ZA200600596B - Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto - Google Patents

Description

® . g | WO 2005/012254 PCT/US2004/023488

DIARYL, AND ARYLHETEROARYL UREA DERIVATIVES AS MODULATORS OF THE S5-HT2A SEROTONIN

RECEPTOR USEFUL FOR THE PROPHYLAXIS AND TREATMENT OF DISORDERS RELATED THERTO

FIELD OF THE INVENTION

The present invention relates to certain diary! and arylheteroaryl urea derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HT;, serotonin receptor,

Compounds and pharmaceutical compositions thereof are directed to methods useful in the prophylaxis or treatment of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or a symptom, behavioral disorders, drug induced psychosis, excitative psychosis,

Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, sleep disorders, diabetic-related disorders and the like.

The present invention also relates to the method of prophylaxis or treatment of 5-HT,, serotonin receptor mediated disorders in combination with a dopamine D2 receptor antagonist such as haloperidol, administered separately or together.

BACKGROUND OF THE INVENTION

G Protein coupled receptors

G Protein coupled receptors share a common structural motif. All these receptors have seven sequences of between 221024 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane. The transmembrane helices are joined by strands of amino acids having a larger loop between the fourth and fifth transmembrane helix on the extracellular side of the membrane. Another larger loop, composed primarily of hydrophilic amine acids, joins transmembrane helices five and six on the intracellular side of the membrane. The carboxy terminus of the receptor lies intracellularly with the amino terminus in the extracellular space. It is thought that the loop joining helices five and six, as well as, the carboxy terminus, interact with the G protein. Currently, Gq, Gs, Gi and Go are G proteins that have been identified. The general structure of G protein coupled receptors is shown in Figure 1.

Under physiological conditions, G protein coupled receptors exist in the cell membrane in equilibrium between two different states or conformations: an “inactive” state and an “active” state. As shown schematically in Figure 2, a receptor in an inactive state is unable to link to the intracellular transduction pathway to produce a biological response, Changing the receptor conformation to the active state allows linkage to the transduction pathway and produces a biological response. Lo

_ _

A receptor may be stabilized in an active state by an endogenous ligand or an exogenous agonist ligand. Recent discoveries such as, including but not exclusively limited to, modifications to the amino acid sequence of the receptor provide means other than ligands to stabilize the active state conformation. These means effectively stabilize the receptor in an active state by simulating the effect of a ligand binding to the receptor. Stabilization by such ligand-independent means is termed “constitutive receptor activation.”

Serotonin receptors

Receptors for serotonin (S-hydroxytryptamine, 5-HT) are an important class of G protein coupled receptors. Serotonin is thought to play a role in processes related to learning and memory, sleep, thermoregulation, mood, motor activity, pain, sexual and aggressive behaviors, appetite, neurodegenerative regulation, and biological rhythms. Not surprisingly, serotonin is linked to pathophysiological conditions such as anxiety, depression, obsessive compulsive disorders, schizophrenia, suicide, autism, migraine, emesis, alcoholism, and neurodegenerative disorders. With respect to anti-psychotic treatment approaches focused on the serotonin receptors, these types of therapeutics can generally be divided into two classes, the “typical” and the “atypical.” Both have anti-psychotic effects, but the typicals also include concomitant 15 .motor-related side effects (extra pyramidal syndromes, e.g., lip-smacking, tongue darting, locomotor movement, etc). Such side effects are thought to be associated with the compounds interacting with other receptors, such as the human dopamine D2 receptor in the nigro-striatal pathway. Therefore, an atypical treatment is preferred. Haloperidol is considered a typical anti-psychotic, and clozapine is considered an atypical anti-psychotic.

Serotonin receptors are divided into seven subfamilies, referred to as 5-HT1 through 5-HT7, inclusive. These subfamilies are further divided into subtypes. For example, the 5-HT2 subfamily is divided into three receptor subtypes: 5-HT;4, 5-HTag, and 5-HT;c. The human 5-HT;c receptor was first isolated and cloned in 1987, and the human 5-HT,4 receptor was first isolated and cloned in 1990.

These two receptors are thought to be the site of action of hallucinogenic drugs. Additionally, antagonists to the 5-HTza and 5-HTxc receptors are believed to be useful in treating depression, anxiety, psychosis, and eating disorders.

U.S. Patent Number 4,985,352 describes the isolation, characterization, and expression of a functional cDNA clone encoding the entire human 5-HTc receptor (now known as the 5-HTc receptor). U.S. Patent Numbers 5,661,024 and 6,541,209 describe the isolation, characterization, and expression of a functional cDNA clone encoding the entire human 5-HTj, receptor.

Mutations of the endogenous forms of the rat 5-HT,, and rat 5-HTy receptors have been reported to lead to constitutive activation of these receptors (5-HTza: Casey, C. et al. (1996) Society for

Neuroscience Abstracts, 22:699.10, hercinafier “Casey”; S-HT,c: Herrick-Davis, K., and Teitler, M. (1996) Society for Neuroscience Abstracts, 22:699.18, hereinafter “Herrick-Davis 17; and Herrick-

Davis, K. er al. (1997) J. Neurochemistry 69(3): 1138, hereinafter “Herrick-Davis-2”). Casey describes a mutation of the cysteine residue at position 322 of the rat 5-HT,4 receptor to lysine (C322K), glutamine (C322Q), and arginine (C322R) which reportedly led to constitutive activation. Herrick-

_ ® WO 2005/012254 PCT/US2004/023488 .

Davis 1 and Herrick-Davis 2 describe mutations of the serine residue at position 312 of the rat 5-HT¢ receptor to phenylalanine (S312F) and lysine (S3 12K), which reportedly led to constitutive activation.

SUMMARY OF THE INVENTION

One aspect of the present invention encompasses certain diary! and arylheteroaryl urea derivatives as shown in Formula (I):

Rea

Rs eee Q

NE) N” “NTR,

Rec Ry Re

Re Rs a or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: i) R, is aryl or heteroaryl each optionally substituted with Ry, Ryo, Ry, Riz, Ris, Ry, and

Ris each selected independently from the group consisting of C, ¢ acyl, C,5 acyloxy, C,4 alkenyl, C5 alkoxy, C,¢ alkyl, C, alkylcarboxamide, C4 alkynyl, C, alkylsulfonamide, C,.¢ alkylsulfinyl, C4 alkylsulfonyl, C, alkylthio, C, 4 alkylureyl, amino, C, alkylamino, C,4 dialkylamino, C, alkylimino, carbo-C, s-alkoxy, carboxamide, carboxy, cyano, Cs; cycloalkyl, C,4 dialkylcarboxamide, C,.4 dialkylsulfonamide, halogen, C, haloalkoxy, C,.¢ haloalkyl, C,.s haloalkylsuifinyl, C, haloalkylsulfonyl, C,, haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent Ry, Ryo, Ry, R32, Ry, Rus, and Rs together with the atoms to which they are attached form a

Cs. cycloalkyl group or heterocyclic group each optionally substituted with F, Cl, or Br; and wherein said Cy alkenyl, Cy alkyl, C,4 alkynyl, C, alkylamino, C,¢ alkylimino, C,4 dialkylamino, heterocyclic, and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C, acyl, C,¢ acyloxy, C,¢ alkenyl, C, alkoxy, Cys alkyl, Cy alkylcarboxamide, C, alkynyl, C, 4 alkylsulfonamide, C, alkylsulfinyl, C4 alkylsulfonyl, C alkylthio, C4 alkylureyl, amino, C, 4 alkylamino, C, dialkylamino, carbo-C 1-s-alkoxy, carboxamide, carboxy, cyano, Cy; cycloalkyl, C4 dialkylcarboxamide, halogen, C, haloalkoxy, C4 haloalkyl, Cy haloalkylsulfinyl, Cy. haloalkylsulfonyl, C,.¢ haloalkylthia, hydroxyl, thiol and nitro; il) R; is selected from the group consisting of H, C, alkyl, Cy alkenyl, C4 alkynyl and

Cs. cycloalkyl; iii) R; is selected from the group consisting of H, C,.4 alkenyl, C,.¢ alkyl, C, alkylcarboxamide, Cy alkynyl, C alkylsulfonamide, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, C; 5 cycloalkyl, Cz dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each of said C,.4 alkenyl, C,.¢ alkyl, C, alkynyl, C, alkylsulfonamide, C;.; cycloalkyl, heteroaryl and phenyl groups can be optionally substituted with 1 to 5 substituents selected independently from the group Co 3

® ® WO 2005/012254 PCT/US2004/023488 consisting of C,.s acyl, C.s acyloxy, C,4 alkenyl, C,, alkoxy, C, 4 alkyl, C, alkylamino, Cy dialkylamine, C, alkylcarboxamide, C, alkynyl, C,4 alkylsulfonamide, C,, alkylsulfinyl, C4 alkylsulfonyl, C, alkylthio, C4 alkylureyl, amino, carbo-C, s-alkoxy, carboxamide, carboxy, cyano,

Cs cycloalkyl, C4 dialkylcarboxamide, halogen, C, haloalkoxy, C,. haloalkyl, C,4 haloalkylsulfinyl, C,4 haloalkylsulfonyl, C,, haloalkylthio, hydroxyl, nitro and sulfonamide; iv) Ry is selected from the group consisting of H, C, acyl, Cy acyloxy, Cz alkenyl, Ci alkoxy, Cs alkyl, C, 4 alkylcarboxamide, C,. alkynyl, C,. alkylsulfonamide, C, alkylsulfinyl, C, alkylsulfonyl, C, alkylthio, C,; alkylureyl, amino, C, alkylamino, C, dialkylamino, carbo-C,- alkoxy, carboxamide, carboxy, cyano, C;.7 cycloalkyl, C,.5 dialkylcarboxamide, Ca. dialkylsulfonamide, halogen, C, haloalkoxy, C, haloalkyl, C, haloalkylsulfinyl, C haloatkylsulfonyl, C, haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; v) Rs is selected from the group consisting of C4 acyl, Cis acyloxy, Ca alkenyl, Ci alkoxy, C,, alkyl, C,¢ alkylcarboxamide, C, alkynyl, C, alkylsuifonamide, C,¢ alkylsulfinyl, C, alkylsulfonyl, C,. alkylthio, Cy alkylureyl, amino, C, alkylamino, C,s dialkylamino, carbo-C, ¢- alkoxy, carboxamide, carboxy, cyano, C;.; cycloalkyl, C,.4 dialkylcarboxamide, Cz.5 dialkylsulfonamide, halogen, C, haloalkoxy, C,¢ haloalkyl, C,¢ haloalkylsulfinyl, Cis haloalkylsulfonyl, C, haloalkylthio, hydroxyl, thiol, nitro and sulfonamide, wherein said C, alkoxy group can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,_s acyl, C,.s acyloxy, C, 4 alkenyl, C,. alkoxy, Cs alkyl, amino, C, alkylamino, C;.¢ dialkylamino, C, alkylcarboxamide, Cp alkynyl, C,, alkylsulfonamide, C, alkylsulfinyl, Cy. alkylsulfonyl, C4 alkylthio, C4 alkylureyl, amino, carbo-C,-alkoxy, carboxamide, carboxy, cyano,

C6 cycloalkyl, C,¢ dialkylcarboxamide, halogen, C, haloalkoxy, C4 haloalkyl, C4 haloalkylsulfinyl, C,.4 haloalkylsulfonyl, C,4 haloalkylthio, hydroxyl, nitro and phenyl, and wherein said amino and phenyl are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and carbo-C,-alkoxy; vi) Rea Rey, and Re, are each independently selected from the group consisting of H, Cy acyl, C,.¢ acyloxy, Ca alkenyl, C, alkoxy, C, alkyl, C,. alkylcarboxamide, Cy alkynyl, Cis alkylsulfonamide, C, alkylsulfinyl, C 4 alkylsulfonyl, C;. alkylthio, C, alkylureyl, amino, Cis alkylamino, C, dialkylamino, carbo-C,¢-alkoxy, carboxamide, carboxy, cyano, C;.4 cycloalkyl, Cz dialkylcarboxamide, C,.; dialkylsulfonamide, halogen, C, haloalkoxy, C, haloalkyl, C1 haloalkylsulfinyl, C,.¢ haloalkylsulfonyl, C, haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; vii) R; and Ry are independently H or Cy alkyl; viii) XisOorS;and ix) Q is C,; alkylene optionally substituted with 1 to 4 substituents selected from the group consisting of C, 3 alkyl, C,. alkoxy, carboxy, cyano, C,; haloalkyl, halogen and oxo; or Q is a bond.

One aspect of the present invention encompasses pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier. oo

One aspect of the present invention encompasses methods for modulating the activity of a 5HTa2, serotonin receptor by contacting the receptor with a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of platelet aggregation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of an indication selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of reducing the risk of blood clot formation in an angioplasty or coronary bypass surgery individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of asthma in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of a symptom of asthma in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of agitation or a symptom thereof in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition. In some embodiments, the individual is a cognitively intact elderly individual.

One aspect of the present invention encompasses methods for prophylaxis or treatment of agitation or a symptom thereof in an individual suffering from dementia comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition. In some embodiments, the

® o dementia is due to a degenerative disease of the nervous system. In some embodiments, the dementia is

Alzheimers disease, Lewy Body, Parkinson's disease or Huntington's disease. In some embodiments, the dementia is due to diseases that affect blood vessels. In some embodiments, the dementia is due to stroke or multi-infarct dementia.

One aspect of the present invention encompasses methods for prophylaxis or treatment of an individual suffering from at least one of the indications selected from the group consisting of behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia and NOS schizophrenia comprising administering to said individual in need thereof a therapeutically effective amount of a dopamine D2 receptor antagonist and a compound according to any of the embodiments described herein or a pharmaceutical composition. In some embodiments, the dopamine D2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methads for prophylaxis or treatment of an individual with infantile autism, Huntington's chorea, or nausea and vomiting from chemotherapy or chemotherapeutic antibodies comprising administering to said individual in need thereof a therapeutically effective amount of a dopamine D2 receptor antagonist and a compound according to any of the embodiments described herein or a pharmaceutical composition. In some embodiments, the dopamine D2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods for prophylaxis or treatment of schizophrenia in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a dopamine D2 receptor antagonist and a compound according to any of the embodiments described herein or a pharmaceutical compasition. In some embodiments, the dopamine D2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods for prophylaxis or treatment of alleviating negative symptoms of schizophrenia induced by the administration of haloperidol to an individual suffering from said schizophrenia, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition. In some embodiments, the haloperidol and the compound or pharmaceutical composition are administered in separate dosage forms. In some embodiments, the haloperidol and the compound or pharmaceutical composition are administered in a single dosage form.

One aspect of the present invention encompasses methods for prophylaxis or treatment of a sleep disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition. In some embodiments, the sleep disorder comprises a fragmented sleep architecture. In some embodiments, the effective amount of a compound according to any of the embodiments described herein, or a pharmaceutical composition described herein, promotes sleep Lo o - @

WO 2005/012254 PCT/US2004/023488 } consolidation. In some embodiments, the effective amount of a compound according to any of the embodiments described herein, or a pharmaceutical composition described herein, increases delta power.

In some embodiments, the sleep disorder is a dyssomnia. In some embodiments, the dyssomnia is selected from the group consisting of psychophysiological insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless leg syndrome, inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association disorder, nocturnal eating or drinking syndrome, hypnotic dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, toxin-induced sleep disorder, time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome and non-24-hour sleep-wake disorder.

In some embodiments, the sleep disorder is a parasomnia. In some embodiments, the parasomnia is selected from the group consisting of confusional arousals, sleepwalking and sleep terrors, rhythmic movement disorder, sleep starts, sleep talking and nocturnal leg cramps.

In some embodiments, the sleep disorder is associated with a medical or psychiatric disorder.

In some embodiments, the medical or psychiatric disorder is selected from the group consisting of psychoses, mood disorders, anxiety disorders, panic disorders, alcoholism, cerebral degenerative disorders, dementia, parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrical status epilepticus of sleep, sleep-related headaches, sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastroesophageal reflux, peptic ulcer disease, fibrositis syndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia and post-surgical sleep disorder.

One aspect of the present invention encompasses methods for prophylaxis or treatment of a . diabetic-related disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

In some embodiments, the diabetic-related disorder is diabetic peripheral neuropathy.

In some embodiments, the diabetic-related disorder is diabetic nephropathy.

In some embodiments, the diabetic-related disorder is diabetic retinopathy.

One aspect of the present invention encompasses processes for preparing a composition comprising admixing a compound according any embodiments described herein and pharmaceutically acceptable carrier.

One aspect of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,, mediated disorder.

® .

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One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT2, mediated disorder wherein the disorder is platelet aggregation.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,, mediated disorder wherein the disorder is selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,, mediated disorder wherein the disorder is a blood clot formation in an angioplasty or coronary bypass surgery individual.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT2, mediated disorder wherein the disorder is a blood clot formation in an individual suffering from atrial fibrillation.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT24 mediated disorder wherein the disorder is asthma.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,, mediated disorder wherein the disorder is a symptom of asthma.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT;, mediated disorder wherein the disorder is agitation or a symptom thereof in an individual. In some embodiments the individual is a cognitively intact elderly individual.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT.4 mediated disorder wherein the disorder is agitation or a symptom thereof in an individual suffering from dementia. In some embodiments the dementia is due to a degenerative disease of the nervous system. In some embodiment the dementia is :

Alzheimers disease, Lewy Body, Parkinson’s disease, or Huntington's disease. In some embodiments the dementia is due to diseases that affect blood vessels. In some embodiments the dementia is due to stroke or multi-infract dementia. :

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT24 mediated disorder further comprising a dopamine D2 receptor antagonist wherein the disorder is selected from the group consisting ofa behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia and NOS schizophrenia. In some embodiments the dopamine D2 receptor antagonist is haloperidol. }

® ® WO 2005/012254 PCT/US2004/023488

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a 5SHT,, mediated disorder further comprising a dopamine D2 receptor antagonist wherein the disorder is infantile autism, Huntington's chorea, or nausea and vomiting from chemotherapy or chemotherapeutic antibodies. In some embodiments the dopamine D2 receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a 5HT,4 mediated disorder further comprising a dopamine D2 receptor antagonist wherein the disorder is schizophrenia. In some embodiments the dopamine D2 receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,a mediated disorder wherein the disorder is a negative symptom or symptoms of schizophrenia induced by the administration of haloperidol. .

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT;, mediated disorder wherein the haloperidol and the compound or pharmaceutical composition are administered in separate dosage forms.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a 5HT»4 mediated disorder wherein the haloperidol and the compound or pharmaceutical composition are administered in a single dosage form.

One aspect of the present invention are compounds according to any of the embodiments described herein for use in a method of treatment of the human or animal body by therapy.

One aspect of the present invention are compounds according to any of the embodiments described herein for use in a method for the prophylaxis or treatment of a 5SHT24 mediated disorder, as described herein, in the human or animal body by therapy.

One aspect of the present invention are compounds according to any of the embodiments described herein for use in a method for the prophylaxis or treatment of a sleep disorder, as described herein, in the human or animal body by therapy.

One aspect of the present invention are compounds according to any of the embodiments described herein for use in a method for the prophylaxis or treatment of platelet aggregation in the human or animal body by therapy.

This application is related to two US Provisional Patent Applications, Serial Nos. 60/489,572 filed July 22, 2003; and 60/503,586 filed September 16, 2003, both which are incorporated by reference in their entirety.

These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.

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BRIEF DESCRIPTION OF THE DRAWINGS

In the following figures, bold typeface indicates the location of the mutation in the non- endogenous, constitutively activated receptor relative to the corresponding endogenous receptor.

Figure 1 shows a generalized structure of a G protein-coupled receptor with the numbers assigned

S to the transmembrane helices, the intracellular loops, and the extracellular loops.

Figure 2 schematically shows the active and inactive states for a typical G protein-coupled receplor and the linkage of the active state to the second messenger transduction pathway.

Figure 3a provides the nucleic acid sequence of the endogenous human 5-HT;, receptor (SEQ.ID.NO: 21).

Figure 3b provides the corresponding amino acid sequence of the endogenous human 5-HT34 receptor (SEQ.ID.NO: 22).

Figure 4a provides the nucleic acid sequence of the endogenous human 5-HT;¢ receptor (SEQ.ID.NO: 23).

Figure 4b provides the corresponding amino acid sequence of the endogenous human 5-HTy¢ receptor (SEQ.1D.NO: 24).

Figure 5a provides the nucleic acid sequence of a constitutively active form of the human 5-

HT.c receptor ("AP-1 cDNA"-SEQ.ID.NO: 25).

Figure 5b provides the corresponding amino acid sequence of the AP-1 cDNA (“AP-I"-

SEQ.ID.NO: 26).

Figure 6a provides the nucleic acid sequence of a constitutively active form of the human 5-

HT}, receptor whereby the IC3 portion and the cytoplasmic-tail portion of the endogenous 5-HTas receptor have been replaced with the 1C3 portion and the cytoplasmic-tail portion of the human 5-HT zc receptor (“AP-3 cDNA”-SEQ.ID.NQ: 27).

Figure 6b provides the corresponding amino acid sequence of the AP-3 cDNA (“AP-3”

SEQ.ID.NOQ: 28).

Figure 6c provides a schematic representation of AP-3, where the dashed-lines represent the portion obtained from the human 5-HT,c receptor.

Figure 7a provides the nucleic acid sequence of a constitutively active form of the human 5-

HT}, receptor whereby (1) the region between the proline of TMS and the proline of TM6 of the endogenous human S-HT4 receptor has been replaced with the corresponding region of the human 5-

HT; receptor (including a S310K point mutation); and (2) the cytoplasmic-tail portion of the endogenous 5-HT, receptor has been replaced with the cytoplasmic-tail portion of the endogenous human 5-HT;c receptor (“AP-4 cDNA” - SEQ.ID.N0:29).

Figure 7b provides the corresponding amino acid sequence of the AP-4 cDNA (“AP-4"-

SEQ.ID.NO: 30).

Figure 7c provides a schematic representation of the mutated 5-HT,a receptor of Figure 7b where the dashed-lines represent the portion obtained from the human 5-HT,c receptor. )

®

Figure 8 is a representation of the preferred vector, pCMV, used herein.

Figure 9 is a diagram illustrating (1) enhanced (**S)GTPYS binding to membranes prepared from COS cells expressing the endogenous human S-HT,¢ receptor in response to serotonin, and (2) inhibition by mianserin using wheatgerm agglutinin scintillation proximity beads. The concentration of (*S)GTPyS was held constant at 0.3 nM, and the concentration of GDP was held at 1 pM. The concentration of the membrane protein was 12.5 pg.

Figure 10 is a diagram showing serotonin stimulation of (**S)GTPyS binding to membranes expressing AP-1 receptors in 293T cells and the inhibition by 30 pM mianserin on Wallac™ scintistrips.

Figure 11 is a diagram showing the effects of protein concentration on (**SYGTPYS binding in membranes prepared from 293T cells transfected with the endogenous human 5-HT;c receptors and

AP-| receptors compared to cells transfected with the control vector (pCMV) alone in the absence (A) and presence (B) of 10 pM serotonin. The radiolabeled concentration of (**S)GTPyS was held constant at 0.3 nM, and the GDP concentration was held constant at 1 pM. The assay was performed on 96-well format on Wallac™ scintistrips.

Figure 12 provides bar-graph comparisons of inositol tris-phosphate (“TP3™) production between the endogenous human SHT,, receptor and AP-2, a mutated form of the receptor.

Figure 13 provides bar-graph comparisons of inositol tris-phosphate (“IP3”) production between the endogenous human SHT., receptor and AP-4, a mutated form of the receptor.

Figure 14 provides bar graph comparisons of 1P3 production between the endogenous human 5-HT;4 receptor and AP-3, a mutated form of the receptor.

Figure 15 provides bar-graph comparisons of IP3 production between the endogenous human 5-HT,¢ receptor and AP-1.

Figures 16A, 16B and 16C shows a grey-scale reproduction of representative autoradiograms demonstrating displacement of '*I-LSD from brain sections by spiperone and an early lead compound identified by the Inventors, referred to herein as S-1610 and has the following name: [3-(4-Bromo-2- methyl-2H-pyrazol-3-y})-phenyl]-carbamic acid 4-methoxy-phenyl ester.

Figure 17 shows the general synthetic scheme for the preparation of intermediate compounds of the present invention. Figure 17 shows a general coupling method between a pyrazole borenic acid and an aryl triflate, it is understood that similar coupling methods can be used wherein the triflate is a halide, such as, 1, Br or Cl.

Figure 18 shows the general synthetic scheme for the preparation of intermediate compounds of the present invention.

Figure 19 shows the general synthetic scheme for the preparation of intermediate compounds useful in the preparation of compounds of the present invention.

Figure 20 shows the general synthetic scheme for the preparation of intermediate compounds useful in the preparation of compounds of the present invention. Lo

( .

J

Figure 21 shows the general synthetic scheme for the preparation of compounds of the present invention. Figure 21 shows a general coupling method between a phenyl amine, as described in previous figures, and an isocyanate or thioisocyanate to give ureas and thioureas respectively.

Figure 22 shows the effect of Compound 1 on DOl-induced hypolocomation in rats.

Figure 23 shows the effect of Compound 26 on DOI-induced hypolocomotion in rats.

Figure 24 shows the experimental design of SHT2A occupancy studies in monkeys.

Figure 25 shows PET scan images of monkey brains 8 or 24 hours after treatment with

Compound 1 compared to a baseline PET scan (transaxial view).

Figure 26 shows PET scan images of monkey brains 8 or 24 hours after treatment with

Compound 1 compared to a baseline PET scan (sagital view).

Figure 27 shows tabulated data for percent occupancy of SHT2A receptors by Compound | in monkeys.

Figure 28 shows the effect in rats of Compound 1 and Compound 26 on sleep and wakefulness, as measured by delta power, compared to zolpidem.

Figure 29 shows the general synthetic scheme for the preparation of intermediate compounds of the present invention. Figure 29 shows a general coupling method between a pyrazole boronic acid and an aryl triflate, it is understood that similar coupling methods known in the art can also be used, and a halide, such as, I, Br or Cl, can be used in place of the triflate.

Figure 30 shows the general synthetic scheme for the preparation of intermediate compounds of the present invention. Figure 30 illustrates the formation of pyrazoles from a variety of substituted chromen-4-ones. Also shown are alkylation and “Mitsunobu-like” examples for modifying the phenol, and illustrative reductions of the nitro to amine.

Figure 31 shows the general synthetic scheme for the preparation of intermediate compounds useful in the preparation of compounds of the present invention. Figure 31 illustrates the alkylation and “Mitsunobu-like” examples for modifying the phenol. It is understood that a variety of halo-alkyls and alcohols can be used in these reactions. Some representative alcohols are, 2-dimethylamino ethanol, 3- dimethylamino propanol, and the like.

Figure 32 shows the general synthetic scheme for the preparation of intermediate compounds useful in the preparation of compounds of the present invention. Figure 32 illustrates general methods for introducing a variety of halogens into compounds of the invention. It is understood that these halogenation reaction can also be conducted later in the synthesis, for example as the last step.

Figure 33 shows the general synthetic scheme for the preparation of compounds of the present invention. Figure 33 shows a general coupling method between a phenyl amine, as described in previous figures, and isocyanates or thioisocyanates to give ureas and thioureas respectively. Figure 33 also shows the general method for introducing R, and Rg into compounds of the invention.

Figure 34 shows an alternate general synthetic scheme for the preparation of compounds of the present invention. oo

DEFINITIONS

The scientific literature that has evolved around receptors has adopted a number of terms to refer to ligands having various effects on receptors. For clarity and consistency, the following definitions will be used throughout this patent document.

AGONISTS shall mean moieties that interact and activate the receptor, such as the 5-HTy, receptor, and initiates a physiological or pharmacological response characteristic of that receptor. For example, when moieties activate the intracellular response upon binding to the receptor, or enhance GTP binding to membranes.

AMINO ACID ABBREVIATIONS used herein are set out in TABLE 1:

TABLE 1 was we |x] rm cre

Gime wom | ana

CE IT cre

CC A IC

EE ILC

I IS ER

ET I moro | ww ron

®

The term ANTAGONISTS is intended to mean moieties that competitively bind to the receptor at the same site as agonists (for example, the endogenous ligand), but which do not activate the intracellular response initiated by the active form of the receptor, and can thereby inhibit the intracellular responses by agonists or partial agonists. Antagonists do not diminish the baseline intracellular response in the absence of an agonist or partial agonist.

CHEMICAL GROUP, MOIETY OR RADICAL:

The term “C, acyl” denotes a C,. alkyl radical attached to a carbonyl] wherein the definition of alky! has the same definition as described herein; some examples include but not limited to, acetyl, propionyl, n-butanoyl, iso-butanoyl, sec-butanoyl, -butanoyl (i.e., pivaloyl), pentanoyi and the like.

The term “C,¢ acyloxy” denotes an acyl radical attached to an oxygen atom wherein acy! has the same definition has described herein; some examples include but not limited to acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy and the like.

The term “C,¢ alkenyl” denotes a radical containing 2 to 6 carbons wherein at least one carbon-carbon double bond is present, some embodiments are 2 to 4 carbons, some embodiments are 2 15 . to 3 carbons, and some embodiments have 2 carbons. Both £ and Z isomers are embraced by the term “alkenyl.” Furthermore, the term “alkenyl” includes di- and tri-alkenyls. Accordingly, if more than one double bond is present then the bonds may be all E or Z or a mixtures of E and Z. Examples of an alkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3- hexenyl, 4-hexenyl, 5-hexanyl, 2,4-hexadienyl and the like.

The term “C,¢ alkoxy” as used herein denotes a radical alkyl, as defined herein, attached directly to an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t- butoxy, iso-butaxy, sec-butoxy and the like.

The term “C4 alkyl” denotes a straight or branched carbon radical containing 1 to 8 carbons, some embodiments are 1 to 6 carbons, some embodiments are 1 to 4 carbons, some embodiments are to 3 carbons, and some embodiments are 1 or 2 carbons. Examples of an alkyl include, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl, iso-pentyl, t-pentyl, neo-pentyl, 1-methylbutyl {i.e., ~CH(CH,)CH,CH,CHj;}, 2-methylbutyl [i.e., -CH,CH(CH;)CH,CH,}, n-hexyl and the like.

The term “C, 4 alkylcarbexamido” or “C,4 alkylcarboxamide” denotes a single C, 4 alkyl group attached to the nitrogen of an amide group, wherein alky) has the same definition as found herein.

The C6 alkylcarboxamido may be represented by the following: 0 oO ay or alkyl Sle, alkyl

® ® WO 2005/012254 PCT/US2004/023488

Examples include, but not limited to, N-methylcarboxamide, N-ethylcarboxamide, N-n- propylcarboxamide, N- iso-propylcarboxamide, N-n-butylcarboxamide, N-sec-butylcarboxamide, N- iso-butylcarboxamide, N-t-butylcarboxamide and the like.

The term “Cy, alkylene” refers to a C,.; divalent straight carbon group. In some embodiments

S C1; alkylene refers to, for example, -CH;-, -CH,CH,-, -CH,CH2CHg-, and the like. In some embodiments, C, ; alkylene refers to -CH-, - CHCH;-, -CHCH;CH;-, and the like wherein these examples relate generally to the variable or claim element “Q”.

The term “C, ¢ alkylimino” denotes a C,.¢ alkyl radical attached directly to the carbon of the —C(=NH)- group wherein the definition of alkyl has the same definition as described herein; some examples include but not limited to, 1-imino-ethy] [i.e., -C(=NH)CHj], l-imino-propyl [i.c., -C(=NH)CH,CH,], 1-imino-2-methyl-propyl {i.e., <C(=NH)CH(CH,),], and the like.

The term “C, ¢ alkylsulfiny!” denotes a C, alkyl radical attached to a sulfoxide radical of the formula: -S(O)- wherein the alkyl radical has the same definition as described herein. Examples include, but not limited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso-propylsulfinyl, n-

IS butylsulfinyl, sec-butylsulfinyl, iso-butylsulfinyl, t-butylsulfiny}, and the like.

The term “C4 alkylsulfonamide” refers to the groups

NY crab SN

Od NT +e NN" Cog allyl wherein C, alkyl has the same definition as described herein.

The term “C, alkylsuifony!)’ denotes a C,¢ alkyl radical attached to a sulfone radical of the 20 formula: -S(O),- wherein the alkyl radical has the same definition as described herein. Examples include, but not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n- butylsulfonyl, sec-butylsulfonyl, iso-butylsulfonyl, -butylsulfonyl, and the like. ,

The term “C,.¢ alkylthio” denotes a C,. alkyl radical attached to a sulfide of the formula: -S- wherein the alkyl radical has the same definition as described herein. Examples include, but not limited 25 to, methylsulfanyl (i.e., CH;S-), ethylsulfanyl, n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, iso-butylsulfanyl, -butylsulfanyl, and the like.

The term “C, alkylthiocarboxamide™ denotes a thioamide of the following formulae: 3] S aye alkyl She hi wherein C, 4 alkyl has the same definition as described herein. 30 The term “C;.¢ alkylthioureyl” denotes the group of the formula: -NC(S)N- wherein one are both of the nitrogens are substituted with the same or different C4 alkyl groups and alkyl has the same definition as described herein. Examples of an alkylthioureyl include,

® ® but not limited to, CH;NHC(S)NH-, NH,C(S)NCHj-, (CH3),N(S)NH-, (CH;),N(S)NH-, (CH;3);N(S)NCHj;-~, CH,CH,NHC(S)NH-, CH;CH,NHC(S)NCHj-, and the like.

The term “C alkylureyl” denotes the group of the formula: -NC(O)N- wherein one are both of the nitrogens are substituted with the same or different C,¢ alkyl group wherein alkyl has the same definition as described herein. Examples of an alkylureyl include, but not limited to, CH;NHC(O)NH-,

NH:C(O)NCHj-, (CH;)NC(0)NH-, (CH;),NC(O)NH-, (CH;);NC(O)NCH;-, CH;CH,NHC(O)NH-,

CH; CH,NHC(O)NCH;-, and the like.

The term “C; alkynyl” denotes a radical containing 2 to 6 carbons and at least one carbon- carbon triple bond, some embodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, and some embodiments have 2 carbons. Examples of an alkynyl include, but not limited to, ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyi, 4-pentynyl, 1-hexynyl, 2-hexynyt, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. The term “alkynyl” includes di- and tri-ynes.

The term “amino” denotes the group —~NH,.

The term “C, alkylamino” denotes one alkyl radical attached to an amino radical wherein the alkyl radical has the same meaning as described herein. Some examples include, but not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, sec-butylamino, iso- butylamin, t-butylamino, and the like. Some embodiments are “C;; alkylamino.”

The term “aryl” denotes an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl.

The term “arylalkyl” defines a C,-C, alkylene, such as —CH;,-, -CH,CH;- and the like, which is further substituted with an aryl group. Examples of an “arylalkyl” include benzyl, phenethylene and the like.

The term “arylcarboxamide” denotes a single aryl group attached to the nitrogen of an amide group, wherein aryl has the same definition as found herein. The example is N-phenylcarboxamide.

The term “arylurey!” denotes the group -NC(O)N- where one of the nitrogens are substituted with an aryl.

The term “benzyl” denotes the group CH,C4Hs.

The term “carbo-C;s-alkoxy” refers to a Cy. alkyl ester of a carboxylic acid, wherein the alkyl group is as defined herein. Examples include, but not limited to, carbomethoxy, carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec-butoxy, carbo-iso-butoxy, carbo-t-butoxy, carbo-n-pentoxy, carbo-iso-pentoxy, carbo-/-pentoxy, carbo-neo-pentoxy, carbo-n-hexyloxy, and the like.

The term “carboxamide” refers to the group —CONH,.

_

The term “carboxy” or “carboxyl” denotes the group —CO,H; also referred to as a carboxylic acid group.

The term “cyano” denotes the group —CN.

The term “Co; cycloalkenyl” denotes a non-aromatic ring radical containing 4 to 7 ring carbons and at least one double bond; some embodiments contain 4 to 6 carbons; some embodiments contain 4 to 5 carbons; some embodiments contain 4 carbons. Examples include cyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the like.

The term “Cj4 cycloalkyl” denotes a saturated ring radical containing 3 to 7 carbons; some embodiments contain 3 to 6 carbons; some embodiments contain 3 to 5 carbons; some embodiments contain 5 to 7 carbons; some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopenyl, cyclohexyl, cycloheptyl and the like.

The term “C,.4 dialkylamino” denotes an amino substituted with two of the same or different

C4 alkyl radicals wherein alkyl radical has the same definition as described herein. Some examples include, but not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, 1s methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino and the like. Some embodiments are “C;4 dialkylamino.”

The term “C, dialkylcarboxamido” or “C,.; dialkylcarboxamide”denotes two alkyl radicals, that are the same ort different, attached to an amide group, wherein alkyl has the same definition as described herein. A Ca, dialkylcarboxamido may be represented by the following groups: 0] lo] a alkyl See. alkyl

Ciq alkyl C14 alky! wherein C,.4 has the same definition as described herein. Examples of a dialkylcarboxamide include, but not limited to, N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide, N,N-diethyicarboxamide,

N-methyl-N-isopropylcarboxamide, and the like.

The term “C4 dialkylsulfonamide” refers to one of the following groups shown below:

QP & QP oy 2 Sie alkyl SNe alkyl :

C1. alkyl C14 alkyl wherein C4 has the same definition as described herein, for example but not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.

The term “C5 dialkylthiocarboxamido” or “C,, dialkylthiocarbox-amide”denotes two alkyl radicals, that are the same or different, attached to a thioamide group, wherein alkyl has the same definition as described herein. A C,4 dialkylthiocarboxamido or C, dialkylthiocarboxamide may be represented by the following groups:

®

S S ay Ce alkyl Se, alkyl

C44 alkyl Cy.4 alkyl .

Examples of a dialkylthiocarboxamide include, but not limited to, N,N-dimethylthiocarboxamide, N- methyl-N-ethylthiocarboxamide and the like. * The term “ethynylene” refers to the carbon-carbon triple bond group as represented below: g—=—2

The term “formyl” rafirs to the group —CHO.

The term “C, 5 haloalkoxy” denotes a haloalkyl, as defined herein, which is directly attached to an oxygen atom. Examples include, but not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2- trifluoroethoxy, pentafluorocthoxy and the like.

The term “C,_ haloalkyl” denotes an C, alkyl group, defined herein, wherein the alkyl is substituted with one halogen up to fully substituted and a fully substituted C; haloalkyl can be represented by the formula C,L;,., wherein L is a halogen and “n” is 1, 2, 3 or 4; when more than one halogen is present then they may be the same or different and selected from the group consisting of F, Cl, Brand I, preferably F. Examples of C4 haloalkyl! groups include, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like.

The term “C, haloalkylcarboxamide” denotes an alkylcarboxamide group, defined herein, wherein the alkyl is substituted with one halogen up to fully substituted represented by the formula

C,L..s, wherein L is a halogen and “n” is 1,2, 3 or 4. When more than one halogen is present they may be the same or different and selected from the group consisting of F, Cl, Br and I, preferably F.

The term “Ci haloalkylsulfinyl” denotes a haloalkyl radical attached to a sulfoxide group of the formula: -S(O)- wherein the haloalky) radical has the same definition as described herein.

Examples include, but not limited to, trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, 2,2- difluoroethylsulfiny! and the like.

The term “C, haloalkylsulfony!l” denotes a haloalkyl radical attached to a sulfone group of the formula: -S(O),- wherein haloalkyl has the same definition as described herein. Examples include, but not limited to, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, 2,2-diflucroethylsulfonyl and the like.

The term “C, haloalkylthio™ denotes a haloalkyl radical directly attached to a sulfur wherein the haloalkyl has the same meaning as described herein. Examples include, but not limited to, trifluoromethylthio (i.e., CF3S-, also referred to as trifluoromethylsulfanyl), 1,1-difluoroethylthio, 2,2,2- trifluoroethylthio and the like.

The term “halogen” or “halo” denotes to a fluoro, chloro, bromo or iodo group. oo

®

The term “heteroaryl” denotes an aromatic ring system that may be a single ring, two fused rings or : three fused rings wherein at least one ring carbon is replaced with a heteroatom selected from, but not limited to, the group consisting of O, S and N wherein the N can be optionally substituted with H, C, acyl or Cy alkyl. Examples of heteroaryl groups include, but not limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinoline, benzoxazole, benzothiazole, 1H- benzimidazole, isoquinoline, quinazoline, quinoxaline and the like. In some embodiments, the heteroaryl atom is O, S, NH, examples include, but not limited to, pyrrole, indole, and the like. Other examples include, but not limited to, those in TABLE 2, TABLE 3, and the like.

The term “heterocyclic” denotes a non-aromatic carbon ring (i.e., Cy. cycloalkyl or C,, cycloalkenyl as defined herein) wherein one, two or three ring carbons are replaced by a heteroatom selected from, but not limited 10, the group consisting of O, S, N, wherein the N can be optionally substituted with H, C,., acyl or Cy alkyl, and ring carbon atoms optionally substituted with oxo or a thiooxo thus forming a carbonyl or thiocarbony! group. The heterocyclic group is a 3-, 4-, 5-, 6- or 7- membered containing ring. Examples of a heterocyclic group include but not limited to aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-y}, azetidin-3-yl, piperidin-1-yl, piperidin-4-yl, morpholin-4-yl, piperzin-1-yl, piperzin4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2-y! and the like.

The term “beterocycliccarboxamido” denotes a heterocyclic group, as defined herein, with a ring nitrogen where the ring nitrogen is bonded directly to the carbonyl forming an amide. Examples include, but not limited to, (o] oO 0 .

CACY

Lo , , and the like.

The term “heterocyclicsulfonyl” denotes a heterocyclic group, as defined herein, with a ring nitrogen where the ring nitrogen is bonded directly to an -SO,-group forming an sulfonamide.

Examples include, but not limited to,

RV RV RV

Lo and the like.

The term “hydroxyl” refers to the group -OH.

The term “hydroxylamine” refers to the group -NHOH.

The term “nitro” refers to the group -NO..

The term “Cs. 0xo0-cycloalkyl” refers to a C,; cycloalkyl, as defined herein, wherein one of the ring carbons is replaced with a carbonyl. Examples of C,.; oxo-cycloalkyl include, but are not limited to, 2-oxo-cyclobutyl, 3-oxe-cyclobutyl, 3-oxo-cyclopentyl, 4-oxo-cyclohexyl, and the like and represented by the following structures respectively:

[ ® oF 5 s% 0 wa RY of 0} 0] , 0] , and [0]

The term “perfluoroalkyl” denotes the group of the formula -C,Fa,,; stated differently, a perfluoroalkyl is an alkyl as defined herein wherein the alkyl is fully substituted with fluorine atoms and is therefore considered a subset of haloalkyl. Examples of perfluoroalkyls include CF,, CF,CF,

CF,CF,CF,, CF(CF;),, CF,CF.CF;CF,, CF,CF(CF,),;, CF(CF;)CF,CF; and the like.

The term “phenoxy” refers to the group CgH;O-.

The term “phenyl” refers to the group C4H;-.

The term”sulfonic acid” refers to the group —SO,H.

The term “thiel” denotes the group —SH.

CODON shall mean a grouping of three nucleotides (or equivalents to nucleotides) which gencrally comprise a nucleoside [adenosine (A), guanosine (G), cytidine (C), uridine (U) and thymidine (T)] coupled to a phosphate group and which, when translated, encodes an amino acid.

COMPOSITION shall mean a material comprising at least two compounds or two components; for example, and without limitation, a Pharmaceutical Composition is a Composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.

COMPOUND EFFICACY shall mean a measurement of the ability of a compound to inhibit or stimulate receptor functionality. as opposed to receptor binding affinity.

CONSTITUTIVELY ACTIVATED RECEPTOR shall mean a receptor subject to constitutive receptor activation.

CONSTITUTIVE RECEPTOR ACTIVATION shall mean stabilization of a receptor in the active state by means other than binding of the receptor with its endogenous ligand or a chemical equivalent thereof.

CONTACT or CONTACTING shall mean bringing the indicated moieties together, whether in an in vitro system or an in vivo system. Thus, “contacting” a 5-HT;, receptor with a compound of the invention includes the administration of a compound of the present invention to an individual, preferably a human, having a 5-HT:, receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or more purified preparation containing a 5-HT34 receptor.

ENDOGENOUS shall mean a material that a mammal naturally produces. ENDOGENOUS in reference to, for example and not limitation, the term “receptor” shall mean that which is naturally produced by a mammal (for example, and not limitation, a human) or a virus.

In contrast, the term NON-ENDOGENOUS in this context shall mean that which is not naturally produced by a mammal (for example, and not limitation, a human) or a virus. For example, and not

® ® WO 2005/012254 PCT/US2004/023488 ] limitation, a receptor which is not constitutively active in its endogenous form, but when manipulated becomes constitutively active, is most preferably referred to herein as a “non-endogenous, constitutively activated receptor.” Both terms can be utilized to describe both “in vivo” and “in vitro” systems. For example, and not a limitation, in a screening approach, the endogenous or non-endogenous receptor may be in reference to an in vitro screening system. As a further example and not limitation, where the genome of a mammal has been manipulated to include a non-endogenous constitutively activated receptor, screening of a candidate compound by means of an in vivo system is viable.

IN NEED OF PROPHYLAXIS OR TREATMENT as used herein refers to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from prophylaxis or treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will be ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention.

In general, “in need of prophylaxis” refers to the judgment made by the caregiver that the individual will become ill. In this context, the compounds of the invention are used in a protective or preventive manner. However, “in need of treatment” refers to the judgment of the caregiver that the individual is already ill, therefore, the compounds of the present invention are used to alleviate, inhibit or ameliorate the disease, condition or disorder.

INDIVIDUAL as used herein refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

INHIBIT or INHIBITING, in relationship to the tern “response” shall mean that a response is decreased or prevented in the presence of a compound as opposed to in the absence of the compound.

INVERSE AGONISTS shall mean moieties that bind the endogenous form of the receptor or to the constitutively activated form of the receptor, and which inhibit the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of agonists or partial agonists, or decrease GTP binding to membranes. Preferably, the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, more preferably by at least 50%, and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist.

LIGAND shall mean an endogenous, naturally occurring molecule specific for an endogenous, naturally occurring receptor.

As used herein, the terms MODULATE or MODULATING shall mean to refer to an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule.

PHARMACEUTICAL COMPOSITION shall mean a composition comprising at least one active ingredient; including but not limited to, salts, solvates and hydrates of compounds of Formula (I); whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal

[ . ® WO 2005/012254 PCT/US2004/023488 (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

THERAPEUTICALLY EFFECTIVE AMOUNT as used herein refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) Preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) Inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) Ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).

COMPOUNDS OF THE INVENTION:

One aspect of the present invention encompasses certain diary] and arylheteroaryl urea derivatives as shown in Formula (I):

Rea « Rs Reb x 2

NE) EN NR,

Rec Rr Re

Ra Ra 0) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein R,, Rz, Rs, Ry, Rs, Rea, Rep,

Rec, Ra, Rg, X, and Q have the same definitions as described herein, supra and infra.

Some embodiments of the present invention encompass certain diaryl and arylheteroaryl urea derivatives as shown in the following Formula

Re me x

Ne

Rr Rs

Ry Rs : wherein:

® i) R, is aryl or heteroaryl optionally substituted with Rg, Rio, Ry1, Ria, Ry3, Ry4, and Rys selected independently from the group consisting of C, acyl, C5 acyloxy, Ca alkenyl, C5 alkoxy,

Cis alkyl, C, 4 alkylcarboxamide, C, 5 alkynyl, C,; alkylsulfonamide, C, alkylsulfinyl, C, 4 alkylsulfonyl, C, alkylthio, C, alkylureyl, amino, C, alkylamino, C,4 dialkylamino, carbo-C, ¢- alkoxy, carboxamide, carboxy, cyano, C;.; cycloalkyl, C, dialkylcarboxamide, Cy 4 } dialkylsulfonamide, halogen, C, haloalkexy, C,. haloalkyl, C,.¢ haloalkylsulfinyl, C, haloalkylsulfonyl, C,. haloalkylthio, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent Rs,

Ro, Rij, Rig, Riz, Rus, and Rs together with the atoms to which they are attached form a Cs; cycloalkyl group or heterocyclic group each optionally substituted with F, Cl, or Br; and wherein each of said Cy alkenyl, C,, alkyl, C;, alkynyl and phenyl groups can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,.¢ acyl, C\ acyloxy, Ca. alkenyl, C,. alkoxy,

Cs alkyl, C4 alkylcarboxamide, Cy alkynyl, C,, alkylsulfonamide, C4 alkylsulfinyl, Cs alkylsulfonyl, C, alkylthio, C, alkylureyl, amino, C, alkylamino, C4 dialkylamino, carbo-C, - alkoxy, carboxamide, carboxy, cyano, C,_; cycloalkyl, C..¢ dialkylcarboxamide, halogen, Ci ~ haloalkoxy, C, haloalkyl, C4 haloatkylsulfinyl, C,, haloalkylsulfonyl, C,¢ haloalkyithio, hydroxyl, thiol and nitro; ii) R; is selected from the group consisting of C4 alkyl, C, 4 alkenyl, C,; alkynyl and C;.4 cycloalkyl; iii) R; is selected from the group consisting of H, C2 alkenyl, C, alkyl, Cis alkylcarboxamide, C. alkynyl, C4 alkylsulfonamide, carbo-C,-alkoxy, carboxamide, carboxy, cyano, Cy cycloalkyl, C,4 dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each of said C, alkenyl, C,_ alkyl, C, alkynyl, C, alkylsulfonamide, C;.; cycloalkyl, heteroaryl and pheny! groups can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of Cy.s5 acyl, C,.s acyloxy, C, alkenyl, C,4 alkoxy, C,.s alkyl, C,¢ alkylamino, Cy. dialkylamino, C, 4 alkylcarboxamide, C, alkynyl, C,_, atkylsulfonamide, C4 alkylsulfinyl, Ci, alkylsulfonyl, C, 4 alkylthio, C,. alkylureyl, amino, carbo-C,s-alkoxy, carboxamide, carboxy, cyano,

C,.6 cycloalkyl, C, dialkylcarboxamide, halogen, C,4 haloalkoxy, C;4 haloalkyl, C4 haloalkylsulfinyl, C, haloalkylsulfonyl, C,4 haloalkylthio, hydroxyl, nitro and sulfonamide; iv) R, is selected from the group consisting of H, C,.¢ acyl, Cy acyloxy, Cy alkenyl, C, alkoxy, Cy, alkyl, Cy. alkylcarboxamide, Cy alkynyl, Cy alkylsulfonamide, C, alkylsuifinyl, C,¢ alkylsulfonyl, C,.¢ alkylthio, Cis alkylureyl, amino, C, alkylamino, C4 dialkylamino, carbo-C, - alkoxy, carboxamide, carboxy, cyano, C;.; cycloalkyl, C,.s dialkylcarboxamide, C5 dialkylsulfonamide, halogen, C, 4 haloalkoxy, C4 haloalkyl, C,.¢ haloalkylsulfinyl, C, halealkylsulfonyl, C;.s haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; v) Rs is selected from the group consisting of C,¢ acyl, Ci acyloxy, C4 alkenyl, Cy alkoxy, Cs alkyl, C, alkylcarboxamide, Ca. alkynyl, Cs alkylsulfonamide, C, alkylsulfiny!, C4 alkylsulfonyl, C, alkylthio, Ci alkylureyl, amino, C, alkylamino, C,. dialkylamino, carbo-C,¢- ]

( ® alkoxy, carboxamide, carboxy, cyano, Cy. cycloalkyl, C,.¢ dialkylcarboxamide, Co. dialkylsulfonamide, halogen, C,_¢ haloalkoxy, C, haloalkyl, C, haloalkylsulfinyl, C, haloalkylsulfonyl, C,. haloalkylthio, hydroxyl, thiol, nitro and sulfonamide, wherein said C,.s alkoxy group can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C, 5 acyl, C,.s acyloxy, C, alkenyl, C,., alkoxy, C,4 alkyl, Cy, alkylamina, Cy dialkylamino, C,. alkylcarboxamide, C,¢ alkynyl, C,., alkylsulfonamide, C, alkylsulfinyl, C4 alkylsulfonyl, C,. alkylthio, C, alkylureyl, amino, carbo-C, s-alkoxy, carboxamide, carboxy, cyano,

Cs. cycloalkyl, Cy dialkylcarboxamide, halogen, C, haloalkoxy, C4 haloalkyl, C,., haloalkylsulfinyl, C4 haloalkylsulfonyl, C, haloalkylthio, hydroxyl, nitro and phenyl, and wherein said phenyl is optionally substituted with 1 to 5 halogen atoms; vi) Re is selected from the group consisting of H, C, acyl, Cis acyloxy, C, alkenyl, Cy alkoxy, C,. alkyl, Cs alkylcarboxamide, C,. alkynyl, C, alkylsulfonamide, C,, alkylsuifinyl, C,¢ alkylsulfonyl, C, 4 alkylthio, C, alkylurey), amino, C, alkylamino, C,4 dialkylamino, carbo-C, - alkoxy, carboxamide, carboxy, cyano, Cs; cycloalkyl, C,; dialkylcarboxamide, C,.4 dialkylsulfonamide, halogen, C, haloalkoxy, C,. haloalkyl, C,. haloalkylsulfinyl, C,¢ haloalkylsulfonyl, C;. haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; vii) R; and Ry are independently H or C4 alkyl; viii) XisO or§; and ix) Q is C,; alkylene optionally substituted with 1 to 4 substituents selected from the group consisting of C,.; alkyl, C, alkoxy, carboxy, cyano, C,.; haloalkyl, halogen and oxo; or Q is a bond; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment

Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

As used herein, “substituted” indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group. When a chemical group herein is “substituted” it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl! group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2,3, 4,5, 6, 0r7 substituents and the like. Likewise, “substituted with one or more substituents” refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different. ]

® ) | WO 2005/012254 PCT/US2004/023488

Compounds of the invention can also include tautomeric forms, such as keto-enol tautomers, and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate . substitution. It is understood that the various tautomeric forms are within the scope of the compounds of the present invention.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates and/or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

Itis understood and appreciated that compounds of the present invention may have one or more chiral centers, and therefore can exist as enantiomers and/or diastereomers. The invention is understood to extend to and embrace all such enantiomers, diastereomers and mixtures thereof, including but not limited, to racemates. Accordingly, some embodiments of the present invention pertain to compounds of the present invention that are R enantiomers. Further, some embodiments of the present invention pertain to compounds of the present invention that are S enantiomers. In examples where more than one chiral center is present, then, some embodiments of the present invention include compounds that 1s are RS or SR enantiomers. In further embodiments, compounds of the present invention are RR or SS enantiomers. It is understood that compounds of the present invention are intended to represent all individual enantiomers and mixtures thereof, unless stated or shown otherwise.

In some embodiments, R, is aryl or heteroaryl each optionally substituted with Rs, Ryo, Ry1, Riz,

Ris, Ry4, and Ris each selected independently from the group consisting of C, acyl, C,¢ acyloxy, Cas alkenyl, C,, alkoxy, C, alkyl, C,¢ alkylcarboxamide, C, alkynyl, C, 4 alkylsulfonamide, C, alkylsulfinyl, C, alkylsulfonyl, C 4 alkylthio, C, alkylureyl, amino, C,.c alkylamino, Cy dialkylamino, C, alkylimino, carbo-C, s-alkoxy, carboxamide, carboxy, cyano, C;_; cycloalkyl, Cy, dialkylcarboxamide, C, 4 dialkylsulfonamide, halogen, C,¢ haloalkoxy, C;¢ haloalkyl, C, haloalkylsulfinyl, C,; haloalkylsuifonyl, C 4 haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl, wherein said C, alkenyl, C,; alkyl, C4 alkynyl, C5 alkylamino, Ci alkylimino, C, 5 dialkylamino, heterocyclic, and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,s acyl, C,¢ acyloxy, C.. alkenyl, C,. alkoxy, C, alkyl,

C,. alkylcarboxamide, C, alkynyl, C,.¢ alkylsulfonamide, C,¢ alkylsulfinyl, C, alkylsulfonyl, Ci alkylthio, C, alkylureyl, amino, C,4 alkylamino, C, dialkylamino, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, Cy.; cycloalkyl, C,s dialkylcarboxamide, halogen, C,- haloalkoxy, C,. haloalkyl, C,¢ haloalkylsulfiny}, C,¢ haloalkyisulfonyl, C,, haloalkylthio, hydroxyl, thiol and nitro;

Some embodiments of the present invention pertain to compounds wherein R, is phenyl or naphthyl each optionally substituted with Re, R10, Ry, Ry2, R13, Ris, and Rs each selected independently from the group consisting of C,4 acyl, C, alkoxy, C,¢ alkyl, C, alkylsulfonyl, amino, C, 3s alkylamino, C, 4 dialkylaming, C,¢ alkylimino, carbo-C, 4-alkoxy, carboxamide, carboxy, cyano, C4 cycloalkyl, halogen, C4 haloalkoxy, C;.¢ haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent Rg, Rio, Ry, Riz, Rus, Rig, and Ry; together with the atoms to which they are attached form a i

® . ® :

Cs. cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said Cy. alkyl, Cy alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C, acyl, C, alkoxy, Cy alkyl, C,. alkylsulfonyl, amino,

Ci alkylamino, C4 dialkylamino, carboxamide, cyano, C,.; cycloalkyl, halogen, C,¢ haloalkoxy, C, haloalkyl, and hydroxyl.

Some embodiments of the present invention pertain to compounds wherein R, is phenyl optionally substituted with Rs, Rg, R}3, Ry2, and R;; each selected independently from the group consisting of C, acyl, C,, alkoxy, Cs alkyl, C,¢ alkylsulfonyl, amino, C, alkylamino, C, 4 dialkylamino, C, 4 alkylimino, carbo-C, 4-alkoxy, carboxamide, carboxy, cyano, Cs; cycloalkyl, halogen, C4 haloalkoxy, C, haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent Ry,

Rie, Ris, Riz, and Ry; together with the atoms to which they are attached form a Cs.; cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C5 alkyl, C, alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,.¢ acyl, C, alkoxy, C4 alkyl, C, alkylsulfonyl, amino, C4 alkylamino, C;5 dialkylamino, carboxamide, cyano, C;.; cycloalkyl, halogen, C,. haloalkoxy, C, haloalkyl, and hydroxyl.

Some embodiments of the present invention pertain to compounds wherein R; is phenyl or naphthyl each optionally substituted with Re, Rie, Ry, Ry2, R13, Ris, and Rs each selected independently from the group consisting of C,, acyl, C, alkoxy, C, alkyl, amino, C, alkylamino, C,4 dialkylamino, C, alkylimino, cyano, halogen, C, 4 haloalkoxy, C, haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent Rs, Ryo, Ryy, Riz, Ry3, Rus, and Rs together with the atoms to which they are attached form a Cs.; cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C4 alkyl, C4 alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of Cy alkyl, amino, C, alkylamino, C;4 dialkylamino, and hydroxyl. }

Some embodiments of the present invention pertain to compounds wherein R, is pheny! optionally substituted with Rg, Ryg, Rij, Riz, and R;; each selected independently from the group consisting of C, 4 acyl, C,. alkoxy, C, alkyl, amino, C4 alkylamino, C,.s dialkylamino, Ci alkylimino, cyano, halogen, C, 4 haloalkoxy, C, haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent Ry, Rip, Ry1, Ria, and R,; together with the atoms to which they are attached form a Cs; cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C, alkyl,

C, alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C, alkyl, amino, C;. alkylamino, C;.5 dialkylamino, and hydroxyl.

Some embodiments of the present invention pertain to compounds wherein R, is phenyl or naphthyl optionally substituted with Rs, Ryo, Rit, Riz, Ris, Ris, and Rys each selected independently from the group consisting of ~C(O)CH;, ~OCH;, —CH;, ~CH(CH;),, -CH(OH)CHj3, ~N(CH3),, (2- oo

® dimethylamino-ethy!l)-methyl-amino (i.c., -N(CH;)CH,CH,N(CH),], (3-dimethylamino-propyl)- methyl-aming {i.¢., -N(CH;)CH,CH,CH,N(CHs),], -C(=NOH)CH,, cyano, -F, —CI, -Br, —OCF;, —CF3, 4-methyl-piperazin-1-yl, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl.

Some embodiments of the present invention pertain to compounds wherein R, is phenyl optionally substituted with Ry, Ryo, Ry, Ry2, and Ry, Ry4 each selected independently from the group consisting of —-C(O)CH,, ~OCH,, ~CH;, —CH(CH,),, -CH(OH)CH,, -N(CH),, (2-dimethylamino- ethyl)-methyl-amino [i.e., -N(CH3)CH,CH, N(CH; )], (3-dimethylamino-propyl)-methyi-amino [i.e., =N(CH;)CH,CH;CH:N(CHs),], ~C(=NOH)CHj, cyano, ~F, ~Cl, -Br, ~OCF3, —CF;, 4-methyl- piperazin-1-yl, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl.

Some embodiments of the present invention pertain to compounds wherein R, is phenyl or naphthyl optionally substituted with Rg, Ryo, Ry1, Riz, Ris, Rye, and Rys each selected independently from the group consisting of ~-OCH;, —CH;, cyano, -F, —Cl, -Br, —OCF;, and —CF;.

Some embodiments of the present invention pertain to compounds wherein R, is phenyl optionally substituted with Rg, Rg, Ry1, R yz, and Ry; each selected independently from the group consisting of -OCH,, —-CH;, cyano, —F, —Cl, —Br, OCF, and —CF;.

Some embodiments of the present invention pertain to compounds wherein R, is phenyl and can be represented by the Formula shown below:

Rea

A Rs Reb . Rg Ry ro) N J N vs Ry 2 oR Rl hg wherein each variable in the above formula has the same meaning as described herein, supra and infra. In some embodiments, R; and Rg are both —H, Q is a bond, and X is O.

Some embodiments of the present invention pertain to compounds wherein R, is phenyl and can be represented by Formula (Ia) as shown below:

Reg

Ry Rs X Rg

Po N L NT Q 1X 10

Ny Py

R; Rg r, Ra R13 I R11 (Ia) 12 wherein:

Rg to R;3 substituents are each selected independently from the group consisting of H, C4 acyl, C, acyloxy, C5 alkoxy, C,.¢ alkyl, C,¢ alkylcarboxamide, C, alkylsulfonamide, C, alkylsulfinyl, C, alkylsulfonyl, C,. alkyithio, amino, C alkylamino, C. dialkylamino, carba-C,¢-alkoxy, )

® ® WO 2005/012254 PCT/US2004/023488 carboxamide, carboxy, cyano, halogen, C,¢ haloalkoxy, C4 haloalkyl, hydroxyl, nitro and phenyl, or two adjacent substituents together with the phenyl form a Cs. cycloalkyl optionally comprising 1 to 2 oxygen atoms; and wherein each said C,.4 alkyl and phenyl groups can be optionally substituted with 1 10 5 substituents selected independently from the group consisting of C, 4 alkoxy, C, alkyl, amino, cyano, halogen, C,¢ haloalkoxy, C,.s haloalkyl, hydroxy! and nitro.

In some embodiments, R, is phenyl optionally substituted with Rg to Ry; substituents selected independently from the group consisting of C,. acyl, C, alkoxy, Cs alkyl, cyano, halogen, Ci haloalkoxy, C,. haloalkyl, nitro and phenyl; and wherein said phenyl can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,.¢ alkoxy, C,4 alkyl, cyano, halogen, C,. haloalkoxy, C, haloalkyl and nitro.

In some embodiments, R, is phenyl optionally substituted with Ry to Ry; substituents selected independently from the group consisting of C,4 acyl, C,¢ alkoxy, C,. alkyl, cyano, halogen, Cs haloalkoxy, C,¢ haloalkyl, nitro and phenyl.

In some embodiments, R, is pheny! optionally substituted with Ry to R;; substituents selected independently from the group consisting of —-C(O)CH,, —C(O)CH,CH,, -C(O)CH(CHjs),, —~C(0)CH,CH,CH,, —-C(0)CH,CH(CHj),, -OCH;, —OCH,CH,, -OCH(CHj);, -OCH,CH,CH;, ~OCH,CH(CH,),, ~CHj, ~CH,CH;, —CH(CH,);, -CH,CH,CH;, -CH,CH(CH3),, —CH,CH,CH,CH;, cyano, F, Cl, Br, §, -OCF;, ~OCHF,, —-OCFH,, -OCF,CF,, -OCH,CF;, —CF;, ~CHF;, -CFH;, ~CF;CF,;, —CH,CF;, nitro and phenyl.

In some embodiments, R, is phenyl optionally substituted with Re to Ry; substituents are each selected independently from the group consisting of —C(O)CHs, -OCH;, ~CH;, ~CH(CH,),, —CH(OH)CHj3, —N(CH,),, (2-dimethylamino-ethyl)-methyl-amine, (3-dimethylamino-propyl)-methy}- amino, -C(=NOH)CH,, cyano, —F, —Cl, —Br, -OCF;, —CF,, 4-methyl-piperazin-1-y}, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl. in some embodiments, R, is pheny! optionally substituted with Rg, Ryo, Rj, Riz and Ryy substituents selected independently from the group consisting of -C(Q)CH,;, “OCHj, —CHj, cyano, -F, —Cl, —Br, “OCF;, —CF;, nitro and phenyl.

Some embodiments of the present invention pertain to compounds wherein R, is naphthyl optionally substituted with Rg Ryo Ry; Riz Riz Ry4 and Ry; substituents selected independently from the group consisting of Cy acyl, C,¢ acyloxy, Ci alkoxy, C,, alkyl, C, alkylcarboxamide, Ci alkylsulfonamide, C,.¢ alkylsulfinyl, C,; alkylsulfonyl, C, alkylthio, amino, C,¢ alkylamino, Cis dialkylamino, carbo-C 4-alkoxy, carboxamide, carboxy, cyano, halogen, C,, haloalkoxy, Cis haloalkyl, hydroxyl and nitro; and wherein said C, alkyl can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,.¢ alkoxy, C, alkyl, amino, cyano, halogen, C,¢ haloalkoxy, C,. haloalkyl, hydroxy! and nitro.

® . ' ® WO 2005/012254 PCT/US2004/023488 .

In some embodiments, R, is naphthyl optionally substituted with Ry, Rig, Ry1, Riz, Ris, Ri4 and

Rus substituents selected independently from the group consisting of C,. acyl, Cs alkoxy, C4 alkyl, cyano, halogen, C, haloalkoxy, C, haloalkyl and nitro.

In some embodiments, R, is naphthyl optionally substituted with Rg, Ry, Ry, Riz, Ris, Rye and

Ris substituents selected independently from the group consisting of -C(O)CH,, —-C(O)CH,CH;, —C(O)YCH(CH;),, -C(O)CH,CH,CH,, —C(O)CH,CH(CH,),, “OCH;, ~OCH,CH,, ~OCH(CHs),, —OCH;CH;CH;, “OCH;CH(CH,),, —CHs, ~CH,CHs, —CH(CH3},, -CH,CH,;CH,, —~CH,CH(CH,),, ~CH;CH,CH,CH, cyano, -F, ~Cl, -Br, ~I, ~OCF;, ~OCHF;, —OCFH,, ~OCF,CF;, ~OCH,CF,, -CF;, —~CHF;, -CFH,, -CF;CF,, -CH,CF; and nitro.

In some embodiments, R, is naphthyl optionally substituted with Ry, Ryo, R,, Riz, Ris, Rys and

Rs substituents selected independently from the group consisting of —~C(O)CH;, --C(O)CH,CH,, ~C(O)CH(CH;),, -C(O)CH,CH,CH,, —C(O)CH,CH(CH,),, OCH, -OCH,CH;, ~OCH(CH;),, ~OCH,CH,CH;, ~OCH,CH(CH,),, CH, —CH,CH,, —CH(CH;);, ~CH;CH,CH;, ~CH,CH(CH,),, =CH,CH,CH,CH;, cyano, -F, -Cl, -Br, -1, ~OCF;, —OCHF,, —~OCFH,, —OCF,CF;, ~OCH,CF;, —CF;, —CHF;, -~CFH,, ~CF,CF,;, —CH,CF,; and nitro.

In some embodiments, R, is naphthyl optionally substituted with Ry, Rg, Ry), Riz, Ris, Ry and

Ry; substituents selected independently from the group consisting of -C(O)CH,, ~OCH,, —CHj, cyano, —F, —CI, -Br, —~OCF;, —CF, and nitro.

Some embodiments of the present invention pertain to compounds wherein R, is heteroaryl optionally substituted with Rs, R;q, R;,, Riz, and Ry; each selected independently from the group consisting of C, acyl, Cy alkoxy, C4 alkyl, amino, C, alkylamino, Cy dialkylamino, C,¢ alkylimino, cyano, halogen, C, haloalkoxy, C; haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent Rg, Ryo, Rij, Ri, Rig, Ryu, and Rs together with the atoms to which they are attached form a Cs; cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C, 4 alkyl, Cy alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C, 4 alkyl, amino, C, alkylamino, C4 dialkylamino, and hydroxyl.

Some embodiments of the present invention pertain to compounds wherein R, is heteroaryl optionally substituted with Rs, Ry, Ry, R,2, and R; each selected independently from the group consisting of ~-C(Q)CHj;, ~OCH,, —CH;, —CH(CHa),, ~CH(OH)CH3, -N(CHj),, (2-dimethylamino- ethy!)-methyl-amino, (3-dimethylamino-propyl)-methyl-amino, -C(=NOH)CHj, cyano, -F, —Cl, -Br, -OCF;, -CF;, 4-methyl-piperazin-1-yl, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl.

Some embodiments of the present invention pertain to compounds wherein R, is heteroaryl 15 optionally substituted with Ry, Ry, R,), R,3, and R; each selected independently from the group consisting of ~OCH;, —~CH;, cyano, ~F, CI, -Br, ~OCF;, and —CF,;. .

® } , ® WO 2005/012254 PCT/US2004/023488

Some embodiments of the present invention pertain to compounds wherein R, is heteroaryl optionally substituted with Ro, Rs, Ri, Riz, and Ry; each selected independently from the group consisting of Cy acyl, C, acyloxy, C, alkoxy, Ci alkyl, C,¢ alkylcarboxamide, C, alkylsulfonamide, C, 4 alkylsulfinyl, C, alkylsulfonyl, C, alkylthio, amino, C, 4 alkylamino, C,54 dialkylamino, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, halogen, C, 4 haloalkoxy, C, haloalkyl, hydroxyl, nitro and phenyl, or two adjacent Ry, Ryo, Ry), Ry2, Rus, Rua, and Rs together with the atoms to which they are attached form a Cs , cycloalkyl group or heterocyclic group; and wherein each of said C, ¢ alkyl and phenyl groups can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,. alkoxy, Cy alkyl, amino, cyano, halogen, C,s haloalkoxy, C,.s haloalkyl, hydroxyl and nitro.

In some embodiments, R, is heteroaryl optionally substituted with Rs, Ryo, R;;, Ry; and Ry; each selected independently from the group consisting of C5 acyl, C,¢ alkoxy, C,¢ alkyl, cyano, halogen,

Ci haloalkoxy, C, ¢ haloalkyl, nitro and phenyl; and wherein said phenyl! can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C, 4 alkoxy, C,¢ alkyl, cyano, halogen, C, haloalkoxy, C, haloalkyl and nitro.

In some embodiments, R, is heteroaryl optionally substituted with Rs, Ro, R;;, Ry; and Ry; each selected independently from the group consisting of C, acyl, Cs alkoxy, C, alkyl, cyano, halogen,

Cs haloalkoxy, C, haloalkyl, nitro and phenyl.

In some embodiments, R, is heteroaryl optionally substituted with Rs, Rig, Ry;, Ry, and Rys each selected independently from the group consisting of ~C(O)CH;, —C(O)CH,CH,, —C(O)CH(CHj;),, ~C(0)CH,CH,CH,, —~C(O)CH,CH(CH;),, OCH, ~OCH,CH;, ~OCH(CH,),, ~QCH.CH,CH;, —OCH,CH(CH,),, -CH,, —CH,CH;, ~CH(CH;),, -CH,CH,CH,, —CH,CH(CH,;);, —-CH,CH,CH,CH,, cyano, ~F, —Cl, -Br, -1, —OCF;, ~-OCHF;, -OCFH,, ~OCF,CF;, ~OCH,CF,, -CF,, CHF, ~CFH,, —CF,CF;, —=CHCF,;, nitro and phenyl.

In some embodiments, R, is heteroaryl optionally substituted with Ry, Ryo, Ry, Ry, and Ry3 each selected independently from the group consisting of —C(O)CH,;, —OCH,, —CH;, cyano, -F, Cl, =Br, —OCF,, ~CF;, nitro and phenyl. In some embodiments, R, is heteroaryl optionally substituted with

Rs, Rie, Riu, Riz, and Ry; selected independently from the group consisting of H, —-C(0)CH;, -OCH;, ~CH;, cyano, ~F, —Cl, —Br, ~OCF;, ~CF;, nitro and phenyl.

In some embodiments R, is heteroaryl having 5-atoms in the aromatic ring examples of which are represented by the following formulae:

TABLE 2

Ce OF OF Co CG 0” s” nN’ AN AN

® ® = N= N= Le N= 3 Ne?

Ls Go 7 O87 UW Nb poy Mm Mmy Sg oN NS No NH NN

MN NR

NZ HNN and wherein the 5-membered heteroaryl is bonded at any available position of the ring, for example, a imidazoly! ring can be bonded at one of the ring nitrogens (i.e., imidazol-1-yl group) or at one of the ring carbons (i.c., imidazol-2-y}, imidazol-4-y! or imiadazol-5-y1 group).

In some embodiments, R, is a 6-membered heteroaryl, for example, a 6-membered heteroaryl as shown in TABLE 3:

TABLE 3

J iJ LA Ln IL NV ey zy NT? 7 3K

I SAT OP ER

~~, NT, N" and N wherein the heteroaryl group is bonded at any ring carbon. In some embodiments, R, is selected from the group consisting of pyridinyl, pyridazinyl, pyrimidiny! and pyrazinyl. In some embodiments, R, is pyridinyl.

In some embodiments R, is a heteroaryl, for example but not limited to those shown in TABLE 2 and 3, optionally substituted with | to 3 substituents selected from the group consisting of C, acyl,

Cy acyloxy, Cy, alkenyl, C, alkoxy, C4 alkyl, C, 4 alkylcarboxamide, C,4 alkynyl, C,5 alkylsulfonamide, C, 4 alkylsulfinyl, C,; alkylsulfonyl, C,. alkylthio, C,¢ alkylureyl, amino, C, atkylamino, C, dialkylamino, carbo-C, g-alkoxy, carboxamide, carboxy, cyano, C,.; cycloalkyl, C5 dialkylcarboxamide, C,.5 dialkylsulfonamide, halogen, C, haloalkoxy, C, haloalkyl, C4 haloalkylsulfinyl, Cy. haloalkylsulfonyl, C, 4 haloalky!lthio, hydroxyl, thiol, nitro, phenoxy and phenyl; and wherein each of said Cy alkenyl, C6 alkyl, C,4 alkynyl and pheny! groups can be optionally substituted with 1 to § substituents selected independently from the group consisting of C4 acyl, Cy acyloxy, Cz, alkenyl, Cy alkoxy, C, alkyl, C, ; alkylcarboxamide, Cy alkyny}, C,.¢ alkylsulfonamide, C, alkylsulfinyl, C, ¢ alkylsulfonyl, C. alkylthio, C, alkylureyl, amino, C, alkylamino, C, ¢ dialkylamino, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyana, C;; cycloalkyl, C, 4

® ®

WO 2005/012254 PCT/US2004/023488 dialkylcarboxamide, halogen, C, 5 haloalkoxy, C,_ haloalkyl, C¢ haloalkylsulfinyl, C, haloalkylsulfonyl, C, haloalkylthio, hydroxy, thiol and nitro.

Some embodiments of the present invention pertain to compounds wherein R; is H or Cy alkyl.

Some embodiments of the present invention pertain to compounds wherein R; is Cy alkyl. In some embodiments, R; is selected from the group consisting of -CH;, -CH,CH;, ~CH(CH;),, -CH;CH,CH,, ~CH,CH(CHj3), and -CH,CH.CH,CH,. In some embodiments, R, is CH; or =CH(CH),.

Some embodiments of the present invention can be represented by Formulae (Ib) and (Ic) respectively as shown below:

Re Re

Rg Rs

R3 X Rj X peel wy, pee! BR

NN, R; Rg Noh R; Rg

HiC (Ib) (Io) wherein each variable in Formulae (1b) and (Ic) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds wherein R; is H.

It is understood that when R; is H, then tautomers are possible. It is well understood and appreciated in the art that pyrazoles can exist in various tautomeric forms. Two possible tautomeric forms are illustrated below:

Rea Rea

Rs Reb H Rs Reb

Hep NEL —~—— 'Q LN ={ Rec RB Ro ) Rec Ry Re

Rq Ra Ry Rs (Id) aa”)

It is further understood that tautomeric forms can also have corresponding nomenclature for each represented tautomer, for example, Formula (Id) and Formula (Id?) can be represented by the general chemical names 1 H-pyrazol-3-yl and 2H-pyrazole-3-y! respectively. Therefore, the present invention includes all tautomers and the various nomenclature designations.

Some embodiments of the present invention pertain to compounds wherein R; is Cy alkenyl.

In some embodiments, R; is -CH,CH=CH,.

Some embodiments of the present invention pertain to compounds wherein R; is Cy alkynyl.

® ® WO 2005/012254 PCT/US2004/023488 }

Some embodiments of the present invention pertain to compounds wherein R; is Ci. cycloalkyl. In some embodiments, R; is cyclopropyl.

Some embodiments of the present invention pertain to compounds wherein R, is selected from the group consisting of H, C, alkenyl, C, alkyl, C, 4 alkylcarboxamide, C4 alkynyl, carbo-C,¢- alkoxy, carboxamide, carboxy, cyano, Cs; cycloalkyl, halogen, heteroaryl ar phenyl; and wherein each of said C4 alkenyl, C4 alkyl, C, alkynyl, heteroaryl and phenyl groups can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,.¢ alkylamino, Cz. dialkylamino, C, ¢ alkenyl, C4 alkoxy, C, alkyl, Co alkynyl, amino, halogen, C,_, haloalkoxy and hydroxyl.

In some embodiments, R; is selected from the group consisting of H, C, alkenyl, C6 alkyl, C,. 6 alkynyl, carbo-C, s-alkoxy, carboxy, cyano, Cs; cycloalkyl, halogen, heteroaryl or phenyl; and wherein each of said Cp alkenyl, C, alkyl, C,¢ alkynyl and pheny! groups can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,.¢ dialkylamino, C, ¢ alkenyl, C\ alkoxy, Cy alkynyl, halogen, C4 haloalkoxy and hydroxyl.

In some embodiments, R; is selected from the group consisting of H, -CH=CH,, -CH., —CH;CH;, ~CH(CH;),, ~CH,CH,CHj3, ~CH,CH(CH,),, -CH,CH,CH,CH;, —C=CH, -C(O)OCH,, -C(0)OCH,CH, carboxy, cyano, cyclopropyl, F, Cl, Br, 1, thiophen-2-yl, thiophen-3-yl, phenyl, —CH,CH,;N(CH;},, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, -CH=CH-C=CH, 4- fluorophenyl, 4-triflucromethoxyphenyl, ~CH,OH and —CH,CH,OH.

Some embodiments of the present invention pertain to compounds wherein R; is H or halogen.

In some embodiments, R; is H, F, Cl or Br.

Some embodiments of the present invention pertain to compounds of Formula (Ie) as shown below:

Rg

Ra Rs X ) On

R7 Rg

Ry (le) wherein each variable in Formula (Ie) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds of Formula (If) as shown below:

® . ® WO 2005/012254 PCT/US2004/023488

Resa ° Rs Reb x 2

NE) EN Na

Rec Re Re

Ry (In wherein each variable in Formula (If) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds of Formula (Ig) as shown below:

Re :

Re x 0 vo,

R7 Rg

Ry F (Ig) ‘wherein each variable in Formula (Ig) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds of Formula (1h) as shown below:

Rea

Rs Ren

Ry Is 0 0 ER,

R, P Rec R; Rg (Ih) wherein each variable in Formula (Ih) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds of Formula (Ii) as shown below:

Re

Ra Rs X

J on,

R7 Rg

Ry @] (I) wherein each variable in Formula (Ii) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds of Formula (Ij) as shown below:

® ® WO 2005/012254 PCT/US2004/023488 }

Rea

Rs Reb tr A

NE N NOR, ) { & cl Ree R; Ry th] wherein each variable in Formula (Ij) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds of Formula (Ik) as shawn below:

Re

Re x

VR

Ry Rg

Ri Br

Ik) wherein each variable in Formula (Ik) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds of Formula (Ik’) as shown below:

Rea

Rs

Ry 1 ] © yw

R, ar Ree R;, Ry (Ik) wherein each variable in Formula (1k’) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds wherein Ry is selected from the group consisting of H, C, alkyl and C, haloalkyl.

In some embodiments, R, is selected from the group consisting of H, -CH,, ~CH,CHs, —CH(CHy),, -CH,CH,CH,, ~CH,CH(CH,),, -CH;CH,CH,CHs, —CF,, —CHF,, ~CFH,, ~CF,CF, and —CH,CF;.

In some embodiments, R is selected from the group consisting of H or —CF;.

Some embodiments of the present invention can be represented by Formulae (Im) and (In) as shown below:

®

Re Re

Ry x Re" x y Sa ILY or

R; Rj Ry Rg

Rs FaC R3 (lm) (In) wherein each variable in Formulae (Im) and (In) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention can be represented by Formulae (Io) and (fo’) as shown below:

Rea Rea . Rs Reb . Rs Reb 2 2

NE) Pog NE) Wong

Rec Ry Ry Ree Ry, Rg

Rj F3C Ra (lo) To") wherein each variable in Formulae (Ro) and (Io’) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds wherein R; is selected from the group consisting of C, 4 alkoxy, C, alkylthio, amino, C,¢ alkylamino, C,, dialkylamino, halogen,

C,, haloalkoxy, and hydroxyl, wherein said C4 alkoxy group can be optionally substituted with I to 5 substituents selected independently from the group consisting of amino, C,. alkylamino, Ca dialkylamino, amino, carbo-C,.¢-alkoxy, carboxamide, carboxy, cyano, halogen, and phenyl, and wherein said amino and phenyl are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and carbo-C,s-alkoxy.

Some embodiments of the present invention pertain to compounds wherein Rs is C, alkoxy, or hydroxyl, wherein said C4 alkoxy group can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C4 alkoxy, C, alkylamino, C4 dialkylamino, alkylsulfinyl, C, alkylsuifonyl, C,4 alkylthio, amino, halogen, C, haloalkoxy, C, haloalkyl, C, haloalkylsulfinyl, C, haloalkylsulfonyl, C,4 haloalkylthio, hydroxy! and phenyl, and wherein said phenyl is optionally substituted with 1 to 5 halogen atoms.

Some embodiments of the present invention pertain to compounds wherein Rs is selected from the group consisting of C, 4 alkoxy, C,. haloalkoxy, and hydroxyl, wherein said C, alkoxy group can be optionally substituted with | to 5 substituents selected independently from the group consisting of amino, C, 5 dialkylamino, carboxy, and phenyl, and wherein said amino and phenyl are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and carbo-C,.¢- alkoxy. .

In some embodiments, Rs is C4 alkoxy, or hydroxyl, and wherein said Cs alkoxy group can be optionally substituted with | to 5 substituents selected independently from the group consisting of

C4 alkoxy, C, alkylamino, C,. dialkylamino, amino, C,4 haloalkoxy, hydroxyl and phenyl), wherein said phenyl is optionally substituted with 1 to 5 halogen atoms.

Some embodiments of the present invention pertain to compounds wherein Rj is selected from the group consisting of ~OCH,, -OCH,CH,, —OCH(CHj;),, -OCEF;, hydroxyl, benzyloxy, 4-chloro- benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy [i.e., -OCH.CH,N(CHj;),], 3-dimethylamino- propoxy [i.e., -OCH,CH,CH;N(CHjs),), carboxymethoxy [i.e., “OCHC(O)OH], and 2-tert- butoxycarbonylamino-ethoxy [i.e., —~OCH,CH,NHC(O)OC(CHs,);).

In some embodiments, R; is selected from the group consisting of ~OCH,, “OCH,CHj, —OCH(CHjs),, —~OCH,CH,CH;, -OCH,CH(CHj),, hydroxyl, -OCH,CH,OH, ~OCH,CH,0CHs, =OCH,CH,0CH.CHj;, -OCH,CH,OCH(CH,),, ~-OCH,CH,0CH,CH,CH,, —OCH;CH;O0CH;CH(CH,),;, -OCH,CH;NH,, “OCH,CH,NHCH,, -OCH,CH;N(CH;);, -0CH,CH,0CF;, ~OCH,;CH,0CHF,, -OCH,CH,0CFH,, ~OCH,CHs, ~-OCH,CH,C Hs, ~OCH,C¢H;-0-Cl, ~OCH,CgH;-m-Cl and ~OCH,C¢H;-p-Cl.

In some embodiments, Rs is selected from the group consisting of ~OCH;, ~OCH,CH,, ~OCH(CH;),, hydroxyl, ~OCH,CH,N(CH,},, “OCH,C¢H;, ~OCH,CH,CsH; and —OCH,CsHs-p-Cl.

In some embodiments, R; is -OCHj.

Some embodiments of the present invention pertains to compounds wherein Rg is selected from the group consisting of H, C, alkoxy, carbo-C,¢-alkoxy, carboxamide, carboxy, cyano, halogen and hydroxyl.

In some embodiments, R; is H.

Some embodiments of the present invention pertain to compounds wherein Re, Reb, and Ry are each independently selected from the group consisting of H, C, alkoxy, C, alkyl, amino, C, alkylamino, C, dialkylamino, cyano, halogen, C,¢ haloalkoxy, C, 4 haloalkyl, hydroxyl, and nitro.

Some embodiments of the present invention pertain to compounds wherein R,, Rg, and Ry, are each independently selected from the group consisting of H, ~OCHj3, ~CH;, —~N(CHs),, cyano, ~F, —Cl, -Br, “OCF, hydroxyl, and nitro.

Some embodiments of the present invention pertain to compounds wherein Rg,, Re, and Re are each independently selected from the group consisting of H, C, alkoxy, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, halogen and hydroxyl.

Some embodiments of the present invention pertain to compounds wherein Rg,, Rg, and Re are all H.

Some embodiments of the present invention pertain to compounds wherein Rs is C, alkoxy and Rg,, Rg, and Re, are all H.

In some embodiments, Rs is OCH, oo

® ® WO 2005/012254 PCT/US2004/023488 !

Some embodiments of the present invention pertain to compounds represented by Formula (Ip) as shown below:

H,3CO. x

R; } 2A oy

R7 Rg

Re @ (1p) wherein each variable in Formula (Ip) has the same meaning as described herein, supra and infra. In some embodiments, compounds of the present invention have Formula (Ip) and Q is a bond.

Some embodiments of the present invention pertain to compounds represented by Formula (Iq) : as shown below:

Rea . H3CO. Rep x 2

Roe Ry Ry

Rq Rj (19) wherein each variable in Formula (Iq) has the same meaning as described herein, supra and infra. In some embodiments, compounds of the present invention have Formula (Iq) and Q is a bond.

Some embodiments of the present invention pertain to compounds wherein Rz is Hor C4 alkyl.

In some embodiments, R, is selected from the group consisting of H, ~CHj, —CH,CH;, —CH(CHj),, —CH,CH,CHj;, -CH,CH(CH;), and —CH,CH,CH,CH;.

In some embodiments, R; is H.

Some embodiments of the present invention pertain to compounds wherein Rg is H or Cs alkyl.

In some embodiments, Ry is selected from the group consisting of H, -CHs, —CH,CH,, ~CH(CHj;),, ~-CH,CH,CHj,, ~CH.CH(CH,), and -CH,CH.CH,CH;.

In some embodiments, Ry is H.

Some embodiments of the present invention pertain to compounds wherein both R; and Ry are

H.

Some embodiments of the present invention pertain to compounds represented by Formula (Ir) as shown below:

® ® WO 2005/012254 PCT/US2004/023488

Re a x

NY EN ~0\ \ J RNR

Ra Ry (Ir) wherein each variable in Formula (Ir) has the same meaning as described herein, supra and infra. “

Some embodiments of the present invention pertain to compounds represented by Formula (Is) as shown below:

Rea

Rs

Re 1 "O Nw

Rec

Rs Rj (Is) ~ wherein each variable in Formula (Is) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention pertain to compounds wherein X is O (i.e., oxygen).

Some embodiments of the present invention pertain to compounds wherein X is S (i.e., sutur).

Some embodiments of the present invention pertain to compounds wherein Q is C, ; alkylene optionally substituted with C,; alkyl, C,.; haloalkyl, halogen and oxo.

Some embodiments of the present invention pertain to compounds wherein Q is a C, ; alkylene optionally substituted with oxo. As used herein, oxo refers to a double bonded oxygen. In some embodiments, Q is —C(O)- (i.¢., a carbonyl).

In some embodiments, Q is —-CH,—.

Some embodiments of the present invention pertain to compounds wherein Q is a bond.

Some embodiments of the present invention can be represented by Formula (It) as shown below: ) Re i x

NT NL

\ J I ]

R7 Rg

Ry Ri

Ie wherein each variable in Formula (It) has the same meaning as described herein, supra and infra.

Some embodiments of the present invention can be represented by Formula (Tu) as shown below:

Rea

Rs Res

Ro ’ i N

R

NO 4 1

Ree R

R, Rs 7 Rs (Tu) wherein each variable in Formula (Iu) has the same meaning as described herein, supra and infra.

In some embodiments, R, is phenyl and can be represented by Formula (Iv) as shown below:

Rg Rio

R

Re 5 X Re Ryy oN J

N

\ J rN Riz

R; Rs Rg

Re Rs

Iv) wherein each variable in Formula (Iv) has the same meaning as described herein, supra and infra. In some embodiments, R, and R, are both H. In some embodiments, X is O (i.e., oxygen).

In some embodiments, R, is pheny! and can be represented by Formula (Iw) as shown below:

Rea Rio

R i. 5 Reb x Rg Ry

AN A

NO L oo Riz

R; Rs Rpg

Ry Ra (Iw) wherein each variable in Formula (Iw) has the same meaning as described herein, supra and infra. In some embodiments, R, and R, are both H. In some embodiments, X is O (i.e, oxygen).

Some embodiments of the present invention pertain to compounds of Formula (IIa): : Rea

Rs Re . fi b X

N Q

N ) No “Rq

I

Rec R, Rg

R4 Rj (Ia) wherein:

R, is phenyl or naphthyl optionally substituted with Rg, Rio, R11, Riz, Ria, R,s, and Rs each selected independently from the group consisting of C, acyl, Cs alkoxy, C4 alkyl, amino, C4 alkylamino, C,4 dialkylamino, Cy alkylimino, cyano, halogen, C, haloalkoxy, Ci haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent Rs, Rie, Rup Riz, Rig, Ryg, and Rs together

® ® WO 2005/012254 PCT/US2004/023488 with the atoms to which they are attached form a Cs.; cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C, alkyl, C,. alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,.¢ alkyl, amine, C, 4 alkylamino, C,.s dialkylamino, and hydroxyl;

R; is C4 alkyl;

R; is H or halogen;

Ry is selected from the group consisting of H, C,.¢ alkyl and C, ¢ haloalkyl;

R; is selected from the group consisting of C.¢ alkoxy, C, haloalkoxy, and hydroxyl, wherein said C, alkoxy group can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of amino, C,.s dialkylamino, carboxy, and phenyl, and wherein said amino and phenyl are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and carbo-C,g-alkoxy;

Rea, Re, and R,, are each independently selected from the group consisting of H, C, 4 alkoxy,

Ci alkyl, amino, C,¢ alkylamino, C,.¢ dialkylamino, cyano, halogen, C, haloalkoxy, C,¢ haloalkyl, hydroxyl, and nitro

R, and R, are both H;

X is O; and

Q is a bond.

Some embodiments of the present invention pertain to compounds of Formula (Ifa):

Rea

R; Rs Reb

NY ) Ng,

Rec Ry, Rg

Ry Ry (IIa) , wherein:

R, is phenyl or naphthyl optionally substituted with Ry, Ryo, Ry, Ria, Ris, Ris, and Rs each selected independently from the group consisting of -C(O)CH;, —OCH,, -CHs, ~CH(CH3),, -CH(OH)CH,, —-N(CH;),, (2-dimethylamino-ethyl}-methyl-amino, (3-dimethylamino- propyl)-methyl-amine, ~C(=NOH)CH,, cyano, -F, —Cl, -Br, -OCF;, ~CF,, 4-methyl-piperazin-1-yl, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl;

Rs is ~CH; or ~CH(CHs);

Ry is H,F, Cl, or Br;

Ry is —H, or -CF;;

®

Rs is selected from the group consisting of -QCH,, ~OCH,CH,, ~OCH(CH;),, -OCF;, hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3-dimethylamino- propoxy, carboxymethoxy, and 2-fert-butoxycarbonylamino-ethoxy;

Rea, Ray, and Re, are each independently selected from the group consisting of H, -OCHj, ~CH3, -N(CH},),, cyano, —F, —Cl, ~Br, OCF, hydroxy}, and nitro;

Ry and Rg are both H;

X is O; and

Q is a bond. .

Some embodiments of the present invention pertain to compounds of Formula (Ila):

Rea

Re Rs Reb x

N N ) LN

Rec Ry Re

Ry Ry : (a) wherein:

R, is phenyl optionally substituted with Rs, Rg, Rj, Ri2, and Ry; each selected independently from the group consisting of -C(O)CH,, ~OCH,, —CHj3, -CH(CHj3),, -CH(OH)CH;, ~N(CH;),, (2- dimethylamino-ethyl)-methyl-amino, (3-dimethylamino-propyl)-methyl-amino, -C(=NOH)CH;, cyano, -F, ~Cl, Br, —OCF;, —CF;, 4-methyl-piperazin-1-yl, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl;

R, is CH; or —CH(CHj;),;

R; is -H, -F, -Cl, or -Br; ’ Ry is -H, or CF;

Rs is selected from the group consisting of ~OCH;, -OCH,CH,, -OCH(CH;),, “OCF, hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3-dimethylamino- propoxy, carboxymethoxy, and 2-fert-butoxycarbonylamino-ethoxy;

Rea, Rep, 3nd Ry. are each independently selected from the group consisting of -H, -OCH;, —CHj, —~N(CH;),, cyano, F, Cl, Br, -OCF;, hydroxyl, and nitro;

R; and Ry are both H; ] X is QO; and

Q is a bond.

Some embodiments of the present invention pertain to compounds of Formula (Ila):

® ® WO 2005/012254 PCT/US2004/023488

Rea

Ra Rs Reb x

NT J oN,

Rec R; Ry

Re Rs (Ia) wherein:

R, is phenyl optionally substituted with Rs, Ryo, Ry, Rs, and Ry; each selected independently from the group consisting of ~C(O)CHs, ~OCH,, -CH, —CH(CHj3);, —N(CHs),, cyano, ~F, -Cl, -Br, —QCF;, —CF;, hydroxyl, and nitro;

R; is —-CHj;

R; is -H, -F, -Cl, or -Br;

Ry is -H; ) R; is selected from the group consisting of ~OCH;, ~0CH;CH;, ~OCH(CH.),, “OCF, hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3-dimethylamino- propoxy, carboxymethoxy, and 2-terr-butoxycarbonylamino-ethoxy;

Rg., Reb, and Ry, are each -H;

R; and Rg are both —H;

X is O; and

Q is a bond.

Some embodiments of the present invention include compounds illustrated in TABLE A as shown below:

TABLE A

Mi J ry © 1-[3{4-Bromo-2-methyl-2H- yo) NN pyrazol-3-yli)-4-methoxy-phenyl}-3-

N" Note (4-chloro-phenyl)-urea

Be Ji Lr F 1-[3-(4-Bromo-2-methyl-2H- yo HI pyrazol-3-yl}-4-methoxy-phenyl]-3-

Ne (4-fluoro-phenyl)-urea a II

MeO cl

Br bi iq) 1-{3-(4-Bromo-2-methyl-2H- = NH pyrazol-3-yl)-4-methoxy-phenyl}-3-

NN al “Me (2,4-dichloro-phenyl)-urea

MeO. OMe

Br J Zr I-{3-(4-Bromo-2-methyl-2H- 4 I NN pyrazol-3-yl)-4-methoxy-phenyl]-3-

Ne (4-methoxy-phenyl)-urea

MeO B

Br 1 £r ‘ 1-{3-(4-Bromo-2-methyl-2H- { J NN pyrazol-3-yl)-4-methoxy-phenyl}-3-

N" me (4-bromo-phenyl)-urea

MeO cl 8 1 Lx 1-[3{4-Bromo-2-methyl-2H-

Cs NH CF, pyrazol-3-yl)-4-methoxy-phenyl}-3-

Ne (4-chloro-3-trifluoromethyl- phenyl)-urea

F

7 MeO o 1-[3-(4-Bromo-2-methyl-2H- y Bo J ; pyrazol-3-yl)-4-methoxy-phenyl]-3-

NN H H (3,5-difluoro-phenyl)-urea “Me

MeO F

Br Ji eq I-[3-(4-Bromo-2-methyl-2H-

CS Ni I pyrazol-3-yl)-4-methoxy-phenyl]-3-

Note (2,4-difluoro-phenyl)-urea

MeO ci

Br I oy 1-[3{4-Bromo-2-methyk-2H-

CS NH I pyrazol-3-yl)-4-methoxy-phenyl]-3-

NNoe } (4-chloro-2-trifluoromethyl- phenyl)-urea

9 WO 2005012254 PCT/US2004/023488

MeO F

Br bt Lx 1-[3«(4-Bromo-2-methyl-2H-

CS HN F pyrazol-3-yl)-4-methoxy-phenyl]-3-

Nove (3,4-difluoro-phenyl)-urea

MeO,

Br J JQ 1-[3-(4-Bromo-2-methyl-2H-

CS NH CFa pyrazol-3-yl)}-4-methoxy-phenyl]-3-

NN (3-trifluocromethyl-phenyl)-urea

MeO CF

Br Ji Lr : 1-34-Bromo-2-methy}-2H-

CS NB pyrazol-3-yl)-4-methoxy-phenyl]-3-

Ne (4-trifluoromethyl-phenyl)-urea

CF

MeO. i 143,5-Bis-trifluoromethyl-phenyl)-

[0] 8 J 3-{34(4-bromo-2-methyl-2H-

Sy N N CF

NN H pyrazol-3-yl)-4-methoxy-phenyl]-

Me urea

Br Meo 1 1-[3{(4-Bromo-2-methyl-2H-

CS NN pyrazol-3-y1)-4-methoxy-phenyl]-3-

Ne naphthalen-2-yl-urea

Br Meo Jt 2 1-[3-(4-Bromo-2-methyl-2H- ( NN NO, pyrazol-3-y1)-4-methoxy-phenyl}-3-

N “Mone (3-nitro-phenyl)-urea

F

8c MeO 1 Lx 1-[3-(4-Bromo-2-methyl-2H-

CS NN NO, pyrazol-3-yl)}-4-methoxy-phenyl]-3-

NT Mme {(4-fluoro-3-nitro-phenyl)-urea

12254 PCT/US2004/023488

MeD 17 Br J qe 1-(3-Acetyl-phenyl)-3-[3-(4-bromo-

Me { I hI ! 2-methyl-2H-pyrazol-3-y}-4-

Ne methoxy-phenyl]-urea

MeO

Br 1 jg 1-{3<(4-Bromo-2-methyl-2H- 4 oT NN F pyrazol-3-yl)-4-methoxy-phenyl]-3-

N" me (3-fluoro-phenyl)-urea

MeO. OCF,

Br Ji ir 1-[3-(4-Bromo-2-methyl-2H- { 7 NN pyrazol-3-yl)-4-methoxy-phenyl}-3-

N" me (4-trifluoromethoxy-phenyl)-urea

MeO.

Br 1 JQ {-[3-(4-Bromo-2-methy}-2H- { NH ct pyrazol-3-yl)-4-methoxy-phenyl}-3-

N" me (3-chloro-phenyl)-urea

MeO

Br J JQ {-[3<4-Bromo-2-methy!-2H-

CS NH CN pyrazol-3 -yl)-4-methoxy-phenyl}-3- -N

Mme (3-cyano-phenyl)-urea

MeO 22 Br 1 4g 1-Bipheny!-2-yl-3-[3-(4-bromo-2-

CS NN methyl-2H-pyrazol-3-yI}-4- -N

N" me C] methoxy-phenylj-urea

MeO o 1-[3-(4-Bromo-2-methyl-2H-

Br 5, A, pyrazol-3-yl)-4-methoxy-phenyl]-3-

LR H (4-isopropyl-phenyl)-urea

® WO 2005, 1012254 PCT/US2004/023488

I I

MeO. or 3 4g 1-{3-(4-Bromo-2-methyl-2H-

CS NN ) pyrazol-3-yl}-4-methoxy-phenyl}-3- ~N ,

N"" me naphthalen-1-yl-urea

MeO

Br 1 Q 1-[3-(4-Bromo-2-methyl-2H-

CS NH pyrazol-3-yl)-4-methoxy-phenyl]-3- ~N F

Ne (2-fluoro-phenyl)-urea

MeO cl cl bi Zr 1-[3-(4-Chloro-2-methyl-2H-

CS HE pyrazol-3-yl)-4-methoxy-phenyl]-3-

Ne (4-chloro-phenyl)-urea

MeO cl 27 £ 1 Lr 1-(4Chloro-phenyl)-3-[3-(4-fluoro-

CS NN 2-methyl-2H-pyrazol-3-yl)}-4-

NN methoxy-phenyl]-urea

MeO. F 28 cl 5 Ly 1-[3<4-Chloro-2-methyl-2H-

CS NH pyrazol-3-yl)-4-methoxy-phenyi]-3-

N Note (4-fluoro-phenyl)-urea

MeO F cl 1 1-[3-(4-Chloro-2-methyl-2H-

ES NON I pyrazol-3-yl)-4-methoxy-phenyl]-3-

N" Mute (2.4-difluoro-phenyl)-urea

MeO. cl 1 Zu I-[3<(4-Chloro-2-methyl-2H-

CS NH OMe pyrazol-3-yl)-4-methoxy-phenyl]-3-

N Move (3-methoxy-phenyl)-urea

8 WO 2005/012254

PCT/US2004/023488

ES

MeO F .

F 1 Lr 1-[3<(4-Fluoro-2-methyl-2H-

CT Non pyrazol-3 -yl)-4-methoxy-phenyl]}-3-

N" me {4-fluoro-phenyl)-urea

MeO F .

F 3 x 13 4-Difluoro-phenyl)-3-{3-(4-

CS NN F fluoro-2-methyl-2H-pyrazol-3-yl)- ~N

Nome 4-methoxy-phenyl}-urea

MeO £ Jt 21 1-[3<4-Fluoro-2-methyl-2H- { NN F pyrazol-3-yt)-4 -methoxy-phenyl}-3-

MN" me (3-fluoro-phenyl)-urea

MeO. a 1 Ig 1-[3-(4-Chloro-2-methyl-2H-

CT NN I. pyrazol-3-yl)-4-methoxy-phenyl}-3-

Ne ? (2-trifluoromethoxy-phenyl)-urea

MeO ol a ee 1 ~(3-Acetyl-phenyl)-3-[3-(4-chloro- v

CS NON © 2-methyl-2H-pyrazol-3-yl)-4- - 0

N Nee methoxy-phenyl]-urea

MeO. a Jit 2 1-[3-(4-Chloro-2-methyl-2H-

CS NN F pyrazol-3 -yl)-4-methoxy-phenyl]-3-

N"Nopre (3-fluoro-phenyl)-urea

MeO F 37 fo 5 ig 1(2,4-Difluoro-phenyl)-3-[3-(4-

CS NN fluoro-2-methyl-2H-pyrazol-3-yl)- - F

N Nove 4-methoxy-phenyl]-urea

Kc

MeO. to} 18 Br 1 Ly 1-[3-(4-Bromo-2-methyl-5-

Fae—S NN trifluoromethyl-2H-pyrazol-3-yl)-4-

NN methoxy-phenyl}-3-(4-chloro- phenyl)-urea

MeO. F

Br J Lr 1-[3-4-Bromo-2-methyl-5-

Xa NN trifluoromethyl-2H-pyrazol-3-yl)-4-

NN methoxy-phenyl}-3-(4-fluoro- phenyl)-urea

F ae 8 Ly 1-[3(4-Chloro-2-methyl-5-

Fic CS N N trifluoromethyl-2H-pyrazol-3-y1)-4-

NN methoxy-phenyl}-3-(4-fluoro- pheny!l)-urea

MeO a al 5 ry 1-[3-(4-Chloro-2-methyl-5-

FiC CS N N trifluoromethyl-2H-pyrazol-3-yl}-4-

NN methoxy-phenyl}-3-(4-chloro- phenyl)-urea cl 2 MeO 5 Lr 1-(4-Chloro-phenyl)-3-{4-methoxy-

Foo NN 3-(2-methyl-5-trifluoromethyl-2H-

NN pyrazol-3-yl)-phenylj-urea

Cl

MeO 1 j $l 1-(4-Chloro-phenyl)-3-[3-(2-

CS N N isopropyl-2H-pyrazol-3-yl)-4- “N methoxy-phenyl]-urea

F

MeO 5 ir 1-(4-Fluoro-phenyl)-3-[3-(2- © NN isopropyl-2H-pyrazol-3-yl)-4- "N methoxy-phenyl]}-urea

PCT/US2004/023488

El I A Ic

MeO cl } cl 1 2 1-{3-(4-Chloro-2-isopropy}-2H-

CY NH pyrazol-3-yl)-4-methoxy-phenyl}-3- . —N

N T (4-chloro-phenyl)-urea

MeO. F 3 Lx 143,4-Difluoro-phenyl)-3-[3-(2-

CS NH F isopropyl-2H-pyrazol-3-yl)-4- ~-N

N T methoxy-phenyl}-urea

MeO F 47 Ji Lx 13-Chloro-4-fluoro-phenyl)-3-{3-

CS NN a (2-isopropyl-2H-pyrazol-3-yl)-4- : -N

N 7 methoxy-phenyl]-urea

MeO. CFs . 0 1-(2-Chloro-4-trifluoromethyl-

CS NN phenyl)-3-[3-(2-isopropyl-2H- ~N Cl

N T pyrazol-3-yl)-4-methoxy-phenyl]- urea

MeO cl .

Br 1 ry 1-[3-(4-Bromo-2-isopropyl-2H-

CS NH pyrazol-3-yl)-4-methoxy-phenyl}-3- -N

N 7 (4-chloro-phenyl)-urea {

MeO F

Br Jie ZY 1-[3-(4-Bromo-2-isopropyl-2H-

CS NN pyrazol-3-yl)-4-methoxy-phenyl]-3- -N

N 7 (4-fluoro-phenyl)-urea

MeO F

Br Jil LX 1-[3<4-Bromo-2-isopropyl-2H-

CS NOH F pyrazol-3-yl)-4-methoxy-phenyl}-3- -N

N 7 (3,4-difluoro-phenyl)-urea

® WO 20 05/012254 PCT/US2004/023488

St

MeO F

Br 1 LX 1-{3+(4-Bromo-2-isopropyl-2H- { I NH a pyrazol-3-yl)-4-methoxy-phenyl]-3-

NT T (3-chloro-4-fluoro-phenyl)-urea

MeO. 0 CF3 :

Br I ig 1-[3<(4-Bromo-2-isopropyl-2H- 4 NN I pyrazol-3-yl)-4-methoxy-phenyl}-3-

NT TY (2-Chloro-4-trifluoromethyl- phenyl)-urea

MeO F a J Lr 1{3-(4-Chloro-2-isopropyl-2H- $ I Noi pyrazol-3-yl)-4-methoxy-phenyl]-3- nN” T {4-fluoro-phenyl)-urea

MeO F al J Lx 1-[3-(4-Chloro-2-isopropyl-2H- ( HE] F pyrazol-3-yl)-4-methoxy-phenyl]-3-

N” 7 (3,4-difluoro-phenyl}-urea

MeO. F cl Js LX 1 «3-Chloro-4-fluoro-phenyl)-3-[3-

CS Na cl (4-Chloro-2-isopropyl-2H-pyrazol- -N

N T 3-yl)-4-methoxy-phenyl]-urea

MeO CF3 . 57 cl Js igs I-[3-(4-Chloro-2-isopropyl-2H-

CS NN I pyrazol-3-yl)-4-methoxy-phenyl}-3- "MN (2-Chloro-4-triflucromethyl- phenyl)-urea

HO Cl

Br J zr 1-[3-(4-Bromo-2-methy}-2H-

CS NA pyrazol-3-yl)-4-hydroxy-phenyl]-3-

NNe (4-chloro-phenyl)-urea h¢ a 1-[3{(4-Bromo-2-methyl-2H-

Br 1 Lr pyrazol-3-yl}-4-isopropoxy- = HI phenyl]-3-(4-chloro-phenyl)-urea

N-N

N “Me he ] 1-[3<(4-Bromo-2-methyl-2H-

Br 1 Zr pyrazol-3-yl)-4-isopropoxy- < 3 NN phenyl]-34-fluoro-phenyl)-urea

N “Me

GN 1-[4-Benzyloxy-3-(4-bromo-2-

J a methyl-2H-pyrazol-3-yl)}-phenyl]-3-

Br 1 Ly (4-chloro-phenyl)-urea = N N - M H

N “Me

GN 1-{4-Benzyloxy-3-(4-bromo-2- 4 . methyl-2H-pyrazol-3-yl)-phenyl]-3-

Br Je Lr (4-fluoro-phenyl)-urea

ES NN

NY H

NN

Ci 1-[3-(4-Bromo-2-methyl-2H- pyrazol-3-yl)-4-(4-chloro- lo} cl er I Lr benzyloxy)-phenyl}-3-(4-chloro-

CS NN phenyl)-urea

N-N.

Me

® WO 2005/012254 . PCT/US2004/023488

KE I SY cl

JON 1-[3-(4-Bromo-2-methyl-2H- . pyrazol-3-yl)-4-(4-chloro- o 8 Is Lr benzyloxy)-phenyl}-3-(4-fluoro-

CT hI phenyl)-urea nN” "Me

CM) . 1-[3-(4-Bromo-2-methyl-2H- 8¢ x1 Ir pyrazol-3-yl)-4-phenethyloxy-

Sl NN phenyl}-3-(4-fluoro-phenyl)-urea

NN

CN) N 1-{3<4-Bromo-2-methyl-2H- 8r 0 Lr pyrazol-3-yl)-4-phenethyloxy- 4 ol NON phenyl}-3-(4-chloro-pheny!)-urea ' N ‘Me 67 hl . 1-{3(4-Bromo-2-methyl-2H- er I pyrazol-3-yl)-4-ethoxy-phenyl]-3-

Ay § J NB (4-chloro-pheny!)-urea

Nome hl ; 1-{3-(4-Bromo-2-methyl-2H-

Br )3 Lr pyrazol-3-yl)-4-ethoxy-phenyl}-3-

A NH (4-fluoro-phenyl}-urea

NN

Me. .Me

N 1-[3-(4-Bromo-2-methyl-2H-

N a pyrazol-3-yl)-4-(2-dimethylamino- o

Br bi Lr ethoxy)-phenyl]-3-(4-chloro-

CS NH phenyl)-urea -~N

NN

2005/012254 PCT/US2004/023488 se [Smee

Me. .Me 70 N 1-[3-(4-Bromo-2-methy}-2H-

N pyrazol-3 -yl}-4-(2-dimethylamino-

F

Br 1 Lr ethoxy)-phenyt}-3-(4-fluore- & IY phenyl)-urea nN.

Me

MeO. [ol] 7 Br i ry 1-(3-(4-Bromo-2-methyl-2H- 4 NB pyrazol-3-yl}-4 -methoxy-phenyl]-3-

N"" Me (4-chloro-pheny!)-thiourea

MeO mn Br 1 JQ 1-[3<4-Bromo-2-methyl-2H-

CS NN OMe pyrazol-3-yl)-4-methoxy-phenyl]-3- -~N !

Ne (3-methoxy-phenyl)-urea

MeO 3 8r Je Q 1-Benzoyl-3-[3-(4-bromo-2-methyl- { N 9 2H-pyrazol-3-yl)-4-methoxy-

Ne phenyl]-urea

MeO 74 er 1 {-Benzyl-3-{3-(4-bromo-2-methyl- { ~ N OC 2H-pyrazol-3-yl)-4-methoxy-

Ne phenyi]-urea

MeO ci 75 1 Ly 1-(4-Chloro-phenyl)-3-[4-methoxy- { pi NN 3 -(2-methyl-2H-pyrazol-3-Y1)-

Ne phenyl}-urea 76 MeO o 1-[3 -(4-Chloro-2-methyl-2H- cl

Se PN N pyrazol-3-yl)-4-methoxy-phenyl]-3-

NN. HH (4-isopropyl-phenyl)-urea

Me

MeO ca 77 a J LF 1-[3<(4-Chloro-2-methyl-2H- = HI pyrazol-3-yl)}-4-methoxy-phenyl]-3-

NN a “Me (2,4-dichloro-phenyl)-urea

MeO 78 a 5 Cd 1-{3{4-Chloro-2-methyl-2H- 1 Di NN $ pyrazol-3-yl)-4-methoxy-phenyl}-3-

Nome naphthalen-1-yl-urea

MeO a 79 cl Jil r 1-(3-(4-Chloro-2-methyl-2H-

CS NN pyrazol-3-y})-4-methoxy-phenyl}-3- ~N CF,

N" ne } (4-chloro-2-trifluoromethyl- phenyl)-urea

MeO CF cl I Lr 1-[3-(4-Chloro-2-methyl-2H-

CS Nd pyrazol-3-yl)}-4-methoxy-phenyi}-3-

N"Noe (4-trifluoromethyl-phenyl)-urea

MeO B a bt zr ' 1-(4-Bromo-phenyl)-3-[3<4-chloro- { I NR 2-methyl-2H-pyrazol-3-yl)-4-

NT me methoxy-phenyl]-urea

CF

82 MeO . ’ 1-(3,5-Bis-trifluoromethyl-phenyl)- “ Je 3-(3-(4-chlora-2-methyl-2H-

SN NTN CFs \-N H H pyrazol-3-yl)-4-methoxy-phenyt]-

Me urea

MeO 83 F 3 JQ 1-(3-Chloro-phenyl)-3-[3-(4-fluoro-

CS NA ci 2-methy!-2H-pyrazol-3-y1)-4-

NM re methoxy-phenyl]-urea

S85

2254 PCT/US2004/023488 ’ al Ei

MeO. cl

F Ji Lx 1<(4-Chloro-3-trifluoromethyl- { T HE CFs pheny!)-3-[3-(4-fluoro-2-methyl- : Ne 2H-pyrazol-3-yl)}-4-methoxy- phenyl]-urea

MeO. Br £ J Zr 1-(4-Bromo-phenyl)-3-{3(4-fluoro- 4 T NN 2-methyl-2H-pyrazol-3-yl)-4-

N" Me methoxy-phenyl}-urea

MeO. CF,

F i r 1-{3-(4-Fluaro-2-methy}-2H-

CS NON pyrazol-3-yl)-4-methoxy-phenyl]-3- -N. . .

Ne (4-trifluoromethyl-phenyl)-thiourea

MeO. OMe 87 F J Lr 1-[3-(4-Fluoro-2-methyl-2H-

CS NN pyrazol-3-yl)-4-methoxy-phenyl}-3- ~N

N" me (4-methoxy-phenyl)-urea

MeO 88 F id Iq 1{3-Acetyl-phenyl)-3-[3-(4-fluoro- mM & HE I © 2-methyl-2H-pyrazol-3-yl)-4- -N

N" me methoxy-phenyl}-urea

MeO CFs

F 1 ry 1-{3<4-Fluoro-2-methy}-2H-

CS Noi pyrazol-3-yl)-4-methoxy-phenyl}-3- ~N

Ne (4-trifluoromethyl-phenyl)-urea

MeO.

F Ji 2 1-[3-(4-Fluoro-2-methyl-2H- ( Bi N i CFy pyrazol-3-yl)-4-methoxy-phenyl]-3-

Ne (3-trifluoromethyl-phenyl)-urea

S56

® ou: 0 2005/012254 PCT/US2004/023488

MeO ct 1 2 1-[3-(4-Chloro-2-methy)-2H- { Di NH c pyrazol-3-yl)-4-methoxy-phenyl]-3-

N" ve (3-chloro-phenyl)-urea

MeO. F a Ji Lx 1-[3-(4-Chloro-2-methyl-2H-

CS NN F pyrazol-3-yl)-4-methoxy-phenyl]-3- -N

N" ve (3,4-difluoro-phenyl)-urea

F

MeO 1-[3-(4-Chloro-2-methyl-2H- a) ye J pyrazol-3-yl)-4-methoxy-phenyl]-3- = F

NN. NR (3,5-difluoro-pheayl)-urea

Me

MeO.

Br 2 ISS 1-[3(4-Bromo-2-methy}-2H-

Me

CS HE 8 pyrazol-3-yl)-4-methoxy-phenyl}-3- -N

N" ne [3-(} -hydroxy-ethyl)-phenyl]}-urea

MeO a. 1 0 1-Benzoyl-3-[3-(4-chloro-2-methyl-

CS N 29 2H-pyrazol-3-yl)-4-methoxy-

NN phenyl}-urea

MeO

Br 5 qe 1-[344-Bromo-2-methyl-2H-

Me

CS NN I pyrazol-3-yl)-4-methoxy-phenyl]-3- -N IN

N" me OH [3-(1-hydroxyimino-ethyl)-phenyl}- urea

MeO cl i 1-[3-(4-Chloro-2-methyl-2H- 97 CS NH pyrazol-3-yl)-4-methoxy-phenyl}-3- ~N F

NT Me (2-fluoro-phenyt)-urea

El

F4CO cl

J Lr 1-(4-Chloro-phenyl)-3-[3-2- { I NN methyl-2H-pyrazol-3-yl)-4- nN" “Me trifluoromethoxy-phenyl]-urea

F4CO F

J ge 1~(2,4-Difluoro-phenyl)-3-[342- 4 T NN I methyl-2H-pyrazol-3-y1)-4-

NT ue trifluoromethoxy-phenyl}-urea

F2CO F 3 Zr 1-(4-Fluoro-phenyl)-3-[3-(2- 4 NN methyl-2H-pyrazol-3-yl)-4-

NT Me trifluoromethoxy-phenyl]-urea

F4CO CF, il Lr 1-[342-Methyl-2H-pyrazol-3-yI)}4- 101 TC BN trifluoromethoxy-phenyl]-3-(4- -N

N" me trifluoromethyl-phenyl)-urea

MeO cl

Br 0 1-[3-(4-Bromo-2-methy}-2H-

A

CS MY { pyrazol-3-yl)-4-methoxy-phenyl]-3- -N

Nome ( ) [4-chloro-2-(4-methyl-piperazin-1- ¥ yl)-phenyl}-urea

HO F

Br J gf 1-[3-(4-Bromo-2-methy}-2H- { p NB I pyrazol-3-yl)-4-hydroxy-phenyl}-3-

Ne (2,4-difluoro-phenyl)-urea

MeO cl

Br 1 IT 1-[3(4-Bromo-2-methyl-2H-

CS NON | pyrazol-3-yl)-4-methoxy-phenyl}-3- -N

Ne () (4-chloro-2-morpholin-4-yl-

Q phenyl)-urea

® WO 2005/012254 , PCT/US2004/023488 ac Ics

MeO cl 1 1-Benzyl-3-[3(4-chloro-2-methyl- 4 oT N O 2H-pyrazol-3-yl)-4-methoxy-

Ne phenyl}-urea

MeO ct

Br 1 Ig 1-[3-(4-Bromo-2-methy}-2H- 4 oT Noy ! pyrazol-3-y))-4-methoxy-phenyl}-3- i [4-chloro-2-(4-methyl-piperidin-1- yl)-phenyl]-urea

MeO ci

Br Ji ie 1-[3-(4-Bromo-2-methyl-2H- 107 { T NOH I pyrazol-3-yl)-4-methoxy-phenyl]-3-

N" ne (4-chioro-2-hydroxy-phenyl)-urea

F1CO cl ar 1 gr 1-{3-(4-Bromo-2-methyl-2H- 4 J NN pyrazol-3-yl)-4-trifluoromethoxy-

RN" me phenyl])-3-(4-chloro-phenyl)-urea i

MeO a 2 21 1-[3-(4-Chloro-2-methy}-2H- { pi NN CN pyrazol-3-yl)-4-methoxy-phenyl]-3-

Ne (3-cyano-phenyl)-urea

MeO. a 1 J@ 1-[3-(4-Chloro-2-methyl-2H- { NN NO; pyrazol-3-yl)-4-methoxy-phenyl}-3-

Nome (3-nitro-phenyl)-urea

MeO el

Br J iq : 1-[3-(4-Bromo-2-methy!-2H-

CS NN pyrazol-3-yl)-4-methoxy-phenyl]-3- nN-N. pe” Me i i

Me \ {4-chloro-2-{(2-dimethylamino-

Me ethyl)-methyl-amino}-phenyl}-urea

( PCT/US2004/023488

RL

MeO o ci 1-3 -(4-Bromo-2-methyl-2H- yt JL Ig pyrazol-3-yl)}-4-methoxy-phenyi}-3- x Me 4 ME {4~chloro-2-[(3-dimethylamino-

NN Mer NINN } y propyl)-methyl-amino]-phenyl}- urea

FaCo. F 8 x1 1-{3+4-Bromo-2-methyl-2H-

CS NN pyrazol-3-yl)-4-trifluoromethoxy- -N F

Nome phenyl]-3<(2,4-difluoro-phenyl)- urea

FCO i 1-(3-Acetyl-phenyl)-3-[3-(2-

M

CS NB © methyl-2H-pyrazol-3-yl)4- -N [o]

Ne trifluoromethoxy-phenyl}-urea

MeO. fo)

Be id Lr NF 1-[3-(4-Bromo-2-methyl-2H-

F

& NN ° pyrazol-3-yl}-4-methoxy-phenyl]-3- -N me (2,2-difluoro-benzo[1,3]dioxol-5- yl)yurea

Me

MeO. N 1-[3(4-Bromo-2-methyl-2H- 0} “Me

So JL Lr pyrazol-3-yl)-4-methoxy-phenyl]-3-

EN N

\-N A H (4-dimethylamino-phenyl)-urea “Me we 1-[3-(4-Bromo-2-methyl-2H -{3-(4-Bromo-2-methyl-2H- .

Me” he { y o a pyrazol-3-yl}-4-(3-dimethylamino-

[0] 117 5A J Lr propoxy)-phenyl}-34{4-chloro- = N \ N, H N phenyl)-urea

Me

® WO 2005/012254 PCT/US2004/023488 .

EE

[o] “ A {2-(4-Bromo-2-methyl-2H-pyrazol- lo} 0 cl 3-yl)-4-[3(4-chloro-phenyl)

[0] 8 J Lr ureido]-phenoxy }-acetic acid

I

ST

NN

HO. Ct

I Lr 1-(4-Chloro-pheny!1)-3-[4-hydroxy- 4 ol NN 3-(2-methyl-2H-pyrazol-3-yl)-

Ne phenyl]-urea

HO F cl bi 1-[3-(4-Chloro-2-methyl-2H- $ I NN I pyrazol-3-y1)}-4-hydroxy-phenyl)-3-

MN" me (2,4-difluoro-phenyl)-urea

HO cl cl bit x 1-[3«(4-Chloro-2-methyl-2H- $ 3 NN pyrazol-3-yl)-4-hydroxy-phenyi}-3-

Ne (4-chloro-pheny!)-urea ue 14-Chloro-phenyl)-3-[4-(3 oro-phenyl)-3-[4-(3-

M eNO o Ci } ] P y

J dimethylamino-propoxy)-3-(2- 122 = N N

NN methyl-2H-pyrazol-3-yl)-phenyl)-

Me urea

Me _.Me

N 1-[3-(4-Bromo-2-methyl-2H- \ pyrazol-3-yl)-4-(2-dimethylamino- lo} F 123 er bs ethoxy)-phenyl}-3-(2,4-difluoro- <S NN phenyl)-urea

NN, F

Me

( PCT/US2004/023488

EE

Me e-N “LO o F 1-(2,4-Difluoro-phenyl)-3-[4-(3-

Py dimethylamino-propoxy)-3-(2- 124 AS N N

NN F methyl-2H-pyrazol-3-yl)-pheayl]-

Me urea

Me ae “0 o F 1-{4-(3-Dimethylamino-propoxy)-3-

J (2-methyl-2H-pyrazol-3-y1)- =

N=. HN H phenyl})-3-(4-fluoro-phenyl)-urea

Me

Me me-Na~0 o : 1-(4-Chloro-benzyl)-3-[4~(3- ; “ JL dimethylamino-propoxy)-3-(2- \ NN TL methyl-2H-pyrazol-3-yl)-pheny!]-

Note cl urea

Me. 0. Cl

NT 1 Lr 1-(4-Chloro-pheny1)-3-[4-(2- 127 4 NN dimethylamino-ethoxy)-3-(2- -N

Nove methyl-2H-pyrazol-3-yl)-phenyl}- urea

Me we ~~ 1-{3-(4-Chloro-2-methyl-2H- 0 o ci pyrazol-3-yl)-4-(3-dimethylamino- ° J Ir propoxy)-phenyl}-3-(4-chloro- : = NH \_N phenyl)-urea

NN,

Me

He 1(2,2-Difl be I,3]dioxol-5 »2-Difluoro-benzo[1,3]dioxol-5- me” NO 0 [o) E [ ]

J SF y1)-3-[4(3-dimethylamino- 129 =

N-N H K propoxy)-3-(2-methyl-2H-pyrazol-

Me 3-yl)-phenylj-urea

® WO 2005/012254 PCT/US2004/023488 .

Me . eM ~_O 0 Me 1-[4-(3-Dimethylamino-propoxy)-3- 130 ~ J Lr (2-methyl-2H-pyrazol-3-yl)-

NN N H phenyl]-3-p-tolyl-urea ‘Me

Me . oN “0 o OMe 1-{4-(3-Dimethylamino-propoxy)-3- ~ A, Lr (2-methyl-2H-pyrazol-3-y1)- \-n H H phenyl}-3-(4-methoxy-phenyl)-urea “Me

Me _Me

N 1-[3-(4-Chloro-2-methyl-2H- 3 pyrazol-3-yl}-4-(2-dimethylamino-

F

. cl Jie ethoxy)-phenyl]-3-(2,4-difluoro-

CS NN pheny!)-urea

N-N, F

Me me 1-{3-(4-Chloro-2-methyl-2H “| oro-Z-methyi-2H-

Me™ A y 0 F pyrazol-3-yl)-4-(3-dimethylamino- lo] 133 3 J y propoxy)-phenyl]-3-(2,4-difluoro- ~ \ Nn A N h phenyl)-urea

Ne

Me

IL NE o 1{(3-Chloro-phenyl)-3 -[4-(3-

JY Lu dimethylamino-propoxy)-3-(2-

ES NTN cl \-N methyl-2H-pyrazol-3-yl)-phenyl)- "Me urea

Me

LN o F 1-(3-Chloro-4-fluoro-phenyl}-3-4-

PY LI (3-dimethylamino-propoxy)-3-(2- 135 A NN cl

NAN methyl-2H-pyrazol-3-yl)-phenyi)-

Me urea

C

Rl I Name

Me me NO o F 1-3 ;4-Difluoro-phenyl)-3-[4-(3-

AE dimethylamino-propoxy)-3-(2-

NN " methyi-2H-pyrazol-3 -yl)-phenyl]- e urea

Me

Me” V0 o CF, 1-[4-(3-Dimethylamino-propoxy)-3- 137 ~~ ps AT (2-methyl-2H-pyrazol-3-yl)-

NN, phenyl]-3-(4-trifluoromethyl-

Me phenyl)-urea

Me me” M0 o 1-{4-(3-Dimethylamino-propoxy)-3- . ~A A (2-methyl-2H-pyrazol-3-yl)-

NN, H F phenyl]-3 -(2-fluoro-phenyl)-urea

Me

Me Me me” NO o 1-{4-(3-Dimethylamino-propoxy)-3- 139 ~~ (2-methyl-2H-pyrazol-3-yl)

NN, H F phenyl}-3-(2-fluoro-5-methyl-

M

) phenyl)-urea

Me

Me~ nO o 1-(2-Chloro-phenyl)-3-[4-(3- ~~ po ye dimethylamino-propoxy)-3-(2-

NH, c methyl-2H-pyrazol-3-yl)-phenyi]- ™ ° urea

Me ~ N ~.0 0 F }

A by or 1-(2,4-Difluoro-phenyl)-3-[42- » N i ; dimethylamino-ethoxy)-3-(2-

Me methyl-2H-pyrazol-3 -yl)-phenyl}- urea

Moon 0 0 F 1-{4-(2-Dimethylamino-ethoxy)-3-

XN ae NN (2-methyl-2H-pyrazol-3-yl)- 3

NM se phenyl]-3-(4-fluoro-phenyl)-urea

Meow 0 13-Acetyl-phenyl)-3-[442- eS on Me dimethylamino-ethoxy)-3-2- § 1 Ne © methyl-2H-pyrazol-3-yl)-phenyl}- urea

Mes ™° 9 LI 1-(2,2-Difluoro-benzo{1,3]dioxol-3-

Mes wo oF | y)-3-[4-(2-dimethylamino-ethoxy)- §

Ne 3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-urea re o 1-[4-(3 -Dimethylamino-propoxy)-3- ue 1 2 (2-methyl-2H-pyrazol-3-yl)- $C NN phenyl]-3-phenyl-urea

NN.

Me

Mean 0 Q J @ 1-{4-(2-Dimethylamino-ethoxy)-3-

U me SS yo OMe (2-methyl-2H-pyrazoi-3-yi)-

Nore phenyl}-3-(3-methoxy-phenyl)-urea i (2-{2-(4-Bromo-2-methyl-2H-

SLA

° KM) £ pyrazol-3-yl)}-4-{32,4-difluoro- 147 8 1 gl : phenyl)-ureido]-phenoxy}-ethyl}- ® LE £ carbamic acid tert-butyl ester -N

N “Me we 1-{3-(4-Bromo-2-methyl-2H. - -Bromo-2-methyl-2H- me” Y 0 F pyrazol-3-yl)-4-(3-dimethylamino- 0

AX J LX propoxy -phenyl}-3-(3,4-difluoro-

ES N N F

\ H H phenyl)-urea

N-N.

Me

He 1-(3(4-B 2-methyl-2H - -Bromo-2-methyl-2H-

Me” . y . 0 pyrazol-3-yl)-4-(3-dimethylamino-

[0] 5 A JS iq propoxy)-phenyl}-3-(2-chloro-

ES N

NN. HR a phenyl)-urea

Me

He 1-[3-(4-Bromo-2-methyl-2H - - mo-. - ~ -

Me” . . 0 pyrazol-3-yl)-4-(3-dimethylamino- 0 5A J Q propoxy)-phenyl}-3-(2-fluoro- \ 7 H N £ phenyl)-urea

N-N,

Me

MeO cl

I Lr 1-(4-Chloro-phenyl)-3-[4-methoxy-

CS NH 3-(2H-pyrazol-3-yl)-phenyl]-urea

N-NH

MeO F

Br J 1-[344-Bromo-2H-pyrazol-3-yl)-4-

CS Noi methoxy-phenyl]-3-(2,4-difluoro- - F

N-NH phenyl)-urea

MeO F © J 142,4-Difluoro-phenyl)-3-{4-

CS NN methoxy-3-(2H-pyrazol-3-yl}-

N—-NH F phenyl}-urea

HO ol}

I Lr 1-(4-Chloro-pheny!)-3-[4-hydroxy- 7 HE 3+(1-methyl-1H-pyrazol-3-yl)- n-N / phenyl]-urea

Mel Me

N 1-(4-Chloro-pheny!)-3-[4-(2-

N dimethylamino-ethoxy)-3-(4-fluoro- cl £ 0 2-methyl-2H-pyrazol-3-y1)-phenyl]-

EN A

N AR urea

N-N,

Me

Me. _Me A

N 1-{4-(2-Dimethylamino-ethoxy)-3- \ (4-fluoro-2-methyl-2H-pyrazol-3- 0 F

F 2 Lr yi)-phenyl]-3-4-fluoro-phenyl)- = NA urea

None

Me. _Me

N 14(2,4-Difluoro-phenyl)-3-[4-(2-

N dimethylamino-ethoxy)-3-(4-fluoro- 0 F 157 F bil ig) 2-methyl-2H-pyrazol-3-yl)-phenyl]-

CO) i N F urea

NN

Me. Me

N 1{4-Chloro-2-hydroxy-phenyl)-3-

N [4-(2-dimethylamino-ethoxy)-3-(4- cl

F i OF fluoro-2-methyl-2H-pyrazol-3-yl)-

CS NN phenyl]-urea

N-N. OH

Me

EE I

Me. Me

N 1-[4-(2-Dimethylamino-ethoxy)-3-

Y (4-fluoro-2-methyl-2H-pyrazol-3-

[0] F

F 1 Lr y1)-phenyl]-3<4-fluoro-2-hydroxy-

CS HE phenyl)-urea

N-N, GH

Me

Me _Me

N 1<(4-Chloro-3-hydroxy-pheny!)-3-

N [4-(2-dimethylamino-ethoxy)-3-(4- 0 Cl

F Ji Lx fluoro-2-methyl-2H-pyrazol-3-yl)-

CS NN OH phenyl]-urea

N-N.

Me

Me. _Me

N 1-[4-(2-Dimethylamino-ethoxy)-3-

N (4-fluoro-2-methyl-2H-pyrazol-3- [lo] F

F 1 Lx yl)-phenyl}-3-(4-fluoro-3-hydroxy-

CS NN OH phenyl)-urea

N-N,

Me

Me, _Me

N 1-[3-(4-Chloro-2-methyl-2H-

N pyrazol-3-yl}-4-(2-dimethylamino- 0 ci cl bie Lr ethoxy)-phenyl}-3-(4-chloro-

CS FA phenyl)-urea

N-N,

Me

Me. _Me ’

N 1-[3{(4-Chloro-2-methy}-2H-

N pyrazal-3-yl)-4-(2-dimethylamino-

Q F cl 1 Zr ethoxy)-phenyl]-3-(4-fluoro-

CS NN phenyl)-urea

N-N,

Me

CE

Mel Me

N 1<4-Chloro-2-hydroxy-phenyl)-3-

N c [3-(4-chloro-2-methyl-2H-pyrazol- 1 a J es 3-yl)-4-(2-dimethylamino-ethoxy)-

CS NN phenyl]-urea

N-N, OH

Me

Med Ne } 1-{3(4-Chloro-2-methyl-2H-

N pyrazol-3-yl)-4-(2-dimethylamino- ) F ct 1 ig) ethoxy)-phenyl}-3-(4-fluoro-2-

CS NN hydroxy-phenyl)-urea

N-N, OH

Me

Me. Me

N 1-(4-Chloro-3-hydroxy-phenyl)-3-

N {3<4-chloro-2-methyl-2H-pyrazol- cl c 1 LX 3-yl)-4-(2-dimethylamino-ethoxy)-

CS HE OH phenyl]-urea

N-N,

Me

Me. _M

NT 1-{3<(4-Chloro-2-methyl-2H-

N pyrazol-3-yl)-4-(2-dimethylamino-

F

167 cl 1 LX ethoxy)-phenyl]-3+4-fluoro-3- { HE OH hydroxy-phenyl)-urea

NN

Me. o cl bi 0 1-(4-Chloro-2-hydroxy-phenyl)-3-

CS HE [4-(2-dimethylamino-ethoxy)-3-(2- ~N OH "ue methyl-2H-pyrazol-3-yl)-phenyl}- urea a)

PCT/US2004/023488 iE

Me. (0) F .

NT Ji jg }-{4-(2-Dimethylamino-ethoxy)-3-

Me

CS NON (2-methy}-2H-pyrazol-3-yl)- ~N OH .

MN" Me phenyl]-3-(4-fluoro-2-hydroxy- ' phenyl)-urea

Me. 0 cl

NT I JQ 1{4-Chloro-3-hydroxy-phenyl)-3-

Me 170 CS NON OH (4-(2-dimethylamino-ethoxy)-3-(2- ~N

Ne methyl-2H-pyrazol-3-yl)-phenyl}- urea

Me. (0) F

NT I x }-{4-2-Dimethylamino-ethoxy)-3-

M i. re NON oH (2-methyl-2H-pyrazol-3-yl)-

NM pe phenyl]-3-(4-fluoro-3-hydroxy- phenyl)-urea

Me. Me

N 1-[3-(4-Bromo-2-methyl-2H-

N pyrazol-3-yl)-4-(2-dimethylamino- 0 c 172 Br 1 ig ethoxy)-phenyl}-3-(4-chloro-2- (CS pb N hydroxy-phenyl)-urea

N-N. OH

Me

Me. Me

N 1-[3-(4-Bromo-2-methy}-2H-

N pyrazol-3-yl)-4-(2-dimethylamino- 0 3 173 Br 1 J ethoxy)-phenyl}-3-(4-fluoro-2-

CS NN hydroxy-phenyl)-urea n-N. OH

Me

Me. Me

N 1-{344-Bromo-2-methyl-2H-

N pyrazol-3-yl)-4-(2-dimethylamino- 0 cl 174 Br J Lx ethoxy)-pheny!}-3-(4-chloro-3-

CS Non OH hydroxy-phenyl)-urea

NN,

Me

® WO 2005/012254 PCT/US2004/023488 )

Me. Me 1-{3-(4-Bromo-2-methyl-2H- 3 . pyrazol-3-yl}-4-(2-dimethylamino- 175 Br J LX ethoxy)-phenyl]}-3-(4-fluoro-3- x= NN OK \ H H hydroxy-phenyl)-urea

N “Me ye c 1-{4-Chloro-phenyl)-3-[4(3- we + oro-phenyl)-3-{4(3 0 o al dimethylamino-propoxy)-3-(4-

F

176 iA, Me Lr fluoro-2-methyl-2H-pyrazol-3-yl)- =

NN HoN phenyl}-urea ‘Me

IN [-{4<3-Dimethyl 3 - -Dimet! ino- y)-3- we ~ (4 ethylamino propoxy) 0 ° F (4-fluoro-2-methyl-2H-pyrazol-3- 177 SAA J Lr y1)-phenyl}-3-(4-fluoro-phenyl)- = \ " KOH urea ‘Me re 142,4-Dif} henyl)-3-[4-(3 ,4-Difluoro- -3-[4-(3- we oro-phenyl)-3-[4-( 0 F dimethylamino-propoxy)-3-(4- fo) 178 3A J Ly fluoro-2-methyl-2H-pyrazol-3-yl)- x N

NN non ¢ phenyl)-urea "Me we 1-(4-C d hloro-2-hydroxy-phenyl)-3- we « ydroxy-phenyt) 0 a [4-(3-dimethylamino-propoxy)-3- o] 179 5A J or (4-fluoro-2-methyl-2H-pyrazol-3- =

N-N No OH y!)-phenylij-urea “Me

I’!

Chemis we 1-{4-(3-Dimethylami 3 - -Dimethylamino-propoxy)-3- wer y -propoxy)- 0 {4-fluoro-2-methy!-2H-pyrazol-3- : ls]

JSS ML ids yl)-phenyl]-3(4-fluaro-2-hydroxy- x

N-H, N N OH phenyl)-urea

Me he 1-{(4-Chloro-3-hyd henyl)-3 oro-3-hydroxy-phenyl)-3-

MeN ydroxy-phenyl)- 0 cl [4-(3-dimethylamino-propoxy)-3- [o] i J Lx (4-fluoro-2-methyl-2H-pyrazol-3- pl BS:

N-N yl)-phenyl]-urea “Me we 1-{4~(3-Dimethylami 3 - -Dimethylamino-propoxy)-3-

MeN y propoxy})- a F (4-fluoro-2-methyl-2H-pyrazol-3- fo)

A J x y))-phenyl}-3(4-fluoro-3-hydroxy- = N N OH

NN phenyl)-urea

N "Me we 1-[3{4-Chloro-2-methyl-2H - oro-2-methyl-2H-

MeN [3« y 0 F pyrazol-3-yl)-4-(3-dimethylamino- 0 yOu ML jg propaxy)-phenyl}-3-(4-fluoro- =

NN Hol phenyl)-urea

N Me

He 1-(4-Chloro-2-hyd henyl)-3 oro-2-hydroxy-phen - me NN y y-pheny o cl [34(4-chloro-2-methyl-2H-pyrazol-

Q

3 JL igs 3-yl)4-(3-dimethylamino- =

NN, NH OH propoxy)-phenyl}-urea

Me o WO 2005/012254 PCT/US2004/023488

He 1-[3-(4 -2- -2H- we “ [3-(4-Chloro-2-methyl-2H

Fo) o F pyrazol-3-yl)-4-(3-dimethylamino-

Cl

JSON A, Or propoxy)-phenyt}-3-(4-fluoro-2-

NN. NN OH hydroxy-phenyl)-urea

Me

Me

UN 1-(4-Chloro-3-hydroxy-phenyl)-3-

Me ~N 0 ° cl {3-(4-chloro-2-methyl-2H-pyrazol-

JO, CX 3-y)-4-(3-dimethylamino- 3A, on yl)-4-(3-dimethylamino

NAN. propoxy)-phenyl]-urea

Me

Me 14 ! - -2H- we ~N [3-(4-Chloro-2-methyl-2H o o F pyrazol-3-yl)-4-(3-dimethylamino- [of] 187 ML LX propoxy)-phenyl}-3-(4-fluoro-3-

CS N N OH

\-, hydroxy-phenyl)-urea

Me

Ye _N 1-(4-Chloro-2-hydroxy-phenyl)-3-

Me ~ . i 0 o ci [4-(3-dimethylamino-propoxy)-3- 188 ~~, A, Kr (2-methy)-2H-pyrazol-3-yl)-

NN. HH dy phenyl]-urea

Me te -[4-(3-Dimethylamino-, -3- eM ~ [4-(3-Dimethylamino-propoxy)-3 0 o F (2-methyl-2H-pyrazol-3-yl)- ~A, A, Lr phenyl}-3 ~(4-fluoro-2-hydroxy- \ oN, HoH phenyl)-urea

Me

® WO 2005/012254 PCT/US2004/023488

Nc ie 1-(4-Chloro-3-hyd 1)-3 oro-3-hydroxy-phen -

WANS ydroxy-phenyl)- 0 ' al [4-(3-dimethylamino-propoxy)-3- fo} ~ J LO (2-methyl-2H-pyrazol-3-yl)-

N-N i N phenyl]-urea ‘Me ne 1-[4-(3-Dimethylami 3 4 -Dimethylamino-propoxy)-3- veh {4 y Propoxy)- 0 F (2-methyl-2H-pyrazol-3-yl)- 0

BY LX phenyl}-3-(4-fluoro-3-hydroxy- x A N OH

N-N phenyl)-urea ‘Me : he 1-[3-(4-Bromo-2-methyl-2H - -Bromo-2-methyl-2H- we methyl-2H 0 F pyrazol-3-yl)}4-(3-dimethylamino- [¢} 5A A LY propoxy)-phenyl}-3-(4-fluoro- =

NN H H phenyl)}-urea

NN he 1-[3-(4-B 2-methyl-2H - -Bromo-2-methyl-2H-

Me" PERE 0 ci pyrazol-3-yl)-4-(3-dimethylamino- [o]

A PY ry propoxy)-phenyl]-3-(4-chloro-2- = \ _N H H OH hydroxy-phenyl)-urea

N ‘Me ne 1-[3-(4-Bromo-2-methyl-2H - -Bromo-2-methyl-2H- me” : o E pyrazol-3-yl)}-4-(3-dimethylamino- fo) yO J Ie propoxy)-phenyl}-3-(4-fluoro-2-

EN N

NN non OH hydroxy-phenyl)-urea

N “Me

® . nN 1-[3{4-Bromo-2-methyl-2H- a cl pyrazol-3-yl)-4-(3-dimethylamino-

A 1 LX propoxy)-phenyl}-3-(4-chloro-3- \ Db H N on hydroxy-phenyl)-urea

N-N.

Me iy 1-[3-(4-Bromo-2-methyi-2H-

Me” ~ F pyrazol-3-yl}4-(3-dimethylamino- yo 1 LX propoxy)-phenyl}-3-(4-fluoro-3- 9 N N oH hydroxy-phenyl)-urea

NN.

Me

Additionally, compounds of the present invention, such as Formula (I) and related Formulae, encompass all pharmaceutically acceptable salts, solvates, and particularly hydrates, thereof.

The compounds of the Formula (T) of the present ipvention may be prepared according to the

S general synthetic schemes in Figures 17 through 21 and Figures 29 through 33 as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter in the working Examples. Protection and deprotection may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and

Wauts, P. G. M., Protecting Groups in Organic Synthesis, 3" Edition, 1999 [Wiley]; incorporated herein by reference in its entirity).

The present invention also encompasses diastereomers as well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds of the invention. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.

Constitutively Active Human SHT;,

For convenience, the sequence information regarding the non-endogenous, constitutively active human 5-HT2A and identifiers are set forth in TABLE 4:

TABLE 4

® ® WO 2005/012254 PCT/US2004/023488 evra | wacerron | seam: | mous

EE TN EE

IE I RE

CTE I EE we [em [ww]

INDICATIONS AND METHODS OF PROPHYLAXIS AND/OR TREATMENT

In addition to the foregoing beneficial uses for the modulators of 5-HTa4 receptor activity disclosed herein, the compounds disclosed herein are believed to be useful in the treatment of several additional diseases and disorders, and in the amelioration of symptoms thereof. Without limitation, these include the following: 1. Antiplatelet Therapies (5-HTjs mediated platelet aggregation):

Antiplatelet agents (antiplatelets) are prescribed for a variety of conditions. For example, in coronary artery disease they are used to help prevent myocardial infarction or stroke in patients who are at risk of developing obstructive blood clots (e.g., coronary thrombosis).

In a myocardial infarction (heart attack), the heart muscle does not receive enough oxygen-rich blood as a result of a blockage in the coronary blood vessels. If taken while an attack is in progress or immediately afterward (preferably within 30 minutes), antiplatelets can reduce the damage to the heart.

A transient ischemic attack ("TIA" or *mini-stroke") is a brief interruption of oxygen flow to the brain due to decreased blood flow through arteries, usually due to an obstructing blood clot. Antiplatelet drugs have been found to be effective in preventing TIAs.

Angina is a temporary and often recurring chest pain, pressure or discomfort caused by inadequate’ oxygen-rich blood flow (ischemia) to some parts of the heart. In patients with angina, antiplatelet therapy can reduce the effects of angina and the risk of myocardial infarction.

Stroke is an event in which the brain does not receive enough oxygen-rich blood, usually due to blockage of a cerebral blood vessel by a blood clot. In high-risk patients, taking antiplatelets regularly has been found to prevent the formation blood clots that cause first or second strokes.

Angioplasty is a catheter based technique used © open arteries obstructed by a blood clot. Whether or not stenting is performed immediately after this procedure to keep the artery open, antiplatelets can reduce the risk of forming additional blood clots following the procedure(s).

Coronary bypass surgery is a surgical procedure in which an artery or vein is taken from elsewhere in the body and grafted to a blocked coronary artery, rerouting blood around the blockage and through the newly attached vessel. After the procedure, antiplatelets can reduce the risk of secondary blood clots.

® ® WO 2005/012254 PCT/US2004/023488

Atrial fibrillation is the most common type of sustained irregular heart rhythm (arrythmia). Atrial fibrillation affects about two million Americans every year. In atrial fibrillation, the atria (the heart's upper chambers) rapidly fire electrical signals that cause them to quiver rather than contract normally. The result is an abnormally fast and highly irregular heartbeat. When given after an episode of atrial fibrillation, antiplatelets can reduce the risk of blood clots forming in the heart and traveling to the brain (embolism). 5-HT;4 receptors are expressed on smooth muscle of blood vessels and 5-HT secreted by activated platelets causes vasoconstriction as well as activation of additional platelets during clotting. There is evidence that a 5-HT;, inverse agonist will inhibit platelet aggregation and thus be a potential treatment as an antiplatelet therapy (see Satimura, K, et al., Clin Cardiol 2002 Jan. 25 (1)28-32; and Wilson, H.C etal,

Thromb Haemost 1991 Sep 2;66(3):355-60).

The 5-HT,. inverse agonists disclosed herein provide beneficial improvement in microcirculation to patients in need of antiplatelet therapy by antagonizing, the vasoconstrictive products of the aggregating platelets in, for example and not limitation, the indications described above. Accordingly, in some embodiments, the present invention provides methods for reducing platelet aggregation in a patient in need thereof comprising administering to said patient a composition comprising a 5-HT, inverse agonist disclosed herein. In further embodiments, the present invention provides methods for treating coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, or a symptom of any of the foregoing in a patient in need of said treatment, comprising administering to said patient a composition comprising a 5-HT, inverse agonist disclosed herein.

In further embodiments, the present invention provides methods for reducing risk of blood clot formation in an angioplasty or coronary bypass surgery patient, ar a patient suffering from atrial fibrillation, comprising administering to a said patient a composition comprising a 5-HT;, inverse agonist disclosed herein at a time where such risk exists. 2. Asthma i

It has been suggested that 5-HT (5-hydroxytryptamine) plays a role in the pathophysiology of acute asthma (see Cazzola, M.. and Matera, M.G., TIPS, 2000, 21, 13; and De Bie, IJ. et al,, British J.

Pharm, 1998, 124, 857-864). The compounds of the present invention disclosed herein are useful in the treatment of asthma, and the treatment of the symptoms thereof. Accordingly, in some embodiments, the 3q present invention provides methods for treating asthma in a patient in need of said treatment, comprising administering to said patient a composition comprising a 5-HT;4 inverse agonist disclosed herein. In further embodiments, methods are provided for treating a symptom of asthma in a patient in need of said treatment, comprising administering to said patient a composition comprising a 5-HT14 inverse agonist disclosed herein. 3. Agitation

® ®

Agitation is a well-recognized behavioral syndrome with a range of symptoms, including hostility, extreme excitement, poor impulse control, tension and uncooperativeness (See Cohen-Mansfield J, and

Billig, N., (1986), Agitated Behaviors in the Elderly. I. A Conceptual Review. J Am Geriatr Soc 34(10): 711-721).

Agitation is a common occurrence in the elderly and often associated with dementia such as those caused by Alzheimer’s disease, Lewy Body, Parkinson's, and Huntington's, which are degenerative diseases of the nervous system and by diseases that affect blood vessels, such as stroke, or multi-infarct dementia, which is caused by multiple strokes in the brain can also induce dementia. Alzheimer’s disease accounts for approximately 50 to 70% of all dementias (See Koss E, et al., (1997), Assessing patterns of agitation in Alzheimer's disease patients with the Cohen-Mansfield Agitation Inventory. The Alzheimer’s

Disease Cooperative Study. Alzheimer Dis Assoc Disord 1 1(suppl 2):545-850).

An estimated five percent of people aged 65 and older and up to 20 percent of those aged 80 and older are affected by dementia; of these sufferers, nearly half exhibit behavioral disturbances, such as agitation, wandering and violent outbursts.

Agitated behaviors can also be manifested in cognitively intact elderly people and by those with psychiatric disorders ather than dementia.

Agitation is often treated with antipsychotic medications such as haloperidol in nursing home and other assisted care settings. There is emerging evidence that agents acting at the 5-HT;a receptors in the brain have the effects of reducing agitation in patients, including Alzheimer's dementia (See Katz, IR, et al, J Clin Psychiatry 1999 Feb, 60(2):107-115; and Street, 1.8, et al., Arch Gen Psychiatry 2000 Oct, 57(10):968-976).

The compounds of the invention disclosed herein are useful for treating agitation and symptoms thereof. Thus, in some embodiments, the present invention provides methods for treating agitation ina patient in need of such treatment comprising administering to said patient a composition comprising a 5-

HT,, inverse agonist disclosed herein. In some embodiments, the agitation is due to a psychiatric disorder other than dementia. In some embodiments, the present invention provides methods for treatment of agitation or a symptom thereof in a patient suffering from dementia comprising administering to said patient a composition comprising a 5-HT.4 inverse agonist disclosed herein. In some embodiments of such methods, the dementia is due to a degenerative disease of the nervous system, for example and without limitation, Alzheimers disease, Lewy Body, Parkinson's disease, and Huntington's disease, or dementia due to diseases that affect blood vessels, including, without limitation, stroke and multi-infarct dementia. In some embodiments, methods are provided for treating agitation or a symptom thereof in a patient in need of such treatment, where the patient is a cognitively intact elderly patient, comprising administering to said patient a composition comprising a 5-HT., inverse agonist disclosed herein. 4. Add-On therapy to Haloperidol in the treatment of schizophrenia and other disorders:

® ® WO 2005/012254 PCT/US2004/023488

Schizophrenia is a psychopathic disorder of unknown origin, which usually appears for the first time in early adulthood and is marked by a number of characteristics, psychotic symptoms, progression, phasic development and deterioration in social behavior and professional capability in the region below the highest level ever attained. Characteristic psychotic symptoms are disorders of thought content (multiple, fragmentary, incoherent, implausible or simply delusional contents or ideas of persecution) and of mentality (loss of association, flight of imagination, incoherence up to incomprehensibility), as well as disorders of perceptibility (hallucinations), of emotions (superficial or inadequate emotions), of self- perception, of intentions and impulses, of interhuman relationships, and finally psychomotoric disorders (such as catatonia). Other symptoms are also associated with this disorder. (See, American Statistical and i] Diagnostic Handbook).

Haloperidol (Haldol) is a potent dopamine D2 receptor antagonist. It is widely prescribed for acute schizophrenic symptoms, and is very effective for the positive symptoms of schizophrenia. However,

Haldo! is not effective for the negative symptoms of schizophrenia and may actually induce negative symptoms as well as cognitive dysfunction. In accordance with some methods of the invention, adding a 5-

HT. inverse agonist concomitantly with Haldot will provide benefits including the ability to use a Jower dose of Haldol without losing its effects on positive symptoms, while reducing or eliminating its inductive effects on negative symptoms, and prolonging relapse to the patient's next schizophrenic event.

Haloperidol is used for treatment of a variety of behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorders, psychosis (organic and NOS), psychotic disorder, psychosis, schizophrenia (acute, chronic and NOS). Further uses include in the treatment of infantile autism, huntington's chorea, and nausea and vomiting from chemotherapy and chemotherapeutic antibodies. Administration of S-HT, inverse agonists disclosed herein with haloperidol also will provide benefits in these indications.

In some embodiments, the present invention provides methods for treating a behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorders, psychosis (organic and NOS), psychotic disorder, psychosis, schizophrenia (acute, chronic and NOS) comprising administering to said patient a dopamine D2 receptor antagonist and a 5-HT,, inverse agonist disclosed herein.

In some embodiments, the present invention provides methods for treating a behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorders, psychosis (organic and NOS), psychotic disorder, psychosis, schizophrenia (acute, chronic and NOS) comprising administering to said patient haloperidol and a 5-HT,, inverse agonist disclosed herein.

In some embodiments, the present invention provides methods for treating infantile autism, huntington's chorea, or nausea and vomiting from chemotherapy or chemotherapeutic antibodies comprising administering to said patient a dopamine D2 receptor antagonist and a 5-HT,, inverse agonist disclosed herein.

_ _

In some embodiments, the present invention provides methods for treating infantile autism, huntington's chorea, or nausea and vomiting from chemotherapy or chemotherapeutic antibodies comprising administering to said patient haloperidol and a 5-HT>, inverse agonist disclosed herein. )

In further embodiments, the present invention provides methods for treating schizophrenia ina patient in need of said treatment comprising administering to said patient a dopamine D2 receptor antagonist and a 5-HT;, inverse agonist disclosed herein. Preferably, the dopamine D2 receptor antagonist is haloperidol. .

The administration of the dopamine D2 receptor antaganist can be concomitant with administration of the 5-HT,, inverse agonist, or they can be administered at different times. Those of skill in the art will easily be able to determine appropriate dosing regimes for the most efficacious reduction or elimination of deleterions haloperidol effects. In some embodiments, haloperidol and the 5-HT, inverse agonist are administered in a single dosage form, and in other embodiments, they are administered in separate dosage forms,

The present invention further provides methods of alleviating negative symptoms of schizophrenia induced by the administration of haloperidol to a patient suffering from said schizophrenia, comprising administering to said patient a S-HT,, inverse agonist as disclosed herein. 5. Sleep disorders

It is reported in the National Sleep Foundation's 2002 Sleep In America Poli, more than one-half of the adults surveyed (58%) report having experienced one or more symptoms of insomnia at least a few nights a week in the past year. Additionally, about three in ten (35%) say they have experienced insomnia- like symptoms every night or almost every night.

The normal sleep cycle and sleep architecture can be disrupted by a variety of organic causes as well as environmental influences. According to the Intemational Classification of Sleep Disorders, there are over 80 recognized sleep disorders. Of these, compounds of the present invention are effective, for example, in any one or more of the following sleep disorders (ICSD — Intemational Classification of Sleep

Disorders: Diagnostic and Coding Manual. Diagnostic Classification Steering Committee, American

Sleep Disorders Association, 1990):

A. DYSSOMNIAS : a. Intrinsic Sleep Disorders:

Psychophysiological insomnia, Sleep state misperception, Idiopathic insomnia, Obstructive sleep apnea syndrome, Central sleep apnea syndrome, Central alveolar hypoventilation syndrome, Periodic limb movement disorder, Restless leg syndrome and Intrinsic sleep disorder NOS. b. Extrinsic Sleep Disorders:

Inadequate sleep hygiene, Environmental sleep disorder, Altitude insomnia, Adjustment sleep disorder, Insufficient sleep syndrome, Limit-setting sleep disorder, SleepOnset association disorder,

Nocturnal eating (drinking) syndrome, Hypnotic dependent sleep disorder, Stimulant-dependent sleep oo

® ® WO 2005/012254 PCTUS2004/023488 ) disorder, Alcohol-dependent sleep disorder, Toxin-induced sleep disorder and Extrinsic sleep disorder

NOS. c. Circadian Rhythm Sleep Disorders:

Time zone change (jet lag) syndrome, Shift work sleep disorder, Irregular sleep-wake pattern,

Delayed sleep phase syndrome, Advanced sleep phase syndrome, Non-24-hour sleep-wake disorder and

Circadian rhythm sleep disorder NOS.

B. PARASOMNIAS a. Arousal Disorders:

Confusional arousals, Sleepwalking and Sleep terrors. b. Sleep-Wake Transition Disorders:

Rhythmic movement disorder, Sleep starts, Sleep talking and Noctumal leg cramps.

C. SLEEP DISORDERS ASSOCIATED WITH MEDICAL/PSYCHIATRIC DISORDERS a. Associated with Mental Disorders;

Psychoses, Mood disorders, Anxiety disorders, Panic disorders and Alcoholism. b. Associated with Neurological Disorders:

Cerebral degenerative disorders, Dementia, Parkinsonism, Fatal familial insomnia, Sleep-related epilepsy, Electrical status epilepticus of sleep and Sleep-related headaches. ¢. Associated with Other Medical Disorders:

Sleeping sickness, Nocturnal cardiac ischemia, Chronic obstructive pulmonary disease, Sleep- related asthma, Sleep-related gastroesophageal reflux, Peptic ulcer disease, Fibrositis syndrome,

Osteoarthritis, Rheumatoid arthritis, Fibromyalgia and Post-surgical.

The effects of sleep deprivation are more than excessive daytime sleepiness. Chronic insomniacs report elevated levels of stress, anxiety, depression and medical illnesses (National Institutes of Health,

National Heart, Lung, and Blocd Institute, Insomnia Facts Sheet, Oct. 1995). Preliminary evidence suggests that having a sleep disorder that causes significant loss of sleep may contribute to increased susceptibility to infections due to immunosuppression, cardiovascular complications such as hypertension, ! cardiac arrhythmias, stroke, and myocardial infarction, comprimised glucose tolerance, increased obesity and metabolic syndrome. Compounds of the present invention are useful to prevent or alleviate these complications by improving sleep quality.

The most common class of medications for the majority of sleep disorders are the benzodiazepines, but the adverse effect profile of benzodiazepines include daytime sedation, diminished motor coordination, and cognitive impairments. Furthermore, the National Institutes of Heaith Consensus conference on

Sleeping Pills and Insomnia in 1984 have developed guidelines discouraging the use of such sedative- hypnotics beyond 4-6 weeks because of concerns raised over drug misuse, dependency, withdrawal and rebound insomnia. Therefore, it is desirable to have a pharmacological agent for the treatment of insomnia, which is more effective and/or has fewer side effects than those currently used. In addition,

C : benzodiazepines are used to induce sleep, but have little to no effect on the maintenance of sleep, sleep consolidation or slow wave sleep. Therefore, sleep maintenance disorders are not currently well treated.

Clinical studies with agents of a similar mechanism of action as are compounds of the present invention have demonstrated significant improvements on objective and subjective sleep parameters in normal, healthy volunteers as well as patients with sleep disorders and mood disorders [Sharpley AL, et al.

Slow Wave Sleep in Humans: Role of SHT,, and SHT,c Receptors. Neuropharmacology, 1994, Vol. 33(3/4):467-71; Winokur A, etal. Acute Effects of Mirtazapine on Sleep Continuity and Sleep

Architecture in Depressed Patients: A Pilot Study. Soc of Biol Psych, 2000, Vol. 48:75-78; and Landolt

HP, et al. Serotonin-2 Receptors and Human Sleep: Effect of Selective Antagonist on EEG Power Spectra.

Neuropsychopharmacology, 1999, Vol. 21(3):455-66].

Some sleep disorders are sometimes found in conjunction with other conditions and accordingly those conditions are treatable by compounds of Formula (I). For example but not limiting, patients suffering from mood disorders typically suffer from a sleep disorder that can be treatable by compounds of

Formula (I). Having one pharmacological agent which treats two or more existing or potential conditions, as does the present invention, is more cost effective, leads to better compliance and has fewer side effects than taking two or more agents.

It is an object of the present invention to provide a therapeutic agent for the use in treating Sleep

Disorders. It is another object of the present invention to provide one pharmaceutical agent, which may be useful in treating two or more conditions wherein one of the conditions is a sleep disorder. Compounds of the present invention described herein may be used alone or in combination with a mild sleep inducer (i.e. antihistamine).

Sleep Architecture:

Sleep comprises two physiological states: Non rapid eye movement (NREM) and rapid eye movement (REM) sleep. NREM sleep consists of four stages, each of which is characterized by progressively slower brain wave patterns, with the slower patterns indicating deeper sleep. So called delta sleep, stages 3 and 4 of NREM sleep, is the deepest and most refreshing type of sleep. Many patients with sleep disorders are unable to adequately achieve the restorative sleep of stages 3 and 4. In clinical terms, patients’ sleep patterns are described as fragmented, meaning the patient spends a lot of time alternating between stages 1 and 2 (semi-wakefulness) and being awake and very little time in deep sleep. As used - herein, the term “fragmented sleep architecture” means an individual, such as a sleep disorder patient, spends the majority of their sleep time in NREM sleep stages | and 2, lighter periods of sleep from which the individual can be easily aroused to a Waking state by limited external stimuli. As a result, the individual cycles through frequent bouts of light sleep interrupted by frequent awakenings throughout the sleep period. Many sleep disorders are characterized by a fragmented sleep architecture. For example, many elderly patients with sleep complaints have difficulty achieving long bouts of deep refreshing sleep (NREM stages 3 and 4) and instead spend the majority of their sleep time in NREM sleep stages [ and 2. o.

® ® WO 2005/012254 PCT/US2004/023488

In contrast to fragmented sleep architecture, as used herein the term "sleep consolidation" means a state in which the number of NREM sleep bouts, particularly Stages 3 and 4, and the length of those sleep bouts are increased, while the number and length of waking bouts are decreased. In essence, the architecture of the sleep disorder patient is consolidated to a sleeping state with increased periods of sleep and fewer awakenings during the night and more time is spent in slow wave sleep (Stages 3 and 4) with fewer oscillation Stage | and 2 sleep. Compounds of the present invention as described are effective in consolidating sleep pattems so that the patient with previously fragmented sleep can now achieve restorative, delta-wave sleep for longer, more consistent periods of time.

As sleep moves from stage 1 into later stages, heart rate and blood pressure drop, metabolic rate and glucose consumption fall, and muscles relax. In normal sleep architecture, NREM sleep makes up about 75% of total sleep time; stage 1 accounting for 5-10% of total sleep time, stage 2 for about 45-50%, stage 3 approximately 12%, and stage 4 13-15%. About 90 minutes after sleep onset, NREM sleep gives way to the first REM sleep episode of the night. REM makes up approximately 25% of total sleep time. In contrast to NREM sleep, REM sleep is characterized by high pulse, respiration, and blood pressure, as well as other physiological patterns similar to those seen in the active waking stage. Hence, REM sleep is also known as “paradoxical sleep.” Sleep onset occurs during NREM sleep and takes 10-20 minutes in healthy young adults. The four stages of NREM sleep together with a REM phase form one complete sleep cycle that is repeated throughout the duration of sleep, usually four or five times. The cyclical nature of sleep is regular and reliable; a REM period occurs about every 90 minutes during the night. However, the first

REM period tends to be the shortest, often lasting less than 10 minutes, whereas the later REM periods may last up to 40 minutes. With aging, the time between retiring and sleep onset increases and the total amount of night-time sleep decreases because of changes in sleep architecture that impair sleep maintenance as well as sleep quality. Both NREM (particularly stages 3 and 4) and REM sleep are reduced. However, stage 1

NREM sleep, which is the lightest sleep, increases with age.

As disclosed herein, compounds of the present invention also have the ability to increase delta power (see Figure 28). As used herein, the term "delta power" means a measure of the duration of EEG activity in the 0.5 to 3.5 Hz range during NREM sleep and is thought to be a measure of deeper, more refreshing sleep. Delta power is hypothesized to be a measure of a theoretical process called Process S and is thought to be inversely related to the amount of sleep an individual experiences during a given sleep period. Sleep is controlled by homeostatic mechanisms; therefore, the less one sleeps the greater the drive to sleep. Itis believed that Process S builds throughout the wake period and is discharged most efficiently during delta power sleep. Delta power is a measure of the magnitude of Process S prior to the sleep period. The longer one stays awake, the greater Process S or drive to sleep and thus the greater the delta power during NREM sleep. However, individuals with sleep disorders have difficulty achieving and maintaining delta wave sleep, and thus have a large build-up of Process S with limited ability to discharge this buildup during sleep. 5-HT2, inverse agonists tested preclinically and clinically mimic the effect of sleep deprivation on delta power, suggesting that subjects with sleep oo

® _ disorders treated with a 5-HT2 , inverse agonist will be able to achieve deeper more refreshing sleep.

These same effects have not been observed with currently marketed pharmacotherapies. In addition, currently marketed pharmacotherapies for sleep have side effects such as hangover effects or addiction that are associated with the GABA receptor. S-HT2 , inverse agonist do not target the GABA receptor and so these side effects are not a concem.

Subjective and objective determinations of sleep disorders:

There are a number of ways to determine whether the onset, duration or quality of sleep (e.g. non- restorative or restorative sleep) is impaired or improved. One method is a subjective determination of the patient, e.g., do they feel drowsy or rested upon waking. Other methods involve the observation of the patient by another during sleep, e.g., how long it takes the patient to fall asleep, how many times does the patient wake up during the night, how restless is the patient during sleep, etc. Another method is to objectively measure the stages of sleep using polysomnography.

Polysomnography is the monitoring of multiple electrophysiological parameters during sleep and generally includes measurement of EEG activity, electroculographic activity and electromyographic activity, as well as other measurements. These results, along with observations, can measure not only sleep latency (the amount of time required to fall asleep), but also sleep continuity (overall balance of sleep and wakefulness) and sleep consolidation (percent of sleeping time spent in delta-wave or restorative sleep) which may be an indication of the quality of sleep.

There are five distinct sleep stages, which can be measured by polysomnography: rapid eye movement (REM) sleep and four stages of non-rapid eye movement (NREM) sleep (stages 1, 2, 3 and 4).

Stage 1 NREM sleep is a transition from wakefulness to sleep and occupies about 5% of time spent asleep in healthy adults. Stage 2 NREM sleep, which is characterized by specific EEG waveforms (sleep spindles and K complexes), occupies about 50% of time spent asleep. Stages 3 and 4 NREM sleep (also known collectively as slow-wave sleep and delta-wave sleep) are the deepest levels of sleep and occupy about 10- 20% of sleep time. REM sleep, during which the majority of vivid dreams occur, occupies about 20-25% of ' total sleep.

These sleep stages have a characteristic temporal organization across the night. NREM stages 3 and 4 tend to occur in the first one-third to one-half of the night and increase in duration in response to sleep deprivation. REM sleep occurs cyclically through the night. Alternating with NREM sleep about every 80-100 minutes. REM sleep periods increase in duration toward the morning. Human sleep also varies characteristically across the life span. After relative stability with large amounts of slow-wave sleep in childhood and early adolescence, sleep continuity and depth deteriorate across the adult age range. This deterioration is reflected by increased wakefulness and stage 1 sleep and decreased stages 3 and 4 sleep.

In addition, the compounds of the invention can be useful for the treatment of the sleep disorders characterized by excessive daytime sleepiness such as narcolepsy. Inverse agonists at the serotonin SHT:4 receptor improve the quality of sleep at nightime which can decrease excessive daytime sleepiness.

® .

Accordingly, another aspect of the present invention relates to the therapeutic use of compounds of the present invention for the treatment of Sleep Disorders. Compounds of the present invention are potent inverse agonists at the serotonin SHT,, receptor and are effective in the treatment of Sleep Disorders by promoting one or more of the following: reducing the sleep onset latency period (measure of sleep induction), reducing the number of nighttime awakenings, and prolonging the amount of time in delta-wave sleep (measure of sleep quality enhancement and sleep consolidation) without effecting REM sleep. In addition, compounds of the present invention are effective either as a monotherapy or in combination with sleep inducing agents, for example but not limiting, antihistamines. 6. Diabetic-Related Pathologies:

Although hyperglycemia is the major cause for the pathogenesis of diabetic complications such as diabetic peripheral neuropathy (DPN), diabetic nephropathy (DN) and diabetic retinopathy (DR), increased plasma serotonin concentration in diabetic patients has also been implicated to play a role in disease progression (Pietraszek, M.H., et al. Thrombosis Res. 1992, 66(6), 765-74; and Andrzejewska-

Buczko J, et al., Klin Oczna. 1996; 98(2), 101-4). Serotonin is believed to play a role in vasospasm and increased platelet aggregability. Improving microvascular blood flow is able to benefit diabetic complications.

A recent study by Cameron and Cotter in Naunyn Schmiedebergs Arch Pharmacol. 2003 Jun; 367(6):607-14, used a SHT;, antagonist experimental drug AT-1015, and other non-specific SHT;, antagonists including ritanserin and sarpogrelate. These studies found that all three drugs were able to produce a marked correction (82.6-99.7%) of a 19.8% sciatic motor conduction deficit in diabetic rats.

Similarly, 44.7% and 14.9% reductions in sciatic endoneurial blood flow and saphenous sensory conduction velocity were completely reversed.

In a separate patient study, sarogrelate was evaluated for the prevention of the development or progression of diabetic nephropathy (Takahashi, T., et al., Diabetes Res Clin Pract. 2002 Nov; 58(2):123-9). In the trial of 24 months of treatment, sarpogrelate significantly reduced urinary albumin excretion level. 7. Glaucoma

Topical ocular administration of 5-HT2 receptor antagonists result in a decrease in intra ocular pressure (10P) in monkeys (Chang et al., J. Ocul Pharmacol 1:137-147 (1985)) and humans (Mastropasqua et al., Acta Ophthalmol Scand Suppl 224:24-25 (1997)) indicating utility for similar compounds such as 5-HT2, inverse agonists in the treatment of ocular hypertensin associated with glaucoma. The S-HT2 receptor antagonist ketanserin (Mastropasqua supra) and sarpogrelate (Takenaka et al., Investig Ophthalmol Vis Sci 36:5734 (1995)) have been shown to significantly lower IOP in glaucoma patients.

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Representative Methods of the Invention:

One aspect of the present invention encompasses methods for modulating the activity of a

SHT., serotonin receptor by contacting the receptor with a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of platelet aggregation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of an indication selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of reducing the risk of blood clot formation in an angioplasty or coronary bypass surgery individual comprising administering to said individual in need thereof a therapeutically effective amount ofa compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of asthma in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment ofa symptom of asthma in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention encompasses methods for prophylaxis or treatment of agitation or a symptom thereof in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein ar a pharmaceutical composition. In some embodiments, the individual is a cognitively intact elderly individual.

One aspect of the present invention encompasses methods for prophylaxis or treatment of agitation or a symptom thereof in an individual suffering from dementia comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of oo

® ® WO 2005/012254 PCT/US2004/023488 ] the embodiments described herein or a pharmaceutical composition. In some embodiments, the dementia is due to a degenerative disease of the nervous system. In some embodiments, the dementia is

Alzheimers disease, Lewy Body, Parkinson's disease or Huntington's disease. In some embodiments, the dementia is due to diseases that affect blood vessels. In some embodiments, the dementia is due to stroke or multi-infarct dementia.

One aspect of the present invention encompasses methods for prophylaxis or treatment of an individual suffering from at least one of the indications selected from the group consisting of behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia and NOS schizophrenia comprising administering to said individual in need thereof a therapeutically effective amount of a dopamine D2 receptor antagonist and a compound according to any of the embodiments described herein or a pharmaceutical composition. 1n some embodiments, the dopamine D2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods for prophylaxis or treatment of an individual with infantile autism, Huntington's chorea, or nausea and vomiting from chemotherapy or chemotherapeutic antibodies comprising administering to said individual in need thereof a therapeutically effective amount of a dopamine D2 receptor antagonist and a compound according to any of the embodiments described herein or a pharmaceutical composition. In some embodiments, the dopamine D2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods for prophylaxis or treatment of schizophrenia in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a dopamine D2 receptor antagonist and a compound according to any of the embodiments described herein or a pharmaceutical composition. In some embodiments, the dopamine D2 receptor antagonist is haloperidol.

One aspect of the present invention encompasses methods for prophylaxis or treatment of . alleviating negative symptoms of schizophrenia induced by the administration of haloperidol to an individual suffering from said schizophrenia, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition. In some embodiments, the haloperidol and the compound or pharmaceutical composition are administered in separate dosage forms. In some embodiments, the haloperidol and the compound or pharmaceutical composition are administered in a single dosage form.

One aspect of the present invention encompasses methods for prophylaxis or treatment of a sleep disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition,

® _

In some embodiments, the sleep disorder is a dyssomnia. In some embodiments, the dyssomnia is selected from the group consisting of psychophysiological insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless leg syndrome, inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient slecp syndrome, limit-setting sleep disorder, sleep-onset association disorder, nocturnal eating or drinking syndrome, hypnotic dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, toxin-induced sleep disorder, time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, and non-24-hour sleep-wake disorder.

In some embodiments, the sleep disorder is a parasomnia. In some embodiments, the parasomnnia is selected from the group consisting of confusional arousals, sleepwalking and sleep terrors, rhythmic movement disorder, sleep starts, sleep talking and nocturnal leg cramps. In some embodiments, the sleep disorder is characterized by excessive daytime sleepiness such as narcolepsy.

In some embodiments, the sleep disorder is associated with a medical or psychiatric disorder.

In some embodiments, the medical or psychiatric disorder is selected from the group consisting of psychoses, mood disorders, anxiety disorders, panic disorders, alcoholism, cerebral degenerative disorders, dementia, parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrical status epilepticus of sleep, sleep-related headaches, sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastroesophageal reflux, peptic ulcer disease, fibrositis syndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia and post-surgical sleep disorder.

One aspect of the present invention encompasses methods for prophylaxis or treatment ofa diabetic-related disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition.

In some embodiments, the diabetic-related disorder is diabetic peripheral neuropathy.

In some embodiments, the diabetic-related disorder is diabetic nephropathy. )

In some embodiments, the diabetic-refated disorder is diabetic retinopathy.

One aspect of the present invention encompasses methods for prophylaxis or treatment of glaucoma or other diseases of the eye with abnormal intraocular pressure.

One aspect of the present invention encompasses processes for preparing a composition comprising admixing a compound according any embodiments described herein and pharmaceutically acceptable carrier.

One aspect of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a 5HT,x mediated disorder.

® ® WO 2005/012254 PCT/US2004/023488

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,, mediated disorder wherein the disorder is platelet aggregation.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,, mediated disorder wherein the disorder is selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,, mediated disorder wherein the disorder is a blood clot formation in an angioplasty or coronary bypass surgery individual.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT;, mediated disorder wherein the disorder is a blood clot formation in an individual suffering from atrial fibrillation.

One embodiment of the present invention is the use of a compound for the production of a

IS medicament for use in the prophylaxis or treatment of a SHT, mediated disorder wherein the disorder is asthma.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,, mediated disorder wherein the disorder is a symptom of asthma.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,4 mediated disorder wherein the disorder is agitation or a symptom thereof in an individual. In some embodiments the individual is a cognitively intact elderly individual.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,. mediated disorder wherein the disorder is agitation or a symptom thereof in an individual suffering from dementia. In some embodiments the dementia is due to a degenerative disease of the nervous system. In some embodiment the dementia is

Alzheimers disease, Lewy Body, Parkinson’s disease, or Huntington's disease. In some embodiments the dementia is due to diseases that affect blood vessels. In some embodiments the dementia is due to stroke or multi-infract dementia.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,. mediated disorder further comprising a dopamine D2 receptor antagonist wherein the disorder is selected from the group consisting of a behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia and NOS schizophrenia. In some embodiments the dopamine D2 receptor antagonist is haloperidol. a

(

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a 5HT24 mediated disorder further comprising a dopamine D2 receptor antagonist wherein the disorder is infantile autism, Huntington's chorea, or nausea and vomiting from chemotherapy or chemotherapeutic antibodies. In some embodiments the dopamine D2 receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT24 mediated disorder further comprising a dopamine D2 receptor antagonist wherein the disorder is schizophrenia. In some embodiments the dopamine D2 receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT;4 mediated disorder wherein the disorder is a negative symptom or symptoms of schizophrenia induced by the administration of haloperidol.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT;a mediated disorder wherein the ‘haloperidol and the compound or pharmaceutical composition are administered in separate dosage forms.

One embodiment of the present invention is the use of a compound for the production of a medicament for use in the prophylaxis or treatment of a SHT,4 mediated disorder wherein the haloperidol and the compound or pharmaceutical composition are administered in a single dosage form.

One aspect of the present invention are compounds according to any of the embodiments described herein for use in a method of treatment of the human or animal body by therapy.

One aspect of the present invention are compounds according to any of the embodiments described herein for use in a method for the prophylaxis or treatment of a SHT,, mediated disorder, as described herein, in the human or animal body by therapy.

One aspect of the present invention are compounds according to any of the embodiments described herein for use in a method for the prophylaxis or treatment of a sleep disorder, as described herein, in the human or animal body by therapy.

One aspect of the present invention are compounds according to any of the embodiments described herein for use in a method for the prophylaxis or treatment of platelet aggregation in the human or animal body by therapy.

PHARMACEUTICAL COMPOSITIONS

A further aspect of the present invention pertains to pharmaceutical compositions comprising one or more compounds as described herein and one or more pharmaceutically acceptable carriers.

Some embodiments pertain to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.

®

Some embodiments of the present invention include a method of producing a pharmaceutical composition comprising admixing at least one compound according to any of the compound embodiments disclosed herein and a pharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid camiers, or both, in the required proportions, and then, if necessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tabletting lubricants, and disintegrants may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampoule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically-acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of

Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro, A. R., et al).

While it is possible that, for use in the prophylaxis or treatment, a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulations comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers thereof and/or prophylactic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a transdermal patch. Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with a minimum of degradation of the drug. Typically, transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner. One of ordinary skill in the art will understand and appreciate the

® ® techniques appropriate for manufacturing a desired efficacious transdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical formulations and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in the form of, for example, a 1ablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate or physiologically functional derivative thereof can be used as active ingredients in pharmaceutical compositions, specifically as 5-HT, receptor modulators. By the term “active ingredient” is defined in the context of a “pharmaceutical composition” and shall mean a component of a pharmaceutical composition that pravides the primary pharmacological effect, as opposed to an “inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can vary within wide limits, and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the present invention. Representative doses of the present invention include, but not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4, doses. Depending on the individual and as deemed appropriate from the patient’s .

® ® WO 2005/012254 PCT/US2004/023488 physician or care-giver it may be necessary to deviate upward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, . 5 the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors. )

Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated or prophylaxis 1s is conducted or on whether further active compounds are administered in addition to the compounds of the present invention and as part of a drug combination. The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.

The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.

The compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of the present invention, the selection of a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. I

C

®

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size. 3 The powders and tablets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary.

Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds accarding to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents Lo o ® WO 2005/012254 PCT/US2004/023488 such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, abtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparatifhs may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.

Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or : oily base and will in general alsa contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of 2 metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant. If the compounds of the present invention or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler.

Pharmaceutical forms for administration of the compounds of the present invention as an aerosol can be prepared by processes well-known to the person skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures or -

o ® } suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example include carbon dioxide,

CFC’s, such as, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier 1] will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.

The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

The compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, p-toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977); incorporated herein by reference in its entirety.

The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of oo.

( . ® WO 2005/012254 PCT/US2004/023488 this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.

Compounds of the present invention can be converted to “pro-drugs.” The term “pro-drugs” refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound.

Pro-drugs can thus be viewed as compounds of the invention containing one or more specialized non- toxic protective groups used in a transient manner to alter or to eliminate a property of the compound.

In one general aspect, the “pro-drug™ approach is utilized to facilitate oral absorption. A thorough discussion 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 hereby incorporated by reference in their entirety.

Some embodiments of the present invention include a method of producing a pharmaceutical composition for “combination-therapy” comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.

It is noted that when the 5-HT., receptor modulators are utilized as active ingredients in a pharmaceutical composition, these are not intended for use only in humans, but in other non-human mammals as well. Indeed, recent advances in the area of animal health-care mandate that consideration be given for the use of active agents, such as 5-HT,, receptor modulators, for the treatment of a 5-HT3, mediated disease or disorder in domestic animals (e.g., cats and dogs) and in other domestic animals (e.g., such as cows, chickens, fish, etc.). Those of ordinary skill in the art are readily credited with understanding the utility of such compounds in such settings.

OTHER UTILITIES

Another object of the present invention relates to radio-labeled compounds of the present invention that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the 5-HT;, receptor in tissue samples, including human, and for identifying 5-HT, 4 receptor ligands by inhibition binding of a radio-labeled compound. It is a further object of this invention to develop novel 5-H Ty, receptor assays of which comprise such radio-labeled compounds.

The present invention embraces isotapically-labeled compounds of the present invention. An “isotopically” or “radio-labeled”” compounds are those which are identical to compounds disclosed herein, but for the fact that one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), *H (also written as T for witium), ''C, °C, C, PN, N, 0, 70, "0, *F, ¥'s, *Cl, “Br, ™Br, “Br, "Br, "21, "I, 1 and *'L. oo

® ® WO 2005/012254 PCT/US2004/023488

The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro 5-HT, receptor labeling and competition assays, compounds that incorporate *H, '*C, #Br, '¥1, "'I, S or will generally be most useful. For radio-imaging applications ''C, "F, "#1, '21, '#1, *'], Br, "Br or "Br will generally be most useful.

It is understood that a “radio-labeled ” or “labeled compound” is a compound of Formula (I) that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected from the group consisting of ’H, “C, '¥I , *’S and Br.

Certain isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays. In some embodiments the radionuclide *H and/or 'C isotopes are useful in these studies. Further, substitution with heavier isotopes such as deuterium (i.e, 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.

Isotopically labeled compounds of the present invention can generally be prepared by following 15 . procedures analogous to those disclosed in the Schemes supra and Examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Other synthetic methods that are useful are discussed infra. Moreover, it should be understood that all of the atoms represented in the compounds of the invention can be either the most commonly occurring isotope of such atoms or the more scarce radio-isotope or nonradio-active isotope.

Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art. These synthetic methods, for example, incorporating activity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas - This procedure normally yields high specific activity products and requires halogenated or unsaturated precursors.

B. Reduction with Sedium Borohydride [’H] - This procedure is rather inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, and the like.

C. Reduction with Lithium Aluminum Hydride {*H ] - This procedure offers products at almost theoretical specific activities. 1t also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, and the like.

D. Tritium Gas Exposure Labeling - This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [*H] - This procedure is usually employed to prepare O- methyl or N-methyl (*H) products by treating appropriate precursors with high specific activity methyl iodide CH). This method in general allows for higher specific activity, such as for example, about 70- 90 C¥mmol.

Synthetic methods for incorporating activity levels of 12%] into target molecules include: Lo

® . . ® WO 2005/012254 PCT/US2004/023488

A. Sandmeyer and like reactions — This procedure transforms an aryl or heteroaryl amine into a diazonium salt, such as a tetrafluoroborate salt, and subsequently to ‘1 labeled compound using

Nal. A represented procedure was reported by Zhu, D.-G. and co-workers in J. Org. Chem. 2002, 67, 943-948.

B. Ortho “lodination of phenols — This procedure allows for the incorporation of '2°I at the ortho position of a phenol as reported by Collier, T. L. and co-workers in J. Labeled Compd

Radiopharm. 1999, 42, S264-5266.

C. Aryl and heteroaryl bromide exchange with '**I — This method is generally a two step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri- alkyltin intermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph,P)] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or bexaalkylditin [e.g., (CH3);SnSn(CH,)s]. A represented procedure was reported by Bas, M.-D. and co-workers in J. Labeled Compd Radiopharm. 2001, 44, S280-S282.

A radio-labeled 5-HT;, receptor compound of Formula (I) can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the “radio-labeled compound of

Formula (I)” to the 5-HT, receptor. Accordingly, the ability of a test compound to compete with the “radio-labeled compound of Formula (I)” for the binding to the 5-HT,, receptor directly correlates to its binding affinity.

The labeled compounds of the present invention bind to the 5-HT:,4 receptor. In one embodiment the labeled compound has an ICs, less than about 500 uM, in another embodiment the labeled compound has an IC; less than about 100 uM, in yet another embodiment the labeled compound has an ICs, less than about 10 pM, in yet another embodiment the labeled compound has an 1Cso less than about 1 pM, and in still yet another embodiment the labeled inhibitor has an ICsp less than about 0.1 pM.

Other uses of the disclosed receptors and methods will become apparent to those in the art based upon, inter alia, a review of this disclosure.

As will be recognized, the steps of the methods of the present invention need not be performed any particular number of times or in any particular sequence. Additional objects, advantages, and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples thereof, which are intended to be illustrative and not intended to be limiting.

EXAMPLES

EXAMPLE 1: Syntheses of compounds of the present invention.

( ®

Illustrated syntheses for compounds of the present invention are shown in Figures 17 through 21 and Figures 29 through 34 where the symbols have the same definitions as used throughout this disclosure.

The compounds of the invention and their synthesis are further illustrated by the following § examples. The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples. The compounds described herein, supra and infra, are named according to the CS Chem Draw Ultra Version 7.0.1, AutoNom version 2.2. In certain instances common names are used and it is understood that these common names would be recognized by those skilled in the art.

Chemistry: Proton nuclear magnetic resonance ( 'H NMR) spectra were recorded on a Varian

Mercury Vx-400 equipped with a 4 nucleus auto switchable probe and z-gradient or a Bruker Avance- 400 equipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse) and z-gradient.

Chemical shifts are given in parts per million (ppm) with the residual solvent signal used as reference.

NMR abbreviations are used as follows: s = singlet, d = doublet, t = triplet, = quartet, m = multiplet, br = broad. Microwave irradiations were carried out using the Emyrs Synthesizer (Personal Chemistry).

Thin-layer chromatography (TLC) was performed on silica gel 60 Fs, (Merck), preparatory thin-layer chromatography (prep TLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman), and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done in vacuo on a Buchi rotary evaporator. Celite 545 ® was used during palladium filtrations.

LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC system controller:

SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: CTC HTS,

PAL, Leap Scientific; Mass spectrometer: AP1 150EX with Turbo lon Spray source, AB/MDS Sciex;

Software; Analyst 1.2. 2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc; HPLC system controller:

SCL-10A VP, Shimadzu Inc.

UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: 215 Liquid Handler, Gilson Inc; Mass spectrometer: API 1S0EX with Turbo lon Spray source, AB/MDS Sciex

Software: Masschrom 1.5.2.

Example 1.1: Preparation of intermediate 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenylamine.

To a stirred solution of 4-bromo-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (1.799 g, 5.76 mmol) in EtOH (20 mL) was added SnCl-2H,0 (5.306 g, 23.05 mmol, 4.0 eq.), the mixture was stirred at reflux for 2 hrs and EtOH was removed under vacuum. The resulting solid was dissolved in

EtOAc, IN NaOH (30 mL) was added, and the mixture was stirred overnight. The white precipitate was filtered off through celite, and the aqueous phase was extracted with EtOAc (3x80 mL). The combined organic phase was dried over anhydrous MgSO, filtered and evaporated. The crude reaction )

® ® WO 2005/012254 PCT/US2004/023488 mixture was purified by SiO, column chromatography (Eluent: EtOAc/Hexane = 1/3 then 1/1) to give 34(4-bromo-2-methyl-2H-pyrazol-3-yl)}-4-methoxy-phenylamine (1.430 g, 5.07 mmol, 88%) as a white solid: LCMS m/z (%) = 282 (M+H™Br, 98), 284 (M+H"'Br, 100). ‘H NMR (400 MHz, CDCl,) 8: 7.52 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 2.8, 8.8 Hz, 1H), 6.22 (d,/=2.4 Hz, 1H), 4.25 ( broad s, 2H), 3.72 (s, 3H), 3.71 (s, 3H).

The intermediate 4-bromo-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole was prepared in the following manner:

A, 2-Methyl-2H-pyrazole-3-boronic acid: N-methyl pyrazole (25 mL, 0.3 mol) was dissolved in 500 mL of THF. The solution was then cooled to -78°C in a dry ice/isopropanol bath.

Once the solution reached —78°C, n-BuLi (140 mL, 0.40 mol) was added dropwise by canula. The reaction mixture was stirred at —78°C for 1.5 hours. Then, triisopropy! borate (280 mL, 1.2 mol) was added to the above mixture via canula. While stirring overnight, the reaction temperature was gradually increased from ~78°C to 0°C. The pH of the mixture was adjusted to 6 with IN HCl. THF was removed under reduced pressure, and the aqueous residue was extracted with EtOAc (2 x 100mL). The solid was then filtered to yield 108 g (100%) of 2-methyl-2H-pyrazole-3-boronic acid as a yellow solid. (Final product contains about 60% inorganic salt).

B. Trifluoro-methanesulfonic acid 2-methoxy-5-nitro-phenyl ester: To a stirred solution of 2-methoxy-5-nitrophenol (5.092 g, 30 mmol) in a mixture of CH,Cl, (3 mL) and pyridine (20 mL) was added triflic anhydride (16.478 g, 9.8 ml., 2.0 eq.) dropwise at 0°C. The mixture was warmed to room temperature and stirred for 2 hrs. Most of the pyridine was removed under vacuum. The residue was diluted with EtOAc, washed with IN HCl and water, the aqueous phase was then extracted with

EtOAc (3x100 mL). The combined organic phase was washed with brine, dried over anhydrous

MgSO, filtered and evaporated. The crude reaction mixture was purified by SiO, column chromatography (Eluent: EtOAc/Hexane = 1/3 then 1/2) to give the triflated compound trifluoro- methanesulfonic acid 2-methoxy-5-nitro-pheny! ester (8.943 g, 30 mmol, 100%) as a yellow solid:

LCMS m/z (%) = 302 (M+H, 100). 'H NMR (400 MHz, CDCl;) 8: 8.30 (dd, J = 4.0, 8.0 Hz, 1H), 8.16 (d, /J=4.0 Hz, IH), 7.15 ( d, J= 8.0 Hz, 1H), 4.06 (s, 3H).

C. 5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole: Trifluoro-methanesulfonic acid 2-methoxy-5-nitro-phenyl ester from Step B. (2.561 g, 8.50 mmol), 2-methyl-2H-pyrazole-3-boronic acid from Step A. (4.283 g, 34.01 mmol, 4.0 eq.) and Na,CO; (10.816 g, 102.04 mmol, 12.0 eq.) were dissolved in a mixture of THF (200 mL) and H,O (100 mL). The resulting mixture was degassed with

N, for 5 mins, followed by the addition of Pd(PPhs) (0.486 g, 0.42 mmol, 0.05 eq.). After degassing for another 5 mins it was stirred under Ar at 70°C overnight. Once the reaction was complete, THF was removed under reduced pressure and the aqueous phase was extracted with EtOAc (4x100 mL). The 3s combined organic phase was dried over anhydrous MgSO, filtered and evaporated. The crude reaction mixture was purified by SiO, column chromatography ( Eluent: EtOAc/Hexane = 1/1) to afford

® ® WO 2005/012254 PCT/US2004/023488 compound 5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (1.799 g, 7.71 mmol, 91%) as a white solid: LCMS m/z (%) = 234 (M+H, 100). 'H NMR (400 MHz, CDCl,) 8: 8.34 (dd, /=2.8,92 Hz, 1H), 8.19 (d, J= 2.8 Hz, 1H), 7.56 (4d, J=2.0 Hz, 1H), 7.08 (d, /=9.2 Hz, 1H), 6.31 (d, J= 1.6 Hz, 1H), 3.96 (s, 3H), 3.74 (s, 3H).

D. 4-Bromo-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole: To a stirred solution of 5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (1.787 g, 7.66 mmol) in DMF (20 mL) was added

NBS (1.515 g, 8.43 mmol, 1.1 eq.) in DMF (5 mL) dropwise at 0 °C. After stirring at 0°C for 3 hrs,

TLC showed completion of the reaction. The mixture was diluted with EtOAc (300 mL), washed with water (3x10 mL) and brine. The EtOAc phase was dried over anhydrous MgSQ,, filtered and evaporated. The crude reaction mixture was purified by SiO, column chromatography (Eluent:

EtOAc/Hexane = 1/3 then 1/1) to give the product 4-bromo-5-(2-methoxy-5-nitro-phenyl)-1-methyl- 1H-pyrazole (2.214 g, 7.09 mmol, 93%) as light yellow solid: LCMS m/z (%0) = 312 (M+H"Br, 100), 314 (M+H®Br, 100). 'H NMR (400 MHz, CDC},) §: 8.40 (dd, J = 2.4, 6.9 Hz, 1H), 8.22 (m, 1H), 7.57 (s, 1H), 7.14 (d, J = 92 Hz, 1H), 3.98 (5, 3H), 3.74 (s, 3H).

Example 1.2: Preparation of 1-{3-(4-Brome-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4- chloro-2-trifluoromethyl-phenyl)-urea (Compound 9).

Urea synthesis (General Procedure): To a stirred solution of 3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenylamine (0.034 g, 0.12 mo}, Example 1.1) in CHCl; (1 mL) was added 4-chloro-2-(trifluoromethyl)phenyl isocyanate (0.029 g, 20.0 nL, 0.13 mmol, 1.05 equiv.) at room temperature. White solid precipitated and was filtered and washed with cold CH,Cl, to afford

Compound 9 (0.037 g, 0.074 mmol, 60 %) as a white solid. LCMS m/z (%) = 503 (M+H"Br, 77), 439 (M+H"'Br, 100). "H NMR (400 MHz, acetone-ds) &: 8.82 (s, 1H), 8.22 (d, J = 9.6 Hz, 1H), 7.62-7.72 (m, 4H), 7.49 (s, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 3.83 (s, 3H), 3.68 (s, 3H). .

Example 1.3: Preparation of 1-[3-(4-Bromo-2-methyl-2 H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4- fluoro-phenyl)-urea (Compound 2). 3<(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (2.965 g, 10.5 mmol) was treated with 4-fluorophenyl isocyanate (1.601 g, 1.31 mL, 11.6 mmol, 1.1 equiv.) in CH;Cl, (20 mL), in a similar manner as described in Example 1.2 to afford Compound 2 (3.755 g, 8.94 mmol, 85 %)as a white solid. LCMS m/z (%) = 419 (M+H"Br, 99), 421 (M+H"'Br, 100). 'H NMR (400 MHz, acetone- de) 8: 8.49 (broad s, 2H), 7.77 (d, J = 9.0 Hz, 1H), 7.50-7.58 (m, 2H), 7.50 (s, 1H), 7.43 (s, 1H), 7.12 (d,

J = 8.9 Hz, 1H), 6.98-7.06 (m, 2H), 3.81 (s, 3H), 3.68 (s, 3H).

Example 1.4: Preparation of 1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(2,4- dichloro-phenyl)-urea (Compound 3).

® ® 3+(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 2,4-dichlorophenyl isocyanate (0.021 g, 0.11 mmol, 1.0 equiv.) in CH,Cl, (2 mL), ina similar manner as described in Example 1.2 to afford Compound 3 (0.036 g, 0.076 mmol, 69 %) as a white solid. LCMS m/z (%) = 469 (M+HBr*CI”’Cl, 60), 471 (M+HBr°CICI&* BCPC, 100), s 473 (M+H*'Br*CI’C1 ”Br’CPCl, 54), 475 (M+HYBr'’CPC), 4). 'H NMR (400 MHz, acetone-ds) 5: 8.81 (s, IH), 8.36 (d, J= 9.0 Hz, 1H), 7.91 (s, 1H), 7.69 (dd, J = 2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.48 (d,

J=2.4 Hz, 1H), 745 (d, J=2.7 Hz, 1H), 7.34 (dd, J=2.4, 9.0 Hz, 1H), 7.15 (d, /= 9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).

Example 1.5: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)}4-methoxy-phenyl]-3-(4- methoxy-phenyl)-urea (Compound 4). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 4-methoxypheny! isocyanate (0.016 g, 14.2 pL, 0.11 mmol, 1.0 equiv.) in CH,Cl, (2 mL), in a similar manner as described in Example 1.2 to afford Compound 4 (0.037 g, 0.086 mmol, 78 %) as a white solid. LCMS m/z (%) = 431 (M+H"Br, 89), 433 (M+H"Br, 100). ‘'H NMR (400 MHz, acetone-ds) 8: 8.02 (s, 1H), 7.89 (s, 1H), 7.67 (dd, /=2.7, 9.0 Hz, 1H), 749 (s, 1H), 743 (s, IH), 742 (d, J=9.0 Hz, 2H), 7.12 (d, J= 9.0 Hz, 1H), 6.85 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.68 (s, 3H).

Example 1.6: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yh)-4-methoxy-phenyl}-3-(4- bromo-phenyl)-urea (Compound 5). 3-(4-Bromo-2-methyl-2H-pyrazol-3-y1)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 4-bromopheny! isocyanate (0.022 g, 0.11 mmo}, 1.0 equiv.) in CH,Cl, (2 mL), in a similar manner as described in Example 1.2 to afford Compound 5 (0.040 g, 0.08 mmol, 75 %) asa white solid.

LCMS m/z (%) = 479 (M+H™B1"Br, 51), 481 (M+H™B:*'Br, 100), 483 (M+H*'Br*'Br, 50). 'H NMR {400 MHz, acetone-d;) 8: 8.22 (s, 1H), 8.14 (s, 1H), 7.68 (dd, J=2.7,9.0 Hz, 1H), 7.48-7.54 (m, 3H), 7.39-7.46 (m, 3H), 7.14 (d, J = 9.0 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).

Example 1.7: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenyl}-3- (4Chloro-3-triflueromethyl-phenyl)-urea (Compound 6). 3-(4-Bromo-2-methyl-2 H-pyrazol-3-y1)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 4-chloro-3-(triflucromethyl)phenyl isocyanate (0.027 g, 0.12 mmol, 1.0 equiv.) in CHCl, (2 mL), in a similar manner as described in Example 1.2 to afford Compound 6 (0.051 g, 0.10 mmol, 81 %) as a white solid. LCMS m/z (%) = 503 (M+H”BrCl, 78), 505 (M+H"'Br°Cl, 100), 507 (M+H*'Br?'Cl, 28). 'H NMR (400 MHz, acetone-dg) 5: 8.52 (s, 1H), 8.27 (s, 1H), 8.13 (5, 1H), 7.74 (4,

® ® WO 2005/012254 PCT/US2004/023488

J=18.7 Hz, tH), 7.68 (d, J=9.0 Hz, 1H), 7.53 (d, /= 8.7 Hz, 1H), 7.49 (5, {H), 743 (5, 1H}, 7.14 (d, J ’ =9.0 Hz, 1H), 3.82 (s, 3H), 3.68 (5, 3H).

Example 1.8: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazo}-3-yl)-4-methoxy-phenyl}-3-3,5- difluoro-phenyl)-urea (Compound 7). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 3,5-difluorophenyl isocyanate (0.018 g, 14 pL, 0.11 mmol, 1.0 equiv.) in CH,Cl, (2 mL), in a similar manner as described in Example 1.2 to afford Compound 7 (0.038 g, 0.09 mmol, 77 %) as a white solid. LCMS m/z (%) = 437 (M+H"Br, 100), 439 (M-+H*'Br, 100). ‘"H NMR (400 MHz, acetone-dg) 8: 8.47 (s, 1H), 8.23 (s, 1H), 7.68 (dd, J= 2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.18-7.27 (m, 2H), 7.15 (d, J= 9.0 Hz, 1H), 6.59 (tt, J= 2.3,9.1, 9.1 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).

Example 1.9: Preparation of 1-[3-(4-Brome-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenyl]-3-2,4- difluoro-phenyl)-urea (Compound 8). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)}-4-methoxy-phenylamine (0.027 g, 0.095 mmot) was treated with 2,4-difluorophenyl isocyanate (0.015 g, 11.5 pL, 0.095 mmol, 1.0 equiv.) in CH,Cl, (2 mL), in a similar manner as described in Example 1.2 to afford Compound 8 (0.030 g, 0.069 mmol, 71 %) as a white solid. LCMS m'z (%) = 437 (M+H"™Br, 100), 439 (M+H"Br, 91). 'H NMR (400 MHz, acetone~d) 6: 8.45 (s, 1H), 8.23 (dt, J=6.1,9.2 Hz, 1H), 7.93 (s, 1H), 7.68 (dd, J = 2.6, 9.0 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 7.07 (ddd, J=2.7, 8.7, 11.3 Hz, 1H), 6.93-7.02 (m, 1H), 3.82 (s, 3H), 3.69 (s, 3H).

Example 1.10: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3- (3Chloro-phenyl)-urea (Compound 20).

To a stirred solution of 3(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.015 g, 0.051 mmol) in CH,Cl; (1 mL) was added 3-chlorophenyl isocyanate (0.008 g, 7 pL, 0.054 mol, 1.05 equiv.). After the TLC showed the consumption of the starting material, it was isolated by preparative thin layer chromatography (TLC) (Eluent: EtOAc/Hexane = 1/1) and Compound 20 (0.020 g, 0.047 mmol, 92%) was obtained as a solid film. LCMS m/z (%) = 435 (M+H™Br, 68), 437 (M+H"'Br, 100). 'H NMR (400 MHz, acetone-ds) 8: 8.29 (s, 1H), 8.19 (s, 1H), 7.80 (t, J = 1.9 Hz, 1H), 7.29 (dd, J=2.7, 9.0 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 7.00 (d,/J=7.8 Hz, 1H), 3.82 (s, 3H), 3.68 (5, 3H).

Example 1.11: Preparation of 1-[3-(4-Bromo-2-methy}-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3- cyano-phenyl)-urea (Compound 21).

® ® WO 2005/012254 PCT/US2004/023488 3+4-Bromo-2-methyl-2H-pyrazol-3-y!)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 3-cyanophenyl isocyanate (0.020 g, 0.14 mol, 1.05 equiv.) in CH,Cl, (1 mL), in a similar manner as described in Example 1.10 to afford Compound 21 (0.032 g, 0.08 mmol, 58 %) as a white powder. LCMS m/z (%) = 426 (M+H™Br, 99), 428 (M+H*'Br, 100). 'H NMR (400 MHz, acetone-ds) 5: 8.45 (s, 1H), 8.26 (d, /=9.6 Hz, 1H), 8.05 (t, J= 1.7 Hz, 1H), 7.74 (dd,J= 1.5, 8.2 Hz, 1H), 7.70 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.48 (t, J = 8.1 Hz, 1H), 7.43 (d,J= 2.7 Hz, 1H), 7.36 (d, J= 7.6

Hz, 1H), 7.15 (d, J= 9.0 Hz, 1H), 3.83 (5, 3H), 3.69 (s, 3H).

Example 1.12: Preparation of 1-[3-(4-Bromao-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3- (3.4-difluoro-phenyl)-urea (Compound 10). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 3,4-difluorophenyl isocyanate (0.021 g, 16.0 pL, 0.13 mmol, 1.05 equiv.) in CHCl; (1 mL), in a similar manner as described in Example 1.2 to afford Compound 10 (0.021 g, 0.047 mmol, 38 %) as a white solid. LCMS m/z (%) = 437 (M+H"*Br, 100), 439 (M+H"'Br, 99). 'H NMR (400 MHz, acetone-d) 8: 8.29 (s, 1H), 8.16 (s, 1H), 7.74 (dddd, J= 2.5, 7.4, 13.4 Hz, 1H), 7.68 (dd, J=2.7, 9.0

Hz, IH), 7.49 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.11-7.26 (m, 2H), 7.13 (d, J= 9.0 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 3H).

Example 1.13: Preparation of 1-Biphenyl-2-yl-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)4- methoxy-phenyl}-urea (Compound 22) 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.036 g, 0.13 mmol) was treated with 2-biphenylyl isocyanate (0.027 g, 24.0 pL, 0.14 mmol, 1.05 equiv.) in CHCl; (1 mL), ina similar manner as described in Example 1.10 to afford Compound 22 (0.031 g, 0.06 mmol, 51 %) as a white powder. LCMS m/z (%) = 477 (M+H™Br, 100), 479 (M+H®'Br, 100). 'H NMR (400 MHz, acetone-dg) 5: B.41 (s, 1H), 8.17 (d, J= 8.3 Hz, 1H), 7.60 (d, J=12.7, 9.0 Hz, 1H), 7.43-7.51 (m, 3H), 7.37-7.43 (m, 3H), 7.29-7.37 (m, 2H), 7.24 (s, 1H), 7.20 (dd, J= 1.6, 7.6 Hz, 1H), 7.11 (dd, J=1.0,7.4

Hz, 1H), 7.08 (d, /= 9.0 Hz, 1H), 3.80 (5, 3H), 3.66 (s, 3H).

Example 1.14: Preparation of 1-[3-(4-Bromo-2-methy}-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(3- trifluoromethyl-phenyl}-urea (Compound 11). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with a,0,a-trifluoro-m-tolyl isocyanate (0.025 g, 18.0 pL, 0.13 mmol, 1.05 equiv.) in CH,ClL, (1 mL), in a similar manner as described in Example 1.2 to afford Compound 11 (0.038 g, 0.080 mmol, 65 %) as a white solid. LCMS m/z (%) = 469 (M+H"Br, 91), 471 (M+H® Br, 100). 'H NMR (400 MHz, acetone-ds) 8: 8.42 (s, 1H), 8.23 (s, 1H), 8.07 (5, 1H), 7.64-7.73 (m, 2H), 7.45-7.53 (m, 2H), 7.44 (s, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.15 (d, J = 8.9 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 3H). ]

® °

Example 1.15: Preparation of 1-{3-(4-Bromo-2-methyl-2H-pyrazo}-3-y[)-4-methoxy-pheny}}-3(4- trifluoromethyl-phenyl)-urea (Compound 12). 34(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with a,a,a-trifluoro-p-tolyl isocyanate (0.024 g, 19.0 pL, 0.13 mmol, 1.05 equiv.) in CHCl; (1 mL), in a similar manner as described in Example 1.2 to afford Compound 12 (0.048 g, 0.102 mmol, 83 %) as a white solid. LCMS m/z (%) = 469 (M+H™Br, 92), 471 (M+H* Br, 100). 'H NMR (400 MHz, acetone) 8: 8.51 (s, 1H), 8.27 (s, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.71 (dd, J=2.3, 9.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.52 (s, 1H), 7.46 (d, J= 2.3 Hz, 1H), 7.16 (d, J= 8.9 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 3H).

Example 1.16: Preparation of 1-[3-(4-Brome-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4-

Chloro-phenyl)-urea (Compound 1). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.260 g, 0.92 mmol) was ‘treated with 4-chlorophenyl isocyanate (0.144 g, 0.92 mmol, 1.0 equiv.) in CHCl; (5 mL), in a similar manner as described in Example 1.2 to afford Compound 1 (0.340 g, 0.78 mmol, 84 %) as a white solid.

LCMS m/z (%) = 435 (M+H”BP’C), 77), 437 M+H*'Br°Cl, 100), 439 (M+H*'Br'C), 25). 'H NMR (400 MHz, CDCl) 6: 7.56 (s, 1H), 7.44 (dd, J=2.7, 8.9 Hz, 1H), 7.34 (d,J=9.0 Hz, 1H), 729d, J = 9.0 Hz, 1H), 7.19 (d, J =2.7 Hz, 1H), 6.59 (s, 1H), 6.47 (s, 1H), 3.84 (5, 3H), 3.74 (s, 3H).

Example 1.17: Preparation of 1-(3,5-Bis-triflucromethyl-phenyl)-3-[3-(4-bromo-2-methy}-2H- pyrazol-3-yl)-4-methoxy-phenyl}j-urea (Compound 13). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 3,5-bis(trifluoromethyl)pheny! isocyanate (0.036 g, 24.0 pL, 0.14 mmol, 1.05 equiv.) in

CHCl, (1 mL), in a similar manner as described in Example 1.2 to afford Compound 13 (0.030 g, 0.06 mmol, 43 %) as a white solid. LCMS m/z (%) = 537 (M+H "Br, 99), 539 (M+H"'Br, 100). 'H NMR (400 MHz, acetone-d,) 8: 8.77 (s, 1H), 8.42 (5, [H), 8.22 (5, 2H), 7.73 (dd, /= 2.5, 9.0 Hz, 1H), 7.51 (s, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.18 (d, J= 9.0 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 3H).

Example 1.18: Preparation of 1-{3-(4-Bromo-2-methyl-2 H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4- isopropyl-phenyl)-urea (Compound 23). 3-(4-Bromo-2-methyl-2H-pyrazol-3-y1)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 4-isopropylphenyl isocyanate (0.022 g, 21.0 pL, 0.13 mmol, 1.05 equiv.) in CHCl, (1 mL), in a similar manner as described in Example 1.10 to afford Compound 23 (0.028 g, 0.06 mmol, 50 %) as a solid film. LCMS m/z (%) = 443 (M+H"Br, 100), 445 (M+H"'Br, 99). 'H NMR (400 MHz,

® acetone-d) 5: 8.08 (s, 1H), 8.00 (s, 1H), 7.68 (dd, J = 2.6, 8.9 Hz, 1H), 7.49 (s, 1H), 7.40-7.46 (m, 3H), 7.09-7.17 (m, 3H), 3.81 (5, 3H), 3.68 (s, 3H), 2.78-2.92 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H).

Example 1.19: Preparation of 1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3- naphthaien-2-yl-urea (Compound 14). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with 2-naphthyl isocyanate (0.023 g, 0.13 mmol, 1.05 equiv.) in CH,Cl, (1 mL), in a similar manner as described in Example 1.2 to afford Compound 14 (0.040 g, 0.09 mmol, 70 %) as a white solid. LCMS m/z (%) = 451 (M+H™Br, 95), 453 (M+H*'Br, 100). 'H NMR (400 MHz, acetone-ds) 5: 8.30 (s, 1H), 8.20 (s, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.56-7.84 (m, 3H), 7.72 (dd, J = 2.7, 9.0 Hz, 1H), 7.56 (dd, J=2.1, 8.8 Hz, IH), 7.50 (s, 1H), 7.48 (d, J = 2.7 Hz, 1H), 7.44 (1, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 3.83 (s, 3H), 3.70 (5, 3H).

Example 1.20: Preparation of 1-[3-(4-Bromo-2-methy)-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3- naphthalen-1-yl-urea (Compound 24). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenylamine (0.036 g, 0.13 mmol) was treated with [-naphthy! isocyanate (0.023 g, 0.14 mmol, 1.05 equiv.) in CH,Cl, (1 mL), in a similar manner as described in Example 1.10 to afford Compound 24 (0.039 g, 0.09 mmol, 68 %) as a white powder. LCMS nvz (%) = 451 (M+H"Br, 95), 453 (M+H" Br, 100). *H NMR (400 MHz, acetone-ds) 5: 8.58 (s, 1H), 8.32 (s, 1H), 8.16 (d, J= 7.0 Hz, 1H), 8.10 (d, J = 7.3 Hz, 1H), 7.91 (d, J = 9.4 Hz, 1H), 7.75 (dd, J =2.7, 9.0 Hz, 1H), 7.65 (d, J = 8.2 Hz, IH), 7.44-7.57 (m, SH), 7.14 (d, J= 9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (5, 3H).

Example 1.21: Preparation of 1-[3-(4-Bromo-2-methy}-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4- chloro-phenyl)-thiourea (Compound 71). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yi}-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 4-chloropheny! isothiocyanate (0.024 g, 0.14 mmol, 1.05 equiv.) in CH,Cl, (1 mL), in a similar manner as described in Example 1.10 to afford Compound 71 (0.048 g, 0.10 mmol, 80 %) as a solid film. LCMS m/z (%) = 451 (M+H"Br°Cl, 85), 453 (M+H"'Br**Cl, 100), 455 (M+H*'Br’C], 35). '"H NMR (400 MHz, CDCl) 8: 8.00 (s, 1H), 7.85 (s, 1H), 7.53 (s, 1H), 7.48 (dd, J= 2.7, 8.8 Hz, 1H), 7.37 (s, 4H), 7.30 (d, J = 2.7 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 3.87 (s, 3H), 3.75 (s, 3H).

Example 1.22: 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(3-nitro-phenyl)- urea (Compound 15). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.036 g, 0.13 mmol) was treated with 3-nitrophenyl isocyanate (0.023 g, 0.13 mmol, 1.05 equiv.) in CH,Cl, (1 mL), in a similar

® ® WO 2005/012254 : PCT/US2004/023488 manner as described in Example 1.2 to afford Compound 15 (0.040 g, 0.09 mmol, 70 %) as a yellow solid. LCMS m/z (%) = 446 (M+H™8r1, 100), 448 (M+H®'Br, 89). 'H NMR (400 MHz, acetone-de) 5: 8.63 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 7.80-7.86 (m, 2H), 7.72(dd, J =2.7,9.0 Hz, 1H), 7.55 (, J = §.2 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J= 2.7 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).

Example 123: Preparation of 1-[3A4-Bromo-2-methyl-2 H-pyrazol-3-y1)-4-methoxy-phenyl}-3-(4- fluoro-3-nitro-phenyl)-urea (Compound 16). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 4-fluoro-3-nitrophenyl isocyanate (0.025 g, 0.14 mmol, 1.05 equiv.) in CHCl; (1 mL), in a similar manner as described in Example 1.2 to afford Compound 16 (0.042 g, 0.09 mmo}, 69 %) as a yellow solid. LCMS m/z (%) = 464 (M+H"Br, 100), 466 (M+H*'Br, 96). 'H NMR (400 MHz, acetone-ds) &: 8.55 (s, 1H), 8.44-8.50 (m, 1H), 8.29 (s, 1H), 7.77-7.83 (s, 1H), 7.70 (dd, J=2.7,9.0 Hz, 1H), 7.49 (s, 1H), 7.37-7.46 (m, 2H), 7.16 (d, J = 8.9 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).

Example 1.24: Preparation of 1-(3-Acetyi-phenyl)-3-{3-(4-bromo-2-methy}-2H-pyrazol-3-yI)-4- methoxy-phenylj-urea (Compound 17). 3(4-Bromo-2-methyl-2H-pyrazoi-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 3-acetylphenyl isocyanate (0.019 g, 15.8 uL, 0.11 mmol, 1.85 equiv.) in CH,Cl; (1 mL), in a similar manner as described in Example 1.2 to afford Compound 17 (0.038 g, 0.09 mmol, 79 %) as a white solid. LCMS m/z (%) = 443 (M+H"Br, 99), 466 (M+H*'Br, 100). 'H NMR (400 MHz, acetone- ds) 8: 8.30 (s, 1H), 8.19 (s, 1H), 8.13 (t, J= 1.8 Hz, 1H), 7.80 (dd, J= 1.4, 8.1 Hz, 1H), 7.70 (dd, J = 2.7,9.0 Hz, IH), 7.62 (d, J= 7.7 Hz, 1H), 7.49 (s, IH), 7.44 (d, J= 2.7 Hz, 1H), 7.41 (1, J= 7.9 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H).

Example 1.25: Preparation of 1-{3(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3- methoxy-phenyl)-urea (Compound 72). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenylamine (0.032 g, 0.12 mmol) was treated with 3-methoxyphenyl isocyanate (0.018 g, 16.0 pL, 0.14 mmol, 1.05 equiv.) in CHCl; (1 mL), in a similar manner as described in Example 1.10 to afford Compound 72 (0.047 g, 0.11 mmol, 94 %) as a solid film. LCMS m/z (%) = 431 (M+H"Br, 100), 433 (M+H*'Br, 93). 'H NMR (400 MHz, acetone-dg) 8: 8.13 (s, 2H), 7.68 (d, J = 8.9 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.12 (d,J= 7.3 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H). 3.68 (5, 3H).

Example 1.26: Preparation of 1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-y[)-4-methoxy-phenyl}-3-(3- fluoro-phenyl)-urea (Compound 18).

® ® WO 2005/012254 PCT/US2004/023488 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)}-4-methoxy-phenylamine (0.033 g, 0.12 mmol) was treated with 3-fluoropheny! isocyanate (0.017 g, 14.3 uL, 0.12 mmol, 1.05 equiv.) in CHCl, (I'mL), in a similar manner as described in Example 1.2 to afford Compound 18 (0.040 g, 0.09 mmol, 82 %) as a white solid. LCMS nvz(%) = 419 (M+H"’Br, 100), 421 (M+H"Br, 91). 'H NMR (400 MHz, acetone- de) 8: 8.31 (s, 1H), 8.17 (5, 1H), 7.69 (dd, J = 2.7, 9.0 Hz, 1H), 7.59 (dt, J = 22,12.0 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J= 2.6 Hz, 1H), 7.27 (dd, J = 8.1, 15.0 Hz, 1H), 7.11-7.19 (m, 2H), 6.73 (ddd, J=2.4,8.4

Hz, 1H), 3.82 (s, 1H), 3.69 (s, 1H).

Example 1.27: Preparation of 1-[3-(4-Bromo-2-methyl-2 H-pyrazol-3-yl)-4-methoxy-phenyl)-3(2- flucro-phenyl)-urea (Compound 25). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.034 g, 0.12 mmol) was treated with 2-fluorophenyl isocyanate (0.018 g, 14.4 pL, 0.12 mmol, 1.05 equiv.) in CHCl, (1 mL), in a similar manner as described in Example 1.10 to afford Compound 25 (0.045 g, 0.11 mmol, 91 %) as a solid film. LCMS m/z (%) = 419 (M+H" Br, 99), 421 (M+H*'Br, 100). '"H NMR (400 MHz, CDCl) 5: 8.08 (t, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.53-7.59 (m, 1H), 7.40 (s, 1H), 7.12 (d,/=1.5

Hz, 1H), 6.95-7.12 (m, 3H), 6.94 (d, J = 5.7 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H).

Example 1.28: Preparation of 1-[3«(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3(4- trifluoromethoxy-phenyl)-urea (Compound 19), 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 4~(trifluoromethoxy)pheny! isocyanate (0.025 g, 18.4 pL, 0.12 mmol, 1.05 equiv.) in

CH,Cl, (1 mL), in a similar manner as described in Example 1.2 to afford Compound 19 (0.032 g, 0.07 mmol, 58 %) as a white solid. LCMS m/z (%) = 485 (M+H "Br, 92), 487 (M+H"'Br, 100). 'H NMR (400 MHz, acetone-ds) 8: 8.31 (s, 1H), 8.19 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.51 (s, 1H), 7.45 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.9 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H).

Example 1.29: Preparation of 1-Benzoyl-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-y1}-4-methoxy- phenyl)-urea (Compound 73). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.033 g, 0.12 mmol) was treated with benzoyl isocyanate (0.020 g, 0.12 mmol, 1.05 equiv.) in CH,Cl; (1 mL), in a similar manner as described in Example 1.2 to afford Compound 73 (0.036 g, 0.08 mmol, 72 %) as a white solid. LCMS mvz (%) = 429 (M+H™Br, 99), 431 (M+H"'Br, 100). 'H NMR (400 MHz, acetone-dg) 8: 10.92 (s, tH), 9.85 (s, 1H), 8.12 (d, J= 7.4 Hz, 2H), 7.76 (dd, J = 2.6, 9.0 Hz, 1H), 7.68 (t, J= 7.3 Hz, 1H), 7.62 (d, J = 2.6 Hz, 1H), 7.57 (1,J = 7.8 Hz, 2H), 7.51 (5, 1H), 7.21 (d, J= 9.0 Hz, 1H), 3.86 (5, 3H), 3.71 (s, 3H).

( ®

Example 1.30: Preparation of 1-Benzyl-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenylj-urea (Compound 74). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenylamine (0.034 g, 0.12 mmol) was treated with benzyl isocyanate (0.017 g, 16.0 uL, 0.13 mmol, 1.05 equiv.) in CH,Cl, (1 mL), in a similar manner as described in Example 1.10 to afford Compound 74 (0.031 g, 0.08 mmol, 62 %) as a solid film. LCMS m/z (%) = 415 (M+H "Br, 86), 417 (M+H*'Br, 100). ‘'H NMR (400 MHz, acetone- de) 5: 8.05 (s, 1H), 7.64 (dd, J =2.7,9.0 Hz, 1H), 7.47 (s, 1H), 7.40 (4, J = 2.7 Hz, 1H), 7.27-7.37 (m, 4H), 7.22 (1, J = 7.0 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.21 (s, 1H), 4.41 (d, J= 4.0 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 3H).

Example 1.31: Preparation of intermediate 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy- phenylamine. 3-(4-Bromo-2-methyl-2H-pyrazol-3-y})-4-ethoxy-phenylamine was prepared in a similar manner as described in Example 1.1 using 4-bromo-5-(2-ethoxy-5-nitro-phenyl)- 1 -methyl-1H-pyrazaole,

SnCly2H,0 in EtOH [0.225 g, 0.76 mmol, 81 % for three steps from 2-(2-methyl-2H-pyrazol-3-yl)-4- nitro-phenol]. LCMS m/z (%) = 296 (M+H™Br, 100), 298 (M+H"'Br, 98). 'H NMR (400 MHz,

CDCL) 8: 7.52 (s, 1H), 6.86 (d, J= 8.7 Hz, 1H), 6.77 (dd, J= 2.2, 8.5 Hz, 1H), 6.62 (d, J = 2.3 Hz, 1H), 3.82-4.00 (m, 2H), 3.73 (s, 3H), 3.24-3.58 (broad s, 2H), 1.24 (t, J= 6.8 Hz, 3H).

The intermediate 4-bromo-5-{2-ethoxy-5S-nitro-phenyl)-1-methyl-1H-pyrazole was prepared in the following manner:

A. 2-(2-Methyl-2H-pyrazol-3-yl)-4-nitro-phenol: To methyl hydrazine (1.106 g, 1.3 mL, 23.5 mmol, 4.0 equiv.) was added 4-nitrochromone in DMSO (1.159 g/40 mL, 5.88 mmol, 1.0 equiv.) dropwise via syringe pump at 70 °C, the crude reaction mixture was isolated by HPLC to afford 2-(2- methyl-2H-pyrazol-3-y1)-4-nitro-phenol (0.567 g, 2.59 mmol, 44%) as a white solid. LCMS m/z = 220 (M+H). 'H NMR (400 MHz, acetone-ds) 8: 8.24 (dd, J=2.9, 9.0 Hz, 1H), 8.13 (d, J=2.8 Hz, 1H), 7.46 (d, J= 1.8 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H), 6.36 (d, J= 1.8 Hz, 1H), 3.77 (s, 3H).

B. 5-2-Ethoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (General Alklyation Procedure):

To a stirred solution of 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol (0.206 g, 0.94 mmol) in a mixture of DMF/THF (1 mL/5 mL) was added NaH (60%, 0.082 g, 1.88 mmol, 2.0 equiv.) at 0 °C. It was stirred for 30 mins, iodoethane (0.444 g, 0.23 mL, 3.0 equiv.) was then added, the mixture was warned up to 70 °C and stirred until the consumption of the starting material. It was quenched with saturated

NHC, diluted with EtOAc, washed with water and the aqueous phase was extracted with EtOAc (3x50 mL). The combined organic phase was washed with brine, dried over MgSO, filtered and evaporated.

The crude reaction mixture was subjected to the bromination without any purification. LCMS m/z = 248 (M+H). 'H NMR (400 MHz, CDCl) 8: 8.33 (dd, J= 2.5, 9.1 Hz, 1H), 821 (d, J=2.5 Hz, 1H),

® _ 7.57(d,J=13 Hz, 1H), 7.07 (d, J = 9.1 Hz, 1H), 6.34 (s, 1H), 4.22 (dd, J = 7.0, 13.9 Hz, 2H), 3.78 (s, 3H), 1.44 (t, J= 6.8 He, 3H).

C. 4-Bromo-5-(2-ethoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole: The crude reaction mixture of 5-(2-ethoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole was treated with NBS in DMF, ina similar manner as described in Example 1.1, Step D, provided brominated compound 4-bromo-5-(2- ethoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole. It was reduced directly to the aniline as described in this cxample above. LCMS m/z (%) = 326 (M+H Br, 88), 328 (M+H"'Br, 100). 'H NMR (400 MHz,

CDCl;) 6: 8.38 (dd, /=2.7,9.2 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H), 7.59 (s, 1H), 7.11 (d, J=92 Hz, 1H), 4.14-4.32 (m, 2H), 3.76 (s, 3H), 1.43 (1, J = 6.8 Hz, 3H).

Example 1.32: Preparation of 1-{3-(4-Bromo-2-methy-2H-pyrazo}-3-y({)-4-ethoxy-phenyl]-3- (4Chloro-phenyl)-urea (Compound 67) 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy-phenylamine (0.040 g, 0.13 mmol) was treated with 4-chlorophenyl isocyanate (0.023 g, 0.15 mmol, 1.1 equiv.) in CH,Cl, (1 mL), in a similar manner as described in Example 1.2 to afford Compound 67 (0.034 g, 0.08 mmol, 56 %) as a white solid. LCMS m/z (%) = 449 (M+H”BrC}, 72), 451 (M+H"'Br¥’Cl, 100), 453 (M+H"BF'C}, 26). 'H

NMR (400 MHz, acetone-ds) 5: 8.22 (s, 1H), 8.14 (5, 1H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.56 d,J= 8.8 Hz, 2H), 7.49 (5, 1H), 7.43 (d, J = 2.7 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 9.0 Hz, 1H), 3.98-4.18 (m, 2H), 3.71 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 20 .

Example 133: Preparation of 1-j3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy-phenyl]-3-(4- fluoro-phenyl)-urea (Compound 68). 3-(4-Bromo-2-methy}-2H-pyrazol-3-yl)-4-ethoxy-phenylamine (0.039 g, 0.13 mmol) was treated with 4-fluorophenyl isocyanate (0.020 g, 16.6 pL, 0.14 mmol, 1.1 equiv.) in CH,Cly (1 mL), in a similar manner as described in Example 1.2 to afford Compound 68 (0.034 g, 0.08 mmol, 59 %) as a white solid. LCMS m/z (%) = 433 (M+H™Br, 100), 435 (M+H™'Br, 99). 'H NMR (400 MHz, acetone- ds) 8: 8.13 (s, IH), 8.11 (s, 1H), 7.66 (dd, J = 2.7, 8.9 Hz, 1H), 7.50-7.57 (m, 2H), 7.49 (s, 1H), 7.42 (d,

J=2.7Hz, 1H), 7.11 (d,J= 8.9 Hz, 1H), 7.04 (t, J = 8.8 Hz, 2H), 3.96-4.18 (m, 2H), 3.71 (5, 3H), 1.28 (t,/=17.1 Hz, 3H).

Example 1.34: Preparation of intermediate 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4- isopropoxy-phenylamine.

The crude reaction mixture of 4-bromo-5-(2-isopropoxy-5-nitro-phenyl)-1-methyl-1 H-pyrazole (as described below) was reduced in the presence of SnCl,2H;Q, in a similar manner as described in

Example 1.1, providing 3-(4-bromo-2-methyl-2H-pyrazol-3-y1)-4-isopropoxy-phenylamine (0.043 g, 0.14 mmol, 50% for three steps). LCMS m/z (%) = 310 (M+H"”Br, 99), 312 (M+H" Br, 100). 'H NMR

® ® : (400 MHz, CDCl3) 8: 7.51 (s, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.76 (dd, J = 2.7, 8.6 Hz, 1H), 6.62 (d, J = 2.7 Hz, 1H), 4.08 (ddd, J=6.1,6.1, 12,2 Hz, 1H), 3.74 (s, 3H), 1.21 (d, /= 6.1 Hz, 3H), 1.0] (d,/=6.1

Hz, 3H).

Intermediate 4-bromo-5-(2-isopropoxy-S-nitro-phenyl)-1-methyl- 1H-pyrazole was prepared in the following manner:

A. 5-(2-Isopropoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole: To a stirred solution of 22- methyl-2H-pyrazol-3-yl)-4-nitro-phenol (0.061 g, 0.28 mmol) in DMF (3 mL) was added K,CO, (0.077 g, 0.56 mmol, 2.0 equiv.) atr.t., it was stirred for 30 mins and isopropyl bromide (110 pL, 0.146 g, 1.16 mmol, 4.0 equiv.) was added. The mixture was stirred at 50 °C until the consumption of starting material was complete. The reaction mixture was diluted with EtOAc, washed with water and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO,, filtered and evaporated. LCMS m/z = 262 (M+H). ‘H NMR (400 MHz, CDCl) 5: 8.31 (dd, J=2.8, 9.2 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H), 7.56 (s, 1H), 7.06 (d, /=9.2 Hz, 1H), 6.3 (s, 1H), 4.74 (ddd, J=6.1, 6.1, 12.1 Hz, 1H), 1.37 (s, 3H), 1.36 (s, 3H).

B. 4-Brémo-5-(2-isopropoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole: The crude reaction mixture of 5-(2-isopropoxy-5-nitro-phenyl}-1-methyl-1H-pyrazole was brominated, in a similar manner as described in Example 1.1, Step D, providing 4.bromo-5-(2-isopropoxy-S-nitro-phenyl)-1-methyl-1H- pyrazole. LCMS m/z (%) = 340 (M+H"Br, 85), 342 (M+H"'Br, 100). 'H1 NMR (400 MHz, CDCl) 8: 8.36 (dd, J =2.8, 9.2 Hz, 1H), 8.20 (d, J= 2.8 Hz, 1H), 7.57 (5, 1H), 7.10 (d, J = 9.2 Hz, 1H), 4.73 (ddd, J=6.1, 6.1, 12.1 Hz, 1H), 1.39 (d, J = 6.1 Hz, 3H), 1.32 (d, J = 6.0 Hz, 3H).

Example 1.35: Preparation of 1-[3-(4-Bromo-2-methy)-2A-pyrazol-3-yl)-4-isopropoxy-phenyl}-3- (4-Chloro-phenyl)-urea (Compound 59). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl}-4-isopropoxy-phenylamine (0.024 g, 0.08 mmol) was treated with 4-chlorophenyl isocyanate (0.014 g, 0.09 mmol, 1.1 equiv.) in CHCl; (1 mL), ina similar manner as described in Example 1.10 to afford Compound 59 (0.034 g, 0.07 mmol, 91 %) as a white solid. LCMS m/z (%) = 463 (M+H"Br*Cl, 82), 465 (M+H"'Br'°C}, 100), 467 (M+H¥Br’CL, 29). 'H

NMR (400 MHz, acetone-dg) 5: 8.24 (s, 1H), 8.17 (s, 1H), 7.65 (dd, J=2.5,89 Hz, 1H), 755d, J = 8.6 Hz, 2H), 7.49 (s, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.28 (d, J= 8.6 Hz, 2H), 4.42-4.52 (m, 1H), 3.70 (s, 3H), 1.26 (d, J = 6.0 Hz, 3H), 1.11 (d, J = 6.0 Hz, 3H).

Example 1.36: Preparation of 1-[3-(4-Bromo-2-methy}-2H-pyrazol-3-yl)-4-isopropoxy-phenyi}-3- (4-fluoro-phenyl)-urea (Compound 60). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-isopropoxy-phenylamine (0.027 g, 0.09 mmol) was treated with 4-fluorophenyl isocyanate (0.013 g, 11.0 pL, 0.10 mmol, 1.1 equiv.) in CHCl; (1 mL), in a similar manner as described in Example 1.2 to afford Compound 60 (0.015 g, 0.03 mmol, 38 %) as a

® ® white solid. LCMS m/z (%) = 447 (M+H™Br, 98), 449 (M+H*'Br, 100). 'H NMR (400 MHz, acetone- : dg) 8: 8.11 (s, 2H), 7.65 (dd, J = 2.4, 8.9 Hz, 1H), 7.54 (dd, J= 4.9, 8.7 Hz, 2H), 7.49 (s, 1H), 7.41 (d,J =2.6 Hz, 1H), 7.12 (d, J= 8.9 Hz, 1H), 7.04 (t, J = 8.8 Hz, 2H), 4.40-4.52 (m, 1H), 3.70 (5, 3H), 1.26 (d,J=6.0 Hz, 3H), 1.11 (d, J= 6.0 Hz, 3H).

Example 1.37: Preparation of 4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine.

The reaction mixture of S-(2-benzyloxy-5-nitro-phenyl}4-bromo-1-methyl-1 H-pyrazole was reduced in the presence of SnCl;2H,0, in a similar manner as described in Example 1.1, providing 4- benzyloxy-3-(4-bromo-2-methy}-2H-pyrazol-3-yl)-phenylamine (0.079 g, 0.22 mmol, 39 % for three steps). LCMS m/z (%) = 358 (M+H"Br, 98), 360 (M+H"®'Br, 100). '"H NMR (400 MHz, CDCl;) &: 7.45 (s, 1H), 7.15-7.26 (m, 3H), 7.10 (d, J = 6.6 Hz, 2H), 6.83 (d, J= 8.7 Hz, 1H), 6.66 (dd, J=2.8, 8.6

Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 4.83 (AB quartet, J = 12.0, 17.2 Hz, 2H), 3.62 (s, 3H).

The intermediate 5+2-benzyloxy-5-nitro-phenyl)-4-bromo-1-methyl-1H-pyrazole was prepared in the following manner: : A. 5-(2-Benzyloxy-5-nitro-pheny!)-1-methyl-1H-pyrazole: 22-Methyl-2H-pyrazol-3-yl)- 4-nitro-phenol (0.124 g, 0.57 mmol) was treated with NaH (0.049 g, 1.13 mmol, 2.0 equiv.) and benzyl bromide (0.297 g, 0.21 mL, 1.70 mmol, 3.0 equiv.) in a mixture of DMF/THF (2 mL/4 mL), in a similar manner as described in Example 1.31, Step B, providing 5<(2-benzyloxy-5-nitro-pheny!)-1-methyl-1H- pyrazole. LCMS m/z = 310 (M+H). 'H NMR (400 MHz, CDCl;) 6: 8.32 (dd, /=2.8, 9.1 Hz, 1H), 8.24 (d, /=2.8 Hz, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.22-7.45 (m, 5H), 7.16 (d,/=9.1 Hz, 1H), 6.37 (d,J = 1.7 Hz, 1H), 5.25 (s, 2H), 3.77 (s, 3H).

B. 542-Benzyloxy-S-nitro-phenyl)-4-bromo-1-methyl-1H-pyrazole: The crude reaction mixture of 5-(2-benzyloxy-5-nitro-phenyl)- 1-methyl-} H-pyrazole was treated with NBS (0.113 g, 0.63 mmol, 1.1 equiv.), in a similar manner as described in Example 1.1, Step D, providing to 5-(2-

Benzyloxy-5-nitro-phenyl)-4-bromo-1-methy!l-1H-pyrazole. LCMS m/z (%) = 388 (M+H™Br, 100), 390 (M+H®Br, 94). 'H NMR (400 MHz, CDCl,) 8: 8.36 (dd, J = 2.8, 9.2 Hz, 1H), 8.23 (d, J=2.8 Hz, 1H), 7.59 (s, 1H), 7.25-7.42 (m, SH), 7.19 (d, J=9.2 Hz, 1H), 5.24 (s, 2H), 3.73 (s, 3H).

Example 1.38: Preparation of 1-[4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyi]-3- (4-Chloro-phenyl)-urea (Compound 61). 4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.023 g, 0.09 mmol) was treated with 4-chlorophenyl isocyanate (0.016 g, 0.10 mmol, 1.1 equiv.) in CH,Cl, (1 mL), in a similar manner as described in Example 1.2 to afford Compound 61 (0.019 g, 0.04 mmol, 42 %) as a white solid. LCMS m/z (%) = 511 (M+HBr’Cl, 82), 513 (M+H*'Br**C}, 100), 515 (M+H*'BrY'Cl, 33). 'H

NMR (400 MHz, acetone-d) §: 8.22 (s, 1H), 8.16 (s, 1H), 7.66 (dd, J=2.4,8.9 Hz, 1H), 7.55(d,J=

Qo . ‘ ® WO 2005/012254 PCT/US2004/023488 8.7 Hz, 2H), 7.50 (s, 1H), 7.46 (d, J= 2.5 Hz, 1H), 7.28-7.35 (m, SH), 7.28 (d, J = 8.7 Hz, 2H), 7.22 (d,

J=8.9 Hz, 1H), 5.13 (AB quartet, J= 12.0, 24.3 Hz, 2H), 3.69 (s, 3H).

Example 1.39: Preparation of 1-[4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- (4-fluoro-phenyl)-urea (Compound 62). 4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.031 g, 0.09 mmol) was treated with 4-fluorophenyl isocyanate {0.013 g, 11.0 pL, 0.10 mmol, 1.1 equiv.) in CH,Cl; (I mL), ina similar manner as described in Example 1.2 to afford Compound 62 (0.011 g, 0.02 mmol, 26 %) as a white solid. LCMS m/z (%) = 511 (M+H"Br, 82), 513 (M+H"Br, 100). 'H NMR (400 MHz, acetone- dq) 8: 8.12 (s, 2H), 7.66 (dd, J = 2.6, 8.9 Hz, 1H), 7.54 (dd, J = 4.8, 9.0 Hz, 2H), 7.50(s, 1H), 747(d, J =2.6 Hz, 1H), 7.25-7.36 (m, 5H), 7.22 (d, J= 8.9 Hz, 1H), 7.04 (1, J = 8.8 Hz, 2H), 5.13 (AB quartet, J =12.0, 24.4 Hz, 2H), 3.69 (s, 3H).

Example 1.40: Preparation of intermediate 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chloro- benzyloxy)-phenylamine.

The crude reaction mixture of 4-bromo-5-[2-(4-chloro-benzyloxy)-S-nitro-phenyl]-1-methyl- 1H-pyrazole (as described below) was treated with SnCl;2H,0 (0.378 g, 1.64 mmol, 4.0 equiv.) in

EtOH (5 mL), in a similar manner as described in Example 1.1, providing aniline 3-(4-bromo-2-methyl- 2H-pyrazol-3-y1}-4~(4-chloro-benzyloxy)-phenylamine (0.114 g, 0.29 mmol, 71% for two steps).

LCMS m/z (%) = 392 (M+H"Br*’Cl, 70), 394 (M+H*'Br*Cl, 100), 396 (M+H*'Br’Cl, 23). 'H NMR (400 MHz, CDCl;) 8: 7.54 (s, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.11 (d, J= 8 2 Hz, 2H), 6.90 (d, J= 8.7

Hz, 1H), 6.76 (dd, J = 2.7, 8.7 Hz, 1H), 6.63 (d, J= 2.7 Hz, 1H), 4.86 (AB quartet, J= 12.1, 20.9 Hz, 2H), 3.71 (5, 3H).

The intermediate 4-bromo-5-[2-(4-chlero-benzyloxy)-S-nitro-phenyl}- 1-methyl- | H-pyrazole was prepared in the following manner:

A. 5-{2{4-Chloro-benzyloxy)-5-nitro-phenyl]-1-methyl- 1 H-pyrazole: 2-(2-Methyl-2H- pyrazol-3-yl)-4-nitro-phenol (0.143 g, 0.65 mmol) was treated with NaH (0.057 g, 1.30 mmol, 2.0 equiv.) and 4-chlorobenzyl bromide (0.332 g, 1.96 mmol, 3.0 equiv.) in a mixture of DMF/THF (0.9 mL/2.5 mL), in a similar manner as described in Example 1.31, Step B, providing 5-[2-(4-chloro- benzyloxy)-5-nitro-phenyl)- 1-methyl- 1H-pyrazole (0.142 g, 0.41 mmol, 63%) as an oil. LCMS m/z (%) = 344 (M+H*C], 100), 346 (M+H'CI, 39). 'H NMR (400 MHz, CDCl;) &: 8.33 (dd, J = 2.8, 9.1

Hz, 1H), 8.23 (d, J= 9.1 Hz, 1H), 7.58 (d. J=1.7 Hz, {H), 7.36 (d, J = 8.3 Hz, 2H), 7.21 (d,/=83

Hz, 1H), 7.13 (d, J=95.1 Hz, 1H), 6.36 (d, J = 1.7 Hz, 1H), 5.20 (s, 2H), 3.75 (s, 3H).

B. 4-Bromo-5-[2-(4-chloro-benzyloxy)-5-nitro-phenyl]- 1-methyl- 1 H-pyrazole: 5-[2<4-

Chloro-benzyloxy)-5-nitro-phenyl]-1-methyl- 1 H-pyrazole was treated with NBS (0.082 g, 0.45 mmol, 1.05 equiv.), in a similar manner as described in Example 1.1, Step D, providing 4-bromo-5-[2-(4-

® ® WO 2005/012254 PCT/US2004/023488 chioro-benzyloxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole. LCMS m/z (%) = 422 (M+H"Br**C}, 85), 424 (M+H*' BrCl, 100), 426 (M+H*'BPCY, 26). 'H NMR (400 MHz, CDCl) 8: 8.37 (dd, J =2.7,9.2

Hz, 1H), 8.22 (d,J= 2.7 Hz, 1H), 7.59 (s, 1H), 7.34 (d, J = 8.3 Hz, 2H), 7.21 (d, J= 8.3 Hz, 2H), 7.16 (d,J=9.2 Hz, 1H), 5.20 (AB quartet, J = 12.1, 15.2 Hz, 2H), 3.72 (5, 3H). s

Example 1.41: Preparation of 1-[3-(4-Bromo-2-methyl-2 H-pyrazol-3-y1)-4-(4-Chloro-benzyloxy)- phenyl]-3-(4-Chloro-phenyl)-urea (Compound 63). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chloro-benzyloxy)-phenylamine (0.029 g, 0.08 mmol) was treated with 4-chloropheny! isocyanate (0.014 g, 0.09 mmol, 1.2 equiv.) in CH,Cl, (1 mL), in a similar manner as described in Example 1.2 to afford Compound 63 (0.027 g, 0.05 mmol, 65 %) as a white solid. LCMS m/z (%) = 545 (M+H”Br’CI’°Cl, 65), 547 (M+H™Br°CP*’CI *'Br*CI*°Cl, 100), 549 (M+H"Br°Cl’CI”BrCs’Cl, 45), 551 (M+H*'Br’CP’Cl, 6). 'H NMR (400 MHz, acetone-ds) 5: 8.23 (s, 1H), 8.17 (s, 1H), 7.66 (dd, J = 2.7, 9.0 Hz, 1H), 7.56 (d, J= 8.9 Hz, 2H), 7.50 (s, 1H), 7.46 (d,

J=27Hz, 1H), 7.37 (d, J=8.7 Hz, 2H), 7.33 (d, J= 8.7 Hz, 2H), 7.28 (d, J=8.9 Hz, 2H), 7.22 (d, J = 9.0 Hz, 1H), 5.14 (AB quartet, J= 12.3, 24.8 Hz, 2H), 3.69 (s, 3H).

Example 1.42: Preparation of 1-[3-(4-Bromo-2-methyi-2 H-pyrazol-3-y1)-4.(4-Chloro-benzyloxy)- phenyl]-3-(4-fluoro-phenyl)-urea (Compound 64). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yI)-4-(4-chloro-benzyloxy)-phenylamine (0.032 g, 0.08 . - mmol) was treated with 4-fluorophenyl isocyanate (0.014 g, 11.1 pL, 0.10 mmol, 1.2 equiv.) in CH,Cl, (1 mL), in a similar manner as described in Example 1.2 to afford Compound 64 (0.023 g, 0.04 mmol, 54 %) as a white solid. LCMS m/z (%) = 545 (M+HPBrCl, 65), 547 (M+H*'Br*Cl, 100), 549 (M+HY'Br'C), 25). 'H NMR (400 MHz, acetone-ds) 8: 8.13 (s, 2H), 7.66 (dd, J =2.7, 9.0 Hz, 1H), 7.51-7.56 (m, 3H), 7.50 (s, 1H), 7.46 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 7.33 (d, /= 8.7 Hz, 2H), 7.21 (d, J= 9.0 Hz, 1H), 7.05-7.75 (m, 2H), 5.14 (AB quartet, J= 12.3, 24.8 Hz, 2H), 3.69 (s, 3H).

Example 1.43: Preparation of intermediate 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4- phenethyloxy-phenylamine.

The crude reaction mixture of 4-bromo-1-methyl-55-nitro-2-phenethyloxy-phenyl)-1H- pyrazole (as described below) was reduced with SnCl,2H,0 (0387 g, 1.68 mmol, 4.0 equiv.) in EtOH, in a similar manner as described in Example 1.1, providing aniline 3-(4-Bromo-2-methyl-2H-pyrazol-3- yl)-4-phenethyloxy-phenylamine (0.124 g, 0.33 mmol, 80% for two steps) as an oil. LCMS m/z (%) = 372 (M+H"Br, 94), 394 (M+H"Br, 100). 'H NMR (400 MHz, CDC) 8: 7.54 (s, 1H), 7.18-7.33 (m, 3H), 7.08 (d,J= 17.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 6.77 (dd, J= 2.7, 8.7 Hz, 1H), 6.61 (d, /=2.6

Hz, 1H), 3.99-4.15 (m, 2H), 3.53 (s, 3H), 3.10-3.40 (broad s, 2H), 2.83-3.00 (m, 2H).

® ® WO 2005/012254 PCT/US2004/023488

The intermediate 4-bromo-1-methyl-5-(5-nitro-2-phenethyloxy-phenyl)- 1 H-pyrazole was prepared in the following manner:

A. 1-Methyl-5-(5-nitro-2-phenethyloxy-pheny!)-1H-pyrazole: 2-(2-Methyl-2H-pyrazol-3- yl)-4-nitro-phenol (0.125 g, 0.57 mmol) was treated with NaH (0.049 g, 1.14 mmol, 2.0 equiv.) and (2- bromoethyl)benzene (0.323 g, 0.24 mL, 1.71 mmol, 3.0 equiv.) in a mixture of DMF/THF (0.9 mL/2.5 mL), in a similar manner as described in Example 1.31, Step B, providing 1-methyl-5-(5-nitro-2- phenethyloxy-phenyl)-1H-pyrazole (0.137 g, 0.42 mmol, 74%) as an oil. LCMS m/z (%) = 324 (M+H). "HNMR (400 MHz, CDCl) 6: 8.31 (dd, J=2.8,9.1 Hz, 1H), 8.17 (d, J= 2.8 Hz, 1H), 7.59 (s, 1H), 1.20-7.36 (m, 3H), 7.09 (d, J = 7.1 Hz, 2H), 7.05 (d, J=9.2 Hz, 1H), 6.26 (5, 1H), 4.33 (t,J= 6.6 Hz, 2H), 3.55 (s, 3H), 3.05 (t, J= 6.6 Hz, 2H).

B. 4-Bromo-1-methyl-5-(5-nitro-2-phenethyloxy-phenyl)-1 H-pyrazole: 1-Methyl-5-(5- nitro-2-phenethyloxy-phenyl)-1 H-pyrazole (0.137 g, 0.42 mmol) was treated with NBS (0.084 g, 0.46 mmol, 1.05 equiv.) in DMF (5 mL), in a similar manner as described in Example 1.1, Step D, providing 4-bromo-1-methyl-5-(5-nitro-2-phenethyloxy-pheny!)- 1H-pyrazole. LCMS m/z (%) = 402 (M+H"Br, 100), 404 (M+H"'Br, 97). 'H NMR (400 MHz, CDC) 8: 8.27 (dd, J =2.8, 9.2 Hz, 1H), 8.10 (d, J = 2.8 Hz, IH), 7.52 (s, 1H), 7.16-7.24 (m, 3H), 6.94-7.03 (m, 3H), 4.18-4.28 (m, 2H), 337 (s, 3H), 2.88- 3.02 (m, 2H).

Example 1.44: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxy-phenyl]- 3~(4-Chloro-phenyl)-urea (Compound 66). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxy-phenylamine (0.028 g, 0.07 mmol) was treated with 4-chloropheny! isocyanate (0.014 g, 0.09 mmol, 1.2 equiv.) in CH,CL (1 mL), ina similar manner as described in Example 1.10 to afford Compound 66 (0.025 g, 0.05 mmol, 66 %) as a solid film. LCMS m/z (%) = 525 (M+HBr*°Cl, 85), 527 (M+H®'Br**Cl, 100), 529 (M+H*'Br'’Cl, 31). 'H NMR (400 MHz, acetone-ds) 8: 8.34 (s, 1H), 8.26 (s, 1H), 7.65 (dd, J = 2.7, 8.9 Hz, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.53 (s, 1H), 7.43 (d, J= 2.7 Hz, 1H), 7.16-7.31 (m, 5 H), 7.09-7.16 (m, 3H), 4.11- 4.30 (m, 2H), 3.51 (s, 3H), 2.86-3.06 (m, 2H).

Example 1.45: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)}-4-phenethyloxy-phenyl]- 3-(4-Nuoro-phenyl)-urea (Compound 65). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl1)-4-phenethyloxy-phenylamine (0.029 g, 0.08 mmol) was treated with 4-fluorophenyl isocyanate (0.013 g, 11.0 pL, 0.09 mmol, }.2 equiv.) in CH,Cl; (1 mL), in a similar manner as described in Example 1.10 to afford Compound 65 (0.030 g, 0.06 mmol, 74 %) as a solid film. LCMS m/z (%) = 509 (M+H "Br, 100), 511 (M+H*'Br, 97). 'H NMR (400 MHz, acetone-ds) 6: 8.22 (s, 2H), 7.63 (d, J = 8.9 Hz, 1H), 7.48-7.56 (m, 3H), 7.41 (s, 1H), 7.15-7.28 (m, 3H), 7.08-7.16 (m, 3H), 7.03 (1, J= 8.7 Hz, 2H), 4.08-4.30 (m, 2H), 3.50 (s, 3H), 2.86-3.06 (m, 2H).

@® . ; ® WO 2005/012254 PCT/US2004/023488

Example 1.46: Preparation of intermediate 3-(4-Bromo-2-methyl-2H-pyrazok-3-yf)-4-(2- dimethylamino-ethoxy)-phenylamine. {2-124 -Bromo-2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl}-dimethyl-amine (0.128 g, 0.35 mmol) was treated with SnChL2H,Q (0.319 g, 1.39 mmol, 4.0 equiv.) in EtOH (20 mL), in a similar manner as described in Example 1.1, providing 3-(4-bromo-2-methyl-2H-pyrazol-3-y1)-4-(2- dimethylamino-ethoxy)-phenylamine (0.067 8, 0.20 mmol, 56 %) as an oil. LCMS m/z (%) = 339 (M+H™Br, 78), 341 (M+H"Br, 100). 'H NMR (400 MHz, acetone-ds) 5: 7.68 (dd, J=2.5, 8.9 Hz, 1H), 7.55 (s, 1H), 7.45-7.51 (m, 2H), 4.62-4.82 (m, 2H), 3.76 (s, 3H), 3.65-3.76 (m, 2H), 2.87 (s, 6H).

The intermediate {2-[2((4-bromo-2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxyl-ethyl}- dimethyl-amine was prepared in the following manner:

A. Dimethyl-{2-{2«(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl} -amine: 2-(2-

Methyl-2H-pyrazol-3-yl)-4-nitro-phenol (0.344 8, 1.57 mmol) was treated with NaH (0.252 g, 6.29 mmol, 4.0 equiv.) and 2-(dimethylamino)ethy! chloride hydrochloride (0.458 g, 3.14 mmol, 2.0 equiv.) in a mixture of DMF/THF (2 mL/10 mL), in a similar manner as described in Example 1.31, Step B, providing dimethyl-{2-[2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenaxy}-ethyl} -amine (0.280 ¢g,0.96 mmol, 62 %) as a yellow solid. LCMS m/z (%) = 291 (M+H). 'H NMR (400 MHz, CDCl) 6: 8.31 (dd, J=2.8,9.1 Hz, 1H), 8.18 (d,J=2.8 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.08 (d, J = 9.1 Hz, 1H), 6.30 (d, /= 1.9 Hz, 1H), 4.20 (t, J = 5.7 Hz, 2H), 3.76 (s, 3H), 2.69 (t, J= 5.7 Hz, 2H), 2.22 (s, 6H).

B. {2-[2-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethy!} -dimethyl-amine:

Dimethyl-{2-{2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenoxy]-ethyl} -amine (0.239 g, 0.82 mmol) in

CHCl, (10 mL) was added Br, (47 pL, 0.145 8, 0.91 mmo}, 1.1 equiv.) in CHCl, (3.5 mL) dropwise at 0°C, the mixture was stirred at this temperature for 3 hrs. More Br, (40 pL) was added and the mixture was stirred for another 2 hrs in order to consume the rest of the starting material. It was quenched by saturated Na,5,0,, washed with saturated NaHCO; and the aqueous phase was extracted with EtOAc.

The combined organic phase was washed with brine, dried over MgSQ,, filtered and evaporated. The crude reaction mixture was purified by HPLC to provide {2-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)}-4- nitro-phenoxy}-ethyl} -dimethyl-amine (0.128 g, 0.35 mmol, 42%). LCMS m/z (%) = 369 (M+H™Br, 100), 371 (M+H®'Br, 97). 'H NMR (400 MHz, CDCl;) 8: 8.45 (dd, J =2.6,9.2 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H), 7.59 (s, 1H), 7.19(d, J = 9.2 Hz, 1H), 4.34-4.56 (m, 2H), 3.60 (s, 3H), 3.23-3.50 (m, 2H), 2.59 (s, 6H).

Example 1.47: Preparation of 1-{3+(4-Brome-2-methyl-2H-pyrazok3-yl)-4-(2-dimethylamino- ethoxy)-phenyl]-3-(4-Chloro-phenyl)-urea (Compound 69). 3s To a stirred solution of 3-4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)- phenylamine (0.033 g, 0.10 mmol) in CH,Cl, (2.0 mL) was added 4-chlorophenyl isocyanate (0.017 g,

® ® WO 2005/012254 PCT/US2004/023488 0.11 mmol, 1.1 equiv.). The solvent was removed after the completion of the reaction and it was purified by the HPLC. The pure fractions were collected and CH;CN was evaporated under vacuum.

The residue was diluted with EtOAc and neutralized with saturated NaHCQ;, the EtOAc phase was washed with brine, dried over MgSO,, filtered and evaporated. Compound 69 was obtained in 85 % yield. LCMS mvz (%) = 492 (M+HBr*Cl, 78), 494 (M+H*'Br¥ Cl, 100), 496 (M+H' BrCl, 28). 'H

NMR (400 MHz, acetone-dy) 8: 8.27 (s, 1H), 8.20 (1H), 7.66 (dd, J = 2.7, 9.0 Hz, 1H), 7.56 (d, J= 8.9

Hz, 2H), 7.48 (s, 1H), 7.43 (d, J =2.7 Hz, 1H), 7.29 (d, J = 8.9 Hz, 2H), 7.14 (d, J = 9.0 Hz, 1H), 3.98- 4.20 (m, 2H), 3.73 (s, 1H), 2.48-2.68 (m, 2H), 2.16 (s, 6H).

Example 1.48: Preparation of 1-[3-(4-Bromo-2-methy}-2H-pyrazol-3-yl)-4-(2-dimethylamino- ethoxy)-phenyl]-3-(4-fluoro-phenyl)-urea (Compound 70). 3-(4-Bromo-2-methyl-2H-pyrazol-3-y1)-4-(2 -dimethylamino-ethoxy)-phenylamine (0.034 g, 0.10 mmol) was treated with 4-fluorophenyl isocyanate (0.015 g, 12.5 uL, 0.11 mmol, 1.1 equiv.) in

CHCl, (2 mL), in a similar manner as described in Example 1.47 to afford Compound 70 (0.020 g, 0.04 mmol, 42%). LCMS m/z (%) = 476 (M+H™Br, 100), 478 (M+H*'Br, 87). 'H NMR (400 MHz, acetone-d;) 0: 8.17 (s, 2H), 7.66 (dd, J = 2.7, 9.0 Hz, 1H), 7.50-7.58 (m, 2H), 7.48 (s, 1H), 7.43 (d, J= 2.7 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 7.04 (t, J = 8.8 Hz, 2H), 3.98-4.20 (m, 2H), 3.73 (s, 3H), 2.49- 2.66 (m, 2H), 2.16 (s, 6H).

Example 1.49: Preparation of 1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yly-4-hydroxy-phenyl]-3-(4- chloro-phenyl)-urea (Compound 58).

To Compound 1 (see Example 1.16) in CH,Cl, (1.170 g, 2.68 mmol) was added anhydrous

AICI; (1.432 g, 10.74 mmo), 4.0 equiv.) slowly at 0 °C, it was stirred under reflux overnight and then quenched with saturated NaHCO;. The mixture was extracted with EtOAc, the combined organic phase was washed with water and brine, dried over MgSQ,, filtered and evaporated. It was first purified with

Si0, column chromatography (Eluent: EtOAc/Hexane = 1/3 to 1/1) and the major fractions containing

Compound 58 were then purified by HPLC. The pure fractions were neutralized with saturated

NaHCO;, extracted with EtOAc and dried with anhydrous MgSO,. MgSQ, was filtered and the solvent was removed under vacuum to provide Compound 58 as a white solid. LCMS m/z (%) = 421 (M+HBr°Cl, 69), 423 (M+H"Br**Cl, 100), 425 (M+H¥B’Cl, 21). 'H NMR (400 MHz, acetone-ds) 5: 8.47 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.44 (d, J= 8.9 Hz, ZH), 7.38-7.43 (m, 1H), 7.35 (s, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.15 (d, J= 8.9 Hz, 2H), 6.87 (d, J= 8.8 Hz, 1H), 3.62 (5, 3H).

Example 1.50: Preparation of Intermediate 4-Methoxy-3-(2-methyl-2H-pyrazol-3-yl)- phenylamine.

® ® WO 2005/012254 PCT/US2004/023488 5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1 H-pyrazole (2.11 g, 9.06 mmol) was treated with

SnCl;2H,0 (8.341 g, 36.22 mmol, 4.0 equiv.) in EtOH (50 mL), in a similar manner as described in

Example 1.1, providing 4-methoxy-3-2-methyl-2H-pyrazol-3-yl)-phenylamine (1.592 g, 7.8 3mmol, 87 %) as an oil. LCMS m/z (%) = 204 (M+H). 'H NMR (400 MHz, CDCl) §: 7.51 d,J=18 Hz, 1H), 6.83 (d, /= 8.7 Hz, 1H), 6.76 (dd, J=28,8.7Hz, 1H), 6.62 (4, J=28 Hz, 1H), 622 (d, J = 1.8 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.24-3.55 {broad s, 2H).

Example 1.51: Preparation of 1-(4-Chloro-phenyl)-3-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yI)- phenyl]-urea (Compound 75). 4-Methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.291 g, 1.43 mmol) was treated with 4-chloropheny! isocyanate (0.247 g, 1.57 mmol, 1.1 equiv.) in CH2Cl, (5 mL), in a similar manner as described in Example 1.2 to afford Compound 75 (0.415 g, 1.16 mmol, 81%) as a white solid. LCMS m/z (%) = 357(M+H). 'H NMR (400 MHz, acetone-dg) 8: 8.21 (s, IH), 8.07 (s, 1H), 7.58 (dd, J=2 8, 8.9 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.44 (d, /=2.7 Hz, 1H), 7.39(d,J=18 Hz, 1H),7.28(d,J=8.8

Hz, 2H), 7.08 (d,J=8.9 Hz, 1H), 6.20 (d, J= 1.8 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 3H).

Example 1.52: Preparation of Intermediate 3H4-Chloro-2-methyl-2H-pyrazol-3-yl)}-4-methoxy- phenylamine. 4-Chloro-5-(2-methoxy-S-nitro-phenyl)-1 -methyl-1H-pyrazole (2.27g, 8.5 mmol) was dissolved in dry EtOH (150 mL) and heated to 75°C. The heated solution was then treated with Sn(Il) chloride dihydrate (9.6g, 42.5 mmol) and stirred at 75°C. A fier three hours, the reaction was found to be complete by TLC and LCMS. The solvent was removed under reduced pressure. The residue was subsequently diluted with EtOAc (100 mL) and IN NaOH, neutralizing the reaction to a pH of approximately 6 or 7. The mix was then filtered through celite. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2x50mL). The organic layers were combined, dried over

Na,SO,, filtered, and the solvent removed under reduced pressure. The residue was then purified by flash chromatography (Biotage, SiO,, Hexanes/EtOAc gradient elution) to afford 1.73g (86%) of 3(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine as a light brown solid. LCMS m/z (%) = 240 (M+HC1, 37), 238 (M+HC, 100). 'H NMR (400 MHz, CDCl,) 5: 7.48 (s, 1H), 6.87 (d, J=8, 1H), 6.81 (dd, J; =8, J; = 4, 1H), 6.63 (d, J =4, 1H), 3.72 (s, 3H), 3.70 (s, 3H).

The intermediate 4-chloro-5~2-methoxy-5-nitro-phenyl)- 1-methyl-1H-pyrazole was prepared in the following manner: 5-(2-Methoxy-5-nitro-phenyl)-1 -methyl-1H-pyrazole (2.37g, 10.17 mmol) was dissolved in

DMF (100mL). The solution was then heated to 80°C. N-Chlorosuccinimide (1.49g, 11.1 mmol) was added at 80°C under Argon gas. After two hours of continuous stirring, the reaction was checked by

TLC and LCMS, and found to be incomplete. An additional aliquot of NCS (0.5g, 3.7 mmol) was

® ® ~ added, bringing the reaction to completion after 1.5 hours. While stirring, a portion of water (200 mL) was added to force the product to precipitate out of solution. After the precipitation was complete, the flask containing the solid was cooled in an ice water bath for 10 minutes. The solid was then filtered under vacuum and rinsed with water, yielding 2.4g (89%) of 4-chloro-5-(2-methoxy-5-nitro-phenyl)-1- methyl-1H-pyrazole. This material was used in the next step without purification. LCMS m/z (%) = 267 (M+H, 100). 'H NMR (400 MHz, CDCl) 8: 8.41 (dd, J, = 8 Hz, J, = 4 Hz, 1H), 822 (d, J=4 Hz, 1H), 7.53 (s, 1H), 7.14 (d, J= 12 Hz, 1H), 3.97 (s, 3H), 3.72 (5, 3H).

Example 1.53: Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4-

Nuoro-phenyl)-urea (Compound 28). 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (20mg, 0.08 mmol) was dissolved in anhydrous CHCl, (150 mL) and treated with 4-Fiuorophenyl isocyanate, Compound 28 began to precipitate out immediately as a white solid. The reaction was stirred at room temperature for three hours. Then, the flask containing the solid was cooled in an ice water bath for 20 minutes. The solid was then filtered under vacuum and rinsed with CH,Cl,, yielding 17.7 mg (26%) of Compound 28. LCMS m/z (%) = 377 (M+HCI, 39), 375 (M+HYCI, 100). 'H NMR (400 MHz, DMSO-d) &: 8.95 (s, 1H), 8.93 (s, 1H), 7.86 (s, 1H), 7.81 (dd, J, = 8 Hz, J, = 4 Hz, 1H), 7.71 (dd, J, = 8 Hz, /; = 4

Hz, 2H), 7.62 (d, J = 2, 1H), 7.41 (d, J = 12 Hz, 1H), 7.38 (t, J= 12 Hz, 2H), 4.01 (s, 3H), 3.86 (s, 3H).

Example 1.54: Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-G- fluoro-phenyl)-urea (Compound 36). 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-

Fluorophenyl isocyanate in a similar manner to as described in Example 1.53, providing 0.5 mg (1%) of

Compound 36: LCMS m/z (%) = 377 (M+H"'CI, 40), 375 (M+H?CI, 100). 'H NMR (400 MHz, acetone-ds) 8: 8.23 (s, 1H), 7.45 (dt, Jy = 12, /,=4,J3= 2 Hz, 1H), 7.37 (5, IH), 7.32 (5, 1H), 7.17 (d, J =24 Hz, 1H), 7.15 (dd, J, = 8 Hz, J; = 2 Hz, 1H), 7.03 (dd, J, = 8 Hz, J; = 4 Hz, 1H), 6.77 (d,J=2 Hz, 1H), 6.63 (td, J, = 8 Hz, ., =4 Hz, 1H), 3.68 (s, 3H), 3.52 (s, 3H).

Example 1.55: Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazot-3-y[)-4-methoxy-phenyi]-3- (2,4-difluoro-phenyl)-urea (Compound 29). 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4- difluorophenyl isocyanate in a similar manner as described in Example 1.53, providing 26.7 mg (36%) of Compound 29: LCMS m/z (%) = 395 (M+H”'C}, 35), 393 (M+H*Cl, 100). 'H NMR (400 MHz,

DMSO-ds) 3: 9.00 (s, 1H), 8.43 (5, 1H), 8.03 (m, J; = 12 Hz, J; = 4 Hz, 1H), 7.56 (s, 1H), 7.50 (dd, J, = 8 Hz, J, = 4 Hz, 1H), 7.34 (d,J = 4 Hz, 1H), 7.28 (m, J, = 12 Hz, J; = 4 Hz, 1H), 7.12(d,J=8 Hz, 1H),7.01 (m, J, = 8 Hz, J, = 2 Hz, 1H), 3.72 (s, 3H), 3.56 (s, 3H).

® ® WO 2005/012254 PCT/US2004/023488

Example 1.56: Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yI)4-methoxy-phenyl]-3-(3- methoxy-phenyl}-urea (Compound 30). 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenylamine was treated with 3-

Methoxypheny! isocyanate in a similar manner as described in Example 1.53, providing 7.5 mg (27%) of Compound 30 (Note: Compound 30 did not precipitate out. Therefore, the CH,Cl; was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC):

LCMS m/z (%) = 389 (M+HY'CI, 39), 387 (M+H?CI, 100). 'H NMR (400 MHz, acetone-ds) 8: 7.99 (s, 1H), 7.49 (dd, J, = 8 Hz, J, = 2 Hz, 1H), 7.29 (d, J = 8 Hz, 1H), 7.28 (s, 1H), 7.12 (t, J= 2 Hz, 1H), 6.95 (d, J=2 Hz, 1H), 6.93 (d, J=4 Hz, 1H), 6.81 (dd, J, =8 Hz, J; =4 Hz, 1H), 6.37 (dd, J, = 8 Hz,

J» =4 Hz, 1H), 3.63 (s, 3H), 3.57 (s, 3H), 3.47 (s, 3H). :

Example 1.57: Preparation of 1-(3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(2- trifluoromethoxy-phenyl)-urea (Compound 34). 344-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2- _ trifluoromethoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.5 mg (3%) of Compound 34: LCMS m/z (%) = 440 (M+H''Cl, 14), 438 (M+H*C), 14). 'H NMR (400 MHz, acetone-d;) 8: 8.19 (s, 1H), 7.90 (s, 1H), 7.43 (d, J=4 Hz, 1H), 7.25 (s, IH), 7.04 (t, J= 12 Hz, ZH), 6.99 (dd, J, = 8 Hz, J; =2 Hz, 1H), 6.75 (d, J= 4 Hz, 1H), 6.72 (d, J= 4 Hz, 1H), 6.66 (d, /=2 Hz, 1H), 3.63 (s, 3H), 3.45 (s, 3H).

Example 1.58: Preparation of 1-(3-Acetyl-phenyl)-3-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl]-urea (Compound 35). 3-(4-Chioro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3- .

Acetylphenyl isocyanate in a similar manner as described in Example 1.53, providing 3.7 mg (6%) of

Compound 35 (Note: Compound 35 did not precipitate out. Therefore, the CH,Cl, was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS m/z (%) = 401 (M+HC], 27), 399 (M+H?*C], 100). 'H NMR (400 MHz, acetone~ds) 5: 8.91 (s, 1H), 8.80 (s, 1H), 8.23 (s, 1H), 7.84 (d, J = 8 Hz, IH), 7.75 (dd, J, = 12 Hz, J, =3 Hz, 1H), 7.62 (d, J= 8 Hz, 1H), 7.56 (d, J= 4 Hz, 1H), 7.49 (s, 1H), 7.43 (t, J= 8 Hz, 1H), 7.16 (d, J = 8 Hz, 1H), 3.84 (5, 3H), 3.69 (s, 3H), 342 (s, 3H).

Example 1.59: Preparation of 1-[3((4-Chloro-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenyl}]-3-(4-

Chloro-phenyl)-urea (Compound 26). 3-(4-Chloro-2-methyl-2 H-pyrazol-3-y])-4-methoxy-phenylamine was treated with 4- chlorophenyl isocyanate in a similar manner as described in Example 1.53, providing 12 mg (30%) of

Compound 26: LCMS m/z (%) = 393 (M+H"'C, 60), 391 (M+H¥ Cl, 100). 'H NMR (400 MHz,

DMSO-d) 6: 8.80 (s, 1H), 8.71 (s, 1H), 7.62 (s, 1H), 7.57 (dd, J, =8 Hz, J =4 Hz, 1H), 7.49 (dd, J, = oo 121

J

® 8 Hz, J, = 2 Hz, 2H), 7.39 (d,J = 4 Hz, 1H), 7.33 (dd, J, = 8 Hz, 2. = 2 Hz, 2H), 7.17 (d, J = § Hz, 1H), 3.77 (s, 3H), 3.62 (5, 3H).

Example 1.60: Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazo}-3-yl)-4-methoxy-phenyl}-3-(4- isopropyl-phenyl)-urea (Compound 76). 3-(4-Chloro-2-methyl-2H-pyrazo}-3-yl)-4-methoxy-phenylamine was treated with 4- isopropylphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.3 mg (2%) of

Compound 76 (Note: Compound 76 did not precipitate out). Therefore, the CH,Cl; was removed under reduced pressure, the residue was dissolved in 5 ml. DMSO, and purified by preparative HPLC): LCMS m/z (%) = 401 (M+H'CI, 31), 399 (M+H?*C}, 100). "H NMR (400 MHz, acetone-ds) 5: 8.63 (s, 1H), 8.52 (s, 1H), 7.59 (dd, J, = 8 Hz, J» = 4 Hz, 1H), 7.41 (d,/=2 Hz, 1H), 7.37 (dd, J, = 12 Hz, J; =2 Hz, 2H), 7.33 (s, 1H), 7.17 (dd, J, = 8 Hz, J, = 2 Hz, 2H), 7.00 (d, J = 12 Hz, 1H), 3.68 (s, 3H), 3.54 (5, 3H).

Example 1.61: Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3- (2,4-dichloro-phenyl)-urea (Compound 77). 3<(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4- dichloropheny! isocyanate in a similar manner as described in Example 1.53, providing 16.4 mg (24%) of Comound 77 (Note: Comound 77 did not precipitate out. Therefore, the CH,Cl, was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative HPLC): LCMS wz (%) = 427 (M+H'Cl, 72), 425 (M+H°Cl, 100). 'H NMR (400 MHz, acetone-d;) 6: 8.85 (s, 1H), 8.26 (dd, J; =12 Hz, J,=4 Hz, 1H) 7.90 (s, 1H), 7.59 (dd, J, = 8 Hz, J, = 4 Hz, 1H), 7.38 (d, J=4 Hz, 1H), 7.36 (s, 1H), 7.36 (s, 1H), 7.24 (dd, J, = 12 Hz, J; = 4 Hz, 1H), 7.05 (4, J = 8 Hz, 1H), 3.72 (s, 3H), 3.56 (s, 3H). 25 .

Example 1.62: Preparation of 1-{3-(4-Chloro-2-methyl-2H-pyrazo}-3-yl)-4-methoxy-phenyl}-3- naphthalen-1-yl-urea (Compound 78). 3-(4-Chloro-2-methyl-2H-pyrazol-3-y!)-4-methoxy-phenylamine was treated with 1-naphthyl isocyanate in a similar manner as described in Example 1.53, providing 21.1 mg (60%) of Compound 78: LCMS m/z (%) = 409 (M+H'Cl, 38), 407 (M+H’C}, 100). *H NMR (400 MHz, DMSO-d) 3: 9.02 (s, 1H), 8.71 (s, 1H), 8.10 (d, J= 8 Hz, 1H), 7.96 (d, J = 8 Hz, 1H), 7.91 (d, J = 8 Hz, 1H), 7.61 (s, IH), 7.59 (t, J= 4 Hz, 1H), 7.58 (s, IH), 7.56 (1, J = 2 Hz, 1H), 7.54 (dd, J, = 4 Hz, J, = 2 Hz, 1H), 745 d,J =8 Hz, 1H), 741 (d, J= 4 Hz, 1H), 7.16 (d, J = 8 Hz, 1H), 3.75 (s, 3H), 3.60 (s, 3H). :

Example 1.63: Preparation of 1-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4- chioro-2-trifluvoromethyl-phenyl)-urea (Compound 79)

34(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-chloro-2- trifluoromethylphenyl isocyanate in a similar manner as described in Example 1.53, providing 4.4 mg (8%) of Compound 79 (Note: Compound 79 did not precipitate out. Therefore, the CH,Cl; was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative

HPLC): LCMS m/z (%) = 461 (M+H”’CI, 60), 459 (M+H™CI, 100). '"H NMR (400 MHz, acetone-d;) 8:8.99 (s, 1H), 8.30 (s, 1H), 8.16 (dd, J, = 8 Hz, J, = 2 Hz, 1H), 8.01 (d, J = 8 Hz, 1H), 7.66 (s, 1H), 7.64 (d,J=4 Hz, 1H), 7.45 (d, J= 4 Hz, 1H), 7.43 (5, 1H), 7.12 (d, J= 8 Hz, 1H), 3.79 (s, 3H), 3.63 (s, 3H).

Example 1.64: Preparation of 1-[3-(4-Chioro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4- trifluoromethyl-phenyl)-urea (Compound 80). 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4- trifluoromethylphenyl isocyanate in a similar manner as described in Example 1.53, providing 8 mg (15%) of Compound 80 (Note: Compound 80 did not precipitate out. Therefore, the CH,Cl, was removed under reduced pressure, the residue was dissolved in 5 mL DMSO, and purified by preparative

HPLC): LCMS m/z (%) = 427 (M+H'Cl, 22), 425 (M+HCl, 100). 'H NMR (400 MHz, acetone-d) 5:8.48 (5, 1H), 8.24 (s, 1H), 7.56 (d, J = 8 Hz, 2H), 7.50 (dd, J, = 8 Hz, J, = 2 Hz, 1H), 7.40 d,J=8

Hz, 1H), 7.28 (d, J= 4 Hz, 1H), 7.27 (s, 1H), 6.96 (d, J = 12 Hz, 1H), 3.62 (s, 3H), 3.46 (s, 3H).

Example 1.65: Preparation of 1-(4-Bromo-pheny!)-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl}-urea (Compound 81). 3~(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4- bromophenyl isocyanate in a similar manner as described in Example 1.53, providing 2.3 mg (6%) of

Compound 81: LCMS m/z (%) = 437 (M+H"'C1, 100), 435 (M+H?*CI, 82). 'H NMR (400 MHz,

DMSO-dq) 8: 8.97 (d, J= 2 Hz, 2H), 8.80 (s, 1H), 8.70 (s, 1H), 7.61 (s, 1H), 7.53 (dd, J,= 12 Hz, Jo=8

Hz, 1H), 7.44 (1, J =4 Hz, 2H), 7.35 (d, J = 4 Hz, 1H), 7.13 (4, J = 8 Hz, 1H), 3.74 (5, 3H), 3.58 (s, 3H).

Example 1.66: Preparation of 1-(3,5-Bis-trifluoromethyl-phenyl)-3-{3-(4-chioro-2-methy- 2H- pyrazol-3-yl)-4-methoxy-phenyl]-urea (Compound 82). 3{4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3,5-

Bis(trifluoromethyl)pheny! isocyanate in a similar manner as described in Example 1.53, providing 21.5 mg (32%) of Compound 82: LCMS m/z (%) = 495 (M+H"C, 41), 493 (M+H>CI, 100). 'H NMR (400

MHz, DMSO-d;) 8: 9.58 (s, 1H), 9.18 (s, 1H), 8.31 (s, 2H), 7.80 (s, 1H), 7.79 (s, 1H), 7.79 (dd, J, = 8

Hz, J2=4 Hz, 1H), 7.59 (d, J = 2 Hz, 1H), 7.36 (d, = 8 Hz, 1H), 3.96 (s, 3H), 3.80 (s, 3H).

® ® WO 2005/012254 PCT/US2004/023488

Example 1.67: Preparation of Intermediate 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenylamine.

Two reduction methods were utilized in the preparation of the 3-(4-Fluoro-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenylamine as shown below:

Reduction Method A: 4-Fluoro-5-(2-methoxy-5-nitro-phenyl)- 1-methyl-1H-pyrazole (205 mg, 0.817 mmol) in EtOH (25mL) was treated with Sn(II) chloride dihydrate (626.3 mg, 2.45 mmol) and heated to 50°C for 12 hours. The reaction was allowed to cool to room temperature and 10% NaOH (100 ml) was added. EtOAc (50 mi) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (2x SO0mL) and the organics combined, dried over Na,SQ,, filtered, and the solvent removed under reduced pressure. The residue was dissolved in DMSO (5 ml), and purified by preparative HPLC to afford 85 mg (47%) of 3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenylamine as a light brown oil. LCMS m/z (%) = 222 (M+H, 100). 'H NMR (400 MHz, CDC};) §: 7.38 (d, Jus= 4.8 Hz, 1H), 6.86 (d, / = 8.8 Hz, 1H), 6.79 (dd, J, = 8.8 Hz, J; =2.8 Hz ,1H), 6.64 (4, J = 2.8 Hz, 1H), 3.75 (s, 3H), 3.69 (s,3H), 3.21 (s, 2H). *F NMR (376 MHz, CDCl) 8: ~175.50 (d, Jus = 5.3 Hz, IF).

Reduction Method B: 4-Fluoro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (109 mg, 0.434 mmol) in EtOH (10mL) was treated with Pd-C (10 wt.%, Degussa) and a balloon of H; was allowed to bubble through the slurry. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure to afford 93 mg (97%) of 3-(4-fluora-2-methyl-2H-pyrazol-3-yl)- 4-methoxy-phenylamine as a light brown oil. LCMS m/z (%) = 222 (M+H, 100). '"H NMR (400 MHz,

CDC) 8: 7.38 (d, Jur = 4.4 Hz, 1H), 6.86 (d, / = 8.8 Hz, 1H), 6.78 (dd, J, = 8.8 Hz, J; = 2.8 Hz, 1H), 6.63 (d, J= 2.8 Hz, 1H), 3.74 (s, 3H), 3.68 (s5,3H), 3.53 (s, 2H). "’F NMR (376 MHz, CDCl) &: - 175.50 (d, Juy= 5.3 Hz, IF).

The intermediate 4-fluoro-5-{2-methoxy-5-nitro-phenyl)- 1-methyl-1H-pyrazole used in

Reduction Methods A and B was prepared in the following manner: 5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (300.0 mg, 1.29 mmol) was dissolved in

ACN (15 ml) in a polypropylene 20 mL scintillation vial. To this solution, Selectfluor (913.9 mg, 2.58 mmol) was added and the mixture was degassed with argon and heated to 80°C for 6 hours. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL EtOAc and 30 mL 3N

HCI. The organic layer was separated and the aqueous layer was extracted with EtOAc (2x50mt). The organic layers were combined, dried over Na;SQ,, filtered, and the solvent removed under reduced pressure. The residue was then purified by flash chromatography (Biotage SiO,, Hexanes (.01%TEA EtOAc gradient elution) to afford 108 mg (33%) of 4-fluoro-5-(2-methoxy-S-nitro-phenyl)- 1-methyl-1H-pyrazole as a white solid. LCMS m/z (%) = 252 (M+H, 100). 'H NMR (400 MHz,

®

CDCl) 8: 8.39 (d, J = 9.2 Hz, 1H), 8.22 (s, 1H), 7.44 (d, Jur= 4.4 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H) 3.98 (s, 3H), 3.77 (5,3H). "F NMR (376 MHz, CDCl) 8: -175.50 (d, Jus = 5.3 Hz, 1F).

Example 1.68: Preparation of 1-(4-Chloro-phenyl)-3-[3-(4-fluoro-2-methy)-2H-pyrazo}-3-yl)4- methoxy-phenyl]-urea (Compound 27). 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)}-4-methoxy-phenylamine (49 mg, 0.22 mmol) was dissolved in 3 mL of CH,Cl,, treated with 4-chlorophenylisocyanate (40 mg, 0.27 mmol), and stirred at room temperature overnight. The solvent was removed under reduced pressure, dissolved in DMSO ®) ml), and purified by preparative HPLC to afford Compound 27 as a white solid, 41 mg, 49% yield:

LCMS mz (%) = 377 (M+H'CI, 31), 375 (M+HCl, 100). 'H NMR (400 MHz, acetone-ds) 5: 8.77 (s, 1H), 8.67 (s, 1H), 7.66 (ddd, J, = 9.0 Hz, J; = 2.6 Hz, 1H), 7.60 (d, J = 9.2 Hz, 2H), 7.54 (d,J=2.8 Hz, 1H), 7.38 (d, Jus= 4.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). °F NMR (376 MHz, acetone-dq) 8: -177.39 (d, Jus = 5.3 Hz, IF).

Example 1.69: Preparation of 1-[3-(4-Fluoro-2-methyi-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4- fluoro-phenyl)-urea (Compound 31). 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)}-4-methoxy-phenylamine (45 mg, 0.20 mmol) was dissolved in 3 mL of CH,Cl,, treated with 4-fluorophenylisocyanate (28 uL, 0.24 mmol), and stirred at room temperature overnight. The compound of interest precipitated out of solution and was filtered and washed with CH,Cl, to afford Compound 31 as a white solid, 56 mg, 77% yield: LCMS nv/z (%) = 359 (M+H, 100). 'H NMR (400 MHz, acetone-ds) 8: 8.12 (s, 1H), 8.08 (s, 1H), 7.63 (ddd, J; =9.0 Hz, J, = 2.6 Hz, 1H), 7.54 (m, 2H), 7.48 (d, J= 2.8 Hz, 1H), 7.38 (d, Jur = 4.8 Hz, 1H), 7.13 (d, J= 8.8 Hz, 1H), 7.05 (dd, J, = 9.0 Hz, J, = 9.0 Hz, 2H), 3.83 (s, 3H), 3.65 (s, 3H). "°F NMR (376 MHz, acetone- dg) 6: -123.08 (m, 1F), 17741 (d, Jug= 5.3 Hz, IF).

Example 1.70: Preparation of 1-(3,4-Difluoro-phenyl)-3-[3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)- 4-methoxy-phenyl]-urea (Compound 32). 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3,4- difluorophenylisocyanate, in a similar manner as described in Example 1.69, providing 27 mg (63% yield) of Compound 32: LCMS mz (%) =377 (M+H, 100). 'H NMR (400 MHz, acetone-ds) 5: 8.28 (s, 1H), 8.12 (s, 1H), 7.74 (ddd, J, = 13.5 Hz, J = 7.3 Hz, J; = 2.5 Hz, 1H), 7.63 (ddd, J,=8.8 Hz, J; =2.8

Hz, 1H), 7.47 (d, J = 2.8 Hz, 1H), 7.38 (d, Jur = 4.4 Hz, 1H), 7.16 (m, 3H), 3.84 (s, 3H), 3.65 (s, 3H). °F NMR (376 MHz, acetone-ds) 8: -138.89 (m, 1F), -148.38 (m, 1F), -177.40 (d, Jus= 53 Hz, IF).

Example 1.71: Preparation of 1-[3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3- fluoro-phenyl)-urea (Compound 33). -

® ® WO 2005/012254 PCT/US2004/023488 3-(4-Fluoro-2-methy}-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3- ’ fluorophenylisocyanate, in a similar manner as described in Example 1.68, providing 15 mg (55% yield) of Compound 33: LCMS m/z (%) = 359 (M+H, 100). 'H NMR (400 MHz, J acetone-dg) 5: 8.38 (s, 1H), 8.21 (s, 1H), 7.64 (dd, J, = 9.0 Hz, J; = 2.6 Hz, 1H), 7.59 (d,J = 12.0 Hz, 1H), 748 (d,/=2.8

Hz, 1H), 7.39 (d, Jur = 4.8 Hz, 1H), 7.27 (dd, J, = 14.8 Hz, J, =8.0 Hz, 1H), 7.15 (4, / = 9.6 Hz, 1H), 7.12 (s, 1H), 6.72 (dd, J, = 9.6 Hz, J, = 7.2 Hz, 1H), 3.83 (s, 3H), 3.65 (5, 3H). "°F NMR (376 MHz, acetone-dg) 8: -114.00 (m, 1F), -177.35 (d, Jur= 3.8 Hz, 1F). ,

Example 1.72: Preparation of 1-(2,4-Difluoro-phenyl)-3-[3-(4-fluero-2-methyl-2H-pyrazol-3-yl)- 4-methoxy-phenyl]-urea (Compound 37). 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4- difluorophenylisocyanate, in a similar manner as described in Example 1.68, providing 21 mg (58% yield) of Compound 37: LCMS m/z (%) = 377 (M+H, 100). 'H NMR (400 MHz, acetone-d;) 5: 8.50 (s, 1H), 8.24 (m, 1H), 7.98 (s, 1H), 7.64 (dd, J, = 9.0 Hz, /,= 2.6 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.38 (d, Juy= 4.8 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.06 (ddd, J, = 11.4 Hz, J, = 8.6 Hz, J; =2.8 Hz, 1H), 6.99 (dd, J, = 9.6 Hz, J, = 9.6 Hz, 1H), 3.83 (5, 3H), 3.65 (5, 3H). "°F NMR (376 MHz, acetone-ds) 8: - 119.93 (m, 1F), -127.63 (m, IF) -177.41 (d, Jur=4.1 Hz, 1F).

Example 1.73: Preparation of 1-(3-Chloro-phenyl)-3-{3-(4-fluoro-2-methy}-2H-pyrazol-3-yl)-4- methoxy-phenyl]-urea (Compound 83). 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3- chlorophenylisocyanate, in a similar manner as described in Example 1.68. An additional purification by flash chromatography (SiO,, Hexanes/EtOAc gradient elution) was necessary, providing a 10 mg (27% yield) of Compound 83: LCMS m/z (%) = 377 (M+H?'C, 25), 375 (M+H™CI, 100). 'H NMR (400 MHz, acetone~ds) 8: 8.28 (s, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 7.64 (dd, J, = 8.8 Hz, J, = 2.8 Hz 1H), 7.48 (d, J = 2.8 Hz, 1H), 7.38 (d, Jur = 4.8 Hz, 1H), 7.34 (dd, /; =9.2 Hz, /, = 0.8 Hz, 1H), 7.26 (dd, J; =82,J,=8.2Hz 1H), 7.13 (d, J= 8.8 Hz, 1H), 7.00 (dd, J, = 8.8 Hz, J); = 0.8 Hz, 1H), 3.83 (5, 3H), 3.65 (s, 3H). "’F NMR (376 MHz, acetone-ds) 8: -177.35 (d, Jus =4.1 Hz, 1F).

Example 1.74: Preparation of 1-(4-Bromo-phenyl)-3-{3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl]-urea (Compound 85). 3<(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4- bromophenylisocyanate, in a similar manner as described in Example 1.68, providing 27 mg (60% yield) of Compound 85: LCMS m/z (%) = 421 (M+HBr, 100), 419 (M+H™Br, 100). 'H NMR (400

MHz, acetone-ds) 5: 8.24 (s, 1H), 8.13 (5, 1H), 7.63 (dd, J, = 9.0 Hz, J, = 2.6 Hz, 1H), 7.51 (d,J=8.8

\

Hz, 2H), 7.48 (d, J = 2.8 Hz, 1H), 7.42 (d, J= 8.8 Hz, 2H), 738 (d, Jus= 4.4 Hz, 1H), 7.13 (d, J= 92

Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). "°F NMR (376 MHz, acetone-~ds) 5: -177.39 (d, Jur=5.3 Hz, IF).

Example 1.75: Preparation of 1-[3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3(4- trifluoromethyl-phenyl)-thiourea (Compound 86). 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4- trifluoromethylphenylthioisocyanate, in a similar manner as described in Example 1.69. An additional purification by flash chromatography (Biotage SiO;, Hexanes/EtOAc gradient elution) was necessary, providing 38 mg (68% yield) of Compound 86: LCMS m/z (%) = 425 (M+H, 100). 'H NMR (400

MHz, acetone-ds) 6: 9.32 (d, J = 20.0 Hz, 2H), 7.83 (d, J= 8.4 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.61 (dd, J, = 8.8 Hz, J; = 2.8 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.38 (d, Jy y= 4.8 Hz, 1H), 7.20 (d, /=8.8

Hz, 1H), 3.88 (s, 3H), 3.67 (5s, 3H). '°F NMR (376 MHz, acetone-ds) 8: -63.10 (s, 3F), -176.49 (d, Jus =4.1 Hz, IF).

Example 1.76: Preparation of 1-(4-Chloro-3-trifluoromethyi-phenyl)-3-[3-(4-fluoro-2-methyl-2H- pyrazol-3-yi)}-4-methoxy-phenyl]-urea (Compound 84). 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-chloro-3- wrifluoromethylphenylisocyanate, in a similar manner as described in Example 1.68, providing 15 mg (29% yield) of Compound 84: LCMS m/z (%) = 445 (M+H*'C], 34), 443 (M+H¥Cl, 100). 'H NMR (400 MHz, acetone-ds) 6: 8.69 (s, 1H), 8.39 (s, LH), 8.15 (d,J= 2.4 Hz, 1H), 7.74 (dd, J,=8.6 Hz, 3;=2.2 Hz 1H), 7.65 (dd, J,=9.0 Hz, J,=2.6 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.38 (d, Jur =4.4 Hz, 1H), 7.14 (d, J=9.2 Hz, 1H) 3.83 (5, 3H), 3.65 (s, 3H). "’F NMR (376 MHz, acetone-dg) 8: -63.75 (s, 3F), -177.40 (d, Jus= 5.3 Hz, IF).

Example 1.77: Preparation of 1-[3-(4-Fluore-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4- methoxy-phenyl)-urea (Compound 87). 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4- methoxyphenylisocyanate, in a similar manner as described in Example 1.68. Additionally the residue was washed with CH;Cl,, providing 18 mg (29% yield) of Compound 87: LCMS m/z (%) = 371 (M+H, 100). 'H NMR (400 MHz, acetone-ds) &: 8.06 (s, 1H), 7.95 (s, 1H), 7.63 (dd, J, = 8.8 Hz, J, = 2.8 Hz, 1H), 7.49 (d, J= 2.8 Hz, 1H), 7.42 (d, /= 8.4 Hz, 2H), 7.37 (d, Jus =4.4 Hz, 1H), 7.11 (d,J= 9.2 Hz, 1H), 6.85 (d, J=9.2 Hz, 2H), 3.82 (5, 3H), 3.75 (s, 3H), 3.65 (s, 3H). “F NMR (376MHz, acetone-d;) 8:-177.41 (d, Jus = 4.1 Hz, 1F).

Example 1.78: Preparation of 1-(3-Acetyl-phenyl)-3-[3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl}-urea (Compound 88). Lo

® ® WO 2005/012254 PCT/US2004/023488 3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenylamine was treated with 3- acetylphenylisocyanate, in a similar manner as described in Example 1.68. An additional purification by flash chromatography (SiO, Hexanes/EtOAc gradient elution) was necessary, providing 36 mg (53% yield) of Compound 88: LCMS m/z (%) = 383 (M+H, 100). 'H NMR (400 MHz, acetone-ds) 5: 8.31 (s,1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.79 (dd, J, = 9.0 Hz, J; =2.2 Hz, 1H), 7.63 (d, J, = 15.5 Hz, J; =8.3 Hz, J;=2.7Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.41 (m, 3H), 7.14 (d, / = 9.2 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 3H), 2.56 (s, 3H). ’F NMR (376 MHz, acetone-ds) 8: -177.39 (d, Jus = 4.1 Hz, IF).

Example 1.79: Preparation of 1-3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4- trifluoromethyl-phenyl)-urea (Compound 89). 3-(4-Fluoro-2-methyl-2H-pyrazol-3-y1)-4-methoxy-phenylamine was treated with 4- trifluoromethylphenylisocyanate, in a similar manner as described in Example 1.69, providing 24 mg (49% yield) of Compound 89: LCMS m/z (%) = 409 (M+H, 100). 'H NMR (400 MHz, acetone-ds) &: 8.56 (s, 1H), 8.29 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.65 (dd, J, = 9.0 Hz, J, = 2.6 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.50 (d, J=2.4 Hz, 1H), 7.38 (d, Jur= 4.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 3H). "’F NMR (376 MHz, acetone-dg) 5: -62.80 (s, 3F), -177.39 (d, Jurs= 4.1 Hz, 1F).

Example 1.80: Preparation of 1-[3(4-Fluoro-2-methyl-2H-pyrazol-3-y{)-4-methoxy-pheny!}-3-(3- trifluoromethyl-phenyl)-urea (Compound 90). 3-(4-Fluoro-2-methyl-2H-pyrazol-3-y1)}-4-methoxy-phenylamine was treated with 3- trifluoromethylphenylisocyanate, in a similar manner as described in Example 1.69, providing 37 mg (48% yield) of Compound 90: LCMS m/z (%) = 409 (M+H, 100). 'H NMR (400 MHz, acetone-ds) 8: 8.50 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.49 (m, 2H), 7.38 (d, Jus = 4.8 Hz, 1H), 7.30 (d, /= 8.0 Hz, IH), 7.14 (d, J = 8.8 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 3H).

IF NMR (376 MHz, acetone-d) 8: -63.85 (5, 3F), ~177.42 (d, Ju y= 4.1 Hz, IF).

Example 1.81: Preparation of Intermediate 3-(4-Bromeo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy- phenylamine.

To a solution of 4-bromo-1-isopropyl-5+(2-methoxy-5-nitro-phenyl)-1H-pyrazole (0.50 g, 1.47 mmol) in ethanol (5.0mL), was added SnCl,.2H,0 (1.3 g, 5.88 mmol) and the mixture was heated at 55°C overnight. The ethanol was evaporated and the residue was taken up in ethyl acetate (50 mL) and washed with 10% NaOH (10 mL). The organic layer was dried over MgSO, and evaporated to yield a light yellow solid. The crude material was purified via Biotage silica chromatography (hexane/EtOAc, 3/1) to yield a pale yellow solid of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.38 g, 85%). LCMS m/z (%) = 311 M+H", (” Br, 100), (*'Br, 96.5), 'H NMR (400 MHz, CDCl) &: 7.47 (s, 1H), 6.78 (d, J = 8.08 Hz, 1H), 6.72 (dd, J, = 8.01 Hz, J; = 2.78 Hz, 1H), 6.54 (d, J=2.78 Hz, 1H), 4.14 (m, 1H), 3.63 (5, 3H), 1.4 (d, J= 6.57 Hz, 3H), 1.23 (d, J= 6.57 Hz, 3H). -

® ® WO 2005/012254 PCT/US2004/023488

The intermediate 4-Bromo-] -isopropyl-5-(2-methaxy-S-nitro-phenyl)-1 H-pyrazole was prepared in the following manner:

A. 1-Isopropyl-1H-pyrazole: To a solution of pyrazole (50.0 g, 735.3 mmol) in aqueous sodium hydroxide (123.5 g NaOH/200 mL of water), was added isopropyl bromide (180.0g, 1470.1 mmol) and the mixture was then heated to reflux for 6-7 days. The reaction mixture was cooled and extracted with ethyl acetate (3x 300m}). The combined organic layers were dried over MgSO,.

Removal of the volatiles in vacuo provided a light yellow oil, which was distilled via Kugelrohr at 140°C and 10 Torr, to provide 1-isopropyl-1H-pyrazole as a colorless oil (43 g, 53%). LCMS m/z (%) = 111 M+H’, (100). '"H NMR (400 MHz, DMS0-de) 8: 7.72 (d, J = 2.3 Hz, 1H), 7.41 (t, 1H), 6.21 (t, 1H), 4.5 (q, 1H), 1.41-1.37(d, J= 11.1 Hz).

B. 2-1sopropyl-2H-pyrazole-3-boronic acid: n-BuLi (1746 g, 110 mL, 273 mM, in hexanes) was slowly added over 30 minutes at —78°C to a THF solution of 1-isopropyl-1H-pyrazole (25.0 g, 227 mmol). The reaction mixture was stirred at —78°C for 2 hours. A solution of cooled triisopropoxy boronate (170.0 g, 909 mmol) was added slowly via canula over 45 minutes. The _ reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was adjusted to pH 6-7 with HCI (IM, 170 mL). The solvent was evaporated to dryness and the resulting residue was triturated with 1:1 ethylacetate:dichloromethane, the suspension filtered and the solvent was evaporated in vacuo to yield 2-isopropyl-2H-pyrazole-3-boronic acid as a colorless solid (20.0 g, 58%). LCMS m/z (%) = 154 M+H", (100). ‘HNMR (400 MHz, DMSO-d) 5: 8.14 (s, 2H), 7.2 (s, 1H), 6.5 (s, 1H), 5.05 (m, 1H), 1.2 (d, J=9.0 Hz, 6H).

C. 1-Isopropyl-5-{2-methoxy-5-nitro-phenyl)-1H-pyrazole: To a mixture of trifluoro- methanesulfonic acid 2-methoxy-5-nitro-phenyl ester, (4.1g, 13.6 mmol; see Example 1.1, Step B for preparation), 2-isopropyi-2H-pyrazole-3-boronic acid (5.2 g, 34.1 mmol), and anhydrous Cs,CO; (17.7 g, 54.4 mmol) in DME under argon was added Pd (PPh) , (0.79 g, 0.68 mmol) and the mixture was heated at 80°C for 16 h. The reaction mixture was cooled, filtered through Celite and evaporated to dryness. The residue was taken up in ethyl acetate and the solution was washed with water. The organic layer was dried over MgSO, and evaporated to afford a crude product as a brown solid. The crude material was purified via Biotage silica chromatography (hexane/EtOAc, 3/1) to yield a colorless solid, l-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (1.88 g, 52%). LCMS m/z (%) = 261

M+H" (100), '"H NMR (400 MHz, CDCl) 8: 8.36 (dd, J, = 9.09 Hz, J, = 2.5 Hz, 1H), 8.18 (d, J= 8.18

Hz, 1H), 7.65 (s, 1H), 7.09 (d, J= 8.08 Hz, 1H), 6.25 (s, 1H), 4.16 (dd, J; = 13.14 Hz, J; = 6.57 Hz, 1H), 3.95 (s, 3H), 1.45 (d, J= 6.82 Hz, 6H).

D. 4-Bromo-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)- 1 H-pyrazole: To a stirred, ice- cooled solution of 1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (1.0 g, 3.83 mmol) in DMF (10 mL) was added NBS (0.75 g, 4.22 mmol) slowly over a period of 10 minutes. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction was poured into an ice-water mixture with vigorous stirring to form a white solid, which was filtered and washed with cold water :

® ® WO 2005/012254 PCT/US2004/023488 until free of DMF. The solid was dried in vacuo to give colorless solid 4-bromo-1-isopropyl-5-(2- methoxy-5-nitro-phenyl)- 1H-pyrazole (1.25g, 96%). LCMS m/z (%) = 340 M+H", (® Br, 100), 342 (Br, 96.5). "HNMR (400 MHz, CDCl) 5: 8.4 (dd, J; = 9.09 Hz, J, = 2.78 Hz, 1H), 8.19 (d, J = 2.78), 1.6 (s, IH), 7.14 (d, J = 9.35 Hz, 1H), 4.11 (m, IH), 3.96 (s, 3H), 1.49 (d, J= 6.52 Hz, 3H), 1.36 (d, J = 6.52 Hz, 3H).

Example 1.82: Preparation of Intermediate 3-(4-Chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy- phenylamine. ]

To a solution of 4-chloro-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (0.18 g, 0.61 mmol) in ethanol (5.0 mL), was added SnCl,.2H,0 (0.56 g, 2.44 mmol) and the mixture was heated at 55°C ovemight. The ethanol was evaporated and the residue was taken up in ethyl acetate (50 mL) and washed with 10% NaOH (10 mL). The organic layer was dried over MgSO, and evaporated to yield a light yellow solid. The crude material was purified via Biotage silica chromatography (hexane/EtOAc, 3/1) 10 yield a pale yellow solid of 3(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.116 g, 75%). LCMS m/z (%) = 267 M+H", (** Cl, 100), 269 (*’Cl, 28.5)), '"H NMR (400 MHz,

CDCl3) 8: 7.47 (s, 1H), 6.78 (d, J= 8.08 Hz, 1H), 6.72 (dd, J; = 8.01 Hz, /, =2.78 Hz, IH), 6.54 (d, J = 2.78 Hz, 1H), 4.14 (m, 1H), 3.63 (s, 3H), 1.4 (d, J = 6.57 Hz, 3H), 1.23 (d, J= 6.57 Hz, 3H).

The intermediate 4-chloro-1-isopropyl-5-2-methoxy-5-nitro-phenyl)- 1H-pyrazole was prepared in the following manner:

To a stirred, ice-cooled solution of 1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole from Example 1.81, Step C (1.0g, 3.83 mmol) in DMF (10 mL) was added NCS (0.56 g, 4.22 mmol) over a period of 10 minutes. The reaction mixture was warmed to ambient temperature and stirred at 55°C for 6 h. The reaction mixture was cooled and poured into an ice-water mixture with vigorous stirring to form a white solid, which was filtered and washed with cold water until free of DMF. The solid was dried in vacuo to yield 4-chloro-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (1.1g, 97%). LCMS m/z (%) = 296 M+H", (**Cl, 100), 298 (*'Cl, 28.5). 'H NMR (400 MHz, CDCl;) 5: 8.4 (dd, J, = 9.09 Hz, J; =2.78 Hz, 1H), 8.19 (d, J = 2.8 Hz), 7.6 (s, IH), 7.14 (d, J = 9.18 Hz, 1H), 4.10 (m, 1H), 3.94 (5, 3H), 1.49 (d, J = 6.62 Hz, 3H), 1.36 (d, J = 6.62 Hz, 3H).

Example 1.83: Preparation of Intermediate 3-(2-Isopropyl-2H-pyrazol-3-yl)-4-methoxy- phenylamine.

To a solution of 1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole, from Example 1.81,

Step C (0.57 g, 2.18 mmol) in ethanol (5.0mL), was added SnCl1;.2H,0 (1.97 g, 8.74 mmol) and the mixture was heated at 55°C overnight. The ethanol was evaporated and the residue was taken in ethyl 3s acetate (50 mL) and washed with 10% NaOH (10 mL). The organic layer was dried over MgSQ, and evaporated to yield a light yellow solid. The crude material was purified via Biotage silica chromatography (hexane/EtOAc, 3/1) to yield a pale yellow solid of 3-(2-isopropyl-2H-pyrazol-3-yl)-4- -

® ® methoxy-phenylamine (0.465 g, 94%). LCMS m/z (%) = 232 M+H" (100), '"H NMR (400 MHz,

CDCly) 8: 7.47 (s, 1H), 6.78 (d, J = 8.08 Hz, 1H), 6.72 (dd, J, = 8.01 Hz, J, = 2.78 Hz, 1H), 6.54 (d, J = 2.78 Hz, 1H), 6.25 (s, 1H), 4.14 (m, 1H), 3.63 (s, 3H), 1.4 (d, J = 6.57 Hz, 3H), 1.23 (d, J = 6.57 Hz, 3H).

Example 1.84: Preparation of 1-(4-Chloro-phenyl)-3-[3-(2-isopropyl-2H-pyrazol-3-yl)4- methoxy-phenyl]-urea (Compound 43).

To a solution of 32-isopropyl-2H-pyrazol-3-yl}-4-methoxy-phenylamine (0.1g, 0.433 mmol) in CH,Cl,, was added 4-chlorophenyl isocyanate (0.0733g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 43 as a colorless solid (0.050 g, 30%). LCMS m/z (%) = 386 M+H" (*’Cl, 26), 385

M+H" (PCI, 94), "H NMR (400 MHz, DMSO~de) §: 8.84 (bs, 1H), 8.77 (bs, 1H), 7.48 (d, J= 1.91 Hz, 1H), 7.46 (d, J= 1.84 Hz, 1H), 7.44 (d, J = 3.65 Hz, 1H), 7.33 (t, 1H), 7.3 (s, 1H), 7.29 (d, J = 7.68 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 6.13 (d, J = 1.83 Hz, 1H), 4.25 (m, 1H), 3.7 (s, 3H), 1.3 (d, J = 6.76 Hz, 6H).

Example 1.85: Preparation of 1-(4-Fluoro-pheny!)-3-{3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy- phenyl}-urea (Compound 44).

To a solution of 3+2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1g, 0.433 mmol) in CH,Cl;, was added 4-fluoro phenyl isocyanate (0.0652g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo 10 yield Compound 44 as a colorless solid (0.050 g, 30%). LCMS m/z (%) = 369 M+H", (100), ‘H

NMR (400 MHz, DMSO-d) 6: 8.59 (bs, 1H), 8.52 (bs, 1H), 7.42-7.35 (m, 4H), 7.28-7.27(d, J=2.7 Hz, 1H), 7.057(m, 3H}, 6.07 (d, J= 1.76 Hz, 1H), 4.10 (m, 1H), 3.66 (s, 3H), 1.24 (d, J = 6.56 Hz, 6H).

Example 1.86: Preparation of 1-(3,4-Difluoro-phenyl)-3-|3-(2-isopropyl-2 H-pyrazol-3-yl)}4- methoxy-phenyl]-urea (Compound 46).

To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl}-4-methoxy-phenylamine (0.1g, 0.433 mmol) in CH,C),, was added 3,4-difluoro phenyl! isocyanate (0.067g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 46 as a colorless solid (0.078 g, 42%). LCMS m/z (%) = 387 M+H", (100), 'H

NMR (400 MHz, acetone-d;) 3: 8.45 (bs, 1H), 8.27 (bs, 1H), 7.65-7.59 (m, 3H), 7.485(d, J= 2.56 Hz, 1H), 7.228-7.009 (m, 4H), 6.245 (d, J= 1.73 Hz, 1H), 4.36 (m, 1H), 3.82 (s, 3H), 1.418 (d, J = 6.61 Hz, 6H).

Example 1.87: Preparation of 1-(3-Chloro-4-fluoro-phenyl)-3-[3-(2-isopropyl-2H-pyrazol-3-yl)4- methoxy-phenyl]-urea (Compound 47). )

@® ® WO 2005/012254 PCT/US2004/023488

To a solution of 3+(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1g, 0.433 mmol) in CH2C12, was added 3-chloro-4-fluoro phenyl isocyanate (0.075g, 0.476 mmol) and stirred overnight.

The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 47 as a colorless solid (0.090 g, 52%). LCMS m/z (%) = 405 M+H+ (Cy, 23) 403 M+H+ (Cl, 60), 'H NMR (400 MHz, acetone-ds) 5: 8.3 (bs, 1H), 8.1 (bs, 1H), 7.82-7.796 (dd,

J1=6.75 Hz, J, = 2.58 Hz, 1H), 7.536 (d, J =2.67 Hz, 2H), 7.514 (d, J = 2.67 Hz, 2H), 7.43 (d, J= 1.57

Hz,1H), 7.368 (d, J = 2.65 Hz, 1H), 7.299 (d, J= 1.23 Hz, 1H), 7.136 (t, 1H), 6.079 (d, J = 1.69 Hz, 1H), 4.224 (m, 1H), 3.73 (s, 3H), 1.308 (d, J = 6.61 Hz, 6H).

Example 1.88: Preparation of 1-2-Chloro-4-trifluoromethyl-phenyl)-3-[3-(2-isopropyl-2H- pyrazol-3-yl)-4-methoxy-phenyl]-urea (Compound 48).

To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1g, 0.433 mmol) in CH.Cl,, was added 2-Chloro-4-trifluoromethylphenyl isocyanate (0.106g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 48 as a colorless solid (0.109 g, 56%). LCMS m/z (%) = 455 M+H+ (C1, 35), 453 M+H+ (**C1, 100), 'H NMR (400 MHz, acetone-ds) 5: 8.78 (bs, 1H), 8.48 (d, J = 8.97

Hz, 1H), 7.99 (bs, 1H), 7.615 (s, 1H), 7.52-7.46 (m, 1H), 7.375 (d, J = 1.41 Hz, 1H), 7.337 (d, J = 2.64

Hz, 1H), 6.973 (d, J = 8.92 Hz,1H), 6.027 (d, J = 1.63 Hz, 1H), 4.151 (m, IH), 3.676 (5, 3H), 1.244 (d,

J=6.61 Hz, 6H).

Example 1.89: Preparation of 1-{3-(4-Bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3- (4Chloro-phenyl)-urea (Compound 49).

To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08g, 0.258 mmol) in CH,Cl,, was added 4-chloro phenyl isocyanate (0.041g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 49 as a colorless solid (0.052 g, 42%). LCMS m/z (%) = 463 (M+H+" Br, 35C, 41), 465 M+H+ (Br Cl 88), 467 H+ (81 Br 37Cl, 21), 'H NMR (400 MHz, acetone-dg) 8: 8.30 (bs, 1H), 8.24 (bs, 1H), 7.685 (d, J= 2.66 Hz, 1H), 7.577 (d,J= 1.92 Hz, 2H), 7.74 (d, J=2.65, 1H), 7.292 (d, J = 1.9 Hz, 2H), 7.280 (d, J = 1.6 Hz, 1H), 7.135 (d,J=9.01 Hz, 1H), 4.256 {m, 1H), 3.811 (s, 3H), 1.447 (4, J = 6.61 Hz, 3H), 1.288 (d, J= 6.61 Hz, 3H).

Example 1.90: Preparation of 1-[3-(4-Bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3- (4-fluoro-phenyl)-urea (Compound 50).

To a solution of 3+(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08g, 0.258 mmol) in CH,Cl;, was added 4-fluoro phenyl isocyanate (0.036g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 50 as a colorless solid (0.037 8, 32%). LCMS m/z (%) = 449 M+H+ =.

® ® WO 2005/612254 PCT/US2004/023488 (*'Br, 58), 447 M+H+ (79 Br, 63), 'H NMR (400 MHz, CDCl) 8: 7.5 (s, 1H), 7.346 (d, 1.95 Hz, 2H), 7.326 9bs, 1H), 7.151 (d, J= 4.77 Hz, 1H), 7.124 {t, 1H), 6.995 (d, J = 1.87 Hz, 2H), 6.869 (d, J=5.42

Hz, 1H), 6.847 (d, J = 4.71 Hz, 1H), 4.045 (m, LH), 3.651 (s, 3H), 1.333 (d, /= 6.61 Hz, 3H), 1.160 (d,

J=6.61 Hz, 3H).

Example 1.91: Preparation of 1-[3-(4-Bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3- (3,4-difluora-phenyl)-urea (Compound 51).

To a solution of 3-(4-bromo-2-isopropy!-2H-pyrazol-3-yl}-4-methoxy-phenylamine (0.08g, 0.258 mmol) in CH,Cl,, was added 3,4-difluoro phenyl isocyanate (0.041g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 51 as a colorless solid (0.096 g, 80%). LCMS m/z (%) = 467 M+H+ (*'Br, 88), 465, M+H+ (Br, 95), 'H NMR (400 MHz, DMSO-d) 6: 8.816 (bs, 1H), 8.681 (bs, 1H), 7.5 (s, 1H), 7.412 (d, J= 2.51 Hz, 2H), 7.389 (d, J= 2.51 Hz, 2H), 7.199 (1, 1H), 7.167 (s, 1H), 6.983 (4, 1H), 3.989 (m, 1H), 3.596 (s, 3H), 1.225 (d, J= 6.61 Hz, 3H), 1.078 (d, J = 6.61 Hz, 3H). is

Example 1.92; Preparation of 1-{3-(4-Bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3- (3-Chloro-4-flucro-phenyl)-urea (Compound 52)

To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08g, 0.258 mmo}) in CH;Cl,, was added 3-chioro-4-fluoro pheny! isocyanate (0.045g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 52 as a colorless solid (0.067 g, 54%). LCMS m/z (%) = 485 M+H* (*'Br C1, 30), 483 M+H" (*Br Cl, 100), 481 M+H" ("Br *C|, 72), 'H NMR (400 MHz,

CDCl) 8: 7.7 (s, 1H), 7.4 (d, J= 1.8 Hz, 1H), 7.3 (d, J= 1.8 Hz, 1H), 7.25 (s, 1H), 7.1-6.8 (m, 3H), 4.2 (m, 1H), 3.8 (s, 3H), 1.5 (d, J =6.61 Hz, 3H), 1.3 (d, J= 6.61 Hz, 3H).

Example 1.93: Preparation of 1-[3-(4-Bromo-2-isopropy}-2H-pyrazol-3-yI)-4-methoxy-phenyl]-3- (2Chloro-4-trifluocromethyl-phenyl)-urea (Compound 53).

To a solution of 3-(4-brome-2-isopropyl-2H-pyrazol-3-y1)-4-methaxy-phenylamine (0.08g, 0.258 mmol) in CH,Cl,, was added 3-chloro-4-trifluoromethyl-phenyl isocyanate (0.059g, 0.263 mmol) and stirred overnight at ambient temperature. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 53 as a colorless solid (0.1 g, 73%). LCMS miz (%) = 535 M+H' (*'Br 37 Cl, 39), 533 M+H" (*'Br 35CJ, 100), 531 M+} (®Br *C|, 63), 'H NMR (400 MHz, DMSO-d;) 6: 8.582 (bs, 1H), 8.456 (bs, IH), 7.864 (s, 1H), 7.654 (d, J = 8.28

Hz, 1H), 7.557 (d, J = 2.76 Hz, LH), 7.536 (d, J = 2.76 Hz, 1H), 7.369 (d,J = 9.13 Hz, 1H), 4.133 (mm, 1H), 3.752 (s, 3H), 1.375 (d, J = 6.61 Hz, 3H), 1.217 (d, J = 6.61 Hz, 3H).

® ®

Example 1.94: Preparation of 1-[3-(4-Chloro-2-isopropyt-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3- (4-Chloro-phenyl)-urea (Compound 45).

To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1g, 0.433 mmol) in CH,Cl,, was added 4-chloro-phenyl isocyanate (0.073g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 45 as a colorless solid (0.097 g, 54%). LCMS m/z (%) = 421 M+H' (Cl, 53), 419 M+H" (°C, 77) 'H NMR (400 MHz, CDCl) 5: 7.689 (bs, 2H), 7.617 (s, 1H), 7.460 (d,

J =2.62 Hz, 1H), 7.438 (d, J = 2.52 Hz, 1H), 7.22-7.28 (m, 3H), 6.947 (d, J = 8.93 Hz, 1H) 4.245 (m, 1H), 3.808 (s, 3H), 1.575 (d, J = 6.35 Hz, 3H), 1.381 (d, J= 6.35 Hz, 3H).

Example 1.95: Preparation of 1-13~(4-Chloro-2-isopropyl-2 H-pyrazol-3-yl)-4-methoxy-phenyl}-3- (4-fluoro-phenyl)-urea (Compound 54).

To a solution of 3(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH,Cl,, was added 4-fluoro-phenyl isocyanate (0.065g, 0.476 mmol) and stirred . overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 54 as a colorless solid (0.055 g, 33%). LCMS m/z (%) = 405

M+HH'CI, 20), 404 M+H+ (Cl, 50), '"H NMR (400 MHz, acetone-d;) 5: 8.62 (bs, 1H), 8.101 (s, 1H), 8.081 (d, J= 2.3 Hz, 2H), 7.967 (t, 1H), 7.885 (d, J= 2.21 Hz, 2H), 7.558 (d, / = 8.91 Hz, 1H), 7.473 (4, 1H), 4.67 (m, 1H), 4.238 (s, 3H), 1.873(d, J= 6.61 Hz, 3H), 1.713 (d, J = 6.61 Hz, 3H).

Example 1.96: Preparation of 1-[3-(4-Chloro-2-isopropyl-2H-pyrazoi-3-yl)-4-methoxy-phenyl}-3- (3,4-difluoro-phenyl)-urea (Compound 55).

To a solution of 3<(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1g, 0.433 mmol) in CH,Cl,, was added 3,4-difluoro-phenyl isocyanate (0.075g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chlaoride/hexane (1:1), and dried in vacuo ta yield Compound 55 as a colorless solid (0.062 g, 35%). LCMS m/z (3%) = 423 M+H+ (Cy, 23), 421 M+H+ (°C), 67), 'H NMR (400 MHz, acetone-dg) 5: 8.199 (d, J = 2.44 Hz, 1H), 8.181 (d, J=2.42 Hz, 1H), 8.166 (d, J = 2.37 Hz, 1H), 8.147 (d, J= 2.08 Hz, 1H), 8.106 (d, J= 2.65 Hz,1H), 8.085 (d, J= 2.68 Hz, 1H), 7.967 (s, 1H), 7.880 (d, J = 2.61 Hz, 1H), 7.627 (t, 1H), 7.594 (d, J = 3.86

Hz, 1H) 7.563 (d, J = 8.96 Hz, 1H), 4.669 (m, 1H), 4.242 (s, 3H), 1.874 (d, J = 6.61 Hz, 3H), 1.713 (d,

J=6.61 Hz, 3H).

Example 1.97: Preparation of 1-(3-Chloro-4-fluoro-phenyl)-3-[3-(4-Chloro-2-isopropy}-2H- pyrazol-3-y})-4-methoxy-phenyl]-urea (Compound 56).

To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1g, 0.433 mmol) in CH,Cl,, was added 3-chloro-4-fluoro-phenyl isocyanate (0.082g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane -

® ® WO 2005/012254 PCT/US2004/023488 (1:1), and dried in vacuo to yield Compound 56 as a colorless solid (0.052 g, 28%). LCMS m/z (%) = : 439 M+H+ (Cl, 29), 437 M+H+ (¥C], 46), 'H NMR (400 MHz, acetone-d;) 8: 8.764 (bs, 1H), 8.673 (bs, 1H), 8.31-8.28 (m, 1H), 8.110 (d, J=2.72 Hz, 1H), 8.088 (d, J =2.71 Hz, 1H), 7.974 (s, 1H), 7.878 (d, J =2.68 Hz, 1H), 7.828-7.788 (m, 1H), 7.68-7.64 (m, 1H), 7.635-7.563 (m, 1H), 4.668 (m, IH), 4.246 (s, 3H), 1.874 (d, J= 6.61 Hz, 3H), 1.713 (d, J = 6.6] Hz, 3H).

Example 1.98: Preparation of 1-3-(4-Chloro-2-isopropyi-2H-pyrazol-3-yl)}-4-methoxy-phenyl}-3- . (2-Chlore-4-triflusromethyl-phenyl)-urea (Compound 57).

To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1g, 0.433 mmol) in CH,Cl,, was added 2-chloro-4-trifluoromethyl-phenyl isocyanate (0.107g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 57 as a colorless solid (0.085 g, 40%).

LCMS m/z (%) = 489 M+H+ (*'C], 25), 488 M+H+ (°C1 Cl, 25), 487 M+H+ (°C, 100), 'H NMR (400 MHz, acetone-d) 5: 8.88 (bs, 1H), 8.544 (bs, 1H), 8.063 (s, 1H), 7.669 (d, J = 1.54 Hz, 1H), 7.606 (d, J=2.69 Hz, 1H), 7.58 (t, IH), 7.549 (d, J= 1.51 Hz, 1H), 7.385 (d, J = 2.68 Hz, 1H), 7.68-7.64 (m, 1H), 7.080 (d, J = 8.98 Hz, 1H), 4.145 (m, 1H), 3.742 (s, 3H), 1.345 (4, J = 6.61 Hz, 3H), 1.188 (d, J = 6.61 Hz, 3H).

Example 1.99: Preparation of Intermediate 3-(4-Bromo-2-methyl-5-trifluoromethyl-2H-pyrazol- 3-yl)-4-methoxy-phenylamine.

To a stirred solution of 4-bromo-5-(2-methoxy-5-nitro-phenyl)-1 -methyl-3-trifluoromethyl-1H- pyrazole (0.08 g, 0.20 mmol) in EtOH (0.7 mL) was added SnCl;2H,0 (0.18 g, 0.80 mmol, 4.0 eq.) and the mixture was stirred at reflux for 2 hours followed by the removal of EtOH under vacuum. The resulting solid was dissolved in EtOAc and IN NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3x50 mL). The combined organic phase was dried over anhydrous MgSO, filtered and evaporated to give 3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)}-4-methoxy-phenylamine (0.06 g, 0.17 mmol, 99% yield after two steps) as a white solid: LCMS m/z (%6) = 350 (M+H™Br, 95), 352 (M+H"'Br, 100). '"H NMR (400 MHz, CDCl,) 8: 6.78 (dd, J = 14.0, 6.0 Hz, 1H), 6.76 (dd, J = 8.0, 4.0

Hz, 1H), 6.54 (d, J= 4.0 Hz, 1H), 3.67 (s, 3H), 3.66 (s, 3H) 3.36 ( broad s, 2H).

The intermediate 4-bromo-5+(2-methoxy-5-nitro-phenyl)-1 -methyl-3-trifluoromethyl-1H- pyrazole was prepared in the following manner:

A. 2-Methyl-5-trifluoromethyl-2H-pyrazole-3-boronic acid: 1-methyl-3 ~trifluromethyl- 1H-pyrazole (1.00 g, 6.66 mmol) was dissolved in THF (25 mL) in an oven-dried round bottom flask and cooled to -78 °C in an acetone/dry ice bath. 2.5 M n-butyl lithium/hexane (3.196 mL, 7.99 mmol) was added drop wise to the stirred solution followed by drop wise addition of triisopropy! borate (5.01

® _ g> 26.64 mmol). The mixture was warmed to room temperature and stirred for three hours. The reaction mixture was adjusted to pH 6 with 1N HCI solution followed by the removal of THF under vacuum. The aqueous phase was extracted with EtOAc (3x100 mL). The combined organic phase was washed with brine and dried over anhydrous MgSO,, filtered and evaporated to give 2-methyl-5- trifluoromethyl-2H-pyrazole-3-boronic acid (1.12 g, 5.80 mmol, 87 % yield) as a white solid: LCMS m/z (%) = 195 (M+H, 100). 'H NMR (400 MHz, DMSO-d;) 5: 8.37-8.40 (m, 2H), 7.57 (dd, J = 4.0 Hz, 1H), 4.06 (s, 3H).

B. 5-(2-Methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethy}-1H-pyrazole: Trifluoro- ‘ methanesulfonic acid 2-methoxy-S-nitro-phenyl ester (0.10 g, 0.34 mmol), 2-methyl-5-trifluoromethyl- 2H-pyrazole-3-boronic acid (0.10 g, 0.52 mmol, 1.5 eq.) and Na,CO; (0.04 g, 0.41 mmol, 1.2 eq.) were dissolved in a mixture of DME (6 mL) and H,0 (0.6 mL) in an argon flushed round bottom flask. The mixture was degassed with argon for 5 minutes, followed by the addition of Pd(PPh;), (0.04 g, 0.03 mmol, 0.01 eq.). The reaction mixture was degassed under argon for another 5 minutes and stirred at 70°C overnight. Once the reaction was complete, the DME was removed under vacuum and the crude reaction mixture was purified by SiO; column chromatography (Eluent: EtOAc/Hexane = 5% to 30%).

Final purification was achieved via reverse phase C-18 HPLC to afford 5-(2-methoxy-5-nitro-phenyl)- 1-methyl-3-trifluoromethyl-1H-pyrazole (0.05 g, 0.17 mmol, 49% yield): LCMS m/z (%) = 302 (M+H, 100). 'H NMR (400 MHz, CDCl,) 5: 8.38 (dd, J = 10.0, 2.0 Hz, 1H), 8.19 (d, J=4.0 Hz, 1H), 7.12 (d,J = 8.0 Hz, 1H), 6.57 (s, 1H), 3.98 (s, 3H), 3.78 (5, 3H).

C. 4-Bromo-5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole: NBS (0.03 g, 0.18 mmol, 1.1 eq.) in DMF (1/3 mL) was added drop wise to a stirred solution at 0 °C of 542- methoxy-5-nitto-phenyl)- 1-methyl-3-trifluoromethyl-1 H-pyrazole (0.05 g, 0.17 mmol) in DMF (2/3 mL). The reaction mixture was stirred at 0°C for 4 hrs and TLC indicated no product. An additional "equivalent of NBS was added and the reaction mixture was stirred at 70 °C overnight. A second and : third equivalent of NBS was added the following day which resulted in completion of the reaction. The

DMF was removed under vacuum and the crude mixture was diluted with EtOAc (50 mL), washed with brine (3%10 mL). The EtOAc phase was dried over anhydrous MgSO, filtered and evaporated to give the partially purified product 4-bromo-5+2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H- pyrazole (0.08 g) as a light yellow solid: LCMS m/z (%) = 380 (M+H"Br, 80), 382 (M+H"'Br, 100). 'H

NMR (400 MHz, CDCl) 3: 8.44 (dd, J = 8.0, 4.0 Hz, 1H), 8.22 (d, 1H), 7.15 (d, / = 8.0 Hz, 1H), 3.98 (s, 3H), 3.78 (s, 3H).

Example 1.100: Preparation of Intermediate 3-(4-Chloro-2-methyl-5-triflucromethyl-2H- pyrazol-3-yl)-4-methoxy-phenylamine.

To a stirred solution of 4-chloro-5-(2-methoxy-S-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H- pyrazole (0.11 g, 0.33 mmol) in EtOH (1.0 mL) was added SnCl,2H,0 (0.30 g, 1.31 mmol, 4.0 eq.) and

® the mixture was stirred at reflux for 2 hours followed by the removal of EtOH under vacuum. The resulting solid was dissolved in EtOAc and IN NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3x50 mL). The combined organic phase was dried over anhydrous MgSO, filtered and evaporated to ) give 3-(4-chloro-2-methyl- 5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.067 g, 022 mmol, 66% yield after two steps) as a white solid: LCMS m/z (%) = 306 (M-+H¥CI, 100), 308 (M+H'C), 33). "H NMR (400 MHz, CDC};) 5: 6.86 (dd, J = 14.0, 6.0 Hz, 1H), 6.84 (dd, J = 8.0, 4.0

Hz, IH), 6.63 (d, J= 4.0 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H).

The intermediate 4-chloro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H- pyrazole was prepared in the following manner:

NCS (0.05 g, 0.37 mmol, 1.1 eq.) dissolved in DMF (2/3 mL) was added drop wise to a stirred solution of 5-(2-methoxy-3-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole, see Example 1.99 (0.1 g, 0.33 mmol) in DMF (1 1/3 mL) at 0 °C. The reaction mixture was stirred 0°C and TLC indicated no product. An additional equivalent of NCS was added and the reaction mixture was stirred at 80 °C

L5 overnight which resulted in completion of the reaction. The DMF was removed under vacuum and the crude mixture was diluted with EtOAc (50 mL) and washed with brine (3x10 mL). The EtOAc phase was dried over anhydrous MgSO, filtered and evaporated to give the partially purified product 4- chloro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.13 g) as a light yellow solid: LCMS m/z (%) = 336 (M+H™Cl, 100), 382 (M+H*'Cl, 33). 'H NMR (400 MHz, CDCl) &: 8.37 (dd, J= 8.0, 4.0 Hz, IH), 8.16 (d, J= 4.0 Hz 1H), 7.09 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 3.69 (s, 3H).

Example 1.101: Preparation of Intermediate 4-Methoxy-3-(2-methyl-5-trifluoromethyl-2H- pyrazol-3-yl)-phenylamine.

SnCly2H,0 (0.15 g, 0.66 mmol, 4.0 eq.) was added to a stirred solution of 5-(2-methoxy-5- nitro-pheny()-1-methyl-3-triflucromethyl-1 H-pyrazole, see Example 1.99, (0.05 g, 0.16 mmol) in EtOH (2.0 mL). The mixture was stirred at reflux for 4 hrs and EtOH was removed under vacuum. The resulting solid was dissolved in EtOAc and IN NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3x50 mL). The combined organic phase was dried over anhydrous MgSO, filtered and evaporated to give 4-methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenylamine (0.04 g, 0.15 mmol, 97% yield): LCMS mvz (%) = 272 (M-+H, 100). '"H NMR (400 MHz, CDCl,) &: 6.82 (dd, J= 16.0, 4.0 Hz, 1H), 6.79 (dd, J= 10.0, 2.0 Hz, 1H), 6.61 (d, 1H), 6.46 (s, 1H), 3.76 (s, 3H), 3.74 (5, 3H).

Example 1.102: 1-|3-(4-Bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]- 3-(4-chloro-phenyl)-urea (Compound 38).

® ®

Urea synthesis for Compound 38 (general procedure for Examples 1.103-1.106): Toa stirred solution of aniline 3-(4-bromo-2-methyl-5-triflucromethyl-2H-pyrazol-3-yl)-4-methoxy- phenylamine (0.03 g, 0.08 mmol) in CH,Cl, (1 mL) was added 4-chlorophenyl isocyanate (0.01 g, 0.08 mmol, 1.0 eq.) at room temperature. White solid precipitated and was filtered and washed with cold

CHCl, to afford Compound 38 (0.02 g, 0.04 mmol, 50% yield) as a white solid: LCMS m/z (%) = 503 (M+H"Br, 67), 505 (M+H"'Br, 100). 'H NMR (400 MHz, MeOH-d,) 5: 7.59 (dd, J= 6.0, 2.0 Hz, 1H), 7.42 (d, J= 8.0 Hz, 2H), 7.38 (d, J = 4.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 3.84 (s,3H), 3.75 (5, 3H). .

Example 1.103; ‘1-[3-(4-Bromo-2-methy}-5-trifluoromethyl-2H-pyrazol-3-yI)-4-methoxy-phenyl]- 3-(4-fluoro-phenyl)-urea (Compound 39). 3-(4-Bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine 0.03 ¢g, 0.08 mmol) was treated with 4-fluorophenyl isocyanate (0.01 g, 8.99 nL, 0.08 mmol, 1.1 equiv.) in

CHCl; (2.0 mL), in a similar manner as described in Example 1.102, to afford Compound 39 (0.03 g,

I5 - 0.05 mmol, 64 % yield) as a white solid: LCMS m/z (%) = 487 (M+H"Br, 100), 489 (M+H"'Br, 93). 'H

NMR (400 MHz, MeOH-d,) 8: 7.58 (dd, J = 10.0, 2.0 Hz, 1H), 7.42 (dd, J = 4.0 Hz, 2H), 7.38 (dd, J = 10.0,2.0 Hz, 1H), 7.16 (d, /= 12.0 Hz, 1H), 7.03 (dd, J = 12.0, 8.0 Hz, 2H), 3.84 (s, 3H), 3.75 (s, 3H).

Example 1.104: 1-[3-(4-Chloro-2-methyl-5-trifluoromethy}-2 H-pyrazol-3-yl)-4-methoxy-phenyl]- 3-<{4-Nluoro-phenyl)-urea (Compound 40). 3-(4-Chloro-2~methiyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.03 g, 0.11 mmol) was treated with 4-fluorophenyl isocyanate (0.02 g, 14.6 pL, 0.13 mmol, 1.2 equiv.) in

CH;Cl; (4.0 mL), in a similar manner as described in Example 1.102. The product was further purified via reverse phase C-18 HPLC to afford Compound 46 (0.03 g, 0.07 mmol, 63 % yield) as a white solid:

LCMS m/z (%) = 443 (M+H'C], 100), 445 (M+H?C, 36). 'H NMR (400 MHz, MeOH-d,) 5: 7.58 (dd,

J=10.0,2.0 Hz, 1H), 7.42 (dd, J = 4.0 Hz, 2H), 7.40 (dd, J = 8.0, 4.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.03 (dd, J= 10.0, 6.0 Hz, 2H), 3.84 (s, 3H), 3.74 (s, 3H).

Example 1.105: 1-{3-(4-Chlore-2-methyl-5-trifluoromethy}-2H-pyrazol-3-yl)-4-methoxy-phenyi}- 3-(4-chloro-phenyl}-urea (Compound 41). 3-(4-Chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.03 g, 0.11 mmol) was treated with 4-chloropheny! isocyanate (0.02 g, 0.13 mmol, 1.2 equiv.) in CH,Cl, (4.0 mL), in a similar manner as described in Example 1.102. The product was further purified via reverse phase C-18 HPLC to afford Compound 41 (0.03 g, 0.06 mmol, 56 % yield) as a white solid: LCMS m/z (%)= 459 (M+H™C], 100), 461 (M+H"CI'Cl, 84), 463 (M+H*"Cl, 10). 'H NMR (400 MHz, MeOH)

® WO 2005/012254 PCT/US2004/023488 8:7.59 (dd, J= 8.0, 4.0 Hz, 1H), 7.41 (dd, J=8.0, 8.0 Hz, 2H), 7.40 (dd, J= 8.0, 1H), 7.27 (d, J = 8.0

Hz, 2H), 7.17 (d,J=12.0 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H).

Example 1.106: 1-(4-Chloro-phenyl)-3-[4-methoxy-3-(2-methy}-S-trifluoromethyl- 2H-pyrazol-3-

YD-phenylj-urea (Compound 42). 4-Methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenylamine (0.02 g, 0.08 mmol) was treated with 4-chloropheny! isocyanate (0.01g, 10.45 uL, 0.093 mmol, 1 2 equiv.) in CHCl, (3.0 mL), in a similar manner as described in Example 1.102. The product was further purified via reverse phase C-18 HPLC to afford Compound 42 (0.03 g, 0.07 mmol, 88 % yield) as a white solid: LCMS m/z (%) = 425 (M+H'CI, 100), 427 (M+HClI, 34). '"H NMR (400 MHz, MeOH-d,) 6: 7.50 (dd, J = 10.0, 2.0 Hz, 1H), 7.42 (dd, J= 8.0 Hz, 3H), 727 (dd, /=6.0,2.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H).

Example 1.107: Preparation of intermediate 1{4-chloro-phenyl)-3-(4-0x0-4H-chromen-6-yl)- urea,

Step 1: Preparation of 6-amino-chromen—4-one.

To a solution of 6-nitrochromone (2.0, 10.5 mmol) in Methanol/Ethyl acetate (100 mL/20 mL) purged with argon, was added 5%Pd/C (Degussa-wet, 0.5g) catalyst. Hydrogen gas was bubbled through the slurry with stirring until (2hrs.) LCMS and TLC showed no starting material. The spent palladium catalyst was filtered off through a celite, and the solid was washed with methanol. The combined filtrate and washings were evaporated to produce 6-amino-chromen-4-one as a light yellow solid (1.58 g, 94%). LCMS m/z (%) = 162 (M+H, 100), 'H NMR (400 MHz, CDCly) 8: 7.79-7.81 (d, J = 3.96 Hz, 1H), 7.38 (d, J = 2.86 Hz, 1H), 7.29-7.31 (d,/=8.88 Hz, 1H), 7.01-7.04 (dd, J = 8.80,2.8

Hz, 1H), 6.26-6.28 (d, J= 5.96 Hz, 1H), 5.299 (s, 2H). 25 . Step 2: Preparation of 1-(4-chloro-phenyl)-3-(4-0x0-4H-chromen-6-yl)-urea.

To the slurry of 6-aminochromone (3.0 g, 18.6 mmol) stirred and heated to 80°C in toluene (200 mL) was added 4~chlorophenyl isocyanate (3.2 g, 20.5 mmol) and the mixture was refluxed for 18hrs. The reaction mixture was cooled and the precipitate was filtered and washed with methanol.

The residue was dried in vacuo to afford a yellow powder (5.8 g, 99%) of 1-(4-chloro-phenyl)-3-(4- 0x0-4H-chromen-6-yl)-urea. LCMS m/z (%) = 315 (M+H, *5Cl 100), 317 (M+H, *'C1 32.2) "H NMR (400 MHz, DMSO-d) 8: 9.098 (bs, 1H), 8.94 (bs, 1H), 8.28-8.30 (d,J = 5.99 Hz, IH), 8.20-8.21 (d,J= 2.69 Hz, 1H), 7.81-7.84 (dd, J=9.0, 2.75 Hz, 1H), 7.62-7.64 (d, J = 9.07 Hz, IH), 7.52-7.55 (dd, J= 6.84, 2.16 Hz, 2H), 7.35-7.37 (dd, J = 6.85, 2.11 Hz, 2H), 6.33-6.34 (d,J=5.98 Hz, 1H).

Example 1.108: Preparation of 1{4-Chioro-phenyl)-3-{4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)- phenylj-urea (Compound 119). -

® ® WO 2005/012254 PCT/US2004/023488

To a cooled and stirred solution of methyl hydrazine (1.46 g, 31.6 mmol) in pyridine was added slurry of 1-(4-Chloro-phenyl)-3-(4-oxo-4H-chromen-6-y!)-urea (2.5 g, 7.9 mmol) in pyridine over a period of 10mins. The reaction mixture was left at this temperature for another 2 hrs and then warmed to room temperature slowly. After 6 hrs the reaction mixture turned clear. The reaction was stirred at this temperature for 18 hrs and pyridine was evaporated. The dark colored residue was dissolved in

DMSO and purified using Varian Prep. HPLC system. (The two regioisomers were separated. The fractions containing Compound 119 were dried in vacuo to produce a colorless powder (1.78 g, 47%) 1- (4-Chloro-phenyl)-3-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)}-phenyl)-urea. LCMS m/z (%) = 343 (M+H, C1100), 345 (M+H, ”’C1, 32.5). 'H NMR (400 MHz, DMSO-d;) 5: 9.59 (bs, 1H), 8.72 (bs, 1H), 8.48 (bs, 1H), 7.43-7.46 (dd, J = 6.8,2.07 Hz, 2H), 7.41 (d, J = 1.83 Hz, 1H), 7.28-7.30 (dd, J = 7.13, 2.09 Hz, 2H), 7.26 (d, /= 2.72 Hz, 1H), 6.88-6.90 (d, J = 9.36 Hz, 1H), 6.21 (d, J= 1.84 Hz, 1H), 3.67 (s, 3H).

Example 1.109: Preparation of 1-(4-Chloro-phenyl)-3-[4-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)- phenyl]-urea (Compound 154),

To a cooled and stirred solution of methyl hydrazine (1.46 g, 31.6 mmol) in pyridine was added slurry of Compound 119 (2.5 g, 7.9 mmol) in pyridine over a period of 10mins. The reaction mixture was left at this temperature for another 2hrs and then warmed to room temperature slowly. After 6 hrs the reaction mixture turned clear. The reaction was stirred at this temperature for 18 hrs. Then pyridine was evaporated. The dark colored residue was dissolved in DMSO and purified using Varian

Preperative HPLC system at a flow rate of 60 mL/Min. and A = 240. The regio isomers were separated.

The fractions containing Compound 154 were dried in vacuo to produce an off-white solid 1-(4-Chloro- phenyl)-3-[4-hydroxy-3-(1 -methyl-1H-pyrazol-3-yl)-phenyl}-urea (0.3 g, 12%). LCMS m/z (%) = 343 (M+H, **Cl1 100), 345 (M+H, ¥'Cl, 32.5). '"H NMR (400 MHz, DMSO-d;) 5: 10.26 (bs, 1H), 8.73 (bs, 1H), 8.46 (bs, 1H), 7.82 (d, J = 2.32 Hz, 1H), 7.77 (d, J= 3.62 Hz, 1H), 7.44-7.49 (m, 2H), 7.16-7.19 (dd, J= 8.74, 2.62 Hz, 1H), 6.83-6.85 (d, J = 8.72 Hz, 1H), 6.71-6.72 (d, J = 2.36 Hz, 1H), 3.91 (s, 3H).

Example 1.110; Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl}-3- (4-chloro-phenyl)-urea (Compound 121).

To a stirred and cooled solution of Compound 119 (0.22 g, 0.63 mmol), in DMF (2.0 mL) was added N-chlorosuccinimide (0.168, 1.26 mmol). The reaction was stirred until the LCMS showed no starting material (2.5 hrs). The reaction mixture was poured into ice cooled water containing Na,S,0; and NaHCO, and the resulting solid was filtered, washed with ice-cooled water and dried in vacuo to afford a off-white solid 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl}-3-(4-chloro- phenyl)-urea (0.14 g, 58%). LCMS m/z (%) = 377 (M+H, CJ, °C, 100), 379 (M+H, *’C, C1, 59.4), 381 (M+H, *’C, *'Cl, 10.0). "HNMR (400 MHz, DMSO-d) 8: 9.76 (bs, 1H), 8.73 (bs, 1H), 8.56 (bs,

® 1H), 7.58 (s, 1H), 7.44-7.46 (dd, J = 8.6, 2.03 Hz, 2H), 7.34-7.37 (dd, J=8.79, 2.7 Hz, 1H), 7.29 (d4, J = 8.85,2.07 Hz, 3H), 6.92-6.94 (d, J = 6.78 Hz, 1H), 3.64 (s, 3H).

Example 1.111: Preparation of 1-[3-(4-Chloro-2-methyl-2 H-pyrazal-3-y}-4-(3-dimethylamine- propoxy)-phenyl]-3-(4chloro-phenyl)-urea (Compound 128).

To a stirred and cooled solution of Compound 119, 14-Chloro-phenyl)-3-[4-hydroxy-3-(2- methyl-2H-pyrazol-3-y!)-phenyl}-urea, (0.1 g, 0.2923 mmol), triphenyl phosphine (0.291 g, 1.1078 mmol) and 3-dimethy] amino propanol (0.114 g, 1.099 mmol) in THF (25 mL) was added diisopropyl azodicarboxylate (0.224 g, 1.104 mmol) slowly over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 4hrs at this temperature. The THF was evaporated and the syrup was dissolved in DMSO and purified using preperative HPLC at 60 mL/min flow and A = 240.

The fractions containing the product were evaporated. The pink colored residue was subjected to 2™ purification using SiO, flash chromatography (eluant: 1% methanol in DCM to 15% methanol in DCM).

The fractions containing the product were evaporated to afford a colorless solid. To a cooled solution of the solid in methanol was added a solution of N-chlorosuccinimide (0.044 g, 0.3215 mmol) in methanol. The reaction mixture was stirred for 60 minutes. Next, the methanol was evaporated and the residue was purified using silica and 15% methanol in DCM as eluant. The fractions containing the product were evaporated and dried in vacuo to produce a off-white solid of 1-[3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-(3-dimethylamino-propoxy)-phenyl)-3(4-chloro-phenyl)-urea (0.015 g, 12%).

LCMS m/z (%) = 462 (M+H *Cl, C1 100), 464 (M+H, *C, *’Cl, 70.2), 466 (M+H, *’Cl, ¥'Cl, 11.2) 'H NMR (400 MHz, acetone-ds) 8: 8.29 (bs, 1H), 8.21 (bs, 1H), 7.61-7.64 (dd, J = 8.94, 2.73 Hz, 1H), 7.53-7.56 (dd, J = 7.09, 2.09 Hz, 2H), 7.46 (s, 1H), 7.43-7.46 (d, J=2.7 Hz, 1H), 7.26-7.28 (dd, J = 7.09, 2.07 Hz, 2H), 7.11-7.13 (d, J = 8.98 Hz, 1H), 3.98-4.1 (m, 2H), 3.67 (s, 3H), 2.21-2.25 (m, 2H), 2.09 (s, 6H), 1.75-1.79 (m, 2H).

Example 1.112: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylamino- propoxy)-phenyl]-3-(3,4-difluoro-phenyl)-urea (Compound 148).

To a cooled and stirred solution of Compound 136 (0.03 g, 0.0698 mmol), in methanol, was added N-bromosuccinimide (0.014 g, 0.077 mmol). The reaction mixture was stirred at this temperature for 10 minutes and warmed to ambient temperature. Methanol was evaporated and the residue was purified on silica using 1%MeOH/DCM to 15%MeOH/DCM as eluent. The fractions containing the product were evaporated in vacuo to produce 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(3- dimethylamino-propoxy)-phenyl}-3-(3,4-difluoro-phenyl)-urea as an off-white solid (0.014 g, 40%).

LCMS m/z (%) = 508 (M+H, Br, 100), 510 (M+H, ®'Br, 82.6), 'H NMR (400 MHz, acetone-ds) 5: 8.69 (bs, 1H), 8.53 (bs, 1H), 7.70-7.76 (m, 1H), 7.59-7.62 (dd, J = 8.95, 2.74 Hz, 1H), 7.46 (s, LH), 7.44 (d, /=2.7 Hz, 1H), 7.08-7.16 (m, 3H), 3.98-4.1 (m, 2H), 3.67 (s, 3H), 2.43-2.47 (m, 2H), 2.25 (s, 6H), 1.85-1.91 (m, 2H). -

® ®

Example 1.113: Preparation of 1-{3<4-Bromo-2-methyl-2H-pyrazol}-3-y1)-4-(3-dimethylamino- propoxy)-phenyl]-3-(2-chloro-phenyl)-urea (Compound 149).

To a cooled and stirred solution of Compound 140 (0.04 g, 0.0936 mmol), in methanol, was added N-bromosuccinimide (0.018 g, 0.102 mmol). The reaction mixture was stirred at this temperature for 10 minutes and warmed to ambient temperature. Methanol was evaporated and the residue was purified on silica using 1%MeOH/DCM to 15%MeOH/DCM as eluent. The fractions containing the product were evaporated in vacuo to produce 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4(3- dimethylamino-propoxy)-phenyl]}-3(2-chloro-phenyl)-urea as an off-white solid (0.02 g, 42%). LCMS m/z (%) = 506 (M+H "Br, Cl, 83.9), 508 (M+H, *'Br, Cl, 100), 510 (M+H, *'Br, ”’Cl, 30) 'H NMR (400 MHz, acetone-d) 8: 8.59 (bs, 1H), 8.09-9.12 (dd, J=9.3, 1.51 Hz, 1H) 7.63 (bs, 1H), 7.43-7.46 (dd, J, = 8.95 Hz, J, = 2.75 Hz, L1H), 7.27 (s, 1H), 7.22-729 (d, J =2.72 Hz, 1H), 7.16-7.18 (dd, J = 8.63, 1.4 Hz, 1H), 7.05-7.08 (m, 1H), 6.91-6.93 (d, J = 8.98 Hz, 1H), 6.77-6.81 (m, 1H), 3.48-3.91 (m, 2H), 3.48 (5, 3H), 2.01-2.05 (m, 2H), 1.89 (s, 6H), 1.56-1.61 (m, 2H).

Example 1.114: Preparation of 1-]3-(4-Bromo-2-methy}-2H-pyrazo}-3-yi)-4-(3-dimethylamino- propoxy)-phenyl}-3-(2-fluoro-phenyl)-urea (Compound 150).

To a cooled and stirred solution of Compound 138 (0.04 g, 0.0972 mmol), in methanol, was added N-bromosuccinimide (0.019 g, 0.107 mmol). The reaction mixture was stirred at this temperature for 10 minutes and warmed to ambient temperature. Methanol was evaporated and the residue was purified on silica using 1%MeOH/DCM to 15%MeOH/DCM as eluant. The fractions containing the product were evaporated in vacuo to produce 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(3- dimethylamino-propoxy)-phenyl]-3-(2-fluoro-phenyl)-urea as a off-white solid (0.02 g, 42%). LCMS m/z (%) = 490 (M+H Br,100), 492 (M+H, "'Br, 99.9). 'H NMR (400 MHz, acetone-ds) 3: 8.59 (bs, 1H), 8.37 (d, = 1.57 Hz, 1H) 8.1 (bs, 1H), 7.72-7.75(dd, J = 8.95, 2.75, 1H), 7.57 (s, 1H), 7.52-7.53 (d, J=2.72 Hz, 1H), 7.18-7.22 (m, 3H), 7.07 (m,1 H) 4.07-4.19 (m, 2H), 3.78 (s, 3H), 2.3-2.35 (m, 2H), 2.19 (s, 6H), 1.85-1.88 (m, 2H).

Example 1.115: Preparation of 1-]3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-pheny}-3- (2,4-difluoro-phenyl)-urea (Compound 103). 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (Compound 8, 1.44 g, 3.30 mmol) was dissolved in anhydrous CH,Cl; (30 mL). The solution was stirred while cooling the temperature to 0°C in an ice water bath. After allowing it to stir for another 10 minutes, AlCl, (1.76 g, 13.20 mmol) was added slowly. This was followed by stirring the reaction for an additional 20 minutes, and subsequently increasing the temperature to 80°C . After one hour, the reaction was shown to be complete by TLC and LC/MS. It was worked up with EtOAc (2 x 50 mL)

® ® and 10% Potassium Sodium Tartrate (2 x 50 mL). Upon being treated to this work up, the aluminum was removed from the solution. The organic layer was then dried with Na,SO,, filtered, and the solvent

Was removed under reduced pressure. The residue was then purified by HPLC, yielding 1.43 g (100%) of Compound 103 LCMS m/z (%) = 425 (M+H* Br, 100), 423 (M+H™Br, 88). 'H NMR (400 MHz,

DMSO0-dg) 8 9.74 (s, 1H), 8.87 (5, 1H), 8.40 (s, 1H), 8.08-8.03 (m, 1H), 7.58 (s, 1H), 7.36 (dd, J, = 8

Hz, J, = 4 Hz, 1H), 7.33-7.27 (m, 1H), 7.28 (d, J=2 Hz, 1H), 7.04-7.01 (m, 1H), 6.95 (d, J= 8 Hz, 1H), 3.67 (s, 3H).

Example 1.116: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino- ethoxy)-phenyl)-3-(2,4-difluoro-phenyl)-urea (Compound 123).

Compound 103 (73.7 mg, 0.17 mmol) was dissolved in anhydrous THF (5 mL). PPh; (173 mg, 0.64 mmol) and 2-Dimethylamino ethanol (65.5 pL, 0.63 mmol) were then added to the solution, and the reaction was stirred at room temperature. A fier stirring for five minutes, DIAD (127 pL, 0.64 mmol) was added to the reaction dropwise. The reaction was found to be complete by TLC and LC/MS - after 30 minutes. The solvent was then removed under reduced pressure. The residue was purified twice by flash chromatography (Biotage, SiO,, Dichloromethane/Methano} gradient elution) and twice by HPLC to afford 26.4mg (31%) of Compound 123 as a light brown oil: LCMS m/z (%) = 496 (M+H"'Br, 100), 494 (M+H"Br, 94). 'H NMR (400 MHz, DMSO-d;) & 8.99 (s, 1H), 8.44 (s, 1H), 8.07-8.01 (m, 1H), 7.59 (s, 1H), 7.52 (dd, J, = 8 Hz, J, = 4 Hz, 1H), 7.35 (d, J = 4, 1H), 7.32-7.26 (m, 1H), 7.17 (d, J = 12 Hz, 1H), 7.05-7.00 (m, 1H), 4.11 (dm, 2H), 3.65 (s, 3H), 2.58 (dm, 2H), 2.11 (s, 6H).

Example 1.117: Preparation of (2-{2-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[3-(2,4-difluoro- phenyl)-ureido]-phenoxy}-ethyl)-carbamic acid tert-butyl ester (Compound 147).

Compound 147 was prepared in a similar manner as described in Example 1.116 using N-Boc- aminoethanol and DEAD, providing 25 mg (39%) of Compound 147. LCMS m/z (%) = 566 (M+H"Br, 21), 568 (M+H"'Br, 12). '"H NMR (400 MHz, DMSO-d;) 9.00 (s, 1H), 8.45 (s, 1H), 8.07- 8.00 (m, tH), 7.59 (s, 1H), 7.51 (dd, J, = 8 Hz, J, = 2 Hz, 1H), 7.35 (d, J= 4 Hz, 1H), 7.32 (m, 1H), 7.16 (d, J= 8 Hz, 1H), 7.05-7.00 (m, 1H), 6.89-6.87 (m, 1H), 4.03-3.98 (m, 1H), 3.98-3.92 (m, 1H), 3.64 (s, 3H), 3.34-3.29 (m, 1H), 3.22-3.17 (m, 1H), 1.36 (s, 9H).

Example 1.118: Preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-hydrexy-phenyl}-3- (4-chloro-phenyl)-urea (Compound 58).

Compound 1, (1.56 g, 3.58 mmol) was dissolved in anhydrous CH,Cl, (50 mL). The solution was stirred while cooling the temperature to 0°C in an ice water bath. After allowing it to stir for another 10 minutes, AlCl; (1.91 g, 14.32 mmol) was added slowly. This was followed by stirring the

® reaction for an additional 20 minutes, and subsequently increasing the temperature to 80°C. Afier one hour, the reaction was shown to be complete by TLC and LC/MS. It was worked up with EtOAc (2 x 50 mL) and 10% Potassium Sodium Tartrate (2 x 50 mL). Upon being treated to this work up, the aluminum was removed from the solution. The organic layer was then dried with Na,SO,, filtered, and the solvent was removed under reduced pressure. The residue was purified by HPLC to afford

Compound 58 (402 mg, 27%): LCMS m/z (%) = 423 (M+H*'Cl, 100), 421 (M+H¥C}, 98). 'H NMR (400 MHz, DMSO-ds) 6 9.74 (s, 1H), 8.76 (s, 1H), 8.59 (s, 1H), 7.60 (s, 1H), 7.48 (d, J= 8 Hz, 2H), 7.39 (dd, J, = 8 Hz, J,=4 Hz, 1H), 7.32 (d, J= 8 Hz, 2H), 7.28 (d, J=2 Hz, 1H), 6.96 (d,J= 12 Hz, 1H), 3.67 (s, 3H).

Example 1.119: Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yI)-4-methoxy-phenyl}-3- (3-chloro-phenyl)-urea (Compound 91). 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (30 mg, 0.13 mmol) was treated with 3-Chlorophenyl isocyanate (17 pL, 0.14 mmol) in a similar manner to Example 1.53, providing 25 mg (46%) of Compound 91: LCMS m/z (%) = 391 (M+H*Cl, 100), 393 (M+HY'C), 70). 'H NMR (400 MHz, acetone-ds) 8: 8.51 (s, 1H), 8.41 (s, 1H), 7.84 (t, 1H), 7.71 (dd, J; =8 Hz, , = 4

Hz, 1H), 7.49 (s, 1H), 7.49 (d, J =2 Hz, 1H), 7.38 (d, J= 8 Hz, 1H), 7.29 (1, 1H), 7.16 (d, J=8 Hz, 1H), 7.01 (d, J = 8 Hz, 1H), 3.84 (s, 3H), 3.68 (s, 3H).

Example 1.120: Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3- (3,4-difluoro-phenyl)-urea (Compound 92). 3-(4-Chlora-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (30 mg, 0.13 mmol) was treated with 3,4-Diflucrophenyl isocyanate (17 pL, 0.14 mmol) in a similar manner to Example 1.53, providing 18.6 mg (34%) of Compound 92: LCMS m/z (%) = 393 (M+H*C, 100), 395 (M+H’'C}, 38). 'H NMR (400 MHz, acetone-ds) 8: 8.18 (s, 1H), 8.05 (s, 1H), 7.65 (m, 1H), 7.57 (dd, J, = 8 Hz, /,=4

Hz, 1H), 7.36 (s, 1H), 7.33 (d, J = 2 Hz, 1H), 7.09 (d, J = 4 Hz, 1H), 7.06 (d, /=2 Hz, 1H), 7.04 (d,J= 8 Hz, 1H), 3.72 (s, 3H), 3.55 (5, 3H).

Example 1.121: Preparation of 1-[3-(4-Chloro-2-methy}-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3- (3,5-difluoro-phenyl)-urea (Compound 93). 3-(4-Chloro-2-methyl-2H-pyrazol-3-y])}-4-methoxy-phenylamine (30 mg, 0.13 mmol) was treated with 3,4-Difluorophenyl isocyanate (17 pL, 0.14 mmol) in a similar manner to Example 1.53, providing 24.6 mg (44%) of Compound 93: LCMS m/z (%) = 393 (M+H*Cl, 100), 395 (M+H’'C], 47). 'H NMR (400 MHz, acetone-ds) 5: 8.26 (s, 1H), 8.01 (s, 1H), 7.47 (dd, J, = 8 Hz, J, = 2 Hz, 1H), 726 (s, 1H), 7.22 (d, J = 2 Hz, 1H), 7.04 (dd, J, = 12 Hz, J, = 4 Hz, 2H), 6.95 (d, J= 8 Hz, 1H), 6.40 (m, 1H), 3.62 (s, 3H), 3.48 (s, 3H).

® WO 2005/012254 PCT/US2004/023488

Example 1.122: Preparation of 1-Benzoyl-3-{3~(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-urea (Compound 95). 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (20 mg, 0.08 mmol) was treated with benzyl isocyanate (14 mg, 0.09 mmol) in a similar manner to Example 1.53, providing 10 mg (31%) of Compound 95: LCMS m/z (%) = 385 (M+H¥C], 11), 387 M+H*'C}, 4). 'H NMR (400

MHz, CDCl) 8: 10.85 (s, 1H), 9.15 (s, 1H), 7.88 (d, J~12 Hz, 2H), 7.58 (dd, J, = 8 Hz, J,= 2 Hz, 1H), 7.34 (d, J = 8 Hz, 1H), 7.49 (5, 1H), 7.43 (d, J = 4 Hz, 1H), 7.41 (d, J= 8 Hz, 2H), 6.95 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.64 (s, 3H).

Example 1.123: Preparation of 1-[3(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyi]-3- (2-fluoro-phenyl)-urea (Compound 97). 3-(4-Chloro-2-methyl-2H-pyrazo)-3-yl)-4-methoxy-phenylamine (20 mg, 0.08 mmol) was treated with 2-Fluorophenyl isocyanate (10 pL, 0.09 mmol) in a similar manner to Example 1.53, providing 8.0 mg (26%) of Compound 97: LCMS m/z (%) = 375 (M+H*Cl, 100), 377(M+H"'C}, 43). 'H NMR (400 MHz, CDCl) 8: 8.26 (t, 1H), 7.73 (dd, J, = 8 Hz, J; =4 Hz, 1H), 7.69 (s, 1H), 7.36 (t, 1H), 7.35 (d, J= 4 Hz, 1H), 729 (1, 1H), 7.24 (d, J= 8 Hz, 1H), 7.19 (d, J= 8 Hz, 1H), 7.17 (d,J=8

Hz, 1H), 3.97 (s, 3H), 3.86 (5, 3H).

Example 1.124: Preparation of 1-[3-(4-Chloro-2-methyl-2 H-pyrazol-3-yl)-4-methoxy-phenyl]-3- (3-cyano-phenyl)-urea (Compound 109). 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (55 mg, 0.23 mmol) was treated with 3- Cyanophenyl isocyanate (37 mg, 0.26 mmol) in a similar manner to Example 1.53, providing 57 mg (65%) of Compound 109: LCMS m/z (%) = 382 (M+H¥ClI, 100), 384 (M+H"'C], 38). ‘HNMR (400 MHz, DMSO-d) 8: 9.02 (s, 1H), 8.85 (s, 1H), 7.98 (t, 1H), 7.68 (d, J = 8 Hz, 1H), 7.62 (s, 1H), 7.59 (dd, J; = 12 Hz, J; = 2 Hz, 1H), 7.50 (t, 1H), 7.42 (1, 1H), 7.42 (d, J= 4 Hz, IH), 7.18 (d, J = 8 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H).

Example 1.125: Preparation of 1-Benzyl-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-urea (Compound 105). 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (59 mg, 0.25 mmol) was treated with benzyl isocyanate (34 yl, 0.28 mmol} in a similar manner to Example 1.53, providing 42.7 mg (46.1%) of Compound 105: LCMS m/z (%) = 371 (M+H¥C}, 100), 373 (M+H*'C], 40). 'H NMR (400 MHz, DMSO-d) 8: 8.55 (s, 1H), 7.58 (s, 1H), 7.50 (dd, J, = 8 Hz, J, = 4 Hz, 1H), 7.33 (m, SH), 7.30 (d, J = 4 Hz, 1H), 7.10 (d, J=12 Hz, 1H), 6.58 (s, 1H), 4.28 (s, 2H), 3.73 (5, 3H), 3.58 (s, 3H).

_

Example 1.126: Preparation of 1-[3-(4-Chloro-2-methy-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3- (3-nitro-phenyl-urea (Compound 110). 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (36 mg, 0.15 mmol) was treated with 3-Nitropheny! isocyanate (28 mg, 0.17 mmol) in a similar manner to Example 1.53, ] providing 8.7 mg (15%) of Compound 110: LCMS m/z (%) = 402 (M+H’Cl, 100), 404 (M+H"'CL, 38). 'H NMR (400 MHz, DMSO-d;) 8: 9.22 (s, 1H), 8.84 (s, 1H), 8.55 (s, 1H), 7.83 (dd, J, =8 Hz, , = 4

Hz, 1H), 7.72 (d,J = 8 Hz, 1H), 7.62 (s, 1H), 7.61 (d, J = 4 Hz, 1H), 7.58 (s, 1H), 7.58 (t, IH), 7.41 (d,

J=4 Hz, 1H), 7.19 (d, J= 12 Hz, 1H), 3.78 (s, 3H), 3.62 (s, 3H).

Example 1.127; Preparation of 1-[3{(4-Bromo-2-methy}-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3- (3-(1-hydroxy-ethyl)-phenyl]-urea (Compound 94).

Compound 17 (30.2 mg, 0.07 mmol, see Example 1.24) was dissolved in ethanol (5 mL).

Sodium Borohydride (3.1 mg, 0.08 mmol) was added under Argon gas. The reaction was stirred overnight and found to be complete by TLC and LC/MS. The mixture was worked up with IN * Hydrogen Chloride solution (10 mL) and EtOAc (2 x 15 mL). The organic layers were combined and washed with water, dried over Na; SO, filtered, and the solvent removed under reduced pressure. The residue was then purified by HPLC to afford 19.4 mg (63%) of Compound 94: LCMS m/z (%) = 445 _ (M+H™Br, 25), 447 (M+H"'Br, 25). 'H NMR (400 MHz, CDCl;) 8: 7.34 (dd, J, =8 Hz, J; =2 Hz, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 7.11 (d, J = 8 Hz, 1H), 7.09 (s, 1H), 7.06 (t, 1H), 6.95 (d, J = 4 Hz, 1H), 6.85 (d, J= 8 Hz, 1H), 6.76 (d, J= 8 Hz, 1H), 4.65 (m, 1H), 3.59 (5, 3H), 3.49 (s, 3H), 1.27 (d, J = 4 Hz, 3H).

Example 1.128: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)}-4-methoxy-pheayl]-3- [3-(1-hydroxyimino-ethyl)-phenyl]-urea (Compound 96).

Compound 17 (54 mg, 0.12 mmol, see Example 1.24) was dissolved in ethanol (10 mL).

Hydroxylamine hydrochloride (17 mg, 0.24 mmol) was added under Argon gas. The pH of the solution was then adjusted to pH=4 with 1N Hydrogen Chloride solution. The reaction was stirred overnight at room temperature and found to be complete by TLC and LC/MS. The ethanol was removed under reduced pressure. Then, the residue was worked up with EtOAc (2 x 20 mL) and Brine (20 mL). The arganic layers were combined, dried over Na,SO,, filtered, and the solvent removed under reduced pressure. The residue was then purified by HPLC to afford 8.8 mg (16%) of Compound 96: LCMS m/z (%) = 458 (M+H™Br, 96), 460 (M+H"'Br, 100). 'H NMR (400 MHz, CDC13) 8: 7.78 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.48 (dd, J; = 12 Hz, J; = 4 Hz, 1H), 7.42 (5, 1H), 7.41(dd, J, = 8 Hz, J; =4 Hz, 1H), 7.39 (d, J= 4 Hz, 1H), 7.30 (t, 1H), 7.19(d, J = 8 Hz, 1H), 7.15 (s, 1H), 7.08 (dd, Hh=12Hz, f= 4 Hz, 1H), 6.88 (dd, J, = 12 Hz, J, = 8 Hz, 1H), 3.66 (s, 3H), 3.58 (s, 3H), 1.99 (5, 3H).

[ . _

Example 1.129: Preparation of 1-{3-(4-Bromo-2-methyl-2H-pyrazotl-3-yl}4-methoxy-phenyl]-3- (4-chloro-2-hydroxy-phenyl)-urea (Compound 107). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenylamine (66 mg, 0.23 mmol) was dissolved in Dichloroethane (1.5 mL). In another flask, 4-nitrophenyl chloroformate was dissolved in

Dichloroethane (3 mL) and the solution was heated until it fully dissolved using a heat gun. The two solutions were combined with a catalytic amount of pyridine, and stirred at room temperature. Once the carbamate formed in solution, “Stratospheres” scavenger was added. The mixture was stirred rapidly and filtered after two hours. 2-Amino-5-chlorophenol was then dissolved in pyridine (1 mL) and added to the reaction. Afier 5 hours of stirring, the reaction was found to be complete by TLC and LC/MS.

The solvent was removed under reduced pressure and the residue was purified by HPLC providing 36.5 mg (35%) of Compound 107: LCMS m/z (%) = 451 (M+H"Br, 80), 453 (M+H"'Br, 100). 'H NMR (400 MHz, CDCly) 8: 7.74 (s, 1H), 7.67 (s, 1H), 7.53 (d, J=8 Haz, 1H), 7.28 (5, 1H), 728 (d, J=12 Hz, 1H), 7.12 (d, J = 8 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J= 8 Hz, 1H), 3.89 (s, 3H), 3.82 (s, 3H).

Example 1.130: Preparation of 1-(3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl|-3- (2,2-difluoro-benzo{1,3]dioxol-5-yl)-urea (Compound 115). 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenylamine (63 mg, 0.22 mmol) was coupled to 5-Amine-2,2-difluoro-1,3-benzodioxole in a similar manner as described in Example 1.129, providing 32 mg (30%) of Compound 115: LCMS m/z (%) = 481 (M+H™Br, 96), 483 (M+H*'Br, 100). "H NMR (400 MHz, acetone-dg) 5: 8.42 (s, 1H), 8.28 (s, 1H), 7.76 (d, J = 4 Hz, 1H), 7.70 (dd, Si =8

Hz, J; =4 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J = 2 Hz, 1H), 7.19 (d, J=12 Hz, 1H), 7.16 (d, J= 2 Hz, 1H), 7.14 (d, /= 4 Hz, 1H), 3.83 (5, 3H), 3.70 (s, 3H).

Example 1.131: Preparation of Intermediate 4-(2-Dimethyla mino-ethaxy)-3~(2-methyl-2H- pyrazol-3-yl)-phenylamine,

Step 1: Preparation of N-[4-Hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylj-acetamide.

A mixture of N-[4-methoxy-3+(2-methyl-2H-pyrazol-3-y1)-phenyl]-acetamide (2.0 g, 8.15 mmol) in anhydrous 1,2-dichloroethane (60 mL) was cooled at 0°C on an ice bath and stirred for 10 minutes. Anhydrous aluminium chloride (4.35 g, 32.6 mmol) was added and the reaction mixture stirred at 0°C for 20 minutes, then moved to an oil bath and stirred at 80°C for 1 hour. Ethyl acetate was added and washed with potasium sodium tartrate (10%) twice. Organic layer was separated, dried over anhydrous Na,SQ,, filtered and concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected and lyophilized to afford N-[4-hydroxy- 3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide as a white solid in 70.0 % yield. LCMS m/z (%) = 232 (M+H, 100). 'H NMR (400 MHz, DMSO-d;) 8: 7.39 (s,1H), 6.86 (d, J= 8.74 Hz, 1H), 6.62 (d, J =

_ ® WO 2005/012254 PCT/US2004/023488 8.70 Hz, 1H), 6.47 (s, 1H), 6.15 (s, 1H), 4.80 (bs, 2H), 3.87(t, J= 5.80 Hz, 2H), 3.63 (s, 3H), 2.44 (1, J = 5.80 Hz, 2H), 2.08 (s, 6H).

Step 2: Preparation of N-[4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-acetamide.

To a solution of N-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (0.85g,3.7 mmol) in THF (40 mL), triphenyl phosphine (2.91 g, 11.1 mmol) and 2-dimethylamino ethanol (1.11 mL, 11.1 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (2.15 mL, 11.1 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was subjected to a purification on preparative HPLC. The corresponding fractions were collected, neutralized with IN NaOH and extracted with EtOAc four times to afford N- [4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl)-acetamide as a colorless waxy solid in 51.2% yield. LCMS mvz (%) = 303 (M+H, 100). 'H NMR (400 MHz, DMSO0-d;) 6: 9.94 (s, 1H), 7.63 (d, J = 8.93 Hz, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.14 (d, J= 8.98 Hz, 1H), 6.25 (s, 1H), 4.07 (t, J = 5.82Hz, 2H), 3.69 (s, 3H), 2.56 (t, J = 5.80 Hz, 2H), 2.15 (5, 6H), 2.05 (s, 3H).

Step 3: Preparation of 4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenylamine.

Compound N-{4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl}-acetamide (0.50 g, 1.7 mmol) was dissolved in ethanol (25 mL), sodium hydroxide (1.5 g, pallets) in 8 mL of water was added and reaction mixture stirred at 80°C overnight then concentrated. Water and brine were added then extracted with EtOAc four times. Organic layers were combined, dried over anhydrous Na,SO, then solvent removed under reduced pressure to afford 4-(2-dimethylamino-ethoxy)- 3+(2-methyl-2H-pyrazol-3-yl)-phenylamine as a light brown oil in 87.5 % yield. LCMS m/z (%) = 261 (M+H, 100). 'H NMR (400 MHz, DMSO-d;) 5: 9.82 (s, 1H), 9.71 (bs, 1H), 7.48-7.45 (m, 3H), 6.93 (d,

J=18.74 Hz, 1H), 6.23 (s, 1H), 3.7 (s, 3H), 2.0 (s, 3H).

Example 1.132: Preparation of 1-(4-Chloro-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3-(2-methyl- 2H-pyrazol-3-yl)-phenyl]-urea (Compound 127). .

A solution of 4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl}-phenylamine (26.0 mg, 0.1 mmol) in methylene chloride (1 mL) was treated with 4-chlorophenyl-isocyanate (13.3 pL, 0.105 mmol) then reaction mixture stirred at room temperature overnight and concentrated to give an oily residue that was subjected to a purification by flash chromatography (SiO,, CH,Cl,/MeOH gradient elution) to afford Compound 127 as a white solid in 69.8 % yield. LCMS m/z (%) = 414 (M+H *Cl, 100), 416 (M+H *'C], 36). 'H NMR (400 MHz, acetone-ds) 5: 8.51 (s,1H), 8.36 (s, 1H), 7.62-7.59 (m, 3H), 7.50 (s, 1H), 7.42 (s, 1H), 7.31 (d, J= 8.90 Hz, 2H), 7.12 (d, J = 8.92 Hz, IH), 6.24 (s, 1H), 4.11 (t, J= 5.86 Hz, 2H), 3.77 (s, 3H), 2.61 (1, J = 5.85 Hz, 2H), 2.20 (s, 6H).

® ® WO 2005/012254 PCT/US2004/023488 }

Example 1.133: Preparation of 1-[4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2 H-pyrazol-3-yl)- phenyt]-3.(4-fluoro-phenyl)-urea (Compound 142). 4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazo!-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 4-fluorophenyl isocyanate (11.8 pL, 0.105 mmol) in a similar manner as described in

Example 1.2 to afford Compound 142 as a white solid in 66.4%yield. LCMS m/z (%) = 398 (M+H, 100). "HNMR (400 MHz, acetone-ds) 5: 8.33 (s, 1H), 8.25 (s, 1H), 7.61-7.56 (m, 3H), 8.49 (s, 1H), 1.42 (s, 1H), 7.11-7.04 (m, 3H), 6.24 (s, 1H), 4.11 (1, J = 5.85 Hz, 2H), 3.77 (s, 3H), 2.62 (1, J=5.85

Hz, 2H), 2.20 (s, 6H). .

Example 1.134: Preparation of 1-(2,4-Difluoro-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl}-urea (Compound 141), 4-(2-Dimethylamino-ethoxy)-3 «2-methyl-2H-pyrazol-3-y1)-phenylamine (26.0 mg, 0.1 mmol) was treated with 2,4-difluorophenyl isocyanate (12.4 pL, 0.105 mmol) in a similar manner as described in Example 1.2 to afford Compound 141 as a white solid in 73.3% yield. LCMS m/z (%) = 416 (M+H, 100). 'H NMR (400 MHz, DMSO-d) 8: 8.95 (s,1H), 8.46 (s, 1H), 8.08-8.02 (m, 1H), 7.45-7.42 (m, 2H), 7.37 (d, J=2.7 Hz, 1H), 7.33-7.27 (m, 1H), 7.12 (d, J = 8.95 Hz, 1H), 7.05-6.98 (m, 1H), 6.24 (d,

J=2.7 Hz, 1H), 4.03 (t, J= 5.80 Hz, 2H), 3.67 (s, 3H), 2.54 (t, J = 5.73 Hz, 2H), 2.12 (s, 6H).

Example 1.135: Preparation of 1-(3-Acetyl-phenyl)-3-|4-(2-dimethylamino-ethoxy)-3-(2-methyl- 2H-pyrazol-3-yl)-phenyl]-urea (Compound 143). 4-(2-Dimethylamino-ethoxy)-3«(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 3-acetylphenyl isocyanate (16.9 pL, 0.105 mmol) in a similar manner as described in

Example 1.2 to afford Compound 143 as a colorless waxy solid in 64.3% yield. LCMS m/z (%) = 422 (M+H, 100). 'H NMR (400 MHz, DMSO-d;) 8: 8.98 (s,1H), 8.73 (s, 1H), 8.10 (s, 1 H), 7.52-7.42 (m, 4H), 7.37 (d, J= 8.06 Hz, 1H), 7.37 (d, J = 6.75 Hz, 1H), 7.33-7.28 (m, 4H), 7.15 (d, J= 8.98 Hz, 1H), 6.28 (s, 1H), 4.08 (1, J= 5.80 Hz, 2H), 3.71 (s, 3H), 2.54 (m, 6H), 2.12 (s, 6H).

Example 1.136: Preparation of 1-[4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-3-(3-methoxy-phenyl)-urea (Compound 146) 4-(2-Dimethylamino-ethoxy)-3+(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 3-methoxyphenyl isocyanate (13.8 pL, 0.105 mmol) in a similar manner as described in Example 1.2 to afford Compound 146 as a colorless waxy solid in 71.1% yield. LCMS m/z (%) = 410 (MH, 100). 'H NMR (400 MHz, DMS0-d,) 6: 8.70 (s,1H), 8.63 (s, IH), 7.45-7.42 (m, 2H), 7.37 (d, J=2.7 Hz, 1H), 7.18-7.10 (m, 3H), 6.91 (dd, J = 8.02 Hz, 1.2 Hz, 1H), 6.53 (dd, J = 7.71 Hz, 2.05

Hz, 1H), 6.24 (d,J= 1.83 Hz, 1H), 4.03 (t, J = 5.80 Hz, 2H), 3.72 (s, 3H), 3.67 (s, 3H), 2.52 (, J= 5.80 Hz, 2H), 2.12 (s, 6H).

® ®

Example 1.137: Preparation of 1-(2,2-Difluoro-benzo{1,3]dioxol-5-yl)-3-{4-(2-dimethylamino- ethoxy)-3-(2-methy}-2H-pyrazol-3-y})-phenyl}-urea (Compound 144).

To a solution of 4-(2-dimethylamino-ethoxy)-3-2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) in methylene chloride (1 mL) pyridine (24.3 pL, 0.3 mmol) and 4-nitrophenyl chloroformate (20.2 mg, 0.1 mmol) were added and the mixture was stirred at room temperature for 1 hour. 5-Amino-2,2-difluoro-1,3-benzodioxole (11.6 pL, 0.1 mmol) was added, the reaction mixture stirred at room temperature for 48 hours and concentrated to give an oily residue that was subjected to a purification by flash chromatography (SiO,, CH;Cl,/MeOH gradient elution) to afford Compound 144 as an off-white solid in 14.0% yield. LCMS m/z (%) = 460 (M+H, 100). 'H NMR (400 MHz, DMSO- dg) 8: 10.30 (s,1H), 7.64 (d, J= 8.96 Hz, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.40-7.34 (m, 4H), 7.13 (4, J = 8.92 Hz, 1H), 6.22 (s, 1H), 4.10 (1, J = 5.56 Hz, 2H), 3.65 (s, 3H), 3.63 (s, 2H), 2.76-2.65 (m, 2H), 2.22 {s, 6H).

Example 1.138: Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl}-3- (2,4-difluoro-phenyl)-urea (Compound 120).

A mixture of 1-[3-(4-Chloro-2-methyl-2 H-pyrazol-3-y1)-4-methoxy-phenyl]-3-(2,4difluoro- phenyl)urea (Compound 77, example 1.61) (0.270 g, 0.69 mmol) in anhydrous 1,2-dichloroethane (10 mL) was cooled to 0°C on an ice bath and stirred for 10 minutes. Anhydrous aluminium chloride (0.368 g, 2.76 mmol) was added and the reaction mixture stirred at 0°C for 20 minutes, then moved to an oil bath and stirred at 80°C for 1 hour. Ethyl acetate was added and washed with potasium sedium tartrate (10 %) twice. Organic layer was separated, dried over anhydrous Na;SO,, filtered and concentrated to give the crude product that was further purified via HPLC. The corresponding fractions were collected and lyophilized to afford Compound 120 as a white solid in 75.0 % yield. LCMS m/z (%) = 379 (M+H ¥Cl, 100), 381 (M+H *'Cl, 40). 'H NMR (400 MHz. DMSO-de) 3: 9.81 (s,1H), 8.92 (s,1H), 8.45 (s, 1H), 8.12-8.06 (m, 1H), 7.63 (s, 1H), 7.40-7.31 (m, 3H), 7.09-7.04 (m, 1H), 6.99 (d, J; = 8.72 Hz, 1H), 3.69 (s, 3H).

Example 1.139: Preparation of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino- ethoxy)-phenyl}-3-(2,4-difluoro-phenyl)-urea (Compound 132).

To a solution of 1-[3-(4-chloro-2-methyl-2 H-pyrazol-3-yl}-4-hydroxy-phenyl]-3-(2,4-difluoro- phenyl)urea (see above) (0.035 g, 0.09 mmol) in THF (3 mL), triphenyl phosphine (0.071 g, 0.27 mmol) and 2-dimethylamino ethanol (27.1 pL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (52.3 pL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was purified via preparative

HPLC. The corresponding fractions were collected, neutralized with IN NaOH and extracted with

EtOAc. A second purification by flash chromatography (SiO,, CH.Cl,/MeOH gradient elution) afforded Compound 132 as an off-white solid in 45.9% yield. LCMS m/z (%) = 450 (M+H *Cl, 100), 452 (M+H YC), 32). '*H NMR (400 MHz. DMSO-dy) 8: 9.11 (s, 1H), 8.56 (s, 1H), 8.06-8.00 (m, 1H), 7.60 (s, 1H), 7.52 (d, J= 8.95 Hz, 1H), 7.38 (s, 1H), 7.33-7.27 (m, 1H), 7.17 (d, J= 9.04 Hz, 1H), 7.05-6.98 (m, 1H), 4.12-3.95 (m, 2H), 3.65 (s, 3H), 2.55-2.51 (m, 2H), 2.10 (s, 6H).

Example 1.140: Preparation of 1-[3{(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylamino- propoxy)-phenyl]-3-(2,4-diflucro-phenyl)-urea (Compound 133).

To a solution of 1-[3-(4-chloro-2-methyl-2 H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro- phenyl)urea (see above) (0.035 g, 0.09 mmol) in THF (3mL), triphenyl phosphine (0.071 g, 0.27 mmol) and 3-dimethylamino propanol (31.6 pL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (52.3 pL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was purified via preparative HPLC.

The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc four times. A second purification by flash chromatography (Si0,, CH,Cl,/ MeOH gradient elution) afforded

Compound 133 as an off-white solid in 25.4% yield. LCMS m/z (%) = 464 (M+H **Cl, 100), 466 (M+H *C1, 39). 'H NMR (400 MHz, DMSO-d) 6: 9.02 (s,1H), 8.47 (s, IH), 8.07-8.01 (m, 1H), 7.62 (s, 1H), 7.51 (d, J= 8.90 Hz, 1H), 7.38 (s, 1H), 7.33-7.28 (m, 1H), 7.15 (d, J= 9.02 Hz, 1H), 7.03-6.97 (m, 1H), 4.11-3.94 (m, 2H), 3.63 (s, 3H), 2.28-2.18 (m, 2H), 2.11 (s, 6H), 1.78-1.69(m, 2H).

Example 1.141: Preparation of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-triflusromethoxy- phenyl]-3-(4-chloro-phenyl)-urea (Compound 108).

Step A: Preparation of (3-bromo-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester.

A solution of 3-bromo-4-(trifluoromethoxy)aniline (3.84 g, 15 mmol) in dioxane (15 mL) was treated with di-zers-butyl-dicarbonate (4.91 g, 22.5 mmol) then the reaction mixture heated at 80°C overnight. The solvent was removed under reduced pressure to give an oily residue that was triturated with hexanes. The precipitate was collected by filtration to give (3-bromo-4-trifluoromethoxy-phenyl)- carbamic acid ferr-butyl ester as a white solid in 61.0% yield. 'H NMR (400 MHz, DMSO-d;) &: 9.78 (bs,1H), 7.87 (s, 1H), 7.54-7.43 (m, 2H),1.51 (s, 9H).

Step B: Preparation of [3-(2-methyl-2H-pyrazol-3-yI)-4-trifluoromethoxy-phenyl}- carbamic acid zert-butyl ester.

A 25-mL round —bottom flask was charged with (3-bromo-4-trifluoromethoxy-phenyl)- carbamic acid teri-butyl ester (230.0 mg, 0.65 mmol), |-methyl pyrazole-5-boronic acid (392.9 mg, 1.93 mmot), sodium carbonate (137.8 mg, 1.3 mmol), DME (5 mL) and water (0.5 mL) under argon atmosphere. Tetrakis(triphenylphosphine)palladium (75.1 mg, 0.065 mmol) was added and reaction

® _ mixture purged with argon again. The reaction mixture was heated at 80°C overnight then cooled to recom temperature. Ethyl acetate (10 mL) was added then washed with brine and water. Organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue that was subjected to a purification by flash chromatography (SiO,, Hexanes/EtOAc gradient elution) to afford [3-(2-methyl-2 H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-carbamic acid rert-butyl ester as an off- white solid in 36.5% yield. LCMS m/z (%) = 358 (M+H, 100). 'H NMR (400 MHz, DMSO-d) §: 9.83 (bs,1H), 7.77 (d, J = 8.95 Hz, 1H), 7.69 (s, IH), 7.63 (s, 1H), 7.57 (d, J = 8.84 Hz, 1H), 6.45 (s, 1H), 3.78 (s, 3H), 1.60 (s, 9H).

Step C: Preparation of {3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]- carbamic acid sert-butyl ester.

To a solution of [3-(2-methyl-2 H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-carbamic acid tert- butyl ester (65 mg, 0.18 mmol) in DMF (1.5 mL) N-bromosuccinimide (35.6 mg, 0.2 mmol) was added at 0°C then reaction mixture stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate, washed with brine and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow oily residue that was subjected to a purification by flash chromatography (SiO,, Hexanes/EtQAc gradient elution) to afford [3-(2-methyl- 2H-pyrazol-3-yi)-4-trifluoromethoxy-phenyi}-carbamic acid tert-butyl ester as a white solid in 89.2% yield. LCMS m/z (%) = 436 (M+H ™Br, 100), 438 (M+H *'Br, 98). 'H NMR (400 MHz, CD,0OD) 5: 7.79 (d, J = 8.90 Hz, 1H), 7.61(s, 1H), 7.55 (5, 1H), 7.43 (d, J= 8.94 Hz, 1H), 3.73 (s, 3H), 1.55 (s, 9H).

Step D: Preparation of 1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yI}-4-triflucro-methoxy- phenyl]-3-(d-chloro-phenyl)-urea (Compound 108).

To a solution of {3-(2-methyl-2 H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-carbamic acid tert- butyl ester (21.8 mg, 0.05 mmol) in methylene chloride (0.5 mL), trifluroacetic acid (0.5 mL) was added and reaction mixture stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure to afford 3(4-bromo-2-methyl-2 H-pyrazol-3-yl)-4-trifluoromethoxy-phenylamine trifluoroacetate as a colorless oil in quantitative yield. LCMS m/z (%) = 336 (M+H "Br, 100), 338 (M+H "Br, 95). This compound was dissolved in methylene chloride (0.8 mL) then treated with N,N- diisopropylethylamine until pH = 7-8. 4-Chlorophenyl isocyanate (8.5 mg, 0.055 mmol) was added and reaction mixture stirred at room temperature overnight and concentrated to give a residue that was subjected to apurification by flash chromatography (SiO,, Hexanes/EtQOAc gradient elution) to afford

Compound 108 as a white solid in 62.0% yield. LCMS m/z (%) = 489 (M+H "Br Cl, 93), 491 (M+H

Big; Cl, 100), 493 (M+H *'Br Cl, 34). 'H NMR (400 MHz, CD,0D) 8: 7.71 (dd, J= 8.98 Hz, 2.72

Hz, 1H), 7.64-7.62 (m, 2H), 7.49-7.45 (m, 3H), 7.33-7.30 (m, 2H), 3.76 (s, 3H).

Example 1.142: Preparation of 1-[3-(4-Bromo-2-methy}-2H-pyrazol-3-yl)-4-triftuoromethoxy- phenyl]-3-(2,4-difluero-phenyl)-urea (Compound 113).

® ® WO 2005/012254 PCT/US2004/023488 }

To a solution of [3-(2-methyl-2 H-pyrazol-3-yl)-4-trifluoromethoxy-pheny!}-carbamic acid tert- butyl ester (21.8 mg, 0.05 mmol) in methylene chloride (0.5 mL), trifluroacetic acid (0.5 mL) was added and reaction mixture stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure to afford 3-(4-bromo-2-methyl-2 H-pyrazol-3-yl)4-trifluoromethoxy-phenylamine trifluoroacetate as a colorless oil in quantitative yield. LCMS m/z (%) = 336 (M+H "Br, 100), 338 (M+H *'Br, 95). This compound was dissolved in methylene chloride (0.8 mL) then treated with N.N- diisopropylethylamine until pH = 7-8. 2,4-Diflucrophenyl isocyanate (8.5 mg, 0.055 mmol) was added and reaction mixture stirred at room temperature overnight and concentrated to give a residue that was subjected to a purification by flash chromatography (SiO, Hexanes/EtOAc gradient elution) to afford

Compound 113 as a white solid in 46.3% yield. LCMS m/z (%) = 491 (M+H Br, 100), 493 (M+H *'Br, 98). '"H NMR (400 MHz, CD;0D) 5: 8.06-8.00 (m, 1H), 7.71 (dd, J= 9.00 Hz, 2.74 Hz, 1H), 7.65- 7.62 (m, 2H), 7.48 (d, /= 9.00 Hz, 1H), 7.09-7.00 (m, 1H), 6.99-6.94 (m, 1H), 3.76 (s, 3H).

Example 1.143: Preparation of 1-2,4-Difluoro-phenyl)-3-[4-(3-dimethylamino-propoxy)-3-(2- methy-2H-pyrazol-3-yl)-phenyl|-urea (Compound 124).

To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methy)-2H-pyrazol-3-yl)-phenylamine (21.4 mg, 0.078 mmol) in CH,Cl, (2 mL) was added 2,4-difluorophenyl isocyanate (0.10 pL, 0.084 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL). The NH; containing fractions were dried in vacuo to afford Compound 124 as a colorless solid (30.2 mg, 73%).

LCMS m/z (%) = 430 (MH") (100), 'H NMR (400 MHz, DMSO-d) 5: 8.94 (bs, 1H), 8.46 (bs, 1H), 8.09-8.00 (m, 1H), 7.45 (d,J=1.80 Hz, 1H), 7.42 (dd, J= 8.89, 2.72 Hz, 1H), 7.34-7.26 (m, 1H), 7.09 (d, J=8.94 Hz, 1H), 7.06-6.99 (m, 1H), 6.24 (d, J= 1.83 Hz, 1), 3.97 (t, J =6.32 Hz, 2H), 3.65 (s, 3H), 2.23 (, J= 7.07 Hz, 2H), 2.10 (5, 6H), 1.78-1.69 (m, 2H).

Example 1.144: Preparation of 1-[4-(3-Dimethylamino-propoxy)-3-(2-methy}-2H-pyrazolk-3-yl)- phenylj-3-(2-fluoro-phenyl)-urea (Compound 138).

To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (60.6 mg, 0.221 mmol) in CH,Cl, (2 mL) was added 2-fluorophenyl isocyanate (0.27 pL, 0.240 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, | gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL). The NH, containing fractions were dried in vacuo to afford Compound 138 as a colorless solid (85.5 mg, 91%).

LCMS mvz (%) = 412 (MH) (100), 'H NMR (400 MHz, DMSO0-ds) 5: 9.36 (bs, 1H), 8.25 (bs, 1H), 8.15 (dd, J = 8.34, 1.52 Hz, 1H), 7.47-7.42 (m, 3H), 7.40 (d, J= 2.78 Hz, 1H), 7.31-7.26 (m, 1H), 7.11 (d, J =9.09 Hz, 1H), 7.05-6.99 (m, 1H), 6.25 (d, J = 2.02 Hz, 1H), 3.98 (t, J = 6.32 Hz, 2H), 3.66 (s, 3H), 2.19 (1, J = 7.07 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).

® WO 2005/012254 PCT/US2004/023488

Example 1.145: Preparation of 1-[4-(3-Dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-3-(4-trifluoromethyl-phenyl)-urea (Compound 137).

To a solution of 4-(3-dimethylamino-propoxy)-3+(2-methyl-2H-pyrazol-3-y()-phenylamine (45.8 mg, 0.167 mmol) in CH,Cl, (2 mL) was added 4-(trifluoromethyl)phenyl isocyanate (0.28 pL, 0.196 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL).

The NH, containing fractions were dried in vacuo to afford Compound 137 as a colorless solid (25.1 mg, 33%). LCMS m/z (%) = 462 (MH") (100), 'H NMR (400 MHz, DMSO-d) 8: 9.11 (bs, 1H), 8.75 (bs, 1H), 7.65 (d, J = 9.08 Hz, 2H), 7.62 (d, J = 9.35 Hz, 2H), 7.47 (dd, J= 9.09, 2.78 Hz, 1H), 7.45 (d,J=1,77 Hz, 1H), 7.39 (d, J = 2.78 Hz, 1H), 7.10 (d, J = 8.84 Hz, 1H), 6.24 (d, J= 1.77 Hz, 1H), 3.98 (t, J = 6.32 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J = 7.07 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).

Example 1.146: Preparation of 1-[4-(3-Dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-3-(2-fluoro-5-methyl-phenyl)-urea (Compound 139).

To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (43.9 mg, 0.160 mmol) in CH,Cl; (2 mL) was added 2-fluoro-5-methylpheny! isocyanate (0.23 pL, 0.176 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL).

The NH; containing fractions were dried in vacuo to afford Compound 139 as a colorless solid (53.2 mg, 78%). LCMS m/z (%) = 426 (MH) (100), 'H NMR (400 MHz, DMSO-d) 5: 8.98 (bs, 1H), 8.42 (bs, 1H), 7.96 (dd, J = 7.89, 1.96 Hz, 1H), 7.45 (d, J = 1.82 Hz, 1H), 7.44-7.38 (m, 2H), 7.13-7.06 (m, 2H), 6.82-6.75 (m, 1H), 6.24 (d, J = 1.85 Hz, 1H), 3.98 (t, J= 6.35 Hz, 2H), 3.66 (s, 3H), 2.25 (s, 3H), 2.19 (t, J = 7.03 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, ZH).

Example 1.147: Preparation of 1-(2-Chloro-phenyl)-3-[4-(3-dimethylamino-propoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-urea (Compound 140).

To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (51.4 mg, 0.187 mmol) in CH,C!, (2 mL) was added 2-chlorophenyl isocyanate (0.25 pL, 0.207 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL). The NH, containing fractions were dried in vacuo to afford Compound 140 as a colorless solid (76.5 mg, 95%).

LCMS m/z (%) = 428 (M+H*C}, 100), 430 (M+H'C}, 37) '"H NMR (400 MHz, DMSO-d;) 5: 9.36 (bs, : 1H), 8.25 (bs, 1H), 8.15 (dd, J = 8.33, 1.48 Hz, 1H), 7.48-7.42 (m, 3H), 7.40 (d, J = 2.70 Hz, 1H), 7.31- 7.26 (m, 1H), 7.11 (d, J = 8.92 Hz, 1H), 7.05-6.99 (m, 1H), 6.25 (d, J= 1.84 Hz, 1H), 3.98 (1, J= 6.36

Hz, 2H), 3.66 (s, 3H), 2.19 (t, J = 7.04 Hz, 21H), 2.07 (5, 6H), 1.77-1.69 (m, 2H).

®

Example 1.148: Preparation of 1-(3-Chloro-phenyl)-3-|4-(3-dimethylamino-propoxy)-3(2- methy}-2H-pyrazol-3-yl)-phenyl]-urea (Compound 134).

To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (47.4 mg, 0.173 mmol) in CHCl; (2 mL) was added 3-chlorophenyl isocyanate (0.24 pL, 0.197 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL). The NH, containing fractions were dried in vacuo to afford Compound 134 as a colorless solid (31.0 mg, 42%).

LCMS m/z (%) = 428 (M+H¥CI, 100), 430 (M+H"'C], 39), '"H NMR (400 MHz, DMSO-ds) 5: 8.64 (bs, 1H), 8.59 (bs, 1H), 7.47-7.41 (m, 3H), 7.45 (d, J= 1.79 Hz, 1H), 7.37 (d, J = 2.71 Hz, 1H), 7.30-7.23 (m, 2H), 7.09 (d, J = 8.97 Hz, 1H), 6.98-6.92 (m, 1H), 6.24 (d, J = 1.85 Hz, 1H), 3.97 (t, J = 6.36 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J = 7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).

Example 1.149: Preparation of 1-[4-(3-Dimethylamine-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-3-(4-methoxy-phenyl)-urea (Compound 131).

To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (38.3 mg, 0.140 mmol) in CH,Cl, (2 mL) was added 4-methoxypheny! isocyanate (0.21 uL, 0.162 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL). The NH; containing fractions were dried in vacuo to afford Compound 131 as a colorless solid (53.1 mg, 90%).

LCMS m/z (%) = 424 (MH) (100), 'H NMR (400 MHz, DMSO-d;) 5: 8.49 (bs, 1H), 8.43 (bs, 1H), 7.44 (d, J= 1.86 Hz, 1H), 7.42 (dd, J= 8.92, 2.73 Hz, 1H), 7.36 (d, J=2.71 Hz, 1H), 7.33 (d, J = 9.09

Hz, 2H), 7.07 (d, J = 8.96 Hz, 1H), 6.85 (d, J= 9.09 Hz, 2H), 6.23 (d,J= 1.82 Hz, 1H), 3.96 (t, J= 6.35 Hz, 2H), 3.71 (s, 3H), 3.65 (s, 3H), 2.18 (t, J = 7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).

Example 1.150: Preparation of 1-{4-(3-Dimethylamine-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-3-p-tolyl-urea (Compound 130).

To a solution of 4-(3-dimethylamino-propoxy)-3~+2-methyl-2H-pyrazol-3-yl)-phenylamine (45.9 mg, 0.167 mmol) in CH,Cl; (2 mL) was added 4-methylphenyl isocyanate (0.24 pL, 0.191 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL). The NH, containing fractions were dried in vacuo to afford Compound 130 as a colorless solid (61.8 mg, 91%).

LCMS m/z (%) = 408 (MH") (100), 'H NMR (400 MHz, DMSO-ds) 8: 8.53 (bs, 1H), 8.52 (bs, 1H), 7.44 (d, J=1.77 Hz, 1H), 7.43 (dd, J= 8.91, 2.73 Hz, 1H), 7.36 (d, J=2.70 Hz, 1H), 7.31 (d, J=8.43

Hz, 2H), 7.08 (d, J= 8.92 Hz, 1H), 7.06 (d, J = 8.32 Hz, 2H), 6.23 (d, J= 1.82 Hz, 1H), 396 (t, J= 6.36 Hz, 2H), 3.65 (s, 3H), 2.23 (5, 3H), 2.19 (t, J = 7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).

® ®

Example 1.151: Preparation of 1-(3-Chloro-4-fluoro-phenyl)-3-[4-(3-dimethylamino-propoxy)-3- (2-methyl-2H-pyrazol-3-yl)-phenyl]-urea (Compound 135).

To a solution of 4-(3-dimethylamino-propoxy)-3+(2-methyl-2H-pyrazol-3-yl}-phenylamine (573 mg, 0.209 mmol) in CH,Cl, (2 mL) was added 3-chloro-4-fluorophenyl isocyanate (0.30 pL, 0.241 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL).

The NH, containing fractions were dried in vacuo to afford Compound 135 as a colorless solid (66.2 mg, 71%). LCMS m/z (%) = 446 (M+H*Cl, 100), 448 (M+H>’C}, 35), 'H NMR (400 MHz, DMSO-dy) 5: 8.87 (bs, 1H), 8.69 (bs, 1H), 7.81-7.77 (m, 1H), 7.47-7.42 (m, 2H), 7.37 (d, J= 2.71 Hz, 1H), 7.35- 7.26 (m, 2H), 7.09 (d, J= 8.98 Hz, 1H), 6.24 (d, J = 1.83 Hz, | H), 3.98 (t, J= 6.36 Hz, 2H), 3.65 (s, 3H), 2.19 (t, J = 7.04 Hz, 2H), 2.07 (3, 6H), 1.77-1.69 (m, 2H).

Example 1,152: Preparation of 1-(3,4-Difluore-phenyl)-3-[4-(3-dimethylamino-propoxy)-3+(2- 1S methyl-2H-pyrazol-3-yl)-phenyl]-urea (Compound 136).

To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (61.1 mg, 0.223 mmol) in CH,Cl, (2 mL) was added 3,4-difluoropheny! isocyanate (0.30 pL, 0.256 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL). The NH; containing fractions were dried in vacuo to afford Compound 136 as a colorless solid (53.3 mg, 56%).

LCMS nvz (%) = 430 (M+H, 100), 'H NMR (400 MHz, DMSO-d) 6: 8.93 (bs, 1H), 8.72 (bs, 1H), 7.71-7.61 (m, 1H), 7.49-7.42 (m, 2H), 7.37 (d, J = 2.68 Hz, 1H), 7.35-7.28 (m, 1H), 7.14-7.06 (m, 1H), 7.09 (d, J = 8.96 Hz, 1H), 6.23 (d, J = 1.82 Hz, 1H), 3.97 (1, J = 6.37 Hz, 2H), 3.65 (5, 3H), 2.19 (t, J= 7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).

Example 1.153: Preparation of 1-{4-(3-Dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-3-phenyl-urea (Compound 145).

To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (45.6 mg, 0.166 mmol) in CH,Cl; (2 mL) was added phenyl isocyanate (0.20 pL, 0.184 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL). The NH; containing fractions were dried in vacuo to afford Compound 145 as a colorless solid (45.3 mg, 69%).

LCMS m/z (%) = 394 (M+H, 100), "H NMR (400 MHz, DMSO-d,) &: 8.64 (bs, 1H), 8.59 (bs, 1H), 7.48-7.41 (m, 4H), 737 (d, J = 2.71 Hz, 1H), 7.29-7.23 (m, 2H), 7.09 (d, J = 8.97 Hz, 1H), 6.98-6.92 (m, 1H), 6.24 (d, J = 1.85 Hz, 1H), 3.97 (t, J = 6.36 Hz, 2H), 3.66 (s, 3H), 2.19 (1, J = 7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).

® ®

Example 1.154: Preparation of 1-[4-(3-Dimethylamino-propoxy)-3-(2-methyl-2 H-pyrazol-3-yl)- phenyl]-3-(4-Nuoro-phenyl)-urea (Compound 125).

To a solution of 4-(3-dimethylamino-propoxy)-32-methyl-2H-pyrazol-3-yl)-phenylamine (24.6 mg, 0.090 mmol) in CH,C), (2 mL) was added 4-fluorophenyl isocyanate (0.12 pL, 0.107 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, I gram cartridge), eluting with methanol (30 mL) followed by 2M NHj in methanol (30 mL). The NH, containing fractions were dried in vacuo to afford Compound 125 as a colorless solid (27.0 mg, 73%).

LCMS m/z (%) = 412 (M+H, 100), "H NMR (400 MHz, DMSO-d;) 5: 8.67 (bs, 1H), 8.58 (bs, 1H), 7.48-7.41 (m, 4H), 7.36 (d, J = 2.70 Hz, 1H), 7.14-7.06 (m, 3H), 6.23 (d, J= 1.82 Hz, IH), 3.97 (t,J= 6.34 Hz, 2H), 3.65 (s, 3H), 2.18 (t, J = 7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).

Example 1.155: Preparation of 1-(4-Chloro-benzyl)-3-[4-(3-dimethylamino-propoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-urea (Compound 126).

To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (20.5 mg, 0.075 mmol) in CH,Cl, (2 mL) was added 4-chlorobenzyl isocyanate (0.17 pL, 0.128 mmol) and stirred overnight. The resulting material was purified by solid phase extraction (SCX, 1 gram cariridge), eluting with methanol (30 mL) followed by 2M NH; in methanol (30 mL). The NH; containing fractions were dried in vacuo to afford Compound 126 as a slightly yellow oil (29.8 mg, 90%). LCMS m/z (%) = 442 (M+H?’CI, 100), 444 (M+H"Cl, 40) 'H NMR (400 MHz, DMSO-d) 5: 8.53 (bs, 1H), 7.43 (d, J = 1.81 Hz, 1H), 7.41-7.36 (m, 4H), 7.34-7.28 (m, 3H), 7.03 (d, J = 8.94 Hz, tH), 6.63 (d, /= 6.00 Hz, 1H), 6.20 (d, J = 1.83 Hz, 1H), 4.26 (d, J = 5.96 Hz, 2H), 3.94 (t,J=6.36

Hz, 2H), 3.63 (s, 3H), 2.18 (t, J = 7.05 Hz, 2H), 2.06 (s, 6H), 1.77-1.69 (m, 2H).

Example 1.156: Preparation of 1-(2,2-Difluoro-benzo(1,3}dioxol-5-yI)-3-[4-(3-dimethylamino- propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl}-urea (Compound 129).

To a solution of 4-nitrophenyl chloroformate (55.1 mg, 0.273 mmol) in 1,2-dichloroethane (7 mL) and pyridine (22 pL, 0.272 mmol) was added 5-amino-2,2-difluoro-1,3-benzodioxole (28 pL, 0.241 mmol) and stirred for one hour. A spatula of StratoSpheres PL-DETA resin was added and stirring continued for an additional hour. The resulting mix was filtered (washing with 3 mL 1,2- dichloroethane) into a flask containing 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenylamine (49.7 mg, 0.181 mmol) and stisring continued overnight. The resulting material was purified by HPLC. The product was dried in vacuo to afford Compound 129 as a white solid (29.0 mg, 34%). LCMS m/z (%) = 474 (M+H, 100), 'H NMR (400 MHz, DMSO-d) 5: 8.91 (bs, 1H), 8.61 (bs,

IH), 7.65 (d, J = 2.09 Hz, 1H), 7.44 (d, J = 1.86 Hz, 1H), 7.44 (dd, J = 8.88, 2.82 Hz, 1H), 7.37 (d, J = 2.7t Hz, 1H), 7.29 (d, J= 8.75 Hz, 1H), 7.09 (d, J= 8.95 Hz, 1H), 7.07 (dd, J = 8.78, 2.18 Hz, LH),

® ) ) 6.23 (d, J= 1.81 Hz, 1H), 3.97 (t, J = 6.35 Hz, 2H), 3.65 (s, 3H), 2.19 (t, J = 7.03 Hz, 2H), 2.07 (s, 6H), 1.77-1.67 (m, 2H).

Example 1.157: Preparation of Dimethy}-{3-[2-(2-methyl-2 H-pyrazol-3-yl)-4-nitro-phenoxy|- propyl}-amine.

Dimethy}-{3-[2(2-methyl-2H-pyrazol-3-yl)}-4-nitro-phenoxy]-propyl}-amine was synthesized from 2-(2-methyl-2H-pyrazol-3-yl)-4-nitro-phenol (4.064 g) using a similar manner as described in

Example 1.139. Yellow oil (3.147 g, 56%). LCMS m/z (%) = 305 (M+H, 100), 'H NMR (400 MHz,

DMSO-dy) 5: 8.35 (dd, J= 9.19, 2.90 Hz, 1H), 8.10 (4, J=2.88 Hz, 1H), 7.50(d, J = 1.86 Hz, 1H), 7.39 (d, J = 9.26 Hz, 1H), 6.37 (d, J = 1.86 Hz, 1H), 4.21 (t, J= 6.40 Hz, 2H), 3.67 (s, 3H), 221 J= 6.98 Hz, 2H), 2.08 (s, 6H), 1.85-1.76 (m, 2H).

Example 1.158: Preparation of N-|4-Hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide.

To a suspension of N-[4-methoxy-3~2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (2.57 g, 10.48 mmol) in 1,2-dichlorocthane (75 mL) was added BBr, (10 mL, 106 mmol) and stirred for three hours. The nonhomogeneous suspension was heated to reflux for 15 minutes and then cooled to room temperature. The reaction was quenched by slow addition of methanol. The resulting material was purified by HPLC. The product was dried in vacuo to afford N-[4-hydroxy-3-(2-methyl-2H-pyrazol-3- yl)-phenyl}-acetamide as a white solid (508 mg, 21%). LCMS m/z (%) = 232 (M+H, 100), 'H NMR (400 MHz, DMSO-d) 5: 9.77 (bs, 1H), 9.66 (bs, 1H), 7.44-7.40 (m, 3H), 6.89 (d, J= 8.85 Hz, 1H), 6.37 (d, J = 1.81 Hz, 1H), 3.66 (s, 3H), 1.99 (s, 3H).

Example 1.159: Preparation of N-|4-(3-Dimethylamino-propoxy)-3-2-methyl-2H-pyrazol-3-yl)- phenyl]-acetamide.

N-[4-(3-Dimethylamino-propoxy)-3 -(2-methyl-2H-pyrazol-3 -yl)-phenyl]-acetamide was synthesized from N-[4-hydroxy-3«2-methyl-2H-pyrazol-3-yl)-phenyl}-acetamide (489 mg) using a similar manner as described in Example 1.139. Colorless oil (375.1 mg, 56%). LCMS m/z (%)=317 (M+H, 100), 'H NMR (400 MHz, DMSO-d) 5: 9.89 (bs, 1H), 7.58 (dd, J = 8.92, 2.66 Hz, 1H), 7.48 (d,

J=2.65 Hz, 1H), 7.44 (d, J = 1.84 Hz, 1H), 7.08 (d, J= 8.98 Hz, 1H), 6.21 (d, J= 1.85 Hg, 1H), 3.97 (t,J= 6.37 Hz, 2H), 3.63 (s, 3H), 2.19 (t, J = 7.03 Hz, 2H), 2.07 (s, 6H), 2.01 (s, 3H), 1.77-1.68 (m, 2H).

Example 1.160: Preparation of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenylamine.

Method I: Dimethyl-{3-[2-(2-methyl-2H-pyrazol-3-yl}-4-nitro-phenoxy]-propyl }-amine (1.4047 g, 4.62 mmol) and 5% Pd/C (114 mg) were stirred in methanol (50 mL) under 1 atm of

® ® WO 2005/012254 PCT/US2004/023488 } hydrogen for 75 minutes. The suspension was filtered through celite and dried in vacuo to afford 43- dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine as an orange oil (1.27 g, 100%).

Method 2. 4-(3-dimethylamino-propoxy)-3(2-methyl-2H-pyrazol-3-yl)-phenylamine (375 mg, 1.18 mmol) and 50% NaOH in H,0 (2.5 mL) were refluxed overnight in methanol (20 mL). The resulting material was purified by HPLC to give an orange oil (230.2 mg, 71%).

LCMS m/z (%) = 275 (M+H, 100), 'H NMR (400 MHz, DMSO-d;) 6: 7.40 (d, J= 1.81 Hz, 1H), 6.85 (d, J = 8.73 Hz, 1H), 6.62 (dd, J = 8.68, 2.82 Hz, 1H), 6.47 (d, J = 2.80 Hz, 1H), 6.15 dJ= 1.83 Hz, 1H), 4.80 (bs, 2H), 3.81 (t, J = 6.35 Hz, 2H), 3.62 (s, 3H), 2.13 (1, J= 7.04 Hz, 2H), 2.05 (s, 6H), 1.69-1.59 (m, 2H). :

Example 1.161: Preparation of 1-[3-(4-Bromo-2-methy}l-2H-pyrazol-3-yl)-4-methoxy-phenylj-3- (4-dimethylamino-phenyl)-urea (Compound 116).

To 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (34.9 mg, 0.124 mmol) in

CH,Cl, (3 mL) was added 4-(dimethylamino)phenyl isocyanate (21 mg, 0.129 mmol) and stirred for two days. The resulting material was purified by HPLC. The product was dried in vacuo to afford

Compound 116 as a waxy solid (13.5 mg, 25%). LCMS m/z (%) = 444 (M+H™Br, 100), 446 (M+H"Br, 95), 'H NMR (400 MHz, DMSO-d¢) 5: 8.51 (bs, 1H), 8.26 (bs, IH), 7.61 (s, 1H), 7.53 (dd, J =8.97,2.71 Hz, 1H), 7.34 (d,J = 2.70 Hz, 1H), 7.24 (d, J = 9.03 Hz, 2H), 7.12 (d, J= 9.05 Hz, 1H), 6.68 (d, J = 9.07 Hz, 2H), 3.75 (s, 3H), 3.63 (s, 3H), 2.82 (5, 6H). 20 .

Example 1.162: Preparation of 1-(4-Chloro-phenyl)-3-[4-(3-dimethylamino-propoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl}-urea (Compound 122).

Compound 122 was synthesized from Compound 119 (79.2 mg, 0.231 mmol) using a similar manner as described in Example 1.139. White solid (19.6 mg, 20%). LCMS m/z (%) = 428 (M+H>°Cl, 100), 430 (M+H’Cl, 39), 'H NMR (400 MHz, DMSO-d) 5: 8.80 (bs, 1H), 8.63 (bs, 1H), 7.50-7.42 (m, 4H), 7.36 (d, J= 2.71 Hz, 1H), 7.31 (d, J = 8.90 Hz, 2H), 7.09 (d, J = 8.96 Hz, 1H), 6.23 (d, /= 1.81

Hz, 1H), 3.97 (1, J = 6.35 Hz, 2H), 3.65 (s, 3H), 2.19 (t, J= 7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.68 (m, 2H).

Example 1.163: Preparation of 1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylamino- propoxy)-phenyl]-3-(4-chloro-phenyl)-urea (Compound 117).

Compound 117 was synthesized from Compound 58 (65.1 mg, 0.154 mmol) using a similar manner as described in Example 1.139. White solid (41.8 mg, 53%). LCMS m/z (%) = 506 (M+H"Br, 100), 508 (M+H*'Br, 81), 'H NMR (400 MHz, DMSO-d) §: 8.81 (bs, 1H), 8.71 (bs, 1H), 7.62 (s, 1H), 7.53 (dd, J =8.96,2.71 Hz, 1H), 7.47 (d, J= 8.92 Hz, 2H), 7.35 (d, J= 2.70 Hz, 1H), 7.31 (d, J= 8.88

Hz, 2H), 7.14 (d, J = 9.03 Hz, 1H), 4.07-3.99 (m, 1H), 3.98-3.89 (m, 1H), 3.64 (s, 3H), 2.18 (t, /=6.58

Hz, 2H), 2.07 (s, 6H), 1.77-1.66 (m, 2H). -

® ® :

WO 2005/012254 PCT/US2004/023488

Example 1.164: Preparation of {2-(4-Bromo-2-methyl-2H-pyrazol-3-y!)4-{3-(4-chloro-phenyl)- ureido}-phenoxy}-acetic acid (Compound 118). {2-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[3-(4-chloro-phenyl}-ureido]-phenoxy}-acetic acid ethyl ester was synthesized from Compound 58 (125.5 mg, 0.298 mmol) using a similar manner as described in Example 1.139. The resulting material was purified by HPLC. The product was dried in vacuo to afford the ethyl ester as an impure brown solid (99.9 mg).

To a solution of the ethyl ester in methanol (1 mL) and THF (5 mL) was added 1M LiOH in

H;0 (1 mL). After 30 minutes the resulting material was purified by HPLC. The product was dried in vacuo to afford Compound 118 as a white solid (54.0 mg, 38% over two steps). LCMS m/z (%) = 479 (M+H"Br, 71), 481 (M+H*'Br, 100), 'H NMR (400 MHz, DMSO-d;) 5: 13.06 (bs, 1H), 8.80 (bs, 1H), 8.73 (bs, 1H), 7.61 (s, 1H), 7.51 (dd, J = 9.02, 2.61 Hz, 1H), 7.47 (d, J= 8.87 Hz, 2H), 7.38 (d, J = 2.67

Hz, 1H), 7.31 (d, J = 8.85 Hz, 2H), 7.00 (d, J = 9.08 Hz, 1H), 4.75 (d, J = 16.65 Hz, 1H), 4.68 (d,J= 16.61 Hz, 1H), 3.72 (s, 3H).

Example 1.165: Preparation of 1-[3(4-Bromo-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3(2,4- difluoro-phenyl)-urea (Compound 152).

Step 1: Preparation of 3-Diethylamino-1- (2-hydroxy-5-nitro-phenyl)-propenone. 6-Nitrochromane (6.64g, 34.78 mmol) was dissolved in pyridine (55 mL) by waming at 55°C.

Diethylamine (3.05g, 41.73 mmol) was added in drops under nitrogen at 55°C with stirring, and the mixture was stirred for 40 minutes [LCMS showed complete conversion to product, peak at 265(M+H)]. The resulting mixture was cooled to room temperature and solvent removed under vacuum to afford the product as a yellow solid (8.94g, 97%). LCMS m/z (%) = 265 (M+H, 100), 'H NMR (Bruker, 400 MHz, CDCl) 5: 15.3 (s, 1H), 8.61 (s, 1H), 8.22 (dd, J= 12,4 Hz, 1H), 8.01 (d,/= 12 Hz, 1H), 6.98 (d, /= 8 Hz, 1 H), 5.85 (d, J= 16 Hz, 1H), 3.45 (q, J = 8 Hz, 4H), 1.31 (1, J= 8 Hz, 6H).

Step 2: Preparation of 3-Diethylamino-1- (2-methoxy-5-nitro-phenyl)-propenone.

To a stirred solution of 3-Diethylamino-1- (2-hydroxy-5-nitro-phenyl)-propenone (6.5g, 24.6 mmole) in acetone (200 mL) was added potassium carbonate (6.8g, 49.2 mmole). After 30 minutes dimethyl sulfate (3.73g, 29.5 mmole) was added to the reaction mixture and stirred at ambient temperature for 20 hrs. The slurry was filtered off and the filtrate was evaporated to furnish a yellow solid. The crude was purified on silica (Biotage) using hexane to 30% ethyl acetate in hexane as eluant.

The fractions containing the product were evaporated in vacuo to afford a light yellow solid (5.2g, 76%). LCMS m/z (%) = 279 (M+H, 100), 'H NMR (Bruker, 400 MHz, CDCl) 5: 8.5 (bs, 1H), 8.23- 8.26 (dd, J = 9.1, 2.1 Hz, 1H), 7.6 (bs, 1H), 6.98-7.01 (d, J =9.0 Hz, 1 H), 5.51-5.54 (d, J= 12.84 Hz, 1H), 3.98 (s, 3H), 3.28-3.31 (q, J = 6.95 Hz, 4H), 1.31 (t, /= 6.68 Hz, 6H).

Step 3: Preparation of 1-(S-Amino-2-methoxy-phenyl)-3-diethylamino-propenone. oo

® ®

To a solution of 3-Diethylamino-1- (2-methoxy-5-nitro-phenyl)-propenone (0.6g, 2.16 mmole) in methanol (30 mL) purged with argon was added 5% Pd-C (Degussa, 0.25g). Then hydrogen gas was bubbled (30minutes) through the mixture until LCMS and TLC showed complete conversion to product. The slurry was filtered off through a celite and the filtrate was evaporated in vacuo to furnish a yellow solid (0.45g, 84%). LCMS m/z (%) = 249 (M+H, 100), 'H NMR (Bruker, 400 MHz, CDCl) 5: 6.9 (bs, 1H), 6.76-6.78 (d, J = 8.6 Hz, 1H), 6.67-6.71 (dd, J = 8.58, 2.61 Hz, 2H), 5.64(bs, 1H), 3.78 (s, 3H), 3.5 (bs, 1H), 3.28-3.31 (q, J= 6.95 Hz, 4H), 1.22-1.24 (t, /= 6.68 Hz, 6H).

Step 4: Preparation of 1-|3«3-Diethylamino-acryloyl)-4-methoxy-phenyl]-3-(2 4-difluoro- phenyl)-urea.

To a solution of 1-{5-Amino-2-methoxy-phenyl)-3-diethylamino-propenone (1.78g, 7.18 mmole) in methylene chloride (60 mL) was added a solution of 2,4-diflucrophenyl isocyanate (1.34g, 8.62 mmole) in methylene chloride (10 mL) over a period of 10 minutes. The reaction mixture was stirred at ambient temperature for 18 hrs. The solvent was evaporated and the resulting solid was purified on silica (Biotage) using DCM to 30% ethyl acetate in DCM as eluant. The fractions containing the product were evaporated in vacuo to furnish a yellow solid (2.7g, 96%). LCMS m/z (%) = 404 (M+H, 100), 'H NMR (Bruker, 400 MHz, DMSO-d;) &: 8.91 (bs, 1H), 8.41 (bs, 1H), 8.06-8.12 (m, 1H), 7.46-7.48 (d, J = 8.68 Hz 1H), 7.42 (bs, 1H), 7.29-7.35 (m, 1H), 7.01-7.08 (m, 2H), 5.5 (bs, 1H), 3.78(s, 3H), 3.27 (bs, 4H), 1.13-1.2 (1, J = 7.01 Hz, 6H).

Step 5: Preparation of 1-(2,4-Difluoro-phenyl)-3-[4-methoxy-3- (2H-pyrazol-3-yl)- phenyl]-urea

To a solution of 1-[3«(3-Diethylamino-acryloyl)-4-methoxy-phenyl]}-3-(2,4-difluoro-phenyl)- urea (1.5g, 3.72 mmole) in methanol/acetic acid (50 mL/2.0 mL) mixture was added hydrazine (0.82g, 37.22 mmole). The reaction mixture was refluxed at 55 C for 20 hrs. The methanol/acetic acid was evaporated from the reaction mixture and the solid was triturated with ether/methanol. The solid was filtered and washed with ether. Next, the solid was dried in vacuo to furnish a colorless solid (1.0g, 76%). LCMS m/z (%) = 345 (M+H, 100), 'H NMR (Bruker, 400 MHz, DMSO-d) 8: 13.0 (bs, 1H), 8.89 ( bs, 1H), 8.37 (bs, 1H), 8.09-810 (d, J = 6.05 Hz, 1H), 7.74-7.97 (bs, 1H), 7.52-7.64 (bs, 1H), 7.39-7.40 (d, J = 5.94 Hz, 1H), 7.27-7.32 (m, 2H), 7.01-7.09 (m, 2H), 6.73 (s, 1H), 3.82 (s, 3H) (major tautomer).

Step 6: Preparation of 1-[3-(4-Bromo-2H-pyrazol-3-yl}-4-methoxy-phenyl}-3-(2,4- difluoro-phenyl)-urea.

To a cooled and stirred solution of 1+(2,4-Difluoro-phenyl)-3-[4-methoxy-3- (2H-pyrazol-3-yl)- phenyl}-urea (0.6¢, 1.74 mmale) in DMF (15 mL) was added N-bromosuccinimide (0.37g, 2.09 mmole) over a period of 15 minutes. The reaction mixture was warmed slowly to ambient temperature and stirred for another 2 hrs. The reaction mixture was poured into well-stirred ice water containing

® (

NaHCO,/Na,S;0;. The resulting solid was filtered and washed with ice water (50 mL). The solid was dried in vacuo to afford off-white solid (0.68g, 92%). LCMS m/z (%) = 425 (M+H, ™Br, 100), 427 (M+H, * Br, 99). 'H NMR (Bruker, 400 MHz, DMSO-d) 5: 8.96 (bs, 1H), 8.44 (bs, 1H), 8.02-8.08 (m, 1H), 7.48 (bs, 2H), 7.27-7.32 (m, 1h), 6.99-7.08 (m, 2H), 3.73 (s, 3H) (major tautomer).

Example 2

A. Construction of Constitutively Active S-HT,¢ receptor cDNA 1. Endogenous Human 5-HT;¢

The cDNA encoding endogenous human 5-HT;¢ receptor was obtained from human brain poly-

A’ RNA by RT-PCR. The S’ and 3’ primers were derived from the 5° and 3’ untranslated regions and contained the following sequences: 5’-GACCTCGAGGTTGCTTAAGACTGAAGCA-3’ (SEQ.ID.NO.:1) 5’-ATTTCTAGACATATGTAGCTTGTACCGT-3’ (SEQ.ID.NO.:2)

PCR was performed using either TaqPlus™ precision polymerase (Stratagene) or rTth™ polymerase (Perkin Elmer) with the buffer systems provided by the manufacturers, 0.25 pM of each primer, and 0.2 mM of each of the four (4) nucleotides. The cycle condition was 30 cycles of 94°C for | minute, 57°C for | minute and 72 °C for 2 minutes. The 1.5 kb PCR fragment was digested with Xho I and Xba I and subcloned into the Sal 1-Xba I site of pBluescript.

The derived cDNA clones were fully sequenced and found to correspond to published sequences. 2. AP-1 cDNA

The cDNA containing a S310K mutation (AP-1 cDNA) in the third intracellular loop of the human 5-HT,¢ receptor was constructed by replacing the Sty I restriction fragment containing amino acid 310 with synthetic double stranded oligonucleotides encoding the desired mutation. The sense strand sequence utilized had the following sequence: 5'-CTAGGGGCACCATGCAGGCTATCAACAATGAAAGAAAAGCTAAGAAAGTC-3’ (SEQ.

ID.NO: 3) . and the antisense strand sequence utilized had the following sequence: 5'-CAAGGACTTTCTTAGCTTTTCTTTCATTGTTGATAGCCTGCATGGTGCCC-3’ (SEQ. ID.

NO: 4).

B. Construction of constitutively active S-HT;, receptor cDNA

C

1. Human 5-HT, (C322K; AP-2)

The cDNA containing the point mutation C322K in the third intracellular loop was constructed by using the Sph I restriction enzyme site, which encompasses amino acid 322. For the PCR procedure, a primer containing the C322K mutation: 5’-CAAAGAAAGTACTGGGCATCGTCTTCTTCCT-3’ (SEQ.ID.NO:5) was used along with the primer from the 3° untranslated region SEQ.ID.NO:6. 5'-TGCTCTAGATTCCAGATAGGTGAAAA CTTG-3’ (SEQ.ID.NO:6)

The resulting PCR fragment was then used to replace the 3° end of the wild type 5-HT;, cDNA by the

T4 polymerase blunted Sph 1site. PCR was performed using pfu polymerase (Stratagene) with the buffer system provided by the manufacturer and 10% DMSO, 0.25 mM of each primer, 0.5mM of each of the 4 nucleotides. The cycle conditions were 25 cycles of 94°C for 1 minute, 60°C for 1 minute, and 72°C for | minute. 2, AP-3 cDNA

The human 5-HT;, cDNA with intracellular loop 3 (IC3) or IC3 and cytoplasmic tail replaced by the corresponding human 5-HT,c cDNA was constructed using PCR-based mutagenesis. (a) Replacement of 1C3 Loop

The IC3 loop of human 5-HT,, cDNA was first replaced with the corresponding human 5-HTyc cDNA. Two separate PCR procedures were performed to generate the two fragments, Fragment A and

Fragment B, that fuse the 5-HTac IC3 loop to the transmembrane 6 (TM6) of 5-HTa4. The 237 bp PCR fragment, Fragment A, containing 5-HT;¢ IC3 and the initial 13 bp of 5-HT;x TM6 was amplified by using the following primers: 5'-CCGCTCGAGTACTGCGCCGACAAGCTTTGAT-3’ (SEQ.ID.NO:7) 5°. CGATGCCCAGCACTTTCGAAGCTTTTCTTTCATTGTTG-3’(SEQ.ID.NO:8)

The template used was human 5-HT;c cDNA.

The 529 bp PCR fragment, Fragment B, containing the C-terminal 13 bp of IC3 from 5-HTsc and the C-terminal of 5-HT>, starting at beginning of TM6, was amplified by using the following primers: 5-AAAAGCTTCGAAAGTGCTGGGCATCGTCTTCTTCCT-3’ (SEQ.ID.NO:9) 5'-TGCTCTAGATTCCAGATAGGTGAAAACTTG-3’ (SEQ.ID.NO: 10)

The template used was human 5-HT,, cDNA.

Second round PCR was performed using Fragment A and Fragment B as co-templates with

SEQ.ID.NO:7 and SEQ.ID.NO:10 (it is noted that the sequences for SEQ.ID.NOS.: 6 and 10 are the same) as primers. The resulting 740 bp PCR fragment, Fragment C, contained the IC3 loop of human 5-HT, fused to TM6 through the end of the cytoplasmic tail of human 5-HT2a. PCR was performed using pfu™ polymerase (Stratagene) with the buffer system provided by the manufacturer, and 10%

DMSO, 0.25 mM of each primer, and 0.5 mM of each of the four (4) nucleotides. The cycle conditions were 25 cycles of 94 °C for 1 minute, 57°C (Ist round PCR) or 60 °C (2nd round PCR) for 1 minute, and 72°C for 1 minute (1st round PCR) or 90 seconds (2nd round PCR).

To generate a PCR fragment containing a fusion junction between the human 5-HT,, TMS and the IC3 loop of 5-HTyc, four (4) primers were used. The two external primers, derived from human 5-

HT, had the following sequences: 5’-CGTGTCTCTCCTTACTTCA-3’ (SEQ.ID.NO.:11)

The other primer used was SEQ.ID.NO.:6 (see note above regarding SEQ.ID.NOS. 6 and | 1). The first intemal primer utilized was an antisense strand containing the initial 13 bp of IC3 of 5-HTc¢ followed by the terminal 23 bp derived from TMS5 of 5-HT;,: 5’-TCGGCGCAGTACTTTGATAGTTAGAAAGTAGGTGAT-3’ (SEQ.ID.NO.:12)

The second internal primer was a sense strand containing the terminal 14 bp derived from TM5 of 5-HT;, followed by the initial 24 bp derived from IC3 of 5-HT;c: 5S’ TTCTAACTATCAAAGTACTGCGCCGACAAGCTTTGATG-3’ (SEQ.ID.NO.:13).

PCR was performed using endogenous human 5-HT, and a co-template, Fragment C, ina 50 mL reaction volume containing | X pfu buffer, 10% DMSO, 0.5 mM of each of the four (4) nucleotides, 0.25 mM of each external primer (SEQ.ID.NOS. 10 and 11), 0.06 mM of each internal primer (SEQ.ID.NOS. 12 and 13) and 1.9 units of pfu polymerase (Stratagene). The cycle conditions were 25 cycles of 94°C for 1 minute, 52°C for 1 minute, and 72 °C for 2 minutes and 10 seconds. The 1.3 kb

PCR product was then gel purified and digested with Pst] and EcoR I. The resulting 1 kb Pst I-EcoR 1 fragment was used to replace the corresponding fragment in the endogenous human 5-HT;, sequence to generate the mutant 5-HT,4 sequence encoding the IC3 loop of 5-HT2C. b) Replacement of the cytoplasmic tail

To replace the cytoplasmic tail of 5-HT;, with that of 5-HT,¢, PCR was performed using a sense primer containing the C-terminal 22 bp of TM7 of endogenous human 5-HT,, followed by the initial 2] bp of the cytoplasmic tail of endogenous human 5-HT;¢: 5-TTCAGCAGTCAACCCACTAGTCTATACTCTGTTCAACAAAATT-3' (SEQ.ID.NO:14)

The antisense primer was derived from the 3° untranslated region of endogenous human 5-HT,c: 5-ATTTCTAGACATATGTAGCTTGTACCGT-3’ (SEQ.ID.NO:15).

The resulting PCR fragment, Fragment D, contained the last 22 bp of endogenous human 5-

HT, TM7 fused to the cytoplasmic tail of endogenous human 5-HT,c. Second round PCR was performed using Fragment D and the co-template was endogenous human 5-HT,, that was previously digested with Acc I to avoid undesired amplification. The antisense primer used was SEQ.ID.NO:15 (the sequences for SEQ.ID.NOS. 15 and 2 are the same) and the sense primer used was derived from endogenous human 5-HT,4:

5"-ATCACCTACTTTCTAACTA-3" (SEQ.ID.NO:16).

PCR conditions were as set forth in Example 2 section B2(g) for the first round PCR, except that the annealing temperature was 48°C and the extension time was 90 seconds. The resulting 710 bp

PCR product was digested with Apa I and Xba I and used to replace the corresponding Apa I-Xba fragment of either (a) endogenous human 5-HT,,, or (b) 5-HT:4 with 2C IC; to generate (a) endogenous human 5-HTa, with endogenous human 5-HT,¢ cytoplasmic tail and (b) AP-3, respectively. 4, AP-4 cDNA

This mutant was created by replacement of the region of endogenous human 5-HT,, from amino acid 247, the middle of TMS right after Pro™®, to amino acid 337, the middle of TM6 just before

Pro’, by the corresponding region of AP-1 cDNA. For convenience, the junction in TMS is referred to as the “2A-2C junction,” and the junction in TM6 is referred to as the “2C-2A junction.”

Three PCR fragments containing the desired hybrid junctions were generated. The 5° fragment of 561 bp containing the 2A-2C junction in TMS was generated by PCR using endogenous human §-

HT;a as template, SEQ.ID.NO.:11 as the sense primer, and the antisense primer was derived from 13 bp of 5-HT;c followed by 20 bp of 5-HT,, sequence: 5'-CCATAATCGTCAGGGGAATGAAAAATGACACAA-3 ’ (SEQ.ID.NO:17)

The middie fragment of the 323 bp contains endogenous human 5-HT,¢ sequence derived from the middle of TMS to the middie of TM6, flanked by 13 bp of 5-HT;, sequences from the 2A-2C junction and the 2C-2A junction. This middle fragment was generated by using AP-1 cDNA as a template, a sense primer containing 13 bp of 5-HT,, followed by 20 bp of 5-HT,¢ sequences across the 2A-2C junction and having the sequence: 5’-ATTTTTCATTCCCCTGACGATTATGGTGATTAC-3 (SEQ.ID.NO:18); and an antisense primer containing 13 bp of 5-HT5, followed by 20 bp of 5-HT,¢ sequences across the 2C-2A junction and having the sequence: 5’-TGATGAAGAAAGGGCACCACATGATCAGAAACA-3’ (SEQ.ID.NO:19).

The 3’ fragment of 487 bp containing the 2C-2A junction was generated by PCR using endogenous human 5-HT, as a template and a sense primer having the following sequence from the 2C-2A junction: 5’-GATCATGTGGTGCCCTTTCTTCATCACAAACAT-3’ (SEQ.ID.NO:20) and the antisense primer was SEQ.ID.NO:6 (see note above regarding SEQ.ID.NOS. 6 and 10).

Two second round PCR reactions were performed separately to link the 5’ and middle fragment (5’M PCR) and the middle and 3’ fragment (M3’ PCR). The 5°M PCR co-template used was the 5’ and

® ® { middle PCR fragment as described above, the sense primer was SEQ.ID.NO:11 and the antisense primer was SEQ.ID.NO.:19. The 5’M PCR procedure resulted in an 857 bp PCR fragment.

The M3’ PCR used the middle and M3* PCR fragment described above as the co-template,

SEQ.ID.NO.: 18 as the sense primer and SEQ.ID.NO.:6 (see note above regarding SEQ.ID.NOS. 6 and 10) as the antisense primer, and generated a 784 bp amplification product. The final round of PCR was performed using the 857 bp and 784 bp fragments from the second round PCR as the co-template, and

SEQ.ID.NO:11 and SEQ.ID.NO: 6 (see note above regarding SEQ.ID.NOS. 6 and 10) as the sense and the antisense primer, respectively. The 1.32 kb amplification product from the final round of PCR was digested with Pst I and Eco RI. Then resulting | kb Pst I-Eco RI fragment was used to replace the corresponding fragment of the endogenous human 5-HT;, to generate mutant 5-HT,,, with 5-HTc:

S310K/IC3. The Apa I-Xba fragment of AP3 was used to replace the corresponding fragment in mutant 5-HT24 with 5-HTy¢: S310K/IC3 to generate AP4.

EXAMPLE 3

Receptor Expression:

A. pCMV

Although a variety of expression vectors are available to those in the art, for purposes of utilization for both the endogenous and non-endogenous receptors discussed herein, it is most preferred that the vector utilized be pCMV. This vector was deposited with the American Type Culture

Collection (ATCC) on October 13, 1998 (10801 University Blvd., Manassas, VA 20110-2209 USA) under the provisions of the Budapest Treaty for the International Recognition of the Deposit of

Microorganisms for the Purpose of Patent Procedure. The DNA was tested by the ATCC and determined to be viable. The ATCC has assigned the following deposit number to pCMV: ATCC #203351. See Figure 8.

B. Transfection procedure

For the generic assay ([*S]GTPyS; Example 4) and the antagonist binding assay (mesulergine;

Example 15), transfection of COS-7 or 293T cells was accomplished using the following protocol.

On day one, 5x10° COS-7 cells or 1x10” 293T cells per 150mm plate were plated out. On day two, two reaction tubes were prepared (the proportions to follow for each tube are per plate): tube A was prepared by mixing 20 pg DNA (e.g., pCMV vector; pCMV vector AP-1 cDNA, etc.) in 1.2 ml serum free

DMEM (Irvine Scientific, Irvine, CA); tube B was prepared by mixing 120 pl lipofectamine (Gibco BRL) in 1.2 ml serum free DMEM. Tubes A and B were then admixed by inversions (several times), followed by incubation at room temperature for 30-45 min. The admixture is referred to as the “transfection mixture”. Plated COS-7 cells were washed with 1X PBS, followed by addition of 10 ml serum free

DMEM. 2.4 ml of the transfection mixture was then added to the cells, followed by incubation for 4 hrs at 37°C/5% CO,. The transfection mixture was then removed by aspiration, followed by the addition of 25 ml of DMEM/10% Fetal Bovine Serum. Cells were then incubated at 37°C/5% CO,. After 72 hr incubation, cells were then harvested and utilized for analysis.

EXAMPLE 4

GTP Membrane Binding Scintillation Proximity Assay

The advantages of using [**SJGTPYS binding to measure constitutive activation are that: (a) [’SIGTPyS binding is generically applicable to all G protein-coupled receptors; and (b) [*SIGTPyS binding is proximal at the membrane surface, thereby making it less likely to pick-up molecules which affect the intracellular cascade. The assay utilizes the ability of G protein-coupled receptors to stimulate [’*S]GTPyS binding to membranes expressing the relevant receptors. Therefore, the assay may be used to directly screen compounds at the disclosed serotonin receptors.

Figure 9 demonstrates the utility of a scintillation proximity assay to monitor the binding of [**SJGTPYS to membranes expressing, e.g., the endogenous human 5-HT;c receptor expressed in COS cells. In brief, a preferred protocol for the assay is such that the assay was incubated in 20 mM HEPES, pH 7.4, binding buffer with 0.3 nM [**S)GTPYS and 12.5 pg membrane protein and 1 pM GDP for 30 minutes.

Wheatgerm agglutinin beads (25 il; Amersham) were then added and the mixture was incubated for another 30 minutes at room temperature. The tubes were then centrifuged at 1500 x g for 5 minutes at room temperature and then counted in a scintillation counter. As shown in FIG. 9, serotonin, which as the endogenous ligand activates the 5-HT,¢ receptor, stimulated [*SJGTPYS binding to the membranes in a concentration dependant manner. The stimulated binding was completely inhibited by 30 pM mianserin, a compound considered as a classical 5-HT,¢ antagonist, but also known as a 5-HT,¢ inverse agonist.

Although this assay measures agonist-induced binding of [**SJGTPYS to membranes and can be routinely used to measure constitutive activity of receptors, the present cost of wheatgerm agglutinin beads may be prohibitive. A less costly but equally applicable alternative also meets the needs of large-scale screening. Flash plates and Wallac™ scintistrips may be used to format a high throughput [P’SIGTYS binding assay. This technique allows one to monitor the tritiated ligand binding to the receptor while simultaneously monitoring the efficacy via [>S)JGTPYS binding. This is possible because the Wallac™ beta counter can switch energy windows to analyze both tritium and S-labeled probes.

Also, this assay may be used for detecting of other types of membrane activation events that result in receptor activation. For example, the assay may be used to monitor **P phosphorylation of a variety of receptors (including G protein-coupled and tyrosine kinase receptors). When the membranes are centrifuged to the bottom of the well, the bound [**S]GTPYS or the *2P-phosphorylated receptor wil activate the scintillant coated on the wells. Use of Scinti® strips (Wallac™) demonstrate this principle.

Additionally, this assay may be used for measuring ligand binding to receptors using radiolabeled ligands.

In a similar manner, the radiolabeled bound ligand is centrifuged to the bottom of the well and activates the

® scintillant. The [*S]GTPYS assay results parallel the results obtained in traditional second messenger ) assays of receptors.

As shown in Figure 10, serotonin stimulates the binding of [*SJGTPYS to the endogenous human 5-HT;¢ receptor, while mianserin inhibits this response; furthermore, mianserin acts as a partial inverse

S agonist by inhibiting the basal constitutive binding of [*S]GTPYS to membranes expressing the endogenous human S-HT,c receptor. As expected, there is no agonist response in the absence of GDP since there is no GDP present to exchange for [*SIGTPyS. Not only does this assay system demonstrate the response of the native SHT;¢ receptor, but it also measures the constitutive activation of other receptors.

Figure 11A and Figure 11B demonstrate the enhanced binding of [**SJGTPYS to membranes prepared from 293T cells expressing the control vector alone, the native human 5-HT>c receptor or the AP- 1 receptor was observed (data not shown). The total protein concentration used in the assay affects the total amount of [**S]GTPYS binding for each receptor. The c.p.m. differential between the CMV transfected and the constitutively active mutant receptor increased from approximately 1000 c.p.m at 10 pg/well to approximately 6-8000 c.p.m. at 75 pg/well protein concentration, as shown in Figure 11.

The AP-1 receptor showed the highest level of constitutive activation followed by the wild type receptor, which also showed enhanced [*S]JGTPYS binding above basal. This is consistent with the ability of the endogenous human 5-HT,¢ receptor to accumulate intracellular IP; in the absence of SHT stimulation (Example 6) and is also consistent with published data claiming that the endogenous human 53-

HT receptor has a high natural basal activity. Therefore, the AP-1 receptor demonstrates that constitutive activity may be measured by proximal [*S]GTPYS binding events at the membrane interface.

EXAMPLE §

Serotonin Receptor Agonist/Antagonist Competitive Binding Assay:

Membranes were prepared from transfected COS-7 cells (see Example 3) by homogenization in 20 mM HEPES and 10 mM EDTA, pH 7.4 and centrifuged at 49,000 x g for 15 min. The pellet was resuspended in 20 mM HEPES and 0.1 mM EDTA, pH 74, homogenized for 10 sec. using a Polytron homogenizer (Brinkman) at 5000 rpm and centrifuged at 49,000 x g for 15 min. The final pellet was resuspended in 20 mM HEPES and 10 mM MgCl,, pH 7.4, homogenized for 10 sec. using polytron homogenizer (Brinkman) at 5000 rpm.

Assays were performed in triplicate 200 pl volumes in 96 well plates. Assay buffer (20 mM

HEPES and 10 mM MgCl, pH 7.4) was used to dilute membranes, 3H-LSD, *H-mesulergine, serotonin (used to define non-specific for LSD binding) and mianserin (used to define non-specific for mesulergine binding). Final assay concentrations consisted of 1 nM *H-LSD or 1 nM "H-mesulergine, 50 pg membrane protein and 100 pm serotonin or mianserin. LSD assays were incubated for 1 hr at 37° C, while mesulergine assays were incubated for 1 hr at room temperature. Assays were terminated

_ ® by rapid filtration onto Wallac Filtermat Type B with ice cold binding buffer using Skatron cell harvester. The radioactivity was determined in a Wallac 1205 BetaPlate counter.

EXAMPLE 6

Intracellular [Py Accumulation Assay:

For the IP; accumulation assay, a transfection protocol different from the protocol set forth in

Example 3 was utilized. In the following example, the protocols used for days 1-3 were slightly different for the data generated for Figures 12 and 14 and for Figures 13 and 15; the protocol for day 4 was the same for all conditions.

A, COS-7 and 293 Cells

On day one, COS-7 cells or 293 cells were plated onto 24 well plates, usually 1x10° cells/well or 2x10° cells/well, respectively. On day two, the cells were transfected by first mixing 0.25 ug DNA (see Example 3) in 50 pl serum-free DMEM/well and then 2 pl lipofectamine in 50 pl serum-free

DMEM/well. The solutions (“transfection media”) were gently mixed and incubated for 15-30 minutes - at room temperature. The cells were washed with 0.5 ml PBS and then 400 ul of serum free media was mixed with the transfection media and added to the cells. The cells were then incubated for 34 hours at 37°C/5%C0,. Then the transfection media was removed and replaced with 1mb/well of regular growth media. On day 3, the media was removed and the cells were washed with 5 ml PBS followed by aspiration. Then 2ml of trypsin (0.05%) is added per plate. After 20-30 seconds, warm 293 media is added to plates, cells are gently resupended, and cells are counted. Then a total of 55,000 cells are added to sterile poly-D-lysine treated 96 well microtiter plates and cells arc allowed to attach over a six- hour incubation in an incubator. Then media is aspirated and 0.1 mL inositol-free/serum-free media (GIBCO BRL) was added to each well with 0.25 uCi of *H-myo-inositol/well and the cells were incubated for 16-18 hours overnight at 37°C/5% CO, . Protocol A.

B. 293 Cells

On day one, 13x10° 293 cells per 150 mm plate were plated out. On day two, 2 ml of serum

Optimeml (Invitrogen Corporation) is added per plate followed by addition of 60 pL of lipofectamine and 16 pg of cDNA. Note that lipofectamine must be added to the Optimeml and mixed well before addition of cDNA, While complexes between lipofectamine and the cDNA are forming, media is carefully aspirated and cells are gently rinsed with Sml of OptimemI media followed by careful aspiration. Then 12 mi of

Optimeml is added to each plate and 2 ml of transfection solution is added followed by a 5 hour incubation at 37°C in a 5% CO; incubator. Plates are then carefully aspirated and 25 mL of Complete Media are added to each plate and cells are then incubated until used. On day 3, cells are trypsinized with 2 ml of 0.05% trypsin for 20-30 seconds followed by addition of 10 mL of warmed media, gently titurated to dissociate cells, and then 13 additional ml of warmed media is gently added. Cells are then counted and then 55,000 cells are added to 96-well sterile poly-D-lysine trated plates. Cells are allowed to attach over a six hour

® incubation at 37°C in a 5% CO, incubator. Media is then carefully aspirated and 100 uL of warm inositol- free media plus 0.5 pCi *H-inositol is added to each well and the plates are incubated for 18-20 hours at 37°C in a 5% CO; incubator.

On day 4, media is carefully aspirated and then 0.1 ml of assay medium is added containing

S inositol-free/serum free media, 10 pM pargyline, 10 mM lithium chloride, and test compound at indicated concentrations. The plates were then incubated for three hours at 37° C and then wells are carefully aspirated. Then 200 pL of ice-cold 0.1M formic acid is added to each well. Plates can then be frozen at this point at -80°C until further processed. Frozen plates are then thawed over the course of one hour, and the contents of the wells (approximately 220 pL) are placed over 400 pL of washed ion- exchange resin (AG 1-X8) contained in a Multi Screen Filtration plate and incubated for 10 minutes followed by filtration under vacoum pressure. Resin is then washed nine times with 200 pL of water and then tritiated inositol phosphates are eluted into a collecting plate by the addition of 200ul of 1M ammonium formate and an additonal 10 minute incubation. The elutant is then transferred to 20 ml scintillation vials, 8 mL of SuperMix or Hi-Safe scintillation cocktails is added, and vials are counted for 0.5-1 minutes in a Wallac 1414 scintilation counter.

Figure 12 is an illustration of IP3 production from the human 5-HT, receptor which was mutated using the same point mutation as set forth in Casey, which rendered the rat receptor constitutively active. The results represented in Figure 12, support the position that when the point mutation shown to activate the rat receptor is introduced into the human receptor, little activation of the receptor is obtained that would allow for appropriate screening of candidate compounds, with the response being only moderately above that of the endogenous human 5-HT), receptor. Generally, a response of at least 2X above that of the endogenous response is preferred.

Figure 13 provides an illustration comparing IP; production from endogenous 5-HT,, receptor and the AP4 mutation. The results illustrated in Figure 13 support the position that when the novel : mutation disclosed herein is utilized, a robust response of constitutive IP3 accumulation is obtained (e.g., over 2X that of the endogenous receptor).

Figure 14 provides an illustration of IP3 production from AP3. The results illustrated in Figure 14 support the position that when the novel mutation disclosed herein is utilized, a robust response of constitutive IP3 accumulation is obtained.

Figure 15 provides bar-graph comparisons of IP3 accurnulation between endogenous human 35-

HT, receptor and AP-1. Note that the endogenous receptor has a high degree of natural constitutive activity relative to the control CMV transfected cells (i.e., the endogenous receptor appears to be constitutively activated).

Example 7: In vitro Binding of SHT;, Receptor.

Animals:

Animals (Sprague-Dawley rats) were sacrificed and brains were rapidly dissected and frozen in isopentane maintained at -42° C. Horizontal sections were prepared on a cryostat and maintained at -20° C.

LSD Displacement Protocol:

Lysergic acid diethylamide (LSD) is a potent SHT, receptor and dopamine D2 receptor ligand.

An indication of the selectivity of compounds for either or both of these receptors involves displacement of radiolabeled-bound LSD from pre-treated brain sections. For these studies, radiolabeled '*I-LSD (NEN Life Sciences, Boston, Mass., Catalogue number NEX-199) was utilized; spiperone (RBI, Natick, Mass. Catalogue number s-128) a SHT,, receptor and dopamine D2 receptor antagonist, was also utilized. Buffer consisted of 50 nanomolar TRIS-HCI, pH 7.4.

Brain sections were incubated in (a) Buffer plus 1 nanomolar "**I-LSD; (b) Buffer plus 1 nanomolar '*I-LSD and 1 micromolar spiperone; or Buffer plus 1 nanomolar ¥I-LSD and 1 micromolar Compound 1 for 30 minutes at room temperature. Sections were then washed 2x 10 minutes at 4° C. in Buffer, followed by 20 seconds in distilled HO. Slides were then air-dried.

After drying, sections were apposed to x-ray film (Kodak Hyperfilm) and exposed for 4 days.

Analysis:

Figures 16A-C provide grey-scale representative autoradiographic sections from this study.

Figure 16A evidences darker bands (derived from '*I-LSD binding) primarily in both the fourth layer of the cerebral cortex (primarily SHT:4 receptors), and the caudate nucleus (primarily dopamine D2 receptors and some SHT34 receptors). As can be seen from Figure 16B, spiperone, which is a SHTya and dopamine D2 antagonist, displaces the I'*-LSD from these receptors on both the cortex and the caudate. As can be further seen from Figure 16C, Compound S-1610, [3-(4-Bromo-2-methyl-2H- pyrazol-3-yl}-phenyl]-carbamic acid 4-methoxy-phenyl ester, appears to selectively displace the '®I-

LSD from the cortex (SHT;,) and not the caudate (dopamine D2).

Example 7

Screening Compounds Known to Have 5-HT,¢c Antagonist Activity Against Non-

Endogenous, Constitutively Activated Human Serotonin Receptor: AP-1

A final concentration of 12.5 pg membranes prepared from COS7 cells (see Example 3) transiently expressing constitutively active mutant human 5HT,c receptor AP-1 were incubated with binding buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 20 mM MgC1,°6H,0, 0.2% saponin, and 0.2 mM ascobate), GDP(l pM) and compound in a 96-well plate format for a period of 60 minutes at ambient room temperature. Plates were then centrifuged at 4,000 rpm for 15 minutes followed by aspiration of the reaction mixture and counting for 1 minute in a Wallac™ MicroBeta plate scintillation counter. A series of compounds known to possess reported SHT,¢ antagonist activity were determined to be active in the [’S]GTPyS binding assay using AP-1. ICs, determinations were made for these commercially available compounds (RBI, Natick, Mass.). Results are summarized in TABLE 5. For o.

[ each determination, eight concentrations of test compounds were tested in triplicate. The negative control in these experiments consisted of AP-1 receptor without test compound addition, and the positive control consisted of 12.5 pg/well of COS7 cell membranes expressing the CMV promoter without expressed AP-1 receptor.

TABLE 5

ICs, (nM) in GTP-y-[*S] ee | meme | 0]

I EL

I EC EL

The ICs, results confirm that the seven tested compounds showed antagonist activity at the AP-1 receptor.

Example 8

Receptor Binding Assay

In addition to the methods described herein, another means for evaluating a test compound is by determining binding affinities to the 5-HT;4 receptor. This type of assay generally requires a radiolabelled ligand to the 5-HT, receptor. Absent the use of known ligands for the 5-HTaa receptor and radiolabels thereof, compounds of the present invention can be labelled with a radioisotope and used in an assay for evaluating the affinity of a test compound to the 5-HT,, receptor.

A radiolabelled 5-HTz4 compound of Formula (I) can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e, test compound) can be evaluated for its ability to reduce binding of the “radiolabelled compound of

Formula (I)” to the 5-HT;a receptor. Accordingly, the ability to compete with the “radiolabelled compound of Formula (I)” or Radiolabelled 5-HT, Ligand for the binding to the 5-HT.4 receptor directly correlates to its binding affinity of the test compound to the 5-HT;, receptor.

ASSAY PROTOCOL FOR DETERMINING RECEPTOR BINDING FOR 5-HTy.:

A. 5-HT:;4» RECEPTOR PREPARATION

® ® 293 cells (human kidney, ATCC), transiently transfected with 10 pg human 5-HTsa receptor and 60 ul Lipofectamine (per 15-cm dish), are grown in the dish for 24 hours (75% confluency) with a media change and removed with 10 mV/dish of Hepes-EDTA buffer ( 20mM Hepes + 10 mM EDTA, pH 7.4). The cells are then centrifuged in a Beckman Coulter centrifuge for 20 minutes, 17,000 pm (JA-25.50 rotor). Subsequently, the pellet is resuspended in 20 mM Hepes + 1 mM EDTA, pH 7.4 and homogenized with a 50- m! Dounce homogenizer and again centrifuged. Afier removing the supernatant, the pellets are stored at -80°C, until used in binding assay. When used in the assay, membranes are thawed on ice for 20 minutes and then 10 mL of incubation buffer (20 mM Hepes, 1 mM MgClz, 100 mM NaCl, pH 7.4) added. The membranes are then vortexed to resuspend the crude membrane pellet and homogenized with a Brinkmann PT-3100 Polytron homogenizer for 15 seconds at setting 6. The concentration of membrane protein is determined using the BRL Bradford protein assay.

B. BINDING ASSAY

For total binding, a total volume of 50ul of appropriately diluted membranes (diluted in assay buffer containing S0mM Tris HCI (pH 7.4), 10mM MgCl,, and 1mM EDTA; 5-50 pg protein) is added to 96-well polyproylene microtiter plates followed by addition of 100 ul of assay buffer and 50 u! of

Radiolabelled 5-HT,4 Ligand. For nonspecific binding, 50 pl of assay buffer is added instead of 100 pl and an additional 50 pi of 10 pM cold S-HT,, is added before 50 pl of Radiolabelled 5-HT;,

Ligand is added. Plates are then incubated at room temperature for 60-120 minutes. The binding reaction is terminated by filtering assay plates throh a Microplate Devices GF/C Unifilter filtration plate with a Brandell 96-well plate harvestor followed by washing with cold 50 mM Tris HC, pH 7.4 containing 0.9% NaCl. Then, the bottom of the filtration plate are sealed, 50 ul of Optiphase Supermix is added to each well, the top of the plates are sealed, and plates are counted in a Trilux MicroBeta scintillation counter. For campound competition studies, instead of adding 100 pl of assay buffer, 100 pl of appropriately diluted test compound is added to appropriate wells followed by addition of 50 ul of Radiolabelled 5-HT,, Ligand.

C. CALCULATIONS

The test compounds are initially assayed at 1 and 0.1 uM and then at a range of concentrations chosen such that the middle dose would cause about 50% inhibition of 2 Radie-5-HT,, Ligand binding (i.e, ICs). Specific binding in the absence of test compound (Bo) is the difference of total binding (By) minus non-specific binding (NSB) and similarly specific binding (in the presence of test compound) (B) is the difference of displacement binding (Bp) minus non-specific binding (NSB). ICs, is determined from an inhibition response curve, logit-log plot of % B/Bgp vs concentration of test compound.

K; is calculated, for example, by the Cheng and Prustoff transformation:

Ki=ICs/ (1 + [LVKo)

where [L] is the concentration of a Radio-5-HT Ligand used in the assay and Kp is the dissociation constant of a Radie-5-HTz2a Ligand determined independently under the same binding conditions. .

Example 9

Activity Of Compounds Of The Present Invention in the IP; Accumulation Assay:

Certain compounds of the present invention and their corresponding activities in the IP

Accumulation Assay are shown in TABLE 6.

TABLE 6 5-HTz4 (ICs0)*

Compound No. IP; Accumulation Assay (nM) ww

IL ER EEL A wm + Reported values are averages of at least two trials.

The majority of the other compounds of the Examples were tested at least once and they showed ICs, activities in the 5-HT;, IP; Accumulation Assay of at least about 10 pM.

Example 10

Efficacy of Compounds of the Invention in the Attenuation of DOl-induced hypolocometion in rats.

In this example, compounds of the invention, such as Compound 1 and Compound 26, were tested for inverse agonist activity by determining whether these compounds could attenuate DOI- induced hypolocomotion in rats in a novel environment. DOI is a potent SHT2A/2C receptor agonist that crosses the blood-brain barrier.

Animals:

Male Sprague-Dawley rats (Harlan, San Diego, CA) weighing between 200-300g were used for all tests. Rats were housed three to four per cage. These rats were naive to experimental testing and drug treatment. Rats were handled one to three days before testing to acclimate them to experimental manipulation. Rats were fasted overnight prior to testing. 174 : ps

[) . ® WO 2005/012254 PCT/US2004/023488 .

Compounds: . (R)-DOI HCI (C;;H (INO, HCI) was obtained from Sigma-Aldrich, and was dissolved in 0.9% saline. Compounds of the invention were synthesized at Arena Pharmaceuticals Inc. and were h3 dissolved in 100%PEG400. DOI was injected s.c. in a volume of 1ml/kg, while compounds of the invention were administered p-0. in a volume of 2mV/kg.

Procedure:

The “Motor Monitor” (Hamilton-Kinder, Poway, CA) was used for all activity measurement.

This apparatus recorded rears using infrared photobeams.

Locomotor activity testing was conducted during the light cycle (0630-1830) between 9:00 a.m, and 4:00 p.m. Animals were allowed 30 min acclimation to the testing room before testing began.

In determining the effects of compounds of the invention on DOI-induced hypoactivity, animals were first injected with vehicle or the compound of the invention (50 pmolkeg) in their home cages.

Sixty minutes later, saline or DOI (0.3 mg/kg salt) was injected. 10 min afer DOI administration, animals were placed into the activity apparatus and rearing activity was measured for 10 minutes.

Statistics and Results:

Results (total rears over 10 minutes) were analyzed by t-test. P<0.05 was considered significant. As shown in Figure 22, Compound 1 attenuated DOI-induced hypolocomotion in rats. In addition, as shown in Figure 23, Compound 26 also attenuated DOI-induced hypolocomotion in rats.

Example 11

Serotonin 5-HT2A Receptor Occupancy Studies in Monkey

In this example, the SHT2A receptor occupancy of a compound of the invention, Compound 1, was measured. The study was carried out in rhesus monkeys using PET and "*F-altanserin.

Radioligand: }

The PET radioligand used for the occupancy studies was "*F-altanserin. Radiosynthesis of "*F- altanserin is achieved in high specific activities and is suitable for radiolabeling SHT2a receptors in vivo (see Staley et al., Nucl. Med. Biol., 28:271-279 (2001) and references cited within). Quality control issues (chemical and radiochemical purity, specific activity, stability etc) and appropriate binding of the radioligand were verified in rat brain slices prior to use in PET experiments.

Drug Doses and Formulations: ‘

® ®

Briefly, the radiopharmaceutical was dissolved in sterile 0.9% saline, pH approx 6-7. The compounds of the invention (Compound 1) were dissolved in 60% PEG 400 - 40% sterile saline on the same day of the PET experiment.

Serotonin SHT2a occupancy studies in humans have been reported for M100,907 (Grunder et al., Neurgpsychopharmacology, 17:175-185 (1997), and Talvik-Lofti et al., Psychophamacology, 148:400-403 (2000). High occupancies of the SHT2a receptors have been reported for various oral doses (doses studied ranged from 6 to 20 mg). For example, an occupancy of >90% was reported for a dose of 20 mg (Talvik-Lofti et al., supra), which translates to approx. 0.28 mg/kg. It may therefore be anticipated that an i.v. dose of 0.1 to 0.2 mg/kg of M100,907 is likely to provide high receptor occupancy. A 0.5 mg/kg dose of Compound I was used in these studies.

PET Experiments:

The monkey was anesthetized by using ketamine (10 mg/kg) and was maintained using 0.7 to 1.25% isoflurane. Typically, the monkey had two i.v. lines, one on each arm. One i.v. line was used to administer the radioligand, while the other line was used to draw blood samples for pharmacokinetic data of the radioligand as well as the cold drugs. Generally, rapid blood samples were taken as the radioligand is administered which then taper out by the end of the scan. A volume of approximately 1 ’ ml of blood was taken per time point, which was spun down, and a portion of the plasma was counted for radioactivity in the blood.

An initial control study was carried out in order to measure baseline receptor densities. PET scans on the monkey were separated by at least two weeks. Unlabeled drug (Compound 1) was . administered intravenously, dissolved in 80% PEG 400:40% sterile saline.

PET Data Analysis:

PET data were analyzed by using cerebellum as the reference region and using the distribution volume region (DVR) method. This method has been applied for the analysis of "*F-altanserin PET data in nonhuman primate and human studies (Smith et al., Synapse, 30:380-392 (1998).

The SHT2A occupancy (rhesus monkey experimental methods) of Compound 1 is shown in

Figures 24-27. The results of both an 8 hour and 24 hour study are shown. The test compound was administered via i.v. infusion in 5.0 ml of 80% PEG400. For the 8 hour study, venous blood samples were drawn at 5 minutes post Compound 1 and 15 minutes before PET scan. For the 24 hour study, venous blood samples were drawn at 5 minutes post Compound 1 and 10 minutes before PET scan.

The results show that SHT2A receptor occupancy of Compound 1 at the dose of 0.5 mg/kg after 8 hours following drug administration was approximately 90% in the cortical regions, which is an area of high SHT2A receptor density. This occupancy dropped to approximately 80% at 24 hours post- injection although no measurable test drug concentrations were apparent in plasma samples after 8 hours. -

® ®

WO 2005/012254 PCT/US2004/023488 ]

Example 12

The Effect of Compounds of the Invention and Zolpidem on Delta Power in Rats

In this example, the effect of Compounds of the Invention, such as Compound 1 and Compound 26, on sleep and wakefullness was compared to the reference drug zolpidem. Drugs were administered during the middle of the light period (inactivity period).

Briefly, four compounds of the invention, including Compound 1 (1.0 mg/kg) and Compound 26 (1.4 mg/kg), were tested for their effects on sleep parameters and were compared to zolpidem (5.0 mg/kg, Sigma, St. Louis, MO) and vehicle control (80% Tween 80, Sigma, St. Louis, MO). A repeated measures design was employed in which each rat was to receive seven separate dosings via oral gavage.

The first and seventh dosings were vehicle and the second through sixth were the test compounds and zolpidem given in counter-balanced order. Since all dosings were administered while the rats were connected to the recording apparatus, 60% C02/40% O, gas was employed for light sedation during the oral gavage process. Rats appeared fully recovered within 60 seconds following the procedure. A minimum of three days elapsed between dosings. In order to test the effect of the compounds on sleep consolidation, dosing occurred during the middle of the rats’ normal inactive period (6 hours following lights on). Dosing typically occurred between 13:15 and 13:45 using a 24 hour notation. All dosing solutions were made fresh on the day of dosing. Following each dosing, animals were continuously recorded until lights out the following day (~30 hours).

Animal Recording and Surgical Procedures:

Animals were housed in a temperature controlled recording room under a 12/12 light/dark cycle (lights on at 7:00 am) and had food and water available ad libitum. Room temperature (24+2 °C), humidity (50+20% relative humidity) and lighting conditions were monitored continuously via computer. Drugs were administered via oral gavage as described above, with a minimum of three days between dosings. Animals were inspected daily in accordance with NIH guidelines.

Eight male Wistar rats (300 + 25 g; Charles River, Wilmington, MA) were prepared with chronic recording implants for continuous electroencephalograph (EEG) and electromyograph (EMG) recordings. Under isoflurane anesthesia (1-4%), the fur was shaved from the top of the skull and the skin was disinfected with Betadine and alcohol. A dorsal midline incision was made, the temporalis muscle retracted, and the skull cauterized and thoroughly cleaned with a 2% hydrogen peroxide solution. Stainless steel screws (#000) were implanted into the skull and served as epidural electrodes.

EEG electrodes were positioned bilaterally at +2.0 mm AP from bregma and 2.0 mm ML and at -6.0 mm AP and 3.0 mm ML. Multi-stranded twisted stainless steel wire electrodes were sutured bilaterally in the neck muscles for recording of the EMG. EMG and EEG electrodes were soldered to a head plug connector that was affixed to the skull with dental acrylic. Incisions were closed with suture (silk 4-0) Lo

® ® and antibiotics administered topically. Pain was relieved by a long-lasting analgesic (Buprenorphine) administered intramuscularly once post-operatively. Post-surgery, each animal was placed in a clean cage and observed until it recovered. Animals were permitted a minimum of one week post-operative recovery before study.

For sleep recordings, animals were connected via a cable and a counter-balanced commutator to a Neurodata model 15 data collection system (Grass-Telefactor, West Warwick, RI). The animals were allowed an acclimation period of at least 48 hours before the start of the experiment and were connected to the recording apparatus continuously throughout the experimental period except to replace damaged cables. The amplified EEG and EMG signals were digitized and stored on a computer using SleepSign software (Kissei Comtec, Irvine CA).

Data Analysis:

EEG and EMG data were scored visually in 10 second epochs for waking (W), REMS,

NREMS. Scored data were analyzed and expressed as time spent in each state per half hour. Sleep bout length and number of bouts for each state were calculated in hourly bins. A “bout” consisted of a minimum of two consecutive epachs of a given state. EEG delta power (0.5-3.5 Hz) within NREMS was also analyzed in hourly bins. The EEG spectra during NREMS were obtained offline with a fast

Fourier transform algorithm on all epochs without artifact. The delta power was normalized to the average delta power in NREMS between 23:00 and 1:00, a time when delta power is normally lowest.

Data were analyzed using repeated measures ANOVA. Light phase and dark phase data were analyzed separately. Both the treatment effect within each rat and the time by treatment effect within each rat was analyzed. Since two comparisons were made, a minimum value of P<0.025 was required for post hoc analysis. When statistical significance was found from the ANOVAs, t-tests were performed comparing all compounds to vehicle and the test compounds to zolpidem.

Results:

Three rats completed the entire dosing protocol of 7 conditions. The remaining § animals completed only 3 to 6 of the 7 conditions, primarily because of loss of the implant. However, all drug conditions were tested on a minimum of 5 rats.

Although duration of the effect varied with each test compound, delta power was significantly increased (p<0.05) initially after dosing for all test compounds as compared to vehicle (see Figure 28).

There was a trend, and statistical significance in some conditions, for all compounds to increase

NREMS bout length, while the number of Waking bouts and NREMS bouts were decreased as compared to vehicle. No significant effects were observed on Waking bout length, REMS bout length and bout number, or total time spent in each state.

These results demonstrate that compounds of the invention promote sleep consolidation in rats during a time in their circadian sleep cycle that their sleep is naturally fragmented. This conclusion is L.

1-04-2005 US0423488 72.WO1 . a. -179 - ® supported by the trend for all compounds to increase NREMS bout length while the number of Waking : : and NREMS bouts decreased. Delta power during NREMS increased during the same period when sleep consolidation was facilitated, indicating that these compounds can promote “deeper” sleep as well as sleep consolidation. Hence, compounds of the invention can be effective treatments for sleep disorders.

No significant differences between the treatments were found for waking, NREMS sleep, or

REMS sleep. Delta power during NREMS, however, was significantly different between drug conditions and vehicle control. Compound 1 and Compound 26 significantly increased delta power during the second hour following dosing (15:00). :

No significant effects were found on either waking sleep bout length or number of bouts.

Significant differences were found, however, in both NREMS and REMS bout length. Compound 1 significantly increased NREMS bout length during the second hour. The number of NREMS bouts did not show significance. REMS bout length was significantly increased by Compound 1 and Compound 26 during the fourth hour. The number of REMS bouts did not show significance. “Those skilled in the art will recognize that various modifications, additions, substitutions, and variations to the illustrative examples set forth herein can be made without departing from the spirit of the invention and are, therefore, considered within the scope of the invention. All documents referenced above, including, but not limited to, printed publications, and provisional and regular patent applications, are incorporated herein by reference in their entirety.

AMENDED SHEET

Claims (1)

1. ® What is claimed is:

   1. A compound of Formula (I): Rea Rs Re “1 . "© Se ]] Rs Ree R; Ry 0) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: i) R; is aryl or heteroaryl each optionally substituted with Ry, Ryo, R11, Riz, Ris, Rus, and Rys each selected independently from the group consisting of C, acyl, Ci acyloxy, Cy alkenyl, Cy alkoxy, C, alkyl, C,, alkylcarboxamide, C,.¢ alkynyl, Cy. alkylsulfonamide, C,4 alkylsulfinyl, C,¢ alkylsulfonyl, C, alkylthio, C,¢ alkylureyl, amino, C,.s alkylamino, C., dialkylamino, C, alkylimino, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, C,.; cycloalkyl, C,4 dialkylcarboxamide, C4 dialkylsulfonamide, halogen, C,, haloalkoxy, C,.s haloalkyl, C,.s haloalkylsulfinyl, C, haloalkylsulfonyl, C4 haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent Ry, Rig, Ry1, Riz, Ry3, Ry, and Rs together with the atoms to which they are attached form a Cs_; cycloalkyl group or heterocyclic group each optionally substituted with F, Cl, or Br; and wherein said C,¢ alkenyl, C, alkyl, Cy alkynyl, C5 alkylamino, C, alkylimino, C,, dialkylamino, heterocyclic, and phenyl are each optionally substituted with 1 to S substituents selected independently from the group consisting of C acyl, Cys acyloxy, C, alkenyl, C,¢ alkoxy, C, alkyl, Cs alkylcarboxamide, C,¢ alkynyl, C, alkylsulfonamide, C,; alkylsulfinyl, C, alkylsulfonyl, C4 alkylthio, C, alkylureyl, amino, C, alkylamino, C,,4 dialkylamino, carbo-C,_¢-alkoxy, carboxamide, carboxy, cyano, C;.5 cycloalkyl, C4 dialkylcarboxamide, halogen, Cy haloalkoxy, C; haloalkyl, C, haloalkylsulfinyl, C,. ¢ haloalkylsulfonyl, C4 haloalkylthio, hydroxyl, thiot and nitro; ii) R; is selected from the group consisting of H, C, alkyl, C,.¢ alkenyl, C5 alkynyl and C;; cycloalkyl; iii) R; is selected from the group consisting of H, C5 alkenyl, C,¢ alkyl, Cis alkylcarboxamide, C,. alkynyl, C, alkylsulfonamide, carbo-C,4-alkoxy, carboxamide, carboxy, cyano, C; 4 cycloalkyl, C,.4 dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each of said C, alkenyl, C4 alkyl, C,4 alkynyl, C LC

   ) : ® alkylsulfonamide, C,.; cycloalkyl, heteroaryl and phenyl groups can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of

   Ci.s acyl, Cys acyloxy, Ca alkenyl, C4 alkoxy, C5 alkyl, C4 alkylamino, C,,4 dialkylamino, C4 alkylcarboxamide, C,. alkynyl, C,4 alkylsulfonamide, C,_ alkylsulfinyl, C, alkylsulfonyl, C,_, alkylthio, C, alkylureyl, amino, carbo-C, ¢- : alkoxy, carboxamide, carboxy, cyano, C; 4 cycloalkyl, Cy dialkylcarboxamide, halogen, C4 haloalkoxy, C, haloalkyl, C,, haloalkylsulfinyl, C, haloalkylsulfonyl,

   C,.« haloalkylthio, hydroxyl, nitro and sulfonamide; iv) R4 is selected from the group consisting of H, C, acyl, C,¢ acyloxy, Cy alkenyl, C;4 alkoxy, C,¢ alkyl, C,¢ alkylcarbexamide, Cp alkynyl, C4 alkylsulfonamide, C, alkylsulfinyl, C, alkylsulfonyl, Cy alkylthio, C, alkylureyl, amino, C, alkylamino, C, dialkylamino, carbo-C, s-alkoxy, carboxamide, carboxy, cyano, Cy, cycloalkyl, C,. dialkylcarboxamide, C,.¢ dialkylsulfonamide, halogen, C,¢ halealkoxy, C,. haloalkyl, C,¢ halealkylsulfinyl, C, haloalkylsulfonyl, C, haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; v) Rs is selected from the group consisting of C, acyl, C acyloxy, C4 alkenyl, Ci alkoxy, Cy alkyl, C4 alkylcarboxamide, Cy 4 alkynyl, C, alkylsulfonamide, C, alkylsulfinyl, C,; alkylsulfonyl, C,. alkylthio, C, alkylureyl, amino, C, alkylamino,

   C;.1 dialkylamino, carbo-C,-alkoxy, carboxamide, carboxy, cyano, Ci; cycloalkyl, C,. g dialkyicarboxamide, C,.¢ dialkylsuifonamide, halogen, C, ¢ haloalkoxy, C, haloalkyl,

   Ci. haloalkylsulfiny), Cy haloalkylsulfonyl, C, haloalkylthio, hydroxyl, thiol, nitro and sulfonamide, wherein said C,. alkoxy group is optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,.s acyl, C,.5 acyloxy, Cas alkenyl, C, alkoxy, C, alkyl, amino, C,. alkylamino, C, dialkylamino, C, alkylcarboxamide, C, alkynyl, C, alkylsulfonamide, C, alkylsulfinyl, C, alkylsulfonyl, C, alkylthio, C,.4 alkylureyl, amino, carbo-C, s-alkoxy, carboxamide, carboxy, cyano, Cy cycloalkyl, C,. dialkylcarboxamide, halogen, C4 haloalkoxy, C, haloalkyl, C,. haloalkylsulfinyl, C, 4 haloalkylsulfonyl, C, haloalkylthio, hydroxyl, nitro and phenyl, and wherein said amino and phenyl substituents are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and carbo-C,¢-alkoxy; vi) Rea, Ra, and Re are each independently selected from the group consisting of H, C,5 acyl, C, acyloxy, Cy alkenyl, C4 alkoxy, C, alkyl, C,.¢ alkylcarboxamide,

   C,.¢ alkynyl, C4 alkylsulfonamide, C, alkylsulfinyl, Cy alkylsulfonyl, Cy alkylthio, -

   : Ci alkylureyl, amino, Cy alkylamino, C, 4 dialkylaming, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, C;; cycloalkyl, C;, dialkylcarboxamide, C,4 dialkylsulfonamide, halogen, C, haloalkoxy, C,.s haloalkyl, C,.s haloalkylsulfinyl, C,. halealtkylsulfonyl, C,, haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; vii) Rj and Ry are independently H or Cs alkyl; viii) XisOorS;and ix) Q is C,; alkylene optionally substituted with 1 to 4 substituents selected from the group consisting of C,.; alkyl, C,4 alkoxy, carboxy, cyano, C,. haloalkyl, halogen and oxo; or Q is a bond.

   2. The compound according to claim 1 wherein R, is phenyl! or naphthyl each optionally substituted with Rs, Rig, R11, Ria, Ris, Ruy, and Rs each selected independently from the group consisting of C,¢ acyl, Cs alkoxy, C,, alkyl, Cs alkylsulfonyl, amino, C,4 alkylamino, C,¢ " dialkylamino, C, alkylimino, carbo-C 1.s-alkoxy, carboxamide, carboxy, cyano, C,_; cycloalkyl, halogen, C, haloalkoxy, C,. haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent Rs, Ryo, R11, Rig, Ris, Rie, and Rs together with the atoms to which they are attached form a Cs.y cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C, alkyl, C,. alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C,¢ acyl, C,¢ alkoxy, C,. alkyl, C, alkylsulfonyl, amino, C,; alkylamino, C,., dialkylamino, carboxamide, cyano, C,.; cycloalkyl, halogen, C, haloalkoxy, C, haloalkyl, and hydroxyl.

   3. The compound accarding to claim | wherein R, is phenyl or naphthyl each optionally substituted with Ry, Ry, R)), Ria, Riz, Rye, and R;5 each selected independently from the group consisting of Cy. acyl, Cs alkoxy, C, alkyl, amino, C, alkylamino, C, dialkylamino, Cs alkylimino, cyano, halogen, C,¢ haloalkoxy, C,, haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent Rg, Ryo, Ris, Riz, Ris, Ryy, and Rs together with the atoms to which they are attached form a Cs; cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C5 alkyl, C,.s alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of Cy alkyl, amino, C, alkylamino, C;., dialkylamino, and hydroxyl.

   4. The compound according to claim | wherein R, is phenyl or naphthyl each optionally substituted with Ry, Rye, Ruy, Riz, Ris, Ry, and Rys each selected independently from the group oo consisting of ~C(Q)CH,, —OCH,, —-CH;, -CH(CH,),, —CH(OH)CHj, -N(CH3;),, (2- dimethylamino-ethyl)-methyl-amino, (3-dimethylamino-propyl)-methyl-amino, ~C(=NOH)CH,, cyano, -F, —Cl, —Br, ~OCF,, —CF,, 4-methyl-piperazin-1-yl, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl.

   5. The compound according to claim 1 wherein R, is phenyl or naphthyl each optionally substituted with Ry, Ryo, Rij, Riz, Ry3, Ria, and Rs each selected independently from the group consisting of ~OCH;, —CH;, cyano, —F, ~Cl, Br, —~OCF;, and —CF,.

   6. The compound according to claim 1 wherein R, is heteroaryl optionally substituted with Ry, Rio, R11, Ry3, and Ry; each selected independently from the group consisting of C4 acyl, C6 alkoxy, C, alkyl, amino, C, alkylamino, C,.4 dialkylamino, C, alkylimino, cyano, halogen, Cs haloalkoxy, C, haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent Ry, Ry, Rip, Riz, Ria, Ris, and Rs together with the atoms to which they are attached form aC,»

   . cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C, alkyl, C, alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of Cy alkyl, amino, C, alkylamino, Ca dialkylamino, and hydroxyl.

   7. The compound according to claim 1 wherein R, is heteroaryl optionally substituted with R,, Rie, Ruy, Riz, and Ry; each selected independently from the group consisting of -C{(O)CH;, —OCH;, -CH;, —CH(CH,),, -CH(OH)CH,, —-N(CH3),, (2-dimethylamino-ethyl)-methyl-amino, (3-dimethylamino-propyl)-methyl-amino, ~-C(=NOH)CHj, cyano, —F, -Cl, -Br, —OCF;, —=CF,, 4-methyl-piperazin-1-yl, morpholin-4-y!, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl.

   8. The compound according to claim | wherein R, is heteroaryl optionally substituted with Rs, Rio, Ru, Riz, and Ry; each selected independently from the group consisting of -OCH3, —CH,, cyano, —F, —Cl, —Br, -OCF;, and -CF;.

   9. The compound according to claim I wherein R; is H or C, ¢ alkyl.

   10. The compound according to claim 1 wherein R, is selected from the group consisting of ~CH;, ~CH;CHj;, ~CH(CH,),, -CH,CH,CH,, -CH,CH(CH,); and ~CH,CH,CH,CH;

   11. The compound according to claim 1 wherein R; is ~CH; or —-CH(CH;),.

   1-04-2005 US0423488

   72.WO1 . oo ‘ -184 -

   12. The compound according to claim 1 wherein Rj is H.

   13. The compound according to claim | wherein R; is H or halogen.

   14. The compound according to claim | wherein R; is H, F, Cl, or Br.

   1S. The compound according to claim | wherein Ry, is selected from the group consisting of H, C alkyl and C,¢ haloalkyl.

   i6. The compound according to claim | wherein Ry is H or -CF;.

   17. The compound according to claim | wherein Rs is selected from the group consisting of C4 alkoxy, Cs alkylthio, amino, Cy. alkylamino, C4 dialkylamino, halogen, C,¢ haloalkoxy, and hydroxyl, wherein said C,¢ alkoxy group can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of amino, C4 atkylamino, C,; dialkylamino, amino, carbo-C, ¢-alkoxy, carboxamide, carboxy, cyano, halogen, and phenyl, and wherein said amino and phenyl substituents are each optionally substituted with | to 5 further substituents selected from the group consisting of halogen and carbo-C, ¢-alkoxy.

   18. The compound according to claim | wherein R; is selected from the group consisting of C, alkoxy, C,.s haloalkoxy, and hydroxyl, wherein said C,¢ alkoxy group can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of amino, Cs dialkylamino, carboxy, and phenyl, and wherein said amino and phenyl are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and ’ carbo-C, s-alkoxy.

   19. The compound according to claim | wherein Rs is selected from the group consisting of ~OCH;, ~OCH,CH;, -OCH(CH;),, ~OCF;, hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3-dimethylamino-propoxy, carboxymethoxy, and 2- tert-butoxycarbonylamino-ethoxy.

   20. The compound according to claim | wherein Rg is ~OCH;.

   21. The compound according to claim | wherein Rg,, Rep, and Rec are each independently selected from the group consisting of H, C;¢ alkoxy, Cs alkyl, amino, C,4 alkylamino, C3 dialkylamino, cyano, halogen, C, haloalkoxy, C,¢ haloalkyl, hydroxyl, and nitro. AMENDED SHEET

   1-04-2005 US0423488

   72.WO01 . . oe ) -185-

   22. The compound according to claim | wherein Re, Rev, and Re are each independently selected from the group consisting of —H, -OCH;, —-CHj, ~N(CHj3),, cyano, —F, -Cl, —Br, —OCF;, hydroxyl, and nitro.

   23. The compound according to claim 1 wherein Rg, Rey, and Re are all —H, ‘ 24. The compound according to claim | wherein R; is —H.

   25. The compound according to claim | wherein Rg is —H.

   26. The compound according to claim | wherein X is O.

   27. The compound according to claim | wherein X is S.

   28. The compound according to claim | wherein Q is -C(O)-.

   29. The compound according to claim 1 wherein Q is —CH,-.

   30. The compound according to claim 1 wherein Q is a bond. 31 The compound according to claim | of Formula (11a): Rea ’ N Q N~ / N NT “R, Ree R; Rg Ry Rj . (IIa) wherein: R; is phenyl or naphthyl optionally substituted with Rs, Ryo, Ry, Ry, Ry3, Ryq, and Ry each selected independently from the group consisting of C,¢ acyl, C,.¢ alkoxy, C;. alkyl, amino, Cy alkylamino, C,.4 dialkylamino, C,¢ alkylimino, cyano, halogen, C,¢ haloalkoxy, C,. ¢ haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent Rg, Ro, Ryy, Rj2, Ry3, Ria, and Rs together with the atoms to which they are attached form a Cs.; cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C4 alkyl, C, alkylimino, and heterocyclic are each optionally substituted with I to 5 substituents selected AMENDED SHEET

   1-04-2005 US0423488

   72.WO1 . . ‘ = 186 - ® independently from the group consisting of C, 4 alky), amino, C, alkylamino, C,., dialkylamino, and hydroxyl; R,; is C,.¢ alkyl; R; is H or halogen; Ry is selected from the group consisting of H, C,.¢ alkyl and C, haloalky!; Rs is selected from the group consisting of Cy. alkoxy, C, haloalkoxy, and hydroxy!, wherein said C, 4 alkoxy group can be optionally substituted with 1 to 5 further substituents selected independently from the group consisting of amino, Cy. dialkylamino, carboxy, and phenyl, and wherein said amino and pheny! are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and carbo-C,¢-atkoxy; Rss, Rep, and Re are each independently selected from the group consisting of H, C, , alkoxy, C, alkyl, amino, C,.¢ alkylamino, C. dialkylamino, cyano, halogen, C, haloalkoxy,

   C..¢ haloalkyl, hydroxyl, and nitro; : R; and Ry are both H; : X is O; and Q is a bond.

   32. The compound according to claim 1 of Formula (Ila): Resa Ry Rs Reb a ) | oy “Og, Ree R; Rg Ry, Rj (lla) wherein: R; is phenyl or naphthyl optionally substituted with Ry, Ryo, Ry, Ry3, Ry, Ri4, and Rs each selected independently from the group consisting of ~C(O)CH,, ~OCH;, ~CHs, —CH(CHj;),, ~-CH(OH)CH;, —N(CHj),, (2-dimethylamino-ethyl)-methyl-amino, - : dimethylamino-propyl)-methyl-amino, -C(=NOH)CH,, cyano, -F, —Cl, -Br, ~OCF 3, —CF3, 4- : methyl-piperazin-1-yl, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl; Rj is ~CHj or ~-CH(CH;),; R; is -H, -F, -Cl, or -Br; Ry is ~H, or -CF;3; R, is selected from the group consisting of ~OCH;, ~OCH,CH,, ~OCH(CH;),, -OCF;, hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3- dimethylamino-propoxy, carboxymethoxy, and 2-tert-butoxycarbonylamino-ethoxy; AMENDED SHEET :

   -04-2005 US0423488

   72.WOl1 . a ) - 187 - ® Ré., Rep, and Ry, are each independently selected from the group consisting of —H, -0OCH;, —=CH;, -N(CH,),, cyano, ~F, ~Cl, =Br, ~OCF3, hydroxyl, and nitro; R; and Ry are both —H; X is O; and Q is a bond.

   33. The compound according to claim | of Formula (11a): Rea fz Rs Reb Q yn Ree R; Rg Rs Ry (11a) ’ wherein: R; is phenyl! optionally substituted with Rg, R10, Ri, Ri2, and Ry; each selected independently from the group consisting of -C(O)CH;, ~OCH;, -CH;, —CH(CHj;),, -CH(OH)CHj;, —N(CH,),, (2-dimethylamino-ethyl)-methyl-amino, (3- dimethylamino-propyl)-methyl-amino, -C(=NOH)CH;, cyano, -F, —Cl, ~Br, —OCF,, ~CF3, 4-methyl-piperazin-1-yl, morpholin-4-yl, 4-methyl-piperidin-1-yl, hydroxyl, nitro, and phenyl; R; is —CHj; or ~CH(CH;);; ’ R; is —H, —F, -C}, or -Br; Riis -H, or -CF;; R; is selected from the group consisting of ~-OCH;, ~OCH,CH;, ~-OCH(CH,),, ~OCF,, hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3- dimethylamino-propoxy, carboxymethoxy, and 2-tert-butoxycarbonylamino-ethoxy; Rea, Res, and Ry are each independently selected from the group consisting of —H, —OCH;, ~CH;, -N(CHa),, cyano, -F, —C}, —Br, —OCF;, hydroxyl, and nitro; : R; and Ry are both —H; X is O; and Q is a bond.

   34. The compound according to claim 1 of Formula (11a): AMENDED SHEET

   '1-04-2005 US0423488

   72.WO1 . co ’ - 188 - ® Rea Ry Rs Rsb x JC, Ree R, Rg Ry Rj; (ila) wherein: R, is phenyl optionally substituted with Ry, Rg, Ry), R}3, and Ry; each selected independently from the group consisting of ~C(O)CH;, ~OCHj, -CHs, ~CH(CH3);, ~N(CHy),, cyano, —F, -Cl, —Br, ~OCF3, —CF3, hydroxyl, and nitro; : R; is —CH;; R; is =H, =F, -C|, or -Br; Rs is —H; R; is selected from the group consisting of -OCH,, ~OCH,CH;, —-OCH(CH3j),, ~OCF;, hydroxyl, benzyloxy, 4-chloro-benzyloxy, phenethyloxy, 2-dimethylamino-ethoxy, 3- dimethylamino-propoxy, carboxymethoxy, and 2-tert-butoxycarbonylamino-ethoxy; Rea, Rep, and Rg. are each —H; R, and Rg are both —H; X is O; and Q is a bond. ’ 35. The compound according to claim | wherein the compound is selected from the group consisting of: 1 -(3H4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4chloro-pheny 1)- urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-y!)-4-methoxy-phenyl}-3-(4-fluoro-phenyl)- : urea; 1-{3-(4-Bromo-2-methy!-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-dichloro- phenyl)-urea; 1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-methoxy-phenyl)- urea; ’ 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-bromo-phenyl)- urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl}-4-methoxy-phenyl]-3{4-chloro-3- trifluoromethyl-phenyl)-urea; AMENDED SHEET

   -04-2005 US0423488 } 72.WO1 EES ) -189- ® 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3,5-difluoro-pheny)- urea; 1-[3-(4-Bromo-2-methy!-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-pheny1)- urea; 1 -[3«(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4-chloro-2- trifluoromethyl-phenyl)-urea; 1-[3+(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(3,4-difluoro-phenyl)- : urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3-trifluoromethyl- phenyl)-urea; 1-[3-(4-Bromo-2-methyi-2H-pyrazoi-3-yl)-4-methoxy-phenyl}-3(4-trifluoromethyl- phenyl)-urea, 1-(3,5-Bis-trifiuoromethyl-pheny!)-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4- methoxy-pheny!]-urea; 1-[3«(4-Bromo-2-methy!-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-naphthalen-2-yl-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3-nitro-phenyl)-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4-fluoro-3-nitro- phenyl)-urea; 1-(3-Acetyl-phenyl)-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]- urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3-fluoro-phenyl)- : urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3(4-trifluoromethoxy- phenyl)-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3(3 —chloro-phenyl)- urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3(3-cyano-phenyl)- urea; 1-Biphenyl-2-yl-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-pheny!]-urea; 1-[3«4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4-isopropyl-phenyl)- urea; . 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-naphthalen-1-yl-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(2-fluoro-pheny)- urea; : 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3(4-chloro-phenyl)- : urea; . AMENDED SHEET

   : -04-2005 US0423488

   72.WO0L1. .o : -190 - ® 1-(4-Chloro-phenyl)-3-[3-(4-fluoro-2-methyl-2 H-pyrazol-3-yl)-4-methoxy-phenyl}- urea; I-[3«(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3(4-fluoro-phenyl)- urea; 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3 ~(2,4-difluoro-phenyl)- urea; : 1-(3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-34(3-methoxy-phenyl)- urea; ] 1-{3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3(4-fluoro-phenyl)- urea; . 1-(3,4-Difluoro-phenyl)-3-[3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}- urea; 1-[3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3-fluoro-phenyl)- ’ urea; 1-[3-(4-Chloro-2-methy!-2H-pyrazol-3-y[)-4-methoxy-phenyl]-3-(2-triflucromethoxy- phenyl)-urea; 1-(3-Acetyl-phenyl)-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]- urea; 1-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-pheny!]-3-(3-fluoro-phenyl)- urea; 1-(2,4-Difluoro-phenyl)-3-[3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]- Co urea; 1-[3(4-Bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4- chloro-phenyl)-urea; : 1-(3-(4-Bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-y1)-4-methoxy-phenyl]-3-(4- fluoro-phenyl)-urea; 1-{3-(4-Chioro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4- fluoro-phenyl)-urea; ) 1-{3-(4-Chloro-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4- chloro-phenyl)-urea; 1-(4-Chloro-phenyl)-3-[4-methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)- phenyl]-urea; 1-(3-Chloro-phenyl)-3-[3{2-isopropyl-2H-pyrazol-3-yl)}-4-methoxy-phenyl]-urea; 1-(4-Fluoro-phenyl)-3-[3-(2-isopropy|-2H-pyrazol-3-yl)-4-methoxy-phenyl]-urea; 1-{3-(4-Chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3(4-chloro-phenyl)- urea; 1-(3,4-Difluoro-phenyl)-3-{3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-urea; AMENDED SHEET

   1-04-2005 US0423488

   7.WoL. -191- ® I-(3-Chloro-4-fluoro-phenyl)-3-[3-(2-isopropy|-2H-pyrazol-3-yl)-4-methoxy-phenyl]- urea; 1-(2-Chloro-4-trifluoromethyl-phenyl)-3-[3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-urea; 1-{3-(4-Bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-chloro-phenyl)- urea, 1-{3-(4-Bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-fluoro-phenyl)- urea; 1-[3-(4-Bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-pheny!}-3+(3,4-difluoro- phenyl)-urea; 1-[3(4-Bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3-chloro-4-fluoro- phenyl)-urea; : 1-{3-(4-Bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2-Chloro-4- trifluoromethyl-phenyl)-urea; 1-[3-(4-Chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4-fluoro-phenyt)- urea; 1 -[3-(4-Chloro-2-isopropy}-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3 -(3,4-difluoro- phenyl)-urea; 1-(3-Chloro-4-fluoro-phenyl)-3-{3(4-Chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy- phenyl]-urea; 1-[3-(4-Chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3(2-Chloro-4- trifiluoromethyl-phenyl)-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)- urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazoi-3-yl)-4-isopropoxy-phenyl}-3-(4-chloro-pheny|)- urea; 1-[3-(4-Bromo-2-methy!-2H-pyrazol-3-yl)-4-isopropoxy-phenyl]-3(4-fluoro-phenyl)- urea; 1-[4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)}-phenyl]-3-(4-chloro-phenyl)- urea; 1-[4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl}-3(4-fluoro-phenyl)- - urea, 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chloro-benzyloxy)-phenyl}-3-(4- chloro-phenyl)-urea, 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4(4chloro-benzyloxy)-phenyl]-3-(4- fluoro-phenyt)-urea; AMENDED SHEET

   1 -04-2005 US0423488

   72.WO1, Lo ’ -192- ® 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxy-phenyl]-3-(4-fluoro- phenyl)-urea; 1-(3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-phenethyloxy-phenyl}-3-(4-chloro- phenyl)-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy-phenyl]-3(4-chloro-phenyl)-urea; -[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy-pheny!]-3-(4-fluoro-phenyl)-urea; = 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenyl}-3-(4- chloro-phenyl)-urea; ] 1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenyl)-3-(4- fluoro-pheny!)-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazoi-3-yl)-4-methoxy-phenyt)-3(4-chloro-phenyi)- . thiourea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3-methoxy-phenyl)- urea; : 14(4-Chloro-phenyl)-3-[4-methoxy-3-(2-methy|-2H-pyrazol-3-yl)-pheny!]-urea; 1-({3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-isopropyl-pheny)- urea; : 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(2,4-dichloro- phenyl)-urea; 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-naphthalen-1-yl-urea; 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-chloro-2- trifluoromethyl-phenyl)-urea; 1-{3 {(4-Chloro-2-methyl-2H-pyrazol-3 -yl)-4-methoxy-phenyl]-3-(4-trifluoromethyi- phenyl)-urea; 1-(4-Bromo-phenyl)-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]- urea; : 14(3,5-Bis-trifluoromethyl-phenyl)-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl]-urea; 1-(3-Chioro-pheny})-3-{3-(4-fluoro-2-methyi-2H-pyrazol-3-yl)-4-methoxy-phenyl]- urea; 1{4-Chloro-3-trifluoromethyl-phenyl)-3-[3(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4- : : methoxy-phenyl]-urea; 1-(4-Bromo-phenyl)-3-[3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]- urea; 1-{3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-triflucromethyl- phenyl)-thiourea; AMENDED SHEET

   -04-2005 US0423488 3 72.WO1, Lo ’ -193 - ® 1-[3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl)-3-(4-methoxy-phenyt)- urea; 1-(3-Acetyl-phenyl)-3-[3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]- urea; 1-[3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-pheny!]-3-(4-triflucromethy!- phenyl)-urea and 1-[3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3(3-triflucromethyl- phenyl)-urea.

   36. The according to claim 1 wherein the compound is selected from the group consisting of: I -[3-(4-Chloro-2-methyl-2H-pyrazol-3-y!)-4-methoxy-phenyl]-3-(3-chloro-phenyl)- urea; 1-[3«(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3,4-difluoro-phenyl)- urea; 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(3,5-difluoro-phenyl)- urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-[3-(1 -hydroxy-ethyl)- phenyl]-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-[3-(1-hydroxyimino- ethyl)-pheny!]-urea; 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyi]-3-(2-fluoro-phenyl)- urea; )-(4-Chloro-phenyl)-3-[3{(2-methyl-2H-pyrazol-3-y})-4-trifluoromethoxy-phenyl}- ‘urea; 14(2,4-Difluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yi)-4-trifluoromethoxy-phenyl)- urea; 1-(4-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-pheny] -urea; 1-[3-(2-Methyl-2H-pyrazol-3-yl)-4-triflucromethoxy-phenyl]-3-(4-trifluoromethy- phenyl)-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-y!)-4-methoxy-phenyl}-3-{4-chloro-2-(4- methyl-piperazin-1-yl)-phenyi}-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyi]-3+(2,4-difluoro-phenyl)- urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(4-chloro-2- morpholin-4-yl-phenyl)-urea, AMENDED SHEET

   -04-2005 US0423488 } 72.WOl.

   Lo ’ - 194 - ® 1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-[4-chloro-2-(4- methyl-piperidin-1-yl)-phenyl]-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-y!)-4-methoxy-phenyl}-3-(4-chloro-2-hydroxy- phenyl)-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-3-(4-chloro- phenyl)-urea; 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yi)-4-methoxy-phenyl]-3-(3-cyano-phenyl)- urea; 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(3-nitro-phenyl)-urea, 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-y!)-4-methoxy-phenyl]-3-{4-chloro-2-[(2- dimethylamino-ethyl)-methyl-amino]-phenyl}-urea; 1-[3«(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-{4-chloro-2-[(3- dimethylamino-propyl)-methyl-amino}-phenyl}-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-3-(2,4-difluoro- phenyl)-urea; 14(3-Acetyi-phenyl)-3-{3-(2-methyl-2H-pyrazol-3-yl)-4-trifluoromethoxy-phenyl]-urea; 1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3 (2,2-difluoro- benzo[1,3])dioxol-5-yl)-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-dimethylamino- phenyl)-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylamino-propoxy)-phenyl]-3-(4- chloro-phenyl)-urea; . {2-(4-Bromo-2-methy|-2H-pyrazol-3-yl)-4-[3(4-chloro-phenyl)-ureido]-phenoxy} - acetic acid; 1<(4-Chloro-phenyl)-3-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea; 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)- urea; 1-[3«(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)- urea; 1-(4-Chloro-phenyl)-3-[4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-urea; 1-[3(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenyl]-3-(2,4- difluoro-phenyl)-urea; 1-(2,4-Difluoro-phenyl)-3-{4-(3-dimethylamino-propoxy)-3+(2-methyl-2H-pyrazol-3- yl)-phenyl]-urea; . 1-{4-(3-Dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-y!)-phenyli}-3-(4-fluoro- phenyl)-urea; AMENDED SHEET

   1 -04-2005 US0423488 Co 72.WO01 -o -195 - ® 1-(4-Chloro-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-urea; -{3-(4-Chloro-2-methyl-2H-pyrazol-3-yi)-4-(3-dimethylamino-propoxy)-phenyi)-3-(4- chloro-phenyl)-urea; 1-(2,2-Difluoro-benzo[ 1,3 ]dioxol-5-yl)-3-[4-(3-dimethylamino-propoxy)-3 -(2-methyl- 2H-pyrazol-3-yl)-phenyl}-urea; - 1-[4-(3-Dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3 -p-tolyl-urea; 1-[4-(3-Dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-y!l)-phenyl}-3 ~(4-methoxy- phenyl)-urea; 1-{3-(4-Chloro-2-methyl-2 H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenyl]-3-(2,4- difluoro-phenyl)-urea; 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3 -yl)-4-(3-dimethylamino-propoxy)-pheny}]-3- (2,4-difluoro-phenyl)-urea; 1-(3-Chloro-phenyl)-3-[4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-urea; I-(3-Chloro-4-fluoro-phenyl)-3-[4-(3-dimethylamino-propoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl}-urea; 1-(3,4-Difluoro-phenyt)-3-[4-(3-dimethylamino-propoxy)-3H(2-methy|-2H-pyrazol-3- yl)-phenyl]-urea; 1-[4~3-Dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4- trifluoromethyl-phenyl)-urea; 1-{4-(3-Dimethylamino-propoxy)-3<(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2-fluoro- phenyl)-urea; 1-[4-(3-Dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2-fluoro-5- methyl-phenyl)-ures; 1-(2-Chloro-phenyl)-3-[4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-urea; 14(2,4-Difluoro-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3«(2-methyl-2H-pyrazol-3-yl)- phenyl)-urea; 1-[4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl}-3-(4-fluoro- pheny!)-urea; " 1-(3-Acetyl-phenyl)-3-[4{(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-urea; 1-(2,2-Difluoro-benzo(1,3]dioxol-5-yl)-3-[4-(2-dimethylamino-ethoxy)-3-(2-methyl- 2H-pyrazol-3-yl)-phenyl]-urea; 1-[4-(3-Dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyi]-3-pheny|- urea; AMENDED SHEET

   ! -04-2005 US0423488

   72.WO01 .o : - 196 - ® I-[4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-methoxy- phenyl)-urea; (2-{2-(4-Bromo-2-methyi-2H-pyrazol-3-yl)-4-[3-(2,4-diflucro-phenyl)-ureido]- phenoxy} -ethyl)-carbamic acid tert-butyl ester; I-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylamino-propoxy)-phenyl]-3- (2,4-difluoro-phenyl)-urea; 1-{3(4-Bromo-2-methyl-2H-pyrazol-3-yI}-4-(3-dimethylamino-propoxy)-phenyl}-3-(2- - chloro-pheny!)-urea; . 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3 -yl)-4-(3-dimethylamino-propoxy)-phenyl]-3-(2- fluoro-phenyl)-urea; 1-(4-Chloro-phenyl)-3-{4-methoxy-3-(2H-pyrazol-3-yl)-phenyl)-urea; 1-[3(4-Bromo-2H-pyrazol-3-yl)-4-methoxy-phenyl}-3-(2,4-difluoro-phenyl)-urea; 1-(2,4-Difluoro-phenyl)-3-[4-methoxy-3-(2H-pyrazol-3-yl)-phenyl]-urea; and 1 -(4-Chloro-phenyl)-3-[4-hydroxy-3< 1-methyl-1H-pyrazol-3-yl)-phenyl}-urea.

   37. The compound according to claim 1 wherein the compound is selected from the group consisting of: 1-Benzoyl-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl}-urea; and 1-Benzyl-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-urea.

   38. The compound according to claim 1 wherein the compound is selected from the group a. consisting of: 1-Benzoyl-3-{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-pheny!]-urea; 1-Benzyl-3-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-urea; and 1-(4-Chloro-benzyl)-3-[4-(3-dimethylamino-propoxy)-3-(2-methyl-2 H-pyrazol-3-yl)- phenyli}-urea.

   39. The compound according to claim | wherein the compound is selected from the group consisting of: : I{4-Chloro-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3-(4-fluoro-2-methyl-2H-pyrazol- 3-yl)-phenyl]-urea; 1 -{4«(2-Dimethylamino-ethoxy)-3-(4-fluoro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(4- fluoro-phenyl)-urea; 1-(2,4-Difluoro-phenyl)-3-[4-(2-dimethylamino-ethoxy)-3-(4-fluoro-2-methyl-2 H- pyrazol-3-yl)-phenyl]-urea; 1 ~(4-Chloro-2-hydroxy-phenyl)-3-[4(2-dimethylamino-ethoxy)-3(4-fluoro-2-methy|- 2H-pyrazol-3-yl)-pheny!}-urea; AMENDED SHEET ‘ :

   1-04-2005 US0423488

   72.W01 Lo ‘ -197 - ® 1-[4-(2-Dimethylamino-ethoxy)-3-(4-fluoro-2-methy}-2 H-pyrazol-3-yl)-phenyl]-3-(4- fluoro-2-hydroxy-phenyl)-urea; : [ ~(4-Chloro-3-hydroxy-phenyl)-3-[4(2-dimethylamino-ethoxy)-3-(4-fluoro-2-methyl- 2H-pyrazol-3-yl)-phenyl]-urea; 1-[4-(2-Dimethylamino-ethoxy)-3-(4-fluoro-2-methyl-2 H-pyrazol-3-yl)-phenyl}-3-(4- fluoro-3-hydroxy-phenyl)-urea; l -[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylam ino-ethaxy)-phenyl)-3-(4- chloro-phenyl)-urea; I1-(3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4(2-dimethylamino-ethoxy)-phenyl]-3-(4- fluoro-phenyl)-urea; 1-(4-Chloro-2-hydroxy-phenyl)-3 -[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2- k dimethylamino-ethoxy)-phenyl]-urea; I-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-pheny!}-3-(4- fluoro-2-hydroxy-phenyl)-urea; 1-(4-Chioro-3-hydroxy-phenyl)-3-[3-(4-chloro-2-methyl-2H -pyrazol-3-yl)-4-(2- dimethylamino-ethoxy)-phenyl]-urea; 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3 -yl)-4-(2-dimethylamino-ethoxy)-phenyl}-3-(4- fluoro-3-hydroxy-phenyl)-urea; 1-(4-Chloro-2-hydroxy-phenyl)-3 -{4-(2-dimethylamino-ethoxy)-3<(2-methyl-2H- pyrazol-3-yl)-phenylj-urea; 1-[4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-pheny|}-3-(4-fluoro-2- hydroxy-phenyl)-urea; . . 1-(4-Chloro-3-hydroxy-phenyl)-3-{4-(2-dimethy lamino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-urea; 1 -[4-(2-Dimethylamino-ethoxy)-3-(2-methyi-2H-pyrazol-3-yl)-phenyl}-3-(4-fluoro-3- hydroxy-phenyl)-urea; 1-[34-B romo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-pheny|]-3-(4- chloro-2-hydroxy-phenyl)-urea; 1 -[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-pheny}-3-(4- fluoro-2-hydroxy-pheny!)-urea; 1-[3«(4-Bromo-2-methyl-2 H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenyl]-3-(4- chloro-3-hydroxy-phenyl)-urea; 1 -[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-pheny!)-3-(4- fluoro-3-hydroxy-phenyl)-urea; l -(4-Chloro-phenyl)-3-[4-(3-dimethylamino-propoxy)-3-(4-fluoro-2-methyl-2 H- pyrazol-3-yl)-phenyl]-urea; AMENDED SHEET

   1 04-2005 US0423488

   72.W01 - 198 - ® l -[443-Dimethylamino-propoxy)-3-(4-fluoro-2-methyl-2 H-pyrazol-3-yl)-phenyl)-3-(4- fluoro-pheny!)-urea; 1-(2,4-Difluoro-phenyl)-3-[4-3-d imethylamino-propoxy)-3 {4-fluoro-2-methyl-2H- pyrazol-3-yl)-phenyl}-urea; ‘ *(4-Chloro-2-hydroxy-phenyl)-3-{4-(3-dimethylamino-propoxy)-3 -(4-fluoro-2- methyl-2H-pyrazol-3-yl)-pheny!]-urea; I-{4~3-Dimethylamino-propoxy)-3 «(4-fluoro-2-methyl-2 H-pyrazol-3-yl)-phenyl}-3-(4- fluoro-2-hydroxy-phenyl)-urea; 1-(4-Chloro-3-hydroxy-phenyl)-3-]4-(3-d imethylamino-propoxy)-3-(4-fluoro-2- methyl-2H-pyrazol-3-yl)-phenyl]-urea; 1 -[4-(3-Dimethylamino-propoxy)-3-(4-fluoro-2-methyl-2 H-pyrazol-3-yl)-phenyi]-3-(4. fluoro-3-hydroxy-phenyl)-urea; 1 [3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylamino-propoxy)-pheny1]-3-(4- fluoro-pheny!)-urea; -(4-Chloro-2-hydroxy-phenyl)-3-[3(4-chloro-2-methyl-2H-pyrazol-3-yl)-4(3- dimethylamino-propoxy)-phenyl}-urea; l -[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylamino- propoxy)-phenyl]-3-(4- fluoro-2-hydroxy-phenyl)-urea; 1-(4-Chloro-3-hydroxy-phenyl)-3-[3 ~(4-chloro-2-methyl-2H-pyrazol-3 -y)4-(3- dimethylamino-propoxy)-phenyl]-urea; 1 -[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylamino-propoxy)-pheny1}-3-(4- fluoro-3-hydroxy-phenyl)-urea; 1 -(4-Chloro-2-hydroxy-phenyl)-3-[4-(3-dimethylamino-propoxy)-3{2-methyl-2H- pyrazol-3-yl)-phenyl}-urea; 1-[4-(3-Dimethylamino-propoxy)-3 -(2-methyl-2H-pyrazol-3 -yl)-pheny!]-3-(4-fluoro-2- hydroxy-phenyl)-urea; 1-(4-Chloro-3-hydroxy-phenyl)-3-[4-(3-dimethylamino-propoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]}-urea; 1-[4-3-Dimethylamino-propoxy)-3-(2-methyl-2 H-pyrazol-3-yl)-phenyl]-3-(4-fluoro-3- } hydroxy-phenyl)-urea; 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylamino-propoxy)-phenyl]-3-(4- fluoro-phenyl)-urea; ' 1-[3(4-Bromo-2-methyl-2H-pyrazol-3 -y})-4-(3-dimethylamino-propoxy)-phenyl]-3-(4- chloro-2-hydroxy-phenyl)-urea; l -[3-(4-Bromo-2-methy|-2H-pyrazol-3-y1)-4-(3-dimethylamino-propoxy)-phenyl]-3-(4- fluorg-2-hydroxy-phenyl)-urea; AMENDED SHEET i

   1-04-2005 US0423488

   72.WO01 Lo : -199 - I-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(3-dimethylamino-propoxy)-pheny1}-3-(d- chloro-3-hydroxy-phenyl)-urea; and 1 -[3-(4-Bromo-2-methy|-2H-pyrazol-3-yl)-4-(3-dimethylamino-propoxy)-pheny|)-3-(4- fluoro-3-hydroxy-phenyl)-urea.

   40. A compound according to claim | that is 1-[3(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4- : methoxy-phenyl]-3-(4-chloro-phenyl)-urea or a pharmaceutically acceptable salt, solvate or : hydrate thereof.

   41. A compound according to claim | that is 1-[3(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4- : methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea or a pharmaceutically acceptable salt, solvate or hydrate thereof. 42, A compound according to claim | that is 1-{3(4-Chloro-2-methyl-2H-pyrazol-3-y1)-4- methoxy-phenyl]-3-(4-chloro-phenyl)-urea or a pharmaceutically acceptable salt, solvate or hydrate thereof.

   43. A compound according to claim | that is 1A3-Chloro-4-fluoro-phenyl)-3-[3-(4-Chloro-2- 1sopropyl-2H-pyrazol-3-yl)}-4-methoxy-phenyl]-urea or a pharmaceutically acceptable sal, solvate or hydrate thereof. 44, A compound according to claim 1 that is 1-{4-Benzyloxy-3-(4-bromo-2-methyl-2H-pyrazol-3- yb)-phenyl}-3-(4-fluoro-phenyl)-urea or a pharmaceutically acceptable salt, solvate or hydrate thereof.

   45. A compound according to claim 1 that is |-{3-(4-Bromo-2-methyl-2H-pyrazol-3-y|)-4- phenethyloxy-phenyl}-3(4-chloro-phenyl)-urea or a pharmaceutically acceptable salt, solvate or hydrate thereof.

   46. A compound according to claim 1 that is 1-(4-Chloro-phenyl)-3-[3-(2-methyi-2H-pyrazol-3- yl)-4-trifluoromethoxy-phenyi]-urea or a pharmaceutically acceptable salt, solvate or hydrate thereof.

   47. A compound according to claim | that is 1-[3(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl}-3-{4-chloro-2-{(2-dimethylamino-ethyl)-methyl-amino}-phenyl} -urea or a pharmaceutically acceptable salt, solvate or hydrate thereof. AMENDED SHEET

   PCT/US2004/023488 ® - 200 -

   48. A compound according to claim 1 that is 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl]-3-(2,2-difluoro-benzo[ 1,3]dioxol-5-yl)-urea or a pharmaceutically acceptable salt, solvate or hydrate thereof.

   49. A compound according to claim 1 that is 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2- dimethylamino-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea or a pharmaceutically acceptable salt, solvate of hydrate thereof.

   50. A compound according to claim 1 that is 1-Benzyl-3-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4- methoxy-phenyl}-urea or a pharmaceutically acceptable salt, solvate or hydrate thereof.

   51. A compound according to claim 1 that is 1-[4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-3-(4-fluoro-2-hydroxy-phenyl)-urea or a phamaceutically acceptable salt, solvate or hydrate thereof.

   52. A pharmaceutical composition comprising a compound according to any one of claims 1 to 51 and a pharmaceutically acceptable carrier.

   53. A mcthod for modulating the activity of a SI1T;4 serotonin receptor by contacting the receptor with a compound according to any one of claims 1 to 51. 54, A method for prophylaxis of platelet aggregation in an individual comprising administering to said individual an effective amount of a compound according to any one of claims I to 51.

   55. A method for prophylaxis of an indication selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation in an individual comprising administering to said individual an effective amount of a compound according to any onc of claims 1 to 51.

   56. A substance or composition for use in a method for prophylaxis or treatment of reducing the risk of blood clot formation in an angioplasty or coronary bypass surgery individual, said substance or composition comprising a compound according to any one of claims 1 to 51, and said method comprising administering to said individual an effective amount of said substance or composition.

   57. A substance or composition for use in a method for prophylaxis or treatment of reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, said substance or AMENDED SHEET

   PCT/US2004/023488 ® -20] - composition comprising a compound according to any one of claims 1 to 51, and said method comprising administering to said individual an cffective amount of said substance or composition.

   58. A method for prophylaxis of a sleep disorder in an individual comprising administering to said individual an effective amount of a compound according to any onc of claims 1 to 51.

   59. The method according to claim 58 wherein said slecp disorder comprises fragmented sleep architecture. :

   60. The method according to claim 58 wherein said effective amount of said compound promotes sleep consolidation.

   61. The method according to claim 58 wherein said effective amount of said compound increases delta power.

   62. The method according to claim 58 wherein said sleep disorder is a dyssomnia.

   63. The method according to claim 62 wherein said dyssomnia is selected from the group consisting of psychophysiological insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnea syndrome, central slcep apnea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless leg syndrome, inadequate sleep hygienc, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association disorder, nocturnal eating or drinking syndrome, hypnotic dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, toxin-induced slecp disorder, time zone change (jet lag) syndrome, shift work sleep disorder, irregular slecp-wake pattern, delayed slecp phase syndrome, advanced sleep phase syndrome and non-24-hour sleep-wake disorder.

   64. The method according to claim 58 wherein said sleep disorder is a parasomnia.

   65. The method according to claim 64 wherein said parasomnia is selected from the group consisting of confusional arousals, sleepwalking and sleep terrors, rhythmic movement disorder, sleep starts, sleep talking and nocturnal leg cramps.

   66. "The method according to claim 58 wherein said sleep disorder is associated with a medical or psychiatric disorder. AMENDED SHEET

   PCT/US2004/023488 ® -202 -

   67. A process for preparing a composition comprising admixing a compound according to any one of claims 1 to 51 and a pharmaceutically acceptable carrier.

   68. Use of a compound according to any one of claims 1 to 51 for production of a medicament for use in prophylaxis or treatment of a SHT,4 mediated disorder.

   69. The usc according to claim 68 wherein said 5S11T;4 mediated disorder is platelet aggregation.

   70. The use according to claim 68 wherein said SHT,, mediated disorder is selected {from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation.

   71. The use according to claim 68 wherein said SH'1;4 mediated disorder is a blood clot formation in an angioplasty or coronary bypass surgery individual.

   72. The usc according to claim 68 wherein said 5HT,, mediated disorder is a blood clot formation in an individual suffering {rom atrial fibrillation.

   73. A compound according to any one of claims 1 to 51 for use in a method of treatment of the human or animal body by therapy.

   74. A compound according to any one of claims 1 to 51 for use in a method for the prophylaxis or treatment of a SHT,, mediated disorder in the human or animal body by therapy.

   75. A compound according to any one of claims 1 to 51 for use in a method for the prophylaxis or treatment of a sleep disorder in the human or animal body by therapy.

   76. A compound according to any one of claims 1 to 51 for use in a method for the prophylaxis or treatment of a diabetic-related disorder in the human or animal body by therapy.

   77. A compound according to any one of claims 1 to 51 for use in a method for the prophylaxis or treatment of platelet aggregation in the human or animal body by therapy. AMENDED SHEET

   PCT/US2004/023488

   78. Use of a compound according to any one of claims 1 to 51 in the manufacture of a medicament for prophylaxis or treatment of a sleep disorder in an individual.

   79. Use according to claim 78 wherein said sleep disorder comprises fragmented sleep architecture.

   80. Use according to claim 78 wherein said medicament promotes sleep consolidation.

   81. Use according to claim 78 wherein said medicament increases delta power.

   82. Use according to claim 78 wherein said sleep disorder is a dyssomnia.

   83. Use according to claim 82 wherein said dyssomnia is selected from the group set out in claim

   63.

   84. Use according to claim 78 wherein said sleep disorder is a parasomnia.

   85. Use according to claim 84 wherein said parasomnia is selected from the group set out in claim

   65.

   86. Use according to claim 78 wherein said sleep disorder is associated with a medical or psychiatric disorder.

   87. Use of a compound according to any onc of claims 1 to 51 in the manufacture of a medicament for the treatment of the human or animal body by therapy.

   88. Usc of a compound according to any one of claims 1 to 51 in the manufacture of a medicament for the prophylaxis or treatment of a diabetic-related disorder in the human or animal body by therapy.

   89. A substance or composition for use in a method for modulating the activity of a SHT,A serotonin receptor, said substance or composition comprising a compound according to any onc of claims 1 to 51, and said method comprising contacting the receptor with said substance or composition.

   90. A substance or composition {or usc in a method for prophylaxis or treatment of platelet aggregation in an individual, said substance or composition comprising a compound according AMENDED SHEET

   PCT/US2004/023488 to any one of claims 1 to 51, and said method comprising administering to said individual an cffective amount of said substance or composition.

   91. A substance or composition for use in a method for prophylaxis or treatment of an indication sclected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation in an individual, said substance or composition comprising a compound according to any one of claims 1 to 51, and said method comprising administering to said individual an effective amount of said substance or composition.

   92. A substance or composition for use in a method for prophylaxis or treatment of a sleep disorder in an individual, said substance or composition comprising a compound according to any one of claims 1 to 51, and said method comprising administering to said individual an cffective amount of said substance or composition.

   93. A substance or composition for use in a method of treatment or prevention according to claim 92 wherein said sleep disorder comprises fragmented slecp architecture.

   94. A substance or composition for use in a method of treatment or prevention according to claim 92 wherein said effective amount of said substance or composition promotes sleep consolidation.

   95. A substance or composition for use in a method of treatment or prevention according to claim 92 wherein said effective amount of said substance or composition increases delta power.

   906. A substance or composition for use in a method of treatment or prevention according to claim 92 wherein said sleep disorder is a dyssomnia.

   97. A substance or composition for use in a method of treatment or prevention according to claim 96 wherein said dyssomnia is selected from the group set out in claim 63.

   98. A substance or composition for use in a method of treatment or prevention according to claim 92 wherein said sleep disorder is a parasomnia.

   99. A substance or composition for use in a method of treatment or prevention according to claim 98 wherein said parasomnia is sclected from the group sect out in claim 05. AMENDED SHEET

   PCT/US2004/023488 <Q - 205 -

   100. A substance or composition for use in a method of treatment or prevention according to claim 92 wherein said sleep disorder is associated with a medical or psychiatric disorder.

   101. A substance or composition for use in a method for the treatment of the human or animal body by therapy, said substance or composition comprising a compound according to any one of claims 1 to 51, and said method comprising administering said substance or composition.

   102. A substance or composition for use in a method for the prophylaxis or treatment of a diabetic- related disorder in the human or animal body by therapy, said substance or composition comprising a compound according to any one of claims 1 to 51, and said method comprising administering said substance or composition.

   103. A compound according to any onc of claims 1 to 51, or 73 to 77, substantially as herein described and illustrated.

   104. A composition according to claim 52, substantially as herein described and illustrated.

   105. A method according to any one of claims 53 to 55 or 58 to 66, substantially as herein described and illustrated.

   106. A substance or composition for use in a method of treatment or prophylaxis according to any onc of claims 56, 57 or 89 to 102, substantially as herein described and illustrated.

   107. A process according to claim 67, substantially as herein described and illustrated.

   108. Use according to any one of claims 68 to 72 or 78 to 88, substantially as herein described and illustrated.

   109. A new compound, a new composition, a new non-therapeutic method of treatment, a substance or composition for a new use in a method of treatinent or prevention, a new process for preparing a compound, or a new use of a compound as claimed in any onc of claims 1 to 51, substantially as herein described. . AMENDED SHEET