOAc). ES-MS: (M+H)+ 353.
Step 4. The above-prepared acid (2.1 g, 6.5 mmol) was dissolved in 50 mL dry DMF. To it were added tert-butylamine (1.4 mL, 13 mmol), DIEA (9.2 mL, 52 mmol) and PyBOP (13 g, 26 mmol) in order. The resulting mixture was stirred for overnight at room temperature. DMF was removed in vacuuo. The residue was taken into EtOAc and washed with brine (X2). The organic phase was dried, concentrated and subjected on 15 flash column to isolate ethyl 3-methyl-1 -(5-N-tert-butylaminocarbonyl-2- methylsulfonylphenyl)-lH-pyrazole-5-carboxylate (0.74 g, 30%). Rf 0.70 (pure EtOAc). ES-MS: (M+H)+408.
Step 5. To a solution of 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine (100 mg, 0.33 mmol) in 2 mL DCM was added trimethylaluminum (2.0M in hexane, 0.66 mL, 1.3 20 mmol) under argon at room temperature. After being stirred for 30 minutes, to the mixture was added the above-prepared ester (90 mg, 0.22 mmol) in 10 mL DCM. The resulting mixture was stirred overnight. The reaction was quenched using 10 mL saturated Rochelle's salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, iotovaped and subjected on flash chromatography 25 column to give the coupled product in 62% yield (90 mg). Rf 0.10 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 666.
Step 6. The above-prepared compound (20 mg) was placed in 5 mL TFA. It was stirred at 70°C for 1 hour and subjected on prep HPLC to isolate the title compound (90%) after evaporation. ES-MS: (M+H)+ 554.
Example 124. 239 PCT/USOO/25195 Step 1. To a solution of 4-biphenylboronic acid (1.0 g, 5.1 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.78 g, 5.1 mmol) in 25 mL dry DCM were added 5 pyridine (1.2 mL, 15 mmol) and anhydrous powder of copper(II) acetate (1.84 g, 10 mmol). Some activated molecular sieve powder was added afterwards. The resulting slurry was refluxed for 2 days under argon. The mixture was diluted with DCM, filtered through celite. The blue filtrate was washed with water (X2), dried, concentrated, purified with flush column to yield ethyl 3-methyl-l-(4-phenylphenyl)-lH-pyrazole-5-caxboxylate 10 (26%), Rf 0.67 (1:2 EtOAc: hexane), ES-MS: (M+H)+ 307; and its regioisomer, ethyl 5-methyl-l-(4-phenyIphenyl)-lH-pyrazole-3-carboxylate (31%), Rf0.50 (1:2 EtOAc: hexane), ES-MS: (M+H)+ 307.
Step 2. To a stirred solution of 4-chloioaniline (24 mg, 0.18 mmol) in 1 mL DCM was added trimethylaluminum (2.0M, 0.43 mL, 0.86 mmol) at room temperature. After 30 15 minutes, to the mixture was added ethyl 3-methyl-l-(4-phenylphenyl)-lH-pyrazole-5-carboxylate (52 mg, 0.17 mmol) in 3 mL DCM. The resulting mixture was stirred for overnight. It was quenched using 5 mL saturated Rochelle's salt aq solution. The mixture was extracted using DCM (X3). The organic phases were combined, dried, concentrated and subjected on flash column to afford the title compound (46 mg, 70%). Rf 0.46 (1:1 20 EtOAc: hexane). ES-MS: (M+H)+ 388. 240 PCT/USOO/25195 Example 125 OMe The title compound was prepared using the same methodology shown for Example 124, with 4-methoxyaniline substituted for 4-chloroaniline. ES-MS: (M+H)+ 384.
Example 126.
Step 1.2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine (1.9 g, 6.2 mmol) was placed in 8 mL concentrate HCI. At 0°C to this stirred mixture was added a cold solution of sodium nitrite (0.43 g, 6.2 mmol in 2 mL water) dropwise. After 30 minutes, to it was 10 added a cold solution of SnCl2.2H20 (4.2 g, 18.4 mmol in 8 mL concentrate HCI). The mixture was stirred at 0°C for 1 hour and the solid was collected with a Buchner funnel. The crude solid hydrazine was dried.
Step 2. The above-prepared crude hydrazine was dissolved in 20 mL acetic acid. To it was added 10 mL THF and ethyl 2-N-(methoxy)imino-4-oxopentanoate (0.93 g, 5.0 IS mmol). The mixture was refluxed for 3 hours. The solvent was removed in vacuuo. The residue was taken into EtOAc, washed with brine, dried, concentrated and purified with PCT/USOO/25195 241 flash column to yield ethyl 3-methyl-l-(4-(2-aminosulfonylphenyI)-phenyl)-lH-pyiazole-5-carboxylate (0.95 g, 40%). Rf 0.51 (1:1 EtOAc: hexane). ES-MS: (M+H)+ 386.
Step 3. The above-prepared ethyl ester was dissolved in 20 mL methanol. To it were added Li0H.H20 (0.31 g, 7.4 mol) and 10 mL water. The mixture was stirred for 3 hours, 5 acidifed till pH 5 with acetic acid, and evaporated in vacuuo. The residue was soaked with acetonitrile and decanted for several times to extract out the' organic product. The acetonitrile solutions were combined and evaporated in vacuuo to give yield 3-methyl-1-(4-(2-aminosulfonyIphenyl)-phenyl)-lH-pyrazole-5-caiboxylic acid (0.81 g, 92%). ES-MS: (M+H)+ 358. It was further purified using prep HPLC.
Step 4. The above-prepared acid (20 mg, 0.056 mmol) was dissolved in 1 mL dry DMF. To it were added 4-bromoaniline (10 mg, 0.056 mmol), DIEA (30 jiL, 0.17 mmol) and PyBOP (58 mg, 0.12 mmol) in order. The reaction mixture was directly loaded on prep HPLC to yield the title compound in 45% yield. ES-MS: (M+H)+ 511,513 (Br pattern).
Example 127.
OMe The title compound was prepared using the same methodology shown for Example 126, with 4-methoxyaniline substituted for 4-bromoaniline. ES-MS: (M+H)+ 463.
WO 01/19798 PCT/USOO/25195 242 Example 128.
The title compound was prepared using the same methodology shown for Example 126, with 4-methoxy-2-nitroaniline substituted for 4-bromoaniline. ES-MS: (M+H)+ 508.
Example 129 nh jy bI The title compound was prepared using the same methodology shown for Example 126, with 6-bromo-2-naphthylamine substituted for 4-bromoaniline. ES-MS: (M+H)+ 562,564 (Br pattern).
Example 130.
The title compound was prepared using the same methodology shown for Example 126, with 2-naphthylamine substituted for 4-bromoaniline. ES-MS: (M+H)+ 483.
Example 131.
The title compound was prepared using the same methodology shown for Example 126, with 7-aminoisoquinoline substituted for 4-bromoaniline. ES-MS: (M+H)+ 484. 244 PCT/USOO/25195 Example 132.
The title compound was prepared using the same methodology shown for Example 126, with 2-amino-S-chloropyridine substituted for 4-bromoaniline. ES-MS: (M+H)+ 468.
Example 133 The title compound was prepared using the same methodology shown for Example 126, with 2-amino-S-bromopyridine substituted for 4-bromoaniline. ES-MS: (M+H)+ 512,154 (Br pattern). 245 PCT/USOO/25195 Example 134.
Step 1. A mixture of 4-cyanophenylhydrazine hydrochloride (5.7 g, 33 mmol), ethyl 2-N-(methoxy)imino-4-oxopentanoate (7.5 g, 40 mmol), 100 mL acetic acid and 50 mL THF was refluxed for 2 hours. The solvent was removed in vacuuo. The residue was taken into 5 500 mL EtOAc, which was washed with brine, dried and evaporated in vacuuo to afford ethyl 3-methyl- l-(4-cyanophenyl)-lH-pyrazole-5-carboxylate (10 g, 99%). ES-MS: (M+H)+ 256.
Step 2. The above-prepared ester (10 g) was dissolved in 100 mL THF. To it were added Li0H.H20 (4.2 g, 100 mmol), 100 mL methanol and 50 mL water. The mixture was 10 stirred for 1 hour. It was acidified to pH 1 with IN HCI. It was evaporated to remove organic solvent. The residue was extracted with EtOAc (X4). The organic phases were combined, dried and evaporated to dryness to afford 3-methyl- l-(4-cyanophenyl)-lH-pyrazole-5-carboxylatic acid (95%). ES-MS: (M+H)+ 228.
Step 3. The above-prepared acid (1.4 g, 6.2 mmol) was dissolved in 20 mL pyridine. To it 15 were added 2-amino-5-bromopyridine (2.2 g, 13 mmol) and DMAP (100 mg). At 0°C to this mixture was added POCU (2.3 mL, 25 mmol). The reaction was allowed for 1.5 hour and quenched with ice chips. After evaporation in vacuuo, the residue was taken into 300 mL EtOAc, which was washed with brine, dried, evaporated and purified with flash column to yield the coupling product (45%). Rf 0.52 (1:1 EtOAc: hexane). ES-MS: 20 (M+H)+ 382,384 (Br pattern).
Step 4. To a solution of the above-prepared nitrile (30 mg) in 10 mL anhydrous methanol at 0°C was bubbled dry HCI gas via a long needle till saturation reached. The mixture was stirred for overnight. The solvent was removed in vacuuo. The dry residue was dissolved in 5 mL anhydrous methanol. To it was added 0.5 mL N-methylethylenediamine. The WO 01/19798 PCT/USOO/25195 246 mixture was refluxed for 1 hour. After evaporation, the reaction mixture was subjected on prep HPLC to isolate the title compound (80% yield). ES-MS: (M+H)+ 439,441 (Br pattern).
Example 13S.
The title compound was prepared using the same methodology shown for Example 134, with ethylenediamine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 425, 427 (Br pattern).
Example 136 The title compound was prepared using the same methodology shown for Example 134, with pyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 453,455 (Br pattern). 247 PCT/USOO/25195 Example 137, Br The title compound was prepared using the same methodology shown for Example 134, with 2-methylpyrrolidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 467, 469 (Br pattern).
Example 138.
The title compound was prepared using the same methodology shown for Example 134, with piperidine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 467,469 (Br pattern).
Br 248 PCT/USOO/25195 Example 139.
The title compound was prepared using the same methodology shown for Example 134, with morpholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 469,471 (Br pattern).
Example 140.
The title compound was prepared using the same methodology shown for Example 134, with thiomorpholine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 485,487 (Br pattern). 249 PCT/USOO/25195 example 141 Br The title compound was prepared using the same methodology shown for Example 134, with N-methylpiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 482, 484 (Br pattern).
Example 142.
The title compound was prepared using the same methodology shown for Example 134, with hexamethyleneimine substituted for N-methylethylenediamine. ES-MS: (M+H)+ 481,483 (Br pattern).
Br 250 PCT/USOO/25195 Example 143 f Br The title compound was prepared using the same methodology shown for Example 134, with 1-methylhomopiperazine substituted for N-methylethylenediamine. ES-MS: (M+H)* 496,498 (Br pattern).
Example 144.
Br The title compound was prepared using the same methodology shown for Example 134, with dimethylamine (2M in THF) substituted for N-methylethylenediamine. ES-MS: (M+H)+ 427,429 (Br pattern). 251 PCT/USOO/25195 Example 145 H Br The title compound was prepared using the same methodology shown for Example 134, with ammonium acetate substituted for N-methylethylenediamine. ES-MS: (M+H)+ 399, 401 (Br pattern). 2'-N-tert-butylaminosulfonyl-[l,r]-biphenyl-4-ylamine (50 mg, 0.16 mmol) was dissolved in 1 mL dry DCM. To this stirred solution was added Me3Al (2.0M, 0.4 mL, 0.8 10 mmol). The mixture was stirred for 30 minutes. To it was added a solution of commercial ethyl 1 -(6-chloro-1,3 -benzothiazol-2-yl)-3-methyl-1 H-pyrazole-5 -carboxylate (50 mg, 0.16 mmol) in 2 mL DCM. The resulting mixture was stirred for 4 hours. After quenched with saturated Rochelle's salt aq solution, this reaction was diluted with DCM. The mixture was washed with brine (X2), dried, evaporated in vacuuo and exposed to 3 mL 15 TFA. After stirring overnight, the reaction mixture was evaporated and purified with reverse-phase prep HPLC to afford the title compound in 55% yield. ES-MS: (M+H)+ 524 (Q pattern).
Example 146. a WO 01/19798 PCT/USOO/25195 252 BIOLOGICAL ACTIVITY EXAMPLES Evaluation of the compounds of this invention is guided by in vitro protease activity assays (see below) and in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters.
The compounds of the present invention are dissolved in buffer to give solutions containing concentrations such that assay concentrations range from 0 to 100 |iM. In the assays for thrombin, prothrombinase and factor Xa, a synthetic chromogenic substrate is added to a solution containing test compound and the enzyme of interest and the residual catalytic activity of that enzyme is determined spectrophotometrically. The IC50 of a 10 compound is determined from the substrate turnover. The IC50's concentration of test compound giving 50% inhibition of the substrate turnover. The compounds of the present invention desirably have an IC50 of less than 500 nM in the factor Xa assay, preferably less than 200 nM, and more preferred compounds have an IC50 ab°ut 100 nM or less in the factor Xa assay. The compounds of the present invention desirably have 15 an IC50 of less than 4.0 fiM in the prothrombinase assay, preferably less than 200 nM, and more preferred compounds have an IC50 of about 10 nM or less in the prothrombinase assay. The compounds of the present invention desirably have an IC50 of greater than 1.0 jiM in the thrombin assay, preferably greater than 10.0 jiM, and more preferred compounds have an IC50 °f greater than 100.0jiM in the thrombin assay.
Amidolvtic Assays for determining protease inhibition activity The factor Xa and thrombin assays are performed at room temperature, in 0.02 M Tris HCl buffer, pH 7.5, containing 0.15 M NaCl. The rates of hydrolysis of the para-nitroanilide substrate S-2765 (Chromogenix) for factor Xa, and the substrate Chromozym 25 TH (Boehringer Mannheim) for thrombin following preincubation of the enzyme with inhibitor for 5 minutes at room temperature, and were determined using the Softmax 96-well plate reader (Molecular Devices), monitored at 405 nm to measure the time dependent appearance of p-nitroaniline.
WO 01/19798 PCT/USOO/25195 253 The prothrombinase inhibition assay is performed in a plasma free system with modifications to the method described by Sinha, U. et al., Thromb. Res., 25,427-436 (1994). Specifically, the activity of the prothrombinase complex is determined by measuring the time course of thrombin generation using the p-nitroanilide substrate 5 Chromozym TH. The assay consists of preincubation (S minutes) of selected compounds to be tested as inhibitors with the complex formed fiom factor Xa (0.S nM), factor Va (2 nM), phosphatidyl serine:phosphatidyI choline (25:75,20 jiM) in 20 mM Tris-HCl buffer, pH 7.5, containing 0.15 M NaCl, 5 mM CaCl2 and 0.1% bovine serum albumin. Aliquots fiom the complex-inhibitor mixture are added to prothrombin (1 nM) and Chromozym 10 TH (0.1 mM). The rate of substrate cleavage is monitored at 405 nm for two minutes.
Eight different concentrations of inhibitor are assayed in duplicate. A standard curve of thrombin generation by an equivalent amount of untreated complex are used for determination of percent inhibition.
Antithrombotic Efficacy in a Rabbit Model of Venous Thrombosis A rabbit deep vein thrombosis model as described by Hollenbach, S. et al., Thromb. Haemost. 71,357-362 (1994), is used to determine the in-vivo antithrombotic activity of the test compounds. Rabbits are anesthetized with I.M. injections of Ketamine, Xylazine, and Acepromazine cocktail. A standardized protocol consists of insertion of a thrombogenic cotton 20 thread and copper wire apparatus into the abdominal vena cava of the anesthetized rabbit A non-occlusive thrombus is allowed to develop in the central venous circulation and inhibition of thrombus growth is used as a measure of the antithrombotic activity of the studied compounds. Test agents or control saline are administered through a marginal ear vein catheter. A femoral vein catheter is used for blood sampling prior to and during steady state infUsion of test 25 compound. Initiation of thrombus foimation begins immediately after advancement of the cotton thread apparatus into the central venous circulation. Test compounds are administered from time = 30 min to time =150 min at which the experiment is terminated. The rabbits are euthanized and the thrombus excised by surgical dissection and characterized by weight and histology. Blood samples are analyzed for changes in hematological and coagulation 30 parameters.
WO 01/19798 PCT/USOO/25195 254 Effects of Compounds in Rabbit Venous Thrombosis model Administration of compounds in the rabbit venous thrombosis model demonstrates antithrombotic efficacy at the higher doses evaluated. There are no significant effects of the 5 compound on the aPTT and FT prolongation with the highest dose (100 |*g/kg + 2.57 Hg/kg/min). Compounds have no significant effects on hematological parameters as compared to saline controls. All measurements are an average of all samples after steady state administration of vehicle or (D)-Arg-Gly-Arg-thiazole. Values are expressed as mean + SD.
Without further description, it is believed that one of ordinary skill in the art can, using 10 the preceding description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention. All 15 the patents, journal articles and other documents discussed or cited above are herein incorporated by reference.

Claims (11)

255 WHAT IS CLAIMED IS:
1. A compound of the formula (I): A-Q-D-E-G-J-X wherein: A is a member selected from the group consisting of -C(=NR2)N(R2,R3) and phenyl, which is independently substituted with 0-2 R1 substituents; each R1 is independently selected from the group consisting of Halo, -CN, -C(=0)-N(R2, R3), -N02, -S02N(R:, R3), -S02R2, -(CH2)mNR2R3, -(CH2)m-C(=NR3)-R2, -(CH2)m-C(=NR2)-N(R2,R3), -(CH2)m-N(R2)-C(=NR2)-N(R2,R3), ' -(CH2)mNR2-C3.6heterocyclics, CMalkyl, Ci^alkenyl, C^alkynyl. Cj.gcycloalkyl, Co^alkylCj-gcycloalkyl. -CF3, -OR2, and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms each independently selected from the group consisting ofN, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic system may be independently replaced with a member selected from the group consisting of halo, Ci_4alkyl-CN, CMalkyl, Ci-salkenyl, C2-6alkynyl, Cs-gcycloalkyl, Co^alkylCj.gcycloalkyl and -N02; each of R2 and R3 are independently selected from the group consisting of -H, -ORa, -N(-Ra, -Rb), -CMalkyl, -C2.6alkenyl, -C2.6alkynyl, -C3.8cycloalkyl, -Co-4alkylC3-8cycloalkyl, -Co.4alkylphenyl and -Co^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, Ci_4alkyl-CN, -CMalkyl, -C2.6alkenyl. -C2-6alkynyl, -Cj.scycloalkyi, -Co-4alkylC3_8cycloalkyl, -CN, and -NO?; or R2 and R3 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms each independently selected from the group consisting ofN, O and S, wherein from 1-4 intellectual property office of n.z. 12 AUG 2003 RECEIVED 256 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, C].4alkyl-CN, -CMalkyl, -C^alkenyl, -Cn^alkynyl, -C.^cycloalkyl, -Co-4alkylC3.8cycloalkyl and -N02; each of Ra and Rb are independently selected from the group consisting of -Ci.4alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-scycloalkyl, -Co^alkylCj-scycloalkyl, or Ra and Rb can be taken together with a nitrogen atom to which they are attached to form a 3-8 heterocyclic ring sytem containing 1-4 heteroatoms each independently selected from the group consisting ofN, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, -CN, -CMalkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-8cycIoalkyI, -Co^alkylCs.gcycloalkyl and -NO2; m is an integer of 0-2; Q is a direct link D is a phenyl, which is independently substituted with 0-2 Rla substituents; each Rla is independently selected from the group consisting of halo, CMalkyl, C2-6alkenyl, C2-6alkynyl, C3.scycloalkyI. Co-4alkylC3.gcycloalkyI, -CN, -N02, (CH2)nNR2aR3a. S02NR2aR3a, S02R2a, CF3, OR2a, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms each independently selected from the group consisting ofN, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, CMalkyl, Co^alkenyl, C2-6alkynyI, Cs.scycloalkyl, Co-4alkylC3.gcycloalkyl, -CN and -N02; R2a and R3a are independently selected from the group consisting of -H, CMalkyl. Ci-ealkenyl, C2_oalkynyl, C3_8cycloalkyl, Co-4alkylC3_8cycloalkyl, Co-4alkylphenyl and Co-4alkylnaphthyl, wherein from 1 -4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, CMalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, Co-4alkylC3.8cycloalkyl, -CN and -NO2; n is an integer of 0-2; E is -NH-C(=0)-; intellectual property office of n.z. 12 AUG 2003 RECEIVED 257 G is a pyrazolyl, which is substituted with 0-2 Rlb groups; each Rlb is independently selected from the group consisting of halo, -Ci_6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3.8cycloalkyl, -Co^alkylCs-scycIoalkyl, -Ci.4alkyl-C(=0)-0H, -CN, -COOR2b, -CONR2bR3b, -N02, -S(=0)2-0H, -N(-R2b, -R3b), -C(=0)-N(-R2b, -R3b), -S(=0)2-N(-R2b, -R3b), -S(=0)2-R2h. -CF3, -0-R2b, -0-CH2-CH2-0-R2b,-0-CH2-C(=0)-0-R2b,-N(-R2b)-CH2-CH2-0-R2b, -N(-CH2-CH2-0-R2b)2, -N(-R2b)-C(=0)-R3b, -N(-R2b)-S(=0)2-R3b, and a 5-6 membered heterocyclic ring containing 1 -4 heteroatoms each independently selected from the group consisting ofN, O and S substituted with 0-4 Rlb groups; each of R2b and R3b are independently selected from the group consisting of -H, -Ci-6alkyl, -Ci.6alkyloxy, -C2-6alkenyl, -C2-6alkynyl, -C3-8Cycloalkyl, -Co-6alkylC3.8cycloalkyl and -Co-6alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may each be independently replaced with a member selected from the group consisting of halo, -Ci^alkyl, -C2-6alkenyl, -C2.6alkynyl, -C3.8cycloalkyl, -Ccutalky^.gcycloalkyl, -S(=0)2-0H, -CN, -CF3 and -N02; J is a direct link; X is a naphthyl. which is substituted with 0-3 Rlc groups; each Rlc is independently selected from the group consisting of halo, -CF3, -Ci-6alkyl, -C2-6alkenyl, -Co^alkynyl, -C3.8cycloalkyl, -Co.6alkylC3.gcycloalkyl, -Ci.4alkyl-C(=0)-0H, -CF3, -CN, -N02, -(CH2)Z-N(-R2c, -R3c), -C(=0)-N(-R2c, -R3c), -C(=NH)-N(-R2c, -R3c), -C(=NMe)-N(-R2c, -R3c), -S(=0)2-N(-R2c, -R3c), -S(=0)2-R2c. -S(=0)2-0H, -CF3, -0-R2c, -0(-CH2)z-0-R2c, -0(-CH2)z-C(=0)-0-R2c, -N(-R2c), -0(-CH2)z-0-R2c, -N[(-CH2)z-0-R2c]2, -(CH2)z-N(-R2c)-C(=0)-R3c, -(CH2)z-N(-R2c)-S(=0)2-R3c, and a 5-6 membered heterocyclic ring containing 1 -4 heteroatoms each independently selected from the group consisting ofN, O and S, wherein Rlc is other than -(CH2)z-N(-R2c, -R3c) and -N(-R2c) when A is phenyl; z is an integer of 0-4; R2c and R3c are independently selected from the group consisting of -H, -C|_6alkyl, -Ci.6aIkyloxy, -C2-6alkenyl, -C2-6alkynyl, -C3.8cycloalkyl, -Co-6alkylC3.scycloalkyl intellectual property office of n.z. 12 AUG 2003 RECEIVED 258 and -Co-6alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety may be independently replaced with a member selected from the group consisting of halo, -CMalkyl, -C2-6alkenyI, -C2-6aIkynyl, -C3.scycloalkyl, -Co^alkylCj.gcycloalkyl, -S(=0)2-0H, -CN, -CF3 and -NO2; and all pharmaceutically acceptable isomers, salts, hydrates and solvates thereof.
2. A compound of claim 1, wherein: A is phenyl, which is substituted with 0-2 R1 groups; R1 is independently selected from the group consisting of halo, -CMalkyl, -CN, -NO2, -(CH:)m-N(-R>R3), -C(=0)-N(-R2,-R3), -S(=0)2-N(-R2,-R3), -S(=0):-R2, -(CH2)m-C(=NR3)-R2, -(CH2)m-C(=NR2)-N(R2,R3), -(CH2)m-N(R2)-C(==NR2)-N(R2,R3), -CF3, -(CH2)m-0-R2 and a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms each independently selected from the group consisting ofN, O and S; each of R2 and R3 are independently selected from the group consisting of -H and -cmalkyl; or R2 and RJ taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 3 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1 -4 heteroatoms each independently selected from the group consisting ofN, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo. Ci-Ci-alkyl-CN. -CMalkyl, -C2-6alkenyl, -C2.6alkynyl, -Ci.gcycloalkyl, -QualkylCs-scycloalkyl and -NO?; m is an integer of 0-2; Q is a direct link; D is phenyl, which is substituted with 0-2 Rla groups; Rla is independently selected from the group consisting of halo, -CMalkyl, -CN, -NO2, -(CH2)n-N(-R2a, -R3a), -S(=0)2-N(-R2\ -R3a), -S(=0)2-R2a, -CF3, -(CH2)„-OR2a, -C(=0)-0-R2a, -C(=0)-N(-R2a, -R3a) and a 5-6 membered aromatic heterocyclic intellectual property OFFICE OF N.Z. 12 AUG 2003 RECEIVEP 259 ring containing 1 -4 heteroatoms each independently selected from the group consisting ofN, O and S; n is an integer of 0-2;. R2a and R3a are independently selected from the group consisting of -H, -CF3 and -CMalkyl; E is -NH-C(=0)-; G is a pyrazolyl, substituted with 0-2 Rlb groups; each Rlb is independently selected from the group consisting of halo, -CMalkyl, -CN, -N02, -N(-R2b, -R3b), -C(=0)-N(-R2b, -R3b), -S(=0):-N(-R2b. -R3b), -S(=0)2-R2b, -CF3, -0-R2b, -0-CH2-CH2-0-R2b, -0-CH2-C(=0)-0-R2b, -N(-R2b)-CH2-CH2-0-R2b,-N(-CH2-CH2-0-R2b)2,-N(-R2b)-C(=0)-R3b, -N(-R" )-S(=0)2-R and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms each independently selected from the group consisting ofN, O and S; each of R2b and R3b are independently selected from the group consisting of -H, -CF3, -C|.4alkyl and -Ci.4alkyI-(carbocyclic aryl); J is a direct link; X is naphthyl, which is substituted with 0-3 Rlc groups; each Rlc is independently selected from the group consisting of halo, -CMalkyl, -CN, -N02, -(CH2)z-N(-R2c, -R3c), -C(=0)-N(-R2c, -R3c). -C(=NH)-N(-R2c, -R3c), -C(=NMe)-N(-R2c, -R3c), -S(=0)2-N(-R2c, -R3c), -S(=0)2-R2c, -S(=0)2-0\ -CF3, -0-R2c, -0-CH2-CH2-0-R2c, -0-CH2-C(=0)-0-R2c, -N(-R2c)-CH2-CH2-0-R2c, -N(-CH2-CH2-0-R2c)2, -(CH2)z-N(-R2c)-C(=0)-R3c, -(CH2)z-N(-R2c)-S(=0)2-R3c, and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms each independently selected from the group consisting ofN, O and S; z is an integer of 0-2; and each of R2c and R3c are independently selected from the group consisting of -H, -CMalkyl and -CMalkyl-(carbocyclic aiyl).
3. A compound of claim 1, wherein: intellectual property office of n.z. 12 AUG 2003 RECEIVED 260 A is selected from the group consisting of: Me Q is a direct link; D is selected from the group consisting of: F F E is -NH-C(=0>; G is a member selected from the group consisting of: Rlb is independently selected from the group consisting of-H, -Me, -CF3, -F. -CI. -Br, -S02Me, -CM, -CONH2, -CONMe2, -NH2, -N02, -NHCOMe, -NHS02Me, -CH2NH2 and -C02H; J is a direct link; and intellectual jr°pekty OFFICE OF N.Z. 12 AUG 2003 RECEIVED 261 X is selected from the group consisting of: INTELLECTUAL PROPERTY OFFICE OF N.Z. 12 AUG 2003 RECEIVED 262 YYl Tfl Tfl Me02S^^^T Me02S''^^XI Me02S"^k-^Br Me02S YTY" YYV YY^ Me02S^^^ MeOzS^^^ h2n02s"^^t h2n02sa^^!#^ci "NlT^T^Tcl hjnozs^^^br h2n02s'^#^ h2n02s'^v^ h2n02s' "vv^ w% vvvf 02njs^s^f o2n^uci 02n'^s^s^br 02n ii :i i° YYV YTl Y^ 02N^^ 02N^^ mc^^y nc^^^ci vv% w\ nca^kabr MC f yy^y01 x|^v^v^br nc- f h2noc'^^t h2noc^^s^ci ^noc^^sr h2noc'^^x^ ...pea, ^OX w'«' w>»° :>»* H)SAL PROPERTY-OFFICE OF N.Z. 12 AUG 2003 263 V^!| ho HO TYY YTY0r MeO CI HO^^^^Br HO' F MeO' CI MeO 3 Br MeO' MeO' racl MeO doc* h2n h2n F H2N ci Me02S Me02S I H2N h2n xxxBr Me02S Br h2n F ci F MeOzS^^^F H2N02S Br F Me02S F ■01 Me02S ci YYt Br ci yyy CI Me02S Br ci Br MeOgS^^^Br Me02S^^^Br H2N02S ci F H2N02S Br F H2N02S CI H2N02S F ci ci H2N02S o2n o2n Br CI H2N02S F F CI CI 02n^kAF YY^fBr 02n'^s^ci Br H2N02S CI o2n o2n ci Br H2N02S Br F Br 02n 02n Br Br ; ci Br <»?XC NC Br XXX JCCX intellectual property OFFICE OF N.Z. 12 AUG 2003 RECEIVED 264 nc nc hznoc' -F T •CI NC^ ^kAC| .CI Br NC^ Br rvY LF H2NOC v^r ■Br ci nc vx f hznoc^^^f h2noc YXY" oc^^xi h2noc ■ci v^/v Br 11 H2N0CBX h>nocUA ' h2noc h2nh2(p^^f h2nh2c'j!^!s1x^f h2nh2c h2nh2c Br 'CI ■f jooc XY^fBr h2nh2c^s^x^ci h2nh2c ' h2nh2c '
4. A compound of claim 1, wherein: A is phenyl, which is substituted with 0-2 R1 groups; each R1 is selected from the group consisting of -S(=0)2-N(-R2, -RJ), -S(=0)2-R2. -CH2N(-R2, -R3), -CN and halo; each of R2 and R3 are independently selected from the group consisting of -H and -CMalkyl; INTELLECTUAL PROPERTY OFFICE OF N.Z. 12 AUG 2003 RECEIVED 265 Q is a direct link; D is phenyl, which is substituted with 0-2 Rla groups; each Rla is selected from the group consisting of -H and halo; E is -NH-C(=0)-; G is pyrazole, substituted with 0-2 Rlb groups; each Rlb is selected from the group consisting of -Me, -Et, -CF3, -C(=0)-NH2, -NH?, -NH-C(=0)-Me, -NH-S(=0)2-Me, -SMe-S(=0)2-Me and halo; J is a direct link; X is naphthyl, which is substituted with 0-3 Rlc groups; each Rlc is independently selected from the group consisting of -H, halo, -Me, -CF3, -OH, -OMe, -NH2, -CN, -N02, -CH2-R2c, -C(=0)-N(-R2c, -R3c), -S(=0)2-R2c, -S(=0)2-N(-R2c, -R3c), -S(=0)2-0H, -C(=NH)-N(-R2c, -R3c), 2-imidazolin-2-yl and l-methyl-2-imidazolin-2-yl; and each of R2c and R3c are independently selected from the group consisting of -H, -OH, -NH2 and -CMalkyl, wherein Rlc is other than -CH2-NH2.
5. A compound of claim 1, according to the formula: wherein: R1 is selected from the group consisting of -S02NH2, -S02Me, -CH2NH2 and -CH2NMe2; Rla is selected from the group consisting of -H, -F, -CI and -Br; Rlb is selected from the group consisting of -CH3, -CF3, -CH2CH3, -S02Me, -CONH? and -NHS02Me; Rlcl is selected from the group consisting of -H, -F, -CI, -Br, -NH2, -OH, -S02Me, -S02Et, -S02NH2, -N02, -CN, -CONH? and -CH2OH; and Rlc2 is selected from the group consisting of -H, -F. -CI and -Br. intellectual property office of n.z. 12 AUG 2003 RECEIVED 266
6. A compound of claim 1, according to the formula: — R1«2 wherein: A-Q is selected from the group consisting of: ^ o- a o a l * \ \ Me Et Me Et CH3 XH a-L wherein: A is selected from the group consisting of: Me Et Me. N— \|— XN— .! / ! / / H H H Me Me Me | \ E,v Et, \ A N_ N— N— [>— [>— <)N- <JN— s Me' Et Me Me MeK)N- Cn- C/- 0~ o O- Me-0- Mev/ \ J \ /~\ / \ / \ / \ JX N— O N— s N— 0,s N— HN N— Me—N N— m /w v_y \ / \_v \_^ O O O O Ot>- ; Rla is selected from the group consisting of -H, -F, -CI and -Br; Rlb is selected from the group consisting of -Me, -CF3, -Et, -S02Me, -CONH? and -NHSOiMe; R,cl is selected from the group consisting of -H, -F, -CI, -Br, -NH?, -OH, -S02Me, -S02Et, -SO2NH2, -N02, -CN, -CONH? and -CH2OH; Rlc2 is selected from the group consisting of -H, -F, -CI and -Br; and Rlc3 is selected from the group consisting of -H, -F, -CI and -Br. intellectual property office of n.z. 12 AUG 2003 RECEIVED 267
7. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1.
8. Use of a compound of claim 1 for the manufacture of a medicament for preventing or treating a condition in a mammal characterized by undesired thrombosis.
9. The use of claim 8, wherein the condition is selected from the group consisting of: acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices.
10. Use of a compound of claim 1 for the manufacture of a medicament for inhibiting the coagulation of biological samples.
11. A compound of the formula (I) substantially as herein described with reference to the accompanying Tables. intellectual property office of n.z. 12 au6 2003 RECEIVED END
NZ517828A 1999-09-17 2000-09-15 Inhibitors having activity against mammalian factor Xa NZ517828A (en)

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