CZ20003687A3 - Methods for inhibiting MRP1 - Google Patents

Abstract

The present invention relates to compounds of formula (I) useful for inhibition resistant neoplasms where resistance is partially or completely caused by MRP 1.

Description

Methods of MRP1 inhibition

Technical field

The invention relates to novel methods of inhibiting MPR1.

BACKGROUND OF THE INVENTION

Along with surgery and radiotherapy, chemotherapy continues to be used as an effective method for the treatment of many cancers. In fact, several types of cancers that are treatable by chemotherapy are already known. These cancers include Hodgkins disease, large cell lymphoma, acute lymphocytic leukemia, testicular cancer, and early stage breast cancer. Other cancers, such as ovarian cancer, small lung cells and advanced breast cancer, are not yet treatable but show a positive response to combination chemotherapy.

One of the most important, yet unresolved, problems in the treatment of cancer is drug resistance. Upon selection by resistance to a single cytotoxic drug, the cells can become bulk resistant to a whole set of drugs with different structures and cellular targets. Such files are, for example, alkylating agents, antimetabolites, hormones, platinum-containing active substances and natural products. This phenomenon is known as multidrug resistance (MDR). In some cell types, this resistance is inherent, while in others, such as small cell lung cancer, it is usually acquired.

This resistance is known to be multifactorial and is conferred by at least two proteins, namely: 170 kDa P glycoprotein (MDR1) and a more recently identified 190 kDa multidrug resistance protein (MRP1). Although both MDR1 and MRP1 belong to a group of transport proteins called ATP-binding cassettes, their molecules are structurally very different and share less than 15% amino acid homology. Although the structure of these proteins differs from each other, there have been no consistent differences since 1994.

in the mechanisms of resistance of MDR1 and MRP1 cell lines. However, there are known cases of correlation as well as cases of independence between MRP1 and resistance to specific oncolytics. See Cole, et. al., Pharmacological Characterization of Multidrug Resistant MRP-transfected Human Tumor Cells, Cancer Research, 54: 5902-5910, 1994. Doxorubicin, daunorubicin, epirubicin, vincristine and etoposide are substrates of MRP1, ie, MRP1 can bind to these oncolytics and redistribute is away from their site of action, which is the cell nucleus and out of the cell. Id. and Marquardt, D. and Center, M. S., Cancer Research, 52: 3157, 1992.

Doxorubicin, daunorubicin and epirubicin are members of the anthracycline class of oncolytics. They isolate various strains of Streptomyces and inhibit nucleic acid synthesis. These agents are useful in the treatment of neoplasms of bone, ovaries, bladder, thyroid, and especially the breast. They are also useful in the treatment of acute lymphoblastic and myeloblastic leukemia, Wilm's tumor, neuroblastoma, sarcoma, Hodgkins and non-Hodgkins lymphomas, and bronchogenic carcinoma.

Vincristine, a member of the vinca-alkaloid oncolytic class, is an isolate of known flowering periwinkle plants (Vinca-rosea Linn). The mechanism of action of vincristine is still being investigated but is already known to be related to the inhibition of microtubule formation in the mitotic process. Vincristine is used in the treatment of acute leukemia, Hodgkins disease, non-Hodgkins malignant lymphomas, rhabdomyosarcoma, neuroblastoma and Wilm's tumor.

Etoposide, a member of the epipodophyllotoxin oncolytic class, is a semisynthetic derivative of podophyllotoxin. Etoposide acts as a topoisomerase inhibitor and is useful in the treatment of testicular and lung neoplasms.

It is currently unknown what determines whether the cell line acquires resistance via the MDR1 or MRP1 mechanism. Given the specificity of the tissues of these transporters and / or if one mechanism predominates or is the only one, it would be useful to have a selective inhibitor that would be - - - · ··· ····· ····· · «« · Dampened one mechanism over another. Furthermore, when administering an active substance (s) having the character of a particular protein, it would be particularly advantageous to administer a selective inhibitor of the protein with them. For these reasons, it is desirable to find compounds that are selective inhibitors of MDR1 or MRP1.

SUMMARY OF THE INVENTION

The invention relates to compounds of formula I:

R is (CH _{2) m} CHRNHR ² O (CH 2) 2 NHR ^2, (CH 2) _m COR ^3, NHR ^2, and (CH _{2) m} CHR ¹ NR ⁴ R ^5;

R 1 is hydrogen, hydroxy or O (C 1 -C 6 alkyl optionally substituted with phenyl or C 3 -C 7 cycloalkyl);

m and m 'are independently 0, 1 or 2 in each case; R ¹ is independently at each occurrence hydrogen or C 1 -C 6 alkyl;

R ² is hydrogen, COR ⁶ , CH ² R ⁶ , SO ² R ⁷ or a group of formula • NH ⁴ R ⁷

R ³ is hydrogen, hydroxy, C 1 -C 6 alkoxy amino ester amino acid or NR ⁴ R ⁵ ;

R ⁴ is hydrogen or C 1 -C ₆ alkyl;

• ·. www ·· ** «» ················

R ⁵ is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 bicycloalkyl, CH 2 CH (CH 3) phenyl, CH (CH 3) CH 2 CO 2 R 'aryl, substituted aryl, (CH 2) n CHR ⁸ NHC (O) OC (CH 3) ₃ ·, ₂ ) _n NH ₂ , (CH ₂ ) ₂ NHCOR ⁶ , (CH ₂ ) ₂ OH, (CH ₂ ) _q -heterocycle, (CH ₂ ) _q substituted heterocycle, or

R ⁴ and R ⁵ together form a pyrrolidin-1-yl, piperidin-1-yl, hex amethylenimine-1-yl or morpholin-4-yl ring;

n is 1, 2, 3 or 4;

q is 0, 1, 2, or 3;

R ⁶ is C 1 -C ⁶ alkyl, substituted C ₃ -C ₆ cycloalkyl aryl, substituted aryl, tert-butoxy, (CH ₂ ) _q -heterocycle, (CH ₂ ) _q - substituted heterocycle, (CH ₂ ) n S (O) _r R 1, C (CH ₃ ) ₂ CH ₂ N (R 1) ₂ , (CH ₂ ) _n CHR ₈ NHC (O) OC (CH ₃ ) ₃ , (CH ₂ ) _n CHR ₈ NH ₂ , (CH ₂ ) _2NH-aryl, or NHR _7;

R 6 is C 1 -C 6 alkyl, substituted C ₃ -C ₆ cycloalkyl aryl, substituted aryl, (CH ₂ ) q -heterocycle, (CH ₂ ) q -substituted heterocycle, (CH 2 SCOKR ¹ , C (CH ₃ ) 2 CH ₂ N (R) _2, (CH _{2) n} CHR ₈ NHC (O) OC (CH3) ₃ · (CH _{2) 8} NH ₂ NCHR or (CH _{2) 2} NH-aryl;

r is 0, 1 or 2;

R ⁷ is C 1 -C 6 alkyl, phenyl or substituted phenyl; and

R is hydrogen or CO ₂ R; or a pharmaceutical salt or solvate thereof.

The invention further relates to a method of inhibiting MRP1 in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of Formula I or a pharmaceutical salt or solvate thereof.

In another embodiment, the invention relates to a method of inhibiting a resistant neoplasm or a susceptible neoplasm in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of formula I or a pharmaceutical salt or solvate thereof in combination with an effective amount of an oncolytic agent. .

The invention also relates to a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutical salt or solvate thereof, in combination with one or more oncolytics, pharmaceutical carriers, diluents or excipients therefor.

The invention relates to the discovery that a selected group of compounds having formula I has been found to be a group of selective inhibitors of multidrug resistant protein (MRP1) and are therefore useful in the treatment of MRP1 acquired multidrug resistance (MDR) resistant neoplasm and neoplasm susceptible to resistance.

The terms inhibiting MRP1 and inhibiting MRP1 mean preventing, mitigating, ameliorating, stopping, preventing, slowing or reversing the development or diminishing the ability of MRP1 to redistribute the oncolytic away from its site of action, most commonly from the neoplasmic nucleus and away from the cell.

As used herein; the term effective amount of a compound of formula I means an amount of a compound of the invention that is capable of inhibiting MRP1. The term effective amount of an oncolytic means an amount of an oncolytic capable of inhibiting the neoplasm, inhibiting its resistance, or otherwise.

The term inhibiting a resistant neoplasm or a susceptibility of a neoplasm to resistance means preventing, arresting, suppressing, slowing or reversing the development, reducing the growth or killing of resistant neoplasms and / or neoplasms susceptible to resistance.

The term resistant neoplasm means a neoplasm that is resistant to chemotherapy and its resistance is partially or completely resistant to chemotherapy. MRP1 induced by MRP1. Such neoplasms include, but are not limited to, bladder, bone, breast, lung (small cell), testes, and thyroid neoplasms, and more or less include several types of cancer, including, but not limited to, acute lymphoblastic and myeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue sarcoma, Hodgkins and non-Hodgkins lymphomas, and bronchogenic carcinoma.

A neoplasm that is susceptible to resistance is a neoplasm whose resistance is neither inherent nor present but can be induced by MRP1 upon initiation of chemotherapy. Thus, the methods of the invention include prophylactic and therapeutic administration of a compound of Formula I.

Chemotherapy refers to the use of one or more oncolytics, wherein at least one oncolytic is a substrate of MRP1. And, the MRP1 substrate is an oncolytic that carries MRP1 and is redistributed away from the oncolytic site (neoplasm nucleus) and out of the cells, and thus makes the therapy less effective.

The terms "treat" or "treat" have the meaning commonly used, which includes preventing, preventing, ameliorating, ameliorating, stopping, reducing, slowing or reversing the development or reducing the severity of MRP1-derived multidrug-resistant tumor resistance.

In the general formula herein, general chemical terms have the usual meanings. For example, the term C 1 -C 4 alkyl means methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, cyclobutyl, s-butyl and t-butyl. The term C 1 -C ₆ alkyl means a monovalent, linear, branched or cyclic saturated hydrocarbon containing from 1 to 6 carbon atoms and contains C 1 -C 4 alkyl groups. Further, C 1 -C 6 alkyl also includes, but is not limited to, cyclopentyl, pentyl, hexyl, cyclohexyl, and the like. The term C3-C6 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term C 5 -C 7 cycloalkyl means up to cyclopentyl, cyclohexyl and cycloheptyl.

• ·

The term C 6 -C 10 bicycloalkyl means up to bicyclo- [2,1,1] hexanyl, [2,2,1] heptanyl, [3,2,1] octanyl, [2,2,2] octanyl, [3,2,2] nonanyanyl , [3,3,1] nonanyanyl, [3,3,2] decanyl and [4,3,1] decanyl ring system, wherein the ring is attached to the parent molecular moiety at any site suitable for substitution on the ring.

The term C 1 -C 4 alkoxy and Ci-Cg alkoxy groups are vzqrce O- _(Ci-C4 alkyl) and O- _(Ci-C6 alkyl).

Substituted C3-C6 cycloalkyl is C3-C6 cycloalkyl substituted with one phenyl, substituted phenyl or the group CO ₂ R.

The term halogen or halide means fluorine, chlorine, bromine and iodine.

The term aryl means phenyl, benzyl and naphthyl. The term substituted aryl means phenyl, benzyl and naphthyl, optionally substituted 1-5 times independently with a group selected from the group consisting of Ci-Ce alkyl, halogen, hydroxy, trifluoromethyl, N ^(R) 2, ^1-SCLNÍR, NH- Pg, C 1 -C 6 alkoxy, benzyloxy, CO ² R ¹ , C 5 -C 7 cycloalkyl, trifluoromethoxy or nitro.

The term heterocycle means a monovalent, saturated, unsaturated or aromatic monocyclic or fused ring system having a total of 5 to 7 or 8 to 10 atoms, optionally containing 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen.

The term substituted heterocycle means a heterocyclic ring substituted 1 or 2 times independently with a group selected from the group consisting of a C 1 -C 5 alkyl, halogen, benzyl, phenyl, trifluoromethyl or oxo group.

• ·

The term amino acid as used herein means N-terminally linked glycine, valine, methionine, phenylalanine, tryptophan, proline aspartic acid, and glutamic acid.

The term aminoester as used herein means an amino acid wherein the carboxy groups of each (aspartic acid and glutamic acid have two, while the others have only one carboxy group in the molecule) are substituted with a C 1 -C 6 alkyl group. That is, an alkyl group, when taken together with a carboxy group, forms a C 1 -C 6 alkyl ester.

The term protecting group or Pg means an amino protecting group or a hydroxy protecting group. The types of protecting groups are apparent from whether the Pg group is attached to a nitrogen atom (amino protecting group) or an oxygen atom (hydroxy protecting group).

The term amino protecting group as used herein means amino substituent (s) commonly used to block or protect an amino function while other functional groups react on the same compound. Examples of these amino-protecting groups are formyl, trityl, phthalimido, acetyl, trichloroacetyl, chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC) and the like; and similar amino protecting groups. The particular protecting group that is used to protect the amino group is not critical since the attached amino group is stable at the subsequent reaction site (s) at other sites in the molecule and can be removed at any location without breaking the molecule. The terms also include similar amino protecting groups used for cephalogensporin, penicillin, and peptide products. Further examples of groups that are encompassed within the scope of these terms are described in T.W. Greene, Protective Groups ·····································

Organic Synthesis, John Wiley & Sons, New York, NY, 1991, Chapter 7, which is incorporated herein by reference. Greene note. A preferred amino protecting group is t-butyloxycarbonyl.

The term hydroxy protecting group refers to a group known to one skilled in the art of organic chemistry described in Chapter 2, Greene. Representative hydroxy protecting groups are, for example, ether groups including methyl and substituted methyl ether groups such as methyl ether, methoxymethyl ether, methylthiomethyl ether, tert-butylthiomethyl ether, (phenyldimethylsilyl) methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether and tert-butoxymethyl ether; substituted ethyl ether groups such as ethoxyethyl ether, 1- (2-chloroethoxy) -ethyl ether, 2,2,2-trichloroethoxymethyl ether and 2 (trimethylsilyl) ethyl ether; isopropyl ether groups; phenyl and substituted phenyl ether groups such as phenyl ether, p-chlorophenyl ether, pmethoxyphenyl ether and 2,4-dinitrophenyl ether; benzyl and substituted benzyl ether groups such as benzyl ether, pmethoxybenzyl ether, o-nitrobenzyl ether and 2,6dichlorobenzyl ether; and alkylsilyl ether groups such as trimethyl triethyl and triisopropylsilyl ethers, mixed alkylsilyl ether groups such as dimethylisopropylsilyl ethers and diethylisopropylsilyl ethers; and ester protecting groups such as formate ester, benzyl formate ester, mono- di- and trichloroacetate esters, phenoxyacetate ester and pchlorophenoxyacetate and the like. The types of hydroxy protecting groups to be used are not critical since the bonded hydroxy group is stable under subsequent reaction (s) at other sites of the molecule and can be removed at any location without breaking the molecule without disrupting the rest of the molecule including any other hydroxy protecting group (s).

The term carbonyl activating group means a carbonyl substituent that causes the carbonyl fragment to tend to undergo nucleophilic addition. Suitable activating groups are those having the ability to tear off an electron on a carbonyl. Among these groups floor, inter alia, alkoxy · alko alko alko * alko * * * * * * skupiny xy skupiny skupiny skupiny skupiny skupiny skupiny skupiny skupiny skupiny patře Aryloxy aromatic heterocycle containing nitrogen or amino groups such as oxybenzotriazole, imidazolyl, nitrophenoxy, pentachlorophenoxy, N-oxysuccinimide, N, N'-dicyclohexylisoure-O-yl, N-hydroxy-N -methoxyamino and the like; acetates, formates, sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenylsulfonate and the like; and halides especially chloride, bromide or iodide.

In general, the term pharmaceutical when used as an adjective means substantially non-toxic to living organisms. For example, the term pharmaceutical salt as used herein means salts of compounds of formula I that are substantially non-toxic to living organisms. See, eg, Berge, S.M, Bighley, L.D. and Monkhouse, D.C., Pharmaceutical Salts, J. Phasm. Sci., 66: 1, 1977. Typical pharmaceutical salts are those prepared by reaction of compounds of Formula I with an inorganic or organic acid or base. Such salts are known as acid addition salts or base addition salts. These pharmaceutical salts often have increased solubility as compared to the compound from which they are derived and thus are often refillable to formulations such as liquids or emulsions.

Examples of acid addition salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide acetate, propionate, decanoate, caprylate acrylate, formate, isobutyrate, caproate, hroate oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, tartrate, methylsulfate, ethylsulfate, propylsulfate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like of Formula I.

Examples of pharmaceutical base addition salts are the ammonium, lithium, potassium, sodium, calcium, magnesium, methylamine, diethylamine, ethylenediamine, cyclohexylamine and ethanolamine salts and the like of the formula

The term solvate means an aggregate that contains one or more molecules of a soluble compound (for example a compound of formula I) with one or more solvent molecules.

The term "suitable solvent" means a solvent which is inert to the subsequent reaction and sufficiently dissolves the reactants, thereby positively affecting the desired reaction. Examples of suitable solvents are, but are not limited to, dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether acetonitrile, ethyl acetate, 1,3-dimethyl-2-imidazolidinone, tetrahydrofuran, dimethylformamide, toluene, chlorobenzene, dimethylsulfoxide, mixtures and the like.

The term carbonyl activating agent refers to an agent that converts carbonyl carboxyl groups to those that are more prone to nucleophilic addition, and includes, but is not limited to, agents such as those disclosed in The Peptides, Gross and Meienhofer, Eds. Academy Press (1979), Ch. 2 and M. Bodanszky, Principles of Peptide Synthesis, 2nd Ed., Springer Verlag Berlin Heidelberg, 1993, hereinafter referred to as The Peptides and Peptide Synthesis. Specifically, carbonyl activating agents include nucleophilic halogen sources such as thionyl bromide, thionyl chloride, oxalyl chloride and the like; alcohols such as nitrophenol, pentachlorophenol and the like; amines such as N-hydroxy-N-methoxyamine and the like; acid halides such as formic, methanesulfonic, ethanesulfonic, benzenesulfonic or p-tolylsulfonic acid, halides and the like; and compounds such as 1,1'-carbonyldiimidazole, benzotriazole, imidazole, N-hydroxysuccinimide, dicyclohexylcarbodiimide and the like.

The term suitable thermodynamic base means a base that acts as a proton trap for any protons that may be formed as byproducts of the desired reaction or base that causes reversible deprotonation of the acidic substrate and is sufficiently reactive to cause the desired reaction without appreciably affecting adverse reactions. Examples of thermodynamic bases are, but are not limited to, carbonates, bicarbonates and hydroxides (e.g., lithium, sodium or potassium carbonates, bicarbonates or hydroxides), tri- (C 1 -C ₄ alkyl) amines, or aromatic nitrogen-containing heterocycles (e.g. pyridine).

While all of the compounds of the invention are useful, some of these compounds are of particular interest and are preferred. The following list sets forth some of the groups in preferred compounds, formulations and methods. It is clear that the listed compounds may be combined with each other to form additional groups of preferred embodiments.

a) m is 0 and m 'is 0;

b) m is 0 and m 'is 1;

c) R is in the meta position;

d) R is CHR ¹ HR ² and R ¹ is methyl;

e) R is COR ³ ;

f) R is (CH ₂ ) COR ³ ;

g) R is (CH ₂₎ NR ⁴ R ^5;

h) R 1 is hydrogen;

i) R ² is 4-aminosulfonylbenzyl;

_t A

j) R is 3,4,5-trimethoxybenzyl;

k) R ³ is (3,4,5-trimethoxyphenyl) amino;

l) R ³ is (4-aminosulfonylphenyl) amino;

m) R ³ is (6-methoxyquinolin-8-yl) amino;

n) R ⁴ is hydrogen;

o) R ⁵ is 5-methylisoxazol-3-oyl;

p) R ⁵ is 3,4,5-trimethoxybenzoyl;

q) R ⁵ is 3,5-dimethoxy-4-hydroxybenzoyl;

r) R ⁵ is 3,4,5-trimethoxybenzyl;

s) The compound is a pharmaceutical salt;

t) The compound is the hydrochloride;

u) Compounds exemplified;

• · · · · · · · · · · · · · ·

v) A method wherein the mammal is a human;

w) A method wherein the oncolytic (a) is (are) selected from the group consisting of: doxorubicin, daunorubicin, epirubicin, vincristine and etoposide;

(x) A method comprising a Wilm-type neoplasm, bladder, bone, breast, lung (small cell), testis or thyroid, or a neoplasm associated with acute lymphoblastic and myeloblastic leukemia, neuroblastoma, soft tissue sarcoma, Hodgkins and non-Hodgkins lymphomas or bronchogenic carcinoma; and

y) A formulation in which the oncolytic (s) is (are) selected from the group consisting of: doxorubicin, daunorubicin, epirubicin, vincristine and etoposide.

The compounds of the invention can be prepared in a number of ways, some of which are illustrated in the schemes below. The particular order of steps required to produce a compound of Formula I is dependent upon the particular compound being synthesized, the parent compound, and the relative lability of the substituted groups.

Compounds of formula I may be prepared from compounds of formula II as illustrated in Scheme 1 below, wherein R, R 'and m are as defined above.

* 9 • 9 • 9

Scheme 1

II I

Compounds of formula I may be prepared by dissolving or stirring a compound of formula II in a suitable solvent and adding a suitable thermodynamic base. A commonly preferred and common solvent is dimethylformamide. Typically, a suitable and preferred thermodynamic base is sodium hydroxide added as 2N in methanol. The reactants are typically mixed at room temperature, but the resulting solution is typically heated to a temperature of up to about 30 ° C to about the reflux temperature of the reaction mixture for 30 minutes to about 18 hours. Preferably, the mixture is heated to at least 50 ° C for about 1 to about 6 hours and most preferably heated to about 65 ° C to about 75 ° C for about 1.5 hours to about 3 hours, the base is usually used in bulk. a molar excess, usually in about four to about eight times the molar excess over the compound of formula II. Preferably, the excess is about 5 to about 7. Certain intermediates for the preparation of compounds of Formula I, which are discussed below, can also be prepared by the method discussed above.

Any hydroxy or amino protecting groups found in the cyclized compound of formula I can optionally be removed as explained in Greene to obtain the free amino or free hydroxy compounds of formula I. Preferred options for protecting groups and methods for their removal can be found in the following preparations. and the examples below.

• · · ·

Compounds of formula I where R is (CH _{2) m} -CHR ¹ -NHR ^2, (CH2) mCHR ¹ NR ⁴ R ⁵ or O (CH 2) 2 NHR ² and R ² is CH ₂ R ⁶ can be prepared from a compound of formula I (a) , I (c) or I (e) as illustrated in Scheme 2 below, wherein R ⁹ is a carbonyl activating group and m, m ', R', R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are as described above .

Scheme 2

Compounds of Formula I (a); I (c); or I (e) prepared according to Scheme 1 may be converted to other compounds of the invention: For example, compounds of formula I (a), I (c) and I (d) may be reductively aminated to form compounds of formula I (b), I (d) and I (f). Reductive amination is a well-known transformation, see, e.g., Larock, Comprehensive Organic.

9 · · ······ · · · · ····

..............

Transformations, p. 421, VCH Publishers, New York, N.Y., 1989, referred to herein as Larock. In the context of the invention, reductive amination can be carried out by conventional solutions or by a combination of synthetic methods.

Compounds of formula III, I (c) or I (e) may be dissolved or stirred in a suitable solvent, optionally in the presence of a suitable thermodynamic base, and a compound of formula I (a) or IV is added to prepare the imine intermediate. To accelerate this reaction, a Lewis acid such as titanium (IV) isopropoxide can be used as the catalyst. If it is found that the compound of formula (I) (a) or (IV) is already substantially consumed, the imine intermediate is usually reacted in situ with a suitable reducing agent to give the compound of formula (I) (b), (d) or (f) . The entire conversion can be carried out at about 0 ° C to the boiling point of the mixture, but the preferred reaction temperature is room temperature. The individual steps of imine formation and reduction of imine to amine can take from 15 minutes to 24 hours. Generally, imine formation is generally complete in 15 minutes to an hour, and imine reduction is usually complete in 30 minutes to 2 hours. Usually methanol is used as the preferred solvent.

The thermodynamic base is usually used when the compound of formula III, I (c) or I (e) is an acid addition salt to convert the salt to the corresponding free amine. Preferred thermodynamic bases for this purpose are Nmethylmorpholine and triethylamine. A preferred Lewis acid for catalytic purposes is titanium isopropoxide. Suitable reducing agents include, but are not limited to, hydrogen on palladium or platinum on carbon, borane or boron complexes such as boranopyridine, tert-butylamine borane, and borane dimethylamine complex; borohydride reducing agents such as sodium borohydride or sodium cyanoborohydride and lithium aluminum hydride. A preferred reducing agent is sodium cyanoborohydride.

The compound of formula III, I (c) or I (e) is usually used in a slight stoichiometric excess. For example, 1 01 to about 1.5 equivalents, for example, * 01 to about 1.5 equivalents, for example.

................

calculated for compound I (a) or IV, is generally used and 1.05 to about 1.15 equivalents is a preferred amount. The reducing agent is preferably used in a stoichiometric amount per compound of Formula I (a) or IV, but a slight excess, from 1.01 to 1.05 equivalents, is acceptable.

Compounds of formula I in which R is (CH2) ¹ m'CHR NHR ^2, or O (CH 2) 2 NHR ^2, R ² is coro, SO 2 R ⁷ or a group of formula g

P-nhr 'can be prepared from compounds of formula I (c) and I (e) as shown in Scheme 3 below, wherein R ¹⁰ is COR ⁶ , SO ₂ R ⁷ , NHR ⁷ or a group of formula

- ^ NHR ⁷

R ¹¹ is O or Sam, m ', R', R ¹ , R ⁶ , R ⁶ ', R ⁷ and R ⁹ are as described above.

Scheme 3

I (e)

VI

The compounds of formula I (c) and I (e) can be converted to other compounds of the invention by conventional methods or a combination of synthetic methods. For example, a compound of formula I (c) or I (e) dissolved or stirred in a suitable solvent, optionally in the presence of a thermodynamic base, can be reacted with a compound of formula IV to give a compound of formula · · · · · · · · Φ · φ · + · + · + · + ·

................

I (g) or I (h), wherein R ¹⁰ is COR ⁶ . A commonly preferred and common solvent is dichloromethane. When a base is used, triethylamine is the most common, which is also preferred. Further, when a base is used, the base and the compound of formula IV are generally used in a slight stoichiometric excess. For example, a 1.01 to 1.40 molar excess, based on the compound of formula I (c) or I (e), can generally be used. About 1.15 to about 1.25 molar excess is usually preferred. When the base is not used, the compound of formula IV is usually used in a relatively larger stoichiometric excess. For example, about 1.5 to about 3 molar excess relative to the compound of formula I (c) or I (e) is usually used. About 1.8 to about 2.2 molar excess is usually preferred. The reaction is generally carried out at a temperature in the range of about 0 ° C to about the reflux temperature of the solvent for a period of from 10 minutes to 18 hours. Preferably, the reaction is performed at about 15 ° C to about 40 ° C for 5 minutes to about 1 hour.

Under the same conditions as in the previous paragraph, a compound of formula I (c) or I (e) may alternatively be reacted with a compound of formula V or VI to obtain compounds of formula I wherein R is (CHmTHR? HR ² or O ( CH 2) 2 NHR ² and R ^2, CONHR ^7, SO 2 R ⁷ or a group of the formula

- ^ - nhr ⁶

Compounds of formula I wherein R is (CH ₂ ) _m COR ³ and R ³ is a C 1 -C 6 alkoxy aminoester or NR ⁴ R ⁵ can be prepared from a compound of formula I (i) as illustrated in Scheme 4 below, wherein R ¹² is NR ₄ R ₅ amino ester or C 1 -C 6 alkoxy am, m ', R', R ₄ ; R ₅ and R ₉ are described above.

•

Scheme 4

VII

HNR4R5III; or

AMINO ACID VIII PROTECTED BY CARBOXY GROUP or (C 1 -C ₆ alkyl) -OH IX

I (j)

Compounds of formula I (i), prepared according to Scheme 1, can also be converted to other compounds of the invention by known solutions or solid phase synthetic techniques. For example, the acids of formula I (i) may be activated to form activated carboxylic acids of formula VII 9, 9, 9, 9, 9 and 9, respectively.

9 · · Α 9 9 · »··

.......... ·· · methods well known in chemistry. See, eg, The Peptides, Peptide Synthesis and the preparations and examples below.

In general, the preparation of compounds of formula I (j) wherein R 12 is NR 4 R 5 or amino ester is carried out similarly to the reaction of compounds of formula I (c) or I (e) and IV described in Scheme 3. Specifically, such compounds of formula I (k) prepared by dissolving or stirring a compound of formula VII in a suitable solvent, optionally in the presence of a suitable thermodynamic base, and adding an amine of formula III or VIII. Typically, the preferred and conventional solvent is dichloromethane. Preferred bases are triethylamine and piperidinylmethyl polystyrene resin. The amine is usually used in molar excess. For example, it is usually used in about 1.5 to about 3 molar excess relative to the compound of Formula VIII. About 1.8 to about 2.2 molar excess is usually preferred. The reaction is usually carried out in a temperature range of about 0 ° C to about the reflux temperature of the solvent for 10 minutes to 18 hours. Preferably, the reaction is carried out at a temperature of about 15 ° C to about 40 ° C for about 5 minutes to about 2.5 hours.

Alternatively, the compound of formula I (i) can be activated and the addition of the compound of formula III, VIII or IX is carried out in situ, as described in Example 41 below.

Compounds of formula I (j) wherein R 12 is C 1 -C 8 alkoxy can be prepared by methods well known in the art of chemistry. For instructions on how to carry out the conversion of activated carboxylic acids to esters, see, e.g., Larock on pages 978-979. Alternatively, these compounds of formula I (j) can be prepared directly from acids of formula I (i) as reported by Larock on pages 966-972 or as described in the example section below.

The pharmaceutical salts of the invention are usually formed by reacting a compound of formula I with an equimolar amount or an excess of acid or base. Generally, the reagents are combined with a solvent such as diethyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, benzene, and the like. • 4 · 4

4 * 44

Similarly used for acid addition salts or alcohol or chlorinated solvents such as dichloromethane for base addition salts. The salts usually precipitate out of solution in an hour to about ten days and can be isolated by filtration or other known methods.

The acids generally used to form pharmaceutical acid addition salts are usually inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphorous acid and the like and organic acids such as ptoluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid. acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, tartaric acid, benzoic acid, acetic acid and the like. Preferred pharmaceutical acid addition salts are those formed with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and those formed with organic acids such as malic acid, tartaric acid, and methanesulfonic acid.

The bases used to prepare the pharmaceutical base addition salts are inorganic bases such as ammonium or alkali metal or alkaline earth metal hydroxide salts, carbonates, bicarbonates and the like. Bases which can be used for the preparation of the compounds of the invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like. Potassium and sodium salts are particularly preferred.

It should be appreciated that the particular preparation of any portion of the salt of the compound of the invention is not critical since the salt as a whole is pharmacologically acceptable and the added ion does not carry undesirable properties for the salt as a whole.

········ 4 4 · 4 4 4 4 4 4 4 4 44 44 44 44 44 44 44 * ·

Starting materials and compounds of the invention, which are intermediates for other compounds of the invention, can be obtained by a number of routes. For example, compounds of formula II, I (a), I (c), I (e), and I (i) can be prepared according to the route shown in Scheme 5 wherein R, R 'and m are as described above.

Scheme 5

R

Compounds of formula II may be prepared by dissolving or stirring a compound of formula X in a suitable solvent and adding a compound of formula XI and a suitable thermodynamic base. Dichloromethane is a common solvent and is usually preferred. Pyridine is usually preferably used as a thermodynamic base. This reaction for the preparation of amides is also preferably carried out in the presence of dimethylaminopyridine (DMAP). The compound of formula XI is typically and preferably employed in equimolar amounts, based on the compound of formula X, but a slight excess (about 0.05 to about 0.25 piers ^r her excess) is acceptable. The thermodynamic base is usually used in a slight molar excess. For example, about 1.01 to about 1: 2 molar excess relative to the compound of Formula X is usually used. An excess of about 1.05 to about 1.15 is generally preferred. DMAP is used as a catalyst, for example, in an amount of about 5 mole percent to about 15 mole percent, based on the compound of formula X. Usually, an amount of 10 mole percent is preferred.

· · · · · · · · · · · · · · · · · · · · · · · · · · ·

Π O · · · · ····

L 3 · · · ···············

Compounds of formula X wherein R is (CH ₂ ) _m COR ¹ , (CH ₂ ) _m NHPg, O (CH ₂ ) ₂ NH-Pg or (CH ₂ ) _m 'CO ₂ (C 1 -C ₆ alkyl) which used to prepare compounds of formula I (a), I (c), I (e) and I (i), are well known in the art and, if not commercially available, are readily synthesized by conventional methods generally used in the art. For example, compounds of formula X can be prepared by reducing commercially available nitro compounds. Methods for reducing the nitro group to an amine are well known. See, e.g., Larock on pages 412-415 or in the Preparations and Examples section below. Further, compounds of formula X wherein R is O (CH ₂ ) ₂ NH-Pg can be prepared from commercially available nitrophenols or nitrobenzyl alcohol as described in the Preparations and Examples 15 and 16 below. In addition, the transformations described in Schemes 2-5 are performed prior to the cyclization described in Scheme 1 to thereby prepare compounds of formula X with the desired R substituent.

Compounds of formulas III, IV, V, VI, VIII, IX, X, and XI are known in the art, and those of which are not commercially available are readily synthesized by conventional methods commonly used in the art.

The optimum duration for the reactions of Schemes 1-5 can be determined by monitoring the reaction by conventional chromatographic techniques. It is further preferred to carry out the reactions according to the invention under an inert atmosphere such as, for example, argon or, in particular, nitrogen. The choice of solvent is generally not critical since a solvent is used which is inert to the ongoing reaction and which sufficiently dissolves the reactants, thereby positively affecting the desired reaction. The compounds of formula II, I (a), I (c), I (e) and I (i) are preferably isolated and purified prior to use in a subsequent reaction. These compounds may crystallize from the reaction solution during their formation and then separated by filtration, or the reaction solvent may be removed by extraction, evaporation or decantation. These intermediates and final products of formula I may be further purified if desired by general techniques such as recrystallization or chromatography on solid supports such as silica gel or alumina.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

One of ordinary skill in the art will recognize that all substituents are not compatible with all reaction conditions, for example, compounds of the invention wherein R 'is hydroxy. These compounds can be protected as the corresponding benzyl ethers and then converted to the hydroxy derivatives at a suitable synthesis site by hydrogenolysis or other methods well known in the art.

The following preparations and examples are provided to better illustrate the practice of the invention and should not be interpreted in any sense as limiting the scope of the invention. Those skilled in the art will recognize that various modifications may be made without departing from the spirit and scope of the invention. All publications mentioned herein are indicative of the level of the art pertaining to the invention. The terms and abbreviations used to describe the preparations and examples have normal meanings unless otherwise indicated. For example, C, N, mmol, g, mL, M, HPLC, IR, MS (FD), MS (IS), MS (FIA), MS (FAB) MS (EI), UV and ^NL H NMR means degrees Celsius, normal or normality, millimol or millimoles, gram or grams, milliliter or milliliters, molar or molarity, high performance liquid chromatography, infrared spectrometry, non-sorptive mass spectrometry (MS), ion spray spectrometry (= ion spray mass spectrometry), (abbreviation MS (FIA) = flow injection analysis mass spectrometry), (abbreviation MS (FAB) = fast atom bombardment mass spectrometry), (abbreviation MS (EI) = electron impact mass spectrometry), ultraviolet spectrometry (abbreviation UV) and proton nuclear magnetic resonance spectrometry (abbreviation ^T H NMR)

- 25 Preparations

Preparation 1

N- (5-methylsulphaz-3-yl) -3-nitrobenzylamine

A solution containing 500 mg (2.65 mmol) of 3-nitrobenzylamine in 20 mL of dichloromethane was stirred at room temperature while 463 mg (3.18 mmol) of 5-methyl-3-isoxazoyl chloride was added. To this solution was added 0.92 mL (6.62 mmol) of triethylamine. The reaction was stirred for an additional 1 hour at room temperature, diluted with 75 mL of ethyl acetate, and the organic phase was washed with 1N aqueous hydrochloric acid (twice), water (twice) and saturated aqueous sodium hydrogen carbonate (three times). The resulting organic solution was dried over sodium sulfate, filtered, and concentrated to give 550 mg (79%) of the title compound as a yellow solid.

MS (FD) m / z 261 (M < + >).

Preparation 2

N- (5-methylsulphaz-3-oyl) -3-aminobenzylamine

To a solution containing 260 mg (1.00 mmol) of N- (5-methylisoxaz-3-oyl) -3-nitrobenzylamine in 20 mL of tetrahydrofuran was added 674 mg (3.00 mmol) of stannous chloride (dihydrate) followed by 2 mL of concentrated acid hydrochloric acid. The reaction was stirred at room temperature for 18 hours and then diluted with 10 mL of ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to give 200 mg (86%) of the title compound as a yellow foam.

MS (FD) m / z 231 (M < + >) · ·

- 26 • *

Preparation 3

N- (5-methyl-soxaz-3-oyl) -N '- (5-methyl-3- (2-chloro-6-fluorophenyl) soxaz-4oyl) -3-aminobenzylamine

To a solution containing 413 mg (1.78 mmol) of N (5-methylisoxaz-3-oyl) -3-aminobenzylamine in 50 mL of dichloromethane was added 538 mg (1.96 mmol) of 3- (2-chloro-6-fluorophenyl) 5- methyl 4-isoxazoyl chloride at room temperature. To this solution was added 0.157 mL (1.96 mmol) of pyridine, then 22 mg (0.18 mmol) of DMAP and the reaction was stirred at room temperature for 3 hours. The reaction was then diluted with 100 mL of ethyl acetate. This organic solution was washed with 1N aqueous hydrochloric acid (twice), brine (twice) and saturated aqueous sodium bicarbonate solution (twice), dried over sodium sulfate, filtered, and concentrated in vacuo to yield 755 mg (90%) of the title compound as a white solid. .

MS (FD) m / z 468 (M < + >).

Preparation 4

N- (5-methylisoxaz-3-oyl) -2-aminobenzylamine

2-Aminobenzylamine (490 mg, 4.01 mmol) and 5-methyl-3-isoxazoyl chloride (437 mg, 3.01 mmol) were converted to the title compound according to Preparation 1 in a yield of 250 mg. (36%).

MS (FD) m / z 231 (M < + >).

1 H NMR was consistent with the desired product.

Preparation 5

N- (5-methyl-soxaz-3-oyl) -N'-2- (2-chloro-6-fluorophenyl) -5-methyl-soxaz-4-yl

N- (5-methylisoxaz-3-oyl) -2-aminobenzylamine (160 mg, 0.692 mmol) and 3- (2-chloro-6-fluorophenyl) 5-methyl-4-isoxazoyl chloride (208 mg)

- 27 0.761 mmol) was converted to the title compound according to Preparation 3 in a yield of 275 mg. (85%).

MS (FD) m / z 468 (M < + >).

IR (KBr) ν = 1669, 1612, 1590; 1455, 1250, 898 cm ^-1 .

Preparation 6

N- (5-methylisoxaz-3-oyl) -4-aminobenzylamine

4-Aminobenzylamine (265 mg, 2.17 mmol) and 5-methyl-3-isoxazoyl chloride (316 mg, 2.17 mmol) were converted to the title compound according to Preparation 1 except that a 2: 1 mixture of mono to bis acylated was formed products which were separated by partitioning the mixture in 100 mL of ethyl acetate and 100 mL of 1N aqueous hydrochloric acid. The organic portion was extracted twice more with acid and the combined acid extracts were made basic (about pH 8) with saturated aqueous sodium bicarbonate. This basic solution was extracted with ethyl acetate and the organic extracts were dried over magnesium sulfate, filtered, and concentrated to yield 94 mg of the monoacylated title compound. (18.7%).

MS (FD) m / z 231 (M < + >).

IR (KBr) ν = 3334, 1646, 1551, 1519, 1459 cm ^-1 .

Preparation 7

N- (5-methylisoxaz-3-oyl) -N'-2- (2-chloro-6-fluorophenyl) -5-methylisoxaz-4-yl-4-aminobenzylamine

N- (5-methylisoxaz-3-oyl) -4-aminobenzylamine (74 mg, 0.32 mmol) and 3- (2-chloro-6-fluorophenyl) 5-methyl-4-isoxazoyl chloride (96 mg, 0.35) mmol) were converted to the title compound according to Preparation 3 in a yield of 150 mg. (100%).

MS (FD) m / z 468 (M < + >). IR (KBr) ν = 3310, 1685, 1655, 1598, 1250 cm ^-1 .

• ·

- 28 Preparation 8

N- (5-Methyl-3-phenylisoxaz-3-oyl) -3-nitrobenzylamine

3-Nitrobenzylamine (500 mg, 2.65 mmol) and 3-phenyl-5-methyl-4-isoxazoyl chloride (705 mg, 3.18 mmol) were converted to the title compound according to Preparation 1 to give 750 mg. (83.9%).

MS (FD) m / z 337 (M < + >).

IR (KBr) ν 3307, 1648, 1524, 1346 cm ^-1 .

Preparation 9

N- (5-methyl-3-phenylisoxaz-3-oyl) -3-aminobenzylamine

N- (5-methyl-3-phenylisoxaz-3-oyl) -3-nitrobenzylamine (650 mg, 1.92 mmol) was converted to the title compound according to Preparation 2 in a yield of 555 mg. (94.2%).

MS (FD) m / z 307 (M < + >).

IR (KBr) ν 3444, 1647, 1612, 1538, 1180 cm ^-1 .

Preparation 10

N- (5-methyl-3-phenylisoxaz-3-oyl) -N'-2- (2-chloro-6-fluorophenyl) -5-methylisoxaz-4-oyl-3-aminobenzylamine

N- (5-methyl-3-phenylisoxaz-3-oyl) -3-aminobenzylamine (555 mg, 1.81 mmol) and 3- (2-chloro-6-fluorophenyl) 5-methyl-4-isoxazoyl chloride (96 mg, 1 (81 mmol) were converted to the title compound according to Preparation 3 to afford 465 mg. (47.2%).

MS (FD) m / z 544 (M < + >).

IR (KBr) ν 3284, 1653, 1610, 1533, 1443, 897 cm ^-1 .

• · · ·

- 30 «·«

Preparation 11

N- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) -3-aminoacetophenone)

To a solution of 3-aminoacetophenone (4.0 g, 29.6 mmol) in dichloromethane (250 mL) under nitrogen atmosphere was added 4-dimethylaminopyridine (542 mg, 4.44 mmol), then pyridine (7: 2 mL) was added dropwise rapidly. , 88.8 mmol). After cooling to 0 ° C, a solution of 3- (2-chloro-6-fluorophenyl) -5-methylisoxazole-4-carbonyl chloride (8.48 g, 31.0 mmol) in dichloromethane (125 mL) was added dropwise over 1 hour. The ice bath was removed and the reaction mixture was allowed to stir for 4 hours. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with 1 N aqueous hydrochloric acid (3 x 125 mL), water (2 x 100 mL), and brine (3 x 75 mL). The ethyl acetate layer was dried (magnesium sulfate) and the volatiles were removed under reduced pressure to give the title compound (11.79 g), which was used as described in subsequent reactions.

1 H NMR (CDCl ₃ ) δ 7.72-7.44 (m, 5 Η), 7.38 (dd, 1H, J = 8 Hz), 7.27 (dd, 1H, J = 8 Hz), 7.11 (br s, 1H), 2.86 (s, 3H), 2.57 (s, 3H).

Preparation 12

N- (t-butyloxycarbonyl) -3-nitrobenzylamine

To a suspension of 4-nitrobenzylamine hydrochloride (10.3 g, 54.7 mmol) and triethylamine (11.1 g, 109 mmol) in dichloromethane (75 mL) was added a solution of di-tert-butyl dicarbonate (15.5 g, 71, 1 mmol) in dichloromethane (25 mL). After stirring overnight at room temperature, the reaction mixture was washed with 10% citric acid (2 x 250 mL), dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate / hexanes with 13.80 g of the title compound. (100%).

4

4 4 4 • «3

-30- ····

Preparation 13

N- (t-butyloxycarbonyl) -3-aminobenzylamine

To a solution of N- (t-butyloxycarbonyl) -3-nitrobenzylamine (13.8 g,

54.7 mmol) of dimethylformamide (200 mL) was added stannous chloride dihydrate (74.1 g, 328 mmol) and the reaction was stirred at room temperature for 48 hours. Dimethylformamide was removed in vacuo. The residue was re-suspended in dichloromethane (300 mL), washed with brine (200 mL), filtered through a celite filter and the solvent removed to give 12.2 g of the title compound. (100%).

Preparation 14

N- (t-butyloxycarbonyl) -N '- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) 3-aminobenzylamine)

A solution of 3- (2-chloro-6-fluorophenyl) -5-methylisoxaz-4-oyl chloride (15 g, 54.7 mmol) in dichloromethane (25 mL) was added to a solution of N- (t-butyloxycarbonyl) -3-aminobenzylamine (12.2 g; 54.7 mmol) and triethylamine (13.8 g, 137 mmol) in dichloromethane (200 mL). After stirring overnight at room temperature, the reaction was washed with 10% citric acid (2 x 200 mL), dried with magnesium sulfate, filtered and the solvent was removed. The residue was purified by liquid chromatography (10% ethyl acetate / hexanes) to give 18.96 g of the title compound. (75%).

Preparation 15

N- t -butyloxycarbonyl-1-aminoethoxy-3-nitrobenzene

To a solution containing 3.0 g (21.6 mmol) of 3-nitrophenol in 100 mL of tetrahydrofuran was added 3.8 g (23.8 mmol) of N- (t-butyloxycarbonyl) aminoethanol and 7.4 g (28.1 mmol) of triphenylphosphine at room temperature. To this solution was added dropwise with stirring

4.4 ml (28.1 mmol) of diethyl azodicarboxylate (DEAD). The resulting solution was stirred at room temperature for an additional 2 hours and then diluted with 200 mL of ethyl acetate. This organic solution was washed twice with 1N aqueous sodium hydroxide, brine and 1N hydrochloric acid, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. The residue was purified by silica gel flash chromatography, using 50% ethyl acetate-hexanes as eluent. The main fractions were combined and concentrated to give 5.50 g (90%) of the title compound as a clear yellow oil.

MS (FD) m / z 282 (M < + >).

Preparation 16

N'-t-butyloxycarbonyl-3-aminoethoxyaniline

To a solution of 3.00 g (10.6 mmol) of N-t-butyloxycarbonyl-1-aminoethoxy-3-nitrobenzene in 25 mL of methanol was added 25 mg of 10% palladium on carbon. This mixture was subjected to hydrogenation at 30 psi in a Parr shaker for 15 hours. The mixture was then filtered through a celite filter and concentrated in vacuo to give 2.20 g (82%) of the title compound as a beige oil.

MS (FD) m / z 252 (M < + >).

Preparation 17

N '- (t-butyloxycarbonyl) -N- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) 3-aminoethoxy aniline

A solution containing 2.00 g (7.93 mmol) of N'-t-butyloxycarbonyl-3-aminoethoxyaniline 50 mL of dichloromethane was stirred at room temperature while 2.17 g (7.93 mmol) of 3- (2-chloro-6-) were added. fluorophenyl) 5-methyl-4-isoxazoyl chloride. To this solution was added 0.70 mL (8.7 mmol) of pyridine, then 97 mg (0.79 mmol) of DMAP, and the reaction was stirred at room temperature for 3 hours. The reaction was then diluted with 100 mL of ethyl acetate and washed twice with 1N aqueous hydrochloric acid, brine and saturated aqueous bicarbonate twice each time. sodium sulfate, dried over sodium sulfate, filtered and concentrated in vacuo to yield 3.55 g (91%) of the title compound as a beige solid.

MS (FD) m / z 489 (M < + >).

Preparation 18

Ethyl N- (5-methyl-3- (2-chloro-6-fluorophenyl) isoxaz-4-oyl) -3-aminobenzoate

3- (2-chloro-6-fluorophenyl) 5-methylisoxaz-4-oyl chloride (7.9g, 29.0 mmol) was added portionwise to a stirred solution of ethyl 3-aminobenzoate (4.0 g, 29.0 mmol) and triethylamine (4.04 mL, 29.0 mmol) in dry dichloromethane at 0 ° C. After the last addition, it was allowed to cool to ambient temperature with stirring for 1 hour. The solution was washed with 0.5 M aqueous hydrochloric acid, brine, aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to a foam which was used in subsequent reactions without further purification.

Preparation 19

Methyl N-5-methyl-3- (2-chloro-6-fluorophenyl) isoxaz-4-oyl) -3-aminophenylacetate

A solution containing 1.93 g (11.7 mmol) of methyl 3 aminophenylacetate in 50 mL of dichloromethane was stirred at room temperature while 3.20 g (11.7 mmol) of 3- (2-chloro-6-fluorophenyl) 5-methylisoxaz-4-oyl were added. chloride. To this solution was added 1.03 mL (12.9 mmol) of pyridine, then 140 mg (1:17 mmol) of DMAP, and the reaction was stirred at room temperature for 3 hours. The reaction was then diluted with 100 mL of ethyl acetate. This organic solution was washed with 1 N aqueous hydrochloric acid solution (twice), brine (twice) and saturated aqueous solution.

sodium bicarbonate solution (twice), dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.45 g (94%) of the title compound as a pale yellow solid.

MS (FD) m / z 402 (M < + >).

Preparation 20

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetyl chloride

To a solution containing 107 mg (0.290 mmol) of 3 (isoxazolo [3,4c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetic acid in 20 mL of dichloromethane was added 30 ml (0.348 mmol) of oxalyl chloride at room temperature. The reaction was stirred at room temperature for 1 hour and concentrated in vacuo to give the title compound as a white solid. This material was used without further purification.

Preparation 21

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzoyl chloride

3- (Isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzoic acid was converted to the title compound according to Preparation 20.

Preparation 22

O-Methanesulfonyl-1-nitro-3- (1-hydroxyethyl) benzene

Sodium borohydride (343 mg, 9.08 mmol) was added portionwise to a solution of 3-nitroacetophenone (5 g, 30.3 mmol) in methanol. After the last portion was added, the reaction mixture was allowed to stir for 1 hour and then the solvent was evaporated. The residue was partitioned between dichloromethane and deionized water. The organic portion was separated, dried over sulfate

Magnesium, filtered and evaporated to give a light brown gum. This was dissolved in dichloromethane containing triethylamine (4.2 mL, 30.3 mmol) and cooled in an ice bath. Mesyl chloride (2.34 mL, 30.3 mmol) was added dropwise and after the last addition the reaction mixture was allowed to warm to room temperature and stirred overnight. The solution was washed successively with aqueous hydrochloric acid (0.5 M), aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered and evaporated to 6.5 g of the title compound, which was used without further purification.

Preparation 23 1-Nitro-3- (1-azidoethyl) benzene

O-Methanesulfonyl-1-nitro-3- (1-hydroxyethyl) benzene (3.1 g,

12.6 mmol) was dissolved in anhydrous dimethylsulfoxide and sodium azide (1.07 g, 16.4 mmol) was added. The reaction mixture was allowed to stir for 18 hours, diluted with ethyl acetate and washed several times with brine. The organic portion was then dried with magnesium sulfate, filtered, evaporated and chromatographed (silica gel, 5: 1 hexane: ethyl acetate) to give

2.9 g of the title compound.

Preparation 24

3-nitro-α-methylbenzylamine 1-nitro-3- (1-azidoethyl) benzene (1.3 g, 6.76 mmol) was dissolved in tetrahydrofuran and triphenylphosphine (1.9 g, 7.4 mmol) was added; the nickel solution was stirred at ambient temperature for 18 hours. 1M Aqueous sodium hydroxide (1 ml) was then added and stirring continued for 48 hours. The reaction was diluted with ethyl acetate, washed several times with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed (silica gel, 2: 1 hexane: ethyl acetate) to give 1.1 g of the title compound. (99%).

- 35 1 H NMR (CDCl ₃ ) δ 1.41 (3H, d, J = 6.7 Hz), 1.60 (2H, br s), 4.28 (1H, q, J = 6.9 Hz) 7.50 (1H, t, J = 7.7Hz), 7.70 (1H, d, J = 7.7Hz); 8.09 (1H, d, J = 7.7Hz), 8.25 (1H, s).

Preparation 25

N-t-butyloxycarbones of 1-3-nitro-α-methylbenzylamine

To a suspension of 3-nitro- and -methylbenzylamine (1.12 g, 6.74 mmol) in dichloromethane (75 mL) was added a solution of di-tert-butyl dicarbonate (1.76 g, 8.09 mmol) in dichloromethane (25 mL). ml). After stirring overnight at room temperature, the reaction was washed with 10% citric acid (2 x 250 mL), dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to give the title compound which was used in subsequent reactions without further purification.

Preparation 26

N-t-butyloxycarbones of 1-3-amino-α-methylbenzylamine

To a solution of Nt-butyloxycarbonyl-3-nitro-α-methylbenzylamine (1.79 g, 6.74 mmol) in dimethylformamide (50 mL) was added stannous chloride dihydrate (9.12 g, 40.4 mmol) and the reaction was stirred at at room temperature for 48 hours. The dimethylformamide was removed in vacuo, the residue was re-suspended in dichloromethane (100 mL), washed with brine (100 mL), filtered through a celite filter, and the solvent was removed to give the crude aniline.

Preparation 27

N- (t-butyloxycarbonyl) -N '- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) 3-amino-α-methylbenzylamine)

A solution of 3- (2-chloro-6-fluorophenyl) -5-methylisoxaz-4-oyl chloride (1.85 g, 6.74 mmol) in dichloromethane (25 mL) was added to a solution of aniline (1.59g, 6, 74 mmol) and triethylamine (2.04 g, 20.2 mmol) in dichloromethane.

36 (100 ml). After stirring overnight at room temperature, the reaction was washed with 10% citric acid (2 x 50 mL), dried with magnesium sulfate, filtered and the solvent removed to give the title compound which was used in subsequent reactions without further purification.

Preparation 28

N- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) -3-nitrobenzylamine)

3-Nitrobenzylamine (511 mg, 2.71 mmol) and 3- (2-chloro-6-fluorophenyl) -5-methylisoxaz-4-oyl chloride (742 mg, 2.71 mmol) were suspended in 10 mL of dichloromethane and added triethylamine (0.95 mL, 6.78 mmol). The reaction mixture became clear and stirred at room temperature for 2 hours. The reaction was then diluted with 100 mL of ethyl acetate and the organic layer was washed twice each time with 1N aqueous hydrochloric acid and 1N aqueous sodium hydroxide. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo to give 1.12 g of the title compound. (> 100%).

MS (IE) mlz 390 (M + 1). IR 3280, 1648, 1532, 1349, 1251 cm ^-1 .

Preparation 29

- (3-Nitrobenzyl) -3-Isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one

N- (5-Methyl-3- (2-chloro-6-fluorophenylsoxaz-4-oyl) -3-nitrobenzylamine (940 mg) was dissolved in 5 mL of dimethylformamide and 5 mL of 2N sodium hydroxide in methanol. at room temperature for 1 hour and additional dimethylformamide was added to dissolve the resulting precipitate The reaction was allowed to stir for an additional hour and then poured into 2N aqueous hydrochloric acid, extracted several times with ethyl acetate. sodium, filtered and concentrated in vacuo to give 852 mg of the title compound.

• · · · ·

- 37 · 4 · 4 # 4 # 4 · 4 44 · 4

MS (IE) m / z 370 (M + 1). IR 3306, 2952, 1718, 1638, 1547, 1211 cm &^lt; -1 & gt ^; .

Examples

Example 1 1- (N-5-methylisoxazol-3-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro

3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

N- (5-methylsulphaz-3-oyl) -N '- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) -3-aminobenzylamine (75 mg, 0.160 mmol) was dissolved in 10 ml of dimethylformamide and 5 ml of 2N sodium hydroxide in methanol After 2 hours, the reaction was diluted with 50 ml of ethyl acetate, washed twice with 1N aqueous hydrochloric acid, sodium bicarbonate and brine twice, dried over sodium sulfate, filtered and concentrated. chromatography (silica gel, 50% ethyl acetate-hexanes) afforded 70 mg (97%) of the title compound as a white solid.

MS (FD) m / z 448 (M < + >). IR (CHC1 ₃₎ 1685, 1632, 1597, 1458 ^cm-first

Example 2

- (N-5-methylisoxazol-3-oyl) -2- (isoxazolo [3,4-c] -1,2-dihydro)

3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

N- (5-methylisoxaz-3-oyl) -N '- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) -2-aminobenzylamine (273 mg, 0.58 mmol) was converted to the title compound as in Example 1, except that the reaction time was 3 hours, 200 mg (77%) was obtained as a yellow powder MS (FD) m / z 448 (M +).

IR (KBr) ν 1682, 1631, 1596, 1455, 1320 cm ^-1 .

Example 3 1- (N-5-methylisoxazol-3-oyl) -4- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine ♦ · · · ·

- 38 N- (5-methylsulphaz-3-oyl) -N '- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) -4-aminobenzylamine (100 mg, 0.213 mmol) was converted to the title compound as in Example 1, except that the reaction time was about 15 minutes to give 59 mg (61%) MS (FD) m / z 448 (M +).

IR (KBr) ν 1681, 1631, 1596, 1540, 1323 cm ^-1 .

Example 4

- (N-3-phenyl-5-methylisoxazol-3-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzy lamin

N- (5-methyl-3-phenylsulphaz-3-oyl) -N '- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) -3-aminobenzylamine (400 mg, 0.734 mmol) was converted to the title compound according to the procedure of Example 1 except that the reaction time was about 18 hours to give 305 mg (79%).

MS (FD) m / z 524 (M < + >).

IR (KBr) ν 3302, 1662, 1596, 1528, 1322 cm ^-1 .

Example 5

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) acetophenone

To a solution of N- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) 3-aminoacetophenone (29.6 mmol) in dimethylformamide (275 mL) was added sodium hydroxide (275 mL, 2N in methanol). The reaction mixture was filtered and the filtrate was diluted with ethyl acetate (1.5 L) and the ethyl acetate solution was washed with 1N aqueous hydrochloric acid (3 x 300 mL), water ( 2 x 250 mL) and brine (300 mL) The organic phase was dried (magnesium sulfate) and the volatiles were removed under reduced pressure The crude residue was chromatographed (silica gel, 1.5-10% methanol / chloroform)

39 to give the title compound as a white solid (4.5 g, 43%), m.p. 78-81 [deg.] C.

¹ H NMR (CDCl ₃ ) δ 8.15 (d, 1H, J = 8Hz), 7.88 (s, IH), 7.75 (dd, IH, J = 8Hz), 7.51 (d (1H, J = 8 Hz); 7.36 (d, 1H, J = 8 Hz), 7.26 (dd, 1H, J = 8 Hz), 6.50 (d, 1H, J = 8 Hz), 2.92 (s, 3 H, 2.64 (s, 3H). MS (FAB) 352.9 (M + 1).

Example 6

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one)

-yl) aniline

3- (2-chloro-6-fluorophenyl) -5-methyl isoxazole-4-carbonyl chloride (7.6 g, 27.7 mmol) was added portionwise to a stirred solution of 1,3-phenylenediamine (3 g, 27.7 mmol). mmol) and triethylamine (4.25 mL, 30.5 mmol) in anhydrous dichloromethane at 0 ° C. After the last addition, the reaction mixture was stirred at ambient temperature for 2 hours. The precipitated solid was collected by filtration and washed with cold methanol to give an off-white solid. The filter cake was suspended in a mixture of tetrahydrofuran and 1M sodium hydroxide in methanol (1: 1 v / v) and the mixture was stirred at ambient temperature for 20 hours. The mixture was cooled in ice, filtered and washed with ice-cold methanol and dried to give 6.5 g of the title compound. (72%).

MS (EI) 326 (M + 1).

¹ H NMR (CDCl ₃ ) 2.9 (3H, s), 3.9 (2H, br s), 6. 55 6.85 (4H, m), 7.22-7.41 (3H, m) .

Example 7 1- (N-t-butyloxycarbonyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

To a solution of N- (t-butyloxycarbonyl) -N '- (5-methyl-3- (2-chloro-6-fluorophenyl) isoxaz-4-oyl) -3-aminobenzylamine (19.0 g, 41.2 mmol) in dry * · «4 • 4 • 5

A solution of sodium hydroxide (8.24 g, 206 mmol) in methanol was added to dimethylformamide (200 mL). After stirring overnight at room temperature, the reaction mixture was poured on ice, the solid was removed by vacuum filtration and purified by liquid chromatography (10% ethyl acetate / hexanes) to obtain 16.31 g of the title compound as a brownish foam. (90%).

MS (FAB) 440 (M + 1).

NMR (CDCl 3) 1.55 (9H, s), 2.9 (3H, s), 4.4 (2H, d), 4.9-5.0 (1H, bs), 6.55 (1H, s), s), 7.15-7.65 (6H, s).

Example 8

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) benzylamine 1- (Nt-butyloxycarbonyl) -3- (isoxazolo [3,4] -c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine (1.20 g, 2.73 mmol) was dissolved in 5 mL of trifluoroacetic acid and stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue azeotroped twice with chloroform to give 1.15 g of an amorphous solid. (93%). MS (FD) m / z 339 (M < + > for free base).

NMR consistent with desired product.

Example 9

- (N-3,5-dimethoxy-4-benzyloxybenzoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

3,5-dimethoxy-4-benzyloxybenzoic acid (317 mg, 1.10 mmol) was dissolved in dichloromethane and EDC (211 mg, 1.10 mmol) was added. 3- (Isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloro-quinolin-2-one-1-yl) -benzylamine (333 mg, 0.734 mmol), N-methylmorpholine and dichloromethane were combined in a separate vessel. A little was added to the amine containing solution prior to coupling with the activated ester solution

Dimethylformamide. A catalytic amount of DMAP was then added and the resulting solution was stirred at room temperature for 18 hours. The reaction was diluted with ethyl acetate and washed twice each time with 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide and brine. The organic layer was concentrated to give 380 mg of the title compound as an amorphous solid (85%).

MS (FIA) m / z 610.

Example 10 1- (N-3,4,5-trimethoxybenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine

3,4,5-trimethoxybenzaldehyde (40 mg, 0.20 mmol) was dissolved in 2 mL dry methanol and N-methylmorpholine (25 µL, 0.22 mmol) and 3- (isoxazolo [3,4-c]) were added. -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) benzylamine (100 mg, 0.22 mmol). The resulting solution was allowed to stir under nitrogen at room temperature for about 30 minutes until a precipitate formed. Methanol (2 mL) and sodium cyanoborohydride (13 mg, 0.20 mmol) were then added. After 1 hour, the precipitate was no longer visible. Completion of the reaction was indicated by TLC (ethyl acetate), therefore the reaction was diluted with ethyl acetate and washed with 25 mL saturated aqueous sodium bicarbonate and brine (3 x 25 mL). The organic layer was dried over sodium sulfate, filtered and removed in vacuo. The residue was taken up in ethyl acetate and purified by silica gel chromatography (ethyl acetate) to give 90 mg of the title compound. (87%).

MS (IS) m / z 518;

EA calcd for C 28 H 26 N 3 O 5 Cl: C, 64.68; H, 5.04; N, 8.08. Found: C, 64.62; H, 5.16; N, 7.87.

Example 11 1- (N-3,5-dimethoxy-4-hydroxybenzoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzy lamin

• ·

- 1- (N-3,5-dimethoxy-4-benzyloxybenzoyl) -3- (isoxazolo [3,4-c] 1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) ) Benzylamine (100 mg, 0.164 mmol) was added to thioanisole (19.2 mL, 0.164 mmol) and the resulting mixture was diluted with trifluoroacetic acid. The reaction was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was pumped overnight using vacuum. The resulting crude solid was purified by chromatography (silica gel, gradient elution 50-100% ethyl acetate: hexanes) to give the title compound.

NMR consistent with desired product.

MS (FD) m / z 519 (M < + >).

Example 12

N- (3,4,5-trimethoxyphenyl) -N- (3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzyl) urea

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) benzylamine (100 mg, 0.22 mmol) was suspended in dry dichloromethane and under nitrogen 25 μ teplotě of N-methylmorpholine was added at room temperature. The reaction was sonicated and 1 mL of dry dimethylformamide was added. The mixture was then added

3,4,5-trimethoxyphenyl isocyanate (48 mg, 0.23 mmol) and the resulting solution was allowed to stir for about 18 hours. The reaction was diluted with ethyl acetate and was washed 3 times each time with 1N aqueous hydrochloric acid and aqueous sodium bicarbonate, dried over sodium sulfate and filtered. The filter cake was washed with methanol and the solvent was removed.

The residue was taken up in dichloromethane / hexane and recrystallized to give 59 mg of the title compound (49%).

MS (IS) 548 (M < + >).

EA calculated for C28H25ClN4O6: C, 61.26; H, 4.59; N, 10.21. Found: C, 60.98; H, 4.87; N, 9.97.

• • •

• ·

- 43 Example 13

N- (3,4,5-trimethoxyphenyl) -N- (3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzyl) thiourea

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) benzylamine (100 mg, 0.22 mmol) and 3,4,5-trimethoxyphenylisothiocyanate (52 mg, 0.22 mmol) was converted to the title compound by the procedure of Example 12, except that the product precipitated from the reaction solution after stirring for about 18 hours was filtered and was not further purified to give 62 mg. 49%.

NMR (d DMSO) consistent with the desired product.

IR (KBr) 1679, 1635, 1576, 1525, 1502 cm ^-1 .

Example 14 1- (N-4-methoxyphenylsulfonyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzyl amine

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) benzylamine (50 mg, 0.147 mmol) was dissolved in 2 mL of dry dimethylformamide and stirred under nitrogen at room temperature. 4-Methoxybenzenesulfonyl chloride (30 mg, 0.147 mmol) was added followed by triethylamine (22 mg, 0.22 mmol) and the resulting mixture was stirred for about 18 hours. The reaction was diluted with ethyl acetate and washed 3 times each time with 1N aqueous hydrochloric acid and brine, dried over sodium sulfate, filtered and the solvent was removed. The residue was treated with dichloromethane / hexanes to give a precipitate of 57 mg of the title compound. (76%).

EA calculated for C 25 H 20 ClN 3 O 5 S: C, 58.88; H, 3.95; N, 8.24. Found: C, 59.11; H, 4.01; N, 8.23. MS (IS) 510 (M < + >).

Example 15 1- (N-t-butyloxycarbonyl) aminoethoxy-3- (isoxazolo [3,4-c] -1,2)

9 9 9 9 9 9 ·

9 9 · 9 9 9 9 9 9 λ Λ 9 9 9 9 9 9 9 9 9 “· hydro hydro hydro hydro di di di hydro hydro hydro hydro hydro hydro hydro on-1-yl) benzene

N '- (t-butyloxycarbonyl) -N' - (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) -3-aminoethoxyaniline (3.50 g, 7.14 mmol) was converted to the title compound as in Example 1, except that the reaction was carried out at 70 ° C and the crude product was purified by recrystallization from 50% ethyl acetate-isooctane to give 2.50 g (74%) of a white crystalline solid.

MS (FD) m / z 469 (M < + >).

Example 16 1-Aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene

To a solution of 1- (Nt-butyloxycarbonyl) aminoethoxy3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-yl) benzene (1.00 g, 2.13) mmol) in 5 mL of dichloromethane was added 5 mL of trifluoroacetic acid. The reaction was stirred at room temperature for 1 hour and concentrated in vacuo. The oily solid was dissolved in 30 mL of ethyl acetate and the organic solution was washed twice with 1 N aqueous sodium hydroxide, dried over sodium sulfate, filtered and concentrated to give 731 mg (93%) of the title compound as a white solid.

MS (FD) m / z 369 (M < + >).

Example 17 1- (N-Benzoyl) aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene

To a solution of 1-aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene (100 mg, 0.270 mmol) in 5 mL of dichloromethane 35 μΐ (0.30 mmol) of benzoyl chloride was added followed by 45 μΐ (0.32 mmol) of triethylamine. The reaction was stirred at room temperature for 30 min.

45 hours and then diluted with 25 ml of ethyl acetate. This organic solution was washed twice each time with 1N aqueous hydrochloric acid, brine and saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to give 105 mg (82%) of the title compound as a white amorphous solid.

MS (FD) m / z 473 (M < + >).

Example 18 1- (N-3,4,5-trimethoxybenzoyl) aminoethoxy-3- (isoxazolo [3,4-c]

1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene

3,4,5-trimethoxybenzoyl chloride (69 mg, 0.297 mmol) and 1 aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one) yl) benzene (100 mg, 0.270 mmol) was converted to the title compound according to the procedure of Example 17 in a yield of 120 mg (79%).

MS (FD) m / z 563 (M < + >).

Example 19

- (N-acetyl) aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene

Acetyl chloride (21 μΐ, 0.297 mmol) and 1-aminoethoxy-3- (isoxazolo [3,4-c] 1,2-dihydro-3-methyl-6-chloroquinolin-2-on-yl) benzene (100 mg, 0.270 mmol) ) were converted to the title compound according to the procedure of Example I7 in a yield of 98 mg (88%).

MS (FD) m / z 411 (M < + >).

Example 20 1- (N-Methanesulfonyl) aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene

Methanesulfonyl chloride (23 mL, 0.297 mmol) and 1-aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene

- 46 (100 mg, 0.270 mmol) were converted to the title compound according to the procedure of Example 17 in a yield of 91 mg (75%).

MS (FD) m / z 447 (M < + >).

Example 21 1- (N-4- (N-acetylamino) benzenesulfonyl) aminoethoxy-3- (isoxazolo [3,4-c] 1,2-dihydro-3-methyl-6-chloroquinolin-2-on-yl) benzene

N-acetylsulfanilyl chloride (63 mg, 0.270 mmol) and 1 aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene (100 mg, 0.270 mmol) was converted to the title compound according to the procedure of Example 17 in a yield of 91 mg (75%).

MS (FD) m / z 565.9 (M < + >).

IR (KBr) ν 1660, 1592, 1330, 1153 cm ^-1 .

Example 22

- (N1-oxo-3- (2-benzoxazolinon-3-yl) propyl) aminoethoxy-3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one) 1-yl) benzene

3- (2-Benzoxazolinon-3-yl) propionic acid (317 mg, 0.405 mmol) was dissolved in 10 mL tetrahydrofuran and hydroxybenzotriazole hydrate (78 mg, 0.405 mmol) was added followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) In a separate vessel was dissolved 1-aminoethoxy-3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene (100 mg, 0.270 mmol) in 5 ml of dimethylformamide were then added to the reaction mixture, 2 mg of dimethylaminopyridine, and the resulting solution was allowed to stir at room temperature for 18 hours, diluted with 50 ml of ethyl acetate and washed twice with 1N aqueous hydrochloric acid, brine, saturated aqueous sodium hydrogen carbonate. The organic layer was dried with magnesium sulfate, filtered and concentrated to give 122 mg (81%) of the title compound.

9

47 MS (FD) m / z 558 (M < + >).

Example 23

- (N1-oxo-4- (Nt-butyloxycarbonyl) amino-4-carbomethoxybutyl) aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) ) benzene

N-Boc-glutamic acid methyl ester (88 mg, 0.338 mmol) and 1-aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) ) Benzene (100 mg, 0: 270 mmol) was converted to the title compound according to the procedure of Example 22 in 110 mg (66%) yield.

MS (FD) m / z 612 (M < + >).

Example 24 1- (N1-oxo-4-Amino-4-carbomethoxybutyl) aminoethoxy-3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-yl) benzene

- (N1-oxo-4- (Nt-butyloxycarbonyl) amino-4 carbomethoxybutyl) aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzene was dissolved in 5 mL of trifluoroacetic acid and stirred at room temperature for 1 hour and concentrated to give 21 mg (100%) of the title compound.

MS (FD) m / z 513 (M < + >).

Example 25

- (Ν-1-oxo-4- (Nt-butyloxycarbonyl) amino-4-carboxy butyl) aminoethoxy-3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl- 6-chloroquinolin-2-one-1-yl) benzene 1- (N1-oxo-4- (N-butyloxycarbonyl) amino-4-carbomethoxybutyl) aminoethoxy-3- (isoxazolo [3,4-c] -1,2-dihydro 3-Methyl-16-chloroquinolin-2-one-1-yl) benzene (77 mg, 0.13 mmol) was dissolved in 5 mL

50% methanol in tetrahydrofuran and 5 mL of 2N aqueous was added

48 sodium hydroxide. The resulting mixture was stirred at room temperature for 2 hours, acidified with 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to give the title compound.

MS (FD) m / z 599 (M < + >).

Example 26 1- (N1-oxo-4-amino-4-carboxybutyl) aminoethoxy-3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one4-yl) benzene 1- (N1-oxo-4- (Nt-butyloxycarbonyl) amino-4-carboxybutyl) aminoethoxy-3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinoline-2- on-1-yl) benzene (25 mg, 0.042 mmol) was dissolved in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid was added. The resulting mixture was stirred at room temperature for 45 minutes and then concentrated in vacuo. No further cleaning was performed.

MS (FD) m / z 498 (M + of free base).

IR (KBr) ν 1674, 1597, 1475, 1197 cm ^-1 .

Example 27

3- (Isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) benzoic acid ethyl ester

3- (N-5-methyl-3- (N-2-chloro-6-fluorophenylisoxaz-4oyl) aminobenzoic acid ethyl ester (4.5 g, 11.6 mmol) was dissolved in dry tetrahydrofuran and cooled in an ice bath. Sodium hydride (428 mg as a 60% dispersion in oil) was added in portions, after which the mixture was allowed to warm to ambient temperature with stirring for 18 hours, quenched with saturated ammonium chloride and diluted with ethyl acetate. , filtered and evaporated to give a yellow solid The residue was suspended in hot 9 9 9 9 9 9 9 9 9 9 9 9

AQ 9 9 9 9 9 9 9 9 9 ~ 9 99 9 9 9 9 9 9 9 9 9 99 9 9 ethyl acetate-hexanes, cooled and filtered, 1.86 g of the title compound was obtained.

MS (FAB) 383 (M + 1).

Example 28

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzoic acid

3- (Isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloro-quinolin-2-one-1-yl) -benzoic acid ethyl ester (1.76 g, 4.60 mmol) was dissolved in 9 : 1 (v / v) tetrahydrofuran: methanol and cooled in an ice bath. Lithium hydroxide hydrate solution (5.1 mL of a 1M solution in water) was added dropwise. The mixture was allowed to warm to ambient temperature with stirring for 18 hours. After this period, tetrahydrofuran (bath temperature <40 ° C) was evaporated. The aqueous residue was cooled in an ice bath and acidified dropwise by the addition of 2M aqueous hydrochloric acid. The solid that precipitated was collected and filtered and dried to yield 1.48 g of the title compound as a white solid.

H (DMSO-d ₆₎ δ 2.8 (3H, s), 6.45 (IH, m), 7.4 7.48 (2H, m), 7.65 (IH, d, J = 7, 2 Hz), 7.68 (1H, t, J = 7.2 Hz), 7.91 (1H, s), 8.11 (1H, d, J = 7.2 Hz). EA calc'd for C ₈ HNN ₂ O4C1.0,8H ₂ O. C, 58.56; H, 3.44; N, 7.59. Found C, 58.48; H, 3.42; N, 7.42.

Example 29

3- (Isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloro-quinolin-2-one-1-yl) -benzoic acid methyl ester

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) benzoyl chloride (50 mg, 0.1.34 mmol) was dissolved in 3 mL dry dichloromethane and stirred under nitrogen at room temperature. Has been added

100 ml of dry methanol were removed and the reaction was stripped after 1 hour to <RTIgt;</RTI> · · · · · · · · · · · · · · · · · · · · ··· uu ^- ································· The residue was taken up in ethyl acetate and washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and precipitated with dichloromethane: hexanes to give a product precipitate. After filtration, 42 mg of the title compound was obtained as an off-white solid. (8%). This material was recrystallized from dichloromethane. hexanes.

EA calculated for C 19 H 13 ClN 2 O 4: C, 61.88; H, 3.55; N, 7.60.

Found: C, 62.17; H, 3.65; N, 7.41.

MS (FD) 368 (M &lt; + &gt;).

Example 30

N-3,4,5-trimethoxyphenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) benzoyl chloride (50 mg, 0.134 mmol) was dissolved in 3 mL dry dichloromethane and stirred under nitrogen at room temperature. 3,4,5-trimethoxyaniline (25 mg, 0.134 mmol) was then added and the reaction was stripped on a rotary evaporator after 1 hour. The residue was taken up in ethyl acetate and washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated to give 45 mg of the title compound. (86%).

MS (FD +) 519. NMR consistent with the title compound.

Example 3 1

N-3,4,5-trimethoxybenzyl-3- (isoxazolo (3,4-c) -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) benzoyl chloride (50 mg, 0.134 mmol) and 3,4,5-trimethoxybenzylamine (2-6) (4 mg, 0.134 mmol) were converted to 76 mg of the title compound according to the procedure of Example 30. (> 100%).

• *

51 MS (FD) 533 (M &lt; + &gt;).

IR ν 3355, 2960, 2931, 1728, 1696, 1653, 1596 cm ^-1 .

Example 32

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) -phenylacetic acid

To a solution containing 4.50 g (11.2 mmol) of the compound of Preparation 13 in 30 mL of dimethylformamide was added 20 mL of 2N sodium hydroxide in methanol. The reaction was stirred at room temperature for 2 hours and then diluted with 200 mL of ethyl acetate. This organic solution was washed with 1N aqueous hydrochloric acid (twice), brine (three times), saturated aqueous sodium bicarbonate solution (twice) and concentrated to an oily yellow solid. This crude material was purified by recrystallization to give 2.20 g (53%) of the title compound as a white crystalline solid.

MS (FD) m / z 368 (M &lt; + &gt;).

Example 33

N-phenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) phenylacetamide

To a solution containing 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride (65 mg, 0.167 mmol) in 1 mL of dichloromethane was added 30 mL. pI (0.334 mmol) of aniline at room temperature. The reaction was stirred at room temperature for 10 minutes and then diluted with 20 mL of ethyl acetate. This organic solution was washed twice with 1N aqueous hydrochloric acid, dried over sodium sulfate, filtered and concentrated in vacuo to give 60 mg (81%) of the title compound as a white solid. MS (FD) m / z 443 (M &lt; + &gt;).

Example 34 • ·

- 52 N-Benzyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) phenylacetamide

Benzylamine (21 μΐ, 0.19 mmol) and 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride (37 mg) , 0.095 mmol) were converted to the title compound according to the procedure of Example 33 in 31 mg (70%) yield.

MS (FD) m / z 457 (M &lt; + &gt;).

Example 35

N- (pyridin-4-ylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

4- (aminomethyl) pyridine (34 μΐ, 0.35 mmol) and 3 (isoxazolo [3,4c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-yl) phenylacetyl chloride (65 mg , 0.18 mmol) were converted to the title compound according to the procedure in Example 33.

MS (FD) m / z 458 (M &lt; + &gt;).

Example 36

N- (pyridin-2-ylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

2- (aminomethyl) pyridine (34 μΐ, 0.36 mmol) and 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-yl) phenylacetyl chloride (65 mg , 0.18 mmol) was converted to the title compound according to the procedure in Example 33. MS (FD) m / z 458 (M +).

Example 37

N-3,4,5-trimethoxybenzyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

53- 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetyl chloride (50 mg, 0.129 mmol) was dissolved in 2 mL dry dichloromethane and stirred under nitrogen at room temperature. 3,4,5-trimethoxybenzylamine (28 mg, 0.142 mmol) was added followed by 21 μΐ of triethylamine. The reaction was stirred for about ₁₈ hours and then diluted with ethyl acetate. The resulting mixture was washed three times each time with 1N aqueous hydrochloric acid, aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated. The residue was precipitated with methylene chloride: hexanes to give 57 mg of the title compound. (80%).

MS (IS) 548 (M &lt; + &gt;).

IR at 3287, 1689, 1643, 1595, 1507.

Example 38

N, N-dimethyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetyl chloride (50 mg, 0.129 mmol) and dimethylamine (6.4 mg, 0.142 mmol) ) were converted to 40 mg of the title compound according to the procedure of Example 37. (78%).

MS (IS) 396 (M &lt; + &gt;).

IR (KBr) ν 1688, 1634, 1595.

Example 39

N-Methyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetyl chloride (50 mg, 0.129 mmol) and methylamine (4.4 mg, 0.142 mmol) ) were converted to 28 mg of the title compound by the procedure of Example

37. (57%).

• • •

54 MS (IS) 382 (MS &lt; + &gt;).

IR (CHC1 ₃₎ in 3011, 1675, 1632, 1597th

Example 40

N-methyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) phenylacetamide

Piperidinylmethyl polystyrene resin (72 mg) was placed in a tube with a screw cap and bottom (with frit bottom). Aminomethylcyclohexane (22 mg, 0.194 mmol) was added followed by 2 mL of dry dichloromethane. 3- (Isoxazolo [3,4-c] 1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetyl chloride (50 mg, 0.129 mmol) was then added and the reaction was shaken for about 1g hours. Isocyanatylmethylpolystyrene resin (103 mg) was added and the vial was shaken for another four hours. The reaction was filtered and the resin was washed twice with methanol and dichloromethane. The solvents were removed in vacuo to give 37 mg of the title compound. (62%).

MS (FD) 463 (M &lt; + &gt;).

IR (CHC1 ₃₎ 3010, 2927, 1675, 1632, 1597 ^cm-first

Example 41

N-3,4,5-trimethoxyphenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

3- (isoxazolo (3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetyl chloride (750 mg, 2.03 mmol) was dissolved in 60 mL of dry dichloromethane and After stirring under nitrogen at room temperature, dimethylaminopyridine (25 mg, 0.203 mmol) and 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (585 mg, 3.05 mmol) were added, after stirring for about 15 minutes. 3,4,5-trimethoxyaniline (745 mg, 4.07 mmol) was added and the resulting mixture was stirred for about 18 hours.The reaction was diluted with ethyl acetate and the mixture was washed three times each time with 1N each. • 4 4 4 4

4 · · 4 4 4 4 • 4 4 444 · 44

C 444 4 4444

O O ”4 4 · · 44 444 44 · 44 44 aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organics were dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from dichloromethane to give 851 mg of the title compound. (78%).

MS (FD) 534 (M &lt; + &gt;).

EA calculated for C ₂₈ H ₂₄ N ₃ O ₆ Cl: C, 62.98; H, 4.53; N, 7.87. Found: C, 62.81; H, 4.63; N, 7.72.

Example 42

N-4-Fluorophenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetyl (50 mg, 0.136 mmol) and 4-fluoroaniline (25.7 μΐ, 0.272 mmol) was converted to 57 mg of the title compound according to the procedure in Example 41. (90%).

Example 43

N-2,3,4,5,6-pentafluorophenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetic acid (50 mg, 0.136 mmol) and 2,3,4,5, 6-Pentafluoroaniline (50 mg, 0.272 mmol) was converted to 51 mg of the title compound according to the procedure of Example 41. (71%) 1 H NMR consistent with the desired product. MS (IS) 534 (M &lt; + &gt;).

Example 44

N-4-Trifluoromethoxy-phenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

• · · · · · · · · · ·

- 56 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetic acid (50 mg, 0.136 mmol) and 4-trifluoromethoxyaniline (37 μΐ) , 0.272 mmol) were converted to 64 mg of the title compound according to the procedure of Example 41. (89%).

1 H NMR consistent with the desired product. MS (IS) 528 (M &lt; + &gt;).

Example 45

N-3,4-dimethoxyphenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) -phenylacetic acid (50 mg, 0.136 mmol) and 4-trifluoromethoxyaniline (42 mg, 0.272) mmol) were converted to 57 mg of the title compound according to the procedure of Example 41. (84%).

MS (IS) 504 (M &lt; + &gt;). UV 316 (4576), 243 (36091), 219 (48616);

Example 46

N-1,3-benzodioxol-6-yl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetic acid (50 mg, 0.136 mmol) and 3,4-methylenedioxyaniline (37 mg , 0.272 mmol) were converted to 51 mg of the title compound according to the procedure of Example 41. (77%).

MS (IS) 488 (M &lt; + &gt;). IR 1684, 1632, 1596, 1567 cm ^-1 .

Example 47

N-4-nitrophenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetic acid (50 mg, 0.136 mmol) and 4-nitroaniline (37 mg; <· •

• ·

- 57 (0.272 mmol) was converted to 98 mg of the title compound according to the procedure of Example 41. (> 100%).

MS (IS) 489 (M &lt; + &gt;). NMR consistent with the title compound.

Example 48

N-4-methylphenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetic acid (50 mg, 0.136 mmol) and 4-methylaniline (29 mg, 0.272) mmol) were converted to 57 mg of the title compound according to the procedure of Example 41. (92%).

MS (IS) 458 (M &lt; + &gt;). NMR consistent with the title compound.

Example 49

N-4-Trifluoromethylphenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-quinolinolin-2-on-1-yl) phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) -phenylacetic acid (50 mg, 0.136 mmol) and 4-trifluoromethylaniline (54 mg, 0.272) mmol) were converted to 47 mg of the title compound according to the procedure of Example 41, (68%).

MS (IS) 512 (M &lt; + &gt;). IR 3467, 3358, 3060, 2957, 2926, 1686, 1631, 1596 cm &^lt; -1 & gt ^; .

Example 50

N-4-methoxyphenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetic acid (50 mg, 0.136 mmol) and 4-methoxyaniline (34 mg,

0: 272 mmol) was converted to 51 mg of the title compound according to the procedure of Example 41. (80%).

• · * ·· ·

58 MS (IS) 474 (M &lt; + &gt;). W 315 (447), 242 (36450), 223 (45246).

Example 51

N-4-carbomethoxyphenyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

3- (isoxazolo [3,4-c) -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetic acid (50 mg, 0.136 mmol) and 4-carbomethoxyaniline (41 mg, 0.272) mmol) were converted to 55 mg of the title compound according to the procedure of Example 41. (81%).

MS (IS) 502 (M &lt; + &gt;). UV 270 (12189), 221 (39859).

Example 52 1- (N-t-Butyloxycarbonyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -α-methylbenzylamine

To a solution of N- (t-butyloxycarbonyl) -N '- (5-methyl-3- (2-chloro-6-fluorophenylisoxaz-4-oyl) -3-amino-α-methylbenzylamine (3.19 g, 6.74 mmol) A solution of sodium hydroxide (0.81 g, 20.2 mmol) in methanol was added in dry dimethylformamide (50 mL) After stirring overnight at room temperature, the reaction mixture was poured onto ice, the solid was removed by vacuum filtration and purified by liquid Chromatography (10% ethyl acetate / hexanes) gave 52 g of the title compound (50% over 4 steps).

MS (FAB) 454.2 (M + 1).

1 H NMR (CDCl ₃ ): δ 1.38-1.44 (9H, m), 1.45-1.5 (3H, m), 2.9 (3H, s), 4.8-4, 95 (2H, bs), 6.48-6.6 (1H, m), 7.1-7.63 (6H, m).

General Procedure for Preparation of Examples 53-82

For individual solutions of commercially available amines • · · · · ·

- 59 (0.0851 mmol, 1.5 eq.) In dichloroethane (150 μΐ) in a 1 mL glass vial was added a solution of 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl- 6-chloroquinolin-2-on-1-yl) acetophenone (0.0567 mmol, 1 eq.) In dichloroethane (150 μΐ). To a vessel containing amines was added triethylamine (0.0964 mmol, 1.7 equivalents per equivalent of hydrochloric acid, where the amine used exists as its chloride salt) in dichloroethane (50 mL). Each vial was purged with nitrogen and then titanium (IV) isopropoxide (120 μ mmol, 0.397 mmol) was added. Each vial was purged again with nitrogen, sealed and then and then vortexed for 7-10 hours. Sodium cyanoborohydride (300 μΐ, 2.84 M in ethanol or methanol) was added to each vial 1. The vials were purged with nitrogen, sealed and vortexed for 12 to 48 hours. The title compounds were isolated by preparative TLC of the crude reaction mixture. Ethyl acetate or methanol / chloroform were used as solvents. Yields ranged from 44 to 80% (25 to 46 mmol).

Example 53 α-Methyl-N- (Pyridin-2-ylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine MS (IS) 444.9 (M &lt; + &gt;). 7.65-7.52 (m, 3H), 1 H NMR (CDCl 3) δ 8.54 7.38-7.1 (m, 6H), (d, 1H, J = 5 Hz), 6.60 -6.50 (m, 1H), 3.99-3.85 (m, 1H), 3.83 (s, 2H), 2.92 (s, 3H), 1.47 (d, 3 H, J = 6 Hz).

Example 54 α-Methyl-N- (4-dimethylaminobenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine

MS (IS) 487.5 (M &lt; + &gt;).

1 H NMR (CDCl ₃ ) δ 7.63-7.57 (m, 2H), 7.387.10 (m, 6H), 6.70-6.50 (m, 3H), 3.98- 3.88 (m, 1H), 3.733.51 (m, 2H), 2.94-2.91 (m, 9H), 1.43 (d, 3H, J = 6 Hz).

• · • ·

Example 55 α-Methyl-N- (carboethoxymethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine MS (IS ) 439.9 (M +).

Example 56

N- [α-methyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzyl] morpholine

MS (IS) 423.9 (M &lt; + &gt;).

Example 57 α-Methyl-N- (2-piperidinylethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine MS (IS) 450.8 (M &lt; + &gt;).

Example 58 α-Methyl-N- (furan-2-ylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) ) benzylamine

MS (IS) 433.9 (M &lt; + &gt;).

Example 59 α-Methyl-N- (2-methoxyethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -benzylamine MS (IS) 411.9 (M &lt; + &gt;).

Example 60 α-Methyl-N- (benzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine MS (IS) 443.9 (M +).

Example 61 α-Methyl-N- (3,5-dimethoxybenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine • • •

MS (IS) 503.9 (M &lt; + &gt;),

Example 62 α-Methyl-N- (tetrahydrofuran-2-ylmethyl) -3- (isoxazolo [3,4-c] 1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) ) benzylamine MS (IS) 437.8 (M &lt; + &gt;).

Example 63 α-Methyl-N- (3-pyrrolidin-2-onylpropyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) ) benzylamine MS (IS) 478.8 (M &lt; + &gt;).

Example 64 α-Methyl-N- (2-acetamidylethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine

MS (IS) 439.5 (M &lt; + &gt;).

Example 65 α-Methyl-N- (cyclohexyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine MS (IS) 439.9 (M &lt; + &gt;).

Example 66 α-Methyl-N- (isopropyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzy lamin

MS (IS) 396.4 (M &lt; + &gt;).

Example 67 α-Methyl-N- (2,6-dimethoxybenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

MS (IS) 504.4 (M &lt; + &gt;).

• ·

Example 68 α-Methyl-N- (4-trifluoromethylbenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzy MS (IS) 512.5 (M &lt; + &gt;).

Example 69 α-Methyl-N- (1-methyl-2-carboisopropoxyethyl) -3- (isoxazolo [3,4c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine MS (IS) 482.5 (M &lt; + &gt;).

Example 70 α-Methyl-N- (1-carboisopropoxy-2- [4-trifluoromethylphenyl] ethyl) -3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinoline- 2-on-1-yl) benzylamine

MS (IS) 544.5 (M &lt; + &gt;).

Example 71 α-Methyl-N- (1-carboisopropoxy-2-methylpropyl) -3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) ) benzylamine MS (IS) 496.6 (M +).

Example 72 α-Methyl-N- (1-carboisopropoxy-2- [Indol-3-yl] ethyl) -3 (isoxazolo [3,4-c]

1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine MS (IS) 544.5 (M +).

Example 73 α-Methyl-N- (1,2-bis-carboisopropoxyethyl) -3- (isoxazolo [3,4-c] 1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1) -yl) benzylamine MS (IS) 554.5 (M &lt; + &gt;).

- 63

Example 74

1- (1- [R-2-carboisopropoxy] pyrrolidinyl) ethyl 1-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene

MS (IS) 494.7 (M &lt; + &gt;).

Example 75 α-Methyl-N- (4-sulfonaminylbenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine MS ( IS) 523.5 (M +).

Example 76 α-Methyl-N- (1-carboisopropoxy-3-methylthiopropyl) -3- (isoxazolo [3,4-c] 1,2-dihydro-3-methyl-6-chloroquinolin-2-one) 1-yl) benzylamine MS (IS) 528.4 (M &lt; + &gt;).

Example 77 α-Methyl-N-carboxymethyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine hydrochloride MS (IS) 412.5 (M &lt; + &gt;).

Example 78 α-Methyl-N- (1-methyl-2-carboxyethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one) 1-yl) benzylamine hydrochloride MS (IS) 440.6 (M +).

Example 79 α-Methyl-N- (1-carboxy-2- [indol-3-yl] ethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2) -one-1-yl) benzylamine hydrochloride MS (IS) 541.5 (M +).

Example 80 • · • «

- 64 α-Methyl-N- (1-carboxy-2-methylpropyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine hydrochloride MS (IS) 454.3 (M +).

Example 81 α-Methyl-N- (1,3-biscarboxyethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine hydrochloride MS (IS) 484.3 (M &lt; + &gt;).

Example 82 1- (1- [R-2-carboxy] pyrrolidinyl) ethyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzene hydrochloride MS (IS) 452.2 (M +).

General Procedure for Combined Preparation of Examples 83-119

To a solution of o- (isoxazolo [3,4-c] 1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline or 3- (isoxazolo [3,4-c] -1,2-dihydro 3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine (0.0809 mmol) in dichloromethane (0.5 mL) was added triethylamine (0.0327g, 0.324 mmol) followed by a 1M solution of commercially available acid chloride , isocyanate or isothiocyanate (0.08999 mmol). After stirring at room temperature for 24 hours, the reaction mixture in each vial was washed with excess aminomethylpolystyrene resin. The solvent in each vial was removed under reduced pressure and the resulting residue was re-suspended in dichloromethane (0.5 mL). The suspension was washed with 1M aqueous hydrochloric acid (0.4 mL), the aqueous layer was removed and the organic solvent was evaporated to give the title compound.

Example 83

N- (benzoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) aniline

4 ·

- 65 4 •• 4 4

Example 84

N- (Cyclohexanoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 85

N- (quinoxalin-2-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 86

N- (1-benzyl-3- t -butylpyrazol-5-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) ) aniline

Example 87

N- (5-methylisoxazol-3-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 88

N- (indol-3-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) aniline

Example 89

N- (morpholinoyl) -3- (isoxazolo [3,4-c] -2,2-Dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) aniline

Example 90

N- (3,5-dimethylisoxazol-4-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 91

N- (2-piperidinylpropanoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

- 66 »

Example 92

N- (1-Phenyl-5-trifluoromethylpyrazol-4-oyl) -3- (isoxazolo [3,4c] -1,2-dihydro)

3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 93

N- (1-methyl-3-t-butylpyrazol-5-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1) -yl) aniline

Example 94

N- (1,4-benzodioxan-2-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 95

N- (benzoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Example 96

N- (cyclohexanoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Example 97

N- (Quinoxalin-2-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Example 98

N- (1-benzyl-3- t -butylpyrazol-5-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzy lamin

Example 99

N- (5-methylisoxazol-3-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

- 67 Example 100

N- (indol-3-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Example 101

N- (morpholinoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Example 102

N- (3,5-dimethylisoxazol-4-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Example 103

N- (2-piperidinylpropanoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-quinolin-2-one-1-yl) benzylamine

Example 104

N- (1-phenyl-5-trifluoromethylpyrazol-4-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Example 105

N- (1-methyl-3- t -butylpyrazol-5-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzy lamin

Example 106

N- (1,4-benzodioxan-2-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Example 107

N- (3,4,5-trimethoxybenzoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

- 67 • · «

Example 108 N- (2-methylbenzoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl 6-chloroquinolin-2-on-1-yl) benzylamine

Example 109

N- (2-chlorothiophen-5-oyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine

Example 110

N- (1-Phenylpyrazol-4-yl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine

Example 111

N- (1- [4-chlorophenyl] cyclopentanoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine

Example 112

N- (1-oxo-3- [benzoxazin-4-on-1-yl] propyl) -3- (isoxazolo [3,4-c] 1,2-dihydro-3-methyl-6-chloroquinoline- 2-on-1-yl) benzylamine

Example 113

N- (n-pentanesulfonyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine

Example 114

N- (4-methylbenzenesulfonyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Example 115

N- (4-t-butylbenzenesulfonyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzylamine

Example 116 • · * · · I • ·

- 69 • · · · · · · ·

N- (4-methylphenyl) -N'-3 - ([isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl] benzyl) urea

Example 117

N- (3,5-ditrifluoromethylphenyl) -N '- (3- [isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl] benzyl) urea

Example 118

N- (4-chlorophenyl) -N '- (3- [isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl] benzyl) urea

Example 119

N- (3,5-ditrifluoromethylphenyl) -N '- (3- [Isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl] benzyl] thio urinary on

General Procedure for Combined Preparation of Examples 120-137

To a solution of 3- (isoxazolo [3,4-c] 1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline or 3- (isoxazolo [3,4-c] -1,2) -dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine (0.0386 mmol) in a 2: 1 system of 1,2-dichloroethane: methanol (0.5 mL) was added 1M solution of commercially available aldehyde ( 0.0425 mmol) and sodium triacetoxyborohydride (0.025 g, 0.116 mmol) in acetic acid (0.05 mL). After stirring for 24 hours at room temperature, the reaction mixture in each tray was filtered through a cellulose frit t and the solvent was removed under reduced pressure. The residue in each vial was then suspended in dichloromethane (0.5 mL), washed with water (0.4 mL) and the solvent removed again in vacuo. The reaction mixtures were redissolved in dichloromethane (0.5 mL) and stirred in excess aminomethylpolystyrene resin overnight. The next day, the contents of each vial were separately filtered through a cellulose frit and the solvent was evaporated to give the title compound.

• ·

- 70 * ·

Example 120

N- (pyridin-4-ylmethyl) -3- (isoxazolol-3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) aniline

Example 121

N- (4-methylthiobutyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-1-chloroquinolin-2-one-1-yl) aniline

Example 122

N- (2-carboethoxycyclopropylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 123

N- (phenylethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 124

N- (4-Trifluoromethylbenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 125

N- (4-hydroxybenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 126

N- (4-dimethylaminobenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 127

N- (piperonyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 128

N- (2-methylfuran-5-ylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 129

N- (3-Dimethylamino-2,2-dimethylpropyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 130

N- (1-methylpyrrol-2-ylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 13 1

N-Benzyl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) aniline

Example 132

N- (indol-3-ylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 133

N- (3,5-difluorobenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 134

N- (2,6-dimethoxybenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Example 135

N- (pyridin-4-ylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

72 Example 136

N- (methylthiobutyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Example 137

N- (2-carboethoxycyclopropylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

General Procedure for the Combined Preparation of Examples 138-147

Piperidinylmethylpolystyrene (72-144 mg, 2-4 equivalents) was placed in a screw cap and bottom vial (with frit bottom). 1 mL of dry dichloromethane was added followed by 1.5 equivalents of a commercially available amine. To each vial was added 3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetyl chloride (50 mg, 0.129 mmol) in 5 mL of dichloromethane . The mixtures were shaken for about 18 hours. Isocyanatylmethylpolystyrene resin (193 mg) was then added to each vial and shaking was continued for 6 hours. The contents of each vial were filtered into another and the resin was washed twice with 1 ml of methanol each and then with 1 ml of dichloromethane. Solvents from the combined individual filtrates and wash fluids from each individual vial were removed (nitrogen passed over the neck of each vial) to give the title compounds.

Example 138

N- (bicyclo [2.2.1] heptan-2-yl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

MS (IS) 444.9.

^X 1 HNMR (CDCl ₃₎ δ 8 54 (d, IH, J = 5 Hz), 7th 65 7.52 (m, 3H), 7.387.11 (m, 6H), 6.60-6.50 (m, 1H), 3.993.85 (m, 1H), 3.83 (s, 2 Η), 2.92 (s, 3 Η), 1.47 (d, 3 H, J with 6 Hz) • ·

73 Example 139

N- (2-Phenylpropyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

MS (IS) 487.5 (M &lt; + &gt;).

¹ H NMR (CDCl ₃ )? 7.63-7.57 (m, 2H), 7.387.10 (m, 6H), 6.70-6.50 (m, 3H), 3.98- 3.88 (m, 1H), 3.703.51 (m, 2H), 2.94-2.91 (m, 9H), 1.43 (d, 3H, J = 6 Hz).

Example 140

N- (Pyrazol-3-yl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

MS (IS) 439.9 (M &lt; + &gt;).

Example 141

N- (1,3-biscarbomethoxypropyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

MS (IS) 423.9 (M &lt; + &gt;).

Example 142

N- (3,5-dimethoxybenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

MS (IS) 450.8 (M &lt; + &gt;).

Example 143

N- (4-cyclohexylphenyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

MS (IS) 433.9 (M &lt; + &gt;).

Example 144

N- (2-indol-3-ylethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

MS (IS) 411.9 (M &lt; + &gt;).

74 Example 145

N- (N-t-butyloxycarbonylaminoethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetamide

MS (IS) 443.9 (M &lt; + &gt;)

Example 146

N- (tetrahydrofuran-2-ylmethyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

MS (IS) 503.9 (M &lt; + &gt;).

Example 147

N- (Naphth-2-yl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) aniline

MS (IS) 437. 8 (M &lt; + &gt;).

Example 148

- (3-Aminobenzyl) -3-isoxazolo [3,4-c] -1,2-dihydro-3-methyl-1-chloroquinolin-2-one

- (3-Nitrobenzyl) -3-isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one (788 mg, 2.13 mmol) was converted to the product as described in preparation 2.

MS (IE) mlz 340 (M + 1). IR 3300, 1683, 1632, 1608, 1462, 1318 cm &lt; -1 &gt;.

Example 149 1- (N-3,4,5-trimethoxybenzoyl-3-aminobenzyl) -3-isoxazolo [3,4]

c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one

- (3-Aminobenzyl) -3-isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-quinolinolin-2-one (160 mg, 0.471 mmol) was dissolved in 10 mL of dimethylformamide and 3,4,5-trimethoxybenzoyl chloride (109 mg, 0.471 mmol) and triethylamine (79 mL, 0.565 mmol) were added. The resulting mixture was

Stirred at room temperature for 15 hours, then diluted with ethyl acetate, washed three times with aqueous sodium hydroxide, 1N aqueous hydrochloric acid, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from methanol to give 85 mg of the title compound.

MS (IE) mlz 534 (M + 1). IR 3250, 1666, 1596, 1130 cm ^-1 .

Example 150

N- (4-methanesulfonylbenzoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

4-Sulfonamylbenzoic acid (44 mg, 0.221 mmol) was dissolved in 3 mL of dry dimethylformamide and 2 mL of dry dichloromethane and stirred at room temperature under nitrogen. DMAP (3 mg, 0.022 mmol) and EDCI (63 mg, 0.331 mmol) were added and the reaction was stirred for 15 minutes. Then 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine (75 mg, 0.221 mmol) was added and the resulting mixture was stirred for about 18 min. hours. The reaction was diluted with ethyl acetate and 1N aqueous hydrochloric acid. The ethyl acetate was separated, washed twice more with 1N hydrochloric acid (25 ml), sodium bicarbonate (3 x 25 ml) and brine (3 x 25 ml), dried over sodium sulfate, filtered and concentrated. The residue was chromatographed (silica gel, ethyl acetate) to give 34.6 mg of the title compound. (63%).

MS (FD) m / z 522 (M &lt; + &gt;). IR (KBr) 3371, 331 L, 1680, 1658 cm ^-1 .

Example 151

N- (4-dipropylaminosulfonylbenzoyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

N, N'-bis-n-propyl-4-sulfonamylbenzoic acid (63 mg,

0.221 mmol) and 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2on-1-yl) benzylamine (75 mg, 0.221 mmol) were converted to 123 mg title compound

76 compounds according to the procedure of Example 150, except for purification by chromatography of the remainder of the product that was not carried out (92%).

EA calculated for C 31 H 31 ClN 4 O 5 S: C, 61.33; H, 5.15; N, 9.23. Found: C, 61.16; H, 5.07; N, 9.12.

MS (FD) m / z 606 (M &lt; + &gt;).

Example 152

N- (3,4,5-triethoxybenzoyl) -3- (isoxazolol _3, 4-c] -l, 2-dihydro-3-methyl-6chlorchinolin-2-one- yl) benzylamine

3,4,5-triethyoxybenzoic acid (37 mg, 0.147 mmol) and 3 (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) benzylamine (50 mg, 0.147 mmol) were converted to the title compound as in Example 150.

Example 153

N- (1-oxo-3- (4-aminosulfonylanilinyl) propyl) -3- (isoxazolo [3,4c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzy lamin

3- (4-Sulfonamylanilinyl) propanoic acid (54 mg, 0.221 mmol) and 3- (isoxazolo [3,4-c ₃ -l, 2-dihydro-3-methyl-6-chloroquinoline-2-one-yl) benzylamine (75 mg, 0.221 mmol) were converted to 106 mg of the title compound according to the procedure of Example 150 except that instead of being purified by chromatography, the residue was precipitated with dichloromethane and hexanes to give a product precipitate. (85%).

MS (FD) m / z 565 (M &lt; + &gt;). IR (KBr) 3381, 3291, 1688, 1651, 1631, 1597 cm &^lt; -1 & gt ^; .

Example 154

N-6-Methoxy-quinolin-8-yl-3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide * • ♦ · • •

77- 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetic acid (50 mg, 0.136 mmol) was dissolved in 2 mL dry dimethylformamide and stirred at room temperature under nitrogen. DMAP (2 mg, 0.014 mmol), EDCI (39 mg, 0.203 mmol) and 6-methoxy-8-aminoquinoline (26 mg, 0.122 mmol) were added and the resulting mixture was stirred for about 18 hours. The reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, and concentrated. The residue was chromatographed (silica gel, 1: 1 ethyl acetate: hexanes) to give 21 mg of the title compound, which was recrystallized from dichloromethane / hexanes. (63%).

MS (IS) m / z 525.1 (M &lt; + &gt;). IR (KBr) 1683, 1628, 1596, 1528 cm ^-1 .

Example 155

N- (4-aminosulfonylphenyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-onl-yl) phenylacetic acid (50 mg, 0.136 mmol) and 4-sulfonamylaniline (47 mg, 0.271 mmol) was converted to 50 mg of the title compound as in Example 155 (70%).

MS (FD) m / z 522 (M &lt; + &gt;). UV (ethanol) λ (ε) 315 (3688), 245 (38968), 22 (37669).

Example 156

N- (4-aminosulfonylbenzyl) -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetamide

3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) -phenylacetic acid (50 mg, 0.136 mmol) and 4-sulfonamylbenzylamine hydrochloride (60 mg, 0.271 mmol) were converted to 62 mg of the title compound according to the procedure of Example 155 except that 1.1 equivalents of DMAP were used. (84%).

- 78 • * · · · · · · · · · · · · · · · · · · · ·

MS (FD) m / z 536 (M &lt; + &gt;). UV (ethanol) 316 (3164), 224 (46243)

Example 157

N- [2-methylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 2-methylaniline, the title compound was prepared as described in Example 41 .

MS (IS) m / z 458 (M + 1).

Example 158

N- [3-methylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetyl chloride and 3-methylaniline, the title compound was prepared as described in Example 41 .

MS (IS) m / z 458 (M + 1).

Example 159

N- [2,3-dimethylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,3-dimethylaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 472 (M + 1).

Example 160

N- [2,4-dimethylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

- 79 · · · · · · · · · · · · · · · ·

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,4-dimethylaniline, the title compound was prepared as described in Example 41 .

MS (IS) m / z 472 (M + 1).

Example 161

N- [2,5-dimethylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,5-dimethylaniline, the title compound was prepared as described in Example 41 .

MS (IS) m / z 472 (M + 1).

Example 162

N- [2,6-dimethylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,6-dimethylaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 472 (M + 1).

Example 163

N- [3,4-dimethylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl)

6-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 3,4-dimethylaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 472 (M + 1);

- 80 · · · · · · · · · · · · · · · · · · ·

Example 164

N- [3,5-dimethylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) -phenylacetamide

Starting from 3- (isoxazolof 3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3,5-methylaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 472 (M + 1).

Example 165

N- [2,4,6-trimethylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,4,6-trimethylaniline, the title compound was prepared as described above. in Example 41.

MS (IS) m / z 486 (M + 1).

Example 166

N- [2,4,5-trimethylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloro-quinolin-2-one-1-yl) -phenylacetyl chloride and 2,4,5-trimethylaniline, the title compound was prepared as described above. in Example 41.

MS (IS) m / z 486 (M + 1).

Example 167

N- [2-methoxyphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methylchloroquinolin-2-on-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl);

6-chloroquinolin-2-on-1-yl) phenylacetyl chloride and 2-methoxyaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 474 (M + 1).

Example 168

N- [3-methoxyphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl- _6- chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3-methoxyaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 474 (M + 1).

Example 169

N- [2,3-dimethyoxyphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,3-dimethoxyaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 504 (M + 1).

Example 170

N- [2,4-dimethoxyphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl- _6- chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,4-dimethoxyaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 504 (M + 1).

Example 171 • 4 4 · 4 ·

Ν- [2,5-dimethoxyphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-5-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 2,5-dimethoxyaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 504 (M + 1).

Example 172

N- [3,4- (methylenedioxy) phenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3,4 (methylenedioxy) aniline, the title compound was prepared as described above. in Example 41.

MS (IS) m / z 488 (M + 1).

Example 173

N- [4-hydroxy-3,5-dimethoxyphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 4-hydroxy-3,5-dimethoxyaniline, the title compound was prepared according to the procedure of as described in Example 41.

MS (IS) m / z 520 (M + 1).

Example 174

N- [2-methoxy-6-methylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide • · · · · · · · · · · · · · · · · · · · ·

- 82 • · · ·

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2-methoxy-6-methylaniline, the title compound was prepared as described in Example 41. MS (IS) m / z 488 (M + 1).

Example 175

N- [3-methoxy-6-methylphenyl] -3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 3-methoxy-6-methylaniline, the title compound was prepared as described above. in Example 41.

MS (IS) m / z 488 (M + 1).

Example 176

N- [2-methyl-4-methoxyphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenyl acetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2-methyl-4-methoxyaniline, the title compound was prepared as described above. in Example 41.

MS (IS) m / z 488 (M + 1).

Example 177

N- [2-methoxy-4-nitrophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2-methoxy-4-nitroaniline, the title compound was prepared as described above. in Example 41.

MS (IS) m / z 518 (M + 1).

84 Example 178

N- [2-methoxy-5-nitrophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2-methoxy-5-nitro-aniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 518 (M + 1).

Example 179

N- [2-nitrophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetyl chloride and 2-nitroaniline, the title compound was prepared as described in Example 41 .

MS (IS) m / z 489 (M + 1).

Example 180

N- [3-nitrophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 3-nitroaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 489 (M + 1).

Example 181

N- [3,5-dinitrophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

- 85 · * 85 85 85 85 85 85 85 85 85 85 85

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3,5-dinitroaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 533 (M + 1);

Example 182

N- [2-nitro-4-methoxy-phenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2-nitro-4-methoxy-aniline, the title compound was prepared according to the procedure as described in Example 41.

MS (IS) m / z 519 (M + 1).

Example 183

N- [2-Fluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2-fluoroaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 462 (M + 1).

Example 184

N- [3-Fluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl)

6-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 3-fluoroaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 462 (M + 1).

- 86 • · · · · · · · · · · ·

Example 185

N- [2,3-difluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,3-difluoroaniline, the title compound was prepared as described in of Example 41.

MS (IS) m / z 480 (M + 1).

Example 186

N- [2,4-difluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetyl chloride and 2,4-difluoroaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 480 (M + 1).

Example 187

N- [2,5-difluorophenyl] 3- (2-oxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,5-difluoroaniline, the title compound was prepared as described in of Example 41.

MS (IS) m / z 480 (M + 1).

Example 188

N- [2,6-difluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide · ·

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,6-difluoroaniline, the title compound was prepared according to the procedure described in in Example 41.

MS (IS) m / z 480 (M + 1).

Example 189

N- [3,4-difluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenyl acetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3,4-difluoroaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 480 (M + 1).

Example 190

N- [3,5-difluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3,5-difluoroaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 480 (M + 1).

Example 191

N- [2,3,4-Trifluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,3,4-trifluoroaniline, the title compound was prepared as described in in Example 41.

MS (IS) m / z 498 (M + 1).

- 88 · * 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88 88

Example 192

N- [2,3,6-trifluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,3,6-trifluoroaniline, the title compound was prepared according to the procedure of as described in Example 41.

MS (IS) m / z 498 (M + 1).

Example 193

N- [2,4,5-trifluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,4,5-trifluoroaniline, the title compound was prepared as described above. in Example 41.

MS (IS) m / z 498 (M + 1).

Example 194

N- [2,4,6-Trifluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,4,6-trifluoroaniline, the title compound was prepared as described above. in Example 41.

MS (IS) m / z 498 (M + 1).

Example 195

N- [2,3,4,5-tetrafluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

- 89 • · · · · · · · · ·

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,3,4,5-tetrafluoroaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 516 (M + 1).

Example 196

N- [2,3,4,6-tetrafluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,3,4,6-tetrafluoroaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 516 (M + 1).

Example 197

N- [2,3,5,6-tetrafluorophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-quinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2,3,5,6-tetrafluoroaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 516 (M + 1).

Example 198

N- [3-fluoro-4-methoxyphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3-fluoro-4-methoxyaniline, the title compound was prepared as described above. in Example 41.

MS (IS) m / z 492 (M + 1).

- 90 Example 199

N- [4-tert-butylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 4-tert-butylaniline, the title compound was prepared as described in of Example 41.

MS (IS) m / z 500 (M + 1).

Example 200

N- [4-cyclohexylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 4-cyclohexylaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 526 (M + 1).

Example 201

N- [4-acetylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 4-acetylaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 486 (M + 1).

Example 202

N- [4-cyanophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

I · · ·

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 4-cyanoaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 469 (M + 1).

Example 203

N- [4-carboxamidophenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 4-carboxamidoaniline, the title compound was prepared as described in Example 41.

MS (IS) mlz 587 (M + 1)

Example 204

N- [4- (N ', N'-Dipropylsulfonamido) phenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2on-1-yl) phenylacetyl chloride and 4- (N ', N'-dipropylsulfonamido) aniline , the title compound was prepared as described in Example 41.

MS (IS) mlz 606 (M-1)

Example 205

N- [3,5-di (trifluoromethyl) phenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3,5-di (trifluoromethyl) aniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 580 (M + 1).

- 92 Example 206

N- [3-Trifluoromethyl-5-methoxyphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3-trifluoromethyl-5-methoxyaniline, the title compound was prepared as described in of Example 41.

MS (LS) mlz 542 (M + 1)

Example 207

N- [2-methoxy-5-tert-butylphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 2-methoxy-5-tert-butylaniline, the title compound was prepared as described above. in Example 41.

MS (IS) m / z 530 (M + 1).

Example 208

N- [3,5-dimethoxybenzyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3,5-dimethoxybenzylamine, the title compound was prepared as described in Example 41.

MS (IS) m / z 518 (M + 1).

Example 209

N- [Naphth-2-yl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl 6-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 2-aminonaphthalene, the title compound was prepared as described in Example 41.

MS (IS) m / z 494 (M + 1).

Example 210

N-methyl N- [3,4,5-trimethoxyphenyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and N-methyl-3,4,5-trimethoxyaniline, the title compound was prepared as described in Example 41.

MS (IS) m / z 548 (M + 1).

Example 211

N- [3,4,5-trimethoxyphenyl] 2- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 2- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3,4,5-trimethoxyaniline, the title compound was prepared as described above. in Example 33.

MS (TS) m / z 534 (M + 1).

Example 212

N- [3,4,5-trimethoxyphenyl] 2- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylpropionamide

Starting from 2- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylpropionyl chloride and 3,4,5-trimethoxyaniline, the title compound was prepared as described above. in Example 33.

• · • ·

- 94 MS (IS) m / z 548 (M + 1).

Example 213

N- [3,4,5-tri methoxyphenyl] 4- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzamide

Starting from 4- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloro-quinolin-2-one-1-yl) -benzoyl chloride and 3,4,5-trimethoxyaniline, the title compound was prepared as described above. in example 33 ..

MS (IS) m / z 520 (M + 1).

Example 214

N- [3,4,5-tri-methoxyphenyl] 4- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetamide

Starting from 4- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -phenylacetyl chloride and 3,4,5-trimethoxyaniline, the title compound was prepared as described above. in Example 33.

MS (IS) m / z 534 (M + 1).

Example 215

N- [3,4,5-tri methoxyphenyl] 2-hydroxy-5- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 2-hydroxy-5- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 3,4,5-trimethoxyaniline, the title compound was prepared as described in Example 33.

MS (IS) m / z 550 (M + 1).

- 95 Example 216

Ν- [3,4,5-tri methoxyphenyl] 2-methoxy-5- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetamide

Starting from 2-methoxy-5- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 3,4,5-trimethoxyaniline, the title the compound was prepared as described in Example 33.

MS (IS) mlz 564 (M + 1)

Example 217

N- [3,4,5-trimethoxyphenyl] 2-benzyloxy-5- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) phenylacetamide

Starting from 2-benzyloxy-5- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenylacetyl chloride and 3,4,5-trimethoxyaniline, the title the compound was prepared as described in Example 33.

MS (IS) m / z 640 (M + 1);

Example 218

N- [3,4,5-tri-methoxyphenyl] 2-cyclohexylmethoxy-5- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) bitches lacetamide

Starting from 2-cyclohexylmethoxy-5- (isoxazolo [3,4-c] -1,2dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) phenyl acetyl chloride and 3,4,5-trimethoxyaniline, the title compound prepared as described in Example 33. MS (IS) m / z 644 (M + 1).

96 Example 219

N-methyl N- [3,4,5-trimethoxybenzoyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-on-1-yl) benzy lamin

Starting from N-methyl 3- (isoxazolo [3,4-c] -1,2-dihydro-3methyl-6-chloroquinolin-2-one-1-yl) benzylamine and 3,4,5-trimethoxybenzoyl chloride, the title the compound prepared as described in the general preparation procedures for Examples 83-119.

MS (IS) m / z 54B (M + 1).

Example 220

N- [4-methyl-3,5-dimethoxybenzoyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) benzylamine

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -benzylamine and 4-methyl-3,5-dimethoxybenzoyl chloride, the title compound was prepared as described in General Preparation Procedures for Examples 83-119:

MS (IS) m / z 518 (M + 1).

Example 221

N- [3,4,5-tri methoxybenzoyl] 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-5-chloroquinolin-2-on-1-yl) aniline

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline and 3,4,5-trimethoxybenzoyl chloride, the title compound was prepared as described above. in the general preparation procedures for Examples 83-119.

MS (IS) m / z 520 (M + 1).

Example 222

N- [3,4,5-trimethoxyphenylglyoxyloyl] 3- (isoxazolo [3,4-c] -1,2- 97- ..........

dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline

Starting from 3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) aniline and 3,4,5-trimethoxyglyoxyloyl chloride, the title compound was prepared as described above. in General Preparation Procedures for Examples 83-119.

MS (IS) m / z 548- (M + 1).

Example 223 1- (3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -2- (2- (N- [3 (4,5-trimethoxybenzoyl] aminocarbonyl) phenyl) ethane

Starting from 1- (3- (isoxazolo [3,4-c] -1,2-dihydro-3-methyl-6-chloroquinolin-2-one-1-yl) -2- (2- (chlorocarbonyl) phenyl) ethane and 3,4,5-trimethoxyaniline, the title compound was prepared as described in Example 33.

MS (IS) mlz 520 (M + 1).

The compounds of the invention are MRP1 inhibitors. Therefore, the compounds of the invention can be used to inhibit any neoplasm having intrinsic and / or acquired resistance, related in part or in whole to MRP1, by addition to the oncolytic or oncolytics. In other words, treating such neoplasms with an effective amount of a compound of the invention makes the neoplasm more susceptible to chemotherapy than could be achieved with agents less potent against MRP1.

Vincristine, epirubicin, daunorubicin, doxorubicin and etoposide are oncolytics which are carriers of MRP1. See Cole, et. al., Pharmacological Characterization of Multidrug Resistant MRP-transfected Human Tumor Cells, Cancer Research, 54: 5902-5910, 1994. Since MRP1 is unequivocally present in mammals, particularly humans, Nooter, K, et. al., Expression of the Multidrug Resistance-Associated Protein

98 (MRP) Gene in Human Cancers, Clin. Can. Res., 1: 1301-1310, (1995), discloses chemotherapy that aims to inhibit neoplasm using any of these agents is less promising than MRP1. Thus, neoplasms of the bladder, bone, breast, lung (small cell), testes and thyroid gland, and more specific cancers such as acute lymphoblastic and myeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue sarcoma, Hodgkins and non-Hodgkins lymphomas and bronchogenic can be combinations of one or more of the aforementioned oncolytics and compounds of the invention.

The biological activity of the compounds of the invention was first evaluated by a screening assay that quickly and accurately determined the ability of the test compound to inhibit MRP1 or MDR1. Assays useful for assessing this suppressive ability are well known in the art. See, e.g., T. McGrath, et al., Biochemical Pharmacology, 38: 3611, 1989; D. Marquardt and M.S. Center, Cancer Research, 52: 3157,1992; Marquardt, D., et al., Cancer Research, 50: 1426, 1990; and Cole, et. al., Cancer Research, 54: 5902-5910 (1994).

MRP1-mediated doxorubicin resistance suppression test and MDR1-mediated suppression of vincristine resistance: HL60 / ADR and HL60 / VCR are continuous cell lines that have been bred for doxorubicin and vincristine resistance from the HL60 culture, which is a human acute myeloblastic leukemia cell line, at high concentrations of doxorubicin or vincristine, which was continued until a highly resistant variety was achieved.

HL60 / ADR and HL60 / VCR cells were expanded in RPMI 1640 nutrient medium (Gibco) containing 10% fetal bovine serum (FBS) and 250 µg / ml GENTAMICIN ™ (Sigma). Cells were harvested; were washed twice with assay medium (same as for culture); counted; and diluted to a concentration of 2 x 10 ⁵ cells / ml in assay medium. Fifty microliters were then transferred in 96-well aliquots into 96-wells.

- 99 Platelets. One column of each 96-well plate served as a negative control and only cell-free culture medium was placed therein.

Test compounds and comparative compounds were then dissolved in dimethylsulfoxide (DMSO) at 5 mM. Samples were diluted to 20 μΜ in assay medium and 25 μΐ of each test compound was added to 6 wells. Test standards were measured using four replicates. Twenty-five microliters of 0.4% DMSO was added to the four wells as a solution control. Test medium was added to all wells in such a quantity as to reach a final volume of 100 μΐ per well.

Plates were incubated at 37 ° C for 72 hours in a humidified incubator with 5% carbon dioxide atmosphere, cell survival and viability was measured by oxidation of tetrazolium salt under standard conditions. Plates were incubated for 3 hours at 37 ° C. The absorbance at 490 nm was measured, and a microtiter plate reader was used.

The ability of test compounds to suppress doxorubicin resistance of HL60 / ADR and HL60 / VCR cells was determined by comparing the absorbance of the wells containing the test compound additive to the oncolytic (doxorubicin) with the absorbance of the wells containing the oncolytic alone and with the test compound. Control tests were performed to eliminate background to ensure that the results were not manipulated. Test results are expressed as percent inhibition of cell growth. The oncolytic alone at the test concentration usually does not inhibit the growth of HL60 / ADR or HL60 / VCR cells at all.

Representative compounds of formula I have a significant ability for MRP1 multidrug resistance. Many compounds showed a very significant increase in activity in combination with an oncolytic agent.

- 100 compared to the oncolytic agent alone. In addition, the bulk of the test compounds showed a significant degree of selective inhibition of the HL60 / ADR cell line over the HL60 / VCR cell line.

When administering oncolytics in practice in the method of the invention, the amount of oncolytic used may be variable. It is to be understood that the amount of oncolytic that is actually administered is determined by the physician in light of the relevant circumstances, including the condition to be treated, the route of administration chosen, the particular oncolytic administered, the age, weight and response of the individual patient ( mammals) and the severity of the patient's symptoms. Of course, the amount of oncolytic administered should be decided and carefully monitored by the physician treating the patient. After deciding which oncolytic to use, a medical guide that is updated annually, such as The Physician's Desk Reference®, published by the Medical Economics Company at Montvale, NJ 07645-1742, can serve as an aid guide for dosing.

Preferred formulations and methods of the invention that employ them are those that do not contain oncolytics. For example, it is preferred to administer the compounds of the invention separately from oncolytics.

The oncolytics mentioned in this specification are commercially available and can be obtained in preformulated forms suitable for the method of the invention.

The compounds of formula I alone or optionally in admixture with an oncolytic are usually administered in the form of pharmaceutical formulations. These formulations can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Such formulations are transported by methods well known in the pharmaceutical art and include at least one compound of formula I.

φ «9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-101 - ···. > ι <· !,

The invention also encompasses methods utilizing pharmaceutical formulations comprising as active ingredient a compound of formula I and optionally an oncolytic associated with pharmaceutical carriers. In making the formulations of the invention, the active ingredient (s) are usually mixed with an excipient, diluted with an excipient, or enclosed in a carrier, which may be in the form of capsules, capsules, paper, or other containers. When the excipient serves as a diluent, it may be solid, semi-solid or liquid and serve as a vehicle, carrier or medium for the active ingredient. Thus, the formulation may take the form of tablets, pills, powders, lozenges, lozenges, capsules, liquid dosage forms, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid), liquid creams containing up to 10% by weight of the active compound. , soft and hard gelatine capsules, supositories, sterile injectable solutions and sterile packaged powders.

In preparing the formulation, it may be desirable to ground the active compound (s) to obtain a suitable particle size of the active compound (s) prior to combination with the other component (s). Most of these compounds are substantially insoluble, usually ground to a certain size, which is less than 200 mesh. If the active compound (s) is substantially water-soluble, the particle size is usually adjusted by milling to obtain a substantially uniform particle size distribution in the formulation, eg, about 40 mesh.

Some examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may also further comprise: lubricants such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; stabilizing agents such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents. The formulations according to the invention can be formulated so as to achieve rapid, long-term or delayed φ * * * * * * * * * * * * * * · ·

The release of the active ingredient after administration to a patient by methods known in the art.

The formulations are preferably formulated in unit dosage forms, each dosage containing 5 to about 100 mg, more usually about 10 to about 30 mg, of each active ingredient. The term unit dosage form means a physically discrete unit suitable for a single dose in a human or other mammal, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The compounds of formula I are effective over a very wide dosage range. For example, a daily dose normally falls within the range of about 0.5 to about 30 mg / kg body weight. In the treatment of adult humans, this range is about 1 to about 15 mg / kg / day, in single or divided doses, particularly preferred. However, it is to be understood that the compound to be administered at the discretion of the physician in light of relevant circumstances, including the condition of the patient to be treated, the route of administration selected, the particular compound selected to be administered, age, weight and the response of the individual patient and the severity of the patient's symptoms, and therefore the above dosage range is in no way intended to limit the scope of the invention. In some cases, dosages below the above-mentioned range may be more than appropriate, while in other cases a much larger dose may be used without any adverse effect, since such a larger dose is first divided into several smaller doses to be administered during the day.

For preparing solid formulations such as tablets, the main active ingredient (s) is mixed with a pharmaceutical excipient to form a preparative solid formulation which comprises a homogeneous mixture of a compound of the invention. In describing these preparation formulations and compositions as homogeneous, it should be noted that the active ingredient (s) are dispersed throughout

The volume of the formulation is such that the formulation can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preparation formulation is then subdivided into dosage amounts of the type described above containing 0.1 to about 500 mg of the active ingredient of the invention.

The tablets or pills of the invention may be coated or otherwise compounded to provide a dosage form for a preferred embodiment of sustained action. For example, the tablet or pill may comprise a dose for the inner and outer components, the latter being in the form of a container over which the first is coated. The two components can still be separated by a layer that dissolves only in the intestine, which serves to prevent disintegration in the stomach and allows the inner component to enter the duodenum or be released with delay. A variety of materials and coatings can be used to form such a layer which comprise polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The novel formulations having liquid forms may be formulated for oral administration or injection and may be aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut peanut oil or peanut oil, as well as liquid dosage forms and similar pharmaceutical vehicles.

Formulations for inhalation or injection include solutions and suspensions in pharmaceutical, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid formulations may contain suitable pharmaceutical excipients as described above. Preferably, the formulations are administered orally or nasally via the airways to achieve a local or systemic effect. Compositions with preferred pharmaceutical solvents can be nebulized in an inert gas.

- 104 (nebulize). The nebulized solutions may be inhaled directly from the misting device or the device may be attached to a face mask, tent, or intermittent inhaled device. The solution, suspension or powder formulation may be administered, preferably orally or nasally, from the delivery device of the formulation in a suitable form.

The following example formulations are illustrative only and are not intended to be limiting in any way. Active ingredient (s) means a compound of formula (I) or a pharmaceutical salt thereof, or a solvate thereof, optionally in admixture with one or more oncolytics.

Formulation Example 1

A hard gelatin capsule containing the following ingredients is prepared

Component Amount (mg / capsule) Active ingredient (s) Starch 305.0 Magnesium stearate 5.0

The above ingredients were mixed and filled into hard gelatin capsules in amounts of 340 mg each.

Formulation Example 2

A tablet formulation is prepared using the ingredients listed below:

• ·

- 105 • · · · · ·

Component Amount (mg / tablet) Active ingredient (s) 25.0 Cellulose, microcrystalline 200.0 Colloidal silica 10.0 Stearic acid. 5.0

The ingredients are mixed and compressed into tablets, each weighing

240 mg.

Formulation example 3

A dry powder inhalation formulation is prepared comprising the following ingredients:

Component Mass % Active ingredient (s) 5 Lactose 95

The active ingredient is mixed with lactose and the mixture is placed in a dry powder inhalation device.

Example of formulation

Tablets are prepared, each containing 30 mg of active ingredient, as follows:

• · · <

• «· ♦

- 106 -

Component Amount (mg / tablet) Active ingredient (s) 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as a 10% aqueous solution) 4.0 mg Carboxymethyl starch, Na salt 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are screened onto 20 mesh U.S. Pat. and mix thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are then passed through a 16 mesh U.S. sieve. The granules so obtained are dried at 50-60 ° C and passed through a 16 mesh U.S. sieve. Sodium carboxymethyl starch, magnesium stearate and talc, pre-screened through a 30 mesh U.S. sieve, are then added, and after mixing, 120 mg tablets are compressed from the mixture on a tabletting machine.

Formulation Example 5

Capsules are prepared, each containing 40 mg of the ingredients listed below:

Component Amount (mg / capsule) Active ingredient (s) 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg

- 107 •

The active ingredient, cellulose, starch and magnesium stearate are blended through a 20 mesh U.S. sieve. and filled into hard gelatin capsules in amounts of 150 mg each.

Formulation Example 6

Suppositories are prepared, each containing 25 mg of active ingredient, having the following composition:

Component Amount Active ingredient (s) 25 mg glycerides of saturated fatty acids to 2,000 mg

The active ingredient is passed through a 60 mesh U.S. sieve. and mixed in pre-ground saturated fatty acid glycerides using as little heat as possible. This mixture is then poured into a suppository mold of nominal size 2.0 and allowed to cool.

Formulation example 7

Suspensions are prepared, each containing 50 mg of the active substance in a dose of 5.0 ml of the following composition:

Component Amount Active ingredient (s) 50.0 mg Xanthan rubber 4.0 mg Carboxymethyl cellulose. Per salt (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1,75 g Sodium benzoate 10.0 mg Flavor and coloring q.v. Clean water to 5.0 ml

- 108

The active ingredient, sucrose and xanthan gum are combined, passed through a 10 mesh U.S. sieve. and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, flavor and color are dissolved in a little water and added to the mixture. Sufficient water is then added to achieve the desired volume.

Formulation example 8

Capsules, each containing 15 mg of the active substance, are prepared having the following composition:

Component Amount (mg / capsule) Active ingredient (s) 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg

The active ingredient, cellulose, starch, and magnesium stearate are mixed, passed through a 20 mesh U.S. sieve. and filled into hard gelatin capsules in amounts of 425 mg each.

Formulation example 9

An intravenous formulation can be prepared as follows:

Component Amount Active ingredient (s) 250.0 mg Isotonic brine 1000 ml

· · · · · · · · · · · · · · · · · · · · · · ·

- 109 • · · · · ·

Formulation Example 10

Formulations for topical application can be prepared as follows:

Component Amount Active ingredient (s) 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g White soft paraffin up to 100 g

IN

The white soft paraffin is heated to melt. The liquid paraffin and emulsifying wax are incorporated into the melt and mixed until dissolved. The active ingredient is then added and stirring is continued until dispersion is formed. The mixture was then cooled until it solidified.

Formulation example 11

Sublingual or buccal tablets, each containing 10 mg of the active ingredient, may be prepared as follows:

Component Amount on tablet Active ingredient (s) 10.4 mg Glycerine 210.5 mg Water 143.0 mg Sodium citrate 4.5 mg Polyvinyl alcohol 26.5 mg Polyvinylpyrrolidone 15,5 mg Total 410.0 mg

Gycerin, water, sodium citrate, polyvinyl alcohol and polyvinylpyrrolidone are mixed together by continuous mixing and maintaining

-110 temperatures at about 90 ° C. When the polymers have dissolved, the solution is cooled to about 50-55 ° C and the active ingredient is slowly added. The homogeneous mixture is then poured into molds formed from an inert material to produce a diffusion matrix containing the active ingredient having a thickness of 2 mm to 2 mm. The diffusion matrix is then chopped to form individual tablets having the desired size.

Another preferred formulation used in the methods of the invention employs a device for transdermal delivery of the active ingredients (patches). Such transdermal patches may be used for continuous or discontinuous infusion of the compounds of the invention in controlled amounts. The construction and use of transdermal patches for the administration of pharmaceutical compositions is well known in the art. See, eg, US Patent

No. 023,252, issued Jun. 11, 1991, which is incorporated herein by reference. Such patches may be constructed as continuous, pulsating or on demand delivery of pharmaceutically active agents.

Often it is necessary to deliver the pharmaceutical formulation, directly or indirectly, to the brain. Direct methods usually require placing the delivery agent in a catheter introduced into the ventricular system to bypass the blood-brain barrier. One such implantable drug delivery system that uses specific anatomical areas of the body to transport biologically active agents is described in U.S. Patent 5,111,472, issued April 30, 1991, which is incorporated herein by reference.

Indirect techniques that are generally preferred usually require the formulation of a composition that uses a latent active ingredient by converting the hydrophilic compound into a fat-soluble form that is the active ingredient or prodrug. Conversion to the latent form of latency is generally achieved by blocking the hydroxyl, carbonyl, sulfate, and primary amino groups present in the molecule.

111 substances to convert to a more lipid-soluble substance that is transportable through the blood-brain interface. Alternatively, the administration of the hydrophilic active ingredient may promote intraarterial infusion of hypertonic solutions that may temporarily open the blood-brain interface.

Claims (28)

1. A compound of formula I: where: R is (CH ₂ ) _m CHR ₁ NHR ² O (CH ₂ ) ₂ NHR ² , (CH ₂ ) _m COR ³ , NHR ² and (CH 2) _m 'CHR ¹ NR ⁴ R ⁵ ; R 1 is hydrogen, hydroxy or O (C 1 -C 6 alkyl optionally substituted with phenyl or C 3 -C 7 cycloalkyl); m and m 'are independently 0, 1 or 2 in each case; R ¹ is independently at each occurrence hydrogen or C 1 -C 6 alkyl; R ² is hydrogen, COR ⁶ , CH ² R ⁶ ', SO ² R ⁷ or a group of the formula •N-NH ⁷ R is hydrogen, hydroxy, C 1 -C 6 alkoxy, amino ester, amino acid, or NR ⁴ R ⁵ ; R ⁴ is hydrogen or C 1 -C 6 alkyl; R ⁵ is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 bicycloalkyl, CH 2 CH (CH 3) phenyl, CH (CH 3) CH ² CO ² R ¹ , aryl, substituted aryl, (CH 2) _n CHR ⁸ NHC (O) OC (CH 3) 3, ( CH 2) n NH ² , (CH 2) ₂ NHCOR ⁶ , (CH 2) ₂ OH, (CH ₂ ) _q -heterocycle, (CH ₂ ) _q -substituted heterocycle, or R ⁴ and R ⁵ together form a pyrrolidin-1-yl, piperidine- 1-yl, hexamethylenimine-1-yl or morpholin-4-yl; n is 1, 2, 3, or 4; • · -113q is 0, 1, 2, or 3; R ⁶ is C 1 -C ⁶ alkyl, substituted C 3 -C 6 cycloalkyl, aryl, substituted aryl, tert-butoxy, (CH ₂ ) _q -heterocycle, (CH ₂ ) _q substituted heterocycle, (CH ₂ ) _n S (O) _r R 6 ', C (CH ₃ ) ₂ CH ₂ N (R') ₂ , (CH ₂ ) n CHR ⁸ NHC (O) OC (CH 3) 3, (CH 2) n CHR ⁸ NH 2, (CH ₂ ) ₂ NH-aryl, or NHR ⁷ ; R ⁶ 'is C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, aryl, substituted aryl, (CH 2) q -heterocycle, (CH 2) q -substituted heterocycle, (CH 2 SO ² ) R ¹ , C (CH 3) ₂ CH ₂ N ( R ¹ ) 2, (CH 2) n CHR ⁸ NHC (O) OC (CH 3) ₃ , (CH ₂ ) n CHR ⁸ NH ₂ or (CH ₂ ) ₂ NH-aryl; r is 0, 1, or 2; R ⁷ is C 1 -C 6 alkyl, phenyl or substituted phenyl; and R ⁸ is hydrogen or CO ₂ R ¹ ; or a pharmaceutical salt or solvate thereof. A compound according to claim 1 wherein m is 0 and m 'is 0 or 1 and R is in the meta position or a pharmaceutical salt or solvate thereof. A compound according to claim 2 wherein R is CHR ¹ HR ² and R ¹ is methyl, or a pharmaceutical salt or solvate thereof. The compound of claim 3 wherein R ² is 4aminosulfonylbenzyl or 3,4,5-trimethoxybenzyl, or a pharmaceutical salt or solvate thereof. A compound according to claim 2 wherein R is COR ³ or (CH ₂ ) COR ³ , or a pharmaceutical salt or solvate thereof. A compound according to claim 5 wherein R ³ is (3,4,5-trimethoxyphenyl) amino, (4-aminosulfonylphenyl) amino or (6-methoxyquinolin-8-yl) amino, or a pharmaceutical salt or solvate thereof. -114 • · A compound according to claim 2 wherein R is (CH 2) NR ⁴ R ⁵ and R ⁴ is hydrogen or a pharmaceutical salt or solvate thereof. A compound according to claim 7 wherein R ⁵ is ⁵ -methylisoxazol-3-oyl, 3,4,5-trimethoxybenzoyl, 3,5-dimethoxy-4-hydroxybenzoyl, or 3,4,5-trimethoxybenzyl, or a pharmaceutical salt or solvate thereof. A method of inhibiting MRPi in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound of Formula I: where: R is (CH ₂ ) _m CHR ¹ NHR ² , O (CH 2) ² NHHR ² , (CH 2) _m COR ³ , NHR ² and (CH ₂ ) _m CHR ¹ NR ⁴ R '. R 'is hydrogen, hydroxy, or O (C 1 -C 6 alkyl optionally substituted with phenyl or C 3 -C 7 cycloalkyl); m and m 'are independently at each occurrence 0, 1, or 2; R ¹ is independently at each occurrence hydrogen or C 1 -C 6 alkyl; R ² is hydrogen, COR ⁶ , CH ² R ⁶ ', SO ² R ⁷ , or a group of formula - ^ - nhr ⁶ R ³ is hydrogen, hydroxy, C 1 -C 6 alkoxy, amino ester, amino acid or NR ⁴ R ⁵ ; R ⁴ is hydrogen or C 1 -C 6 alkyl; - 11 5 - ...... .......... R ⁵ is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 bicycloalkyl, CH 2 CH (CH 3) phenyl, CH (CH 3) CH ² CO ² R ¹ , aryl, substituted aryl, (CH 2) _n CHR ⁸ NHC (O) OC (CH 3) 3, ( CH 2) n NH ² , (CH 2) ₂ NHCOR ⁶ , (CH 2) ₂ OH, (CH ₂ ) _q -heterocycle, (CH ₂ ) _q -substituted heterocycle or R ⁴ and R ⁵ together form pyrrolidin-1-yl, piperidin-1- yl, hexamethylenimine-1-yl, or morpholin-4-yl ring; n is 1, 2, 3, or 4; q is 0, 1, 2, or 3; R ⁶ is C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, aryl, substituted aryl, t-butoxy, (CH 2) q -heterocycle, (CH 2) q -. substituted heterocycle, (CH 2) n S (O) r R ¹ , C (CH 3) ₂ CH ₂ N (R ¹ ) 2, (CH ₂ ) n CHR ⁸ NHC (O) OC (CH 3) ₃ , (CH ₂ ) n CHR ⁸ NH ₂ , (CH ₂ ) ₂ NH-aryl, or NHR ⁷ ; R ⁶ 'is C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, aryl, substituted aryl, (CH 2) q -heterocycle, (CH 2) q -substituted heterocycle, (CH 3 StO 2 R ¹ , C (CH 3) ₂ CH ₂ N ( R ¹ ) ₂ , (CH ₂ ) n CHR ⁸ NHC (O) OC (CH 3) 3 ', (CH 2) n CHR ⁸ HR ² or (CH 2) 2 NH-aryl; r is 0, 1 or 2; R ⁷ is C 1 -C 6 alkyl, phenyl, or substituted phenyl; and R ⁸ is hydrogen or CO ₂ R 11 ^. ; or a pharmaceutical reindeer or solvate thereof. The method of claim 2 wherein the mammal is a human. The method of claim 10 wherein the compound of Formula I is a compound wherein m is 0 and m 'is 0 or 1 and R is in the meta position, or a pharmaceutical salt or solvate thereof. The method of claim 11 wherein the compound of Formula I is a compound wherein R is CHR ¹ HR ² and R ¹ is methyl, or a pharmaceutical salt or solvate thereof. • · -11613. The method of claim 12, wherein the compound of Formula I is a compound wherein R ² is 4-aminosulfonylbenzyl or 3,4,5-trimethoxybenzyl, or a pharmaceutical salt or solvate thereof. The method of claim 11, wherein the compound of Formula I is a compound wherein R is COR ³ or (CH ₂ ) COR ³ , or a pharmaceutical salt or solvate thereof. The method of claim 14, wherein the compound of Formula I is a compound wherein R ³ is (3,4,5-trimethoxyphenyl) amino, (4-aminosulfonylphenyl) amino or (6-methoxyquinolin-8-yl) amino, or a pharmaceutical salt or solvate thereof . The method of claim 11, wherein the compound of Formula I is a compound wherein R is (CH ₂ ) NR ⁴ R ⁵ and R ⁴ is hydrogen, or a pharmaceutical salt or solvate thereof. The method of claim 1, wherein the compound of Formula I is a compound wherein R ⁵ is 5-methylisoxazol-3-oyl, 3,4,5-trimethoxybenzoyl, 3,5-dimethoxy-4-hydroxybenzoyl or 3,4,5-trimethoxybenzyl, or a pharmaceutical salt or solvate thereof. 18. A method of inhibiting a resistant neoplasm, or a neoplasm susceptible to resistance in a mammal which comprises administering to a mammal in need of ⁺ of an effective amount of a compound of formula I: (AND) -117where: R is (CH ₂ ) _m CHR ¹ NHR ² , O (CH 2) ² NHHR ² , (CH 2) _m , COR ³ , NHR ² , and (CH ₂ ) _m CHR * NR ⁴ R ⁵ ; R 'is hydrogen, hydroxy, or O (C 1 -C 6 alkyl optionally substituted with phenyl or C 3 -C 7 cycloalkyl); m and m 'are independently 0, 1 or 2 in each case; R ¹ is independently at each occurrence hydrogen or C 1 -C 6 alkyl; R ² is hydrogen, COR ⁶ , CH ² R ⁶ ', SO ² R ⁷ , or α, moieties of the formula; R ³ is hydrogen, hydroxy, C 1 -C 6 alkoxy, amino ester, amino acid or NR ⁴ R ⁵ ; R ⁴ is hydrogen or C 1 -C 6 alkyl; R ⁵ is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 bicycloalkyl, CH 2 CH (CH 3) phenyl, CH (CH 3) CH ² CO ² R ¹ , aryl, substituted aryl, (CH 2) _n CHR ⁸ NHC (O) OC (CH 3) 3 ', (CH 2) n NH ² , (CH 2) ₂ NHCOR ⁶ , (CH 2) ₂ OH, (CH ₂ ) _q -heterocycle, (CH ₂ ) _q -substituted heterocycle or R ⁴ and R ⁵ together form pyrrolidin-1-yl, piperidin-1 a-1, hexamethylenimine-1-yl or morpholin-4-yl ring; n is 1, 2, 3, or 4; q is 0, 1, 2, or 3; R ⁶ is C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, aryl, saturated aryl, tert-butoxy, (CH 2) q -heterocycle, (CH 2) q -substituted heterocycle, (CH 2) n S (O) r R ¹ , C (CH 3) ₁₂ CH ₂ N (R ¹ ) ₂ , (CH ₂ ) _n CHR ⁸ NHC (O) OC (CH 3) 3, (CH ₂ ) _n CHR ⁸ NH 2, (CH ₂ ) ₂ NH-aryl, or NHR ⁷ ; R ⁶ 'is C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, aryl, substituted aryl, (CH 2) q -heterocycle, (CH 2) q -substituted heterocycle, (CH 2 nSiO 3) R ¹ , C (CH 3) ₂ CH ₂ N ( R ¹ ) 2, (CH 2) n CHR ⁸ NHC (O) OC (CH 3) ₃ ', (CH ₂ ) n CHR ⁸ NH ₂ , or (CH ₂ ) ₂ NH-aryl; r is 0, 1, or 2; R 'is C 1 -C 6 alkyl, phenyl, or substituted phenyl; and R ⁸ is hydrogen or CO ₂ R '; or a pharmaceutical salt or solvate thereof; in combination with an effective amount of one or more oncolytics. • · · · -11819. The method of claim 18, wherein the mammal is a human. The method of claim 19, wherein the oncolytic (tic) is (s) selected from the group consisting of: doxorubicin, daunorubicin, epirubicin, vincristine and etoposide. The method of claim 19, wherein the neoplasm is of Wilm type, bladder, bone, breast, lung (small cell), testis or thyroid gland, or is associated with acute lymphoblastic and myeloblastic leukemia, neuroblastoma soft tissue sarcoma, Hodgkins and non-Hodgkins lymphomas, and bronchogenic carcinoma. The method of claim 19, wherein the compound of Formula I is a compound wherein m is 0 and m 'is 0 or 1 and R is in the meta position or a pharmaceutical salt or solvate thereof. The method of claim 22 wherein the compound of Formula I is a compound wherein R is CHR ¹ HR ² and R ¹ is methyl, or a pharmaceutical salt or solvate thereof. The method of claim 23 wherein the compound of Formula I is a compound wherein R ² is 4-aminosulfonylbenzyl or 3,4,5-trimethoxybenzyl, or a pharmaceutical salt or solvate thereof. The method of claim 22 wherein the compound of Formula I is a compound wherein R is COR ³ or (CH ² -COR ³ , or a pharmaceutical salt or solvate thereof. -11926. The method of claim 25 wherein the compound of Formula I is a compound wherein R ³ is (3,4,5-trimethoxyphenyl) amino, (4-aminosulfonylphenyl) amino, or (6-methoxyquinolin-8-yl) amino, or a pharmaceutical salt or solvate thereof. The method of claim 22 wherein the compound of Formula I is a compound wherein R is (CH ₂ ) NR ⁴ R ⁵ and R ⁴ is hydrogen, or a pharmaceutical salt or solvate thereof. The method of claim 27 wherein the compound of Formula I is a compound wherein R ⁵ is 5-methylisoxazol-3-oyl, 3,4,5-trimethoxybenzoyl, 3,5-dimethoxy-4-hydroxybenzoyl, or 3,4,5-trimethoxybenzyl, or a pharmaceutical salt or solvate thereof. A pharmaceutical formulation comprising a compound of Formula I, wherein: R is (CH ₂ ) _m CHR ¹ NHR ² , O (CH 2) ² NHHR ² , (CH 2) _m COR ³ , NHR ² and (CH ₂ ) _m CHR ¹ NR ⁴ R ⁵ ; R 'is hydrogen, hydroxy, or O (C 1 -C 6 alkyl optionally substituted with phenyl or C 3 -C 7 cycloalkyl); m and m 'are independently at each occurrence 0, 1, or 2; R ¹ is independently at each occurrence hydrogen or C 1 -C 6 alkyl; R ² is hydrogen, COR ⁶ , CH ² R ⁶ ', SO ² R ⁷ or a group 4-H-nhr ^{7 of the} formula; • •> 99 120 R ³ is hydrogen, hydroxy, C 1 -C 6 alkoxy, amino ester, amino acid, or NR ⁴ R ⁵ ; R ⁴ is hydrogen or C 1 -C 6 alkyl; R ⁵ is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 bicycloalkyl, CH 2 CH (CH 3) phenyl, CH (CH 3) CH ² CO ² R ¹ , aryl, substituted aryl, (CH 2) _n CHR ⁸ NHC (O) OC (CH 3) 3 ', (CH 2) n NH ² , (CH 2) ₂ NHCOR ⁶ , (CH 2) ₂ OH, (CH ₂ ) _q -heterocycle, (CH ₂ ) _q -substituted heteracyclic or R ⁴ and R ⁵ together form a pyrrolidin-1-yl, piperidine- 1-yl, hexamethyleneimine-1-yl or morpholin-4-yl ring; n is 1, 2, 3, or 4; q is 0, 1, 2 or 3; R ⁶ is C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, aryl, substituted aryl, tert-butoxy, (CH 2) q -heterocycle, (CH 2) q -substituted heterocycle, (CH 2) n S (O) r R ¹ , C ( CH 3) ₂ CH ₂ N (R ¹⁾ _{2, (CH2)} "CHR ⁸ NHC (O) OC (CH3) 3, (CH2)" CHR ⁸ NH 2, (CH _{2) 2} NH-aryl, or NHR ^7; R ⁶ 'is C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, aryl, substituted aryl, (CH 2) q -heterocycle, (CH 2) q -substituted heterocycle, (CH ₂ ) _n S (O) r R ¹ , C (CH 3) ₂ CH ₂ N (R ¹ ) ₂ , (CH ₂ ) _n CHR ⁸ NHC (O) OC (CH 3) 3 ·, (CH ₂ ) _n CHR ⁸ NH 2, or (CH ₂ ) ₂ NH-aryl; r is 0, 1 or 2; R ⁷ is C 1 -C 6 alkyl, phenyl, or substituted phenyl; and R ⁸ is hydrogen or CO ₂ R ¹ ; or a pharmaceutical salt or solvate thereof. A pharmaceutical formulation comprising: - 121 (a) a compound of formula I: (I) where: R is (CH ₂ ) _m 'CHR 1 ^; NHR ² . O (CH ₂ ) ² NH ² , (CH 2) _m COR ³ , NHR ² and (CH 2) _m CHR ¹ NR ⁴ R ⁵ ; R 'is hydrogen, hydroxy, or O (C 1 -C 6 alkyl optionally substituted with phenyl or C 3 -C 7 cycloalkyl); m and m 'are independently at each occurrence 0, 1, or 2; R ¹ is independently at each occurrence hydrogen or C 1 -C 6 alkyl; R ² is hydrogen, COR ^6, CH 2 R ⁶ ·, SO 2 R ⁷ or a group of formula - ^ NHR ⁷ β R 'is hydrogen, hydroxy, C 1 -C 6 alkoxy, amino ester, amino, or NR ⁴ R ⁵ ; R ⁴ is hydrogen or C 1 -C 6 alkyl; R ⁵ is hydrogen, C 1 -C 6 alkyl, C 6 -C 10 bicycloalkyl, CH 2 CH (CH 3) phenyl, CH (CH 3) CH ² CO ² R ¹ , aryl, substituted aryl, (CH 2) _n CHR ⁸ NHC (O) OC (CH 3) 3 ', (CH 2) n NH 2, (CH 2) 2 NHCOR ⁶ , (CH 2) ₂ OH, (CH ₂ ) _q -heterocycle, (CH ₂ ) _q -substituted heterocycle, or R ⁴ and R ⁵ together form a pyrrolidin-1-yl, piperidin-1-yl, hexamethyleneimine-1-yl or morpholin-4-yl ring; n is 1, 2, 3 or 4; q is 0, 1, 2, or 3; - 122 R ⁶ is C 1 -C 6 alkyl, substituted C ₃ -C 6 cycloalkyl, aryl, substituted aryl, tert-butoxy, (CH ₂ ) _q -heterocycle, (CH ₂ ) _q substituted heterocycle, (CH ₂ ) _n S (O ) _R R ¹ , C (CH ₃ ) 2 CH ₂ N (R ¹ ) 2, (CH ₂ ) n CHR ⁸ NHC (O) OC (CH 3) 3, (CH 2) n CHR ⁸ NH 2, (CH ₂ ) ₂ NH-aryl or NHR ⁷ ; R ⁶ 'is C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl, aryl, substituted aryl, (CH 2) q -heterocycle, (CH 2) q -substituted heterocycle, (CH 2 SiOTR ¹ , C (CH 3) ₂ CH ₂ N ( R ¹ ) 2, (CH ₂ ) _n CHR ⁸ NHC (O) OC (CH 3) ₃ ·, (CH ₂ ) _n CHR ⁸ NH ₂ , or (CH ₂ ) ₂ NH-aryl; r is 0, 1 or 2; R is C 1 -C 6 alkyl, phenyl, or substituted phenyl; and R is hydrogen or CO ² R ¹ ; or a pharmaceutical salt or solvate thereof. (b) one or more oncolytically active agents; and (c) one or more pharmaceutical carriers, diluents or excipients. The formulation of claim 30, wherein the oncolytic (tic) is (are) selected from the group consisting of: doxorubicin, daunorubicin, epirubicin, vincristine, and etoposide.