KR101091101B1 - ω-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS - Google Patents

Abstract

The present invention relates to the use of aryl urea groups for the treatment of raf mediated diseases and pharmaceutical compositions for use in the treatment of such diseases.

Description

ω-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS as a rA kinase inhibitor

Cross Reference to Related Application

This application is part of an ongoing application of 09 / 257,266, filed February 25, 1999, and 60 / 115,877, filed January 13, 1999.

The present invention relates to the use of aryl urea groups to treat raf mediated diseases and pharmaceutical compositions for use in such therapies.

The p21 ^ras oncogene is a major contributing factor in the development and progression of human solid cancer and variates in 30% of all human cancers (Bolton et al ., Ann . Rep . Med . Chem . 1994, 29 , 165-® Bos. Cancer Res . 1989, 49 , 4682-9). The standard, unmutated form of the ras protein is the answer to the signal transduction cascade dominated by growth factor receptors in nearly all tissues (Avruch et al., Trends Biochem . Sci . 1994, 19 , 279-83). Biochemically, ras is a guanine nucleotide that binds to a protein, and the circulatory movement between activated GTP-binding and resting GDP-binding forms is tightly regulated by ras' endogenous GTPase activity and other regulatory proteins. In the ras variant of cancer cells, endogenous GTPase activity is attenuated, thus the protein carries constitutive growth signals to sub-effectors such as the enzyme raf kinase. This allows cells carrying these strains to grow cancerous (Magnuson et al . , Semin . Cancer) . Biol . 1994, 5 , 247-53). It is known to inhibit the effects of active ras by administering an inactive antibody to raf kinase or co-expressing dominant negative raf kinase or dominant negative MEK to block the signaling pathway of raf kinase. Substrates of raf kinases return transformed cells to phenotypes of standard growth (Daum et al., Trends Biochem . Sci . 1994, 19 , 474-80; Fridman et al . , J. Biol . Chem . 1994, 269 , 30105-8). Kolch et al . ( Nature 1991, 426-28) further pointed out that inhibiting raf expression by antisense RNA interferes with cell proliferation in membrane-bound tumor genes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) is associated with growth inhibition of various human tumors in vitro and in vivo (Monia et al . , Nat . Med . 1996, 2, 668-75).

It is an object of the present invention to provide compounds, generally described as aryl ureas, which include both aryl and heteroaryl homologs and which interfere with the raf kinase pathway.

It is another object of the present invention to provide a method of treating raf mediated disease in humans or mammals.

It is still another object of the present invention to provide a compound which inhibits the enzyme raf kinase, a compound for treating raf kinase mediated cancer cell growth, a composition and a method of treatment.

Summary of the Invention

The present invention provides compounds that inhibit the enzyme raf kinase. Because this enzyme is a sub- ^affector of p21 ^ras , the inhibitor is useful as a pharmaceutical composition for human or veterinary use by inhibiting the raf kinase pathway, such as in the treatment of tumors and / or in cancer cell growth by raf kinase mediated. . Specifically, since the progression of these cancers depends on the transducing cascade of ras protein signals, and thus can be treated by interfering with the cascade, i.e. inhibiting raf kinase, the present compositions can be used in human or animal solid cancers such as mice. Useful for cancer treatment Accordingly, the compounds of the present invention may be used in solid cancers such as cancers, including carcinomas (eg, lungs, pancreas, thyroid gland, bladder or colon), myeloid diseases (eg, myeloid leukemia) or adenomas (eg, chorionic colon adenoma). It is useful for treatment.

Accordingly, the present invention provides compounds, generally described as aryl ureas, which include both aryl and heteroaryl homologs and interfere with the raf kinase pathway. The invention also provides a method of treating a raf mediated disease in humans or mammals. Accordingly, the present invention relates to compounds that inhibit the enzyme raf kinase, and also relates to compounds, compositions, and methods for treating cancer cell growth mediated by raf kinase, wherein the compound of Formula 1 or a pharmacologically acceptable The salt is administered.

[ Formula 1 ]

A-D-B

In Formula 1, D is -NH-C (O) -NH-,

A is a substituted part of up to 40 carbon atoms and has the formula -L- (ML ¹ ) q, wherein L is a 5- or 6-membered ring structure directly bonded to D, and L ¹ is a 5- or more member A substituted ring moiety, M is a bridging group having one or more atoms, q is an integer of 1-3; Each ring structure of L and L ¹ comprises 0-4 members of the group consisting of nitrogen, oxygen and sulfur.

B is substituted or unsubstituted, which is directly bonded to D and consists of up to 30 carbon atoms having at least one 6-membered ring structure, having 0-4 members of the group consisting of nitrogen, oxygen and sulfur Aryl or heteroaryl moieties up to the third ring.

In this case, L ¹ is substituted with at least one substituent selected from the group consisting of -SO ₂ R _x , -C (O) R _x and -C (NR _y ) R _z ,

R _y is hydrogen or a carbon-based moiety of up to 24 carbon atoms optionally containing a hetero atom selected from N, S and O and optionally substituted halo up to per-halo,

R _z is hydrogen or optionally contains heteroatoms selected from N, S and O, and contains 24 heteroatoms, optionally substituted by halogen, halogen, hydroxy and optionally heteroatoms selected from N, S and O A carbon based moiety consisting of up to 30 carbon atoms optionally substituted by a carbon based substituent consisting of up to carbon atoms,

R _x is R _z or NR _a R _b , where R _a and R _b are

a) independently hydrogen,

A carbon base of up to 24 carbon atoms optionally containing a hetero atom selected from N, S and O, and containing halogen, hydroxy, and optionally a hetero atom selected from N, S and O and optionally substituted by halogen A carbon based moiety consisting of up to 30 carbon atoms optionally substituted by substituents, or

-OSi (R _f ) ₃ , wherein R _f is hydrogen or optionally contains a hetero atom selected from N, S and O, and contains a halogen, hydroxy, and optionally a hetero atom selected from N, S and O And a carbon based moiety consisting of up to 24 carbon atoms optionally substituted by a carbon based substituent consisting of up to 24 carbon atoms optionally substituted by halogen; or

b) R _a and R _b together form a 5-7 membered hetero ring structure having 1-3 hetero atoms selected from N, S and O, or halogen, hydroxy, and optionally N, S And a carbon-based substituent containing up to 24 carbon atoms containing a hetero atom selected from O and optionally substituted by halogen, and having 1-3 hetero atoms selected from N, S and O To form a substituted 5-7 membered hetero ring structure; or

c) R _a or R _b -C one is in combination with the portion L to form a 5 or more-membered ring structure of the (O) -, a divalent C _{1 -5} alkyl group or a substituted divalent C _{1 -5} alkyl group, the substituted divalent C Substituents for _1-5 alkylene groups are selected from the group consisting of halogen, hydroxy, and carbon-based substituents consisting of up to 24 carbon atoms optionally containing a hetero atom selected from N, S and O and optionally substituted by halogen Will,

When B is substituted, L is substituted or L ¹ is further substituted, the substituent is selected from the group consisting of halogen and W _{n up} to a maximum overhalo, n is 0-3;

Each W is independently -CN, -CO ₂ R ⁷ , -C (O) NR ⁷ R ⁷ , -C (O) -R ⁷ , -NO ₂ , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) OR ⁷ , -NR ⁷ C (O) R ⁷ , -Q-Ar, and optionally a hetero atom selected from N, S and O, and -CN, -CO ₂ R ⁷ , -C (O) R ⁷ , -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NO ₂ , -NR ⁷ C (O) R ⁷ , -NR ⁷ Each R is selected from the group consisting of up to 24 carbon atoms optionally substituted by one or more substituents independently selected from the group consisting of C (O) OR ⁷ and halogen up to halo; ⁷ is independently selected from hydrogen or a carbon based moiety consisting of up to 24 carbon atoms optionally containing a hetero atom selected from N, S and O and optionally substituted by halogen;

Q is -O-, -S-, -N (R ⁷ )-,-(CH ₂ ) _m , -C (O)-, -CH (OH)-,-(CH ₂ ) _m O-,-( _{CH 2) m S-, - (} CH 2) m N (R 7) -, -O (CH 2) m -CHX a -, -CX a 2 -, -S- (CH 2) m - and -N (R ⁷ ) (CH ₂ ) _m −, m = 1-3, X ^a is halogen,

Ar is a 5- or 6-membered aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted with halogen up to _overhalo , optionally substituted with Z _n1 , and n1 is 0 to 3, and each Z is independently -CN, -CO ₂ R ⁷ , -C (O) R ⁷ , -C (O) NR ⁷ R ⁷ , -NO ₂ , -OR ⁷ , -SR ⁷ , -NR ⁷ R ⁷ , -NR ⁷ C (O) R ⁷ , -NR ⁷ C (O) OR ⁷ , And optionally a hetero atom selected from N, S and O and comprises -CN, -CO ₂ R ⁷ , -C (O) R ⁷ , -C (O) NR ⁷ R ⁷ , -OR ⁷ , -SR ⁷ , Consisting of up to 24 carbon atoms optionally substituted by one or more substituents selected from the group consisting of -NO ₂ , -NR ⁷ R ⁷ , -NR ⁷ C (O) R ⁷ and -NR ⁷ C (O) OR ⁷ Is selected from the group consisting of carbon-based moieties, and R ⁷ is as defined above.

In Formula 1, suitable hetaryl groups include, but are not limited to, aromatic rings consisting of 5-12 carbon atoms or ring systems having 1-3 rings, at least one of which is aromatic, and at least one, for example one or more One to four carbon atoms in the ring may be replaced with oxygen, nitrogen or sulfur atoms. For example, B is 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5 Imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5- Thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazole- 1-,-4- or -5-yl, 1,2,4-triazol-1-,-3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazole -4- or -5-yl, 1,2,4-oxadiazole-3- or -5-yl, 1,3,4-thiadiazol-2-, or -5-yl, 1,2, 4-oxadiazole-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyra Nyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7 -Benzothienyl, 1-, 2-, 3-, 4 -, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- Or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1 -, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2- , 4-, 5-, 6-, 7- or 8-quinazolinyl, or further optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyryl, 3 -Pyrazolyl, 2-thiazolyl or 5-thiazolyl and the like. For example, B is 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyryl, 1-methyl-3-pyrazolyl, 5-methyl -2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.

Suitable alkyl groups, such as alkyl alkoxy, such as alkoxy, include methyl, ethyl, propyl, butyl and the like, and include all straight and branched isomers such as isopropyl, isobutyl, sec -butyl, tert -butyl and the like.

Suitable aryl groups that do not contain hetero atoms include, for example, phenyl and 1- and 2-naphthyl.

As used herein, "cycloalkyl" refers to a ring structure with or without alkyl substituents, for example "C ₄ cycloalkyl" includes cyclobutyl groups as well as methyl substituted cyclopropyl groups. The term "cycloalkyl" herein also includes saturated heterocyclic groups.

Suitable halogen groups include F. Cl, Br and / or I, and it is possible for the alkyl group to be substituted by halogen from one to per-substituted (i.e. all H atoms are replaced by halogen atoms) and also given moieties. Mixed substitution of halogen atoms in is also possible.

The invention also relates to the compound of formula 1 itself.

The invention also relates to pharmacologically acceptable salts of compounds of formula (I). Suitable pharmacologically acceptable salts are well known to those skilled in the art and include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, Trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid. Succinic acid, fumaric acid. Maleic acid. Benzoic acid. Salicylic acid. Basic salts of inorganic and organic acids such as phenylacetic acid and mandelic acid. In addition, pharmacologically acceptable salts include, for example, triethylamine, N, N -diethylamine, N, N -dicyclohexylamine, lysine, pyridine, N, N -dimethylaminopyridine (DMAP), 1,4 Diazabiclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7 Alkali metal cations (eg, acidic salts) as well as acidic salts of organic bases including aliphatic and aromatic substituted ammonium and quaternary ammonium cations such as those derived by protonation or peralkylation of DBU Li ⁺ , Na ⁺ or K ⁺ ), alkaline earth metal cations (eg, Mg ⁺² , Ca ⁺² or Ba ⁺² ), salts of inorganic bases such as salts containing ammonium cations.

Many of the compounds of formula (1) have asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separating the enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The present invention includes both isolated racemic or optically active forms of the compound represented by Formula 1, having raf inhibitory activity.

General manufacturing method

Compounds of formula 1 may be prepared using conventional chemical reactions and methods, and some of the starting materials are commercially available. Nevertheless, general methods of preparation are provided to assist those skilled in the art in synthesizing these compounds, and the following examples provide more detailed embodiments.

Substituted anilines are generated using standard methods (March. Advanced Organic Chemistry, 3 ^rd Ed .; John Wiely: New York (1985). Larock. Comprehensive Organic Transformations ; VCH Publishers: New York (1989). As indicated in Scheme 1, aryl amines are generally prepared by reducing nitroaryl using metal catalysts such as Ni, Pd or Pt and H ₂ or hydride transfer agents such as formate, cyclohexadiene or borohydride. (Rylander, Hydrogenation Methods ; Academic Press: London, UK (1985)). Nitro aryl is also often in acidic media, a strong hydride source, such as LiAlH _4, or from (Seyden-Penne a. Reduction by the Alumino - and Borohydrides in Organic Synthesis ; VCH Publishers: New York (1991)), which can be directly reduced using a zero-valent metal such as Fe, Sn or Ca. There are many ways to synthesize nitroaryl (March. Advanced Organic Chemistry , 3 ^rd Ed .; John Wiley: New York (1985). Larock. Comprehensive Organic Transformation ; VCH Publishers: New York (1989).

Scheme 1

Nitroaryl  Aryl With amine  restoration

Nitroaryls are produced by electrophilic aromatic nitration, generally using HNO ₃ or an optional NO ₂ − source. Nitroaryl can be further refined prior to reduction. Thus, nitroaryl substituted with potential leaving groups (eg, F, Cl, Br, etc.)

*

Substitution reactions can be achieved by treatment with nucleophiles such as thiolates (exemplified in Scheme 2) or phenoxide. Nitroaryl may also be subjected to Ullman-type coupling reactions (Scheme 2).

Scheme 2

Nitroaryl  Used, selected Nucleophilicity  Aromatic substitution

Nitroaryl can also be cross-coupled via a transition metal. For example, nitroaryl electrophiles such as nitroaryl bromide, iodine or triflate can be prepared, for example, nucleophiles such as arylboronic acid (Suzuki reaction, illustrated below), aryltin (Stille reaction) or arylzinc (Negishi reaction). And a cross-coupling reaction via palladium to obtain biaryl (5).

Nitroaryl or aniline can be converted to the corresponding arerensulfonyl chloride (7) by treatment with chlorosulfonic acid. Sulfonyl chloride is then reacted with a fluoride source such as KF to give sulfonyl fluoride (8). Sulfonyl fluoride is reacted with trimethylsilyl trifluoromethane in the presence of a fluoride source such as tris (dimethylamino) sulfonium difluorotrimethylsiliconate (TASF) to give the corresponding trifluoromethylsulphone (9) . Optionally, the sulfonyl chloride (7) can be reduced to arehenthiol (10), for example using zinc amalgam. Thiol 10 can be reacted with CHClF _{2 in the} presence of a base to give difluoromethyl mercaptam (11), which can be oxidized to sulfone (12) using any of a variety of oxidants including CrO ₃ -acetic anhydride (Sedova etc., Zh. Org. Khim. 1970 , 6, (568)).

Scheme 3

Fluorinated aryl Sulfone  Chosen Method of Synthesis

As shown in Scheme 4, asymmetric urea formation will include the reaction of aryl isocyanate (14) with aryl amine (13). Heteroaryl isocyanates are heteroaryl amines equivalent to phosgene or phosgene such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene) or N, N' -carbonyldiiimi It can be synthesized by treatment with dozol (CDI). Isocyanates can also be derived from anhydrides by rearrangement reactions of heterocyclic carboxylic acid derivatives such as esters, acid halides or Curtius types. Thus, the reaction of the acid derivative 16 with an azide source followed by a rearrangement reaction provides the isocyanate. Corresponding carboxylic acids 17 may also undergo a Curtis type rearrangement reaction using diphenylphosphoryl azide (DPPA) or similar agent.

Scheme 4

Asymmetry Urea  Selected method of formation

Finally, urea will be further manipulated in a manner familiar to those skilled in the art.

The invention also relates to a pharmaceutical composition comprising a compound of formula 1 and a physiologically acceptable carrier.

The compounds may be administered in dosage unit combinations orally, topically, parenterally, by inhalation or by spray, or rectally. "Administration by injection" includes intravenous, intramuscular, intradermal and parenteral infusion as well as the use of infusion techniques. One or more compounds may be present in combination with one or more non-toxic pharmacologically acceptable carriers and, if desired, in combination with other active ingredients.

Oral compositions can be prepared according to any suitable method in the art for preparing pharmaceutical compositions. Such compositions may include one or more agents selected from the group consisting of diluents, sweeteners, flavors, colorants, and preservatives to provide mouth-to-mouth preparations. Tablets contain the active ingredient in admixture with nontoxic pharmacologically acceptable excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating and disintegrating agents such as corn starch or alginic acid; And binders such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or coated to delay degradation and absorption in the gastrointestinal tract to provide lasting action for longer periods of time. For example, a time-delaying substance such as glyceryl monostearate or glyceryl distearate can be applied. These compounds can also be prepared in solid, rapidly released form.

Oral formulations may also be present in hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. Or soft gelatin capsules, wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, rubber tracanta and rubber acacia; Dispersing or wetting agents include, but are not limited to, natural phosphides such as lecithin, or condensation products of alkylene oxides with condensation products or fatty acids, such as polyoxyethylene stearate, or ethylene oxide with long chain aliphatic alcohols, for example Condensation products of, for example, heptadecaethylene oxycetanol, or ethylene oxide with partial esters derived from hexitol, such as fatty acids and polyoxyethylene sorbitol monooleate, or fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono Condensation products of ethylene oxide with partial esters derived from oleates. The aqueous suspension may also include one or more preservatives, such as ethyl, or n-propyl p -hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents have already been described above. Additional excipients such as sweeteners and flavoring and coloring agents may also be added.

The compounds may also be in the form of non-aqueous liquid formulations, for example oily suspensions which are formulated by suspending the active ingredient in vegetable oils such as arachis oil, olive oil, sesame oil or mineral oils such as peanut oil or liquid paraffin. have. Oily suspensions include thickening agents, for example beeswax, hard paraffin or cetyl alcohol. The sweetener and flavoring agent described above are added to provide an oral preparation for the mouth. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase is a vegetable oil such as olive oil or arachis oil or a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers are esters or partial esters derived from natural rubbers such as rubber acacia or rubber tracanta, natural phosphides such as soybean, lecithin and fatty acids and hexitol anhydrides such as sorbitan monooleate and Condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion also contains sweeteners and flavoring agents.

Syrups and elixirs may be combined with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations also include emollients, preservatives and flavoring and coloring agents.

The compound may be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a non-irritating excipient which is solid at room temperature or liquid at the rectal temperature and is therefore suitable for dissolution in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

For all regimens of the use described herein for compounds of Formula 1, the daily dosage is preferably 0.01 to 200 mg / kg of total body weight. In administration by infusion, including intravenous, intramuscular, intradermal and parenteral infusion and the use of infusion techniques, the daily dosage is preferably 0.01 to 200 mg / kg of total body weight. A daily rectal dosage is preferably 0.01 to 200 mg / kg of total body weight. A daily topical dosage is preferably 0.1 to 200 mg administered between one hour and four hours per day. The daily inhalation dose is preferably 0.01 to 10 mg / kg of total body weight.

It will be understood by those skilled in the art that the particular method of administration depends on a variety of factors, all of which are considered customary in dosage for treatment. Those skilled in the art will also understand that a particular level of dosage for a given patient will depend on a variety of factors including the particular activity, age, weight, health, sex, diet, time and route of administration, rate of excretion, etc. of the compound being administered. . In addition, it will be appreciated that the optimal number of doses of the compound of formula 1 or a pharmacologically acceptable salt thereof may be evident to those skilled in the art through routine therapeutic tests for the optimal course of treatment, ie the method of treatment and a limited number of periods of time.

However, the specific dosage level for any particular patient includes the activity, age, weight, overall health, sex, diet, time of administration, route and excretion of administration, combination of drugs and the severity of the condition being treated for the particular compound to which it applies. Will depend on various factors.

The entire contents of all the applications, patents, and publications described above and below are incorporated herein by reference, including 60 / 115,877, filed January 13, 1999, and 09 / 257,266, filed February 25, 1999. do.

The present compounds can be prepared in conventional compounds (or in other words in starting materials which can be produced from conventional compounds), for example via the general preparation methods described below. The activity of a given compound that inhibits raf kinase can be assayed customarily, such as by the method described below.

In accordance with the present invention, compounds that inhibit the enzyme raf kinase, compounds, compositions, and methods of treatment for treating cancer cell growth mediated by raf kinase mediation are provided.

The following embodiments are illustrative only and are not intended to be limiting or in any way limiting the invention.

Example

All reactions are carried out in flame dried or oven dried glass articles under positive pressure of dry argon or dry nitrogen and magnetically stirred unless otherwise stated. The sensitive liquid and solution are conveyed through a syringe or cannula and introduced into the reaction vessel through the rubber septum. Unless stated otherwise, 'concentration under dark' is the use of a Buchi rotary evaporator at about 15 mmHg. Unless stated otherwise, 'high vacuum' means a vacuum of 0.4-1.0 mmHg.

All temperatures are uncorrected degrees Celsius (° C.). Unless stated otherwise, all parts and percentages are based on weight.

Commercial grade agents and solvents are used without further purification. N -cyclohexyl- N ' -(methylpolystyrene) carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3- tert -butylaniline, 5- tert -butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl) aniline, 4-chloro-3- (trifluoromethyl) aniline, 2- Methoxy-5- (trifluoromethyl) aniline, 4- tert -butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N -acetyl-4-chloro-2 -Methoxy-5- (trifluoromethyl) aniline and 4-chloro-3- (trifluoromethyl) phenyl isocyanate were purchased and used without further purification. 3-amino-2-methoxyquinoline (E. Cho et al., WO 98/00402; A. Cordi et al ., EP 542,609; IBID Bioorg. Med . Chem ., 3, 1995 , 129), 4- (3-carbamoyl Phenoxy) -1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959 , 760; Chem . Abstr . 53, 1959 , 12761b), 3- tert -butylphenyl isocyanate (O. Rohr et al., DE 2,436,108) and 2- Methoxy-5- (trifluoromethyl) phenyl isocyanate (K. Inukai et al., JP 42,025,067; IBID Kogyo Kakaku The synthesis of Zasshi 70, 1967 , 491) is described above.

의 유리판에 미리 코팅된 실리카겔 60A F-254 250㎛ 플레이트를 이용하여 박막 크로마토그래피(TLC)를 수행하였다. 플레이트의 가시화는 (a) 자외선 일루미네이션, (b) 요오드 증기에 노출, (c) 10% 포스포몰리브덴산의 에탄올 용액에 플레이트를 담그고 이어서 가열, (d) 세륨 술페이트 용액에 플레이트를 담그고 이어서 가열, 및/또는 (e) 2,4-디니트로페닐히드라진의 산성 에탄올 용액에 플레이트를 담그고 이어서 가열하는 것 중의 한가지 이상의 기술에 의하여 달성하였다. 230-440 메쉬의 EM Science

실리카겔을 이용하여 칼럼 크로마토그래피(플래쉬 크로마토그래피)를 수행하였다. Whatman

Thin layer chromatography (TLC) was performed using a silica gel 60A F-254 250 μm plate precoated on a glass plate of. Visualization of the plate may include (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) dipping the plate in ethanol solution of 10% phosphomolybdic acid and then heating, (d) dipping the plate in cerium sulfate solution and then heating And / or (e) immersing the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. EM Science of 230-440 mesh

Column chromatography (flash chromatography) was performed using silica gel.

Melting point (mp) was measured using Thomas-Hoover melting point apparatus or Mettler FP66 automated melting point apparatus and was not calibrated. Fourier transform infrared spectroscopy was performed using a Mattson 4020 Galaxy series spectrophotometer. Quantum ( ¹ H) nuclear magnetic resonance (NMR) spectra were analyzed using General Electric using Me ₄ Si (δ0.00) or residual protonation solvents (CHCl ₃ δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as reference. It was measured with a GN-Omega 300 (300 MHz) spectrometer. Carbon ( ¹³ C) NMR spectra were measured on a General Electric GN-Omega 300 (75 MHz) spectrometer using solvents (CDCl ₃ δ 77.0; MeOD-d ₃ δ 49.0; DMSO-d ₆ δ 39.5) as reference. Measured. The low resolution mass spectrum (MS) and the high resolution mass spectrum (HRMS) were obtained as an electron impact (EI) mass spectrum or a rapid atomic bombardment (FAB) mass spectrum. Electron impact mass spectra (EI-MS) were obtained on a Hewlett Packard 5989A mass spectrometer using Vacuumetrics' absorption chemical ionization probe for sample introduction. The ion source was kept at 250 ° C. Electron impact ionization was performed using an electron energy of 70 eV and a trap current of 300 μA. An updated version of the rapid atom bombardment of liquid cesium secondary ion mass spectrum (FAB-MS) was obtained using the Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using Hewlett Packard MS engine (5989A) with methane or ammonia (1 × 10 ⁻⁴ Torr to 2.5 × 10 ⁻⁴ Torr) as working gas. Directly inserted absorption chemical ionization (DCI) probes (Vaccumetrics, Inc.) make slopes at 0-1.5 amps for 10 seconds and remain at 10 amps until all traces of the sample disappear (~ 1-2 minutes). Spectra are scanned at 50-800 amu at 2 seconds per scan. HPLC-electron spray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPCL equipped with a Finnigan LCQ ion trap mass spectrometer using a quaternary pump, wavelength shift detector, C-18 column and electron atomization ionization. Spectra were examined at 120-800 amu using various ion times depending on the number of ions in the source. Gas chromatography-ion selective mass spectra (GC-MS) were obtained from a Hewlett Packard 5890 gas equipped with an HP-1 methyl silicon column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 mass selector detector (ionization energy 70 eV). Obtained using chromatography. Elemental analysis was performed by Robertson Microlit Labs, Madison NJ.

All compounds showed NMR spectra, LRMS and HRMS consistent with elemental analysis or designated structures.

Abbreviation Acronym  List

AcOH acetic acid

anh anhydrous

atm air pressure (s)

BOC tert -butoxycarbonyl

CDI 1,1'-carbonyl diimidazole

conc thickening

d days (s)

dec decomposition

DMAC N, N -dimethylacetamide

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone

DMF N, N -dimethylformamide

DMSO dimethyl sulfoxide

DPPA diphenylphosphoryl azide

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

EtOAc ethyl acetate

EtOH ethanol (100%)

Et ₂ O diethyl ether

Et ₃ N triethylamine

h hour (s)

HOBT 1-hydroxybenzotriazole

m- CPBA 3-chloroperoxybenzoic acid

MeOH Methanol

pet.ether petroleum ether (boiling range 30-60 ℃)

temp. Temperature

THF tetrahydrofuran

TFA trifluoroAcOH

Tf trifluoromethanesulfonyl

A. General Synthesis of Substituted Anilines

A1. Ester hydrolysis, leading to ether formation degradation, increased Tears (Curtius) rearrangement and general method for producing an arylamine undergo carbamate deprotection. Synthesis of 2-amino-3-methoxynaphthalene

Step 1. methyl  3- Methoxy -2- Naphthoate

A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K ₂ CO ₃ (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temperature for 15 minutes and iodine methane (3.43 mL) , 55.1 mmol). The mixture was stirred overnight at room temperature and treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 × 200 mL). The mixed organic layer was washed with saturated NaCl solution (100 mL), concentrated to dryness (MgSO ₄ ) and under reduced pressure (overnight at about 0.4 mmHg) to give methyl 3-methoxy-2-naphthoate (10.30 g) as an amber oil. Got:

Step 2. 3- Methoxy -2- Naphthoic acid

A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) was treated with 1N NaOH solution (33.4 mL, 33.4 mmol) at room temperature. The mixture was heated at reflux for 3 hours, cooled to room temperature and acidified with 10% citric acid solution. The resulting solution was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated with hexanes and washed several times with hexanes to give 3-methoxy-2-naphthoic acid (5.40 g, 92%) as a white solid:

Step 3. 2- ( N -( Carbobenzyloxy Amino-3- Methoxynaphthalene

Anhydrous toluene (70 mL) solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et ₃ N (2.59 mL, 18.6 mmol) was stirred at room temperature for 15 minutes, using a pipette to DPPA toluene (10 mL). ) Solution (5.12 g, 18.6 mmol). The resulting mixture was heated at 80 ° C. for 2 hours. The mixture was cooled to room temperature and benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then warmed to 80 ° C. overnight. The resulting mixture was cooled to room temperature, quenched with 10% citric acid solution and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc / 86% hexanes) to give 2- ( N- (carbenzyloxy) amino-3-methoxynaphthalene (5.1 g, 100%) as a pale yellow oil.

Step 4. 2-Amino-3- Methoxynaphthalene

를 통하여 여과하고 감압하에 농축시켜 엷은 분홍색 분말로서 2-아미노-3-메톡시나프탈렌(2.40g, 85%)를 얻었다:A slurry of 2- ( N- (carbenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd / C (0.5 g) in EtOAc (70 mL) overnight at room temperature in H ₂ (Balloon) The resulting mixture was Celite

Filtration through and concentration under reduced pressure gave 2-amino-3-methoxynaphthalene (2.40 g, 85%) as pale pink powder:

A2. The formation of carbamylpyridine followed by aryl amines and Synthesis of ω-carbamyl aniline via nucleophilic coupling

Step 1a. Synthesis of 4-chloro -N- methyl-2-pyridine carboxamide with meni between (Menisci) reaction

Warning: This is a very dangerous and explosive reaction. To a solution of N-methylformamide (250 mL) solution of 4-chloropyridine (10.0 g) at room temperature was added to conc. H ₂ SO ₄ (3.55 mL) is added to generate a pyrogenic product. H ₂ O ₂ (30 wt.% In H ₂ O, 17 mL) was added to this mixture followed by FeSO ₄ · 7H ₂ O (0.56 g) to generate another exotherm. The resulting mixture was stirred for 1 hour in the dark at room temperature and then slowly warmed to 45 ° C. over 4 hours. When the foam had settled, the reaction was heated at 60 ° C. for 16 hours. The resulting opaque brown solution was diluted with H ₂ O (700 mL) followed by 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phase was washed separately using saturated NaCl solution (3 × 150 mL) and filtered through a pad of silica gel with the help of mixing, drying (MgSO ₄ ) and EtOAc. The resulting brown oil was purified by column chromatography (gradient 50% EtOAc / 50% hexanes to 80% EtOAc / 20% hexanes). The resulting yellow oil was crystallized at 0 ° C. for at least 72 hours to give 4-chloro- N -methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc / 50% hexanes) R _f 0.50 ;

Step 1b. Synthesis of 4 -chloropyridine -2-carbonyl chloride HCl salt via picolinic acid

Anhydrous DMF (60 mL) was added to SOCl ₂ (180 mL) between 40 ° C and 50 ° C. The solution was stirred for 10 minutes in the same temperature range and picolinic acid (60.0 g, 487 mmol) was added over 30 minutes in distribution. The resulting solution was heated for 16 h at 72 ° C. (active SO ₂ release) to yield a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 mL. The toluene addition / concentration process was repeated twice. The resulting almost dried residue was filtered and the solid washed with toluene (2 x 200 mL) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride HCl salt as a yellow-orange solid (92.0 g, 89 %) Was obtained.

Step 2. methyl  4- Chloropyridine -2- Carboxylate HCl Synthesis of Salts

Anhydrous DMF (10.0 mL) was added to SOCl ₂ (300 mL) at 40-48 ° C. The solution was stirred for 10 minutes in the same temperature range and picolinic acid (100 g, 812 mmol) was added over 30 minutes. The resulting solution was heated at 72 ° C. (active SO ₂ release) for 16 hours to yield a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 ml) and concentrated to 200 mL. The toluene addition / concentration process was repeated twice. The resulting almost dried residue was filtered and the solid was washed with toluene (50 mL) and dried under high vacuum for 4 hours to give 4-chloropyridine-2-carbonyl chloride HCl salt as an off-white solid ( 27.2 g, 16%). This material was set aside.

A red precipitate was added to MeOH (200 mL) at a rate such that the internal temperature was kept below 55 ° C. The contents were stirred at room temperature for 45 minutes, cooled to 5 ° C. and treated dropwise with Et ₂ O (200 mL). The resulting solid was filtered, washed with Et ₂ O (200 mL) and dried under reduced pressure at 35 ° C. to afford methyl 4-chloropyridine-2-carboxylate HCl salt (110 g, 65%) as a white solid: mp 108-112 ° C .;

Step 3a. Synthesis of 4 -chloro - N - methyl -2-pyridinecarboxamide from Methyl 4 -chloropyridine -2 -carboxylate

Suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0 ° C., 2.0 M methyl in THF (1 L) at a rate such that the internal temperature was kept below 5 ° C. Treated with amine solution. The resulting mixture was stored at 3 ° C. for 5 hours and concentrated under reduced pressure. The resulting solid was suspended in EtOAc (1 L) and filtered. The precipitate was washed with saturated NaCl solution (500 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to afford 4-chloro- N -methyl-2-pyridinecarboxamide (71.2 g, 97 as pale-yellow crystals). %) Was obtained: mp 41-43 ° C .;

Step 3b. Synthesis of 4 -chloro - N - methyl -2-pyridinecarboxamide from 4 - chloropyridine- 2-carbonyl chloride

4-chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added at 0 ° C. to a mixture of 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL). The resulting mixture was stored at 3 ° C. for 4 hours and concentrated under reduced pressure. The resulting almost dried solid was suspended in EtOAc (100 mL) and filtered. The precipitate was washed with saturated NaCl solution (2 × 100 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to give 4-chloro- N -methyl-2-pyridinecarboxamide (4.95 g, as a yellow crystalline solid). 88%) was obtained: mp 37-40 ° C;

Step 4. 4- (2- (N- Methylcarbamoyl )-4- Pyridyloxy Synthesis of Aniline

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anhydrous DMF (150 mL) was treated with potassium tert -butoxide (10.29 g, 91.7 mmol) and the reddish-brown mixture was stirred at room temperature for 2 hours. It was. The contents were treated with 4-chloro- N -methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K ₂ CO ₃ (6.50 g, 47.0 mmol) and then heated at 80 ° C. for 8 hours. The mixture was cooled to room temperature and separated between EtOAc (500 mL) and saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with saturated NaCl solution (4 × 100 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The resulting solid was dried at 35 ° C. under reduced pressure for 3 hours to give 2- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline (17.9 g, 84%) as a light-brown solid:

A3. General method for synthesizing aniline by nucleophilic aromatic addition reaction followed by nitroarene reduction . 5- (4-aminophenoxy) isoindolin-1,3-dione

Step 1. 5- Hydroxyisoindolin -1,3- Dion's  synthesis

conc. To the mixture of ammonium carbonate (5.28 g, 54.9 mmol) in AcOH (25 mL) was added slowly 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120 ° C. for 45 minutes and the clear, clear yellow mixture was heated at 160 ° C. for 2 hours. The resulting mixture was maintained at 160 ° C. and concentrated to about 15 mL, then cooled to room temperature and adjusted to pH 10 with 1N NaOH solution. The mixture was cooled to 0 ° C. and acidified slowly to pH 5 with 1N HCl solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give 5-hydroxyisoindolin-1,3-dione (3.24 g, 72%) as a pale yellow powder product: ¹ H NMR (DMSO-d ₆ ) δ 7 .00-7.03 (m, 2H), 7.56 (d, J = 9.3 Hz, 1H).

Step 2. 5- (4- Nitrophenoxy ) Isoindolin -1,3- Dion's  synthesis

To a stirred slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) was added dropwise a solution of 5-hydroxyisoindolin-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) at 0 ° C. . The bright yellow-green mixture was returned to room temperature and stirred for 1 hour, after which 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added in 3-4 doses through a syringe. The resulting mixture was heated at 70 ° C. overnight and cooled to room temperature, diluted slowly with water (150 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to afford 5- (4-nitrophenoxy) isoindolin-1,3-dione (3.3 g, 62%) as a yellow solid: TLC (30% EtOAc / 70% hexane) R _f 0.28;

Step 3. 5- (4- Aminophenoxy ) Isoindolin -1,3- Dion's  synthesis

conc. A solution of 5- (4-nitrophenoxy) isoindolin-1,3-dione (0.6 g, 2.11 mmol) and water (0.1 mL) in AcOH (12 mL) was added iron powder (0.59 g, 55.9 mmol). Slowly added and stirred under argon vapor. The mixture was stirred at rt for 72 h, diluted with water (25 mL) and extracted with EtOAc (3 × 500 mL). The combined organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give 5- (4-aminophenoxy) isoindolin-1,3-dione (0.4 g, 75%) as a brownish solid: TLC (50 % EtOAc / 50% hexanes) R _f 0.27;

A4. General synthetic method of pyrrolyl aniline . Synthesis of 5- tert -butyl-2- (2,5- dimethylpyrrolyl ) aniline

Step 1. 1- (4- tert -Butyl-2- Nitrophenyl ) -2,5- Dimethylpyrrole  synthesis

To a solution of 2-nitro-4- tert -butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (0.1 mL) and acetonyl acetone (0.299 g, 2.63 mmol) via syringe. . The reaction mixture was heated at 120 ° C. for 72 hours while azeotropically removing volatiles. The reaction mixture was cooled to room temperature and diluted with CH ₂ Cl ₂ (10 mL), washed successively with 1N HCl solution (15 mL), 1N NaOH solution (15 mL) and saturated NaCl solution (15 mL) and dried (MgSO ₄ ) And concentrated under reduced pressure. The resulting orange-brown solid was purified by column chromatography (60 g SiO ₂ ; gradient 6% EtOAc / 94% hexanes to 25% EtOAc / 75% hexanes) to give 1- (4- tert -as an orange-yellow solid. Butyl-2-nitrophenyl) -2,5-dimethylpyrrole (0.34 g, 49%) was obtained: TLC (15% EtOAc / 85% hexanes) R _f 0.67;

Step 2. 5- tert -Butyl-2- (2,5- Dimethylpyrrolyl Synthesis of Aniline

패드를 통하여 여과하였다. 여과물을 감압하에 농축시켜 노란색을 띠는 고체로서 5-tert-부틸-2-(2,5-디메틸피롤릴)아닐린(0.30g, 99%)을 얻었다: TLC (10% EtOAc/ 90% 헥산) R_f 0.43;1- (4- tert -butyl-2-nitrophenyl) -2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd / C (0.056 g) and EtOAc (50 mL) under H ₂ atmosphere (balloon) Of the slurry was stirred for 72 hours

Filter through the pad. The filtrate was concentrated under reduced pressure to afford 5- tert -butyl-2- (2,5-dimethylpyrrolyl) aniline (0.30 g, 99%) as a yellowish solid: TLC (10% EtOAc / 90% hexanes) ) R _f 0.43;

A5. General method for synthesizing aniline from aniline by nucleophilic aromatic substitution reaction . Synthesis of 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-methylaniline HCl Salt

A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert -butoxide (10.86 g, 96.77 mmol) and the flask temperature reached room temperature The black mixture was stirred at room temperature until. The reaction was then treated with 4-chloro- N -methyl-2-pyridinecarboxamide (method A2, step 3b; 7.52 g, 44.2 mmol) and heated at 110 ° C. for 8 hours. The mixture was cooled to room temperature and diluted with water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with saturated NaCl solution (200 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. The remaining black oil was treated with Et ₂ O (50 mL) and sonicated. The solution was then treated with HCl (1M in Et ₂ O; 100 mL) and stirred for 5 minutes at room temperature. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed from the solution by filtration and stored at 0 ° C. in anaerobic conditions prior to use:

A6. General method for synthesizing aniline from hydroxyaniline by N -protection, nucleophilic aromatic substitution and deprotection . Synthesis of 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline

Step 1. 3- Chloro -4- (2,2,2- Trifluoroacetylamino Synthesis of Phenol

Iron (3.24 g, 58.00 mmol) was added to TFA (200 mL) with stirring. 2-Chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride (20 mL) were added to this slurry. This gray slurry was stirred for 6 days at room temperature. Iron was filtered from the solution and the remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added saturated NaHCO ₃ solution (50 mL). The precipitated solid was removed from the solution. The filtrate was slowly quenched in sodium bicarbonate solution until the product was clearly separated from the solution (determined using a small precision rubber vial). The slightly cloudy yellow solution was extracted with EtOAc (3 × 125 mL). The combined organic layers were washed with saturated NaCl solution (125 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. ¹ H NMR (DMSO-d ₆ ) indicates the 1: 1 ratio of nitrophenol starting material and intended product 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol. Crude material was used in the next step without further purification.

Step 2. 4 - Synthesis of (2- (N-methyl-carbamoyl) -4-pyridyloxy) -2-chlorophenyl (222- to triple Luo) acetamide

A solution of crude 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was added to potassium tert -butoxide (5.16 g, 45.98 mmol). ) And a brownish black mixture was stirred at room temperature until the flask temperature reached room temperature. The resulting mixture was treated with 4-chloro- N -methyl-2-pyridinecarboxamide (method A2, step 3b; 1.99 g, 11.7 mmol) and heated to 100 ° C. for 4 days under argon. The black reaction mixture was cooled to room temperature and poured into cold water (100 mL). This mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The remaining brown oil was purified by column chromatography (gradient from 20% EtOAc / pet ether to 40% EtOAc / pet ether) to 4- (2- ( N -methylcarbamoyl) -4 as a yellow solid. -Pyridyloxy) -2-chlorophenyl (222-trifluoro) acetamide (8.59 g, 23.0 mmol) was obtained.

Step 3. 4- (2- ( N - Methylcarbamoyl )-4- Pyridyloxy )-2- Chloroaniline  synthesis

Crude 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chlorophenyl (222-trifluoro) acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) ) Was treated with 1N NaOH solution (20 mL). This brown solution was stirred for 8 hours. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 × 40 mL) and the solvent was left to concentrate and left as a solidified green oil as 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline ( 2.86 g, 10.30 mmol) was obtained:

A7. General deprotection method of acylated aniline . 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline Synthesis of

A suspension of 3-chloro-6- ( N -acetyl) -4- (trifluoromethyl) anizol (4.00 g, 14.95 mmol) in 6M HCl solution (24 mL) was heated at reflux for 1 h. The resulting solution was cooled to room temperature while it slowly solidified. The resulting mixture was diluted with water (20 mL) and treated with solid NaOH and saturated NaHCO ₃ solution together until the solution was basic. The organic layer was extracted with CH ₂ Cl ₂ (3 × 500 mL). The combined organics were dried (MgSO ₄ ) and concentrated under reduced pressure to afford 4-chloro-2-methoxy-5- (trifluoromethyl) aniline (3.20 g, 14.2 mmol) as a brown oil: ¹ H NMR (DMSO- d ₆ ) δ 3.84 (s. 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. General method for obtaining ω-alkoxy-ω- carboxyphenyl aniline. Synthesis of 4- (3- ( N - methylcarbamoyl) -4-methoxyphenoxy) aniline

Step 1. 4- (3- Methoxycarbonyl -4- Methoxyphenoxy Synthesis of 1-nitrobenzene

패드를 통하여 여과하였다. 생성된 용액을 감압하에 농축시키고 SiO₂상에서 흡수 후, 칼럼 크로마토그래피(50% EtOAc/ 50% 헥산)에 의하여 정제하여 노란색 분말로서 4-(3-메톡시카르보닐-4-메톡시페녹시)-1-니트로벤젠(3g)을 얻었다: mp 115-118℃.4- (3-carboxy-4-hydroxyphenoxy) -1-nitro (prepared from 12 mmol of 2,5-dihydroxybenzoic acid by similar means as described in Method A13, step 1) in acetone (50 mL) To a solution of benzene was added K ₂ CO ₃ (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated to reflux overnight and cooled to room temperature before Celite

Filter through the pad. The resulting solution was concentrated under reduced pressure and absorbed on SiO ₂ and then purified by column chromatography (50% EtOAc / 50% hexanes) to give 4- (3-methoxycarbonyl-4-methoxyphenoxy) as a yellow powder. -1-nitrobenzene (3 g) was obtained: mp 115-118 ° C .;

Step 2. 4- (3- Carboxy -4- Methoxyphenoxy Synthesis of 1-nitrobenzene

A mixture of 4- (3-methoxycarbonyl-4-methoxyphenoxy) -1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (5 mL) was stirred overnight at room temperature And heated at reflux for 4 hours. The resulting mixture was concentrated to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 mL) and the aqueous mixture was acidified with 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to afford 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (1.04 g).

Step 3. 4- (3- ( N - Methylcarbamoyl )-4- Methoxyphenoxy Synthesis of 1-nitrobenzene

To a solution of 4- (3-carboxy-4-methoxyphenoxy) -1-nitrobenzene (0.50 g, 1.75 mmol) in CH ₂ Cl ₂ (12 mL), add SOCl ₂ (0.64 mL, 8.77 mmol) in a partitioned manner. It was. The resulting solution was heated to reflux for 18 hours, cooled to room temperature and concentrated under reduced pressure. The resulting yellow solid was dissolved in CH ₂ Cl ₂ (3 mL) and then the resulting solution was partitioned into a solution of methylamine (2.0 M in THF, 3.5 mL, 7.02 mmol) (warning: gas evolution). This was stirred for 4 hours at room temperature. The resulting mixture was treated with 1N NaOH solution and extracted with CH ₂ Cl ₂ (25 mL). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to afford 4- (3- ( N -methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene (0.50 g, 95%) as a yellow solid.

Step 4. 4- (3- ( N - Methylcarbamoyl )-4- Methoxyphenoxy ) -Aniline Synthesis

패드를 통하여 여과하였다. 생성된 용액을 감압하에 농축시켜 회색이 도는 백색 고체로서 4-(3-(N-메틸카바모일)-4-메톡시페녹시)-아닐린(0.68g, 96%)을 얻었다; TLC (0.1% Et₃N/ 99.9% EtOAc) R_f 0.36.Slurry of 4- (3- ( N -methylcarbamoyl) -4-methoxyphenoxy) -1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd / C (0.20 g) in EtOH (55 mL) H ₂ (balloon) stirred at 1 atmosphere for 2.5 days and Celite

Filter through the pad. The resulting solution was concentrated under reduced pressure to afford 4- (3- ( N -methylcarbamoyl) -4-methoxyphenoxy) -aniline (0.68 g, 96%) as a grayish white solid; TLC (0.1% Et ₃ N / 99.9% EtOAc) R _f 0.36.

A9. A general method for producing ω- alkylphthalimide containing aniline. Synthesis of 5- (4 - aminophenoxy) -2-methylisoindolin-1,3-dione

Step 1. 5- (4- Nitrophenoxy )-2- Methylisoindolin -1,3- Dion's  synthesis

A slurry of 5- (4-nitrophenoxy) isoindolin-1,3-dione (A3 step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred for 1 hour at room temperature. Was stirred and treated with methyl iodine (0.3 mL, 4.57 mmol). The resulting mixture was stirred at rt overnight, then cooled to C and treated with water (10 mL). The resulting solid was recovered and dried under reduced pressure to give 5- (4-nitrophenoxy) -2-methylisoindolin-1,3-dione (0.87 g, 83%) as a clear yellow solid: TLC (35% EtOAc / 65% hexanes) R _f 0.61.

Step 2. 5- (4- Aminophenoxy )-2- Methylisoindolin -1,3- Dion's  synthesis

패드를 통하여 여과시키고 감압하에 농축시켰다. 생성된 노란색 고체를 EtOAc(3mL)에 용해시키고 SiO₂의 플러그(60% EtOAc/ 40% 헥산)를 통하여 여과시켜 노란색 고체로서 5-(4-아미노페녹시)-2-메틸이소인돌린-1,3-디온(0.67g, 86%)을 얻었다; TLC (40% EtOAc/ 60% 헥산) R_f 0.27.A slurry of nitrophenoxy-2-methylisoindolein-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd / C (0.10 g) in MeOH was stirred for 2.5 days under 1 atmosphere of H ₂ (balloon) It was. The resulting mixture was purified by Celite

Filter through pad and concentrate under reduced pressure. The resulting yellow solid was dissolved in EtOAc (3 mL) and filtered through a plug of SiO ₂ (60% EtOAc / 40% hexanes) to give 5- (4-aminophenoxy) -2-methylisoindolin-1 as a yellow solid. , 3-dione (0.67 g, 86%) was obtained; TLC (40% EtOAc / 60% hexanes) R _f 0.27.

A10. ω - carbamoylaryl by reacting an amine with an ω- alkoxycarbonylaryl precursor General way to synthesize aniline. Synthesis of 4- (2- ( N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline

Step 1. 4- Chloro -2-( N -(2-morpholine-4- Ethyl ) Cabamo Synthesis of Pyridine

4- (2-aminoethyl) morpholine (2.55 mL, 19.4 mmol) in a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (method A2, step 2; 1.01 g, 4.86 mmol) in THF (20 mL) ) Was added dropwise and the resulting solution was heated to reflux for 20 hours and then cooled to room temperature and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to afford 4-chloro-2- ( N- (2-morpholin-4-ylethyl) carbamoyl) pyridine (1.25 g, 95%) as a yellow oil; TLC (10% MeOH / 90% EtOAc) R _f 0.50.

Step 2. Synthesis of 4- (2- ( N- (2-morpholin-4- ylethyl ) carbamoyl ) pyridyloxy ) aniline

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert -butoxide (0.53 g, 4.75 mmol) in DMF (8 mL) was stirred at room temperature for 2 hours, followed by 4-chloro-2- ( N − Treated with (2-morpholin-4-ylethyl) carbamoyl) pyridine (1.22 g, 4.52 mmol) and K ₂ CO ₃ (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 ° C. overnight and cooled to room temperature, then separated between EtOAc (25 mL) and saturated NaCl solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with saturated NaCl solution (3 × 25 mL) and concentrated under reduced pressure. The resulting brown solid was purified by column chromatography (58 g, gradient from 100% EtOAc to 25% MeOH / 75% EtOAc) to 4- (2- ( N- (2-morpholin-4-ylethyl) carbamoyl ) Pyridyloxy) aniline (1.0 g, 65%) was obtained: TLC (10% MeOH / 90% EtOAc) R _f 0.32.

A11. General method of reducing nitroarene to arylamine. Synthesis of 4- (3 -carboxyphenoxy ) aniline

패드를 통하여 여과시키고 감압하에 농축시켜 갈색 고체로서 4-(3-카르복시페녹시)아닐린(2.26g, 48%)을 얻었다; TLC (10% MeOH/ 90% CH₂Cl₂) R_f 0.44(스트리킹).Slurry of 4- (3-carboxyphenoxy) -1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd / C (0.50 g) in MeOH (120 mL) for 2 days under 1 atmosphere of H ₂ (balloon) Stirred. The resulting mixture was purified by Celite

Filtered through a pad and concentrated under reduced pressure to afford 4- (3-carboxyphenoxy) aniline (2.26 g, 48%) as a brown solid; TLC (10% MeOH / 90% CH ₂ Cl ₂ ) R _f 0.44 (stripping).

A12. General method for synthesizing isoindolinone- containing aniline. Synthesis of 4- (1- oxoisoindolin -5-yloxy) aniline

Step 1. 5- Hydroxyisoindolin Synthesis of 1-membered

To the solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was added slowly, distributing zinc powder (47.6 g, 729 mmol), and the mixture was heated at reflux for 40 minutes and immediately filtered. And concentrated under reduced pressure. The reaction was repeated on the same scale and the mixed oily residue was purified by column chromatography (1.1 kg SiO ₂ ; gradient from 60% EtOAc / 40% hexane to 25% MeOH / 75% EtOAc) to give 5-hydroxy. Soindoline-1-one (3.77 g) was obtained: TLC (100% EtOAc) R _f 0.17; HPLC ES MS m / z 150 (M + H) ⁺ ).

Step 2. 4- (1- Isoindolinone -5- Iloxy Synthesis of 1-nitrobenzene

To a slurry of NaH (0.39 g, 16.1 mmol) in DMF was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions at 0 ° C. The resulting slurry was allowed to warm to room temperature and stirred for 45 minutes, and 4-fluoro-1-nitrobenzene was added and the mixture was heated at 70 ° C. for 3 hours. The mixture was cooled to 0 ° C. and water was added dropwise until a precipitate formed. The resulting solid was recovered, giving 4- (1-isoindolinone-5-yloxy) -1-nitrobenzene (3.23 g, 89%) as a dark yellow solid: TLC (100% EtOAc) R _f 0.35 .

Step 3. 4- (1- Oxoisoindolin -5- Iloxy Synthesis of Aniline

패드를 통하여 여과하였다. 여과물을 감압하에 농축시켜 어두운 노란색 고체로서 4-(1-옥소이소인돌린-5-일옥시)아닐린을 얻었다; TLC (100% EtOAc) R_f 0.15.A slurry of 4- (1-isoindolinone-5-yloxy) -1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd / C (0.20 g) in EtOH (50 mL) was charged with H ₂ (balloon). Stir under air for 4 hours and Celite

Filter through the pad. The filtrate was concentrated under reduced pressure to afford 4- (1-oxoisoindolin-5-yloxy) aniline as a dark yellow solid; TLC (100% EtOAc) R _f 0.15.

A13. EDCI - A general method for synthesizing ω-carbamoyl aniline via mediated amide formation followed by nitroarene reduction . Synthesis of 4- (3- N -methylcarbamoylphenoxy) aniline

*

Step 1. 4- (3- Ethoxycarbonylphenoxy Synthesis of 1-nitrobenzene

Mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate (25 g, 150 mmol) and K ₂ CO ₃ (41 g, 300 mmol) in DMF (125 mL) overnight at reflux temperature Heated, cooled to room temperature and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic phases were washed successively with water (3 x 100 mL) and saturated NaCl solution (2 x 100 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc / 90% hexanes) to give 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene (38 g) as an oil.

Step 2. 4- (3- Carboxyphenoxy Synthesis of 1-nitrobenzene

LiOH.H in water (36 mL) to a mixture of 4- (3-ethoxycarbonylphenoxy) -1-nitrobenzene (5.14 g, 17.9 mmol) vigorously stirred in a 3: 1 THF / water solution (75 mL). A solution of ₂ O (1.50 g, 35.8 mmol) was added. The resulting mixture was heated at 50 ° C. overnight, cooled to room temperature and concentrated under reduced pressure and adjusted to pH 2 with 1M HCl solution. The resulting clear yellow solid was removed by filtration and washed with hexane to give 4- (3-carboxyphenoxy) -1-nitrobenzene (4.40 g, 95%).

Step 3. 4- (3- ( N - Methylcarbamoyl ) Phenoxy Synthesis of -1-nitrobenzene

4- (3-carboxyphenoxy) -1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63 g, 18.6 mmol) in CH ₂ Cl ₂ (45 mL), N -methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) were stirred at room temperature for 3 days and concentrated under reduced pressure. This residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted using 1M HCl (50 mL) solution. The aqueous layer was back extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with saturated NaCl (50 mL) solution, dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to give 4- (3- ( N -methylcarbamoyl) phenoxy-1-nitrobenzene (1.89) as an oil. g0 was obtained.

Step 4. 4- (3- ( N - Methylcarbamoyl ) Phenoxy Synthesis of Aniline

패드를 통하여 여과시키고 감압하에 농축시켰다. 이 잔사를 칼럼 크로마토그래피(5% MeOH/95% CH₂Cl₂)에 의하여 정제하였다. 생성된 오일을 진공하에 밤새도록 고체화시켜 노란색 고체로서 4-(3-(N-메틸카바모일)페녹시)아닐린(0.95g, 56%)을 얻었다. A slurry of 4- (3- ( N -methylcarbamoyl) phenoxy-1-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd / C (0.24 g) in EtOAc (20 mL) was heated in an H ₂ (balloon) atmosphere. The mixture was stirred overnight under Celite.

Filter through pad and concentrate under reduced pressure. This residue was purified by column chromatography (5% MeOH / 95% CH ₂ Cl ₂ ). The resulting oil was solidified under vacuum overnight to afford 4- (3- ( N -methylcarbamoyl) phenoxy) aniline (0.95 g, 56%) as a yellow solid.

A14. EDCI - A general method for synthesizing ω-carbamoyl aniline via mediated amide formation followed by nitroarene reduction . Synthesis of 4-3- (5-methylcarbamoyl) pyridyloxy) aniline

Step 1. 4- (3- (5- Methoxycarbonyl ) Pyridyloxy Synthesis of 1-nitrobenzene

To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL), and the mixture was heated at 70 ° C. overnight and cooled to room temperature followed by MeOH (5 mL) followed by water ( 50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. This residue was purified by column chromatography (30% EtOAc / 70% hexane) to give 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g).

Step 2. 4- (3- (5- Methoxycarbonyl ) Pyridyloxy Synthesis of Aniline

Slurry of 4- (3- (5-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd / C in MeOH / EtOAc under H ₂ atmosphere (balloon) Stir for hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc / 90% hexane to 30% EtOAc / 70% hexane, 50% EtOAc / 50% hexane) to give 4- (3- (5-methoxycarbonyl) pyridine. Dyloxy) aniline (0.28 g, 60%) was obtained:

A15. Electrophilicity Synthesis of Aniline by nitration followed by reduction. Synthesis of 4- (3-methylsulfamoylphenoxy) aniline

Step 1. N - methyl -3- Bromobenzenesulfonamide  synthesis

To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) was added methylamine (2.0 M in THF; 28 mL, 56 mmol) at 0 ° C. The resulting solution was allowed to warm up to room temperature and stirred overnight at room temperature. The resulting mixture was separated between EtOAc (25 mL) and 1M HCl solution (25 mL). The aqueous phase was back extracted with EtOAc (2 x 25 mL). The combined organic phases were washed successively with water (2 × 25 mL) and saturated NaCl (25 mL) solution, dried (MgSO ₄ ), and concentrated under reduced pressure to yield N -methyl-3-bromobenzenesulfonamide as a white solid. (2.8 g, 99%) was obtained.

Step 2. 4- (3- ( N - Methylsulfamoyl ) Phenyloxy Synthesis of Benzene

N -methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol) in a slurry of phenol (1.9 g, 20 mmol), K ₂ CO ₃ (6.0 g, 40 mmol) and CuI (4 g, 20 mmol) in DMF (25 mL). Was added and the resulting mixture was stirred at reflux overnight, cooled to room temperature and separated between EtOAc (50 mL) and 1N.HCl solution (50 mL). The aqueous layer was back extracted with EtOAc (2 x 50 mL). The combined organic phases were washed successively with water (2 x 50 mL) and saturated NaCl (50 mL) solution, dried (MgSO ₄ ), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc / 70% hexanes) to give 4- (3- ( N -methylsulfamoyl) phenyloxy) benzene (0.30 g).

Step 3. 4- (3- ( N - Methylsulfamoyl ) Phenyloxy Synthesis of 1-nitrobenzene

Distribute NaNO ₂ (0.097 g, 1.14 mmol) over 5 minutes at a solution of 4- (3- ( N -methylsulfamoyl) phenyloxy) benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at −10 ° C. And added. The resulting solution was stirred at −10 ° C. for 1 hour, warmed up to room temperature and concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was washed successively with water (10 mL) and saturated NaCl (10 mL) solution, dried (MgSO ₄ ), and concentrated under reduced pressure to afford 4- (3- ( N -methylsulfamoyl) phenyloxy) -1 Nitrobenzene (0.20 g) was obtained. This material was used for the next step without further purification.

Step 4. 4- (3- ( N - Methylsulfamoyl ) Phenyloxy Synthesis of Aniline

패드를 통하여 여과하였다. 그 여과물을 감압하에 농축시켰다. 이 잔사를 칼럼 크로마토그래피(30% EtOAc/70% 헥산)로 정제하여 4-(3-(N-메틸술파모일)페닐옥시)아닐린(0.070g)을 얻었다.A slurry of 4- (3- ( N -methylsulfamoyl) phenyloxy) -1-nitrobenzene (0.30 g) and 10% Pd / C (0.030 g) in EtOAc (20 mL) overnight under H ₂ atmosphere (balloon) Was stirred. The resulting mixture was purified by Celite

Filter through the pad. The filtrate was concentrated under reduced pressure. This residue was purified by column chromatography (30% EtOAc / 70% hexane) to give 4- (3- ( N -methylsulfamoyl) phenyloxy) aniline (0.070 g).

A16. deformation of ω-ketone. 4- (4- (1- (N - methoxy) imino) phenoxy aniline HCl Synthesis of Salts

To the slurry of EtOH (prepared by the method A13, step 4, and the similar means) of a mixture of (10mL) and pyridine (1.0mL) 4- (4- acetylphenoxy) aniline HCl salt (1.0g, 3.89mmol) O - Methylhydroxylamine HCl salt (0.65 g, 7.78 mmol, 2.0 equiv) was added. The resulting solution was heated to reflux for 30 minutes, cooled to room temperature and concentrated under reduced pressure. The resulting solid was triturated with water (10 mL) and washed with water to give 4- (4- (1- ( N -methoxy) iminoethyl) phenoxyaniline HCl salt (0.85 g) as a yellow solid: TLC ( 50% EtOAc / 50% pet ether R _f 0.78:

A17. Synthesis of N- (ω- silyloxyalkyl ) amide. Synthesis of 4- (4- (2- ( N- (2 -triisopropyl silyloxy) ethylcarbamoyl) pyridyloxyaniline

Step 1. Synthesis of 4 -chloro - N- (2 -triisopropylsilyloxy ) ethylpyridine-2 -carboxamide

Tree in a solution of 4-chloro- N- (2-hydroxyethyl) pyridine-2-carboxamide (1.5 g, 7.4 mmol) in anhydrous DMF (7 mL) (prepared by means similar to Method A2, step 3b) Isopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv) were added. The resulting yellow solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was separated between water (10 mL) and EtOAc (10 mL). The organic layer was extracted with EtOAc (3 × 100 mL). The combined organic phases were dried (MgSO ₄ ) and concentrated under reduced pressure to afford 4-chloro-2- ( N- (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide (2.32 g, 88%) as an orange oil. . This material was used for the next step without further purification.

Step 2. Synthesis of 4- (4- (2- ( N- (2 -triisopropylsilyloxy ) ethylcarbamoyl ) pyridyloxycyanine

Potassium tert -butoxide (0.67 g, 6.0 mmol, 1.0 equiv) was added to the solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anhydrous DMF (8 mL) to cause exotherm. When the mixture was cooled to room temperature, a solution of 4-chloro-2- ( N- (2-triisopropylsilyloxy) ethyl) pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv) in DMF (4 mL) was added and K ₂ CO ₃ (0.42 g, 3.0 mmol, 0.50 equiv) was then added. The resulting mixture was heated at 80 ° C. overnight. An additional portion of potassium tert -butoxide (0.34 g, 3 mmol, 0.5 equiv) was added and the mixture was further stirred at 80 ° C. for 4 h. The mixture was cooled to 0 ° C. using an ice / water solution and water (about 1 mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated NaCl (20 mL) solution, dried (MgSO ₄ ), and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO ₂ ; 30% EtOAc / 70% pet ether) to give 4- (4- (2- ( N- (2-triisopropylsilyloxy) ethyl as clear light brown oil). Carbamoyl) pyridyloxyaniline (0.99 g, 38%) was obtained.

A18. Synthesis of 2-pyridin-2-carboxylate ester via oxidation of 2-methyl-pyridine. Synthesis of 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline

Step 1. 4- (5- (2- methyl ) Pyridyloxy Synthesis of 1-nitrobenzene

5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol) in DMF (100 mL), 1-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv) and K ₂ CO ₃ (25 g, 183 mmol) , 2.0 equivalents) was heated to reflux overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed successively with water (2 x 100 mL) and saturated NaCl (100 mL) solution, dried (MgSO ₄ ), and concentrated under reduced pressure to afford 4- (5- (2-methyl) pyri as a brown solid. Dyloxy) -1-nitrobenzene (12.3 g) was obtained.

Step 2. 4- (5- (2- Methoxycarbonyl ) Pyridyloxy Synthesis of 1-nitrobenzene

A mixture of 4- (5- (2-methyl) pyridyloxy) -1-nitrobenzene (1.71 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv) in pyridine (20 mL) at reflux temperature Heated for 5 hours and cooled to room temperature. The resulting slurry was filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with conc HCl solution (7 mL), heated to reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. This residue was separated between EtOAc (50 mL) and 1N NaOH (50 mL) solution. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed successively with water (2 × 50 mL) and saturated NaCl (50 mL) solution, dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ; 50% EtOAc / 50% hexane) to give 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.70 g).

Step 3. 4- (5- (2- Methoxycarbonyl ) Pyridyloxy Synthesis of Aniline

패드를 통하여 여과시키고 그 여과물을 감압하에 농축시켰다. 잔사를 칼럼 크로마토그래피(SiO₂; 70% EtOAc/ 30% 헥산)로 정제하여 4-(5-(2-메톡시카르보닐)피리딜옥시)아닐린(0.40g)를 얻었다. Slurry of 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene (0.50 g) and 10% Pd / C (0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) Was kept overnight under H ₂ atmosphere (balloon). The resulting mixture was purified by Celite

Filter through the pad and concentrate the filtrate under reduced pressure. The residue was purified by column chromatography (SiO ₂ ; 70% EtOAc / 30% hexanes) to afford 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline (0.40 g).

A19. Synthesis of ω- sulfonylphenyl aniline. Synthesis of 4- (4 -methylsulfonylphenoxy ) aniline

Step 1. 4- (4- Methylsulfonylphenoxy Synthesis of 1-nitrobenzene

To a solution of 4- (4-methylthiophenoxy) -1-nitrobenzene (2.0 g, 7.7 mmol) in CH ₂ Cl ₂ (75 mL) m- CPBA (57-86%, 4.0 g) at 0 ° C. Slowly added and the reaction mixture was stirred for 5 hours at room temperature. The reaction mixture was treated with 1N NaOH (25 mL) solution. The organic layer was washed successively with 1N NaOH (25 mL) solution, water (25 mL) and saturated NaCl (25 mL) solution, dried (MgSO ₄ ), and concentrated under reduced pressure to give 4- (4-methylsulfonyl as a solid. Phenoxy) -1-nitrobenzene (2.1 g) was obtained.

Step 2. 4- (4- Methylsulfonylphenoxy Synthesis of 1-aniline

4- (4-methylsulfonylphenoxy) -1-nitrobenzene was reduced to aniline by means similar to Method A18, step 3.

B. Urea  Synthesis of Precursors

B1. General method for synthesizing isocyanates from aniline using CDI . Synthesis of 4-bromo-3- (trifluoromethyl) phenyl isocyanate

Step 1. 4- Bromo -3- ( Trifluoromethyl )aniline HCl  salt

To a solution of 4-bromo-3- (trifluoromethyl) aniline (64 g, 267 mmol) in Et ₂ O (500 mL) was added dropwise HCl solution (1M in Et ₂ O; 300 mL) and the resulting mixture was stirred at room temperature 16 Stir for hours. The resulting pink-white precipitate was removed by filtration and washed with Et ₂ O (50 mL) to afford 4-bromo-3- (trifluoromethyl) aniline HCl salt (73 g, 98%).

Step 2. 4- Bromo -3- ( Trifluoromethyl ) Phenyl  Synthesis of Isocyanates

A suspension of 4-bromo-3- (trifluoromethyl) aniline HCl salt (36.8 g, 133 mmol) in toluene (278 mL) was treated by dropwise addition of trichloromethyl chloroformate and the resulting mixture was refluxed for 18 hours. Heated to. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL) and concentrated under reduced pressure. The residue was treated with CH ₂ Cl ₂ (500 mL) and concentrated under reduced pressure. CH ₂ Cl ₂ The resulting amber oil was repeated 16 hours at −20 ° C. by repeating the treatment / concentration protocol to give 4-bromo-3- (trifluoromethyl) phenyl isocyanate (35.1 g, 86%) as a tan solid: GC-MS m / z 265 (M ⁺ ).

C. Urea  Manufacturing method

C1a . General method for synthesizing urea by reacting isocyanate with aniline . Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea

CH ₂ Cl ₂ (35mL) of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (14.60g, 65.90mmol) solution of CH ₂ Cl ₂ (35mL) of 4- (2- (N in-methylcarbapenem Moyl) -4-pyridyloxy) aniline (method A2, step 4; 16.0 g, 65.77 mmol) was added at 0 ° C. The resulting mixture was stirred at rt for 22 h. The resulting yellow solid was removed by filtration, washed with CH ₂ Cl ₂ (2 × 30 mL) and dried under reduced pressure (about 1 mmHg) to give N- (4-chloro-3- (trifluoro) as a grayish white solid. Romethyl) phenyl) -N '-(4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea (28.5 g, 93%) was obtained: mp 207-209 ° C;

C1b . General method for synthesizing urea by reacting isocyanate with aniline . Synthesis of N- (4-bromo-3- (trifluoromethyl) phenyl) -N '-(4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea

A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (method B1, step 2; 8.0 g, 30.1 mmol) in CH ₂ Cl ₂ (80 mL) was added with 4- (in CH ₂ Cl ₂ (40 mL). To a solution of 2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline (method A2, step 4; 7.0 g, 28.8 mmol) was added at 0 ° C. The resulting mixture was stirred at rt for 16 h. The resulting yellow solid was removed by filtration, washed with CH ₂ Cl ₂ (2 × 50 mL) and dried under reduced pressure at 40 ° C. (about 1 mmHg) to give N − (4-bromo-3- as pale yellow solid. (Trifluoromethyl) phenyl) -N '-(4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea (13.2 g, 90%) was obtained: mp 203-205 ° C ;

C1c . General method for synthesizing urea by reacting isocyanate with aniline . N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(2-methyl-4- (2- ( N -methylcarbamoyl) (4-pyridyloxy)) phenyl) urea synthesis

A solution of 2-methyl-4- (2- ( N -methylcarbamoyl) (4-pyridyloxy)) aniline (method A5; 0.11 g, 0.45 mmol) in CH ₂ Cl ₂ (1 mL) was diluted with Et ₃ N ( 0.16 mL) and 4-chloro-3- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred for 6 days at room temperature and treated with water (5 mL). The aqueous layer was back extracted with EtOAc (3 x 5 mL). The mixed organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(2-methyl-4- (2- ( N- ) as a brown oil. Methylcarbamoyl) (4-pyridyloxy)) phenyl) urea (0.11 g, 0.22 mmol) was obtained:

C1d . General method for synthesizing urea by reacting isocyanate with aniline . Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(4-aminophenyl) urea

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (2.27 g, 10.3 mmol) in CH ₂ Cl ₂ (308 mL) was added p -phenylenediamine (3.32 g, 30.7 mmol) in one portion. . The resulting mixture was stirred at rt for 1 h, treated with CH ₂ Cl ₂ (100 mL) and concentrated under reduced pressure. The resulting pink solid was dissolved in a mixture of EtOAc (110 mL) and MeOH (15 mL) and this clear solution was washed with 0.05N HCl solution. The organic layer was concentrated under reduced pressure to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(4-aminophenyl) urea (3.3 g) mixed with impurities: TLC (100% EtOAc) R _f 0.72.

C1e . General method for synthesizing urea by reacting isocyanate with aniline . Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(4-ethoxycarbonylphenyl) urea

To a solution of 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH ₂ Cl ₂ (30 mL) was added 4-chloro-3- (trifluoromethyl) aniline (3.21 g, 16.4 mmol). The solution was stirred overnight at room temperature. The resulting slurry was diluted in CH ₂ Cl ₂ (50 mL) and filtered to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(4-ethoxycarbonylphenyl) urea as a white solid. (5.93 g, 97%) was obtained: TLC (40% EtOAc / 60% hexanes) R _f 0.44.

C1f . General method for synthesizing urea by reacting isocyanate with aniline . Synthesis of N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(3-carboxyphenyl) urea

4- (3-carboxyphenoxy) aniline (method A11; 0.81 g, 5.76) in a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.21 g, 5.46 mmol) in CH ₂ Cl ₂ (8 mL). mmol) was added and the resulting mixture was stirred at rt overnight, then treated with MeOH (8 mL) and further stirred for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solid was triturated with 1: 1 EtOAc / hexane solution to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N '-(3-carboxyphenyl) urea as a grayish white solid. (1.21 g, 76%) was obtained.

C2a . Aniline and N, N '- carbonyl di general method for synthesis of urea by reacting already imidazole was then added to the secondary ah aniline. Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '-(4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea

CDI (0.13 g) was added to 2-methoxy-5- (trifluoromethyl) aniline (0.15 g) in dry CH ₂ Cl ₂ (15 mL) at 0 ° C. The resulting solution was allowed to warm to room temperature over 1 hour, stirred for 16 hours at room temperature and then treated with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at rt for 72 h and treated with H ₂ O (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 × 150 mL). The combined organics were washed with saturated NaCl solution (100 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexanes). The resulting white solid was collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the remaining oil was purified by column chromatography (33% EtOAc / 67% hexanes to 50% EtOAc / 50% hexanes, gradient to 100% EtOAc) to give N- (2-meth) as a light tan solid. Toxy-5- (trifluoromethyl) phenyl) -N '-(4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.098 g, 30%) was obtained: TLC (100% EtOAc) R _f 0.62;

C2b . Aniline and N, N '- carbonyl di general method for synthesis of urea by reacting already imidazole was then added to the secondary ah aniline. N, N' -carbonyl diimidazole reaction symmetrical ureas as a by-product of progress. Synthesis of bis (4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea

To a solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH ₂ Cl ₂ (15 mL) at 0 ° C. was added CDI (0.13 g). The resulting solution was allowed to warm to room temperature over 1 hour and stirred at room temperature for 16 hours. The resulting mixture was treated with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at rt for 72 h and treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 × 150 mL). The combined organic phases were washed with saturated NaCl solution (100 mL) and dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was triturated (90% EtOAc / 10% hexanes). The resulting white solid was collected by filtration and washed with EtOAc to give bis (4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.081 g, 44%): TLC ( 100% EtOAc) R _f 0.50;

C2c . General method for synthesizing urea by reacting isocyanate with aniline . Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '-(4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea

5- (4-aminophenoxy) isoindolin-1 in a solution of 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.47 mmol) in CH ₂ Cl ₂ (1.5 mL) , 3-dione (method A3, step 3; 0.12 g, 0.47 mmol) was added in one portion. The resulting mixture was stirred for 12 h and treated with CH ₂ Cl ₂ (10 mL) and MeOH (5 mL). The resulting mixture was washed successively with 1N HCl solution (15 mL) and saturated NaCl solution (15 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to yield N- (2-methoxy-5- (trifluoro) as a white solid. Romethyl) phenyl) -N '-(4- (1,3-dioxoisoindolin-5-yloxy) phenyl) urea (0.2 g, 96%) was obtained: TLC (70% EtOAc / 30% hexanes) R _f 0.50;

C2d . Aniline and N, N '- carbonyl di general method for synthesis of urea by reacting already imidazole was then added to the secondary ah aniline. N- (5- ( tert -butyl) -2- (2,5-dimethylpyrrolyl) phenyl) -N '-(4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) Synthesis of Urea

5- ( tert -butyl) -2- (2.5-dimethylpyrrolyl) aniline (method A4, step 2; 0.30 g, 1.24) in a stirred solution of CDI (0.21 g, 1.30 mmol) in CH ₂ Cl ₂ (2 mL) mmol) was added in one portion. The resulting mixture was stirred at rt for 4 h, then 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline (0.065 g, 0.267 mmol) was added in one portion. The resulting mixture was heated at 36 ° C. overnight, cooled to room temperature and diluted with EtOAc (5 mL). The resulting mixture was washed successively with a solution of water (15 mL) and 1N HCl (15 mL), dried (MgSO ₄ ), and filtered through a pad of silica gel (50 g) to give N- (5- ( tert −) as a yellowish solid. Butyl) -2- (2,5-dimethylpyrrolyl) phenyl) -N '-(4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea (0.033 g, 24%) Obtained: TLC (40% EtOAc / 60% hexanes) R _f 0.24;

C3 . Triposgene  using Diphenyl Urea  Combination method to synthesize

One of the anilines to be coupled was dissolved in dichloroethane (0.10M). This solution was added to an 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis (trichloromethyl) carbonate solution (0.12 M dichloroethane solution, 0.2 mL, 0.4 equiv) followed by diisopropylethylamine (0.35 M dichloroethane solution, 0.2 mL, 1.2 equiv). The vial was capped and heated at 80 ° C. for 5 hours and then cooled at room temperature for about 10 hours. Secondary aniline (0.10 M dichloroethane solution, 0.5 mL, 1.0 equiv) was added followed by diisopropylethylamine (0.35 M dichloroethane solution, 0.2 mL, 1.2 equiv). The resulting mixture was heated at 80 ° C. for 4 hours, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the product was purified by reverse phase HPLC.

C4 . General method for synthesizing urea by reacting aniline with phosgene and then adding secondary aniline . Synthesis of N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '-(4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea

To a solution of phosgene (1.9 M in toluene; 2.07 mL, 0.21 g, 1.30 mmol) in CH ₂ Cl ₂ (20 mL) was stirred with anhydrous pyridine (0.32 mL) followed by 2-methoxy-5- (trifluoro Methyl) aniline (0.75 g) was added at 0 ° C. While the precipitate formed, the yellow solution was allowed to warm up to room temperature. The yellow mixture was stirred for 1 h and concentrated under reduced pressure. The resulting solid was treated with anhydrous toluene (20 mL) followed by 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline (prepared as described in Method A2; 0.30 g) and the resulting The suspension was heated at 80 ° C. for 20 hours and then cooled to room temperature. The resulting mixture was diluted with water (100 mL) and basified with saturated NaHCO ₃ (2-3 mL) solution. The basic solution was extracted with EtOAc (2 × 250 mL). The organic layer was washed separately using saturated NaCl solution, mixed, dried (MgSO ₄ ), and concentrated under reduced pressure. The resulting pink-brown residue was dissolved in MeOH and absorbed onto SiO ₂ (100 g). Column chromatography (300 g SiO ₂ ; gradient from 1% Et ₃ N / 33% EtOAc / 66% hexane to 1% Et ₃ N / 99% EtOAc, 1% Et ₃ N / 20% MeOH / 79% EtOAc) Concentration under reduced pressure at 45 ° C. gave a warm concentrated EtOAc solution, which was treated with hexane (10 mL) and slowly N- (2-methoxy-5- (trifluoromethyl) phenyl) -N '-(4- (2 -( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea crystals (0.44 g) were formed: TLC (1% Et ₃ N / 99% EtOAc) R _f 0.40.

D. Urea  Interchange

D1a . ω -aminophenyl Urea ω- ( aroylamino ) phenyl Switch to urea . N - (4- chloro-3-methyl) phenyl ((trifluoromethyl) - N '- (4- ( 3- methoxycarbonylphenyl) carboxymethyl-amino-phenyl) Synthesis of the urea

N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(4-aminophenyl) urea (method C1d; 0.050 g, 1.52 mmol), mono -methyl isophthalate in DMF (8 mL) EDCI.HCl (0.29 g, 1.52 mmol) was added to a solution of (0.25 g, 1.38 mmol), HOBT.H ₂ O (0.41 g, 3.03 mmol), and N -methylmorpholine (0.33 mL, 3.03 mmol). The resulting mixture was stirred at rt overnight, diluted with EtOAc (25 mL), washed successively with water (25 mL) and saturated NaHCO ₃ (25 mL) solution The organic layer was dried (Na ₂ SO ₄ ) and reduced pressure The resulting solid was triturated with EtOAc solution (80% EtOAc / 20% hexanes) to give N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(4- (3 -Methoxycarbonylphenyl) carboxyaminophenyl) urea (0.27 g, 43%) was obtained: mp 121-122 ° C .; TLC (80% EtOAc / 20% hexanes) R _f 0.75.

D1b . ω- carboxyphenyl Urea ω- ( arylcarbamoyl ) phenyl Switch to urea . Synthesis of N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea

N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol) in DMF (3 mL) , 3-methylcarbamoylaniline (0.080g, 0.53mmol), HOBT.H ₂ O (0.14g, 1.07mmol) and N -methylmorpholine (0.5mL, 1.07mmol) in a solution of EDCIHCl 0.53 mmol) was added at 0 ° C. The resulting mixture was warmed to room temperature and stirred overnight The resulting mixture was treated with water (10 mL) and extracted with EtOAc (25 mL) The organic phase was concentrated under reduced pressure. The resulting yellow solid was dissolved in EtOAc (3 mL) and filtered through a pad of silica gel (17 g, gradient from 70% EtOAc / 30% hexanes to 10% MeOH / 90% EtOAc) to give N- (4-chloro- as a white solid. 3-((trifluoromethyl) phenyl) -N ' -(4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea (0.097 g, 41%) was obtained: mp 225-229 ° C .; TLC (100 % EtOAc) R _f 0.23.

D1c . ω- carboxyphenyl Urea ω- ( arylcarbamoyl ) phenyl A combined approach to converting to urea . N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(4- ( N- (3- ( N- (3-pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) Synthesis of Urea

N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(3-carboxyphenyl) urea (method C1f; 0.030 g, 0.067 mmol) in 1,2-dichloroethane (1 mL) A mixture of N -cyclohexyl- N ' -(methylpolystyrene) carbodiimide (55 mg) was treated with a solution of 3-aminopyridine in CH ₂ Cl ₂ (1M; 0.074 mL, 0.074 mmol) (insoluble or turbidity). If so, add a small amount of DMSO) The resulting mixture was heated overnight at 36 ° C. The turbid reaction was then treated with THF (1 mL) and heating continued for 18 hours. 4- (isocyanatomethyl) styrene) (0.040 g) and the resulting mixture was stirred for 72 h at 36 ° C., then cooled and filtered to room temperature. Concentrated under reduced pressure to give N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(4- ( N- (3- ( N- (3-pi Ridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (0.024 g, 59%) was obtained: TLC (70% EtOAc / 30% hexanes) R _f 0.12.

D2 . ω -carboalkoxyaryl Urea ω- carbamoylaryl Switch to urea . N - (4- chloro-3-methyl) phenyl ((trifluoromethyl) - N '- (4- ( 3- carbamoyl-phenyl-methyl) carboxy-aminophenyl) Synthesis of urea

Methylamine in a sample of N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(4- (3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) (2M in THF; 1 mL, 1.7 mmol) was added and the resulting mixture was stirred at rt overnight, then concentrated under reduced pressure to give N- (4-chloro-3-((trifluoromethyl) phenyl)-as a white solid. N ′ -(4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea was obtained: mp 247 ° C .; TLC (100% EtOAc) R _f 0.35.

D3 . ω -carboalkoxyaryl Ω- carboxyaryl urea Switch to urea . N - (4- chloro-3-methyl) phenyl ((trifluoromethyl) - N '- (4- carboxyphenyl) Synthesis of urea

To a slurry of N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(4-ethoxycarbonylphenyl) urea (method C1e; 5.93 g, 15.3 mmol) in MeOH (75 mL) Aqueous KOH solution (2.5 N, 10 mL, 23 mmol) was added The resulting mixture was heated to reflux for 12 h, cooled to room temperature and concentrated under reduced pressure The residue was diluted with water (50 mL) and the pH was 2-3 Treated with 1N HCl solution to adjust to 3. The resulting solids were collected and dried under reduced pressure as N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(4- as white solid). Carboxyphenyl) urea (5.05 g, 92%) was obtained.

D4 . General method for converting ω-alkoxy esters to ω- alkyl amides. N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea synthesis

Step 1.Synthesis of N- (4 -chloro- 3-(( trifluoromethyl ) phenyl ) -N ' -((4- (3- (5 - carboxypyridyl) oxyphenyl) urea

Similar methods and means C1a from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- (3- (5-methoxycarbonyl-pyridyl) oxy-aniline (Method A14, Step 2) N - (4 -Chloro-3- (trifluoromethyl) phenyl) -N '-((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea was synthesized. N- (in MeOH (10 mL) Water suspension of 4-chloro-3- (trifluoromethyl) phenyl) -N '-((4- (3- (5-methoxycarbonylpyridyl) oxyphenyl) urea (0.26 g, 0.56 mmol) Treated with a solution of KOH (0.14 g, 2.5 mmol) in (1 mL) and stirred for 1 hour at room temperature The pH of the resulting mixture was adjusted to 5 with 1N HCl solution The resulting precipitate was filtered. The resulting solid was dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure EtOH / concentration was repeated twice to give N- (4-chloro-3-((trifluoromethyl) phenyl ) - N '- ((4- (3- (5- carboxy-pyrido ) Oxyphenyl) urea was obtained (0.18g, 71%).

Step 2. N - (4- chloro-3- (methyl) phenyl-trifluoromethyl) - N '- ((4- (3- (5- (2- butyl-dimethoxy-aminoethyl) carbamoyl) pyridyl) oxyphenyl Synthesis of Urea

N- (4-chloro-3- (trifluoromethyl) phenyl) -N ' -((4- (3- (5-carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011) in DMF (2.5 mL) mmol), N, N' -dimethylethylenediamine (0.22mg, 0.17mmol), HOBT (0.028g, 0.17mmol), N -methylmorpholine (0.035g, 0.28mmol) and EDCIHCl (0.032g, 0.17mmol) The resulting solution was separated between EtOAc (50 mL) and water (50 mL) The organic phase was washed with water (35 mL), dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was dissolved in a very small amount of CH ₂ Cl ₂ (approx. 2 mL) N- (4-chloro-3- (trifluoromethyl) phenyl) as a white precipitate by treatment by dropwise addition of Et ₂ O to the resulting solution. N '-((4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea (0.48 g, 84%) was obtained:

D5 . General method for deprotecting N- (ω- silyloxyalkyl ) amides . N- (4 - chloro - 3-((trifluoromethyl) phenyl) -N ' -(4- (4- (2- ( N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) Synthesis of Urea

N- (4-Chloro-3-((trifluoromethyl) phenyl) -N ' -(4- (4- (2- ( N- (2-triisopropylsilyloxy) ethyl) in anhydrous THF (2 mL) To a solution of carbamoyl) pyridyloxyphenyl) urea (prepared by means similar to Method C1a; 0.25 g, 0.37 mmol) was added tetrabutylammonium fluoride (1.0 M in THF; 2 mL) The mixture was stirred at room temperature for 5 minutes. Stir and treat with water (10 mL) The aqueous mixture was extracted with EtOAc (3 × 100 mL) The combined organic layers were dried (MgSO ₄ ) and concentrated under reduced pressure The residue was column chromatography (SiO ₂ ; Purification by 100% hexanes to 40% EtOAc / 60% hexanes gradient) yields N- (4-chloro-3-((trifluoromethyl) phenyl) -N ' -(4- (4- ( 2- ( N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea (0.019 g, 10%) was obtained.

The following compounds synthesized according to the detailed experimental procedure described above are listed in the table.

Synthesis of Illustrated Compounds

(See table for compound properties)

Generation 1: 4- (3- N -methylcarbamoylphenoxy) aniline was prepared according to Method A13. According to method C3, 3- tert -butylaniline was reacted with bis (trichloromethyl) carbonate and then with 4- (3- N -methylcarbamoylphenoxy) aniline to give urea.

Production 2: According to Method A13, 4-fluoro-1-nitrobenzene and p -hydroxyacetophenone were reacted to obtain 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-acetylphenoxy) -1-nitrobenzene was reduced according to Method A13, Step 4 to give 4- (4-acetylphenoxy) aniline. According to method C3, 3- tert -butylaniline was reacted with bis (trichloromethyl) carbonate and then with 4- (4-acetylphenoxy) aniline to give urea.

Generation 3: Treatment of 3- tert -butylaniline with CDI according to Method C2d, followed by 4- (3- N -methylcarbamoyl) -4-methoxyphenoxy) aniline prepared according to Method A8 Got urea.

Generation 4: 5- tert -butyl-2-methoxyaniline was converted to 5- tert -butyl-2-methoxyphenyl isocyanate according to Method B1. 4- (3- N -methylcarbamoylphenoxy) aniline prepared according to Method A13 was reacted with an isocyanate according to Method C1a to obtain urea.

Generation 5: Reacting 5- tert -butyl-2-methoxyaniline with CDI according to method C2d, which was then 4- (3- N -methylcarbamoyl) -4-methoxyphenoxy prepared according to method A8 Reaction with aniline gave urea.

Generation 6: 5- (4-aminophenoxy) isoindolin-1,3-dione was prepared according to Method A3. According to method 2d, 5- tert -butyl-2-methoxyaniline was reacted with CDI followed by 5- (4-aminophenoxy) isoindolin-1,3-dione to give urea.

Generation 7: 4- (1-oxoisoindolin-5-yloxy) aniline was synthesized according to Method A12. According to method 2d, 5- tert -butyl-2-methoxyaniline was reacted with CDI followed by 4- (1-oxoisoindolin-5-yloxy) aniline to give urea.

Generation 8: According to Method A13, 4- (3- N -methylcarbamoylphenoxy) aniline was synthesized. According to method C2a. 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI followed by 4- (3- N -methylcarbamoylphenoxy) aniline to obtain urea.

Production 9: 4-hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine according to Method A3, step 2 to give 4- (4-acetylphenoxy) -5-nitropyridine. According to Method A8, step 4, 4- (4-acetylphenoxy) -5-nitropyridine was reduced to 4- (4-acetylphenoxy) -5-aminopyridine. 2-methoxy-5- (trifluoromethyl) aniline was converted to 2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B1. This isocyanate was reacted with 4- (4-acetylphenoxy) -5-aminopyridine according to Method C1a to give urea.

Production 10: 4-Fluoro-1-nitrobenzene and p -hydroxyacetophenone were reacted according to Method A13, Step 1 to obtain 4- (4-acetylphenoxy) -1-nitrobenzene. 4- (4-acetylphenoxy) -1-nitrobenzene was reduced according to Method A13, Step 4 to give 4- (4-acetylphenoxy) aniline. According to Method C3, 5- (trifluoromethyl) -2-methoxybutylaniline and bis (trichloromethyl) carbonate are reacted, followed by 4- (4-acetylphenoxy) aniline to react urea. Got it.

Production 11: 4- (Chloro- N -methyl-2-pyridinecarboxamide synthesized according to Method A2 was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in the presence of DMF, -2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline was obtained. According to method C4, 2-methoxy-5- (trifluoromethyl) aniline is reacted with phosgene followed by 3-(-2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline To obtain urea.

Production 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, step 3b to form 4-chloro-2-pyridinecarboxamide. 4-chloro-2-pyridinecarboxamide is reacted with 3-aminophenol according to Method A2, step 4 using DMAC in the presence of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline Got it. 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene according to method C2a followed by 3- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Production 13: 4-Chloro- N -methyl-2-pyridinecarboxamide was synthesized according to Method A2, step 3b. 4-Chloro- N -methyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, step 4 using DMAC in the presence of DMF to give 4- (2- ( N -methylcarbamoyl) 4-pyridyloxy) aniline was obtained. According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline is reacted with CDI, followed by 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline to urea Got.

Production 14: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, step 3b to form 4-chloro-2-pyridinecarboxamide. 4-chloro-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, step 4 using DMAC in the presence of DMF to give 4- (2-carbamoyl-4-pyridyloxy) aniline. Got it. According to method C4, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene followed by 4- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Production 15: According to Method C2d, 5- (trifluoromethyl) -2-methoxyaniline was reacted with CDI and then 4- (3- ( N -methylcarbamoyl) -4- prepared according to Method A8. Reaction with methoxyphenoxy) aniline gave urea.

Production 16: According to Method A5, 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. Isocyanates were reacted with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-methylaniline according to process C1e to give urea.

Production 17: 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline according to Cla to give urea.

Production 18: According to Method A2, step 4, 5-amino-2-methylphenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide prepared according to Method A2, step 3b to give 3- (2 -( N -methylcarbamoyl) -4-pyridyloxy) -4-methylaniline was obtained. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 3- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -4-methylaniline according to Cla to give urea.

Production 19: According to Method A2, step 3b, 4-chloropyridine-2-carbonyl chloride was reacted with ethylamine. The resulting 4-chloro- N -ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, step 4 to 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) Aniline was obtained. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) aniline according to Cla to give urea.

Production 20: According to Method A2, step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide synthesized according to Method A2, step 3b to give 4- (2 -( N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline was obtained. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline according to Cla to give urea.

Production 21: 4- (4-methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. Nitrobenzene was reduced according to Method A19, Step 2 to afford 4- (4-methylsulfonylphenoxy) -1-aniline. According to Method C1a, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to obtain urea.

Production 22: 4- (3-carbamoylphenoxy) -1-nitrobenzene was reduced to 4- (3-carbamoylphenoxy) aniline according to Method A15, step 4. According to Method C1a, 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3-carbamoylphenoxy) aniline to give urea.

Generation 23: 5- (4-aminophenoxy) isoindolin-1,3-dione was synthesized according to Method A3. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindolin-1,3-dione according to Method C1a to obtain urea.

Production 24: 4-Chloropyridine-2-carbonyl chloride and dimethylamine were reacted according to Method A2, step 3b. The resulting 4-chloro- N, N' -dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, step 4 to 4- (2- ( N, N' -dimethylcarbamoyl)- 4-pyridyloxy) aniline was obtained. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate and 4- (2- ( N, N' -dimethylcarbamoyl) -4-pyridyloxy) aniline were reacted according to Method C1a to obtain urea.

Production 25: 4- (1-oxoisoindolin-5-yloxy) aniline was synthesized according to Method A12. 5- (trifluoromethyl) -2-methoxyaniline was treated with CDI and then reacted with 4- (1-oxoisoindolin-5-yloxy) aniline according to Method C2d to give urea.

Production 26: 4-hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4- (4-acetylphenoxy) nitrobenzene. This nitrobenzene was reduced according to Method A13, Step 4 to obtain 4- (4-acetylphenoxy) aniline, which was subjected to 4- (4- (1- ( N -methoxy) iminoethyl) phenoxy according to Method A16. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. Fluoromethyl) -2-methoxyphenyl isocyanate and 4- (4- (1- ( N -methoxy) iminoethyl) phenoxyaniline HCl salt were reacted according to Method C1a to obtain urea.

Production 27: 4-Chloro- N -methylpyridinecarboxamide was synthesized according to Method A2, step 3b. This chloropyridine was reacted with 4-aminophenol according to Method A2, Step 4 to obtain 4- (4- (2- ( N -methylcarbamoyl) phenylthio) aniline.5- (trifluoromethyl) -2 -Methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1 5- (trifluoromethyl) -2-methoxyphenyl isocyanate and 4- (4- ( 2- ( N -methylcarbamoyl) phenylthio) aniline was reacted according to Method C1a to obtain urea.

Production 28: 5- (4-Aminophenoxy) -2-methylisoindolin-1,3-dione was synthesized according to Method A9. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate and 5- (4-aminophenoxy) -2-methylisoindolin-1,3-dione were reacted according to Method C1a to obtain urea.

Production 29: 4-Chloro- N -methylpyridinecarboxamide was synthesized according to Method A2, step 3b. This chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- N -methylcarbamoyl) phenylthio) aniline. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate and 3- (4- (2- N -methylcarbamoyl) phenylthio) aniline were reacted according to Method C1a to obtain urea.

Production 30: 4-Chloropyridine-2-carbonyl chloride and isopropylamine were reacted according to Method A2, step 3b. The resulting 4-chloro- N -isopropyl-2-pyridinecarboxamide is reacted with 4-aminothiophenol according to Method A2, step 4 to 4- (2- ( N -isopropylcarbamoyl) -4-pyridine Dialkyl) aniline was obtained. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate and 4- (2- ( N -isopropylcarbamoyl) -4-pyridyloxy) aniline were reacted according to Method C1a to obtain urea.

Generation 31: According to Method A14, 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to give urea. N- (5-trifluoromethyl) -2-methoxyphenyl) -N ' -(4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl urea is synthesized according to Method D4, step 1 Digestion and the corresponding acid were coupled with 4- (2-aminoethyl) morpholine to afford the amide according to Method D4, step 2.

Generation 32: According to Method A14, 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to give urea. N- (5-trifluoromethyl) -2-methoxyphenyl) -N ' -(4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl urea is synthesized according to Method D4, step 1 Decomposition and the corresponding acid were coupled with methylamine to afford an amide according to method D4, step 2.

Production 33: According to Method A14, 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 5- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to give urea. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ' -(4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl urea according to Method D4, step 1 Hydrolysis and the corresponding acid were coupled with N. N′ -dimethylethylenediamine to afford an amide according to Method D4, step 2.

Generation 34: According to Method A11, 4- (3-carboxyphenoxy) aniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl ) -N ' -(3-carboxyphenyl) urea was obtained, which was coupled with 3-aminopyridine according to Method D1c.

Generation 35: According to Method A11, 4- (3-carboxyphenoxy) aniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl ) -N ' -(3-carboxyphenyl) urea was obtained, which was coupled with N- (4-fluorophenyl) piperazine according to Method D1c.

Generation 36: According to Method A11, 4- (3-carboxyphenoxy) aniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl ) -N ' -(3-carboxyphenyl) urea was obtained, which was coupled with 4-fluoroaniline according to Method D1c.

Production 37: According to Method A11, 4- (3-carboxyphenoxy) aniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl ) -N ' -(3-carboxyphenyl) urea was obtained, which was coupled with 4- (dimethylamino) aniline according to method D1c.

Generation 38: According to Method A11, 4- (3-carboxyphenoxy) aniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl ) -N ' -(3-carboxyphenyl) urea was obtained, which was coupled with 5-amino-2-methoxypyridine according to Method D1c.

Generation 39: According to Method A11, 4- (3-carboxyphenoxy) aniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl ) -N ' -(3-carboxyphenyl) urea was obtained, which was coupled with 4-morpholinoaniline according to Method D1c.

Generation 40: According to Method A11, 4- (3-carboxyphenoxy) aniline was synthesized. 5- (trifluoromethyl) -2-methoxyaniline was converted to 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method B1. 4- (3-carboxyphenoxy) aniline is reacted with 5- (trifluoromethyl) -2-methoxyphenyl isocyanate according to Method C1f to give N- (5- (trifluoromethyl) -2-methoxyphenyl ) -N ' -(3-carboxyphenyl) urea was obtained, which was coupled with N- (2-pyridyl) piperazine according to Method D1c.

Production 41: According to Method A13, 4- (3- ( N -methylcarbamoyl) phenoxy) aniline was synthesized. According to method C3, 4-chloro-3- (trifluoromethyl) aniline was converted to isocyanate and then reacted with 4- (3- ( N -methylcarbamoyl) phenoxy) aniline to give urea.

Generation 42: According to method A2, 4- (2- ( N -methylcarbamoyl-4-pyridyloxy) aniline was synthesized According to method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate Was reacted with 4- (2- ( N -methylcarbamoyl-4-pyridyloxy) aniline to give urea.

Production 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, step 3b to prepare 4-chloro-2-pyridinecarboxamide. 4-chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, step 4 to give 4- (2-carbamoyl-4-pyridyloxy) aniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Production 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, step 3b to prepare 4-chloro-2-pyridinecarboxamide. 4-chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, step 4 to afford 3- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C1a 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2-carbamoyl-4-pyridyloxy) aniline to give urea.

Production 45: 4-chloro- N -methyl-2-pyridinecarboxamide prepared according to Method A2, step 3a, with 3-aminophenol according to Method A2, step 4 to give 3- (2- ( N -methyl Carbamoyl) -4-pyridyloxy) aniline was obtained. According to Method C1a 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Generation 46: According to Method A3, 5- (4-aminophenoxy) isoindolin-1,3-dione was synthesized. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindolin-1,3-dione to obtain urea.

Production 47: According to Method A5, 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-methylaniline was synthesized. According to Method C1c, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-methylaniline to obtain urea. .

Generation 48: According to Method A15, 4- (3- ( N -methylsulfamoyl) phenyloxy) aniline was synthesized. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N -methylsulfamoyl) phenyloxy) aniline to obtain urea.

Generation 49: According to Method A6, 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline to give urea. .

Production 50: According to Method A2, step 4, 5-amino-2-methylphenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide prepared according to Method A2, step 3b to give 3- (2 -( N -methylcarbamoyl) -4-pyridyloxy) -4-methylaniline was obtained. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -4-methylaniline to obtain urea. .

Production 51: According to Method A2, step 3b, 4-chloropyridine-2-carbonyl chloride and ethylamine were reacted. The resulting 4-chloro- N -ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, step 4 to 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) Aniline was obtained. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) aniline to give urea.

Production 52: According to Method A2, step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide prepared according to Method A2, step 3b to give 4- (2 -( N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline was obtained. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline to obtain urea. .

Production 53: 4- (4-Methylthiophenoxy) -1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy) -1-nitrobenzene. This nitrobenzene was reduced according to Method A19, Step 2 to give 4- (4-methylsulfonylphenoxy) -1-aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-methylsulfonylphenoxy) -1-aniline to give urea.

Production 54: 4-Bromobenzenesulfonyl chloride and methylamine were reacted according to Method A15, Step 1 to obtain N -methyl-4-bromobenzenesulfonamide. N -methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, step 2 to afford 4- (4- ( N -methylsulfamoyl) phenoxy) benzene. 4- (4- ( N -methylsulfamoyl) phenoxy) benzene was converted to 4- (4- ( N -methylsulfamoyl) phenoxy) -1-nitrobenzene according to Method A15, step 3. 4- (4- ( N -methylsulfamoyl) phenoxy) -1-nitrobenzene was reduced to 4- (4- ( N -methylsulfamoyl) phenoxy) aniline according to Method A15, step 4. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- N -methylsulfamoyl) phenyloxy) aniline to give urea.

Generation 55: According to Method A18, step 1, 5-hydroxy-2-methylpyridine was subjected to 4- (5- (2-methyl) pyridyloxy) -1 by guffling 5-hydroxy-2-methylpyridine with 1-fluoro-4-nitrobenzene. Nitrobenzene was obtained. This methylpyridine was oxidized with carboxylic acid and esterified according to Method A18, Step 2 to obtain 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. Nitrobenzene was reduced according to Method A18, step 3 to afford 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. This aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to method C1a to give urea.

Generation 56: According to Method A18, step 1, 5-hydroxy-2-methylpyridine was subjected to 4- (5- (2-methyl) pyridyloxy) -1 by guffling 5-hydroxy-2-methylpyridine with 1-fluoro-4-nitrobenzene. Nitrobenzene was obtained. This methylpyridine was oxidized with carboxylic acid and esterified according to Method A18, Step 2 to obtain 4- (5- (2-methoxycarbonyl) pyridyloxy) -1-nitrobenzene. Nitrobenzene was reduced according to Method A18, step 3 to afford 4- (5- (2-methoxycarbonyl) pyridyloxy) aniline. This aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method C1a to give N- (4-chloro-3- (trifluoromethyl) phenyl) -N ' -(4- (2 -(Methoxycarbonyl) -5-pyridyloxy) phenyl) urea was obtained. The methyl ester is reacted with methylamine according to method D12 to yield N- (4-chloro-3- (trifluoromethyl) phenyl) -N ' -(4- (2- ( N -methylcarbamoyl) -5-pyri Diyloxy) phenyl) urea was obtained.

Production 57: According to Method C1d, N- (4- (chloro-3- (trifluoromethyl) phenyl- N ' -(4-aminophenyl) urea was prepared. N- (4- (chloro-3- (Trifluoromethyl) phenyl- N ' -(4-aminophenyl) urea was coupled with mono -methyl isophthalate according to method D1a to give urea.

Production 58: According to Method C1d, N- (4- (chloro-3- (trifluoromethyl) phenyl- N ' -(4-aminophenyl) urea was prepared. N- (4- (chloro-3- (Trifluoromethyl) phenyl- N ' -(4-aminophenyl) urea is coupled with mono -methyl isophthalate according to method D1a to give N- (4- (chloro-3- (trifluoromethyl) phenyl- N ' -(4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea was obtained.According to Method D2, N- (4- (chloro-3- (trifluoromethyl) phenyl- N' -( 4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea was reacted with methylamine to give the corresponding methyl amide.

Production 59: According to Method A2, step 3b, 4-chloropyridine-2-carbonyl chloride and dimethylamine were reacted. The resulting 4-chloro-N, N '- dimethyl-2-pyridine carboxylic method carboxamide A2, was reacted with 4-aminophenol according to Step 4 4- (2- (N. N' - dimethyl carbamoyl) 4-pyridyloxy) aniline was obtained. According to the method C1a, 4- chloro-3- (trifluoromethyl) phenyl isocyanate and 4- (2- (N. N '- dimethyl-carbamoyl) -4-pyridyloxy) aniline were reacted to give the urea.

Production 60: According to Method A13, step 1, 4-hydroxyacetophenone and 4-fluoronitrobenzene were reacted to give 4- (4-acetylphenoxy) nitrobenzene. Nitrobenzene was reduced according to Method 13, step 4 to obtain 4- (4-acetylphenoxy) aniline, which was subjected to 4- (4- (1- ( N -methoxy) iminoethyl) phenoxy according to Method A16. Converted to aniline HCl salt According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-acetylphenoxy) aniline to obtain urea.

Production 61: 4- (3-carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-carboxyphenoxy) -1-nitrobenzene was coupled with 4- (2-aminoethyl) morpholine according to Method A13, step 3 to give 4- (3- ( N- (2-morpholinyl) Ethyl) carbamoyl) phenoxy) -1-nitrobenzene was obtained. According to Method A13, step 4, 4- (3- ( N- (2-morpholinylethyl) carbamoyl) phenoxy) -1-nitrobenzene was replaced with 4- (3- ( N- (2-morpholinyl). Reduced to ethyl) carbamoyl) phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N- (2-morpholinylethyl) carbamoyl) phenoxy) aniline to obtain urea.

Production 62: 4- (3-carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, Step 2. 4- (3-carboxyphenoxy) -1-nitrobenzene was coupled with 1- (2-aminoethyl) piperidine according to Method A13, step 3 to 4- (3- ( N- (2-piperi) Diethyl) carbamoyl) phenoxy) -1-nitrobenzene was obtained. According to Method A13, step 4, 4- (3- ( N- (2-piperidylethyl) carbamoyl) phenoxy) -1-nitrobenzene was replaced with 4- (3- ( N- (2-piperidyl). Reduced to ethyl) carbamoyl) phenoxy) aniline. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N- (2-piperidylethyl) carbamoyl) phenoxy) aniline to obtain urea.

Production 63: 4- (3-carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, step 2. 4- (3-carboxyphenoxy) -1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, step 3 to obtain 4- (3- ( N- (tetrahydrofurylmethyl) carbamoyl) phenoxy ) -1-nitrobenzene was obtained. According to Method A13, step 4, 4- (3- ( N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) -1-nitrobenzene was replaced with 4- (3- ( N- (tetrahydrofurylmethyl) carbamoyl Phenoxy) aniline was reduced. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- ( N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline to obtain urea.

Production 64: 4- (3-carboxyphenoxy) -1-nitrobenzene was synthesized according to Method A13, step 2. 4- (3-carboxyphenoxy) -1-nitrobenzene was coupled with 2-aminomethyl-1-ethylpyrrolidine according to Method A13, step 3 to obtain 4- (3- ( N -((1-methyl Pyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene was obtained. According to Method A13, step 4, 4- (3- ( N -((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) -1-nitrobenzene was converted to 4- (3- ( N -((1 -Methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline. According to Method C1a, urea is reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- (3- ( N -((1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline Got.

Production 65: According to Method A2, step 3b, 4-chloro- N -methylpyridinecarboxamide was synthesized. Chloropyridine and 4-aminothiophenol were reacted according to Method A2, Step 4 to obtain 4- (4- (2- ( N -methylcarbamoyl) phenylthio) aniline According to Method C1a, 4-chloro-3 Urea was obtained by reacting-(trifluoromethyl) phenyl isocyanate with 4- (4- (2- ( N -methylcarbamoyl) phenylthio) aniline.

Production 66: According to Method A2, step 3b, 4-chloropyridine-2-carbonyl chloride and isopropylamine were reacted. The resulting 4-chloro- N -isopropyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, step 4 to 4- (2- ( N -isopropylcarbamoyl) -4-pyridyl Oxy) aniline was obtained. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N -isopropylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Generation 67:. N - (4-chloro-3- (trifluoromethyl) phenyl - N '- (4-ethoxycarbonylphenyl) urea was synthesized according to Method C1e N - (4-chloro-3 (Trifluoromethyl) phenyl- N '-(4-ethoxycarbonylphenyl) urea is hydrolyzed according to Method D3 to give N- (4-chloro-3- (trifluoromethyl) phenyl- N '-( 4-carboxyphenyl) urea was obtained, according to method D1b, a couple of N- (4-chloro-3- (trifluoromethyl) phenyl- N '-(4-carboxyphenyl) urea and 3-methylcarbamoylaniline Ringing yielded N- (4-chloro-3- (trifluoromethyl) phenyl- N '-(4- (3-methylcarbamoylphenyl) carbamoylphenyl) urea.

Generation 68: According to Method A9, 5- (4-aminophenoxy) -2-methylisoindolin-1,3-dione was synthesized. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 5- (4-aminophenoxy) -2-methylisoindolin-1,3-dione were reacted to obtain urea.

Production 69: According to Method A2, step 3b, 4-chloro- N -methylpyridinecarboxamide was synthesized. Chloropyridine was reacted with 3-aminothiophenol according to Method A2, step 4 to afford 3- (4- (2- ( N -methylcarbamoyl) phenylthio) aniline According to Method C1a, 4-chloro-3 Urea was obtained by reacting-(trifluoromethyl) phenyl isocyanate with 3- (4- (2- ( N -methylcarbamoyl) phenylthio) aniline.

Production 70: According to Method A10, 4- (2- ( N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- ( N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline Got urea.

Production 71: According to Method A14, 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline was synthesized. 4-Chloro-3- (trifluoromethyl) -2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to give urea. N- (4-chloro-3- (trifluoromethyl) phenyl) -N ' -(4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl urea according to method D4, step 1 Hydrolysis and the corresponding acid were coupled with 4- (2-aminoethyl) morpholine to afford an amide.

Generation 72: According to Method A14, 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline was synthesized. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to give urea. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ' -(4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl urea according to method D4, step 1 Was hydrolyzed and the corresponding acid was coupled with methylamine according to method D4, step 2 to afford an amide.

Production 73: According to Method A14, 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline was synthesized. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method C1a to give urea. N- (5- (trifluoromethyl) -2-methoxyphenyl) -N ' -(4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl urea according to method D4, step 1 Was hydrolyzed and the corresponding acid was coupled with N, N' -dimethylethylenediamine according to method D4, step 2 to afford an amide.

Production 74: 4-Chloro- N- (2-triisopropylsilyloxy) ethylpyridine- by reacting 4-chloropyridine-2-carbonyl chloride HCl salt with 2-hydroxyethylamine according to Method A2, step 3b. 2-carboxamide was prepared. 4-Chloro- N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride followed by reaction with 4-aminophenol according to Method A17 to 4- (4- (2- ( N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline was prepared. 4-Chloro-3- (trifluoromethyl) phenyl isocyanate was prepared according to Method C1a. - (2- (N - (2- triisopropylsilyl) ethyl carbamoyl) pyridyloxy aniline to react with N - (4- chloro-3-methyl ((trifluoromethyl) phenyl) - N '- ( 4- (4- (2- ( N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea was obtained.

Production 75: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. According to method C1f, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline to obtain urea, which is according to method D1c. Coupling with 3-aminopyridine.

Production 76: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. According to method C1f, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline to obtain urea, which is N- (4-acetylphenyl) according to method D1c. Coupling with piperazine.

Production 77: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. According to method C1f, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline to obtain urea, which is coupled with 4-fluoroaniline according to method D1c. I was.

Production 78: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. According to Method C1f, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline to obtain urea, which is obtained according to Method D1c with 4- (dimethylamino) aniline. Coupling.

Production 79: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. According to method C1f, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline to obtain urea, which is coupled with N -phenylethylenediamine according to method D1c. I was.

Production 80: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. According to Method C1f, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline to obtain urea, which is coupled with 2-methoxyethylamine according to Method D1c. Ring.

Production 81: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. According to method C1f, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline to obtain urea, which according to method D1c is 5-amino-2-methoxy. Coupling with pyridine.

Production 82: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. According to Method C1f, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline to obtain urea, which is coupled with 4-morpholinoaniline according to Method D1c. Ring.

Production 83: 4- (3-carboxyphenoxy) aniline was synthesized according to Method A11. According to method C1f, 4-chloro-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (3-carboxyphenoxy) aniline to obtain urea, which is N- (2-pyridyl) according to method D1c. Coupling with piperazine.

Production 84: According to Method A2, step 3b, 4-chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-hydroxyethylamine to 4-chloro- N- (2-triisopropylsilyloxy) ethylpyridine -2-carboxamide was prepared. 4-Chloro- N- (2-triisopropylsilyloxy) ethylpyridine-2-carboxamide is reacted with triisopropylsilyl chloride followed by reaction with 4-aminophenol according to Method A17 to 4- (4- (2- ( N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline was formed. According to Method C1a, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was 4- ( 4- (2- (N - (2- triisopropylsilyl) ethyl carbamoyl) pyridyloxy aniline to react with N - (4- chloro-3-methyl) phenyl ((trifluoromethyl) - N '- (4- (4- (2- ( N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea was obtained. This urea was deprotected according to method D5 to give N- (4-chloro 3-((trifluoromethyl) phenyl) -N '-(4- (4- (2- ( N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea was obtained.

Production 85: 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Production 86: 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, urea is reacted by reacting 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline. Got it.

Production 87: According to Method A2, step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide synthesized according to Method A2, step 3b to give 4- (2 -( N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline was obtained. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, urea is reacted by reacting 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline. Got it.

Production 88: 4-chloropyridine-2-carbonyl chloride and ethylamine were reacted according to Method A2, step 3b. The resulting 4-chloro- N -ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, step 4 to 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) Aniline was obtained. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Production 89: 4-chloro- N -methyl-2-pyridinecarboxamide synthesized according to Method A2, step 3a, was reacted with 3-aminophenol according to Method A2, step 4 to obtain 3-(-2- ( N- Methyl carbamoyl) -4-pyridyloxy) aniline was obtained. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3-(-2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Production 90: According to Method A2, step 4, 5-amino-2-methylphenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide synthesized according to Method A2, step 3b to give 3- (2 -( N -methylcarbamoyl) -4-pyridyloxy) -4-methylaniline was obtained. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, urea is reacted by reacting 4-bromo-3- (trifluoromethyl) phenyl isocyanate with 3- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -4-methylaniline. Got it.

Production 91: 4-Chloropyridine-2-carbonyl chloride was synthesized according to Method A2, step 3b. According to Method A2, step 4, 4- (2- ( N, N -dimethylcarbamoyl)-was reacted by reacting the resulting 4-chloro- N, N' -dimethyl-2-pyridinecarboxamide with 4-aminophenol. 4-pyridyloxy) aniline was obtained. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- ( N, N -dimethylcarbamoyl) -4-pyridyloxy) aniline to obtain urea.

Production 92: 4-Chloro- N -methylpyridinecarboxamide was synthesized according to Method A2, step 3b. According to method A2, step 4, chloropyridine and 4-aminothiophenol were reacted to give 4- (4- (2- ( N -methylcarbamoyl) phenylthio) aniline.4-Bromo- according to method B1. 3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate According to method C1a, with 4-bromo-3- (trifluoromethyl) phenyl isocyanate 4- (4- (2- ( N -methylcarbamoyl) phenylthio) aniline was reacted to obtain urea.

Production 93: 4-Chloro- N -methylpyridinecarboxamide was synthesized according to Method A2, step 3b. According to method A2, step 4, chloropyridine and 3-aminothiophenol were reacted to obtain 3- (4- (2- ( N -methylcarbamoyl) phenylthio) aniline.4-Bromo- according to Method B1. 3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate According to method C1a, with 4-bromo-3- (trifluoromethyl) phenyl isocyanate 3- (4- (2- ( N -methylcarbamoyl) phenylthio) aniline was reacted to obtain urea.

Production 94: 4- (2- ( N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized according to Method A10. 4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3- (trifluoromethyl) phenyl isocyanate is reacted with 4- (2- ( N- (2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline To obtain urea.

Production 95: 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to Method C1a, urea is reacted by reacting 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline. Got it.

Production 96: 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline was synthesized according to Method A6. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate and 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -2-chloroaniline Reaction gave urea.

Production 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro- N -methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3b. -( N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline was obtained. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to Method C1a, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate and 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) -3-chloroaniline Reaction gave urea.

Production 98: 4-chloro- N -methyl-2-pyridinecarboxamide synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to obtain 3-(-2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline was obtained. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to Method C1a, urea is reacted with 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate and 3-(-2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline Got.

Production 99: 4-chloropyridine-2-carbonyl chloride and ethylamine were reacted according to Method A2, step 3b. The resulting 4-chloro- N -ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, step 4 to 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) Aniline was obtained. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to Method C1a, urea is reacted by reacting 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate with 4- (2- ( N -ethylcarbamoyl) -4-pyridyloxy) aniline. Got it.

Production 100: 4-Chloropyridine-2-carbonyl chloride and dimethylamine were reacted according to Method A2, step 3b. The resulting 4-chloro- N, N -dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, step 4 to 4- (2- ( NN -dimethylcarbamoyl) -4-pyridyl Oxy) aniline was obtained. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7. 4-chloro-2-methoxy-5- (trifluoromethyl) aniline was converted to 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to method B1. According to Method C1a, urea is reacted by reacting 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate with 4- (2- ( NN -dimethylcarbamoyl) -4-pyridyloxy) aniline. Got it.

Production 101: 4-Chloro- N -methyl-2-pyridinecarboxamide synthesized according to Method A2, step 3a, was reacted with 3-aminophenol according to Method A2, step 4 to obtain 3-(-2- ( N- Methyl carbamoyl) -4-pyridyloxy) aniline was obtained. 2-amino-3-methoxynaphthalene was synthesized according to Method A1. According to method C3, 2-amino-3-methoxynaphthalene and bis (trichloromethyl) carbonate are reacted, followed by 3-(-2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline Reacted to obtain urea.

Production 102. 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline was synthesized according to Method A2. 5- tert -butyl-2- (2,5-dimethylpyrrolyl) aniline was synthesized according to Method A4. 5- tert -butyl-2- (2,5-dimethylpyrrolyl) aniline is reacted with CDI followed by 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline according to method C2d Reaction gave urea.

Production 103: 4-Chloro- N -methyl-2-pyridinecarboxamide was synthesized according to Method A2, step 3b. 4-Chloro- N -methyl-2-pyridinecarboxamide is reacted with 4-aminophenol according to Method A2, step 4 using DMAC in the presence of DMF to give 4- (2- ( N -methylcarbamoyl) -4 Pyridyloxy) aniline was obtained. According to method C2b, 3-amino-2-methoxyquinoline is reacted with CDI and then with 4- (2- ( N -methylcarbamoyl) -4-pyridyloxy) aniline to give bis (4- (2 -( N -methylcarbamoyl) -4-pyridyloxy) phenyl) urea was obtained.

The compounds synthesized according to the detailed experimental procedure described above are listed in the table below.

table

In accordance with the general method described above, the compounds listed in Tables 1-6 described below were synthesized, and a more detailed example was prepared by the above-listed production, and the characteristics thereof are shown in the table.

TABLE 1

TABLE 2

[Table 3a]

TABLE 3b

[Table 3c]

Table 3d

[Table 4a]

[Table 4b]

TABLE 4c

Table 4d

Table 4e

TABLE 5

TABLE 6

TABLE 7

The preceding embodiments may be repeated to achieve similar performance by using general or specific reactants and / or operating conditions of the present invention instead of those used in the above-described examples.

From the above description, those skilled in the art can easily identify the essential features of the present invention, and various changes and modifications of the present invention can be made to adapt it to various uses and conditions without departing from its spirit and scope.

Claims (22)

As a compound of formula (I), or a pharmaceutically acceptable salt thereof
Formula I
ADB
In the formula,
D is -NH-C (O) -NH-,
A is represented by the formula -LML ¹ ,
L is unsubstituted phenyl or phenyl substituted with a substituent selected from the group consisting of halogen and C ₁ -C ₁₀ alkyl,
L ¹ is phenyl substituted with -C (O) R _x ,
M is one or more linking groups selected from the group consisting of -O- and -S-,
R _x is NR _a R _b, where R _a and R _b are independently
a) hydrogen,
b) C ₁ -C ₁₀ alkyl or
c) C ₃ -C ₁₂ cycloalkyl having 1 to 3 heteroatoms selected from C ₁ -C ₁₀ alkyl substituted with a hydroxy group, O, N and S, or —OSi (R _f ) _3, wherein R _f is C ₁ -C ₁₀ alkyl,
B is an unsubstituted phenyl group or a phenyl group substituted with a substituent selected from the group consisting of halogen and Wn to perhalo, n is 0 to 3, and each W is
a) C ₁ -C ₁₀ alkyl,
b) C ₁ -C ₁₀ alkoxy,
c) halo substituted C ₁ -C ₁₀ alkyl and
d) C ₃ -C ₁₂ cycloalkyl optionally substituted with C ₁ -C ₁₀ alkyl having 1 to 3 heteroatoms selected from O, N and S
It is selected independently from the group consisting of. The compound of claim 1, wherein B of Formula I is a phenyl group substituted with a substituent selected from the group consisting of halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy and halo substituted C ₁ -C ₁₀ alkyl. 2. The compound of claim 1, wherein B of Formula I is a phenyl group substituted with 1 to 3 substituents independently selected from the group consisting of chlorine, bromine, fluorine, trifluoromethyl, methoxy and t-butyl. The compound of claim 1, wherein L is unsubstituted phenyl or phenyl substituted with halogen. The compound of claim 1, wherein L is unsubstituted phenyl or phenyl substituted with 1 to 3 substituents independently selected from the group consisting of chlorine and methyl groups. The compound of claim 1, wherein M is —O—. The compound of claim 2, wherein M is —O—. The compound of claim 3, wherein M is —O—. The compound of claim 4, wherein M is —O—. The compound of claim 1, wherein R _a and R _b are independently selected from hydrogen and C ₁ -C ₁₀ alkyl. The compound of claim 3, wherein R _a and R _b are independently selected from hydrogen and C ₁ -C ₁₀ alkyl. The compound of claim 6, wherein R _a and R _b are independently selected from hydrogen and C ₁ -C ₁₀ alkyl. 8. The compound of claim 7, wherein R _a and R _b are independently selected from hydrogen and C ₁ -C ₁₀ alkyl. The compound of claim 8, wherein R _a and R _b are independently selected from hydrogen and C ₁ -C ₁₀ alkyl. The compound of claim 9, wherein R _a and R _b are independently selected from hydrogen and C ₁ -C ₁₀ alkyl. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
Formula I
ADB
In the formula,
D is -NH-C (O) -NH-,
A is of the formula -LML ¹ ,
Wherein L is unsubstituted phenyl or phenyl substituted with 1 to 3 substituents independently selected from the group consisting of methyl and halogen,
L ¹ is phenyl substituted with -C (O) NR _a R _b ,
M is selected from the group consisting of -O- and -S-,
R _a and R _b are each independently,
Hydrogen,
C ₁ -C ₁₀ alkyl or
C ₁ -C ₁₀ alkyl substituted with a hydroxy group,
B is an unsubstituted phenyl group or a phenyl group substituted with a substituent selected from the group consisting of halogen and Wn, where n is 0 to 3 and each W is substituted with C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy and halo It is independently selected from the group consisting of C ₁ -C ₁₀ alkyl. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
Formula I
ADB
In formula, D is -NH-C (O) -NH-,
A is of the formula -LML ¹ ,
L is phenyl,
M is O,
L ¹ is phenyl substituted with -C (O) NR _a R _b ,
R _a and R _b are independently
Hydrogen or C ₁ -C ₁₀ alkyl,
B is a phenyl group substituted with a substituent selected from the group consisting of halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy and halo substituted C ₁ -C ₁₀ alkyl. The compound of claim 16, wherein R _a and R _b are independently selected from hydrogen and C ₁ -C ₁₀ alkyl. 18. The compound of claim 17, wherein R _a and R _b are independently selected from hydrogen and methyl. The method of claim 1,
a) hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p -toluene sulfonic acid (tosylate salt), 1-naphthalene sulfonic acid, 2-naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid Base salts of organic and inorganic acids selected from the group consisting of tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid,
b) salts of organic and inorganic bases containing cations selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium cations, aliphatic substituted ammonium cations and aromatic substituted ammonium cations
A pharmaceutically acceptable salt of a compound of Formula I, selected from the group consisting of: The method of claim 16,
a) hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p -toluene sulfonic acid (tosylate salt), 1-naphthalene sulfonic acid, 2-naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid Base salts of organic and inorganic acids selected from the group consisting of tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid,
b) salts of organic and inorganic bases containing cations selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium cations, aliphatic substituted ammonium cations and aromatic substituted ammonium cations
A pharmaceutically acceptable salt of a compound of Formula I, selected from the group consisting of: The method of claim 17,
a) hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p -toluene sulfonic acid (tosylate salt), 1-naphthalene sulfonic acid, 2-naphthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid Base salts of organic and inorganic acids selected from the group consisting of tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid,
b) salts of organic and inorganic bases containing cations selected from the group consisting of alkali metal cations, alkaline earth metal cations, ammonium cations, aliphatic substituted ammonium cations and aromatic substituted ammonium cations
A pharmaceutically acceptable salt of a compound of Formula I, selected from the group consisting of: