WO2012061337A1 - Fgfr2 modulators - Google Patents

Abstract

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:R^3a, R², R^3b, R^4b, L¹, G and J are as defined in the specification, pharmaceutical compositionsthereof, and methods of use thereof.

Description

FGFR2 MODULATORS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of US Provisional Application 61/409,465, filed November 2, 2010, the contents of which is hereby incorporated by reference in its entirety

BACKGROUND OF THE INVENTION

Field of the Invention

[0002] This invention relates to compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Even more specifically, the invention relates to compounds that inhibit, regulate and/or modulate kinases, particularly FGFR2. Kinase receptor signal transduction pathways related to the changes in cellular activities as mentioned above are modulated using compounds of the invention. Methods of using the compounds to treat kinase-dependent diseases and conditions are also an aspect of the invention.

Summary of Related Art

[0003] Fibroblast growth factors (FGFs) (FGF1 - 10 and 16 - 23) are mitogenic signaling molecules that have roles in angiogenesis, wound healing, cell migration, neural outgrowth and embryonic development. FGFs bind heparan sulfate glycosaminoglycans (HSGAGs), which facilitates dimerization (activation) of FGF receptors (FGFRs). FGFRs are transmembrane catalytic receptors that have intracellular tyrosine kinase activity. There are four human genes encoding FGFRs, which produce different receptors (FGFR1, FGFR1, FGFR2, FGFR3, and FGFR4). HSGAG-FGF-FGFR binding initiates FGFR dimerization, enabling the cytoplasmic kinase domains to transphosphorylate tyrosine residues and become activated. HSGAGs also function to stabilize FGF-FGFR binding and prevent FGF degradation. FGFRs couple to the PLCgamma, MAPK and PI3-K/Akt intracellular signaling cascades and there is evidence of cross talk with the Notch signaling pathway. In addition, some activated FGF-FGFR complexes are endocytosed and function directly in the cytosol and/or nucleus of the cell.

[0004] Alterations in the activity (expression) of the FGFR2 gene are associated with certain cancers. The altered gene expression may enhance several cancer-related events such as cell division (proliferation), cell movement, and the development of new blood vessels that nourish a growing tumor.

[0005] The FGFR2 gene is overexpressed in certain types of stomach cancers, and this amplification is associated with a poorer outcome. Abnormal expression of the FGFR2 gene is also found in patients with prostate cancer. Altered FGFR2 gene expression is also associated with ovarian, cervical, pancreatic, and head and neck cancers.

[0006] Accordingly, the identification of small-molecule compounds that specifically inhibit, regulate and/or modulate FGFR2 is desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis.

SUMMARY OF THE INVENTION

One aspect of the in ntion relate to a compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein:R^3a, R², R^3b, R^4b, L¹, G and J are as defined in the specification.

Other aspects of the invention relate to pharmaceutical compositions and methods of using the compounds described in the specification.

DETAILED DESCRIPTION OF THE INVENTION

[0007] The compositions of the invention are used to treat diseases associated with abnormal and or unregulated cellular activities. Disease states which can be treated by the methods and compositions provided herein include, but are not limited to, cancer (further discussed below), immunological disorders such as rheumatoid arthritis, graft-host diseases, multiple sclerosis, psoriasis; cardiovascular diseases such as atherosclerosis, myocardioinfarction, ischemia, pulmonary hypertension, stroke and restenosis; other inflammatory and degenerative diseases such as interbowel diseases, osteoarthritus, macular degeneration, diabetic retinopathy. One aspect of the in ntion relates to a compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein:

G is CH or ;

L¹ is a bond or -C(0)-N(H)-;

each R² is independently -H, halo, or (Ci-C4)alkyl;

_R3a

is a phenyl or a 5-9 membered heteroaryl, wherein R^3a is optionally substituted with 1, 2 or 3 R⁵ groups;

R^4b is H, alkyl, or dialkylaminoalkyl;

R^4b is H or alkyl;

each R⁵ group, when R⁵ exists, is selected from halo, alkyl, hydroxyalkyl, haloalkyl, (Ci- C6)cycloalkyl optionally substituted with hydroxyl, alkoxyl, alkynyl, phenyl, aloxycarbonyl, or -N(R^C)R^D;

R^c is H or alkyl; and

R^D is H or alkyl.

In another embodiment, the compound of Formula I is a compound according to Formula II,

or a pharmaceutically acceptable salt thereof, wherein: R^3a is pyrazolyl, phenyl, pyrimidinyl, thiadiazoly, benzimidazolyl, oxazolyl, oxadiazolyl, or benzoxazolyl, wherein R^3a is substituted with 1, 2 or 3 R⁵ groups;

each R⁵ group is selected from halo, alkyl, hydroxyalkyl, haloalkyl, (Ci-C6)cycloalkyl optionally substituted with hydroxyl, alkoxyl, alkynyl, phenyl, aloxycarbonyl, or

-NH_2; and

L¹, R², G, R^3b and R^4b are as defined in claim 1.

In another embodiment, the compound of any of the above aspects or embodiments is a compound of Formula III, IV, V, VI or VII:

or a pharmaceutically acceptable salt of any one of formula III, IV, V or VI, wherein

A is N or CH;

B is N or CH;

D is N or O; and

each R⁵ , when R⁵ exists, is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci- C6)cycloalkyl optionally substituted with hydroxyl, and alkoxyl,

provided that at least one of A or B is N.

In another embodiment, the compound of any of the above aspects or embodiments, where it may apply, is a compound of Formula Ilia, III or IIIc

or a pharmaceutically acceptable salt thereof, wherein:

R^5a is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, or alkoxyl; and

R^5b is halo, (Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, halo(Ci-C₆)alkyl, or alkoxyl.

In another embodiment, the compound of any of the above aspects or embodiments, where it may apply, is a compound of Formula Ilia,

Ilia,

or a pharmaceutically acceptable salt thereof, wherein:

R^5a is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, or alkoxyl; and

R^5b is halo, (Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, halo(Ci-C₆)alkyl, or alkoxyl.

In another embodiment, the compound of any of the above aspects or embodiments, where it may apply, is a compound of Formula Illb .

or a pharmaceutically acceptable salt thereof, wherein:

R^5a is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, or alkoxyl; and

R^5b is halo, (Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, halo(Ci-C₆)alkyl, or alkoxyl.

In another embodiment, the compound of any of the above aspects or embodiments, where it may apply, is a compound of Formula IIIc

or a pharmaceutically acceptable salt thereof, wherein:

R^5a is halo, (Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, halo(Ci-C₆)alkyl, (Ci-C₆)cycloalkyl optionally substituted with hydroxyl, or alkoxyl; and

R^5b is halo, (Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, halo(Ci-C₆)alkyl, (Ci-C₆)cycloalkyl optionally substituted with hydroxyl, or alkoxyl.

In another embodiment, the compound of any of the above aspects or embodiments, where it may apply, is a compound of Formula Vila

Vila

or a pharmaceutically acceptable salt thereof, wherein

R^5a is (Ci-C₆)alkyl or halo(Ci-C₆)alkyl.

In other aspects of any of the above embodiments, R^5a is (Ci-C3)alkyl or halo(Ci- C₃)alkyl. Another aspect of the invention relates to a pharmaceutical composition comprising the compound according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier.

Another aspect of the invention relates to method of modulating FGFR2, the method comprising administering to a mammal a compound according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof,, or a composition comprising according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention relates to method of treating diseases or disorders comprising administering to a mammal, in need the treatment, a compound according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof,, or a composition comprising according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment of this method, the disease or disorder is cancer. In another embodiment of this method, the cancer is prostate cancer, ovarian cancer, cervical cancer, pancreatic cancer, or head and neck cancers.

Another aspect of the invention relates to amethod of inhibiting proliferative activity in a cell, the method comprising administering to said cell an effective amount of a compound according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof,, or a composition comprising according to Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

08] In another embodiment, the compound of the invention is one of the following compound in Table 1, or a pharmaceutically acceptable salt of any of the compound in Table 1.

TABLE 1

STRUCTURE NAME ACTIVITY

3- (1 ,1 -dimethylethyl)phenyl

4- (3-{[(2-ami nopyri mid i n-4-

A

yl)methyl]oxy}pyridin-2- yl)piperazine-1-carboxylate

4-(3-{[(2-ami nopyri mid i n-4- yl)methyl]oxy}pyridin-2-yl)-

N-[2-ethyl-6-(1 -

A

methylethyl)pyrimidin-4- yl]piperazine-1 - carboxamide

4-(3-{[(2-ami nopyri mid i n-4- yl)methyl]oxy}pyridin-2-yl)-

N-[4-(trifluoromethyl)pyridin- C

2-yl]piperazine-1 - carboxamide

4-(3-{[(2-ami nopyri mid i n-4- yl)methyl]oxy}pyridin-2-yl)-

0 A N-(4-ethylpyridin-2- C yl)piperazine-1 -

¾ ^{N N¾} carboxamide

4-(3-{[(2-ami nopyri mid i n-4- yl)methyl]oxy}pyridin-2-yl)-

N-(6-cyclopropyl-2-

C

methylpyrimidin-4- yl)piperazine-1 - carboxamide STRUCTURE NAME ACTIVITY

4-(3-{[(2-ami nopyri mid i n-4- yl)methyl]oxy}pyridin-2-yl)- N-biphenyl-3-ylpiperazine- c 1-carboxamide

4-{[(2-{4-[6-(1 -methylethyl)- 1 ,3-benzoxazol-2- yl]piperazin-1 -yl}pyridin-3- c

0 Q ft yl)oxy] methyljpy rim id in-2- amine

methyl 3-({[4-(3-{[(2- aminopyrimidin-4-

0 ojfX yl)methyl]oxy}pyridin-2- c yl)piperazin-1- yl]carbonyl}amino)benzoate

H ⁰

4-(3-{[(2-ami nopyri mid i n-4- yl)methyl]oxy}pyridin-2-yl)- N-[3-(1- A methylpropyl)phenyl]pipera zine-1 -carboxamide

4-(3-{[(2-ami nopyri mid i n-4- yl)methyl]oxy}pyridin-2-yl)- N-[5-(1 ,1 -dimethylethyl)-

A

2,4- difluorophenyl]piperazine-1 - carboxamide

F

4-(3-{[(2-ami nopyri mid i n-4- yl)methyl]oxy}pyridin-2-yl)- N-[4-fluoro-3-(1 -hydroxy-1 - A methylpropyl)phenyl]pipera zine-1 -carboxamide

[0009] Activity A is defined as an FGFR2 IC₅₀ value of less than 50 nM. Activity B is defined as an FGFR2 IC50 value of less than 200 nM and greater than 50 nM. Activity C is defined as an FGFR2 IC5₀ value of less than 5000 nM and greater than 200 nM.

[0010] Other embodiments of this invention relate to compounds in Table I, or a pharmaceutically acceptable salt of any of these compounds, that fall within the definition of either Formula I, II, III, Ilia, Illb, IIIc, IV, V, VI, or VII.

[0011] Another embodiment of this invention relate to compounds in Table I that have Activity A.

[0012] Other embodiments of this invention relate to compounds in Table I that have Activity A and Actvity B.

[0013] Another embodiment of this invention relate to compounds in Table I that have Actvity B.

[0014] Another embodiment of this invention relate to compounds in Table I that have Activity C. Definitions

Pharmaceutical Formulations and Dosage Forms

[0001] Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, trans dermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

[0002] The compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc.

[0003] Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0004] If desired, a pharmaceutical composition of the compounds in this disclosure can also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.

[0005] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4, 107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

[0006] Compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[0007] One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.

[0008] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0009] Solid dosage forms, as described above, can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They can contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0010] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

[0011] Suspensions, in addition to the active compounds, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

[0012] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.

[0013] Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure.

[0014] Compressed gases can be used to disperse a compound of this disclosure in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

[0015] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.

[0016] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.

[0017] The compounds of this disclosure, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of this disclosure can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.

[0018] The compositions will include a conventional pharmaceutical carrier or excipient and a compound of this disclosure as the/an active agent, and, in addition, can include other medicinal agents and pharmaceutical agents. Compositions of the compounds in this disclosure can be used in combination with anticancer and/or other agents that are generally administered to a patient being treated for cancer, e.g. surgery, radiation and/or chemotherapeutic agent(s). Chemotherapeutic agents that can be useful for administration in combination with compounds of Formula I in treating cancer include alkylating agents, platinum containing agents.

[0019] If formulated as a fixed dose, such combination products employ the compounds of this disclosure within the dosage range described above and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of this disclosure can alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate. [0020] The compounds described herein, as well as their pharmaceutically acceptable salts or other derivatives thereof, can exist in isotopically-labeled form, in which one or more atoms of the compounds are replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, . ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶C1, respectively. Isotopically labeled compounds of the present invention, as well as pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or other derivatives thereof, generally can be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0021] In the compounds of the invention, unless otherwise stated, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom at its natural abundance. When a position is designated as "H" or "hydrogen", the position is to be understood to have hydrogen at its natural abundance isotopic composition, with the understanding that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. When a particular position is designated as "D" or "deuterium", it is to be understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015%, and typically has at least 50% deuterium incorporation at that position.

[0022] The methods disclosed herein also include methods of treating diseases by administering deuterated compounds of the invention or other isotopically-labeled compounds of the invention alone or as pharmaceutical compositions. In some of these situations, substitution of hydrogen atoms with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).

[0023] Moreover, certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays such as positron emission tomgraphy (PET). Tritiated, (³H) and carbon- 14 (¹⁴C) isotopes are useful for these embodiments because of their detectability.

Definitions [0024] Terms used herein may be preceded and/or followed by a single dash, or a double dash, "=", to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read "left to right" unless a dash indicates otherwise. For example, Ci-C₆alkoxycarbonyloxy and -OC(0)OCi-C₆alkyl indicate the same functionality. Also, for instance, when variable R⁵ of formula I is defined as -OR⁶, the bond is only to indicate attachment points and the bond is not meant to add additional bonds to the parent structure.

[0025] "Administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., surgery, radiation, chemotherapy, and the like), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.

[0026] "Alkoxy" means the group -OR wherein R is alkyl, as defined herein. Representative examples include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 4-methylhexyloxy, 4-methylheptyloxy, 4,7-dimethyloctyloxy, and the like.

[0027] "Alkoxycarbonyl" means an alkoxy group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(O)OR⁰, wherein R° is alkyl, as defined herein). Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and n- hexylcarbonyl.

[0028] "Alkyl" means a linear or branched hydrocarbon group having from 1 to 10 carbon atoms unless otherwise defined. Representative examples for alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, 4-methylhexyl, 4-methylheptyl, 4,7-dimethyloctyl, and the like. -(Ci-C4)alkyl, which means exactly the same as (Ci_4)alkyl, includes groups selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,

> isobutyl, and tert-butyl.

[0029] "Alkylamino" means an alkyl group, as defined herein, appended to a parent moiety through an -NH- group (i.e., substituents of the form -N(H)R°, where R° is an alkyl group). Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, hexylamino, and the like.

[0030] "Alkylaminocarbonyl" means an alkylamino group, as defined herein, appended to a parent moiety via a carbonyl group (i.e., a group of the form, -C(0)N(H)R°, wherein R° is alkyl, as defined herein). Examples of alkylaminocarbonyl groups include, but are not limited to, methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t- butylaminocarbonyl, and n-hexylaminocarbonyl.

[0031] "Amino" means a -ΝΙ¾ group.

[0032] "Aryl" means a monovalent, monocyclic, or polycyclic radical having 6 to 14 ring carbon atoms. The monocyclic aryl radical is aromatic and whereas the polycyclic aryl radical may be partially saturated, where at least one of the rings comprising a polycyclic radical is aromatic. The polycyclic aryl radical includes fused, bridged, and spiro ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the aryl group, valency rules permitting. Representative examples include phenyl, naphthyl, indanyl, and the like.

[0033] "Carbonyl" means a -C(O)- group.

[0034] "Cycloalkyl" means a monocyclic or polycyclic hydrocarbon radical having 3 to 13 carbon ring atoms. The cycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring. The cycloalkyl radical includes fused, bridged and spiro ring systems. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0035] "Dialkylamino" means two alkyl groups, each independently as defined herein, appended to a parent moiety through a nitrogen atom (i.e., substituents of the form -N(R°)₂, where each R° is an alkyl group). Examples of dialkylamino groups include, but are not limited to N,N-dimethylamino, Ν,Ν-diethylamino, N-isopropyl-N-methylamino, N-ethyl-N- hexylamino, and the like.

[0036] - "Fused ring system" and "fused ring" refer to a polycyclic ring system that contains bridged or fused rings; that is, where two rings have more than one shared atom in their ring structures. In this application, fused-polycyclics and fused ring systems are not necessarily all aromatic ring systems. Typically, but not necessarily, fused-polycyclics share a vicinal set of atoms, for example naphthalene or 1,2,3,4-tetrahydro-naphthalene. The fused ring structure may contain heteroatoms and may be optionally substituted with one or more groups. It should additionally be noted that saturated carbons of such fused groups (i.e., saturated ring structures) can contain two substitution groups. [0037] "Halo" and "halogen" mean a fluoro, chloro, bromo or iodo group.

[0038] "Haloalkyl" means an alkyl radical, as defined herein, substituted with one or more halo atoms. For example, halo-substituted (Ci_4)alkyl includes trifluoromethyl,

2.2- dichloroethyl, 2,2,2-trifluoroethyl, perchloroethyl, 2-bromopropyl, and the like.

[0039] "Heteroaryl" means a monovalent monocyclic or poly cyclic radical having 5 to 14 ring atoms of which one or more of the ring atoms, for example one, two, three, or four ring atoms, are heteroatoms independently selected from -0-, -S(0)_n- (n is 0, 1, or 2), -N-, -N(R^X)-, and the remaining ring atoms are carbon atoms, where R^x is hydrogen, alkyl, hydroxy, alkoxy, -C(O)R⁰ or -S(0)2R°, where R° is alkyl. The monocyclic heteroaryl radical is aromatic and whereas the polycyclic heteroaryl radical may be partially saturated, where at least one of the rings comprising a polycyclic radical is aromatic. The polycyclic heteoaryl radical includes fused, bridged and spiro ring systems. Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting. In particular, when the point of valency is located on the nitrogen, then R^x is absent. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl,

2.3- dihydro-lH-indolyl (including, for example, 2,3-dihydro-lH-indol-2-yl, 2,3-dihydro-lH-indol-5-yl, and the like), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-6-yl, and the like), 2,3,3a,7a-tetrahydro-lH- isoindolyl, pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl, pyrrolo[3,2-c]pyridin-7-yl, and the like), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and the N-oxide derivatives thereof.

[0040] "Heterocyclyl" means a monovalent, monocyclic or polycyclic hydrocarbon radical having 3 to 13 ring atoms of which one or more of the ring atoms, for example 1, 2, 3 or 4 ring atoms, are heteroatoms independently selected from -0-, -S(0)_n- (n is 0, 1, or 2), -N= and -N(R^y)- (where R^y is hydrogen, alkyl, hydroxy, alkoxy, -C(O)R⁰ or -S(0)2R°, where R° is alkyl, as defined herein), and the remaining ring atoms are carbon. The heterocycloalkyl radical may be saturated or partially unsaturated, but cannot contain an aromatic ring. The heteocycloalkyl radical includes fused, bridged and spiro ring systems. More specifically the term heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahydrofuryl, l,4-dioxa-8-azaspiro[4.5]decan-8-yl and tetrahydropyranyl, and the N-oxide derivatives thereof.

[0041] "Heterocyclylalkyl" means a heterocyclyl group appended to a parent moiety via an alkyl group, as defined herein. Examples of heterocyclylalkyl groups include, but are not limited to, morpholin-4-ylmethyl, 2-(morpholin-4-yl)ethyl, morpholin-2-ylmethyl, 2- (morpholin-2-yl)ethyl, morpholin-3-ylmethyl, 2-(morpholin-3-yl)ethyl, piperazin- 1 -ylmethyl, 2-(piperazin-l-yl)ethyl, piperidin-1 -ylmethyl, 2-(piperidin-l-yl)ethyl, piperidin-2 -ylmethyl, 2-(piperidin-2-yl)ethyl, piperidin-4-ylmethyl, 2-(piperidin-4-yl)ethyl, pyrrolidin-1 -ylmethyl, 2-(pyrrolidin- 1 -yl)ethyl, pyrrolidin-2 -ylmethyl, 2-(pyrrolidin-2-yl)ethyl.

[0042] "Hydroxyalkyl" means an alkyl group, as defined herein, substituted with at least one, for example one, two, or three, hydroxy group(s), provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2 -hydroxy ethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylbutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3 -dihydroxypropyl, 1 -(hydroxymethyl)-2-hydroxyethyl, 2,3 -dihydroxybutyl,

3,4-dihydroxybutyl, 2-(hydroxymethyl)-3-hydroxypropyl, 2 -hydroxy ethylene,

2,3 -dihydroxypropyl, l-(hydroxymethyl)-2-hydroxyethyl, and the like.

[0043] The term "optionally substituted" means the substitution may or may not occur and includes instances where said substitution occurs and instances in which it does not. One of ordinary skill in the art would understand that with respect to any molecule described as containing one or more substituents, only sterically practical and/or synthetically feasible compounds are meant to be included. Unless otherwise specified in this specification, when a variable is said to be optionally substituted or substituted with a substituent(s), this is to be understood that this substitution occurs by replacing a hydrogen that is covalently bound to the variable with one these substituent(s). This meaning shall apply to all variables that are stated to be substituted or optionally substituted in the specification.

[0044] "Isomers" means compounds having identical molecular formulae but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers." A carbon atom bonded to four nonidentical substituents is termed a "chiral center." A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture." A compound that has more than one chiral center has 2^{n l} enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see "Advanced Organic Chemistry," 3rd edition, March, Jerry, John Wiley & Sons, New York, 1985). The names and illustration used in this application to describe compounds of the invention, unless indicated otherwise, are meant to be encompassed all possible stereoisomers and any mixture, racemic or otherwise, thereof.

[0045] "Metabolite" refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; for example, biotransformation to a more polar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics" 8.sup.th Ed., Pergamon Press, gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one example, a prodrug may be used such that the biologically active form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclosure.

[0046] "Patient" and "subject" for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In another embodiment the patient is a mammal, and in another embodiment the patient is human. [0047] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington 's Pharmaceutical Sciences, 17^th ed., Mack Publishing Company, Easton, PA, 1985, or S. M. Berge, et al, "Pharmaceutical Salts," J. Pharm. Sci., 1977;66: 1-19. It is also understood that the compound can have one or more pharmaceutically acceptable salts associated with it.

[0048] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0049] Examples of a pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferable salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0050] "Prodrug" refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Aommon examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0051] "Therapeutically effective amount" is an amount of a compound of the invention, that when administered to a patient, effectively treats the disease. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending upon a sundry of factors including the activity, metabolic stability, rate of excretion and duration of action of the compound, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapies and the severity of the disease for which the therapeutic effect is sought. The therapeutically effective amount for a given circumstance can be determined without undue experimentation.

[0052] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, the age, weight, general health, sex, diet and species of the patient, the mode and time of administration of the compound, the concurrent administration of adjuvants or additional therapeutically active ingredients and the severity of the disease for which the therapeutic effect is sought may be necessary, and will be ascertainable with routine experimentation.

[0053] The compounds disclosed herein and their pharmaceutically acceptable salts can exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds disclosed herein can also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of the compounds disclosed herein.

[0054] It is assumed that when considering generic descriptions of compounds disclosed herein for the purpose of constructing a compound, such construction results in the creation of a stable structure. That is, one of ordinary skill in the art would recognize that theoretically some constructs which would not normally be considered as stable compounds (that is, sterically practical and/or synthetically feasible, supra).

[0055] Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Enantiomers (R- and S-isomers) can be resolved by methods known to one of ordinary skill in the art, for example by: formation of diastereoisomeric salts or complexes which can be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which can be separated, for example, by crystallization, selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, enriched in a particular enantiomer, the major component enantiomer can be further enriched (with concomitant loss in yield) by recrystallization. [0056] In addition, the compounds of this disclosure can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds of this disclosure.

[0057] In addition, it is intended that the present disclosure cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like.

[0058] The examples and scheme below depict the general synthetic procedure for the compounds disclosed herein. Synthesis of the compounds of Formulae I disclosed herein, and embodiments thereof, are not limited by these examples and schemes. One skilled in the art will know that other procedures can be used to synthesize the compounds of Formulae I disclosed herein, and that the procedures described in the examples and schemes is only one such procedure. In the descriptions below, one of ordinary skill in the art would recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure. All intermediate compounds described below, for which there is no descripton of how to synthesize such intermediates within these examples below, are commercially available compounds unless otherwise specified.

Utility of compounds of the invention as screening agents

[0146] To employ the compounds of the invention in a method of screening for candidate agents that bind to, for example FGFR2, the protein is bound to a support, and a compound of the invention is added to the assay. Alternatively, the compound of the invention is bound to the support and the protein is added. Classes of candidate agents among which novel binding agents may be sought include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptide analogs, etc. Of particular interest are screening assays for candidate agents that have a low toxicity for human cells. A wide variety of assays may be used for this purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.) and the like.

[0147] The determination of the binding of the candidate agent to, for example, FGFR2 protein may be done in a number of ways. In one example, the candidate agent (the compound of the invention) is labeled, for example, with a fluorescent or radioactive moiety and binding determined directly. For example, thus may be done by attaching all or a portion of the FGFR2 protein to a solid support, adding a labeled agent (for example a compound of the invention in which at least one atom has been replaced by a detectable isotope), washing off excess reagent, and determining whether the amount of the label is that present on the solid support. Various blocking and washing steps may be utilized as is known in the art.

[0148] By "labeled" herein is meant that the compound is either directly or indirectly labeled with a label which provides a detectable signal, for example, radioisotope, fluorescent tag, enzyme, antibodies, particles such as magnetic particles, chemiluminescent tag, or specific binding molecules, and the like. Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin, and the like. For the specific binding members, the complementary member would normally be labeled with a molecule which provides for detection, in accordance with known procedures, as outlined above. The label can directly or indirectly provide a detectable signal.

[0149] In some embodiments, only one of the components is labeled. For example, FGFR2 protein may be labeled at tyrosine positions using ¹²⁵I, or with fluorophores. Alternatively, more than one component may be labeled with different labels; using ¹²⁵I for the proteins, for example, and a fluorophor for the candidate agents.

[0150] The compounds of the invention may also be used as competitors to screen for additional drug candidates, "candidate bioactive agent" or "drug candidate" or grammatical equivalents as used herein describe any molecule, e.g., protein, oligopeptide, small organic molecule, polysaccharide, polynucleotide, etc., to be tested for bioactivity. They may be capable of directly or indirectly altering the cellular proliferation phenotype or the expression of a cellular proliferation sequence, including both nucleic acid sequences and protein sequences. In other cases, alteration of cellular proliferation protein binding and/or activity is screened. In the case where protein binding or activity is screened, some embodiments exclude molecules already known to bind to that particular protein. Exemplary embodiments of assays described herein include candidate agents, which do not bind the target protein in its endogenous native state, termed herein as "exogenous" agents. In one example, exogenous agents further exclude antibodies to FGFR2.

[0151] Candidate agents can encompass numerous chemical classes, though typically they are organic molecules having a molecular weight of more than about 100 and less than about 2,500 daltons. Candidate agents comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding and lipophilic binding, and typically include at least an amine, carbonyl, hydroxyl, ether, or carboxyl group, for example at least two of the functional chemical groups. The candidate agents often comprise cyclical carbon or heterocyclyl structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Candidate agents are also found among biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogs, or combinations thereof.

[0152] Candidate agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. For example, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or readily produced. Additionally, natural or synthetically produced libraries and compounds are readily modified through conventional chemical, physical and biochemical means. Known pharmacological agents may be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification to produce structural analogs.

[0153] In one example, the binding of the candidate agent is determined through the use of competitive binding assays. In this example, the competitor is a binding moiety known to bind to FGFR2, such as an antibody, peptide, binding partner, ligand, etc. Under certain circumstances, there may be competitive binding as between the candidate agent and the binding moiety, with the binding moiety displacing the candidate agent.

[0154] In some embodiments, the candidate agent is labeled. Either the candidate agent, or the competitor, or both, is added first to FGFR2 protein for a time sufficient to allow binding, if present. Incubations may be performed at any temperature that facilitates optimal activity, typically between 4°C and 40°C.

[0155] Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high throughput screening. Typically between 0.1 and 1 hour will be sufficient. Excess reagent is generally removed or washed away. The second component is then added, and the presence or absence of the labeled component is followed, to indicate binding.

[0156] In one example, the competitor is added first, followed by the candidate agent. Displacement of the competitor is an indication the candidate agent is binding to FGFR2 and thus is capable of binding to, and potentially modulating, the activity of the FGFR22. In this embodiment, either component can be labeled. Thus, for example, if the competitor is labeled, the presence of label in the wash solution indicates displacement by the agent. Alternatively, if the candidate agent is labeled, the presence of the label on the support indicates displacement.

[0157] In an alternative embodiment, the candidate agent is added first, with incubation and washing, followed by the competitor. The absence of binding by the competitor may indicate the candidate agent is bound to FGFR2 with a higher affinity. Thus, if the candidate agent is labeled, the presence of the label on the support, coupled with a lack of competitor binding, may indicate the candidate agent is capable of binding to FGFR2.

[0158] It may be of value to identify the binding site of FGFR2. This can be done in a variety of ways. In one embodiment, once FGFR2 has been identified as binding to the candidate agent, the FGFR2 is fragmented or modified and the assays repeated to identify the necessary components for binding.

[0159] Modulation is tested by screening for candidate agents capable of modulating the activity of FGFR2 comprising the steps of combining a candidate agent with FGFR2, as above, and determining an alteration in the biological activity of the FGFR2. Thus, in this embodiment, the candidate agent should both bind to (although this may not be necessary), and alter its biological or biochemical activity as defined herein. The methods include both in vitro screening methods and in vivo screening of cells for alterations in cell viability, morphology, and the like.

[0160] Alternatively, differential screening may be used to identify drug candidates that bind to native FGFR2, but cannot bind to modified FGFR2.

[0161] Positive controls and negative controls can be used in the assays. For example, all control and test samples are performed in at least triplicate to obtain statistically significant results. Incubation of samples is for a time sufficient for the binding of the agent to the protein. Following incubation, samples are washed free of non-specifically bound material and the amount of bound, generally labeled agent determined. For example, where a radiolabel is employed, the samples can be counted in a scintillation counter to determine the amount of bound compound.

[0162] A variety of other reagents can be included in the screening assays. These include reagents like salts, neutral proteins, e.g., albumin, detergents, etc which may be used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions. Also reagents that otherwise improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, etc., may be used. The mixture of components can be added in any order that provides for the requisite binding.

[0163] One of ordinary skill in the art would understand that certain crystallized, protein- ligand complexes, in particular FGFR2 -ligand complexes, and their corresponding x-ray structure coordinates can be used to reveal new structural information useful for understanding the biological activity of FGFR2 kinase's as described herein. As well, the key structural features of the aforementioned proteins, particularly, the shape of the ligand binding site, are useful in methods for designing or identifying selective modulators of FGFR2 kinase's and in solving the structures of other proteins with similar features. Ligands of such complexes may include compounds of the invention as described herein.

[0164] As well, one of ordinary skill in the art would appreciate that such suitable x-ray quality crystals can be used as part of a method of identifying a candidate agent capable of binding to and modulating the activity of FGFR2 kinases. Such methods may be characterized by the following aspects: a) introducing into a suitable computer program, information defining a ligand binding domain of a FGFR2 kinase in a conformation (e.g. as defined by x-ray structure coordinates obtained from suitable x-ray quality crystals as described above) wherein the computer program creates a model of the three dimensional structures of the ligand binding domain, b) introducing a model of the three dimensional structure of a candidate agent in the computer program, c) superimposing the model of the candidate agent on the model of the ligand binding domain, and d) assessing whether the candidate agent model fits spatially into the ligand binding domain. Aspects a-d are not necessarily carried out in the aforementioned order. Such methods may further entail: performing rational drug design with the model of the three-dimensional structure, and selecting a potential candidate agent in conjunction with computer modeling.

[0165] Additionally, one skilled in the art would appreciate that such methods may further entail: employing a candidate agent, so-determined to fit spatially into the ligand binding domain, in a biological activity assay for FGFR2 kinase modulation, and determining whether said candidate agent modulates FGFR2 kinase activity in the assay. Such methods may also include administering the candidate agent, determined to modulate FGFR2 kinase activity, to a mammal suffering from a condition treatable by FGFR2 kinase modulation, such as those described above. [0166] Also, one skilled in the art would appreciate that compounds of the invention can be used in a method of evaluating the ability of a test agent to associate with a molecule or molecular complex comprising a ligand binding domain of a FGFR2 kinase. Such a method may be characterized by the following aspects: a) creating a computer model of a FGFR2 kinase binding pocket using structure coordinates obtained from suitable x-ray quality crystals of the FGFR2 kinase, b) employing computational algorithms to perform a fitting operation between the test agent and the computer model of the binding pocket, and c) analyzing the results of the fitting operation to quantify the association between the test agent and the computer model of the binding pocket.

Abbreviations and their Definitions

[0167] The following abbreviations and terms have the indicated meanings throughout:

Abbreviation Meaning

Abbreviation Meaning

Synthesis of Compounds

[0169] Schemes 1 and 2 depict general synthetic routes for compounds of the invention and are not intended to be limiting. Specific examples are described subsequently to these general synthetic descriptions. In the generalizations below, specific reaction conditions, for example, added bases, acids, solvents, temperature, and the like were not described so as not to confuse the discussion. The general routes in conjunction with the specific examples contain sufficient information to allow one skilled in the art to synthesize compounds of the invention.

Scheme 1

[0170] Referring to Scheme 1, an aromatic starting material, 1, having ortho leaving groups Li and L₂ (and assuming there may be optional substituents on Ar), is combined with a first nucleophilic reagent Nu¹ to afford intermediate 2. Examples of starting material 1 include, but are not limited to, 3,4-dichloro-l,2,5-thiadiazole, 3,4-dichloro-pyrazine, 5,6-dichloro-2,3- dicyanopyrazine, and the like. Examples of first nucleophilic reagent Nu¹ include, but are not limited to, Boc-piperazine, t-butyl 1-homopiperazine carboxylate, 2,6-dimethyl-piperazine, 2,5-dimethyl-piperazine, and the like. Intermediates of type 2 may also be purchased, obviating the need for the aforementioned synthetic conversion 1→2.

[0171] Leaving groups and nucleophiles are chosen to effect desired regiochemical outcome of the particular synthesis, as is more fully exemplified below. Nu¹ may be a preformed intermediate corresponding to "-X" in formula I, or a precursor to "-X," in some instances as will be apparent from the examples below. Intermediate 2 is combined with a second nucleophilic reagent, Nu², to afford intermediate 3. Again, in some instances Nu² may be a preformed intermediate corresponding to "-Y-L-Z" in formula I, or a precursor to "-Y-L-Z." Examples of Nu² include, but are not limited to, pyridin-4-yl-methanol, 3-(dimethylamino- phenyl)-methanol, and the like. Therefore, there may be needed additional manipulation of Nu¹ and Nu² to synthesize compounds of formula I (as depicted), or intermediate 3 may itself be a compound according to formula I. As mentioned, intermediate 3 may be coverted to compounds of formula I. Intermediate 3 may be purchased, made as depicted in Scheme 1, or a commercially available or other starting material is coverted into 3, for example. This may entail, for example, a simple removal of a protecting group, reduction of an electrophilic moiety to make either of Nu¹ or Nu², or in some cases a more complex manipulation.

[0172] Scheme 2 shows one example of a conversion strategy 3→I to which any of the aforementioned scenarios would apply. Intermediate 3 (where Nu¹ has a nucleophilic group thereon) is combined with an electrophile, E¹ to afford intermediate 4. An example of this strategy is where Nu¹ is a piperazine (where in formation of 3 one of the piperazine nitrogens is attached to the aromatic ring) and in conversion to 4, a ring -NH- is "capped" with electro file E¹. Conversion of 4→5 may proceed in much the same way, for example when Nu² has a free nucleophilic site, then an electrophile E² may be added as depicted. There may be needed additional manipulation of 5 to synthesize compounds of formula I (as depicted), or intermediate 5 may itself be a compound according to formula I.

Scheme 2

3 4

EXAMPLES

73] The following examples serve to more fully describe the manner of using the above- described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these examples in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes. All references cited herein are incorporated by reference in their entirety. Generally, each example is set out below with a corresponding multi-step synthesis scheme. Following specific examples are lists of compounds that were made in a similar way.

4-((2-(Piperazin-l-yl)pyridin-3-yl)ethynyl)pyrimidin-2-amine. To a stirred solution of tert-butyl 4-(3-hydroxypyridin-2-yl)piperazine-l-carboxylate 1 (200 mg, 0.716 mmol), Ets (0.30 ml, 2.15 mmol) and dichloromethane (2 ml) at room temperature was added N-phenyl- bis(trifluoromethanesulfonimide) (255 mg, 0.716 mmol). After stirring for 30 min, the reaction mixture was concentrated under reduced pressure. To a stirred solution of the resulting crude material, bis(triphenylphosphino)palladium(II) dichloride (25.1 mg, 0.0358 mmol), copper(I) iodide (10.2 mg, 0.0537 mmol) and DMF (3 ml) at room temperature were added ethynyltrimethylsilane (0.20 ml, 1.43 mmol) and Ets (0.20 ml, 1.43 mmol) in sequence. After stirring for 4 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (Hexane/EtOAc/CEbCk = 9: 1 : 1) to give tert-butyl 4-(3-((trimethylsilyl)ethynyl)pyridin-2-yl)piperazine-l-carboxylate (250 mg, 97%) as a dark brown oil. MS (EI) for Ci₉H₂9N₃0₂Si: 360.2 (MH⁺).

To a stirred solution of tert-butyl 4-(3-((trimethylsilyl)ethynyl)pyridin-2- yl)piperazine- 1 -carboxylate (250 mg, 0.695 mmol) and THF (3 ml) at room temperature was added tetrabutylammonium fluoride (0.77 ml, 1M in THF, 0.765 mmol). After stirring for 20 min, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (Hexane/EtOAc/CH2Cl2 = 6: 1 : 1) to give tert-butyl 4-(3- ethynylpyridin-2-yl)piperazine-l -carboxylate (193 mg, 97%) as a pale yellow oil. MS (EI) for Ci₆H₂₁ 30₂: 288.2 (MH⁺).

To a stirred solution of 4-chloropyrimidin-2-amine (103 mg, 0.793 mmol), bis(triphenylphosphino)palladium(II) dichloride (27.8 mg, 0.0397 mmol), copper(I) iodide (11.3 mg, 0.0595 mmol) and DMF (2 ml) at room temperature were added tert-butyl 4-(3- ethynylpyridin-2-yl)piperazine-l -carboxylate (190 mg, 0.661 mmol) in DMF (2 ml) and Et₃N (0.22 ml, 1.59 mmol) in sequence. After stirring for 17 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (Hexane/EtOAc/CH₂Cl₂ = 1 :2: 1 -> 1 :3 : 1) to give tert-butyl 4-(3-((2-aminopyrimidin-4- yl)ethynyl)pyridin-2-yl)piperazine-l -carboxylate. (148 mg, 59%) as a yellow solid. MS (EI) for C₂oH₂₄N₆0₂: 381.2 (MH⁺).

To a stirred solution of tert-butyl 4-(3-((2-aminopyrimidin-4-yl)ethynyl)pyridin-2- yl)piperazine- 1 -carboxylate (46.0 mg, 0.121 mmol) and dichloroethane (1 ml) at room temperature was added trifluoroacetic acid (0.014 ml, 0.182 mmol). After stirring for 150 min at 70 °C, the reaction mixture was concentrated under reduced pressure to afford 4-((2- (piperazin-l-yl)pyridin-3-yl)ethynyl)pyrimidin-2-amine as a TFA salt.

4-((2-(piperazin-l-yl)pyridin-3-ylamino)methyl)pyrimidin-2-amine hydrochloride. A mixture of tert-butyl 4-(3-nitropyridin-2-yl)piperazine-l -carboxylate 5 (350 mg, 1.14 mmol), Pd/C (60.4 mg, 10%, 0.0568 mmol) and MeOH (6 ml) was subjected to the hydrogenation condition with hydrogen balloon at room temperature. After stirring for 2 h, the resulting solution was filtered through celite. The resulting organic solution was concentrated under reduced pressure and purified by silica gel column chromatography (Hexane/EtOAc/CH₂Cl2 = 1 : 1 : 1) to give tert-butyl 4-(3-aminopyridin-2-yl)piperazine-l -carboxylate (246 mg, 78%) as a white powder. MS (EI) for Ci₄H_{22 4}02: 279.2 (MH⁺).

To a stirred solution of tert-butyl 4-(3-aminopyridin-2-yl)piperazine-l -carboxylate (78.4 mg, 0.282 mmol), 2-aminopyrimidine-4-carbaldehyde (45.0 mg, 0.366 mmol) and toluene (3 ml) at room temperature was added acetic acid (0.07 ml, 0.2M in PhMe, 0.0141 mmol). After stirring for 9 h at 70 °C, the reaction mixture was concentrated under reduced pressure. To a stirred solution of the resulting crude material, dichloromethane (0.5 ml) and methanol (3 ml) at room temperature was added sodium cyanoborohydride (35.4 mg, 0.564 mmol). After stirring for 5 h at 70 °C, water (2 ml) was added and the resulting solution was extracted with EtOAc (5x2 ml). The combined organic layers were concentrated and purified by silica gel column chromatography (Hexane/EtOAc = 1 :2, then CH₂Cl₂/MeOH = 30: 1→ 20: 1) to give tert-butyl 4-(3 -((2-aminopyrimidin-4-yl)methylamino)pyridin-2-yl)piperazine- 1 -carboxylate (60.0 mg, 55%) as a pale brown oil. MS (EI) for Ci₉H_{27 7}0₂: 386.2 (MH⁺).

A mixture of tert-Butyl 4-(3-((2-aminopyrimidin-4-yl)methylamino)pyridin-2-yl)piperazine- 1-carboxylate 7 (1 1.3 mg, 0.0293 mmol) and HCI solution (0.5 ml, 4M in 1,4-dioxane) was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure to afford 4-((2-(piperazin-l-yl)pyridin-3-ylamino)methyl)pyrimidin-2-amine as a HC1 salt.

90 °C

4N HCI/Dioxane, rt

4-((2-(piperazin-l-yl)pyridin-3-yloxy)methyl)pyrimidin-2-amine . To a mixture of 2- bromo-3-hydroxypyridine (10.0 g, 57.4 mmol), chloroacetone (4.58 mL, 57.4 mmol), and DMF (100 mL) at 0 °C was added K₂CO₃ (8.73 g, 63.3 mmol). The reaction mixture was stirred for 1 h before the ice bath was removed and it was allowed to warm to ambient temperature and stirred for an additional 3 h. After the reaction completion was observed by LC/MS, the mixture was diluted with EtOAc and H₂0, extracted with EtOAc (2X), washed with brine (2X), dried with Na₂S0₄, filtered, and concentrated. The product (12.20 g, 92%) was provided as an off-white solid which was carried forward without further purification. ^lH NMR (400 MHz, CDC1₃) δ 8.06 (dd, 1H), 7.23 (dd, 1H), 7.04 (dd, 1H), 4.60 (s, 2H), 2.40 (s, 3H). MS (EI) for C₈H₈BrN0₂: 231 (MH⁺).

To l-(2-bromopyridin-3-yloxy)propan-2-one (10.8 g, 46.6 mmol) was added toluene (100 mL) followed by N,N-dimethylformamide dimethyl acetal (15.4 mL, 116 mmol). The reaction mixture was heated to 100 °C for 16 h at which time it was placed in an ice bath and stirred for 30 min then filtered using toluene to rinse. The solid contained exclusively undesired isomer which was discarded. The mother liquor was concentrated and filtered, using a minimal amount of cold toluene to rinse, which provided the product (3.54 g, 27%) as a ~3: 1 mixture of isomers. The mixture of products was carried forward to the next reaction without further purification.

Minor isomer: 3-(2-bromopyridin-3-yloxy)-4-(dimethylamino)but-3-en-2-one: ^XH NMR (400 MHz, CDC1₃) δ 8.23 - 7.89 (m, 1H), 7.42-7.07 (m, 3H), 3.24 - 2.72 (m, 6H), 2.29 - 1.73 (m, 3H).

Major isomer: l-(2-bromopyridin-3-yloxy)-4-(dimethylamino)but-3-en-2-one: ¾ NMR (400 MHz, CDCI₃) δ 8.01 (dd, 1H), 7.78 (d, 1H), 7.21 (dd, 1H), 7.11 (dd, 1H), 5.55 (d, 1H), 4.58 (s, 2H), 3.14 (s, 3H), 2.88 (s, 3H).

To l-(2-bromopyridin-3-yloxy)-4-(dimethylamino)but-3-en-2-one (3.54 g, 12.4 mmol, -75% pure) was added to a pre-formed mixture of NaOMe (10.7 g, 25 wt% in methanol, 49.5 mmol)) and guanidine HC1 (3.54, 37.4 mmol). Methanol (20 mL) was added and the reaction mixture was heated to 90 °C for 1.5 h then cooled to ambient temperature, diluted with sat. NH₄CI (aq., 40 mL), and H₂0 (40 mL). The solid was filtered, washed with H₂0, and dried under vacuum for 1.5 h to provide the crude product which was dissolved in hot toluene (200 mL), allowed to cool to ambient temperature for 1.5 h, then filtered to give the product (1.63 g, 47%) as a colorless solid. ^XH NMR (400 MHz, DMSO-d6) δ 8.29 (d, 1H), 8.01 (dd, 1H), 7.54 (dd, 1H), 7.42 (dd, 1H), 6.80 - 6.61 (m, 3H), 5.10 (s, 2H).

To 4-((2-bromopyridin-3-yloxy)methyl)pyrimidin-2-amine (1.0 g, 3.56 mmol), tert-butyl piperazine-l-carboxylate (0.993 g, 5.34 mmol), and DMA (5 mL) was added triethylamine (1.84 mL, 14.2 mmol) and the reaction was stirred in a sealed tube at 140 °C for 4 days. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and ¾0, extracted with EtOAc (2X), washed with brine (2X), dried with Na₂S0₄, filtered, and concentrated. The light brown solid collected (1.0 g) was carried forward without further purification. MS (EI) for Ci₄H₁₈N₆0: 287 (MH⁺).

To tert-butyl 4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)piperazine-l-carboxylate (1.3 g, 3.38 mmol) was added HC1 (4N in dioxane, 20 mL) and the reaction mixture was stirred at ambient temperature for 3 h. After completion was observed by LC/MS, the reaction mixture was filtered using dioxane to rinse. The HC1 was basified with NaOH (4N, aq.) and the aqueous layer was saturated with solid NaCl, extracted with EtOAc (3X), dried with Na₂S0₄, filtered, and concentrated. LC/MS indicated that no product remained in the aqueous layer. The solid was placed under high vacuum for 48 h to remove -0.2 eq. of piperazine that remained affording 4-((2-(piperazin-l-yl)pyridin-3-yloxy)methyl)pyrimidin- 2-amine (0.510 g, 50% over 2 steps) as an off-white solid. ^XH NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1H), 7.81 (dd, 1H), 7.24 (d, 1H), 6.85 (dd, 1H), 6.77 - 6.58 (m, 3H), 4.95 (s, 2H), 3.25-3.22 (m, 4H), 2.94 - 2.76 (m, 4H), 1.54 (s, 1H). MS (EI) for Ci₄H₁₈N₆0: 287 (MH⁺).

2) H₂, 1 0% Pd/C

l-teri-Butyl-lH-pyrazol-4-amine. To a solution of 4-nitro- IH-pyrazole which was prepared as described in J. Med Chem. 2005, 48, 5780 (0.5 g, 4.4 mmol) in dioxane (8 mL) was added tert-butylacetate (3 mL) and cone. Ι¾80₄ (0.26 mL) and the mixture was stirred for 18 h at room temperature. The reaction mixture was diluted with sat. NaHC03, volatiles were evaporated and mixture was extracted with ethyl acetate. The organic phase was dried (MgS0₄), filtered and evaporated to afford a crude residue which was purified by

chromatography on silica gel (CH2CI2). Isolated l-tert-butyl-4-nitro-lH-pyrazole (250 mg): 1H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 1H), 8.09 (s, 1H), 1.63 (s, 9H). To a solution 1- tert-butyl-4-nitro-lH-pyrazole (250 mg, 1.5 mmol) in methanol (10 mL) was added 10% Pd/C (80 mg) and the mixture was stirred under hydrogen for lh. The reaction was filtered and the filtrate was evaporated to afford l-tert-butyl-lH-pyrazol-4-amine which was used directly without any further purification.

Example 5

2) H₂, 1 0% Pd/C

l-(2,2,2-Trifluoroethyl)-lH-pyrazol-4-amine. To a solution of 4-nitro- IH-pyrazole (300 mg, 2.7 mmol) in N.N-dimethylformamide (3 mL) was added l, l, l-trifluoro-2-iodoethane (1.13 g, 5.4 mmol) and cesium carbonate (1 g, 3.1 mmol) and the mixture was stirred at 60 °C for 18 h. The reaction was partitioned between ether and 5% aqueous lithium chloride solution. The organic phase was dried (MgS0₄) filtered and evaporated to afford a crude residue which was purified by silica gel chromatography (dichloromethane) to give 4-nitro- 1- (2,2,2-trifluoroethyl)- m-pyrazole (198 mg) as a solid. 1Η NMR (400 MHz, CDC1₃) δ 8.29 (s, 1H), 8.16 (s, 1H), 4.77 (q, 2H). To a solution of 4-nitro-l-(2,2,2-trifluoroethyl)-lH- pyrazole (190 mg, 0.97 mmol) in methanol (10 mL) was added 10% Pd/C (80 mg) and the mixture was stirred under hydrogen for 3 h. The reaction was filtered and the filtrate was evaporated to afford l-(2,2,2-trifluoroethyl)-lH-pyrazol-4-amine which was used directly without any further purification.

2) H₂, 10% Pd/C

l-Isobutyl-lH-pyrazol-4-amine. l-isobutyl-4-nitro-lH-pyrazole was synthesized from 4- nitro-lH-pyrazole and isobutyl alcohol using a similar procedure as described in Tetrahedron Lett. 2008, 49, 2996. 1H NMR (400 MHz, CDC1₃) δ 8.10 (s, 1H), 8.08 (s, 1H), 3.95 (d, 2H), 2.31 - 2.19 (m, 1H), 0.95 (d, 7H). To a solution of l-isobutyl-4-nitro-lH-pyrazole (200 mg, 0.12 mmol) in methanol (15 mL) was added 10% Pd/C (80 mg) and the mixture was stirred under hydrogen for 2 h. The reaction was filtered and the filtrate was evaporated to afford 1- isobutyl- lH-pyrazol-4-amine as an oil which was used directly without any further purification.

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(l-isobutyl-lH-pyrazol-4- yl)piperazine-l-carboxamide. To a solution of triphosgene (47 mg, 0.16 mmol) in dichloromethane (2 mL) at 0 °C was added a solution of 1 -isobutyl- lH-pyrazol-4-amine (60 mg, 0.43 mmol) and N,N-diisopropylethylamine (142 μL, 0.83 mmol) in dichloromethane (2.5 mL) over a period of 40 min. After stirring an additional 20 min. 4-((2-(piperazin-l- yl)pyridin-3-yloxy)methyl)pyrimidin-2-amine (75 mg, 0.26 mmol) and N,N- diisopropylethylamine (89 μΐ_^, 0.52 mmol) and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was purified by

chromatography on silica gel (5% methanol/CEbCk) to afford 4-(3-((2-aminopyrimidin-4- yl)methoxy)pyridin-2-yl)-N-( 1 -isobutyl- 1 H-pyrazol-4-yl)piperazine- 1 -carboxamide (69 mg, ) as a solid. IH NMR (400 MHz, DMSO-d₆) δ 8.58 (s, IH), 8.30 (d, IH), 7.84 (dd, IH), 7.69 (s, IH), 7.36 (s, IH), 7.30 (dd, IH), 6.91 (dd, IH), 6.73 - 6.67 (m, 3H), 4.99 (s, 2H), 3.82 (d, 2H), 3.58 - 3.51 (m, 4H), 3.37 - 3.30 (m, 4H), 2.10 - 1.98 (m, IH), 0.81 (d, 6H).

The following compounds were prepared by a similar procedure as in Example 7 using the appropriate amine and 4-((2-(piperazin-l-yl)pyridine-3-yloxy)methyl)pyrimidin-2- amine (Example 3) or 4-((3-(piperazin-l-yl)pyrazin-2-yloxy)methyl)pyrimidin-2-amine (WO 2004083235) or 4-((2-(piperazin-l-yl)pyridin-3-yl)ethynyl)pyrimidin-2-amine (Example 1) or 4-((2-(piperazin-l-yl)pyridin-3-ylamino)methyl)pyrimidin-2-amine (Example 2).

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(l-tert-butyl-lH-pyrazol-4- yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, DMSO-d6) δ 8.56 (s, IH), 8.29 (d, J = 5.0 Hz, IH), 7.84 (dd, lH), 7.77 (s, IH), 7.39 (s, IH), 7.30 (dd, IH), 6.91 (dd, IH), 6.75 -

6.65 (m, 3H), 4.99 (s, 2H), 3.55 (m, 4H), 3.32 (m, 4H), 1.47 (s, 9H); MS (EI) for

C22H29N9O2: 452.2 (MH⁺)

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(l-(2,2,2-trifluoroethyl)-lH- pyrazol-4-yl)piperazine-l-carboxamide. IH NMR (400 MHz, DMSO-d6) δ 8.73 (s, IH), 8.30 (d, IH), 7.88 (s, IH), 7.85 (dd, IH), 7.52 (s, IH), 7.31 (dd, IH), 6.92 (dd, IH), 6.75 -

6.66 (m, 3H), 5.05 (q, 2H), 4.99 (s, 2H), 3.56 (m, 4H), 3.34 (m, 4H).

4-(3-((2-Aminopyrimidin-4-yl)ethynyl)pyridin-2-yl)-7V-(3-teri-butylphenyl)piperazine-l- carboxamide. ^XH-NMR (400MHz, DMSO-d₆) 68.52 (s, IH), 8.30 (d, IH), 8.29 (dd, IH), 7.88 (dd, IH), 7.47 (s, IH), 7.37 (d, IH), 7.15 (t, IH), 6.97 (d, IH), 6.95 (dd, IH), 6.85 (s, 2H), 6.75 (d, IH), 3.66 - 3.58 (m, 8H), 1.26 (s, 9H). MS (EI) for C2₆H2₉N7O: 456.3 (MH⁺). 4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyrazin-2-yl)-iV-(3-teri-butylphenyl)piperazine- 1-carboxamide. ^XH-NMR (400MHz, DMSO-d₆) δ 8.50 (s, IH), 8.22 (d, IH), 7.81 (d, IH), 7.59 (d, IH), 7.45 (t, IH), 7.34 (ddd, IH), 7.13 (t, IH), 6.95 (ddd, IH), 6.67 (s, 2H), 6.56 (d, IH), 5.23 (s, 2H), 3.61 - 3.50 (m, 8H), 1.24 (s, 9H). MS (EI) for C24H₃₀N₈O2: 463.2 (MH⁺). 4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-iV-(3-teri-butylphenyl)piperazine- 1-carboxamide. ¾-NMR (400MHz, DMSO-d₆) δ 8.51 (s, IH), 8.30 (d, IH), 7.85 (dd, IH), 7.47 (t, IH), 7.38 - 7.35 (m, IH), 7.31 (dd, IH), 7.15 (t, IH), 6.99 - 6.96 (m, IH), 6.92 (dd, IH), 6.71 (s, 2H), 6.70 (d, IH), 5.00 (s, 2H), 3.64 - 3.57 (m, 4H), 3.40 - 3.34 (m, 4H), 1.26 (s, 9H). MS (EI) for C25H₃1 7O2: 462.3 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]amino}pyridin-2-yl)-N-[3-(l,l- dimethylethyl)phenyl]piperazine-l-carboxamide. 1H-NMR (400MHz, DMSO-d₆) δ 8.51 (s, IH), 8.15 (d, IH), 7.60 (dd, IH), 7.48 (t, IH), 7.39 - 7.36 (m, IH), 7.16 (t, IH), 6.97 (dd, IH), 6.88 (t, IH), 6.68 (dd, IH), 6.65 (s, 2H), 6.49 (d, IH), 5.81 (t, IH), 4.20 (d, 2H), 3.70 - 3.65 (m, 4H), 3.05 - 3.01 (m, 4H), 1.26 (s, 9H). MS (EI) for C25H₃2 ₈O: 461.3 (MH⁺).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(l-sec-butyl-lH-pyrazol-4- yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, CDC1₃) δ 8.34 (d, IH), 7.93 (dd, IH), 7.80 (s, IH), 7.36 (s, IH), 7.27 (s, 2H), 7.07 (dd, IH), 6.86 (dd, IH), 6.82 (d, IH), 6.35 (s, IH), 5.13 (s, 2H), 4.99 (s, 2H), 4.24 - 4.05 (m, IH), 3.64 (dd, 4H), 3.51 (dd, 4H), 2.01 - 1.55 (m, 2H), 1.47 (d, 3H), 0.81 (t, 3H). MS (EI) for C22H2₉ N₉O2: 452 (MH⁺).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(3-propylphenyl)piperazine-l- carboxamide. ^XH NMR (400 MHz, DMSO-d₆) δ 8.49 (s, IH), 8.28 (d,lH), 7.85 - 7.79 (m, IH), 7.33 - 7.23 (m, 3H), 7.11 (t, IH), 6.89 (dd, IH), 6.75 (d, IH), 6.68 (d, 3H), 4.97 (s, 2H), 3.69 (d, 4H), 3.43 (d, 4H), 1.60-1.50 (m, 2H), 0.87 (t, 3H). MS (EI) for C24H2₉FN7O2:

448(MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(trifluoromethyl)pyridin- 4-yl]piperazine-l-carboxamide. ^XH NMR (400 MHz, CDC1₃) δ 8.71 (s, IH), 8.62 (d, IH), 8.34 (m, 2H), 7.92 (dd, IH), 7.11 (br s, IH), 7.07 (dd, IH), 6.87 (dd, IH), 6.80 (d, IH), 5.12 (br s, 2H), 5.00 (s, 2H), 3.69 (m, 4H), 3.56 (m, 4H).

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(l-propyl-lH-pyrazol-4- yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, DMSO-d₆) δ 8.59 (s, IH), 8.30 (d, IH), 7.84 (dd, IH), 7.71 (s, IH), 7.36 (s, IH), 7.31 (dd, IH), 6.91 (dd, IH), 6.71 (s, 2H), 6.69 (d, IH), 4.99 (s, 2H), 3.97 (t, 2H), 3.57 - 3.52 (m, 4H), 3.35 - 3.31 (m, 4H), 1.73 (sextet, 2H), 0.80 (t, 3H). MS (EI) for C21H27N₉O2 : 438.1 (MH⁺).

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(3-(3-hydroxypentan-3- yl)phenyl)piperazine-l-carboxamide. Prepared from 3-(3-aminophenyl)pentan-3-ol (Example 8). ^XH NMR (400 MHz, DMSO-d₆) δ 8.52 (s, IH), 8.30 (d, IH), 7.85 (d, IH), 7.45 - 7.35 (m, 2H), 7.31 (d, IH), 7.14 (t, IH), 6.97 - 6.88 (m, 2H), 6.76 - 6.66 (m, 3H), 5.00 (s, 2H), 4.45 (s, IH), 3.61 (m, 4H), 3.36 (m, 4H), 1.76 - 1.60 (m, 4H), 1.29 - 1.21 (m, IH), 0.65 (t, 6H); MS (EI) for C2₆H₃₃N7O₃: 492.2 (MH⁺). 4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(3-(l- hydroxycyclopentyl)phenyl)piperazine-l-carboxamide. Prepared from l-(3- aminophenyl)cyclopentanol (Example 8). ^XH NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.30 (d, 1H), 7.85 (dd, 1H), 7.54 (br s, 1H), 7.38 (d, 1H), 7.31 (d, 1H), 7.15 (t, 1H), 7.05 (d, 1H), 6.92 (dd, 1H), 6.75 - 6.67 (m, 3H), 5.00 (s, 2H), 4.72 (s, 1H), 3.65 - 3.56 (m, 4H), 3.40 - 3.34 (m, 4H), 1.89 - 1.69 (m, 8H). MS (EI) for C₂₆H₃i ₇0₃: 490.2 (MH⁺).

3-(3-aminophenyl)pentan-3-ol. To a solution of

3-[bis(trimethylsilyl)amino]phenylmagnesium chloride ( 3 mL of 1.0 M in THF, 3 mmol, Aldrich) in THF (2 mL) at 0 °C was added 3-pentanone (349 μί, 3.3 mmol). The ice bath was removed and the reaction was stirred at room temperature for 3 h. To the reaction was added 1 M HC1 (5 mL) and the mixture was stirred for 10 min. Excess saturated NaHC03 was added, and the mixure was extracted twice with ether. The combined ether extracts were dried (Na₂S0₄), filtered and evaporated. The residue was suspended in ethyl acetate / hexane (2/3) and the precipitated solid was filtered, rinsed with hexane and dried to afford 3-(3- aminophenyl)pentan-3-ol (164 mg) as a white solid.

1H NMR (400 MHz, CDC1₃) δ 7.12 (t, 1H), 6.76 (t, 1H), 6.73-6.71 (m, 1H), 6.56 (ddd, 1H), 3.65 (s, 2H), 1.88 - 1.71 (m, 4H), 1.61 (s, 1H), 0.76 (t, 6H).

The following compounds were prepared as described in Example 8

l-(3-aminophenyl)cyclopentanol. Prepared from

3-[bis(trimethylsilyl)amino]phenylmagnesium chloride and cyclopentanone as a solid.

6-teri-Butyl-2-methylpyrimidin-4-amine. To a solution of methyl 4,4-dimethyl-3- oxopentanoate (1.1 g, 7.0 mmol) in ethanol (15 mL) was added acetamidine hydrochloride (0.66 g, 7.0 mmol) and sodium ethoxide (2.38 g, 35 mmol) and the mixture was heated to reflux for 9 h. The solvent was evaporated and the residue was dissolved in water, acidified with acetic acid and extracted with ethyl acetate. The organic phase was washed with saturated NaCl, dried (MgS0₄), filtered and evaporated. The residue was purified by chromatography on silica gel (3% to 5% methanol/CH^C^) to afford 6-tert-butyl-2- methylpyrimidin-4-ol (627 mg) as a solid. A suspension of 6-tert-butyl-2-methylpyrimidin- 4-ol (300 mg, 1.8 mmol) in phosphorus oxychloride (2 mL) was heated at 90 °C for 1.5 h. The reaction mixture was cooled to room temperature, poured into ice-water, 5 N NaOH was added until the pH was approximately 7 and the mixture was extracted with (¾(¾. The organic phase was dried (MgS0₄), filtered and evaporated to afford 4-tert-butyl-6-chloro-2- methylpyrimidine (231 mg). The chloropyrimidine was dissolved in ethanol (3 mL), cooled to -10 °C, saturated with ammonia and the reaction flask was sealed and heated at 90 °C for 40 h. The solvent was evaporated and the residue was partitioned between saturated NaCl and CH₂CI₂. The aqueous phase was extracted sequentially with CH₂CI₂ and ethyl acetate. The combined organic extracts were dried ( a2S0₄) filtered, evaporated and purified by chromatography on silica gel (5% MeOH/CT^C^) to afford 6-tert-butyl-2-methylpyrimidin- 4-amine (152 mg) as a solid. ¾ NMR (400 MHz, CDC1₃) δ 6.24 (s, IH), 4.68 (s, 2H), 2.50 (s, 3H), 1.27 (s, 9H).

The following compounds were prepared using a similar procedure as in Example 9:

6-Isopropyl-2-(trifluoromethyl)pyrimidin-4-amine. Prepared from ethyl acetoacetate and 2,2,2-trifluoroacetamidine. ^XH NMR (400 MHz, DMSO-d₆) δ 7.40 (s, 2H), 6.44 (s, IH),

2.84- 2.74 (m, IH), 1.17 (d, 6H).

2,6-Diethylpyrimidin-4-amine. Prepared from methyl 3-oxopentanoate and propionamidine hydrochloride. ¾ NMR (400 MHz, CDC1₃) δ 6.13 (s, IH), 4.78 (s, 2H), 2.74 (q, 2H), 2.62 (q, 2H), 1.30 (t, 3H), 1.24 (t, 3H).

2-Ethyl-6-isopropylpyrimidin-4-amine. Prepared from ethyl isobutyrylacetate and propionamidine hydrochloride. IH NMR (400 MHz, CDC1₃) δ 6.11 (s, IH), 4.76 (s, 2H),

2.85 - 2.76 (m, IH), 2.72 (q, 2H), 1.29 (t, 3H), 1.23 (d, 6H).

2,6-Diisopropylpyrimidin-4-amine. Prepared from ethyl isobutyrylacetate and

2-methylpropanimidamide hydrochloride. IH NMR (400 MHz, CD₃OD) δ 6.22 (s, IH), 2.94 - 2.85 (m, IH), 2.81 - 2.70 (m, IH), 1.22 (2d, 12H).

2-Ethyl-6-(trifluoromethyl)pyrimidin-4-amine. Prepared from ethyl 4,4,4-trifluoro-3- oxobutanoate and propionamidine hydrochloride.

2-Isopropyl-6-methylpyrimidin-4-amine. Prepared from methyl acetoacetate and

2-methylpropanimidamide hydrochloride.

2-tert-Butyl-6-methylpyrimidin-4-amine. Prepared from ethyl acetoacetate and 2,2- dimethylpropanimidamide hydrochloride. Exam le 10

6-tert-Butyl-N²,N²-dimethylpyrimidine-2,4-diamine. Using a similar procedure as in Example X, 4-tert-butyl-6-chloro-N,N-dimethylpyrimidin-2-amine was prepared by reaction of methyl 4,4-dimethyl-3-oxopentanoate (1.58 g, 10 mmol) and dimethylguanidine sulfate (1.36 g, 5 mmol) to yield the hydroxypyrimidine (698 mg) which was treated with phosphorus oxy chloride, To a solution of the crude chloropyrimidine (700 mg, 3.3 mmol) in 2-propanol (1 mL) was added 2,4-dimethoxybenzylamine (1.5 mL, 9.9 mmol) and the mixture was heated for 100 °C for 4 h and was partitioned between ether and 10% K2CO₃. The organic phase was washed with saturated NaCl, dried (MgS0₄), filtered, and evaporated. The residue was purified by chromatography on silica gel (10% ethyl acetate/hexane) to afford 6-tert-butyl-N⁴-(2,4-dimethoxybenzyl)-N²,N²-dimethylpyrimidine-2,4-diamine (670 mg) as a clear oil. The dimethoxybenzylamine adduct was treated with trifluoroacetic acid (5 mL) and was stirred for 30 min at room temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate and saturated NaCl. A solid was filtered from both phases and was discarded. The organic phase was washed with saturated NaCl, dried (MgS0₄), filtered and evaporated to afford 6-tert-Butyl-N²,N²-dimethylpyrimidine-2,4- diamine (350 mg) as a solid. ^XH NMR (400 MHz, CDC1₃) δ 5.73 (s, 1H), 4.42 (s, 2H), 3.12 (s, 6H), 1.23 (s, 9H). MS (EI) for Ci₀H₁₈N₄: 195.1 (MH⁺)

The following compounds were prepared using a similar procedure as in Example 10:

6-tert-butyl-2-(trifluoromethyl)pyrimidin-4-amine. Prepared from methyl 4,4-dimethyl-3- oxopentanoate and 2,2,2-trifluoroacetamidine. ¾ NMR (400 MHz, CDC1₃) δ 6.49 (s, 1H), 5.30 (s, 2H), 1.31 (s, 9H).

6-tert-Butyl-2-ethylpyrimidin-4-amine. Prepared from methyl 4,4-dimethyl-3- oxopentanoate and propionamidine hydrochloride. Example 11

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[6-(l,l- dimethylethyl)pyrimidin-4-yl]piperazine-l-carboxamide. To suspension of sodium hydride (60% dispersion in mineral oil, 160 mg, 4.00 mmol, 3.74 equiv) in THF (2 mL) was slowly added via syringe a solution of 4-amino-6-tert-butylpyrimidine (162 mg, 1.07 mmol, 1.2 equiv) in THF (2 mL). The mixture was stirred for 30 min at room temperature and carbonyl diimidazole (208 mg, 1.28 mmol, 1.2 equiv) in dimethylacetamide (2 mL) was added via syringe. The reaction was then heated to 50 °C for 4.25 hours, at which time a solution of 4-((2-(piperazin-l-yl)pyridine-3-yloxy)methyl)pyrimidin-2-amine (Example 3, 252 mg, 0.880 mmol) and triethylamine (0.3 mL, 2.15 mmol) in dimethylacetamide (4 mL) was added and the reaction was allowed to stir at 50 °C overnight. The reaction was poured onto aqueous LiCl and extracted with CH₂CI₂ (3 X 50 mL). The combined organic extracts were collected, dried (Na₂S0₄), filtered, and concentrated. The crude product was purified by chromatography on silica gel (2% 7M NH₃ in methanol/ethyl acetate) to afford 4-(3- {[(2- aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[6-(l, l-dimethylethyl)pyrimidin-4- yl]piperazine-l-carboxamide (176 mg, 43 %) as a solid. ^XH NMR (CDC1₃) δ 8.73 (m, 1H), 8.35 (d, 1H), 8.09 (br s, 1H), 7.92 (dd, 1H), 7.55 (br s, 1H), 7.07 (dd, 1H), 6.87 (dd, 1H), 6.80 (d, 1H), 5.30 (br s, 2H), 5.00 (s, 2H), 3.72 (m, 4H), 3.54 (m, 4H), 1.36 (s, 9H).

The following compounds were prepared using a similar procedure as in Example 1 1 using the appropriate amine and 4-((2-(piperazin-l-yl)pyridine-3-yloxy)methyl)pyrimidin-2-amine (Example 3) or 4-((3-(piperazin-l-yl)pyrazin-2-yloxy)methyl)pyrimidin-2-amine (WO 2004083235) or 4-((2-(piperazin-l-yl)pyridin-3-yl)ethynyl)pyrimidin-2-amine (Example 1) or 4-((2-(piperazin-l-yl)pyridin-3-ylamino)methyl)pyrimidin-2-amine (Example 2) or 4-((3- (piperazin- 1 -yl)pyridin-2-yloxy)methyl)pyrimidin-2-amine (Example 15).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(6-tert-butyl-2- (dimethylamino)pyrimidin-4-yl)piperazine-l-carboxamide. IH NMR (400 MHz, CDCI₃) δ 8.35 (d, IH), 7.93 (dd, IH), 7.28 (s, IH), 7.07 (dd, IH), 7.00 (s, IH), 6.86 (dd, IH), 6.82 (d, IH), 5.08 (s, 2H), 4.99 (s, 2H), 3.71-3.69 (m, 4H), 3.53-3.51 (m, 5H), 3.14 (s, 6H), 1.29 (s, 9H); MS (EI) for C25H₃4 1₀O2: 507.2 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(6-cyclopropyl-2- methylpyrimidin-4-yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, CDCI₃) δ 8.35 (d, IH), 7.93 (dd, IH), 7.64 (s, IH), 7.20 (br s, IH), 7.08 (dd, IH), 6.87 (dd, IH), 6.81 (d, IH), 5.14 (br s, 2H), 5.00 (s, 2H), 3.70 (m, 4H), 3.52 (m, 4H), 2.41 (s, 3H), 1.96 (m, IH), 1.08 (m, 2H), 1.03 (m, 2H). MS (EI) for C2₃H27N₉O2: 462.16 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2-methyl-6-(l- methylethyl)pyrimidin-4-yl]piperazine-l-carboxamide. ^XH NMR (400 MHz, CDCI₃) δ 8.35 (d, IH), 7.93 (dd, IH), 7.75 (s, IH), 7.39 (br s, IH), 7.08 (dd, IH), 6.87 (dd, IH), 6.80 (d, IH), 5.27 (br s, 2H), 5.00 (s, 2H), 3.71 (m, 4H), 3.52 (m, 4H), 2.94 (septet, IH), 2.56 (s, 3H), 1.29 (d, 6H). MS (EI) for C2₃H2₉N₉O2: 464.27 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2,6- bis(trifluoromethyl)pyrimidin-4-yl]piperazine-l-carboxamide. ^XH NMR (400 MHz, DMSO-d₆) δ 11.07 (s, IH), 8.36 (s, IH), 8.26 (m, IH), 7.84 (m, IH), 7.25 (m, IH), 6.88 (m, IH), 6.69 (m, IH), 6.59 (s, IH), 4.98 (s, 2H), 3.71 (br s, 4H), 3.44 (br s, 4H). MS (EI) for C2iH₁₉F₆N90₂: 543.74 (M⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(4-ethylpyridin-2- yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, CDC1₃) δ 8.30 (d, IH), 7.94 (m, 3H), 7.06 (dd, IH), 6.83 (m, 3H), 5.54 (br s, 2H), 4.99 (s, 2H), 3.75 (m, 4H), 3.52 (m, 4H), 2.65 (q, 2H), 1.25 (t, 3H). MS (EI) for C₂₂H₂₆N₈0₂: 435.36 (MH⁺).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(2-isopropyl-6-methylpyrimidin- 4-yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, DMSO-d₆) δ 9.53 (s, IH), 8.29 (d, IH), 7.84 (d, IH), 7.47 (s, IH), 7.30 (d, IH), 6.91 (dd, IH), 6.80 - 6.54 (m, 3H), 4.99 (s, 2H), 3.72 - 3.51 (m, 4H), 3.39-3.36 (m, 4H), 3.05 - 2.80 (m, IH), 2.34 (s, 3H), 1.23 (d, 6H). MS (EI) for C₂₃H₂₉N₉02: 464 (MH⁺). 4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(4,6-dimethylpyrimidin-2- yl)piperazine-l-carboxamide. ¾ NMR (400 MHz, CDC1₃) δ 8.33 (d, IH), 8.13 (d, IH), 7.58 (br s, IH), 7.05 (d, IH), 6.82 (m, 2H), 6.65 (br s, IH), 5.29 (br s, 2H), 4.98 (s, 2H), 3.73 (m, 4H), 3.50 (m, 4H), 2.40 (s, 6H). MS (EI) for 0₂ιΗ₂₅Ν₉0₂: 436.34 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[4-(l,l- dimethylethyl)pyridin-2-yl]piperazine-l-carboxamide. ^XH NMR (400 MHz, CDCI₃) δ 8.35 (d, IH), 8.11 (m, 2H), 7.93 (dd, IH), 7.40 (br s, IH), 7.07 (dd, IH), 6.97 (dd, IH), 6.86 (dd, IH), 6.82 (d, IH), 5.15 (br s, 2H), 5.00 (s, 2H), 3.72 (m, 4H), 3.53 (m, 4H), 1.33 (s, 9H). MS (EI) for C₂₄H_{30 8}O₂: 463.29 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(4,6-dimethylpyridin-2- yl)piperazine-l-carboxamide. ¾ NMR (400 MHz, CDC1₃) δ 8.33 (d, IH), 7.92 (dd, IH), 7.68 (s, IH), 7.06 (dd, IH), 6.85 (dd, IH), 8.62 (d, IH), 6.64 (s, IH), 5.23 (br s, 2H), 4.99 (s, 2H), 3.71 (m, 4H), 3.50 (m, 4H), 2.37 (s, 3H), 2.29 (s, 3H). MS (EI) for C₂₂H_{26 8}0₂: 435 (MH⁺).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyrazin-2-yl)-N-(6-tert-butylpyrimidin-4- yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, DMSO-d₆) δ 9.77 (s, IH), 8.71 (d, IH), 8.23 (d, IH), 7.87 (d, IH), 7.82 (d, IH), 7.61 (d, IH), 6.69 (s, 2H), 6.56 (d, IH), 5.26 (s, 2H), 3.72 - 3.60 (m, 4H), 3.60 - 3.50 (m, 4H), 1.27 (s, 9H). MS (EI), C₂₂H₂₈Nio0₂: 465.0 (MH⁺). 4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[5-(l,l-dimethylethyl)-l,3,4- thiadiazol-2-yl]piperazine-l-carboxamide. 'H NMR (400 MHz, CDC1₃) δ 8.32 (dd, IH), 7.93 (m, IH), 7.06 (d, IH), 6.83 (m, 2H), 5.17 (br s, 2H), 5.00 (s, 2H), 3.89 (m, 4H), 3.57 (m, 4H), 1.41 (s, 9H). MS (EI) for C₂iH₂₇N₉0₂S: 470.29 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[5-(l,l- dimethylethyl)isoxazol-3-yl]piperazine-l-carboxamide. ¾ NMR (400 MHz, CDCI₃) δ 8.79 (br s, IH), 8.33 (d, IH), 7.92 (dd, IH), 7.06 (dd, IH), 6.85 (ddlH), 6.82 (d, IH), 6.66 (s, IH), 5.16 (br s, 2H), 5.00 (s, 2H), 3.76 (m, 4H), 3.54 (m, 4H), 1.31 (s, 9H). MS (EI) for C₂₂H₂₈N₈0₃: 453.32 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[4-(trifluoromethyl)pyridin- 2-yl]piperazine-l-carboxamide. ^XH NMR (400 MHz, CDC1₃) δ 8.38 (m, IH), 8.32 (d, IH), 7.92 (dd, IH), 7.86 (br s, IH), 7.15 (dd, IH), 7.06 (dd, IH), 8.86 (dd, IH), 6.80 (d, IH), 5.36 (br s, 2H), 4.99 (s, 2H), 3.72 (m, 4H), 3.53 (m, 4H). MS (EI) for C₂iH₂₁F₃N₈0₂: 475.26 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(l,l- dimethylethyl)isoxazol-5-yl]piperazine-l-carboxamide. ^XH NMR (400 MHz, DMSO-d6) δ 9.66 (s, IH), 8.27 (d, IH), 7.83 (d, IH), 7.24 (d, IH), 6.87 (m, IH), 6.70 (d, IH), 6.62 (s, IH), 6.47 (s, IH), 4.98 (s, 2H), 3.64 (s, 4H), 3.39 (s, 4H), 1.30 (s, 9H). MS (EI) for C₂2H_{28 8}03: 453.19 (MH⁺).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(5-tert-butylpyridazin-3- yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, DMSO-d₆) δ 9.77 (s, IH), 8.71 (d, IH), 8.23 (d, IH), 7.87 (d, IH), 7.82 (d, IH), 7.61 (d, IH), 6.69 (s, 2H), 6.56 (d, IH), 5.26 (s, 2H), 3.79 - 3.60 (m, 4H), 3.60 - 3.47 (m, 4H), 1.27 (s, 9H). MS (EI) for C2₃H2₉N₉O2: 464 (MH⁺). 4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(2,6-diethylpyrimidin-4- yl)piperazine-l-carboxamide. ¾ NMR (400 MHz, CDC1₃) δ 8.35 (d, IH), 7.93 (dd, IH), 7.73 (s, IH), 7.28 (s, IH), 7.08 (dd, IH), 6.87 (dd, IH), 6.81 (d, IH), 5.09 (s, 2H), 5.00 (s, 2H), 3.84 - 3.63 (m, 4H), 3.53 (dd, 4H), 2.80 (q, 2H), 2.73 (q, 2H), 1.30 (q, 6H). MS (EI), C23H29N9O2: 464.0 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(8,8-dimethyl-5,6,7,8- tetrahydroquinazolin-4-yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, CDCI₃) δ 8.69 (s, IH), 8.35 (d, IH), 8.01 (s, IH), 7.93 (dd, IH), 7.06 (m, IH), 6.84 (m, 2H), 5.19 (m, 2H), 5.00 (s, 2H), 4.07 (m, IH), 3.76 (m, 3H), 3.49 (m, 4H), 2.56 (m, 2H), 1.76 (m, 4H), 1.29 (m, 6H). MS (EI) for C25H₃1N₉O2: 489.9 (MH⁺).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(2-ethyl-6-isopropylpyrimidin-4- yl)piperazine-l-carboxamide. ^XH-NMR (400MHz, CD₃OD) δ 8.28 (d,lH), 7.84 (dd, IH), 7.62 (s, IH), 7.29 (dd, IH), 7.19 (m, IH), 6.92 (1, IH), 6.83 (d, IH), 5.03 (s, 2H), 3.72 (dd, 4H), 3.45 (dd, 4H), 2.91 (septet, IH), 2.78 (q, 2H), 1.33-1.25 (m, 9H). MS (EI) for

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(6-isopropyl-2- (trifluoromethyl)pyrimidin-4-yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, DMSO- d₆) δ 10.32 (s, IH), 8.29 (d, IH), 7.88 (s, IH), 7.84 (dd, IH), 7.30 (dd, IH), 6.92 (dd, IH), 6.81 - 6.57 (m, 3H), 5.00 (s, 2H), 3.76 - 3.58 (m, 4H), 3.38-3.36 (m, 4H), 3.02-2.97 (m, IH), 1.23 (d, 6H).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(2-ethyl-6-

(trifluoromethyl)pyrimidin-4-yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, DMSO- d₆) δ 9.60 (s, IH), 8.29 (d, IH), 7.84 (d, IH), 7.68 (s, IH), 7.30 (d, IH), 6.91 (dd, IH), 6.78 - 6.58 (m, 3H), 4.99 (s, 2H), 3.74 - 3.55 (m, 4H), 3.44-3.42 (m, 4H), 2.73 (q, 2H), 1.27-1.25 (m, 12H).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(6-tert-butyl-2-ethylpyrimidin-4- yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, DMSO-d₆) δ 9.60 (s, IH), 8.29 (d, IH), 7.84 (d, IH), 7.68 (s, IH), 7.30 (d, IH), 6.91 (dd, IH), 6.78 - 6.58 (m, 3H), 4.99 (s, 2H), 3.74 - 3.55 (m, 4H), 3.44-3.42 (m, 4H), 2.73 (q, 2H), 1.27-1.25 (m, 12H).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2-(l,l- dimethylethyl)pyridin-4-yl]piperazine-l-carboxamide. ^XH NMR (400 MHz, CDC1₃) δ 8.40 (d, IH), 8.34 (d, IH), 7.93 (dd, IH), 7.40 (d, IH), 7.22 (dd, IH), 7.08 (dd, IH), 6.87 (dd, IH), 6.81 (d, IH), 6.72 (br s, IH), 5.17 (br s, 2H), 5.00 (s, 2H), 3.70 (m, 4H), 3.53 (m, 4H), 1.35 (s, 9H). MS (EI) for C24H_{30 8}O2: 463.26 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[4-(l,l-dimethylethyl)-6- methylpyridin-2-yl]piperazine-l-carboxamide. *H NMR (400 MHz, CDC1₃) δ 8.36 (d, IH), 7.93 (m, 2H), 7.07 (dd, IH), 6.86 (ddlH), 6.83 (m, 2H), 5.14 (br s, 2H), 4.99 (s, 2H), 3.72 (m, 4H), 3.52 (m, 4H), 2.43 (s, 3H), 1.31 (s, 9H). MS (EI) for C25H₃2 ₈O2: 477.28 (MH⁺).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(6-tert-butyl-2-methylpyrimidin- 4-yl)piperazine-l-carboxamide. ¾ NMR (400 MHz, CDC1₃) δ 8.35 (d, IH), 7.93 (dd, IH), 7.88 (s, IH), 7.22 (d, IH), 7.08 (dd, IH), 6.87 (dd, IH), 6.81 (d, IH), 5.06 (s, 2H), 5.00 (s, 2H), 3.71 (dd, 4H), 3.53 (dd, 4H), 2.56 (s, 3H), 1.33 (s, 9H). MS (ES) for C24H₃1 ₉O2: 478.0 (MH⁺).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(6-tert-butyl-2- (trifluoromethyl)pyrimidin-4-yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, CD₃OD) δ 8.28 (d, IH), 8.06 (s, IH), 7.84 (dd, IH), 7.29 (dd, IH), 6.93 (dd, IH), 6.83 (d, IH), 5.04 (s, 2H), 3.79-3.69 (m, 4H), 3.50-3.43 (m, 4H), 1.35 (m, 9H). MS (EI) for C24H28

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyrazin-2-yl)-N-(6-isopropyl-2- (trifluoromethyl)pyrimidin-4-yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, CDCI₃) δ 8.30 (d, IH), 8.08 (s, IH), 7.79 (d, IH), 7.60 (d, IH), 7.54 (bs, IH), 6.67 (d, IH), 5.35 (s, 2H), 5.13 (bs, 2H), 3.73 - 3.66 (b, 8H), 3.07 (m, IH), 1.32 (d, 3H) MS (EI) for

C₂2H2₅F3N₁₀O2,: 519 (MH⁺).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyrazin-2-yl)-N-(6-tert-butyl-2- methylpyrimidin-4-yl)piperazine-l-carboxamide. 'H NMR (400 MHz, DMSO-d₆) δ 9.67 (s, IH), 8.23 (d, IH), 7.82 (d, IH), 7.70 (s, IH), 7.61 (d, IH), 6.68 (s, 2H), 6.56 (d, IH), 5.25 (s, 2H), 3.64 - 3.54 (m, 8H), 2.47 (s, 3H), 1.25 (s, 9H). MS (EI) for C2₃H₃₀N1₀O2: 479 (MH⁺). 4-(3-((2-Aminopyrimidin-4-yl)ethynyl)pyridin-2-yl)-7V-(6-teri-butyl-2-methylpyrimidin- 4-yl)piperazine-l-carboxamide. ^XH-NMR (400 MHz, DMSO-d₆) δ 9.67 (s, IH), 8.30 (d, IH), 8.28 (dd, IH), 7.87 (dd, IH), 7.70 (s, IH), 6.94 (dd, IH), 6.85 (s, 2H), 6.74 (d, IH), 3.67 - 3.57 (m, 8H), 2.47 (s, 3H), 1.25 (s, 9H). MS (EI) for C25H2₉N₉O: 472.3 (MH⁺).

4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(2,6-diisopropylpyrimidin-4- yl)piperazine-l-carboxamide. ^XH NMR (400 MHz, CD₃OD) δ 8.28 (d, IH), 7.84 (dd, IH), 7.60 (s, IH), 7.29 (dd, IH), 6.93 (dd, IH), 6.84 (d, IH), 5.04 (s, 2H), 3.73 (dd, 4H), 3.46 (dd, 4H), 3.07 - 2.98 (m, IH), 2.98 - 2.86 (m, IH), 1.31-1.26 (m, 6H). MS (EI) for C25H33N9O2: 492 (MH⁺).

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[l-(l-methylethyl)-lH- pyrazol-4-yl]piperazine-l-carboxamide. 'H NMR (400 MHz, CDC1₃) δ 8.34 (m, IH), 7.93 (m, IH), 7.81 (m, IH), 7.35 (m, IH), 7.28 (m, IH), 7.07 (m, IH), 6.86 (m, IH), 6.82 (m, IH), 6.56 (br s, IH), 5.27 (br s, 2H), 5.00 (app m, 2H), 4.43 (m, IH), 3.65 (m, 4H), 3.50 (m, 4H), 1.48 (m, 6H). MS (EI) for C21H27 ₉O2: 438.43 (MH⁺).

4-(2-((2-Aminopyrimidin-4-yl)methoxy)pyridin-3-yl)-iV-(6-teri-butyl-2-methylpyrimidin- 4-yl)piperazine-l-carboxamide. ¾-NMR (400 MHz, DMSO-d₆) δ 9.69 (s, IH), 8.23 (d, IH), 7.74 (dd, IH), 7.70 (s, IH), 7.28 (dd, IH), 6.97 (dd, IH), 6.65 (s, 2H), 6.58 (d, IH), 5.22 (s, 2H), 3.68 - 3.63 (m, 4H), 3.10 - 3.06 (m, 4H), 2.47 (s, 3H), 1.25 (s, 9H). MS (EI) for C24H31N9O2: 478.3 (MH⁺).

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-7V-(2-teri-butyl-6-methylpyrimidin- 4-yl)piperazine-l-carboxamide. ^XH-NMR (400 MHz, DMSO-d₆) δ 9.32 (s, IH), 8.27 (d, IH), 7.83 (dd, IH), 7.41 (s, IH), 7.28 (dd, IH), 6.89 (dd, IH), 6.68 (s, 2H), 6.67 (d, IH), 4.97 (s, 2H), 3.63 - 3.59 (m, 4H), 3.38 - 3.34 (m, 4H), 2.33 (s, 3H), 1.29 (s, 9H). MS (EI) for C24H31N9O2: 478.3 (MH⁺).

4-((2-(4-(6-Isopropyl-lH-benzo[d]imidazol-2-yl)piperazin-l-yl)pyridin-3- yloxy)methyl)pyrimidin-2-amine. A mixture of 4-isopropyl-2-nitroaniline (445 mg, 2.47 mmol), Pd/C (132 mg, 10%, 0.123 mmol), ammonium formate (623 mg, 9.88 mmol) and EtOH (6 ml) in a sealed tube was stirred for 1 h at 60 °C. After cooling down, EtOAc (5 ml) was added and the resulting mixture was filtered through celite. The organic filtrate was concentrated and dissolved in EtOAc (5 ml). The mixture was filtered through celite again. Concentration of the organic filtrate gave isopropylbenzene-l,2-diamine (345 mg, 93%) as a brown oil. MS (EI) for C₉H₁₄N₂: 151.2 (MH⁺).

A mixture of 4-isopropylbenzene-l,2-diamine (100 mg, 0.666 mmol), 1,1 '- carbodiimidazole (129 mg, 0.799 mmol) and DMF (2 ml) was stirred for 1 h at 80 °C. After cooling down to room temperature, aqueous saturated NH₄C1 (3 ml) was added. The resulting mixture was extracted with EtOAc (3x3 ml), and the combined organic extracts were concentrated under reduced pressure. The residue was dissolved in EtOAc (30 ml) and dried by MgS0₄. After concentration, the crude material was mixed with MeCN (2 ml) and POCI₃ (1 ml). After stirring for 40 min at 100 °C, the resulting mixture was concentrated under reduced pressure and purified by preparative HPLC to give 2-chloro-6-isopropyl-lH- benzo[d]imidazole (39.0 mg, 30%) as a pale brown powder. MS (EI) for C1₀H11CI 2, found 195.1 (MH⁺).

A mixture of 2-chloro-6-isopropyl-lH-benzo[d]imidazole (20.0 mg, 0.103 mmol), 4- ((2-(piperazin-l-yl)pyridin-3-yloxy)methyl)pyrimidin-2-amine (44.2 mg, 0.155 mmol) and n- butanol (0.8 ml) in a sealed tube was stirred for 4 h at 120 °C. After cooling down to room temperature, NH₃ (0.2 ml, 7N in MeOH) was added. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC to give 4-((2-(4-(6-Isopropyl-lH- benzo[d]imidazol-2-yl)piperazin-l-yl)pyridin-3-yloxy)methyl)pyrimidin-2-amine (1 1.0 mg, 24%) as a beige solid. ^XH-NMR (400MHz, DMSO-d₆) δ 11.4 (br s, IH), 8.30 (d, IH), 7.86 (dd, IH), 7.32 (dd, IH), 7.1 1 (d, IH), 7.07 (s, IH), 6.93 (dd, IH), 6.83 (d, IH), 6.72 (d, IH), 6.71 (s, 2H), 5.01 (s, 2H), 3.64 - 3.60 (m, 4H), 3.49 - 3.45 (m, 4H), 2.91 (hept, IH), 1.22 (d, 6H). MS (EI) for C₂4H₂₈N₈0: 445.3 (MH⁺).

The following compounds were prepared using a similar procedure as in Example 12.

4-((2-(4-(6-teri-Butyl-lH-benzo[d]imidazol-2-yl)piperazin-l-yl)pyridin-3- yloxy)methyl)pyrimidin-2-amine. Prepared from 4-tert-butylbenzene-l,2-diamine. ^XH- NMR (400MHz, DMSO-d₆) δ 1 1.9 (br s, IH), 8.30 (d, IH), 7.86 (dd, IH), 7.33 (dd, IH), 7.24 (d, IH), 7.17 (d, IH), 7.07 (dd, IH), 6.94 (dd, IH), 6.72 (s, 2H), 6.71 (d, IH), 5.01 (s, 2H), 3.68 - 3.63 (m, 4H), 3.52 - 3.47 (m, 4H), 1.31 (d, 9H). MS (EI) for CzsHso gO: 459.3 (MH⁺).

4-((2-(4-(2-teri-Butyl-6-methyl-9H-purin-8-yl)piperazin-l-yl)pyridin-3- yloxy)methyl)pyrimidin-2-amine. Prepared from 2-ter?-butyl-6-methyl-5-nitropyrimidin-4- amine. ¾-NMR (400MHz, DMSO-d₆):6l2.4 (s) and 1 1.4 (s) for IH, 8.28 (t, IH), 7.86 - 7.82 (m, IH), 7.30 (t, IH), 6.94 - 6.88 (m, IH), 6.71 - 6.67 (m, IH), 6.69 (s, 2H), 4.99 (s, 2H), 3.79 - 3.65 (m, 4H), 3.49 - 3.42 (m, 4H), 2.48 (s, 3H), 1.32 (d, 9H). MS (EI) for C24H₃₀ 1₀O: 475.3 (MH⁺).

4-((2-(4-(6-(Trifluoromethyl)-lH-benzo[d]imidazol-2-yl)piperazin-l-yl)pyridin-3- yloxy)methyl)pyrimidin-2-amine. Prepared from 4-(trifluoromethyl)benzene- 1 ,2-diamine. 1H-NMR (400MHz, DMSO-d6):6 11.9 (br s, IH), 8.30 (d, IH), 7.86 (dd, IH), 7.52 - 7.23 (m, 4H), 6.94 (dd, IH), 6.72 (d, IH), 6.71 (s, 2H), 5.01 (s, 2H), 3.73 - 3.68 (m, 4H), 3.51 - 3.47 (m, 4H). MS (EI) for C₂2H₂₁F_{3 8}0: 471.2 (MH⁺).

4-((2-(4-(5-Isopropylbenzo[d]oxazol-2-yl)piperazin-l-yl)pyridin-3- yloxy)methyl)pyrimidin-2-amine. Prepared from 2-chloro-5-isopropylbenzo[d]oxazole, (J. Med Chem. 1988, 31, 1719) using a similar procedure. ^XH-NMR (400MHz, DMSO-d₆):6 8.30 (d, IH), 7.86 (dd, IH), 7.32 (dd, IH), 7.30 (d, IH), 7.18 (d, IH), 6.93 (dd, IH), 6.91 (dd, IH), 6.72 (d, IH), 6.71 (s, 2H), 5.01 (s, 2H), 3.77 - 3.73 (m, 4H), 3.51 - 3.47 (m, 4H), 2.96 - 2.88 (m, IH), 1.22 (d, 6H). MS (EI) for C₂4H₂7 ₇02: 446.2 (MH⁺). Example 13

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-iV-(3-teri-butyl-4- fluorophenyl)piperazine-l-carboxamide. Commercially available 2-fluoroacetophenone was treated with T1CI₄ and Me₂Zn (J. Org. Chem. 1983, 48, 254) to afford l-tert-butyl-2- fluorobenzene which was subsequently converted to 2-tert-butyl-l-fluoro-4-nitrobenzene. The nitro group was reduced to afford 3-tert-butyl-4-fluoroaniline. ^- MR (400MHz, DMSO-d₆) δ 6.73 (dd, 1H), 6.52 (dd, 1H), 6.35 (ddd, 1H), 4.84 (s, 2H), 1.27 (d, 9H). The aniline was coupled to 4-((2-(piperazin-l-yl)pyridin-3-yloxy)methyl)pyrimidin-2-amine as described in Example 7 to afford 4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(3- tert-butyl-4-fluorophenyl)piperazine-l-carboxamide. ^- MR (400MHz, DMSO-d₆) δ 8.53 (s, 1H), 8.28 (d, 1H), 7.83 (dd, 1H), 7.41 - 7.36 (m, 1H), 7.39 (d, 1H), 7.29 (dd, 1H), 6.96 (dd, 1H), 6.90 (dd, 1H), 6.69 (s, 2H), 6.68 (d, 1H), 4.97 (s, 2H), 3.59 - 3.55 (m, 4H), 3.37 - 3.33 (m, 4H), 1.30 (s, 9H). MS (EI) for

480.2 (MH⁺).

The following compounds were prepared using similar procedures as described in Example

13:

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-iV-(5-teri-butyl-2,4- difluorophenyl)piperazine-l-carboxamide. Prepared from 2, 4-difluoroacetophone using similar conditions as in Example 13. ¾-NMR (400MHz, DMSO-d₆) δ 8.34 (s, 1H), 8.28 (d, 1H), 7.83 (dd, 1H), 7.29 (dd, 1H), 7.27 (t, 1H), 7.14 (dd, 1H), 6.90 (dd, 1H), 6.69 (s, 2H), 6.68 (d, 1H), 4.97 (s, 2H), 3.58 - 3.54 (m, 4H), 3.38 - 3.34 (m, 4H), 1.30 (s, 9H). MS (EI) for C₂5H₂9F_{2 7}02: 498.2 (MH⁺).

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-iV-(5-teri-butyl-2- fluorophenyl)piperazine-l-carboxamide. Commercially available 1 -tert-butyl-4- fluorobenzene was nitrated and the nitro group was reduced to afford 5-tert-butyl-2- fluoroaniline which was coupled ((2-(piperazin-l-yl)pyridin-3-yloxy)methyl)pyrimidin-2- amine to afford 4-(3-((2-aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-N-(5-ter?-butyl-2- fluorophenyl)piperazine-l-carboxamide. ^XH-NMR (400MHz, DMSO-d₆) δ 8.33 (s, IH), 8.30 (d, IH), 7.85 (dd, IH), 7.40 (dd, IH), 7.31 (dd, IH), 7.16 - 7.06 (m, 2H), 6.92 (dd, IH), 6.71 (s, 2H), 6.70 (d, IH), 5.00 (s, 2H), 3.62 - 3.57 (m, 4H), 3.38 - 3.34 (m, 4H), 1.26 (s, 9H). MS (EI) for C25H₃₀FN7O2: 480.2 (MH⁺).

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyrazin-2-yl)-iV-(5-teri-butyl-2- fluorophenyl)piperazine-l-carboxamide. Prepared from 5-tert-butyl-2-fluoroaniline and 4- ((3-(piperazin-l-yl)pyrazin-2-yloxy)methyl)pyrimidin-2-amine. ^XH NMR (400MHz, DMSO- d₆) δ 8.36 (s, IH), 8.24 (d, IH), 7.83 (d, IH), 7.62 (d, IH), 7.40 (dd, IH), 7.17 - 7.07 (m, 2H), 6.69 (s, 2H), 6.58 (d, IH), 5.26 (s, 2H), 3.62 - 3.54 (m, 8H), 1.26 (s, 9H). MS (EI) for C₂4H₂9F ₈02: 481.2 (MH⁺).

Example 14

4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-iV-(4-fluoro-3-(2-hydroxybutan-2- yl)phenyl)piperazine-l-carboxamide. 2-(5-amino-2-fluorophenyl)butan-2-ol (prepared from 2'-fluoropropiophenone) was reacted with 4-((2-(piperazin-l-yl)pyridin-3- yloxy)methyl)pyrimidin-2-amine (Example 3) as described in Example 7. ^XH-NMR

(400MHz, DMSO-d₆) δ 8.62 (s, IH), 8.30 (d, IH), 7.85 (dd, IH), 7.61 (dd, IH), 7.43 (dddd, IH), 7.31 (dd, IH), 6.95 (dd, IH), 6.91 (dd, IH), 6.71 (s, 2H), 6.70 (d, IH), 5.00 (s, IH), 4.99 (s, 2H), 3.62 - 3.58 (m, 4H), 3.38 - 3.34 (m, 4H), 1.89 - 1.81 (m, IH), 1.77 - 1.67 (m, IH), 1.46 (s, 3H), 0.69 (t, 3H). MS (EI) for C25H₃₀FN7O₃: 496.2 (MH⁺).

The following compound was prepared using similar procedures as described in Example 14: 4-(3-((2-Aminopyrimidin-4-yl)methoxy)pyridin-2-yl)-iV-(4-fluoro-3-(2-hydroxypropan- 2-yl)phenyl)piperazine-l-carboxamide. 2-(5-amino-2-fluorophenyl)propan-2-ol was prepared from 2-fluoroacetophenone and was reacted with 4-((2-(piperazin-l-yl)pyridin-3- yloxy)methyl)pyrimidin-2-amine as described in Example 7. ^- MR (400MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.28 (d, 1H), 7.83 (dd, 1H), 7.63 (dd, 1H), 7.39 (m, 1H), 7.28 (dd, 1H), 6.94 (dd, 1H), 6.89 (dd, 1H), 6.69 (s, 2H), 6.68 (d, 1H), 5.20 (s, 1H), 4.97 (s, 2H), 3.60 - 3.55 (m, 4H), 3.37 - 3.34 (m, 4H), 1.44 (s, 6H). MS (EI) for C₂4H₂₈F ₇0₃: 482.2 (MH⁺).

4-((3-(piperazin-l-yl)pyridin-2-yloxy)methyl)pyrimidin-2-amine.

A mixture of tert-butyl 4-(2-chloropyridin-3-yl)piperazine-l-carboxylate (820 mg, 2.76 mmol), CS2CO₃ (1.80 g, 5.52 mmol) and 2-methylprop-2-en-l-ol (8 ml) in a sealed tube was stirred for 8 h at 170 °C. The mixture was cooled to room temperature and B0C2O (301 mg, 1.38 mmol) was added. After stirring for 10 min, dichloromethane (2 ml) was added and the resulting mixture was filtered through celite. The organic filtrate was concentrated and purified by silica gel column chromatography (Hexane/EtOAc = 10: 1 8: 1) to give tert- butyl 4-(2-(2-methylallyloxy)pyridin-3-yl)piperazine-l-carboxylate (500 mg, 54%) as a clear oil. MS (EI) for CisH^ sOs, found 334.3 (MH⁺).

To a stirred solution of tert-butyl 4-(2-(2-methylallyloxy)pyridin-3-yl)piperazine-l- carboxylate (500 mg, 1.50 mmol), NMO (228 mg, 1.95 mmol), acetone (7 ml) and water (0.7 ml) at room temperature was added Os0₄ (0.05 ml, 4 wt% in H₂0, 0.00750 mmol). After stirring 150 min, 10% aqueous aHS03 (5 ml) was added and the mixture was stirred for additional 1 h. The resulting solution was extracted with EtOAc (3x5 ml) and the combined organic layers were concentrated under reduced pressure. To a stirred solution of the resulting pale yellow oil and THF (6 ml) at 0 °C was added NaI0₄ (642 mg, 3.00 mmol) in water (6 ml). After stirring for 50 min at room temperature, the resulting mixture was extracted with EtOAc (3x5 ml). The combined organic extracts were concentrated and purified by silica gel column chromatography (Hexane/EtOAc = 2: 1) to give 4-(2-(2-oxopropoxy)pyridin-3- yl)piperazine-l-carboxylate (500 mg, quant) as a clear oil. MS (EI) for C17H25N3O4, found

336.2 (MH⁺).

A solution of tert-butyl 4-(2-(2-oxopropoxy)pyridin-3-yl)piperazine-l-carboxylate 2 (200 mg, 0.596 mmol) and N,N-dimethyl formamide dimethyl acetal (142 mg, 1.19 mmol) in DMF (2 ml) was stirred for 15 h at 80 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc, then EtOAc/MeOH = 30: 1 12: 1) to give tert-butyl 4-(2-(4-(dimethylamino)-2-oxobut-3-enyloxy)pyridin-3- yl)piperazine-l-carboxylate (150 mg, 64%) as a clear oil. MS (EI) for C2₀H₃₀N4O4, found

391.3 (MH⁺). A regioisomer, tert-butyl 4-(2-(l-(dimethylamino)-3-oxobut-l-en-2- yloxy)pyridin-3-yl)piperazine-l-carboxylate (54 mg, 23%) was also isolated as a beige foam. MS (EI) for C2₀H₃₀N4O4, found 391.3 (MH⁺).

To a stirred solution of tert-butyl 4-(2-(4-(dimethylamino)-2-oxobut-3-enyloxy)pyridin-3- yl)piperazine-l-carboxylate (155 mg, 0.397 mmol), guanidine HC1 (75.8 mg, 0.794 mmol) and MeOH (3 ml) at room temperature was added sodium methoxide (257 mg, 25 wt% in MeOH, 1.19 mmol). After stirring for 3 h at 90 °C, aqueous saturated NH₄C1 (5 ml) was added. The resulting mixture was extracted with dichloromethane (3x4 ml), and the combined organic extracts were concentrated and purified by silica gel column

chromatography (CH^CVMeOH = 20: 1) to give tert-butyl 4-(2-((2-aminopyrimidin-4- yl)methoxy)pyridin-3-yl)piperazine-l-carboxylate (126 mg, 82%) as a white solid. MS (EI) for Ci₉H₂₆N₆0₃, found 387.3 (MH⁺).

To a stirred solution of tert-butyl 4-(2-((2-aminopyrimidin-4-yl)methoxy)pyridin-3- yl)piperazine- 1 -carboxylate 3 (43.0 mg, 0.1 11 mmol) and dichloroethane (1 ml) at room temperature was added trifluoroacetic acid (55.3 mg, 0.485 mmol). After stirring for 13 h at 80 °C, the reaction mixture was concentrated under reduced pressure to afford 4-((3- (piperazin-l-yl)pyridin-2-yloxy)methyl)pyrimidin-2-amine as the TFA salt.

4-(2-((2-Aminopyrimidin-4-yl)methoxy)pyridin-3-yl)-N-(3,5- bis(trifluoromethyl)phenyl)piperazine-l-carboxamide. To a stirred solution of 4-((3- (piperazin-l-yl)pyridin-2-yloxy)methyl)pyrimidin-2-amine prepared in Example 15 (0.171 mmol), diisopropylamine (0.12 ml, 0.683 mmol) and dichloromethane (1 ml) at room temperature was added 3,5-bis(trifluoromethyl)phenyl isocyanate (52.4 mg, 0.205 mmol) in dichloromethane (1 ml). After stirring for 30 min, the resulting mixture was concentrated under reduced pressure and purified by preparative HPLC to give 4-(2-((2-Aminopyrimidin- 4-yl)methoxy)pyridin-3-yl)-N-(3,5-bis(trifluoromethyl)phenyl)piperazine-l-carboxamide (36.0 mg, 39%) as a white solid. ^XH-NMR (400MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.24 (s, 2H), 8.23 (d, 1H), 7.76 (dd, 1H), 7.62 (s, 1H), 7.31 (dd, 1H), 6.98 (dd, 1H), 6.67 (s, 2H), 6.60 (d, 1H), 5.23 (s, 2H), 3.70 - 3.66 (m, 4H), 3.14 - 3.10 (m, 4H). MS (EI) for C₂3H₂₁F_{6 7}0₂: 542.2 (MH⁺).

Assays

74] One measure of inhibition is ¾. For compounds with ICso's less than 1 μΜ, the ¾ or Ka is defined as the dissociation rate constant for the interaction of the agent with a FGFR2. Exemplary compositions have Ki's of, for example, less than about 100 μΜ, less than about 10 μΜ, less than about 1 μΜ, and further for example having Ki's of less than about 100 nM, and still further, for example, less than about 10 nM. The Ki for a compound is determined from the IC5₀ based on three assumptions. First, only one compound molecule binds to the enzyme and there is no cooperativity. Second, the concentrations of active enzyme and the compound tested are known (i.e., there are no significant amounts of impurities or inactive forms in the preparations). Third, the enzymatic rate of the enzyme-inhibitor complex is zero. The rate data (i.e. compound concentration) are fitted to the equation:

where V is the observed rate, V_max, is the rate of the free enzyme, I₀ is the inhibitor concentration, Eo is the enzyme concentration, and ¾ is the dissociation constant of the enzyme-inhibitor complex.

[0175] Kinase activities of FGF receptors (FGFR1, FGFR2, FGFR3 and FGFR4) are measured by monitoring the phosphorylation of a tyrosine-containing, fluorescein-labeld peptide substrate(Glu:Tyr, 4: 1). The extent of phosphorylation of the substrate peptide is quantified using a terbium labeled phosphospecific antibody, which upon binding and excitation at 340 nm leads to a time resolved FRET signal due to its proximity to the fluorescent label. In a black 384-well plate enzyme and test compound are combined and incubated for 10 min, followed by addition of ATP and fluorescently labeled substrate. After an incubation time of 60 min terbium labeled phosphospecific antibody (final 2 nM) is added and incubated for another 60 min, followed by a time resolved fluorescence read using an excitation wavelength of 340 nm, and detection of emission at 490 and 520 nm. The data are expressed as the ratio of emission intensity at 520nm/490 nm. The ATP concentrations used in the various assays were approximately equal to or less than the KM for each of the respective kinases. Dose-response experiments were performed using an intra-plate dilution scheme with 10 different inhibitor concentrations in a 384-well microtiter plate. IC50 values were calculated by nonlinear regression analysis.

[0176] From the foregoing it will be appreciated that, although specific embodiments of this disclosure have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

What is claimed is:

1. A compound of Formula I,

I

or a pharmaceutically acceptable salt thereof, wherein:

G is CH or ;

L¹ is a bond or -C(0)-N(H)-;

each R² is independently -H, halo, or (Ci-C4)alkyl;

_R3a

is a phenyl or a 5-9 membered heteroaryl, wherein R^3a is optionally substituted with 1, 2 or 3 R⁵ groups;

R^4b is H, alkyl, or dialkylaminoalkyl;

R^4b is H or alkyl;

each R⁵ group, when R⁵ exists, is selected from halo, alkyl, hydroxyalkyl, haloalkyl, (Ci- C6)cycloalkyl optionally substituted with hydroxyl, alkoxyl, alkynyl, phenyl, aloxycarbonyl, or -N(R^C)R^D;

R^c is H or alkyl; and

R^D is H or alkyl.

2. The compound according to claim 1 having Formula II

Π, or a pharmaceutically acceptable salt thereof, wherein:

R^3a is pyrazolyl, phenyl, pyrimidinyl, thiadiazoly, benzimidazolyl, oxazolyl, oxadiazolyl, or benzoxazolyl, wherein R^3a is substituted with 1, 2 or 3 R⁵ groups;

each R⁵ group is selected from halo, alkyl, hydroxyalkyl, haloalkyl, (Ci-C6)cycloalkyl optionally substituted with hydroxyl, alkoxyl, alkynyl, phenyl, aloxycarbonyl, or

-NH_2; and

L¹, R², G, R^3b and R^4b are as defined in claim 1.

3. The compound according to any of the above claims having any one of Formula III,

or a pharmaceutically acceptable salt of any one of formula III, IV, V or VI, wherein

A is N or CH;

B is N or CH;

D is N or O; and

each R⁵ , when R⁵ exists, is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, (Ci- C6)cycloalkyl optionally substituted with hydroxyl, and alkoxyl,

provided that at least one of A or B is N.

4. The compound according to any of the above claims having formula Ilia, III or IIIc

or a pharmaceutically acceptable salt thereof, wherein:

R^5a is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, or alkoxyl; and R^5b is halo, (Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, halo(Ci-C₆)alkyl, or alkoxyl.

5. The compound according to any of the above claims having formula Ilia,

Ilia, or a pharmaceutically acceptable salt thereof, wherein:

R^5a is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, or alkoxyl; and R^5b is halo, (Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, halo(Ci-C₆)alkyl, or alkoxyl.

6. The compound according to any of claims 1-4 having formula Illb .

or a pharmaceutically acceptable salt thereof, wherein:

R^5a is halo, (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, or alkoxyl; and R^5b is halo, (Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, halo(Ci-C₆)alkyl, or alkoxyl.

7. The compound according to any of claims 1-4 having formula IIIc

or a pharmaceutically acceptable salt thereof, wherein:

R^5a is halo, (Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, halo(Ci-C₆)alkyl, (Ci-C₆)cycloalkyl optionally substituted with hydroxyl, or alkoxyl; and

R^5b is halo, (Ci-C₆)alkyl, hydroxy(Ci-C₆)alkyl, halo(Ci-C₆)alkyl, (Ci-C₆)cycloalkyl optionally substituted with hydroxyl, or alkoxyl.

8. The compound according to any of claims 1-3 having formula Vila

Vila

or a pharmaceutically acceptable salt thereof, wherein

R^5a is (Ci-C₆)alkyl or halo(Ci-C₆)alkyl.

9. A compound according to claim 1 selected from one of the following compounds:

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2-fluoro-5-(1 - methylethyl)phenyl]piperazine-1-carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[6-(1 ,1-dimethylethyl)-2- ethyl py ri m id i n-4-y I] pi perazi ne- 1 -carboxam ide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]amino}pyridin-2-yl)-N-[3-(1 ,1- dimethylethyl)phenyl]piperazine-1 -carboxamide; 1 -(3 [(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(1 ,1- dimethylethyl)phenyl]piperidine-4-carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(1 ,1-dimethylethyl)isoxazol-5- yl]piperazine-1 -carboxamide;

N-[3-(1 J -dimethylethyl)phenyl]-4-[3-({[2-(methylamino)pyrimidin-4-yl]methyl}oxy)p yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(1-hydroxy-1 - methylpropyl)phenyl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2-(1 ,1-dimethylethyl)pyridin-4- yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin^-yl)methyl]oxy}pyridin-2-yl)-N-[2,4-difluoro-5-(1 - methylethyl)phenyl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-[5-(1 ,1 -dimethylethyl)-2- fluorophenyl] pi perazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[5-(1 ,1-dimethylethyl)isoxazol-3- yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[1 -(1 ,1-dimethylethyl)-1 H-pyrazol- 4-yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(1-ethyl-1- hydroxypropyl)phenyl] pi perazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[4-fluoro-3-(1 -hydroxy-1 - methylethyl)phenyl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[5-(1 ,1-dimethylethyl)-1 ,3,4- thiadiazol-2-yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-[6-(1 ,1 -dimethylethyl)pyrimidin-4- yl]piperazine-1 -carboxamide;

3- {[(2-aminopyrimidin-4-yl)methyl]oxy}-N-[3-(1 ,1 -dimethylethyl)phenyl]-3',6'-dihydro-2,4'- bipyridine-1 '(2'H)-carboxamide;

4- (3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[6-(1 ,1-dimethylethyl)pyrimidin-4- yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(2- methylpropyl)phenyl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3-propylphenyl)piperazine-1 - carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[6-(1 -methylethyl)-2- (trifluoromethyl)pyrimidin-4-yl]pi perazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3-cyclopentylphenyl)piperazine-1 - carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[5-(1 ,1-dimethylethyl)pyridazin-3- yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(1 - hydroxypropyl)phenyl] pi perazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[4-fluoro-3- (trifluoromethyl)phenyl]pi perazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2,6-bis(1-methylethyl)pyrimidin-4- yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(diethylamino)phenyl]piperazine- 1 -carboxamide; 4-(3 [(2-aminopyrimidin^-yl)methyl]oxy}pyridin-2-yl)-N-[2-methyl-6-(1 - methylethyl)pyrimidin-4-yl]piperazine-1 -carboxamide;

(2R)-4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(1 ,1 -dimethylethyl)phenyl]-

2- methylpiperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)oxy]methyl}pyridin-2-yl)-N-[3-(1 ,1- dimethylethyl)phenyl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[6-(1 ,1-dimethylethyl)-2- methylpyrimidin-4-yl]piperazine-1 -carboxamide;

4-(3 [(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2-(dimethylamino)-6-( dimethylethyl)pyrimidin-4-yl]piperazine-1-carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[1 -(1 -methylpropyl)-1 H-pyrazol-4- yl]piperazine-1 -carboxamide;

4-(3 [(2-aminopyrimidin^-yl)methyl]oxy}pyridin-2-yl)-N-[6-methyl-2-(1 - methylethyl)pyrimidin-4-yl]piperazine-1 -carboxamide;

4-[({2-[4-(6-ethyl-1 H-benzimidazol-2-yl)piperazin-1 -yl]pyridin-3-yl}oxy)methyl]pyrimidin-2- amine;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin^^

4-yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2-ethyl-6- (trifluoromethyl)pyrimidin-4-yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2,6-bis(trifluoromethyl)pyrimidin-4- yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(2,6-diethylpyrimidin-4- yl)piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin^-yl)methyl]oxy}pyridin-2-yl)-N-[1-(1-methylethyl)-1 H-pyrazol-4- yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3-methylphenyl)piperazine-1 - carboxamide;

4-{3-[2-(2-aminopyrimidin-4-yl)ethyl]pyridin-2-yl}-N-[3-(1 ,1 -dimethylethyl)phenyl]piperazine- 1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[1 -(2-methylpropyl)-1 H-pyrazol-4- yl]piperazine-1 -carboxamide;

1 -(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(1 - methylethyl)phenyl]piperidine-4-carboxamide;

4-{[(2-{4-[6-(trifluoromethyl)-1 H-benzimidazol-2-yl]piperazin-1 -yl}pyridin-3- yl)oxy]methyl}pyrimidin-2-amine;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(1 -propyl-1 H-pyrazol-4- yl)piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3- (dimethylamino)phenyl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[6-(1 ,1-dimethylethyl)-2- (trifluoromethyl)pyrimidin-4-yl]piperazine-1 -carboxamide;

3- (1 , 1-dimethylethyl)phenyl 4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2- yl)piperazine-1 -carboxylate;

4- (3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2-ethyl-6-(1-methylethyl)pyrimid 4-yl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[4-(trifluoromethyl)pyridin-2- yl]piperazine-1 -carboxamide; 4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(4-ethylpyridin-2-^

carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(6-cyclopropyl-2-methylpyrimidin-^ yl)piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-biphenyl-3-ylpiperazi

carboxamide;

4-{[(2-{4-[6-(1 -methylethyl)-1 ,3-benzoxazol-2-yl]piperazin-1 -yl}pyridin-3- yl)oxy]methyl}pyrimidin-2-amine;

methyl 3-({[4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)piperazin-1 - yl]carbonyl}amino)benzoate;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3-(1 - methylpropyl)phenyl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[5-(1 ,1-dimethylethyl)-2,4- difluorophenyl]piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[4-fluoro-3-(1 -hydroxy-1 - methylpropyl)phenyl]piperazine-1 -carboxamide;

4-{3-[(2-aminopyrimidin-4-yl)ethynyl]pyridin-2-yl}-N-[3-(1 ,1 -dimethylethyl)phenyl]piperazine- 1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-{3-[(1 - methylethyl)oxy]phenyl}piperazine-1 -carboxamide;

4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[5-(1 ,1-dimethylethyl)-1 ,3,4- oxadiazol-2-yl]piperazine-1 -carboxamide;

or a pharmaceutically acceptable salt of any of the above compounds.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 - 9 and a pharmaceutically acceptable carrier.

1 1. A method of modulating FGFR2, the method comprising administering to a mammal a compound according to any of claims 1-9, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound according to any of claims 1-8, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A method of treating diseases or disorders comprising administering, to a mammal, in need the treatment a compound according to any of claims 1-9, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound according to any of claims 1-9, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. The method according to claim 11, wherein the disease or disorder is cancer.

14. The method according to claim 12, wherein the cancer is prostate cancer, ovarian cancer, cervical cancer, pancreatic cancer, or head and neck cancers.

15. A method of inhibiting proliferative activity in a cell, the method comprising administering to said cell an effective amount of a compound according to any of claims 1-9, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound according to any of claims 1-8, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier.