OA17968A

OA17968A - P-substituted asymmetric ureas and medical uses thereof

Info

Publication number: OA17968A
Application number: OA1201600330
Authority: OA
Inventors: Claudio Giuliano; Silvina Garcia Rubio; Antoine Daina; Angelo GUAINAZZI; Claudio Pietra
Original assignee: Helsinn Healthcare Sa
Priority date: 2014-03-07
Filing date: 2015-03-06
Publication date: 2018-03-12

Abstract

Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the ghrelin receptor. The compounds have the general Formula I : or pharmaceutically acceptable salts thereof.

Description

The présent invention relates to novel asymmetric urea compounds, medical uses thereof, particularly in the treatment of medical conditions modulated by the ghrelin receptor.

BACKGROUND

The growth hormone secretagogue receptor (GHS-R) régulâtes a number of physiological processes, including growth hormone (GH) release, metabolism, and appetite. Ghrelin, a circulating hormone produced predominantly by endocrine cells in the stomach, is its endogenous ligand. Ghrelin is a 28 amino acid peptide with an acyl side chain required for biological activity (Kojima et al., Nature, 402, 656-660, 1999). Ghrelin has been shown to stimulate growth hormone (GH) release and to increase food intake when administered both centrally and peripherally (Wren et al., Endocrinology, 141, 4325-4328, 2000).

Endogenous levels of ghrelin rise on fasting and fall on re-feeding in humans (Cummings et al., Diabètes, 50, 1714-1719, 2001). Ghrelin also appears to play a rôle in maintaining long term energy balance and appetite régulation. Chronic administration of ghrelin in rodents leads to hyperphagia and weight gain that are independent of growth hormone sécrétion (Tschop et al.,

Nature, 407, 908-913, 2000). Circulating ghrelin levels decrease in response to chronic overfeeding and increase in response to chronic négative energy balance associated with anorexia or exercise. Obese people generally hâve low plasma ghrelin levels (Tschop et al., Diabètes, 50, 707-709,2001) accordingly to the physiological response of the body in reducing calories intake. Intravenous ghrelin is effective in stimulating food intake in humans. A recent study showed a 28% food intake increase from a buffet meal with a ghrelin infusion compared with saline control (Wren et al., J. Clin. Endocrinology and Metabolism, 86, 5992, 2001).

In view of the above experimental evidence, compounds that modulate ghrelin receptor activity hâve been proposed for preventing and/or treating disorders associated with ghrelin receptor physiology. For example, antagoniste at ghrelin receptor might one day be developed to

reduce appetite, reduce food intake, induce weight loss and treat obesity without affecting or reducing the circulating growth hormone levels. On the other hand, agonists at ghrelin receptor might also be developed for stimulating food intake and thus be useful in treating eating disorders, for example anorexia nervosa, or in treating cachexia resulting from cancer, AIDS or Chronic Obstructive Pulmonary Disease (COPD). Ghrelin agonists may also be useful as gastroprokinetic agents which can enhance gastrointestinal motility by increasing the frequency of contractions in the small intestine or making them stronger, but without disrupting their rhythm. Gastroprokinetic agents are used to relieve gastrointestinal symptoms such as abdominal discomfort, bloating, constipation, heart bum, nausea, and vomiting, and are used to treat a number of gastrointestinal disorders, including but not limiting to, irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia. Furthermore, compounds that modulate ghrelin receptor activity might also be used to prevent or treat diseases related to substance abuse, for example, alcohol or drug (e.g., amphétamines, barbiturates, benzodiazépines, cocaïne, methaqualone, and opioids) abuse, which refers to a maladaptive pattern of use of a substance that is not considered dépendent.

A number of compounds acting on the ghrelin receptor hâve been reported in the literature. YIL-781, for example, is a small molécule ghrelin receptor antagonist from Bayer that reportedly improves glucose tolérance, suppresses appetite and promûtes weigh loss (Esler et al., Endocrinology 148 (11):5175-5185); LY444711 is an orally active ghrelin receptor agonist from Lilly that reportedly induces adiposity by stimulating food consumption and sparing fat utilization (Bioorg. & Med. Chem. Lett., 2004, 14, 5873-5876); anamorelin is an orally available ghrelin receptor small molécule agonist from Helsinn Therapeutics that is in clinical trials for the treatment of anorexia and cachexia in cancer patients. Ghrelin receptor agonists and antagonists based on asymmetric ureas are disclosed in US 2012/0220629, which is incorporated herein by reference in its entirety. Other small molécule ghrelin receptor modulators can be found in WO

2008/092681, US 2009/0253673, WO 2008/148853, WO 2008/148856, US 2007/0270473 and

US 2009/0186870.

In view of the above, it is désirable to find new compounds which modulate ghrelin receptor activity.

SUMMARY

The présent invention provides compounds of Formula I:

(R⁸)s

I, with X, Z, R¹-R⁸, r, s, and n as defïned herein, and pharmaceutically acceptable salts thereof. Compounds of Formula I, also referred to herein as asymmetric ureas, are particularly useful for preventing and/or treating diseases that are pathophysiologically related to the ghrelin 10 receptor in a subject. Accordingly, in another embodiment the invention provides a method of treating a disease that is mediated by the ghrelin receptor, comprising administering to said subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable sait thereof.

Also disclosed are pharmaceutical compositions for preventing and/or treating diseases which are pathophysiologically related to ghrelin receptor in a subject, comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable sait thereof, and one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows Highly Palatable Food (HPF) intake in rats at different times after initial 20 access to HPF. The values shown are the mean ± S.E.M. of HPF intake. Statistical différences from controls (non-Restricted + non-Stressed; NR + NS): ** P < 0.01.

Figure 2 showns the effect of Topiramate (60 mg/kg) or vehicle in a rat model of binge eating. The values shown are the mean ± S.E.M. of HPF intake. Différence between R + S (Restricted and Stressed) vehicle and R + S treated rats: *P <0.05; ** P <0.01.

Figure 3 shows the effect of compound H0816 (3 and 30 mg/kg) or vehicle in a rat model of binge eating. The values shown are the mean ± S.E.M. of HPF intake. Différence between R + S vehicle and R + S treated rats: *P <0.05.

Figure 4 shows the effect of compound H0860 (3 and 30 mg/kg) or vehicle in a rat model of binge eating. The values shown are the mean ± S.E.M. of HPF intake. Statistical différence 30 from vehicle-treated rats was not statistically signifîcant.

Figure 5 shows the effect of compound H0847 (3 and 30 mg/kg) or vehicle in a rat model of binge eating. The values shown are the mean ± S.E.M. of HPF intake. Différence between R + S vehicle and R + S treated rats: ** P <0.01; * P <0.05.

Figure 6 shows the effect of compound H0900 (3 and 30 mg/kg) or vehicle in a rat model of binge eating. The values shown are the mean ± S.E.M. of HPF intake. Différence between R + S vehicle and R + S treated rats: ** P <0.01; * P <0.05.

Figure 7 shows the effect of Topiramate, compounds H0816, H0860, H0847H0900 and vehicle on 2 h (A) and 24 h (B) chow food intake during and after a binge eating test. The values shown are the mean ± S.E.M. of HPF intake. Différence between R + S vehicle and R + S treated rats: * P <0.05,** P <0.01.

Figure 8 shows the effect of H0816 (3, 10 and 30 mg/kg) or vehicle in a rat model of binge eating. The values shown are the mean ± S.E.M. of HPF intake. Différence between R + S vehicle and R + S treated rats: *P <0.05; **P <0.05.

Figure 9 shows the effect of compound H0847 on alcohol self-administration in msP rats.

Figure 10 shows the effect of compound H0860 on alcohol self-administration in msP rats.

Figure 11 shows the effect of compound H0816 on alcohol self-administration in msP rats.

Figure 12 shows the effect of compound H0900 on alcohol self-administration in msP rats.

DETADLED DESCRIPTION

Before the présent compounds, compositions, articles, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to spécifie synthetic methods or spécifie treatment methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

In a first principal embodiment, the présent invention provides compounds of Formula I:

(R⁸)s

I, or a pharmaceutically acceptable sait thereof, wherein:

a dashed line indicates an optional bond;

Xis CH or N;

Z is NR⁹, CR¹⁰Rⁿ, or O;

R¹ is H, Ci-6 alkyl, benzyl, OH, or Ci-6 alkoxy, wherein said Ci-6 alkyl, benzyl, or Ci-6 alkoxy is optionally substituted with 1-3 substituents selected from halo, OH, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 hydroxyalkyl, CO(Ci-6 alkyl), CHO, CO2H, CO2(Ci-6 alkyl), and C1-6 haloalkyl;

R² is H or C1-6 alkyl;

R³ and R⁴ are each, independently, H, CN, halo, CHO, or CO2H, or optionally substituted

C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkylcycloalkyl, C1-6 haloalkyl, Ci-6 alkoxy, CO(Ci-6 alkyl), CO₂(Ci-₆ alkyl), or CONR¹²R¹³;

or R³ and R⁴ taken together with the C atom to which they are attached form a 3-6membered ring;

R⁵ is halo, CN, CHO, CO₂H, CO(Ci-₆ alkyl), CO₂(Ci-6 alkyl), NR¹⁴R¹⁵, NHCONR¹⁴R¹⁵,

CONR¹⁴R¹⁵, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said CO(Ci-6 alkyl), CO2(Ci-6 alkyl), NR¹⁴R¹⁵, NHCONRⁱ⁴R¹⁵, CONR¹⁴R¹⁵, Ci-6 alkyl, Ci-₆ alkoxy, Ci-₆ haloalkyl, Ci_₆ hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halo, CN, OH, NO2, Si(CH3)4, CHO, and CO2H, or optionally substituted CO(Ci-₆ alkyl), CO₂(Ci-6 alkyl), NR¹⁴R¹⁵, NHCONR¹⁴R¹⁵, CONR¹⁴R¹⁵, CH=NOH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;

R⁶ is absent or H;

R⁷ is H, CN, or halo;

or two R⁷ can be taken together with the atoms to which they are attached form a 5-6memebered ring;

or R⁵ and R⁷ taken together with the atoms to which they are attached form an optionally substituted 5-6-membered ring;

R⁸ is H or Ci-6 alkyl;

R⁹ is H, Ci-6 alkyl, CO(Ci-₆ alkyl), CHO, CO₂H, or CO₂(C^ alkyl);

R¹⁰ and R¹¹ are each, independently, H, Ci-6 alkyl, or halo;

R¹² and R¹³ are each, independently, H or Ci-ô alkyl;

R¹⁴ and R¹⁵ are each, independently H, Ci-6 alkyl, CO(Ci-6 alkyl), CO(heteroaryl), heteroaryl, or cycloalkyl;

r is 1 or 2;

s is 0-4; and n is 0-3.

In the first principal embodiment, as well as the second and third principal embodiments discussed below, in one subembodiment X is CH.

In the first, second and third principal embodiments, in one subembodiment, X is N.

In the first, second and third principal embodiments, in one subembodiment, Z is NR⁹.

In the first, second and third principal embodiments, in one subembodiment, Z is N(Ci-ô alkyl).

In the first, second and third principal embodiments, in one subembodiment, Z is NCH3.

In the first, second and third principal embodiments, in one subembodiment, Z is CR¹⁰Rⁿ.

In the first, second and third principal embodiments, in one subembodiment, Z is CF₂

In the first, second and third principal embodiments, in one subembodiment, Z is O.

In the first, second and third principal embodiments, in one subembodiment, R¹ is C1-6 alkyl.

In the first, second and third principal embodiments, in one subembodiment, R¹ is CH3.

In the first, second and third principal embodiments, in one subembodiment, R¹ is benzyl.

In the first, second and third principal embodiments, in one subembodiment, said benzyl is optionally substituted with CO2(Ci-6 alkyl) or C1-6 hydroxyalkyl.

In the first, second and third principal embodiments, in one subembodiment, R¹ is OH.

In the first, second and third principal embodiments, in one subembodiment, R¹ is Cm alkoxy.

In the first, second and third principal embodiments, in one subembodiment, said Ci-6 alkoxy is methoxy, ethoxy or propoxy.

In the first, second and third principal embodiments, in one subembodiment, R² is H.

In the first, second and third principal embodiments, in one subembodiment, R³ and R⁴ are each, independently selected from Ci-6 alkyl, CN, Ci-6 alkylcycloalkyl, Ci-6 hydroxyalkyl, CO₂(Ci-₆ alkyl), Ci-₆ haloalkyl and CONH₂,.

In the first, second and third principal embodiments, in one subembodiment, said C1-6 alkyl is methyl or ethyl.

In the first, second and third principal embodiments, in one subembodiment, said C1-6 alkylcycloalkyl is Ci alkylcylopropyl.

In the first, second and third principal embodiments, in one subembodiment, said C1-6 hydroxyalkyl is Ci hydroxyalkyl optionally substituted with a substituted or unsubstituted benzyl group.

In the first, second and third principal embodiments, in one subembodiment, said CO2(Ci6 alkyl) is CO2CH3.

In the first, second and third principal embodiments, in one subembodiment, said C1-6 haloalkyl is CF3.

In the first, second and third principal embodiments, in one subembodiment, R³ and R⁴ taken together with the C atom to which they are attached form a 3-6-membered ring.

In the first, second and third principal embodiments, in one subembodiment, R³ and R⁴are taken together with the C atom to which they are attached to form a cyclopropyl ring.

In the first, second and third principal embodiments, in one subembodiment, R³ and R⁴are taken together with the C atom to which they are attached form a tetrahydropyranyl ring.

In the first, second and third principal embodiments, in one subembodiment, R⁵ is halo,

CN, CHO, CO2H, CO(Ci-₆ alkyl), CO₂(Ci-₆ alkyl), NR¹⁴R¹⁵, NHCONR¹⁴R¹⁵, CONR¹⁴R¹⁵, Ci-₆alkyl, C1-6 alkoxy, C1-6 haloalkyl, Ci-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said CO(Ci-6 alkyl), CO2(Ci-6 alkyl), NR¹⁴R¹⁵, NHCONR¹⁴R¹⁵, CONR¹⁴R¹⁵, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halo, CN, OH, NO2, Si(CH3)4, CHO, and CO2H, or optionally substituted CO(Ci_₆ alkyl), CO₂(Ci-₆ alkyl), NR¹⁴R¹⁵, NHCONR¹⁴R¹⁵, CONR¹⁴R¹⁵, CH=NOH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, Ci-β hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;

In some embodiments R⁵ is not H;

In some embodiments, R⁵ is not alkoxy;

In some embodiments, R⁵ is not methoxy;

In some embodiments, R⁵ is not OH;

In some embodiments, R⁵ is not halo;

In some embodiments, R⁵ is not fluoro;

In some embodiments, R⁵ is not chloro;

In some embodiments, R⁵ is not SO2Me;

In some embodiments, R⁵ is not amino;

In some embodiments, R⁵ is not NHAc;

In some embodiments, R⁵ is not N(Me)2;

In some embodiments, R⁵ is not alkyl;

In some embodiments, R⁵ is not methyl;

In the fïrst, second and third principal embodiments, in one subembodiment, R⁵ is halo;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is CN;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is CHO;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is CO2H;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is CO(Ci6 alkyl);

In the first, second and third principal embodiments, in one subembodiment, R⁵ is CO2(Ci-6 alkyl);

In the first, second and third principal embodiments, in one subembodiment, R⁵ is NR¹⁴R¹⁵;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is NHCONR¹⁴R¹⁵;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is CONR¹⁴R¹⁵;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is Ci-6 alkyl;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is Ci-6 alkoxy;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is Ci-6 haloalkyl;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is Cm hydroxyalkyl;

In the fîrst, second and third principal embodiments, in one subembodiment, R⁵ is C2-6 alkenyl;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is C2-6 alkynyl;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is aryl;

In the fîrst, second and third principal embodiments, in one subembodiment, R⁵ is cycloalkyl;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is heteroaryl;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is heterocycloalkyl;

In the first, second and third principal embodiments, in one subembodiment, R⁵ is Ci_6 haloalkyl, heteroaryl, aryl, halo, C1-6 alkoxy, CC>2(Ci-6 alkyl), C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl,

In the first, second and third principal embodiments, in one subembodiment, said cycloalkyl is cyclopropyl, cyclohexanyl or cyclohexenyl.

In the first, second and third principal embodiments, in one subembodiment, said C1-6 haloalkyl is CHF2.

In the first, second and third principal embodiments, in one subembodiment, said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, triazinyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl or furanyl,

In the first, second and third principal embodiments, in one subembodiment, said aryl is phenyl.

In the first, second and third principal embodiments, in one subembodiment, said halo is Cl orl.

In the first, second and third principal embodiments, in one subembodiment, said Ci-6 alkoxy is methoxy.

In the first, second and third principal embodiments, in one subembodiment, said CO2(Ci6 alkyl) is CO₂Me.

In the first, second and third principal embodiments, in one subembodiment, said C2-6 alkynyl is C2 alkynyl.

In the first, second and third principal embodiments, in one subembodiment, said C2-6 alkenyl is C2 alkenyl.

In the first, second and third principal embodiments, in one subembodiment, R⁶ is absent.

In the first, second and third principal embodiments, in one subembodiment, R⁶ is H.

In the first, second and third principal embodiments, in one subembodiment, R⁷ is halo.

In the first, second and third principal embodiments, in one subembodiment, said halo is Cl or F.

In the first, second and third principal embodiments, in one subembodiment, 2 R⁷ corne together to form a phenyl group.

In the first, second and third principal embodiments, in one subembodiment, R⁵ and R⁷corne together to form a 5-membered heterocyclic ring.

In the first, second and third principal embodiments, in one subembodiment, R⁸ is H.

In the first, second and third principal embodiments, in one subembodiment, R⁸ is C1-6 alkyl.

In the first, second and third principal embodiments, in one subembodiment, R⁸ is methyl.

In the first, second and third principal embodiments, in one subembodiment, R¹⁰ is H;

In the first, second and third principal embodiments, in one subembodiment, R¹⁰ is Ci-6 alkyl;

In the first, second and third principal embodiments, in one subembodiment, R¹⁰ is halo;

In the first, second and third principal embodiments, in one subembodiment, R¹¹ is H;

In the first, second and third principal embodiments, in one subembodiment, R¹¹ is C1-6 alkyl;

In the first, second and third principal embodiments, in one subembodiment, R¹¹ is halo;

In the first, second and third principal embodiments, in one subembodiment, R¹² is H;

In the first, second and third principal embodiments, in one subembodiment, R¹² is Ci-6 alkyl;

In the first, second and third principal embodiments, in one subembodiment, R¹³ is H;

In the first, second and third principal embodiments, in one subembodiment, R¹³ is Ci-6 alkyl;

In the first, second and third principal embodiments, in one subembodiment, R¹⁴ is H;

In the first, second and third principal embodiments, in one subembodiment, R¹⁴ is Ci-6 alkyl;

In the first, second and third principal embodiments, in one subembodiment, R¹⁴ is CO(Ci-₆ alkyl);

In the first, second and third principal embodiments, in one subembodiment, R¹⁴ is CO(heteroaryl);

In the first, second and third principal embodiments, in one subembodiment, R¹⁴ is heteroaryl;

In the first, second and third principal embodiments, in one subembodiment, R¹⁴ is cycloalkyl;

In the first, second and third principal embodiments, in one subembodiment, R¹⁵ is H;

In the first, second and third principal embodiments, in one subembodiment, R¹⁵ is Ci-6 alkyl;

In the first, second and third principal embodiments, in one subembodiment, R¹⁵ is CO(Ci-₆ alkyl);

In the first, second and third principal embodiments, in one subembodiment, R¹⁵ is CO(heteroaryl);

In the first, second and third principal embodiments, in one subembodiment, R¹⁵ is heteroaryl;

In the first, second and third principal embodiments, in one subembodiment, R¹⁵ is cycloalkyl;

In the first, second and third principal embodiments, in one subembodiment, r is 1;

In the first, second and third principal embodiments, in one subembodiment, r is 2;

In the first, second and third principal embodiments, in one subembodiment, s is 0; In the first, second and third principal embodiments, in one subembodiment, s is 1; In the first, second and third principal embodiments, in one subembodiment, s is 2; In the first, second and third principal embodiments, in one subembodiment, s is 3 ; In the first, second and third principal embodiments, in one subembodiment, s is 4; In the first, second and third principal embodiments, in one subembodiment, n is 0; In the first, second and third principal embodiments, in one subembodiment, n is 1; In the first, second and third principal embodiments, in one subembodiment, n is 2; In the first, second and third principal embodiments, in one subembodiment, n is 3

In a second principal embodiment, the compounds hâve the structure of Formula II:

R⁸

Π, or a pharmaceutically acceptable sait thereof.

In a third principal embodiment, the compounds hâve the structure of Formula ΙΠ:

m, or a pharmaceutically acceptable sait thereof.

In fourth and fîfth principal embodiments, the compounds hâve the structure of Formula

Ilia orlllb:

nia Illb, or a pharmaceutically acceptable sait thereof, wherein:

R¹⁶ is H, cyclopropyl or thiazolyl; and

R¹⁷ is H or halo.

In some forms, the compounds as presently disclosed are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein the compound of Formula I is a compound selected from the group consisting of:

Compound No.	Chemical Structure	Chemical Name
H0494	O Me Cl L^'n'^1I'n'^IY^!Y^c' ώ. ^H	3-(1-(2,3 -dichloro-4cyclopropylphenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0621	O Me Cl °^{H H} F	3-(1-(2,3 -dichloro-4- (difluoromethyl)phenyl)ethyl)-l-hydroxy- 1 -( 1 -methylpiperidin-4-yl)urea
H0496	0 Me Cl <Α^Λ·ΑΑ-·^αώβ ^H	3-(1-(2,3 -dichloro-4-(pyridin-3yl)phenyl)ethyl)-l-methyl-l-(lmethylpiperidin-4-yl)urea
H0617	0 Me Cl dAW Me ^H έ	3-(1-(2,3-dichloro-4-(pyridin-3yl)phenyl)ethyl)-l-methyl-l-(lmethylpiperidin-4-yl)urea

H0539	0 Me Cl AAXV MeO₂C^^	methyl 4-((3-( 1 -(2,3-dichloro-4-(pyridin- 3- yl)phenyl)ethyI)-1 -( 1 -methylpiperidin- 4- yl)ureido)methyl)benzoate
H0546	^Me'NU O Me Cl AAW xÿ ^hXXû ho^A> V	3 -( 1 -(2,3-dichloro-4-(pyridin-3 yl)phenyl)ethyl)-1 -(4(hydroxymethyl)ben2yl)-1 -( 1 methylpiperidin-4-yl)urea
H0526	/—i 0 Me Cl “'WAV ». ^H LU IV	3-( 1 -(2,3-dichloro-4-(pyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3-yl)urea
H0527	^:*_Ν-γ-'·”₀ Me C! w-AV¹ Me ^H ΐΧγγ IV	3 -( 1 -(2,3 -dichloro-4-(pyridin-3yl)phenyl)ethyl)-1 -( 1,3 dimethylpiperidin-4-yl)-1 -methylurea
H0497	0 Me Cl Xaw ώθ U	3-(1-(2,3-dichloro-4-(pyridm-4yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0650	’^'N'U 0 Me Cl Xaw Λ H Me N^J	3-(1-(2,3-dichloro-4-(pyridin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0849	^Me'N^> O Me Cl AA-W ώο ^H (U n^-L	3-(1-(2,3 -dichloro-4-(5cyclopropylpyridin-2-yl)phenyl)ethyl)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea
H0578	^Me'N^xU 0 Me M· ^H LU^, U	1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(pyridin-4-yl)naphthalen-1 yl)ethyl)urea

H0511	0 Me Cl ώ. ^h Ή^ΌΜθ	3 -( 1 -(2,3 -dichloro-4-(6-methoxypyridin- 3 -yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0820	^Me'N^/A O Me CI i H Me	3-(1-(2,3 -dichloro-4-(6cyclopropylpyridin-3-yl)phenyl)ethyl)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea
H0613	^M®N'^xx> 0 Me Cl UAW ¹ H Me ⁿ	3-(1-(2,3-dichloro-4-(5-cyanopyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0614	^Me'N^> 0 Me Cl Α_ΝΑ_ΒλΧα Me ^H	3-(1-(2,3-dichloro-4-(5-fluoropyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0635	^Me'N^x^> 0 Me Cl <A_nAn-Mv^ci ¹ H Me A'A^/'^^COzMe	methyl 5-(2,3-dichloro-4-(l-(3-methyl-3( 1 -methylpiperidin-4- yl)ureido)ethyl)phenyl)nicotinate
H0636	Μθ'Ν^·! 0 Me Cl <A_nAnW^ci i ^H Me Ογ-γ^οΗ	3-( 1 -(2,3-dichIoro-4-(5(hydroxymethyl)pyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0637	^Me'N^A O Me Cl ^Ιχ^Ν^χ^Ν^χ1'γ\''⁰¹ F ' h 1 Me ^hF	3-(1-(2,3-dichloro-4-(5(difluoromethyl)pyridin-3 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0638	0 Me Cl <AA\V Λ H Mo Sr	3-(l -(2,3-dichloro-4-(5- (fluoromethyl)pyridin-3-yl)phenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea

H0639	O Me Cl Me ^H ^isr	3-(1-(2,3-dichloro-4-(5-methylpyridin-3yl)phenyl)ethyl)-1 -methyl-1 -(1 methylpiperidin-4-yl)urea
H0642	^MeN^X O Me Cl ' H ^Me	3-(1-(2,3 -dichloro-4-(5-fonnylpyridin-3 yl)phenyl)ethyl)-l -methyl-1 -( 1 metb.ylpiperidin-4-yl)urea
H0704	^ΜθΝ^Χ 0 Me Cl Xn^An+A<^ci ¹ H Me ⁿ ^X^NH₂	3-(l-(4-(5-aminopyridin-3-yl)-2,3dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0705	O Me Cl r—\ Me ^H	3-(1-(2,3-dichloro-4-(5-(cyclopent-l-en- 1 -yl)pyridin-3 -yl)phenyl)ethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0707	^MeNX 0 Me Cl Me ^H υγγζ'^ΝΗ ^hF	3-( 1 -(4-(5-(lH-pyrazol-4-yl)pyridin-3-yl)- 2,3-dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0711	^Me'NX 0 Me Cl N=\ Λ H / NH Me	3-(l-(4-(5-(lH-imidazol-4-yl)pyridin-3yl)-2,3-dichlorophenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0716	Μθ'Ν'Χ 0 Me Cl <^'n^An^Ay⁴V^ci st. M· UyYOⁿ II	3-(1-(2,3-dichloro-4-(5-(thiazol-5yl)pyridin-3-yl)phenyl)ethyl)-l-methyl-l( 1 -methylpiperidin-4-yl)urea
H0717	Μθ'-Χ O Me Cl ΜίΛΛΥ _St ^H ΙΧγΟ	3-(1-(2,3 -dichloro-4-(5-(thiophen-2yl)pyridin-3-yl)phenyl)ethyl)-l-methyl-l( 1 -methylpiperidin-4-yl)urea

H0718	0 Me Cl Ο'ΛνΑΑ-⁰¹ γλ ώ. ^Η UÇAU	3-(1-(2,3-dichloro-4-(5cyclopentylpyridin-3-yl)phenyl)ethyl)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea
H0719	^Me'N^5 Ο Me Cl Μβ ^Η V Αγ^ΐγ-Ν../	3-( 1 -(2,3-dichloro-4-(5-(pyrrolidin-1 yl)pyridin-3-yl)phenyl)ethyl)-l-methyl-l( 1 -methylpiperidin-4-yl)urea
H0712	^Μθ'Ν^Α 0 Me Cl TAAAAa „ ¹ H H Me ΪΎ n IL o N	N-(5-(2,3-dichloro-4-(l -(3-methyI-3-( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)pyridin-3yl)acetamide
H0708	^MeN^5 0 Me Cl M-._nA_nAJ_vci Λ H M· Sr	3-(1-(2,3-dichloro-4-(5(methoxymethyl)pyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0714	^Me'N^A O Me Cl aa\v ¹ H Me ^IM	3-(1-(2,3-dichloro-4-(5-(2- methoxyethyl)pyridin-3-yl)phenyl)ethyl)- 1 -methyl-1 -(1 -methylpiperidin-4-yl)urea
H0715	^M®'N'^X^\| 0 Me Cl '-ΑΑ,αα^ Me ^H ^hr	3 -( 1 -(2,3 -dichloro-4-(5 -ethy lpyridin-3 yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0706	^Me'N'^XXsi 0 Me Cl -ArA^aώ= ^H	3-(1-(2,3-dichloro-4-(5-vinylpyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0710	^Me'N^5 O Me Cl Java Me ^H	3-(1-(2,3 -dichloro-4-(5-ethynylpyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0666	O CN Cl Me ^H	3-(cyano(2,3-dichloro-4-(5-cyanopyridin- 3-yl)phenyl)methyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0739	^M®'N‘^xx> 0 CN Cl HN-T\ Μθ ^H	3-((4-(5-(1 H-pyrrol-2-yl)pyridin-3 -y 1)- 2,3-dichlorophenyl)(cyano)methyl)-l- methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0667	^MeN^^xi 0 Me Cl '•UV'N^ÀY_Y ^CI ¹ H OH k^k^JON	3-( 1 -(2,3-dichloro-4-(5-cyanopyridin-3yl)phenyl)ethyl)-1 -hydroxy-1 -( 1 methylpiperidin-4-yl)urea
H0821	^Μθ'ΝΥ O Me Cl Άλ-ΑυΥ' H Me ^π	3-( 1 -(2,3-dichloro-4-(5-cyano-6-(4methylpiperazin-1 -yl)pyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0646	^Me'N'^> O Me Cl Ο'ΛνΑΑτ⁰¹ _n-^oh ^H LApA	(E)-3 -( 1 -(2,3 -dichloro-4-(5((hydroxyimmo)methyl)pyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0720	^M®N^b 0 (CI ύ. ^H UL^	3 -(2-cyclopropyl-1 -(2,3 -dichloro-4(pyridin-3-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0721	0 (CI ΦΑν i H Me ⁿ	3 -( 1 -(4-(5-aminopyridin-3-yl)-2,3 dichlorophenyl)-2-cyclopropylethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea

H0516	0 Me CI XAAV¹ - ^H Up V	3-( 1 -(2,3-dichloro-4-(pyrimidin-5yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0579	^Me'N'^xx> 0 Me XX lX.A'W - ^H VL-n V	1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(pyrimidin-5-yl)naphthalen-1 yl)ethyl)urea
H0649	^ΜβΝ^χχι O Me Cl ÜAW i H Me f/oMO	3-(1-(2,3 -dichloro-4-(2methoxypyrimidin-5 -yl)phenyl) ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0797	Μθ'Ν'^'Α 0 Me Cl LAAArV' ' H Me -Ap. Άόη	3-(1-(2,3-dichloro-4-(2hydroxypyrimidin-5-yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0798	^MeN^xx> 0 Me Cl W^AA⁰ i H M= l A N NH_Z	3-( 1 -(4-(2-aminopyrimidin-5-yl)-2,3dichlorophenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0799	^M®'N^xA O Me Cl ^ιΑνΑΑ/ - ^H Up ^Π'Μβ	3-(1-(2,3-dichloro-4-(2-(4methylpiperazin-1 -yl)pyrimidin-5 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0800	^MeN^X 0 Me Cl UAW -^H tx_rN LAf	3-(1-(2,3 -dichloro-4-(2-fluoropyrimidin5-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0801	^M®A^A 0 Me Cl ώβ H IX_Cn LAci	3 -( 1 -(2,3 -dichloro-4-(2-chloropyrimidin5-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0802	^ΜβΝ^> 0 Me Cl χΑ',ΛΛ³' H Me	3-( 1 -(2,3 -dichloro-4-(2-cyanopyrimidin5-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0803	O Me Cl UAW Λ ^H Μθ Vy,,	3-( 1 -(4-(2-( 1 H-imidazol-1 -yl)pyrimidin- 5-yl)-2,3-dichlorophenyl)ethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0804	^Me'N^/A 0 Me Cl CAAAAa i H Me ^nA-^m’ Me	3-(1-(2,3 -dichloro-4-(2(dimethylamino)pyrimidin-5yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0805	^MeN~% O Me Cl <V_Nw ώ. ΙΧ^_Ν Ià A N N H	3-( 1 -(2,3-dichloro-4-(2(cyclopropylatnino)pyrimidin-5yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0806	^Me'N^x^A O Me Cl UAW - ^H Ά_ΓΓ^Μβ H	3-(1-(2,3 -dichloro-4-(2(methylamino)pyrimidin-5 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0807	^Μθ'Ν^/Α O Me Cl GVAV - UL· ₀	N-(5-(2,3-dichloro-4-( 1 -(3-methyl-3 -( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)pyrimidin-2yl)cyclopropanecarboxamide
H0854	^Me'N^> O Me Cl üaw lie ^H LA^_n ^N^V	3-(1-(2,3-dichloro-4-(2- cyclopropylpyrimidin-5-yl)phenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea

H0813	^ΜθΝ^χ^Ί 0 Me Cl ό H	3 -( 1 -(2,3-dichloro-4-(2-(pyrrolidin-1 yl)pyrimidin-5-yl)phenyl)ethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0814	^Μβ'Ν'^ΛΝ O Me Cl ό H Me	3-(1-(2,3-dichloro-4-(2-(4-ethyl-3oxopiperazin-1 -yl)pyrimidin-5 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0703	Μθ'Ν'^ι 0 Me CN Çl <^ν^ΛνΑΑτ⁰¹Λ H Me N	3-( 1 -cyano-1-(2,3 -dichloro-4-(pyrimidin5-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0709	Μθ'Ν^Ί 0 CN Cl AïA-W¹ah \|I1 'Me ί ') N	3-(cyano(2,3-dichloro-4-(pyrimidin-5yl)phenyl)methyl)-1 -methoxy-1 -( 1 methylpiperidin-4-yl)urea
H0584	r^> 0 Me Cl ΑΑΛνΑΑα¹ ό H Μθ W-γ^Ν IL N	1 -cyclohexyl-3 -( 1 -(2,3 -dichloro-4(pyrimidin-5-yl)phenyl)ethyl)-1 methylurea
H0586	0 Me Cl u/au, ¹ H Me ^H N	3 -( 1 -(2,3 -dichloro-4-(pyrimidin-5yl)phenyl)ethyl)-1 -methyl-1 -(tetrahydro2H-pyran-4-yl)urea
H0587	F-V^> O Me Cl laAn'W¹ - ^H VÇ-N M	3-(1-(2,3-dichloro-4-(pyrimidin-5yl)phenyl)ethyl)-1 -(4,4difluorocyclohexyl)-! -methylurea

H0588	0 0 Me Cl - ^H UÇ-n V	1 -( 1 -acetylpiperidin-4-yl)-3-( 1 -(2,3 dichloro-4-(pyrimidin-5-yl)phenyl)ethyl)1-methylurea
H0663	0 Me Cl xkJ^CI OMe Λ H I Me U<A_n l A N OMe	3-(1-(2,3-dichloro-4-(2,4dimethoxypyrimidin-5-yl)phenyl)ethyl)1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0620	A ^Me'N^! o _r° Cl ^0H Al_nAnAA^c' Me ^H 1J N	3 -( 1 -(2,3-dichloro-4-(pyrimidin-5yl)phenyl)-2-((3(hydroxymethyl)benzyl)oxy)ethyl)-1 methyl-1 -(1 -methylpiperidin-4-yl)urea
H0624	^MeN'^XX> 0 Me Cl ΑΑΑΛλ ÔH H IX^_NU	3-(1-(2,3 -dichloro-4-(pyrimidin-5yl)phenyl)ethyl)-1 -hydroxy-1 -( 1 methylpiperidin-4-yl)urea
H0662	Me^,^\ „ 0^ OMe O.A i H Me l J N	methyl 2-(2,3 -dichloro-4-(pyrimidin-5yl)pheny 1)-2-(3 -methyl-3 -( 1 methylpiperidin-4-yl)ureido)acetate
H0670	“•sr'·, o _r ^0H _cl AaAA· - ^H LU V	3-(1-(2,3 -dichloro-4-(pyrimidin-5yl)phenyl)-2-hydroxyethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0673	^MeO î v ? i H Me UV,_N l 'J N	3-(1-(2,3-dichloro-4-(pyrimidin-5yl)phenyl)cyclopropyl)-1 -methyl-1 -( 1 methylpiperidm-4-yl)urea

H0727	^Me'N^, 0 A _C\| QaXv¹ - ^H Up l J N	3-(4-(2,3-dichloro-4-(pyrimidin-5yl)phenyl)tetrahydro-2H-pyran-4-yl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0631	^MeN'^xU 0 CN Cl AAW - ^H U	3-(cyano(2,3-dichloro-4-(pyrimidin-5yl)phenyl)methyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0686	^Me'N^> 0 CF₃ Cl LAAW ' H N	3-(l -(2,3-dichloro-4-(pyrimidin-5- yl)phenyl)-2,2,2-trifluoroethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0619	^Me'N'^xU 0 Me Cl LAAAArci Me ^HaO	3-(1-(2,3 -dichloro-4-(pyrimidin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0768	^MeN'^X% 0 Me Cl A/nVy” Me ^H T \|	3-(1-(2,3 -dichloro-4-(pyrimidm-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0808	^Me'N^U O Me Cl Me ^H *1 Me	3- (1-(2,3 -dichloro-4-(6-methylpyrimidin- 4- yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0700	^M®'N^ 0 Me Cl U/AV Me ^H HQ N	3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0816	^Me'N^A 0 Me Cl ^Î^A'^I’A/^CI Me ^H LÂa O N	(S)-3-(l-(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0817	^Me'N^A O Me Cl tAl-yV Me ^H KaL-N. U N	(R)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -(1 methylpiperidin-4-yl)urea
H0722	AA 0 ( Cl Μθ ^H N	3-(2-cyclopropyl-1 -(2,3 -dichloro-4(pyrazin-2-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0741	^M®N^xA 0 ζDI ΑΛΆ¹ ¹ H OMe ^π O N	3 -(2-cyclopropyl-1-(2,3 -dichloro-4(pyrazin-2-yl)phenyl) ethyl)-1 -methoxy-1 ( 1 -methylpiperidin-4-yl)urea
H0752	^MeN^A 0 {DI AAW OEt ^H L T ' . . O N	3 -(2-cyclopropyl-1 -(2,3-dichloro-4(pyrazin-2-yl)phenyl)ethyl)-l -ethoxy-1 ( 1 -methylpiperidin-4-yl)urea
H0743	Μθ'Ν'Ά ^{0 Me cl} At-a ¹ H °Me O N	3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methoxy-1 -( 1 methylpiperidin-4-yl)urea
H0750	O Me Cl <^n^XnAy^ci OEt ^H L T .^.N. O N	3-( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-l -ethoxy-1 -( 1 methylpiperidin-4-yl)urea
H0756	^M®N^A O Me Cl ^AW^CI oh ^H O N	3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -hydroxy-1 -( 1 methylpiperidin-4-yI)urea

H0761	0 Λ OH ^H ULn_xO N	3-(2-cyclopropyl-1 -(2,3 -dichloro-4(pyrazin-2-yl)phenyl)ethyl)-1 -hydroxy-1 ( 1 -methylpiperidin-4-yl)urea
H0781	^Me'Np 0 (CI OH ^H ^(S'^R) Il N	3-(2-cyclopropyl-1 -(2,3 -dichloro-4(pyrazin-2-yl)phenyl)ethyl)-1 -hydroxy-1 ( 1 -methylpiperidin-4-yl)urea (single enantiomer)
H0782	^MeN'P 0 ( Cl OH ^H ^(S,R) iî î N	3-(2-cyclopropyl-1 -(2,3 -dichloro-4(pyrazin-2-yl)phenyl)ethyl)-1 -hydroxy-1 ( 1 -methylpiperidin-4-yl)urea (single enantiomer)
H0824	^Me'_NA U	Λθ ^χΜθΟ Me Cl Me ^H O N	3-( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -((R)-1,3,3trimethylpiperidin-4-yl)urea
H0890	“'-N''-'· U	/le.. ^χΜθΟ Me Cl Me ^H IÔAn. U N	3-((S)-l-(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -((R)-l ,3,3trimethylpiperidin-4-yl)urea
H0858	“'-N''''· U	p% _r% ^Ln^XnW^ci Me ^H U N	3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -methyl-1 -((R)-1,3,3trimethylpiperidin-4-yl)urea
H0865	Μθ._Νρΐ^Μθο cf₃ Cl pp Me ^H N U N	3 -( 1 -(2,3-dichloro-4-(pyrazin-2- yl)phenyl)-2,2,2-trifluoroethyl)-l-methyll-((R)-l,3,3-trimethylpiperidin-4-yl)urea

H0825	^Μθ'Ν^ 0 Me Cl <AAAA^CIo A3	1 -benzyl-3 -( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -( 1 -methylpiperidin-4yl)urea
H0826	0 Me Cl A^ÀAV A N	3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -ethyl-1 -( 1 methylpiperidin-4-yl)urea
H0889	^MeN^> 0 Me Cl a N	(S)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -ethyl-1 -( 1methylpiperidin-4-yl)urea
H0896	0 A A ^H 1¾ N	3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -ethyl-1 -( 1 methylpiperidin-4-yl)urea
H0827	Μθ'Ν^Α 0 Me Cl Oaaaa !> IXn Me M N	3-( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -( 1 -methylpiperidin-4yl)-l-propylurea
H0829	^Me'N^ O^M% Cl ^ALV¹ Me ^H LL/A U N	3-( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0859	^Μβ'Ν^\| θ'⁹'. Cl UAW Me ^H AA^A U N	(R)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer)
H0860	““'Ν'·, <FS C! AMA° 1 H Me ⁿ U N	(S)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)propyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer)

H0922	“''u-y ί?·°γ°₀₁ Me ^H O N	methyl 2-(2,3 -dichloro-4-(pyrazin-2yl)pheny 1)-2-(3 -methyl-3 -( 1 methylpiperidin-4-yl)ureido)acetate
H0924	^Me'N^. Ο^Η0Ί C! LAnAhÀUyCi Me ^H U N	3 -( 1 -(2,3 -dichloro-4-(pyrazm-2yl)phenyl)-2-hydroxyethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0830	0 CF₃ Cl ^^An\V Me ^H U N	3-( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0899	^ΜθΝ^> 0 CF₃ Cl Me ^H U N	(S)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0900	^Μ®'Ν^χΧΧ> 0 CF₃ Cl U/AA' Me ^H l j N	(R)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0909	^MeN^A O CF₃ Cl Ο,ΑΑΑΑ N	3-( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-1 -ethyl-1 ( 1 -methylpiperidin-4-yl)urea
H0856	^Μθ'Ν^> O Me F Me ^H U N	3-(l-(3-chloro-2-fluoro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0837	Me Ν-η 0 Me Cl ÛAW Me ^H O N	3-((S)-1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3 -yl)urea (diasteromeric mixture)

H0861	Me ,^N-1 0 Me Cl i H Me (R/S) Ύ Ί N	3 -((S)-1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3-yl)urea (single diastereoisomer)
H0862	Me ,^N—1 0 Me Cl Me ^H ^(RZS) T J N	3 -((S)-1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3 -y l)urea (single diastereoisomer)
H0857	Me 'Νη O^M®> Cl ^VA-ci i H Me ^π O N	3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpyrrolidin-3-yl)urea
H0871	Me N-x 0 CF₃ Cl <A^_n^c, i H Me ⁿ U N	3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-l-methyl- 1 -( 1 -methylpyrrolidin-3-yl)urea
H0874	Me N-η O < Cl 1 H Me ^{π L}C_ÿÿk/N N	3-(2-cyclopropyl-l-(2,3-dichloro-4(pyrazin-2-yl)phenyl)ethyl)-l -methyl-1 ( 1 -methylpyrrolidin-3-yl)urea
H0853	^Me'N^I 0 Me Cl Me ^H i: N	N-( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-2-(4-methylpiperazin-1 yl)propanamide
H0815	^ΜθΝ^> 0 Me Cl Me ^H Me II N	3-( 1 -(2,3 -dichloro-4-(6-methylpyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0831	O Me Cl ΆΑ-Μγ⁰¹Me ^H Oü Me^N	3-(1-(2,3 -dichloro-4-(3 -methylpyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0843	Μθ·. N O Me Cl <.a_na_N'Mv^ci Me ^H KUL.N Me^N	3 -( 1 -(2,3-dichloro-4-(3 -methylpyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -((R)-1,3,3trimethylpiperidin-4-yl)urea
H0844	O / Cl U^An-Mv⁰¹ Me ^H UÀyN. Me^rr	3-(2-cycIopropyl-1 -(2,3 -dichloro-4-(3methylpyrazin-2-yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0738	“θ'Ν'Α 0 Me Cl LAVA⁰ Me H ü N. .OMe N	3-(1-(2,3 -dichloro-4-(6-methoxypyrazin- 2-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0780	^Me'N^A O Me Cl UA\Ÿ Me ^H CxX .ΙΨ^,ΝΗ, N	3-(l -(4-(6-aminopyrazin-2-yl)-2,3 dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0786	^MeN^A 0 Me Cl ^ΑΛΛΑγ⁰¹ lie ^H lÂAp	3-( 1 -(2,3-dichIoro-4-(6- (chloromethyl)pyrazin-2-yl)phenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0791	’^θ'Ν'^ι O Me Cl ^n^n^zMy^ci i H Me IT N	3-(1-(2,3-dichloro-4-(6-chloropyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0795	^Me'N^> O Me Cl Me ^H V	3-(1-(2,3 -dichloro-4-(6-fluoropyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0847	0 Me Cl dAM/' ¹ H Me F	(S)-3 -( 1 -(2,3-dichloro-4-(6-fluoropyrazin2-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0848	O Me Cl i H Me ⁿ F V	(R)-3 -( 1 -(2,3-dichloro-4-(6fluoropyrazin-2-yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0863	^M®'N^A O Et Cl i H Μθ k^k/î'k/F AT N	3-(1-(2,3 -dichloro-4-(6-fluoropyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpiperidin-4-yI)urea
H0908	^Ms'n''A O CF₃ Cl Me ^H .F AT N	3-( 1 -(2,3 -dichloro-4-(6-fluoropyrazin-2yl)phenyI)-2,2,2-trifluoroethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0864	Me \ N-, 0 Et Cl U/xb Me ^H A^\/N^.F IT N	3 -( 1 -(2,3 -dichloro-4-(6-fluoropyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpyrrolidin-3 -yl)urea
H0872	Me N-n O Me Cl ÛAW i H Me k-<Æ/N^/F AT N	3-((S)-l-(2,3-dichloro-4-(6-fluoropyrazin- 2-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3 -yl)urea
H0840	^MeN^A 0 Me Cl UAW Me ^H IT F N	3-(1-(2,3 -dichloro-4-(3 -fluoropyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0910	^MeN^A O Me Cl ΑΛΑγ⁰¹ Me ^Π U\z^N^zCF₃ II N	3-( 1 -(2,3 -dichloro-4-(6(trifluoromethyl)pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0788	O Me Cl W-AV i H Me ^π ^^k^N^CN IT N	3 -( 1 -(2,3 -dichloro-4-(6-cyanopyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0789	^MeN^A 0 Me Cl ^n^n\V^ci 0 Μθ ^H AA/^NAA j\| y OMe	methyl 6-(2,3-dichloro-4-( 1 -(3-methyl-3( 1 -methylpiperidin-4- yl)ureido)ethyl)phenyl)pyrazine-2carboxylate
H0760	^Μθ'Ν^ O Me Cl ^A^A^Ay⁰¹ Me ^H O	5-(2,3 -dichloro-4-( 1 -(3-methyl-3 -( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)pyrazine-2carboxamide
H0769	^MeN^% 0 Me Cl Me ^H AA^y Μγ^0Μβ 0	methyl 5-(2,3 -dichloro-4-( 1 -(3 -methyl-3 ( 1 -methylpiperidin-4- yl)ureido)ethyl)phenyl)pyrazine-2carboxylate
H0771	^'N^i O Me Cl ^N^CI 1 H Me ⁿ k^kyN ΙζΧ^ΝΜ., O	5-(2,3-dichloro-4-( 1 -(3-methyl-3-( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)-N,Ndimethylpyrazine-2-carboxamide
H0770	^MeN^/^\| O Me Cl Φαα« Me ^H AA/^N\ ^XOH	3-(1-(2,3 -dichloro-4-(5(hydroxymethyl)pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0828	O Me Cl UAÎV _ώ. H	3-(1-(2,3 -dichloro-4-(quinoxalin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0822	^Μθ'Ν^> 0 Me Cl TFA Me ^H —N'Me	3-(1 -(2,3 -dichloro-4-(5-(4methylpiperazin-1 -yl)pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0850	0 Me Me ^H N	1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(pyrazin-2-yl)naphthalen-l yl)ethyl)urea
H0881	^MeN^A 0 Me Cl TAUvU Me ^H 1 O N	3-( 1 -(4,5-dichloro-6-(pyrazin-2yl)pyridin-3-yl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0729	^MeN^> 0 Me Cl Me ^H '·ί/'.ζ-^Ν;_Ν	3-( 1 -(2,3-dichloro-4-(pyridazin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0783	^MeN^A 0 Me Cl <AAW ώ. ^H UL^,	3-(1-(2,3 -dichloro-4-(pyridazin-4yl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea
H0793	O Me Cl A^ah\V Me ^H Ύ 'f t'W	3-( 1 -(2,3 -dichloro-4-( 1,2,4-triazin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0796	^Μθ'Ν^χΑ O Me Cl ^N^N^VV^CI A^O i H 1 I ^Me T T ΝγΝ 0	3-( 1 -(2,3-dichloro-4-(4,6-dimorpholino- 1,3,5-triazin-2-yl)phenyl)ethyl)-l -methyl- 1 -( 1 -methylpiperidin-4-yl)urea

H0498	^Me'N'^xU O Me Cl UVyV Me ^H UL·	3-(1-(2,3-dichloro-4-(thiophen-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0531	C-1 O Me Cl “'νΆΑϋ ^H LU ^-s	3-(1-(2,3 -dichloro-4-(thiophen-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3 -yl)urea
H0594	O _r°C! ™ A/AV ώθ ^H UL·	3-( 1 -(2,3 -dichloro-4-(thiophen-3 yl)phenyl)-2-((3(hydroxymethyl)benzyl)oxy)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0644	0 CN Cl UAU/¹ Me ^-s⁷	3-(cyano(2,3-dichloro-4-(thiophen-3yl)phenyl)methyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0536	^Μβ'Ν·^\| O Me Cl <ΛΑ_ν^ο, Me ^H UL· S-#	3-(1-(2,3 -dichloro-4-(thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0563	^Me'N'^xU O Me Cl LVAM Me ^H UU R/S T > S—y	3-(1-(2,3 -dichloro-4-(thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer)
H0564	^Me'N^xU ° ^{Me cl} i ^HMe R/S V z> SY	3-(1-(2,3 -dichloro-4-(thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -(1 methylpiperidin-4-yl)urea (single enantiomer)

H0627	^Me'N'^xA 0 Me Cl UZAV OH ^H UL·	3-(1-(2,3 -dichloro-4-(thiophen-2yl)phenyl)ethyl)-1 -hydroxy-1 -( 1 methylpiperidin-4-yl)urea
H0660	Me_x_ Ck OMe cvXV ώθ ^H UA s~#	methyl 2-(2,3 -dichloro-4-(thiophen-2yl)pheny 1)-2-(3 -methyl-3 -( 1 methylpiperidin-4-yl)ureido)acetate
H0661	''«-N-·, 0 _r°^H _c\| ΑΛγ ώ. ^H UL· S-y	3-(1-(2,3-dichloro-4-(thiophen-2yl)phenyl)-2-hydroxyethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0672	^Me'N^, 0 „ _C\| UA5ZA Λ H Me	3-( 1 -(2,3-dichloro-4-(thiophen-2yl)phenyl)cyclopropyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0651	^MeA^A O Me Cl ÜAW “< ^H UL· ^s \ CHO	3-( 1 -(2,3-dichloro-4-(5-formylthiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0653	^Me'N^\| O Me Cl UAW ώθ ^H UL ^s \ '—OH	3-(l-(2,3-dichloro-4-(5(hydroxymethyl)thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0668	^'N^A O Me Cl M· ” UL· ^s \ '—F	3-(1-(2,3-dichloro-4-(5(fluoromethyl)thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0654	^Me'N'^xA O Me Cl k-AAAAr-⁰¹ώ. ^H IA ^s \ f^^F	3-( 1 -(2,3-dichloro-4-(5(difluoromethyl)thiophen-2yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0655	0 Me Cl AAAnAAa¹ώ. ^Η ^s \ X-Me 0	3-( 1 -(4-(5-acetylthiophen-2-yl)-2,3dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0691	O Me Cl Λθ ^H UL· ^s \ X-nh₂0	5-(2,3-dichloro-4-(l-(3-methyl-3-(lmethylpiperidin-4- yl)ureido)ethyl)phenyl)thiophene-2carboxamide
H0728	^Μθ'Ν^> O / Cl M-n^Xn-Vv^ci Me ^H ^S \ >~νη₂O	5-(2,3-dichloro-4-(2-cyclopropyl-l-(3methyl-3 -( 1 -methylpiperidin-4yl)ureido)ethyl)phenyl)thiophene-2carboxamide
H0726	^Me'N^ O Me Cl UA\V ώ. ^H UUv ^s \ y~ NMe₂0	5-(2,3-dichloro-4-( l-(3-methyl-3-( 1 - methylpiperidin-4yl)ureido)ethyl)phenyl)-N,Ndimethylthiophene-2-carboxamide
H0689	^Me'N^x^> 0 Me Cl AAW ώ. ^H ^s \ koH O	5-(2,3-dichloro-4-( 1 -(3-methyl-3-(l - methylpiperidin-4- yl)ureido)ethyl)phenyl)thiophene-2carboxylic acid
H0692	^Μθ'Ν'Α O Me Cl ώ. ^H UL· S-γ \ _zOMe N ⁰ Me	5-(2,3-dichloro-4-( 1 -(3-methyl-3-( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)-N-methoxy-NmethyIthiophene-2-carboxamide

H0656	^MeNA O Me Cl UAW ώο ^H UL· ^s \ 2—OH Me	3 -( 1 -(2,3-dichloro-4-(5-( 1 hydroxyethyl)thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0652	Μθ'Ν'Ά O Me Cl UAW¹ώ. ^h LL·. ^s \ CHO	3-( 1 -(2,3-dichloro-4-(5-formylthiophen-2yl)phenyl)ethyl)-1 -methyl-1 -(1 methylpiperidin-4-yl)urea
H0713	^MeNA O Me Cl Α'_ΝΑ_ΝΑγΧ,ει ώ_β ^H LU ^s \ CN	3-( 1 -(2,3-dichloro-4-(5-cyanothiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0688	AU 0 Me Cl A^AAV t ώ. ^H UyC	3-(l-(4-(3-acetylthiophen-2-yl)-2,3dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0774	^Me'NA O Me Cl UAW °_K ώ. ^H M' A'™²	2-(2,3-dichloro-4-( 1 -(3-methyl-3 -( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)thiophene-3carboxamide
H0664	^Me'N^xU O Me Cl '^x^N^N''\i^X^'^xCI <^0Hώβ ^H UyC	3-( 1 -(2,3-dichloro-4-(3(hydroxymethyl)thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0535	^MeN^A ° Me ^Cl ώ_β ^H HN~<7	3 -( 1 -(2,3-dichloro-4-( 1 H-pyrrol-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0499	^MeNA O Me Cl UAW Me ^H Αλ- Τ N Ah	3-( 1 -(2,3 -dichloro-4-( 1 H-pyrazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0693	^Me'N^A 0 Me Cl λ. ^HY N N^O	3-(1-(2,3 -dichloro-4-( 1 -(2-hydroxyethyl)- 1 H-pyrazol-4-yl)phenyl)ethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0694	^Μθ'Ν^Α 0 Me Cl Φ,Μζ» 1 ^HMe Y N N__^OMe	3-( 1 -(2,3 -dichloro-4-( 1 -(2-methoxyethyl)- 1 H-pyrazol-4-yl)phenyl)ethyl)-l -methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0657	0 CN Cl aaw ι H Me Ï.N ^NH	3-(cyano(2,3-dichloro-4-(lH-pyrazol-4yl)phenyl)methyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0553	^Μθ'Ν·^Α O Me Cl iaAnAV⁰¹îY ^hXXo	3-(1-(2,3 -dichloro-4-( 1 H-pyrazol-4yl)phenyl)ethyl)-1 -(4(hydroxymethyl)benzyl)-1 -( 1 methylpiperidin-4-yl)urea
H0842	^MeN^A O Me Cl <àaâaa M· ^H UL·. Y. b	3-(1-(2,3 -dichloro-4-( 1 -cyclopropyl-1 Hpyrazol-4-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0542	“θ'Ν'Α 0 Me Cl Me ^H YyY-N ^NH	3 -( 1 -(2,3 -dichloro-4-( 1 H-imidazol-4yl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea
H0568	^Me'N^ 0 Me Cl AAW i H II 1 Me V>	3-( 1 -(2,3 -dichloro-4-(thiazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidm-4-yl)urea
H0794	^MeN^> O Me Cl UAW ¹ H Me [f -y-NHa ’Ύ	3-(l-(4-(2-aminothiazol-4-yl)-2,3dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0841	^Me'N^> 0 Me Cl LAAI/V* ώθ ^H ULn . ^-s	3-( 1 -(2,3 -dichloro-4-(2cyclopropylthiazol-4-yl)phenyI)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0792	^Me'N^ O Me Cl Me H Ύ ^^NH2 '-N	3 -( 1 -(4-(2-aminothiazol-5-yl)-2,3 dichlorophenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0569	^Me'N^ 0 Me Cl <AAW ¹ H Μθ	3-(1-(2,3 -dichloro-4-(oxazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0565	^Me'N^ O Me Cl A%A_NÂyVci ώθ ^H ^/^N	3-(1-(2,3-dichloro-4-(lH-l, 2,3-triazol-lyl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yI)urea
H0604	^Μ®'νΎ O Me Cl LAjA-MvC! “·^H T NH N=n	3-( 1 -(2,3 -dichloro-4-( 1 H-1,2,3-triazol-4yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0595	^Me'N^> O Me Cl ΆΛΑΑ/“ Me ^H I,,0 N n-_n	3-( 1 -(2,3 -dichloro-4-( 1,3,4-oxadiazol-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0596	^Μ®νΎ 0 Me Cl U/AV Me ΎίΑ,Ο « ?N Me	3-(1-(2,3 -dichloro-4-(3-methyl-1,2,4oxadiazol-5 -yl)phenyl) ethyl) -1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0851	^MeN^Y O Me Cl UAW ¹ H Me U .N	3 -( 1 -(2,3 -dichloro-4-(3 -cyclopropyl- 1,2,4-oxadiazol-5-yl)phenyl)ethyl)-l methyl-1 -( 1 -methylpiperidin-4-yl)urea

H0537	^Μ6'Ν·^Α Ο Me Cl MecyA^ ^νη	methyl 4-((3 -( 1-(2,3 -dichloro-4-( 1Hpyrazol-4-yl)phenyl)ethyl)-1 -( 1 methylpiperidin-4yl)ureido)methyl)benzoate
H0529	/~~-ι 0 Me CI Me-N 1 χ Τ Γ ci lie ^H UL· Y N ^-NH	3 -( 1 -(2,3 -dichloro-4-( 1 H-pyrazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3 -yl)urea
H0528	‘‘-/'-“'o Me Cl LAAAXy' ώθ ^H UL. T N ^NH	3-( 1 -(2,3 -dichloro-4-( 1 H-pyrazol-4yl)phenyl)ethyl)-1-(1,3dimethylpiperidin-4-yl)-1 -methylurea
H0501	^Μβ'Ν·^> 0 Me Cl lAa-Ça⁰¹ Me ^H LA Y N ^~N Me	3-(1-(2,3 -dichloro-4-( 1 -methyl-1Hpyrazol-4-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0507	^ΜβχΝ'^\| 0 Me Cl ^nA^A lie ^H ζΑ ^o	3-(1-(2,3 -dichloro-4-(furan-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0665	^Me'N^> O Me Cl υυ,ΛΛζ «ie ^H IA ° \ Me	3-(1-(2,3-dichloro-4-(5-methylfuran-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0508	^Me'N'~A O Me Cl aaâv lie ^H IA ^ΑΑ_Ομ_θ	3 -( 1 -(2,3 -dichloro-4'-methoxy- [ 1, Γbiphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0509	’^θ'Ν'Α O Me Cl AAA M· ^H UA	3- (1-(2,3 -dichloro-[l, 1 '-biphenyl]-4yl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea

H0510	^Me'N'^x^j 0 Me Cl V-nLAV⁰Me ^H	3-( 1 -(3 '-amino-2,3 -dichloro-[ 1,1'biphenyl]-4-yl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0606	^Me'N^ 0 Me Cl AAAV¹ Me ^H \^Α\/^χΟΜβ	3-( 1 -(2,3 -dichloro-3'-methoxy-[ 1,1'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0810	^ΜθΝ^Α O Me Cl LAnAn-Mv⁰¹ώθ ULy	3-(1-(2,3 -dichloro-3 '-fluoro-[ 1,1'biphenyl]-4-yl)ethyI)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0696	O Me Cl - « ΐΑρρ,π F	3- (1-(2,3 -dichloro-3 '-fluoro-5'(hydroxymethyl)-[l, 1 '-biphenyl]-4yl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea
H0611	^Me'NA 0 Me Cl ¹ H Me <^yk^^,OMe OMe	3-(1-(2,3 -dichloro-3 ',5'-dimethoxy-[ 1,1'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0612	^MeN'^> O Me Cl <A_NA_NAAyi ¹ H Me	2',3 '-dichloro-4'-( 1 -(3 -methyl-3-( 1 methylpiperidin-4-yl)ureido)ethyl)-[ 1,1'biphenyl]-3-carboxamide
H0615	^Me'N^x^ 0 Me Cl ΟΆνΑΑα¹ώβ ^H Uy^ ^^CONHa	2', 3 '-dichloro-4'-( 1 -(3 -methyl-3 -( 1 methylpiperidin-4-yl)ureido)ethyl)-[l,l'biphenyl]-4-carboxamide

H0809	^Μ®'νΧ Ο Me Cl «θ^H UL· X_CN	3 -( 1 -(2,3-dichloro-4'-cyano-[ 1,1 'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0699	0 Me Cl UAW Λ H Μθ	3-(1-(2,3-dichloro-4-(5- (cyanomethyl)pyridin-3-yl)phenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0607	^M®'nX 0 Me Cl <AA\V' ¹ H Me	3-( 1 -(2,3-dichloro-4-(5-methoxypyridin- 3 -y l)phenyl) ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0695	^Μ®'νΧ O Me Cl Me H \^\/γ^ΒΓ	3-( 1 -(4-(5-bromopyridin-3-yl)-2,3dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yI)urea
H0635	^M®'nX 0 Me Cl YMA/¹ Me ^H ^Ι\Γ	methyl 5-(2,3 -dichloro-4-( 1 -(3 -methyl-3( 1 -methylpiperidin-4yl)ureido)ethyl)phenyl)nicotinate
H0690	^Me'NX O Me Cl LAYm+yY⁰¹ 0 ^H LUX >\| Me	3-(l-(4-(5-acetylpyridin-3-yl)-2,3dichlorophenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yI)urea
H0735	^Me'NX O Me Cl LA_N ^ANYY^c\| nt. Λ.^H UyJ	3-( 1 -(2,3-dichloro-4-(5-(pyrimidin-2yl)pyridin-3-yl)phenyl)ethyl)-l-methyl-l( 1 -methylpiperidin-4-yl)urea

H0746	^Me'N^xA O Me Cl ώ. ^H UVAU	3 -( 1 -(2,3-dichloro-4-(5-(furan-3 yl)pyridin-3-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0747	^Me'N^A O Me Cl aA-_na_naa>y^ci «-s ώ. ^h UUAU	3-(1-(2,3 -dichloro-4-(5-(thiophen-3 yl)pyridin-3 -yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0748	^Me'N^A 0 Me Cl m· ^H VL-AA	3 -( 1 -(2,3 -dichloro-4-(5-( 1 -methyl-1Hpyrazol-4-yI)pyridin-3 -yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0765	O Me Cl '-/AA _Λ i H A Me	3-(1-(2,3-dichloro-4-(5cyclopropylpyridin-3-yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0766	^Me'N^ O Me Cl A_na_nAA<^ci Me aA\/<^NO₇ ^isr	3-(1-(2,3 -dichloro-4-(5-nitropyridin-3 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0608	‘^θ'Ν'Α O Me Cl Ά_νΑ_νΛΑοι - ^H VV) Me 1Λ A N O Me	3-(1-(2,3 -dichloro-4-(6isopropoxypyridin-3 -yl)phenyl)ethyl)-l methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0616	^Me'N'^XA 0 Me Cl ΑΛΜα ώθ ^H UA AAN	3-( 1 -(2,3 -dichloro-4-(6-cyanopyridin-3 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0618	^Me'N'^XA 0 Me Cl lÀLVa Ma ^H Vf	3-(1-(2,3-dichloro-4-(6-fluoropyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0623	O Me Cl ώ. ^H Γτ.^ν	3-(1-(2,3 -dichloro-4-( 1 H-pyrazolo [3,4b]pyridin-5-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0610	^M®'nA 0 Me Cl ¹ H Me \^ZV^CN	3-( 1 -(2,3 -dichloro-3 '-cyano-[ 1,1'biphenyl]-4-yl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0517	AA 0 Me Cl A_na_naJLci ώβ ^H UÇy ^^nh₂	3 -( 1 -(4'-amino-2,3 -dichloro-[ 1,1'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0518	^M6'nA 0 Me Cl A^AAY ώ. ^H Μγγ ^^NMez	3-(1-(2,3 -dichloro-4'-(dimethylamino)[1,1 '-biphenyl]-4-yl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0512	^M%A 0 Me Cl <Α^Λν AA^CI „n Me ^H AAA^NMe	3-(1-(2,3 -dichloro-4-( 1 -methyl-1Hindazol-4-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0513	^M®'nA O Me Cl <AVyM' r=N Me ^H LA^V^NH	3 -( 1 -(2,3-dichloro-4-( 1 H-indazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0514	^M®'nA O Me Cl AvA liie ^H Μγγ. An	3-(1-(2,3-dichloro-4-(lH-pyrrolo[2,3b]pyridin-5-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea

H0515	^ΜθΑΑ 0 Me Cl LVAA » ^H AA~N H	3-( 1 -(2,3 -dichloro-4-( 1 H-indol-5yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0520	^'N^A 0 Me Cl AVW¹ Me ^H	3-(1-(2,3-dichloro-2', 3', 4', 5'-tetrahydro[1,1 '-biphenyl]-4-yl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0787	0 Me U-/_N AyO, ' ^H 1 z,^N Me HN-^-y	3- (1-(3- (cyclopropylamino)benzo[d]isoxazol-6yl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea
H0582	^MeN'^xU O Me F <AAAV' Me ^H	3-(l-(3-chloro-2-fluoro-4-(thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0571	^M®'nA O Me F <ΛΛ\νι ώβ ^H UL Y N ^NH	3-( 1 -(3-chloro-2-fluoro-4-( 1 H-pyrazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0605	^MeN'^/% O Me Cl U/av Me ^H A^AAAAj/F F	3-( 1 -(2,3 -dichloro-3 ',5'-difluoro-[ 1,1'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0573	^'N^A 0 Me AA - ^H V_Br	3-( 1 -(4-bromonaphthalen-l -yl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0574	^Me'NA 0 Me AA gAa/aJ¹ώβ ^H LA ^~s	1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(thiophen-3-yl)naphthalen-1 yl)ethyl)urea

H0575	^Μ®'Ν'^Ί 0 Me Me ^H	1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(thiophen-2-yl)naphthalen-l yl)ethyl)urea
H0576	O Me m· ^H UL· T N ^NH	3- (1-(4-(1 H-pyrazol-4-yl)naphthalen-1 yl)ethyl)-l -methyl-1 -(1 -methylpiperidin- 4- yl)urea
H0577	O Me Λ H Me YaY/A, ^i\r	1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(pyridin-3-yl)naphthalen-1 yl)ethyl)urea
H0591	“θ'ΝΛ 0 Me AA O._na_nZXJ ¹ H Me ⁿ	3- (l-(4-(3-aminophenyl)naphthalen-lyl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea
H0597	^Me'N^> 0 Me r^i) Me ^H />	1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(thiazol-5-yl)naphthalen-l yl)ethyl)urea
H0598	“θ'Ν^Ί 0 Me UAW ώ= ^H LA ^0	3- (l-(4-(furan-3-yl)naphthalen-lyl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea
H0599	^Μ®'Ν·^\| 0 Me A^ji Me ^H ^v>	3- ( 1 -(4-( 1 H-imidazol-5-yl)naphthalen-1 yl)ethy 1)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea

H0790	^MeN^A O Me ' ^H ^Μθ ^CN	3-( 1 -(4-cyanonaphthalen-1 -yl)ethyl)-l methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0381	^Me'Np 0 Me Cl Υ-ι/νγν” «· ^h ΙΛ	1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (2,3,4-trichlorophenyl)ethyl)urea
H0519	^MeNp 0 Me Cl ώθ ^H UL,	3 -( 1 -(2,3 -dichloro-4-iodophenyl)ethyl)-l methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0629	^Μ®'Ν·ρ 0 CN Cl LA_NA_NA^L,Br t ^H Ux,	3-((3-bromo-2-chloro-4iodophenyl)(cyano)methyl)-l -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0658	^Μθ'Ν'Ρ 0 CN Cl ^Α_νΑ_νΑΧ.βγ ^ώθ^H UL· OMe	3-((3-bromo-2-chloro-4- methoxyphenyl)(cyano)methyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0669	^Me'Np O CN Cl LA_nA_nAA_!,ci - ^H U._0Me	3-(cyano(2,3-dichloro-4methoxyphenyl)methyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0671	^Me'p O Me CN ci ^AnW⁰¹- ^H V_0Me	3-( 1 -cyano-1 -(2,3-dichloro-4methoxyphenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0659	o °V^NH2C! Me ^H AA_nMOMe	2-(3-bromo-2-chloro-4-methoxyphenyl)2-(3-methyl-3-(l-methylpiperidin-4yl)ureido)acetamide
H0521	0 Me Cl A>AÂA^a - ^H V.co₂m.	methyl 2,3-dichloro-4-( 1 -(3-methyl-3-( 1 methylpiperidin-4yl)ureido)ethyl)benzoate

H0602	0 Me Cl lie ^H HA TMS	3-(1-(2,3 -dichloro-4((trimethylsilyl)ethynyl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0603	^Me'N^V 0 Me Cl ^G_nA_nAX/CI M» «	3-( 1 -(2,3 -dichloro-4ethynylphenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0677	^MeN^V 0 Me Cl ^h vv R/S ^CH	3-(1-(2,3 -dichIoro-4ethynylphenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer)
H0678	^MeN^xV O Me Cl d^AW⁰¹ώβ H VV R/S ^CH	3-(1-(2,3 -dichloro-4ethynylphenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer)
H0832	^MeN^V 0 Me Cl d_NA_N^c. Λ h Me \A\ Me	3-( 1 -(2,3-dichloro-4-(prop-1 -yn-1 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0852	^M®'nV O Me Cl Φ/V ώ. ^H Vk Me	3-(1-(2,3 -dichloro-4-(3-methylbut-1 -yn-1 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0701	^M®'N^V 0 Me Cl <InVVV^ci Λ H Me Vr^\ Me	3-(1-(2,3 -dichloro-4-(3-oxobut-l -yn-1 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0733	^ΜθΝ^Α 0 Me Cl Me	3-(1-(2,3-dichloro-4-(3-hydroxybut-l-yn- 1 -yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0755	^M®N^A 0 Me Cl AA-W' Λ H Me AA	3-( 1 -(2,3-dichloro-4-(3-hydroxyprop-1 yn-1 -yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0757	^M®N^A O Me Cl ^A_n^C. Λ H Me ^<,OEt OEt	3-( 1 -(2,3-dichloro-4-(3,3 -diethoxyprop-1 yn-1 -yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0734	^M®'N^A 0 Me Cl ^ÀAAAx Λ H Me AaA. ^YS	3-(1-(2,3 -dichloro-4-(pyridin-2ylethynyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0737	^'N^A 0 Me Cl ^AAAAx¹lie ^H LA	3-(1-(2,3 -dichloro-4-(thiophen-2ylethynyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0775	O Me Cl uaw Μθ ^H U\ ^A^S OH	3-(1-(2,3 -dichloro-4-((5 (hydroxymethyl)thiophen-2yl)ethynyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0776	^Me'NA O Me Cl UAW Λ H Me AA ^nh₂	5-((2,3-dichloro-4-(l-(3-methyl-3-(lmethylpiperidin-4- yl)ureido)ethyl)phenyl)ethynyl)thiophene2-carboxamide

H0779	^Μθ'ΝΑ O Me Cl AVA¹ώ. ^H ΙΑ, A\___s OMe	methyl 5-((2,3-dichloro-4-(l-(3-methyl-3( 1 -methylpiperidin-4- yl)ureido)ethyl)phenyl)ethynyl)thiophene- 2-carboxylate
H0762	^Me'N^> 0 Me Cl aau-Aa ' H Me AA ^^Ap-0	3-(1-(2,3-dichloro-4-(furan-2ylethynyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0751	^MeN^A 0 Me Cl '-.AA ' H Me AA\ N^/^S	3-( 1 -(2,3 -dichloro-4-(thiazol-4ylethynyl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0763	^M®'N^A 0 Me Cl <AAAA^CI ώθ » IL2 JA'^NH	3-(l -(4-((lH-imidazol-4-yl)ethynyl)-2,3dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0759	“θ'ΝΑ O Me Cl i H Me AA\ ΙΣ»	3-( 1 -(2,3 -dichloro-4-(thiophen-3 ylethynyl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0785	^Me'N^A 0 Me Cl O-_na_nAA<^ci Me ^H S-λ ΑζΛ)	3-(1-(2,3-dichloro-4-(3-(thiophen-2yl)prop-l -yn-1 -yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0754	^Me'N^/A 0 Me Cl AAXV Λ H Me s lO	3 -( 1 -(2,3 -dichloro-4-(thiazol-2ylethynyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-y!)urea

H0753	0 Me Cl i H Me N	3-( 1 -(2,3-dichloro-4-(pyrimidin-5ylethynyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0609	0 Me Cl ώβ ^H	3-(1-(2,3 -dichloro-4- (phenylethynyl)phenyl)ethyl)-l -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0764	^Me'N·^ O Me Cl ÜAW i H Me	3-( 1 -(2,3 -dichloro-4(cyclopropylethynyl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0818	^MeN^A O Me Cl Λ H Me (S/R)	3 -( 1 -(2,3 -dichloro-4(cyclopropylethynyl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea (single enantiomer)
H0819	^MeN^x^> O Me Cl i H Me (S/R)	3-( 1 -(2,3-dichloro-4(cyclopropylethynyl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea (single enantiomer)
H0838	Me^ N-, O Me Cl Iaml Λ H Me	3-((S)-l-(2,3-dichloro-4(cyclopropylethynyl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpyrrolidin-3 -yl)urea
H0855	^Me'N'^x^i 0 Me F <I_na_naJLc_Ii H Me	3-(l-(3-chloro-4-(cyclopropylethynyl)-2fluorophenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0884	0 Me Cl ώ. ^H LA a.	3-( 1 -(4,5-dichloro-6- (cyclopropylethynyl)pyridin-3-yl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0811	0 Me Cl ό H Me	3 -( 1 -(2,3 -dichIoro-4(cyclopentylethynyl)phenyl)ethyl)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea
H0812	^Me'N^A ° Me ⁰¹ UALV _m Me Γ N	3-( 1 -(2,3-dichloro-4-(3-(4methylpiperazin-1 -yl)prop-1 -yn-1 yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0740	^MeN^A 0 [ Cl LVAV OMe^H	3-(2-cyclopropyl-1-(2,3 -dichloro-4ethynylphenyl)ethyl)-1 -methoxy-1 -( 1 methylpiperidin-4-yl)urea
H0742	^MeN^A O Me Cl ^A^VV⁰¹°Me^H	3-(1-(2,3 -dichloro-4ethynylphenyl)ethyl)-1 -methoxy-1 -( 1 methylpiperidin-4-yl)urea
H0745	^MeN^L 0 Me Cl ^N^N^Af^CIô«^H	3 -( 1 -(2,3 -dichloro-4ethynylphenyl)ethyl)-1 -hydroxy-1 -( 1 methylpiperidin-4-yl)urea
H0749	^MeN^A 0 Me Cl	3 -( 1 -(2,3 -dichloro-4ethynylphenyl)ethyl)-1 -ethoxy-1 -( 1 methylpiperidin-4-yl)urea
H0744	^Me'N^> O ( Cl kAAArV¹ OEl ^H LA	3-(2-cyclopropyl-l-(2,3-dichloro-4ethynylphenyl)ethyl)-1 -ethoxy-1 -( 1 methylpiperidin-4-yl)urea

H0626	^Me'N^U O Me Cl k ^H UU	3-(1-(2,3-dichloro-4-vinylphenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0767	O Me Cl aaav Me ^H	(E)-3-(l-(2,3-dichloro-4-(2-(thiophen-2yl)vinyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0772	^Me'N^U O Me Cl AA A AA^^CI ° ^ώθ ^ηΊΑ	N-(2,3-dichloro-4-( 1 -(3 -methyl-3 -( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)thiophene-2carboxamide
H0773	^Me'NU 0 Me Cl UAnÛUc'h ^Me Aⁿt>	2,3-dichloro-4-( 1 -(3 -methyl-3 -( 1 methylpiperidin-4-yl)ureido)ethyl)-N(thiophen-2-yl)benzamide
H0784	^Me'N^U O Me Cl Uùio H H	3-( 1 -(2,3-dichloro-4-(3-(thiophen-2yl)ureido)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0777	O Me Cl UUvMy⁰ s-i ώ. ^H UL_nA> H	3-(1-(2,3 -dichloro-4-(thiophen-2ylamino)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0846	^MeNU 0 Me Cl ώ. ^h Là_na H	3-( 1 -(2,3 -dichloro-4(cyclopropylamino)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0875	^Μθ'Ν^Υ O Me Cl UA_nA_nAjA^ci ώ. ^H La_oa	3-( 1 -(2,3-dichloro-4cyclopropoxyphenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea

H0628	0 Me Cl Me ^H ^ÿÀ^Me	3 -( 1 -(2,3 -dichloro-4-ethylphenyI)ethyl)-1 methyl-1 -( l-methylpiperidin-4-yl)urea
H0630	0 Me Cl Me ^H 1^X^.CN	3-(l -(2,3-dichloro-4(cyanomethyl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0633	^MeN'^> 0 Me Cl Me ^H AA/OH	3-(1-(2,3 -dichloro-4- (hydroxymethyl)phenyl)ethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0634	^Μθ'Ν^Α 0 Me Cl LA_nA_nAyyCI - ^H VCch_2F	3 -( 1 -(2,3 -dichloro-4(fluoromethyl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea
H0640	^Μθ'^,Ν^χ^> 0 Me Cl /ΑίΑΑ/' - ^H u._CH0	3-( 1 -(2,3-dichloro-4-formylphenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0645	^Μθ'Ν^Α 0 Me Cl AA^A/CI Me ^H ΧΑγΟ o~~y	3 -( 1 -(2,3 -dichloro-4-( 1,3 -dioxolan-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea
H0641	^MeN^A 0 Me Cl LAAAAyC! lie ^H	methyl (E)-3-(2,3-dichloro-4-( 1 -(3 methyl-3-( 1 -methylpiperidin-4yl)ureido)ethyl)phenyl)acrylate
H0702	^MeN^A 0 Me Cl AMnAV - ^H U^COMe Cl	(Z)-3-( 1 -(2,3-dichloro-4-( 1 -chloro-3 oxobut-l-en-l-yl)phenyl)ethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea
H0643	^M®'N^ 0 Me Cl Μθ ^H LÆ^/OH	3-( 1 -(2,3-dichloro-4-(3hydroxypropyl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea

H0522	^Me'NX O Me Cl Me ^H LA_CONH2	2,3-dichloro-4-( 1 -(3-methyl-3 -( 1 methylpiperidin-4yl)ureido)ethyl)benzamide
H0523	^Me'NX O Me Cl Me ^H LA_cn	3-(1-(2,3-dichloro-4-cyanophenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea
H0876	O Me Cl -^H V_CI	1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4,5,6-trichloropyridin-3-yl)ethyl)urea.

At various places in the présent spécification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term Ci-6 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Cô alkyl.

For compounds of the invention in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defîning the variable. For example, where a structure is described having two R groups that are simultaneously présent on the same compound; the two R groups can represent different moieties selected from the

Markush group defined for R.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can 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, can also be provided separately or in any 20 suitable subcombination.

As used herein, the term alkyl is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to 25 about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.

As used herein, alkenyl refers to an alkyl group having one or more double carboncarbon bonds. Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like.

As used herein, alkynyl refers to an alkyl group having one or more triple carboncarbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like.

As used herein, haloalkyl refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include CF3, C2F5, CHF2, CCI3, CHCI2, C2CI5, and the like.

As used herein, “hydroxylalkyl” refers to an alkyl group having one or more OH substituents. Example hydroxyalkyl groups include CH2OH, C2CH4OH, C3H6OH, and the like.

As used herein, aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups hâve from 6 to about 20 carbon atoms.

As used herein, cycloalkyl refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 20 3 or 4 fused rings) ring Systems as well as spiro ring Systems. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the définition of cycloalkyl are moieties that hâve one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo dérivatives of 25 pentane, pentene, hexane, and the like. In some embodiments, cycloalkyl groups can hâve from about 3 to about 10, or about 3 to about 7 ring-forming carbon atoms.

As used herein, heterocyclyl or heterocycle refers to a saturated or unsaturated cyclic hydrocarbon wherein one or more of the ring-forming carbon atoms of the cyclic hydrocarbon is replaced by a heteroatom such as O, S, or N. Heterocyclyl groups can be aromatic (e.g., heteroaryl) or non-aromatic (e.g., heterocycloalkyl). Heterocyclyl groups can also correspond to hydrogenated and partially hydrogenated heteroaryl groups. Heterocyclyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring Systems. Heterocyclyl groups can be characterized as having 3-14 or 3-7 ring-forming atoms. In some embodiments, heterocyclyl groups can contain, in addition to at least one heteroatom, from about 1 to about 13, about 2 to about 10, or about 2 to about 7 carbon atoms and can be attached through a carbon

atom or heteroatom. In further embodiments, the heteroatom can be oxidized (e.g., hâve an oxo substituent) or a nitrogen atom can be quatemized. Examples of heterocyclyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like, as well as any of the groups listed below for heteroaryl and heterocycloalkyl. Further example heterocycles include pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 3,6dihydropyridyl, 1,2,3,6-tetrahydropyridyl, 1,2,5,6-tetrahydropyridyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-I,2,5-thia-diazinyl, 1,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,520 triazolyl, 1,3,4-triazolyl, xanthenyl, octahydro-isoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzo-thiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, deca-hydroquinolinyl, 2H,6Hl,5,2dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, carbazolyl, 4aHcarbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, imidazolidinyl, imidazolinyl, imidazolyl, ΙΗ-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl and isoxazolyl.

Further examples of heterocycles include azetidin-l-yl, 2,5-dihydro-lH-pyrrol-l-yl, piperindinlyl, piperazin-l-yl, pyrrolidin-l-yl, isoquinol-2-yl, pyridin-l-yl, 3,6-dihydropyridin-l-yl, 2,3dihydroindol-l-yl, l,3,4,9-tetrahydrocarbolin-2-yl, thieno[2,3-c]pyridin-6-yl, 3,4,10,10atetrahydro-lH-pyrazino [1,2-a] indol-2-yl, 1,2,4,4a, 5,6-hexahydro-pyrazino [l,2-a]quinolin-3 -yl, pyrazino[l,2-a]quinolin-3-yl, diazepan-1 -yl, 1 ,4,5,6-tetrahydro-2H-benzo[fJisoquinolin-3-yl, 1 ,4,4a,5,6, 10b-hexahydro-2H-benzo[f]isoquinolin-3-yl, 3,3a,8,8a-tetrahydro- 1 H-2-azacyclopenta[a]inden-2-yl, and 2,3,4,7-tetrahydro- 1 H-azepin- 1 -yl, azepan- 1 -yl.

As used herein, heteroaryl groups refer to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) Systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, heterocycloalkyl refers to non-aromatic heterocycles including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Example heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3dihydrobenzofuryl, 1,3-benzodioxole, benzo- 1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also included in the définition of heterocycloalkyl are moieties that hâve one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocychc ring, for example phthalimidyl, naphthalimidyl, and benzo dérivatives of heterocycles such as indolene and isoindolene groups. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

As used herein, halo or halogen includes fluoro, chloro, bromo, and iodo.

As used herein, alkoxy refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

As used herein, thioalkoxy refers to an -S-alkyl group.

As used here, haloalkoxy refers to an -O-haloalkyl group. An example haloalkoxy group is OCF.

As used herein, cycloalkyloxy refers to -O-cycloalkyl.

As used herein, aralkyl reires to an alkyl group substituted by an aryl group.

As used herein, cycloalkylalkyl refers to an alkyl group substituted by an cycloalkyl group.

As used herein, heterocyclylalkyl refers to an alkyl moiety substituted by a heterocarbocyclyl group. Example heterocyclylalkyl groups include heteroarylalkyl (alkyl substituted by heteroaryl) and heterocycloalkylalkyl (alkyl substituted by heterocycloalkyl). In some embodiments, heterocyclylalkyl groups hâve from 3 to 24 carbon atoms in addition to at least one ring-forming heteroatom.

As used herein oxo refers to =0.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). The description of a compound without specifying its stereochemistry is intended to capture mixtures of stereoisomers as well as each of the individual stereoisomer encompassed within the genus.

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

The phrase pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animais without excessive toxicity, irritation, allergie response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The présent invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, pharmaceutically acceptable salts refers to dérivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its sait form. Examples of pharmaceutically acceptable salts include, but are not limited to, minerai or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the présent invention include the conventional non-toxic salts or the quatemary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the présent invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, éthanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. .

Synthesis

Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the températures at which the reactions are carried out, e.g., températures which can range from the solvent's freezing température to the solvent's boiling température. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

Préparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the sélection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic résonance spectrometry (e.g., Ή or ³C) inffared spectroscopy, spectrophotometry (e.g., UVvisible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

Pharmaceutical Compositions

Pharmaceutical compositions for preventing and/or treating a subject are further provided comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable sait thereof, and one or more pharmaceutically acceptable excipients.

A pharmaceutically acceptable excipient is one that is not biologically or otherwise undesirable, i.e., the material can be administered to a subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier can be selected to minimize any dégradation of the active ingrédient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. The carrier can be a solid, a liquid, or both.

The disclosed compounds can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prévention intended. The active compounds and compositions, for example, can be administered orally, rectally, parenterally, ocularly, inhalationaly, or topically. In particular, administration can be epicutaneous, inhalational, enema, conjunctival, eye drops, ear drops, alveolar, nasal, intranasal, vaginal, intravaginal, transvaginal, ocular, intraocular, transocular, enterai, oral, intraoral, transoral, intestinal, rectal, intrarectal, transrectal, injection, infusion, intravenous, intraarterial, intramuscular, intracérébral, intraventricular, intracerebroventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavemosal, intramedullar, intraocular, intracranial, transdermal, transmucosal, transnasal, inhalational, intracistemal, épidural, péridural, intravitreal, etc.

Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy ( 19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, Pa., 1995. Oral administration of a solid dose form can be, for example, presented in discrète units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one of the disclosed compound or compositions. In some forms, the oral administration can be m a powder or granule form. In some forms, the oral dose form is sublingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of Formula I are ordinarily combined with one or more adjuvants. Such capsules or tablets can contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents or can be prepared with enteric coatings.

In some forms, oral administration can be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable émulsions, solutions, suspensions, syrups, and élixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfiiming agents.

In some forms, the disclosed compositions can comprise a parentéral dose form. Parentéral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrastemal injections, and infusion. Injectable préparations (e.g., stérile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. Typically, an appropriate amount of a pharmaceutically acceptable carrier is used in the formulation to render the formulation isotonie. Examples of the pharmaceutically acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution. Other acceptable excipients include, but are not limited to, thickeners, diluents, buffers, preservatives, surface active agents and the like.

In some forms, the disclosed compositions can comprise a topical dose form. Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation can include a compound which enhances absorption or pénétration of the active ingrédient through the skin or other affected areas. When the compounds and compositions are administered by a transdermal device, administration will be accomplished using a patch either of the réservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, minerai oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Pénétration enhancers can be incorporated—see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).

Formulations suitable for topical administration to the eye include, for example, eye drops wherein the disclosed compound or composition is dissolved or suspended in suitable carrier. A typical formulation suitable for ocular or aurai administration can be in the form of drops of a micronised suspension or solution in isotonie, pH-adjusted, stérile saline. Other formulations suitable for ocular and aurai administration include ointments, biodégradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particuiate or vesicular Systems, such as niosomes or liposomes. A polymer such as crossedlinked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, can be incorporated together with a preservative, such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

Other carrier materials and modes of administration known in the pharmaceutical art can also be used. The disclosed pharmaceutical compositions can be prepared by any of the wellknown techniques of pharmacy, such as effective formulation and administration procedures. The above considérations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3.sup.rd Ed.), American Pharmaceutical Association, Washington, 1999.

The disclosed compounds can be used, alone or in combination with other therapeutic agents, in the treatment or prévention of various conditions or disease states. The administration of two or more compounds in combination means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two or more compounds can be administered simultaneously, concurrently or sequentially.

Disclosed are pharmaceutical compositions comprising an effective amount of a compound of the invention or a pharmaceutically accepted sait thereof; and a pharmaceutically

acceptable carrier or vehicle. These compositions may further comprise additional agents. These compositions are useful for modulating the activity of ghrelin receptor, thus to improve the prévention and treatment of ghrelin receptor associated human diseases such as obesity and/or metabolic disorders.

Methods

Ail of the methods of the invention may be practiced with a compound of the invention alone, or in combination with other agents.

The above-described compounds and compositions are useful for the inhibition, réduction, prévention, and/or treatment of diseases which are pathophysiologically modulated by 15 the ghrelin receptor. Accordingly, in some forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the ghrelin receptor, comprising administering to a subject a therapeutically effective amount of a compound of Formula I as disclosed above, or a pharmaceutically acceptable sait thereof.

Suitable subjects can include mammalian subjects. Mammals include, but are not limited 20 to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In some forms, humans are the subjects. Human subjects can be of either gender and at any stage of development.

Diseases modulated by the ghrelin receptor, and potentially treatable by the methods disclosed herein, include obesity, overweight, eating disorder, diabètes, metabolic syndrome, 25 cachexia resulting from cancer, congestive heart failure, wasting due to ageing or AIDS, chronic liver failure, chronic obstructive pulmonary disease, gastrointestinal disease, gastric disorder or substance abuse. Metabolic disorders potentially treatable by the instant methods include diabètes, Type I diabètes, Type II diabètes, inadéquate glucose tolérance, insulin résistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, 30 dyslipidemia, obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease. Gastric disorders potentially treatable by the instant methods include post-operative iléus (POI), diabetic gastroparesis, and opioid induced bowel dysfunction. Gastrointestinal diseases potentially treatable by the instant methods include irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia. Substance abuse

potentially treatable by the instant methods includes alcohol and drug abuse, and said drug includes amphétamines, barbiturates, benzodiazépines, cocaïne, methaqualone, and opioids.

In some embodiments of the invention, the compound of Formula I is useful in the treatment of Prader-Willi Syndrome, a genetic disorder usually involving chromosome 15. Prader-Willi is characterized by obesity, hypotonia, or poor muscle tone, and significant developmental delays in children afflicted with this disorder.

In some embodiments of the invention, the compound of Formula I is useful in the treatment of an over-eating disorder. An over-eating disorder is a complex compulsion to eat. The eating may be excessive (compulsive over-eating); may include normal eating punctuated with épisodes of purging; or may include cycles of bingeing and purging. The most prévalent 15 over-eating disorder is Bulimia nervosa. Another widely and rapidly spreading over-eating disorder is compulsive over-eating, also termed Binge Eating Disorder (BED). In some embodiments, the compound of Formula I is used in the treatment of BED.

' In some embodiments, the compound of Formula I is useful in the treatment of

Parkinson-induced constipation and gastric dysmotility. In some embodiments, the compound of 20 Formula I is useful in the treatment of chemotherapy-induced nausea and vomiting (CINV).

In some embodiments, the compound of Formula I is useful in the treatment of inflammation, acute and chronic pain, and motion sickness.

In some embodiments, the compound of Formula I is useful in the treatment of drug and alcohol abuse.In some methods the compound of Formula I is a ghrelin receptor modulator. In 25 some other methods the compound of Formula I is a ghrelin receptor agonist. In some methods the compound of Formula I is a ghrelin receptor antagonist. In some methods, the compound of Formula I or a pharmaceutically acceptable sait thereof, is administered by one or more routes selected from the group consisting of rectal, buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parentéral and topical administration.

In some other methods, administration is accomplished by administering an oral form of the compound of Formula I or a pharmaceutically acceptable sait thereof.

A therapeutically effective amount may vary widely depending on the severity of the disease, the âge and relative health of the subject, the potency of the compound used and other factors. Therapeutically effective amounts of compounds of Formula I may range from approximately 0.01 microgram per Kg (pg/Kg) body weight per day to about 100 mg/Kg body

weight per day, or from about 0.1 pg/Kg/day to about 10 mg/Kg/day, or from about 1 pg/Kg/day to about 5 mg/Kg/day, or from about 10 pg/Kg/day to about 5 mg/Kg/day, or from about 100 pg/Kg/day to about 5 mg/Kg/day, or from about 500 pg/Kg/day to about 5 mg/Kg/day.

Définitions ofTerms

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifîcally incorporated by reference herein for the material contained in them 15 that is discussed in the sentence in which the reference is relied upon.

1. A, an, the

As used in the spécification and the appended daims, the singular forms a, an and the include plural referents unless the context clearly dictâtes otherwise. Thus, for example, 20 reference to a pharmaceutical carrier includes mixtures of two or more such carriers, and the like.

2. Abbreviations

Abbreviations, which are well known to one of ordinary skill in the art, may be used (e.g., h or hr for hour or hours, g or gm for gram(s), mL for milliliters, and rt for room température, nm for nanometers, M for molar, and like abbreviations).

3. About

The term about, when used to modify the quantity of an ingrédient in a composition, concentrations, volumes, process température, process time, yields, flow rates, pressures, and like values, and ranges thereof, employed in describing the embodiments of the disclosure, refers to variation in the numerical quantity that can occur, for example, through typical measuring and handling procedures used for making compounds, compositions, concentrâtes or use formulations; through inadvertent error in these procedures; through différences in the manufacture, source, or purity of starting materials or ingrédients used to carry out the methods;

and like considérations. The term about also encompasses amounts that differ due to agmg of a composition or formulation with a particular initial concentration or mixture, and amounts that differ due to mixing or processing a composition or formulation with a particular initial concentration or mixture. Whether modified by the term about the claims appended hereto include équivalents to these quantities.

4. Comprise

Throughout the description and claims of this spécification, the word comprise and variations of the word, such as comprising and comprises, means including but not limited to, and is not intended to exclude, for example, other additives, components, integers or steps.

5. Ghrelin Receptor Agonist

A ghrelin receptor agonist is any molécule that binds to and activâtes the Ghrelin receptor in the cells.

6. Ghrelin Receptor Antagonist

A ghrelin receptor antagonist is any molécule that binds to and inhibits the activity of Ghrelin receptor.

7. Pathophysiologically Mediated by Ghrelin Receptor

Something is pathophysiologically mediated by the ghrelin receptor if the ghrelin receptor is involved in the functional changes in body associated with or resulting from disease or injury.

8. Obesity

Obesity is a medical condition in which excess body fat has accumulated to the extent that it may hâve an adverse effect on health, leading to reduced life expectancy and/or increased health problems. Obesity treatment includes inducing weight loss, reducing bodyweight, reducing food intake, reducing appetite, increasing metabolic rate, reducing fat intake, reducing carbohydrate craving; or inducing satiety. The obesity-related disorders herein are associated with, caused by, or resuit from obesity. Examples of obesity-related disorders include overeating, binge eatmg, and buhmia, hypertension, diabètes, elevated plasma insulin concentrations and insulin résistance, dyslipidemias, hyperlipidemia, endométrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniophaiyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-defïcient subjects, normal variant short stature, Tumer's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome, insulin résistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastroesophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, goût, and kidney cancer, nicotine addiction, substance addiction and alcoholism. The compositions of the présent invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.

9. Metabolic Disorder

A metabolic disorder is a disorder of metabolism, such as diabètes, Type I diabètes, Type II diabètes, inadéquate glucose tolérance, insulin résistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease.

10. Congestive Heart Failure

Congestive heart failure (CHF) is a condition in which the heart's function as a pump to deliver oxygen rich blood to the body is inadéquate to meet the body's needs. Congestive heart failure can be caused by diseases that weaken the heart muscle, or diseases that cause stiffening of the heart muscles, or diseases that increase oxygen demand by the body tissue beyond the capability of the heart to deliver. Many diseases can impair the pumping action of the ventricles. For example, the muscles of the ventricles can be weakened by heart attacks or infections

(myocarditis). The diminished pumping ability of the ventricles due to muscle weakening is called systolic dysfunction. After each ventricular contraction (systole) the ventricle muscles need to relax to allow blood from the atria to fill the ventricles. This relaxation of the ventricles is called diastole. Diseases such as hemochromatosis or amyloidosis can cause stiffening of the heart muscle and impair the ventricles' capacity to relax and fill; this is referred to as diastolic dysfunction. The most common cause of this is longstanding high blood pressure resulting in a thickened (hypertrophied) heart. Additionally, in some patients, although the pumping action and filling capacity of the heart may be normal, abnormally high oxygen demand by the body's tissues (for example, with hyperthyroidism) may make it difïïcult for the heart to supply an adéquate blood flow (called high output heart failure). In some patients one or more of these factors can be présent to cause congestive heart failure. Congestive heart failure can affect many organs of the body. For example, the weakened heart muscles may not be able to supply enough blood to the kidneys, which then begin to lose their normal ability to excrete sait (sodium) and water. This diminished kidney function can cause to body to retain more fluid. The lungs may become congested with fluid (pulmonary edema) and the person's ability to exercise is decreased. Fluid may likewise accumulate in the liver, thereby impairing its ability to rid the body of toxins and produce essential proteins. The intestines may become less efficient in absorbing nutrients and medicines. Over time, untreated, worsening congestive heart failure will affect virtually every organ in the body.

11. Agonism Action

Agonism action refers to the binding of a molécule to a receptor that leads to the activation of the receptor, thus triggering a cellular response similar to the cellular response for a known agonist for the receptor.

12. Antagonism Action

Antagonism action refers to the binding of a molécule to a receptor that leads to the inhibition of the receptor.

13. Modulate

To modulate, or forms thereof, means either increasing, decreasing, or maintaimng a cellular activity mediated through a cellular target. It is understood that wherever one of these words is used it is also disclosed that it could be 1%, 5%, 10%, 20%, 50%, 100%, 500%, or 1000% increased from a control, or it could be 1%, 5%, 10%, 20%, 50%, or 100% decreased from a control.

14. Optional

Optional or optionally means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

15. Or

The word or or like terms as used herein means any one member of a particular list and also includes any combination of members of that list.

16. Publications

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by référencé into this application in order to more fully describe the state of the art to which this pertains. The référencés disclosed are also individually and specifically incorporated by référencé herein for the material contained in them that is discussed in the sentence in which the référencé is relied upon.

17. Subject

As used throughout, by a subject is meant an individual. Thus, the subject can include, for example, domesticated animais, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animais (e.g., mouse, rabbit, rat, guinea pig, etc.) mammals, non-human mammals, primates, non-human primates, rodents, birds, reptiles, amphibians, fish, and any other animal. The subject can be a mammal such as a primate or a human. The subject can also be a non-human.

18. Treating

By treating or treatment is meant the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. These tenus include active treatment, that is, treatment directed specifïcally toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. These terms can mean that the symptôme of the underlying disease are reduced, and/or that one or more of the underlying cellular, physiological, or biochemical causes or mechanisms causing the symptoms are reduced. It is understood that reduced, as used in this context, means relative to the state of the disease, including the molecular state of the disease, not just the physiological state of the disease. In certain situations a treatment can inadvertently cause harm. In addition, these terms include palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplément another spécifie therapy directed toward the improvement of the associated disease, pathological condition, or disorder. These terms mean both treatment having a curing or alleviating purpose and treatment having a préventive purpose. The treatment can be made either acutely or chronically. It is understood that treatment can mean a réduction or one or more symptoms or characteristics by at least 5% 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.9%, 99.99%, 100%, relative to a control. In the context of these terms, preventing refers to the ability of a compound or composition (such as the disclosed compounds and compositions) to prevent a disease identified herein in patients diagnosed as having the disease or who are at risk of developing such disease. In this context, preventing includes the delaying the onset of the disease relative to a control. These terms do not require that the treatment in fact be effective to produce any of the intended results. It is enough that the results are intended.

19. Therapeutically Effective

The term therapeutically effective means that the amount of the composition used is of sufficient quantity to treat a subject as defined herein.

20. Toxicity

Toxicity is the degree to which a substance, molécule, is able to damage something, such as a cell, a tissue, an organ, or a whole organism, that has been exposed to the substance or molécule. For example, the liver, or cells in the liver, hépatocytes, can be damaged by certain substances. The methods of the présent invention are preferably non-toxic.

The invention will be described in greater detail by way of spécifie examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recongnize a variety of noncritical parameters which can be changed or modified to yield essentially the same results.

EXAMPLES

Example 1

Synthesis of Intermediate lk

Step 1:

To a solution of la (100 g, 0.62 mol) in DMF (1.2 L) was added TV-bromosuccinimide (110 g, 0.62 mol) at 0 °C. The mixture was stirred at room température for 4 h, then water (800 mL) was added and the resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over anhydrous NazSCU and concentrated under reduced pressure. The residue was triturated with petroleum ether to provide lb (133.7 g, 89% yield) as a brown solid. *H10 NMR (CDCh, 300 MHz): δ= 7.30 (d, 1 H), 6.59 (d, 1 H), 4.22 (br, 2 H). LC-MS: 241 [M+l]⁺.

Step 2:

To a solution of lb (133.7 g, 0.55 mol) in dry CH2CI2 (1.5 L) was added acetic anhydride (110 g, 0.62 mol) dropwise over a period of 20 minutes at room température. The mixture was stirred at room température overnight, then diluted with CH2CI2 (300 mL) and washed with water (150 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous Na2SÛ4 and concentrated under reduced pressure. The residue was triturated with petroleum ether (300 mL) to provide compound le (143.0 g, 91% yield) as a white solid. ^!H-NMR (CDCI3, 400 MHz): δ= 8.26 (d, 1 H), 7.63 (br, 1 H), 7.54 (d, 1 H), 2.26 (s, 3 H). LC-MS: 280 [M-l]’.

Step 3:

A mixture of compound le (50.0 g, 0.18 mol), butyl vinyl ether (ld, 89.0 g, 0.89 mol), bis(l,3diphenylphosphino)propane (DPPP, 22.0 g, 0.053 mol), TEA (100 mL, 0.71 mol) and Pd(OAc)2 (6.4 g, 0.027 mol) in DMSO (1.2 L) was heated at 130 °C under N2 overnight. After the reaction was completed, the mixture was cooled to 0 °C and 2N HCl (480 mL) was added dropwise over a period of 30 minutes. Then, the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc: PE=l:10) to provide le (19.5 g, 45% yield) as a yellow solid. ’H-NMR (CDCI3, 400 MHz): δ= 8.46 (d, 1 H),

7.82 (br, 1 H), 7.51 (d, 1 H), 2.63 (s, 3 H), 2.29 (s, 3 H). LC-MS: 244 [M-l]'.

Step 4:

To a solution of le (21.9 g, 89.4 mmol) in MeOH (350 mL) was added 2N NaOH solution (350 mL) at room température. The mixture was heated at 50 °C overnight, then cooled and concentrated under reduced pressure. The resulting solid was triturated with water (100 mL) for

30 min and filtered to provide lf (18.0 g, 98% yield) as a brown solid. ANMR (CDCh, 400

MHz): δ= 7.48 (d, 1 H), 6.68 (d, 1 H), 4.56 (br, 2 H), 2.62 (s, 3 H). LC-MS: 202[M-l]-.

Step 5:

To a mixture of compound lf (18.0 g, 89.2 mmol) and ice (360 g) in conc. HCl (180 mL) was added a solution of NaNCh (9.2 g, 133.7 mmol) in water (20 mL) dropwise over a period of 30 minutes, and the resulting mixture stirred in an ice bath for 30 min. A solution of Kl (74.0 g, 446 mmol) in water (360 mL) was added dropwise over 45 min at 0 °C. The mixture was stirred for 30 min and then extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous NaîSCU and concentrated under reduced pressure. The residue was purifïed by column chromatography (silica, EtOAc: PE=l:40) to provide lg (23.9 g, 86% yield) as ayellow solid. ’H-NMR (CDCh, 400 MHz): <5= 7.6 (d, 1 H), 7.06 (d, 1 H), 2.62 (s, 3 H).

Step 6:

To a solution of lg (23.9 g, 76.1 mmol) in MeOH (100 mL)/THF (100 mL) was slowly added

NaBH4 (2.9 g, 76.1 mmol) at 0 °C. The mixture was stirred at room température for 5 min, and then quenched with water (100 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purifïed by column chromatography (silica, EtOAc: PE=l:10) to provide lh (22.4 g, 93% yield) as a white solid. ’H-NMR (CDCh, 400 MHz): <5= 7.81 (d, 1 H),

7.26 (d, 1 H), 5.23 (q, 1 H), 2.17 (br, 1 H), 1.47 (d, 3 H).

Step 7:

To a mixture of lh (22.4 g, 70.9 mmol), phthalimide (12.5 g, 85.0 mmol) and PPI13 (22.3 g, 85.0 mmol) in dry THF (450 mL) was added DIAD (21.5 g, 106.3 mmol) at room température under 30 N2 protection. The mixture was stirred at room température ovemight and then concentrated under reduced pressure. The residue was purifïed by column chromatography (silica, EtOAc: PE=1:15) to provide li (18.5 g, 58% yield) as a white solid. ’H-NMR (CDCh, 400 MHz): δ= 7.78-7.84 (m, 3 H), 7.70-7.73 (m, 2 H), 7.41-7.43 (d, 1 H), 5.76-5.81 (q, 1 H), 1.84 (d, 3 H).

Step 8:

A solution of li (7.2 g, 16.2 mmol) and hydrazine hydrate (98%, 4.0 g, 80.9 mmol) in MeOH (150 mL) was heated under reflux for 2 h, then cooled and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with CH2CI2 (3 * 100 mL). The combined organic layers were dried over anhydrous Na2SO₄ and concentrated under reduced pressure to give lj (3.8 g, 75% yield) as a white solid. ’H-NMR (CDCI3, 400 MHz): <5= 7.81 (d, 10 1 H), 7.25 (d, 1 H), 4.55 (q, 1 H), 1.36-1.38 (d, 3 H). LC-MS: 316 [M+l]⁺.

Step 9:

To a solution of lj (41.0g, 0.13 mol) in methyl tert-butyl ether (750 mL) was added slowly a solution of D-mandelic acid (7.8 g, 0.052 mol) in methyl tert-butyl ether (110 mL) at 45°C. The mixture was stirred at this température for 30 min then cooled and filtered. White solid obtained was partitioned between 5% NaOH solution (300 mL) and methyl tert-butyl ether (300 mL). The bi-phases were separated and the aqueous phase was extracted with methyl tert-butyl ether (300 mL). The combined organic layer was concentrated to provide Intermediate lk (12 g, 58.5% yield) as a white solid (ee%=98.0%, Chiralpak AD-H, 5 pm, 4.6*250mm, mobile phase: Hex:

EtOH : DEA=80 : 20 : 0.2), rétention time = 6.408 min).

Example 2

Synthesis of Compound 2b

ii HCl.dioxane

i. MeNH_z

Pd/C, H₂(50 psi)

A suspension of A’-methyl-4-piperidone 2a (13.3 g, 58.6 mmol), bffibMe (30% in MeOH, 100 mL) and Pd/C (0.66 g) in MeOH (200 mL) was heated at 60 °C under H2 atmosphère (50 psi) overnight, then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in HCl in dioxane (3N, 100 mL) and stirred for 30 min. The precipitate was filtered and washed with EtOAc (50 mL) to provide 2b (7.7g, 54% yield) as white powder.

Ή-NMR (DMSO, 400 MHz): <5= 9.50 (br, 2 H), 3.48 (d, 2 H), 3.15-3.16 (m, 1 H), 2.96-3.01 (m, 2 H), 2.70 (s, 3 H), 2.51 (s, 3 H), 2.22-2.28 (m, 2 H), 1.94-2.02 (m, 2 H), LC-MS: 129 [M+l]⁺ .

Example 3

Synthesis of Compound H0603

2b Compound 1k 3a

i) Pd(PPh₃)₂CI₂/Cul

TMS—= ii) K₂CO₃/MeOH

Step 1:

To a solution of lk (1.83 g, 5.8 mmol) in CH2C12(70 mL) was added TEA (5.6 mL, 40.6 mmol) and triphosgene (1.29 g, 4.4 mmol) at 0 °C. The mixture was stirred for 20 min, then 2b (1.14 g, 6.97 mmol) was added. The ice bath was removed and the mixture stirred for 30 min, then concentrated under reduced pressure. The residue was partitioned between CH2CI2 (50 mL) and saturated NaHCCh solution (50 mL). The organic phase was separated, washed with brine, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was triturated with a mixture of EtOAc (1 mL) and petroleum ether (20 mL) to provide compound 3a (2.31 g, 85% yield) as a white solid. Ή-NMR (CDCh, 400 MHz): δ= 7.74 (d, 1 H), 6.94 (d, 1 H), 5.195.21 (m, 1 H), 4.95 (d, 1 H), 4.48-4.51 (m, 1 H), 3.54-3.57 (m, 2 H), 2.72-2.84 (m, 8 H), 2.202.27 (m, 2 H), 1.70-1.77 (m, 2 H), 1.45 (d, 3 H). LC-MS: 470 [M+l]⁺.

Step 2:

A mixture of3a (3 g, 6.38 mmol), Trimethylsilylacetylene (3.1 g, 31.9 mmol), Pd(PPh3)2Ch (210 mg, 0.3 mmol) and Cul (85 mg, 0.45 mmol) in TEA (60 mL) was heated at 80 °C under N2 overnight, then cooled, diluted with CH2CI2 (40 mL) and filtered. The fîltrate was concentrated under reduced pressure and the residue was partitioned between EtOAc (40 mL) and water (40 mL). The organic phase was separated, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, methanol: dichloromethane 1:30, 1% NH4OH) to provide 2.4 g of light yellow solid which was dissolved in a suspension of K2CO3 (0.75 g, 5.45 mmol) in MeOH (40 mL) and stirred at room température for 30 min. The mixture was filtered and concentrated under reduced pressure and the residue

was partitioned between EtOAc (40 mL) and water (40 mL). The organic phase was separated, dried with anhydrous NaiSCL and concentrated under reduced pressure to provide H0603 (1.9 g, 82% yield) as a white powder. ’H-NMR (CDCh, 400 MHz): δ= 7.43 (d, 1 H), 7.21 (d, 1 H), 5.27-5.31 (m, 1 H), 4.81 (d, 1 H), 4.09-4.17 (m, 1 H), 3.38 (s, 1 H), 2.86-2.91 (m, 2 H), 2.80 (s, 3 H), 2.27 (s, 3 H), 1.98-2.09 (m, 2 H), 1.61-1.65 (m, 2 H), 1.48-1.52 (m, 2 H), 1.46 (d, 3 H). LC10 MS: 368 [M+l]⁺.

Example 4

Synthesis of Compound H0700

Compound 3a ^^N<^^SnBu3

Pd(PPh₃)₄/Cul

A mixture of 3a (3.0 g, 6.38 mmol), 3b (3.54 g, 9.57 mmol), Cul (243 mg, 1.27 mmol) and Pd(PPh3)4 (1.47 g, 1.27 mmol) in 1,2-dimethoxyethane (60 mL) was heated at 100 °C under N2 ovemight, then diluted with CH2CI2 (100 mL) and filtered. The filtrate was washed with brine 20 (100 mL). The organic phase was separated, dried with anhydrous ISfeSCU and concentrated under reduced pressure. The residue was purifîed by column chromatography (silica, MeOH: CH2CI2 1:30, 1% NH4OH) to provide H0700 (1.3 g, 48% yield) as a white solid. 'H-NMR (CDCh, 400 MHz): <5= 8.90 (d, 1 H), 8.66-8.67 (m, 1 H), 8.58 (d, 1 H), 7.45 (d, 1 H), 7.38 (d, 1

H), 5.35-5.39 (m, 1 H), 4.87 (d, 1 H), 4.13-4.14 (m, 1 H), 2.85-2.90 (m, 2 H), 2.81 (s, 3 H), 2.26 25 (s, 3 H), 1.98-2.05 (m, 2 H), 1.69-1.77 (m, 2 H), 1.54-1.64 (m, 2 H), 1.51 (d, 3 H). LC-MS: 422 [M+l]⁺.

Example 5

Synthesis of Compound H0722

A mixture of compound 4a (1.39 g, 4.08 mmol), 2b (1.0 g, 6.1 mmol), DPPA (1.23 g, 4.5 mmol) and TEA (3 mL) in dry toluene (100 mL) was heated under reflux overnight, then cooled and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and 10 saturated NaoCCh solution (50 mL). The organic phase was separated, washed with brine (50 mL), dried with anhydrous Na₂SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, methanol: dichloromethane 1:40, 1% NH4OH) to provide H0722 (1.03 g, 55% yield) as a white solid. ’H-NMR (CDCh, 400 MHz): <5= 8.89 (d, 1 H), 8.66-8.67 (m, 1 H), 8.58 (d, 1 H), 7.43 (d, 1 H), 7.37 (d, 1 H), 5.35-5.38 (m, 1 H), 5.21 (d, 1 15 H), 4.15-4.17 (m, 1 H), 2.85-2.90 (m, 2 H), 2.83 (s, 3 H), 2.26 (s, 3 H), 1.97-2.05 (m, 2 H), 1.661.80 (m, 6 H), 0.68-0.70 (m, 1 H), 0.50-0.54 (m, 2 H), 0.14-0.15 (m, 2 H) LC-MS: 462 [M+l]⁺.

Example 6

Synthesis of Compound H0751

5a

TMS—=

Pd(PPh₃)₂CI₂/Cul

TEA/THF

TBAF/THF

-----------* \ S

TBME, rt N=/

5c

Pd(PPh₃)₄/Cul TBME/TEA/DMF

Step 1:

The mixture of 5a (5 g, 30.5 mmol), Trimethylsilylacetylene (3.6 g, 36.6 mmol), Pd(PPh3)₂Cl₂(210 mg, 0.3 mmol) and Cul (85 mg, 0.45 mmol) in TEA (150 mL) was heated at 80 °C for 3h

under N2, then cooled, diluted with Et2O (100 mL) and washed with brine (100 mL). The organic phase was separated, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc/petroleum ether 1:15) to provide 5b (4.3 g, 79% yield) as a yellow oil. ANMR (CDCh, 400 MHz): δ= 8.74 (d, 1H), 7.53 (d, 1H), 0.26 (s, 9H)

Step 2:

To a solution of compound 5b (4.1g, 22.5 mmol) in TBME (100 mL) at room température was added BmNF (1 M in THF) (22.5 ml, 22.5 mmol). The mixture was stirred at room température for 30 min, then quenched with water (100 mL). The organic phase was separated, dried over anhydrous Na2SO4 and filtered to afford crude compound 7c in TBME (80 mL) which was used directly in next step without further purification.

Step 3:

A solution of crude compound 5c in TBME was added to a mixture of 3a (3 g, 6.3 mmol),

Pd(PPh3)2C12 (660 mg, 0.95 mmol), Cul (180 mg, 0.95 mmol) in DMF (50 ml) and TEA(10 mL). The mixture was heated at 110 °C under N2 ovemight in a sealed tube, then cooled, diluted with CH2CI2 (100 mL) and filtered. The filtrate was washed with brine (100 mL) and the organic phase was separated, dried over anhydrous Na2SÛ4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, methanol: dichloromethane 1:30,

1% NH4OH) to provide H0751 (1.18 g, 40% yield) as a yellow solid. 'H-NMR (CDCI3, 400

MHz): 5= 8.76 (d, 1 H). 7.59 (d, 1 H), 7.42 (d, 1 H), 7.16 (d, 1 H), 5.22-5.26 (m, 1 H), 4.73-4.74 (d, 1 H), 4.03-4.09 (m, 1 H), 2.81 (br, 2 H), 2.73 (s, 3 H), 2.19 (s, 3 H), 1.91-1.99 (m, 2 H), 1.631.69 (m, 2 H), 1.52-1.62 (m, 2 H), 1.41 (d, 3 H). LC-MS: 451 [M+l]⁺.

Example 7

Synthesis of Compound H0754

A mixture of H0603 (2.2 g, 6 mmol), 6a (2.97 g, 18 mmol), Pd(PPh3)2C12 (0.66 g, 0.9 mmol) and Cul (264 mg, 1.38 mmol) in TEA (50 mL) was heated at 65 °C under N2 overnight, then cooled, diluted with CH2CI2 (100 mL) and filtered. The fîltrate was concentrated under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was separated, dried with anhydrous Na2SÛ4 and concentrated under reduced pressure. The residue was purifîed by column chromatography (silica, methanol: dichloromethane 1:30, 1% NH4OH) to provide H0754 (990 mg, 37% yield) as a white solid. ’H-NMR (CDCh, 300 MHz): <5= 7.91 (d, 1 H), 7.54 (d, 1 H), 7.46 (d, 1 H), 7.22 (d, 1 H), 5.32-5.26 (m, 1 H), 4.99 (d, 1 H),

4.47-4.60 (m, 1 H), 3.40-3.62 (m, 2 H) , 2.88 (s, 3 H), 2.76-2.91 (m, 2 H), 2.82 (s, 3 H), 1.701.90 (m, 4 H), 1.51 (d, 3 H). LC-MS: 451 [M+l]⁺.

Example 8

Synthesis of Compound H0761

A mixture of compound 4a (2.3 g, 6.78 mmol), DPPA (1.86 g, 6.78 mmol) and TEA (10.2 mL) in dry toluene (200 mL) was stirred at 110 °C for 2 h, then cooled to room température and compound 7a (1.75 g, 13.56 mmol) was added. The mixture was stirred at room température overnight, and then concentrated under reduced pressure. The residue was partitioned between EtOAc (100 mL) and saturated Na2CÛ3 solution (100 mL). The organic phase was separated, washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purifîed by column chromatography (silica, methanol:

dichloromethane 1:30, 1% NH4OH) to provide H0761 (1.4 g, 48.3% yield) as a white solid. ’H17968

NMR (CDC1₃, 400 MHz): <5= 10.11 (s, 1 H), 8.91 (d, 1 H), 8.66 (m, 1 H), 8.57 (d, 1 H), 7.46 (d, 1 H), 7.36 (d, 1 H), 6.84 (d, 1 H), 5.35 (m, 1 H), 3.97-4.04 (m, 1 H), 2.86-2.93 (m, 2 H), 2.25 (s, 3 H), 1.93-2.13 (m, 4 H), 1.79-1.86 (m, 1 H), 1.64-1.72 (m, 2 H), 1.55-1.58 (d, 1 H), 0.65-0.70 (m, 1 H), 0.46-0.50 (m, 2 H), 0.11-0.14 (m, 2 H). LC-MS: 464 [M+l]⁺.

Example 9

Synthesis of Compound H0764

To a solution of 3a (2.0 g, 4.26 mmol) and 8b (1.4 g, 21.2 mmol) in dry THF (10 mL) and TEA (1.8 g, 17 mmol) was added Pd(PPh3)2Ch(597 mg, 0.85 mmol) and Cul (220 mg, 1.16 mmol) at room température under N2. The mixture was heated at 80 °C overnight in a sealed tube, then cooled, diluted with CH2CI2 (50 mL) and filtered. The filtrate was washed with brine (50 mL) and the organic phase was separated, dried over anhydrous NaaSCU and concentrated under reduced pressure. The residue was purified by column chromatography (silica, methanol: dichloromethane 1:30, 1% NH4OH) to provide H0764 (990 mg, 37% yield) as a white solid. ^!HNMR (CDCh, 400 MHz): <5= 7.27 (d, 1 H), 7.12 (d, 1 H), 5.24-5.29 (m, 1 H), 4.78 (d, 1 H), 4.074.14 (m, 1 H), 2.74-2.88 (m, 2 H), 2.76 (s, 3 H), 2.24 (s, 3 H), 1.96-2.04 (m, 2 H), 1.40-1.73 (m, 5 H), 1.38 (d, 3 H), 0.70-0.90 (m, 4 H). LC-MS: 408 [M+l]⁺.

Example 10

Synthesis of Compound H0795

SI

9a

i) Bu₃SnCI, n-BuLi, TMP, THF, -78 to 0 °C ii) -78 to -40 °C, THF

Bu₃Sn

9b

Step 1:

To a 2.5 M solution of «-butyllithium (40 mL, 0.1 mol) in anhydrous THF (250 mL) cooled to °C under N2 protection was added TMP (2,2,6,6-tetramethylpiperidine, 15 g, 0.106 mol) dropwise over a period of 20 minutes. The mixture was warmed to 0 °C by replacing the dry ice/acetone bath with an ice bath and stirred for 1.5 h. The mixture was cooled back to -78 °C and a solution of 9a (3 g, 0.03 mol) and tributyltin chloride (10 g, 0.03 mol) in 50 mL of dry THF was added over 10 min. The mixture was stirred at -78°C for 6 h, then warmed to -40 °C by replacing the dry ice/acetone bath with an dry ice/acetonitrile bath. A solution of 35% HCl, éthanol and THF (1:4:5) was added. The mixture was warmed to room température and washed with saturated NaHCCh solution (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc: petroleum ether=l:15) to provide 9b (3.4 g, 29% yield) as light yellow oil. ^-NMR (CDCI3, 300 MHz): δ= 8.41 (d, 1 H), 8.17 (d, 1 H), 1.8-0.53 (m, 27 H).

Step 2:

To a solution of 3a (2.0 g, 4.4 mmol) and 9b (3.4 g, 9.35 mmol) in 1,2-dimethoxyethane (200 mL) were added Pd(PPh3)4 (800 mg, 0.69 mmol) and Cul (40 mg, 0.21 mmol) at room température under N2. The mixture was then heated at 90 °C ovemight, then cooled, diluted with CH2CI2 (100 mL) and filtered. The filtrate was washed with brine (100 mL) and the organic phase was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, MeOH:CH2C12, 1:30, 1% NH4OH) to provide compound H0795 (1.0 g, 51% yield) as a white solid. ’H-NMR (CDCI3, 400 MHz):

Example 11

Synthesis ofH0816

Me Cl

Pd(PPh₃)₄, Cul DME, 100 °C

1k

Step 1:

To a solution of lk (12.0 g, 38.1 mmol), sat.NaHCCh solution (120 mL) in THF (480 mL), was 15 added (Boc^O (16.6g, 76.2 mmol) at r.t.. Then the mixture was stirred at r.t. overnight. Ethyl acetate (500 mL) and water (500 mL) were added to the mixture. The organic layer was separated, washed with brine (500 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EA: PE=1:5) to provide 10b (15.4 g, 97.5% yield) as a white solid. ’H-NMR (CDCh, 400 MHz): δ= 7.76 (d,

1H), 6.99 (d, 1H), 5.05 (s, 1H), 4.97 (s, 1H), 1.27 (s, 12H).

Step 2:

To a solution of 10b (5.0 g, 12.0 mmol) and 3b (5.3 g, 14.4 mmol) in 1,2-dimethoxyethane (150 mL) were added Pd(PPh3)4 (1.39 g, 2.4 mmol), Cul (228 mg, 2.4 mmol) and LiCl (50.4 mg, 2.1 mmol) at r.t. under N2. The mixture was then heated at 105°C overnight, then cooled and concentrated under reduced pressure. Ethyl acetate (200 mL) and water (200 mL) were added to the above mixture which was then filtered. The organic phase was separated, dried over anhydrous Na2SCU and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EA: PE=l:10) to provide compound 10c (3.47 g, 78.5% yield) as yellow solid. ’H-NMR (CDCh, 300 MHz): δ= 8.93 (d, 1H), 8.69-8.70 (m, 1H), 8.60 (d, 1H), 7.48-7.51 (m, 1H), 7.42-7.45 (m, 1H), 5.19-5.23 (m, 1H), 5.06 (s, 1H), 1.45 (s,12 H).

Step 3:

To a solution of 10c (3.47g, 9.5 mmol) in DCM (100 mL) cooled to 0 °C was added TFA (35 mL) dropwise. The mixture was stirred at r.t for 1 h and then concentrated under reduced pressure. DCM (100 mL) was added to the above residue and cooled to 0 °C. Sat. NaaCCh solution was added dropwise to the above mixture at 0 °C until pH=8. The organic layer was separated, washed with brine (200 mL), then dried over anhydrous NaaSCh and concentrated under reduced pressure. The residue was purified by column chromatography (silica, MeOH :

DCM =1:100) to provide lOd (1.7 g, 68.0% yield) as ayellow solid. LC-MS: 268 [M+l]⁺.

Step 4:

To a solution of lOd (1.7 g, 6.4 mmol) and TEA (17 mL) in DCM (340 mL), was added triphosgene (1.42 g, 4.8 mmol) in portions at 0 °C. The solution was then warmed to r.t. and stirred for 0.5 h. 2b (1.57 g, 9.6 mmol) was added to the above mixture at r.t. The mixture was then stirred for another 0.5 h, and finally evaporated under reduced pressure. EtOAc (150 mL) was added to the residue and washed with water (100 mL) and brine (100 mL). The separated organic phase was dried over anhydrous NaiSCL and concentrated. The residue was purified by column chromatography (silica, MeOH: DCM =1:10) to provide H0816 (2.04 g, 75.8% yield) as a yellow solid. ’H-NMR (CDCh, 400 MHz): <5= 8.82 (s, 1H), 8.60 (s, 1H), 8.51 (d, 1H), 7.367.38 (m, 1H), 7.29-7.31 (m, 1H),5.28-5.31 (m, 1H), 4.79 (d, 1H), 4.04-4.10 (m, 1H), 2.78-2.83 (m, 1H), 2.74 (s, 2H), 2.19 (s, 3H), 1.91-1.99 (m, 2H), 1.61-1.70 (m, 2H), 1.47-1.57 (m, 2H), 1.44 (d, 3H). LC-MS: 422 [M+l]⁺.

Example 12

Synthesis of H0824

Cl Me

BOC2O, THF

Cl Me

11b

i TFA, DCM ii Na₂CO₃ (aq.)

Step 1:

Me Cl

I

11e Me triphosgene DCM, TEA

To a solution of lj (2 g, 6.36 mmol) and di-tert-butyl dicarbonate (2.75 g, 12.72 mmol) in THF (30 mL) was added saturated aqueous NaiCCL solution (5 mL) at 0 °C. The mixture was then stirred at room température for 1 h, and eventually diluted with ethyl acetate (40 mL). The resulting mixture was washed with brine (10 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was triturated with petroleum ether (40 mL) to provide 11b (1.86 g, 70% yield) as a white solid. Tl-NMR (CDCls, 400 MHz): <5=7.76 (d, 1 H), 7.00 (d, 1 H), 4.96-5.06 (m, 2 H), 1.41-1.43 (m, 12 H). LC-MS: 416 [M+l]⁺.

Step 2:

To a solution of lb (1.8 g, 4.5 mmol) and 3b (2.4 g, 6.5 mmol) in 1,2-dimethoxyethane (160 mL) were added Pd(PPh3)4 (780 mg, 0.67 mmol) and Cul (90 mg, 0.45 mmol) at room température under the protection of N2. The mixture was then heated to 90 °C and stirred overnight at this température. It was subsequently cooled down and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica, ethyl acetate: petroleum ether 1:10) to provide 11c (1.2 g, 73% yield) as a white solid. LC-MS: 368 [M+l]⁺.

Step 3:

To a solution of 11c (600 mg, 1.63 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL) at 0 °C. After the addition, the mixture was stirred at room température for 2 h and then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCCL solution (15 mL) and dichloromethane (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide lid (350 mg, 80% yield) as a colorless oil. Ή-NMR (CDC1₃, 400 MHz): 5= 8.92 (d, 1 H), 8.69 (dd, 1 H), 8.59 (d, 1 H), 7.69 (d, 1 H), 7.49 (d, 1 H), 4.67-4.69 (m, 1 H), 1.43 (d, 3 H). LC-MS: 268 [M+l]⁺.

Step 4:

To a solution of compound lld (60 mg, 0.225 mmol) and TEA (0.5 mL) in dichloromethane (10 mL) was added triphosgene (46 mg, 0.158 mmol) at 0 °C. The mixture was then stirred at room température for 15 min before the addition of lie (53 mg, 0.337 mmol). Then stirred for another 30 min, diluted with dichloromethane (10 mL), washed with brine (10 mL), dried over anhydrous Na2SÛ4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica, methanol: dichloromethane 1:40, 1% NH4OH) to provide H0824 (60 mg, 57% yield) as a white solid. ’H-NMR (CDCh, 400 MHz): <5= 8.84 (dd, 1 H), 8.61 (d, 1 H), 8.51 (d, 1 H), 7.37 (dd, 1 H), 7.30 (dd, 1 H), 5.23-5.27 (m, 1 H), 4.82 (dd, 1 H), 4.02 (d, 1 H), 2.86 (d, 2 H), 2.80 (s, 3 H), 2.23 (d, 3 H), 1.90-2.01 (m, 2 H), 1.76 (d, 1 H), 1.45 (d, 3 H), 1.40 (d, 1 H), 1.05 (s, 3 H), 0.70 (s, 3 H). LC-MS: 450 [M+l]⁺.

Example 13

Synthesis of H0890 (enantiomer of H0824)

Step 1-4: Compound H0890 was synthesized in a similar manner to H0824 (overall yield 31% from lk). ’H-NMR (CDCh, 400 MHz): 5= 8.91 (dd, 1 H), 8.68 (d, 1 H), 8.58 (d, 1 H), 7.46 (dd, 1 H), 7.40 (dd, 1 H), 5.30-5.34 (m, 1 H), 4.86 (d, 1 H), 4.09 (d, 1 H), 2.95 (d, 2 H), 2.87 (s, 3 H),

2.40 (d, 3 H), 2.46-2.51 (m, 2 H), 2.22 (s, 3 H), 2.01-2.09 (m, 2 H), 1.84 (d, 1 H), 1.51 (d, 3 H),

1.47 (d, 1 H), 1.08 (s, 3 H), 0.76 (s, 3 H). LC-MS: 450 [M+l]

Example 14

Synthesis of H0826

i EtNH₂ HCl, Pd/C, H₂ (50 psi)

li HCI/dloxane

Step 1:

A mixture of 13a (3g, 26.5 mmol), EtNH₂HCl (11.2 g, 132.7 mmol), TEA (5 ml) and Pd/C (300 mg) in MeOH (50 mL) was heated at 60 °C under H₂ (50 psi) ovemight, then cooled and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in HCl/dioxane (4 N, 100 mL) and stirred for 30 min. The precipitate was filtered and washed with ethyl acetate (50 mL) to provide 13b (4.1 g, 87% yield) as white powder. ’H-NMR (DMSO-î/6, 400 MHz): 5= 9.12 (br, 2 H), 3.72 (d, 2 H), 3.25-3.29 (m, 1 H), 3.04 (q, 2 H), 2.84-2.90 (m, 2 H), 2.70 (s, 3 H), 2.22-2.28 (m, 2 H), 1.94-2.02 (m, 2 H), 1.26 (t, 3 H), LC-MS: 129 [M+l]⁺ .

Step 2:

To a solution of lid (60 mg, 0.225 mmol) and TEA (0.5 mL) in dichloromethane (5 mL) was added triphosgene (46 mg, 0.158 mmol) at 0 °C. After the addition, the mixture was stirred at room température for 15 min before the addition of 13b (60 mg, 0.337 mmol). The resulting mixture was stirred for another 30 min at room température, then diluted with dichloromethane (10 mL), washed with brine (10 mL). The organic layer was separated, dried over anhydrous Na₂SC>4 and concentrated under vacuum. The residue was purified with silica gel column chromatography (silica, methanol: dichloromethane 1:40, 1% ΝΉ4ΟΗ) to provide H0826 (44 mg, 45% yield). ’H-NMR (CDCh, 400 MHz): 5=8.89 (d, 1 H), 8.66 (dd, 1 H), 8.57 (d, 1 H), 7.45 (d, 1 H), 7.36 (d, 1 H), 5.36-5.39 (m, 1 H), 4.85 (d, 1 H), 4.13-4.18 (m, 1 H), 3.22 (q, 2 H), 2.84-2.88 (m, 2 H), 2.25 (s, 3 H), 1.95-2.03 (m, 2 H), 1.55-1.73 (m, 4 H), 1.53 (d, 3 H), 1.24 (t, 3 H).. LC-MS: 436 [M+l]⁺.

Example 15

Synthesis of H0889 (enantiomer of H0826)

The synthesis of H0889 (49 mg. 30% yield) is similar to that of H0826. 1H-NMR (CDCh, 400 MHz): δ= 8.90 (d, 1 H), 8.67 (dd, 1 H), 8.57 (d, 1 H), 7.45 (d, 1 H), 7.37 (d, 1 H), 5.35-5.39 (m,

H), 4.85 (d, 1 H), 4.11-4.17 (m, 1 H), 3.22 (q, 2 H), 2.85-2.88 (m, 2 H), 2.25 (s, 3 H), 1.97-2.04 (m, 2 H), 1.54-1.73 (m, 4 H), 1.52 (d, 3 H), 1.23 (t, 3 H). LC-MS: 436 [M+l]⁺.

Example 16

Synthesis of H0830

Step 1:

To a solution of 14a (3.1 g, 7.88 mol) in dichloromethane (60 mL) was added Dess-Martin periodinane (5.0 g, 11.83 mmol) at room température. The mixture was stirred at room température for 2 h, then concentrated under vacuum. The residue was purified by column chromatography (silica, ethyl acetate: petroleum ether=l:15) to provide 14b (3.05 g, 99% yield)

as a light yellow solid. ’H-NMR (CDCls, 400 MHz): <5= 10.40 (s, 1 H), 7.97 (d, 1 H), 7.52 (d, 1

H).

Step 2:

To a solution of 14b (1.5 g, 3.8 mmol) and 3b (2.12 g, 5.7 mmol) in 1,2-dimethoxyethane (40 mL) were added Pd(PPh3)4 (887 mg, 0.76 mmol) and Cul (147 mg, 0.76 mmol) at room température under the protection of N2. The mixture was heated at 90 °C overnight, and then concentrated under reduced pressure. The residue was purifîed with silica gel column chromatography (silica, ethyl acetate: petroleum ether=l:10) to provide 14c (826 mg, 86% yield) as a light yellow solid. ’H-NMR (CDCI3,400 MHz): <5= 10.55 (s, 1 H), 8.97 (d, 1 H), 8.74 (dd, 1

H), 8.66 (d, 1 H), 7.98 (d, 1 H), 7.64 (d, 1 H). LC-MS: 253 [M+l]⁺.

Step 3:

To a solution of 14c (980 mg, 3.5 mmol) and (trifluoromethyl)trimethylsilane (1.1 g, 7.8 mmol) in THF (20 mL) was slowly added TBAF (1 M solution in THF, 5.8 mL, 5.8 mmol,) at 0 °C.

After the mixture was stirred at room température overnight, water was added (30 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated reduced pressure. The residue was purifîed by column chromatography (silica, ethyl acetate: petroleum ether=l:5) to provide 14d (640 mg, 52 % yield) as a white solid. ’H-NMR (CDCh, 400 MHz): <5= 8.92 (s, 1 H), 8.72 (s, 1 H), 8.66 (s, 1 H), 7.75 (d, 1 H), 7.53 (d, 1 H), 5.70 (q, 1 H), 3.68(br, 1 H). LC-MS: 323 [M+l]⁺.

Step 4:

To a solution of 14d (750 mg, 2.33 mmol) and TEA (709 mg, 7.02 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (320 mg, 2.8 mmol) at 0 °C. After the addition was 30 finished, the mixture was stirred at room température for 20 min, then diluted with dichloromethane (50 mL). The mixture was washed with saturated aqueous NaHCCh solution (40 mL), dried over anhydrous Na2SÜ4 and concentrated under vacuum to provide crude 14e (910 mg, 97% yield) as a colorless oil which was used in the next step without further purification. ’H-NMR (CDCI3, 400 MHz): <5= 8.96 (d, 1 H), 8.73 (dd, 1 H), 8.67 (d, 1 H), 7.74 35 (d, 1 H), 7.64 (d, 1 H), 6.54 (q, 1 H), 3.15(s, 3 H).

Step 5:

To a solution of compound 14e (910 mg, 2.27 mmol) in DMSO (20 mL) was added NaN3 (296 mg, 4.55 mmol) at room température. The mixture was stirred at 100 °C ovemight, then cooled and water was added (100 mL). The resulting mixture was extracted with ethyl acetate (50 mL x

3). The combined organic layers were dried over anhydrous NaaSCL and concentrated under vacuum. The residue was purifïed by column chromatography (silica, ethyl acetate: petroleum ether=l:5, v:v) to provide 14f (340 mg, 44% yield) as a yellow oil. 'H-NMR (CDCh, 400 MHz): 5= 8.89 (d, 1 H), 8.78 (dd, 1 H), 8.62 (d, 1 H), 7.74 (d, 1 H), 7.60 (d, 1 H), 6.02 (q, 1 H). LC-MS: 348 [M+l]⁺.

Step 6:

To a solution of 14f (34.7 mg, 0.1 mmol), HCOOH (46 mg, 1.0 mmol) and Ν2Η4Ή2Ο (50 mg, 1.0 mmol) in EtOH (10 mL) was added Raney-Ni (50 mg). The mixture was stirred at room température for 1 h, then filtered and concentrated under vacuum. The residue was diluted with dichloromethane (20 mL), washed with water (15 mL), dried over anhydrous Na2SÛ4 and concentrated under vacuum to provide 14g (30 mg, 93% yield) as a colorless oil. ¹ H-NMR (CDCh, 400 MHz): <5= 8.92 (d, 1 H), 8.67 (dd, 1 H), 8.61 (d, 1 H), 7.67 (d, 1 H), 7.55 (d, 1 H), 5.17 (q, 1 H), 1.86 (br, 2 H). LC-MS: 322 [M+l]⁺.

Step 7:

To a solution of 14g (24 mg, 0.07 mmol), 2b (14.7 mg, 0.09 mmol) and TEA (0.5 mL) in dichloromethane (10 mL) was added triphosgene (46 mg, 0.158 mmol) at room température. The resulting mixture was stirred at 35 °C under the protection of N2 for 2 h, then diluted with dichloromethane (10 mL). The mixture was washed with saturated aqueous Na2CÛ3 solution (10 mL) and brine (10 mL), dried over anhydrous Na2SC>4 and concentrated under vacuum. The residue was purifïed with silica gel column chromatography (silica, methanol: dichloromethane 1:40, 1% NH4OH) to provide H0830 (10 mg, 28% yield) as a white solid. 1H-NMR (CDCI3, 400 MHz): δ= 8.85 (d, 1H), 8.62 (dd, 1H), 8.55 (d, 1H), 7.48 (d, 1H), 7.40 (d, 1H), 6.22-6.26 (m, 1H), 5.21 (d, 1H), 4.38-4.45 (m, 1H), 3.30-3.12 (m, 2H), 2.84 (s, 3H), 2.59-2.71 (m, 5H), 1.611.66 (m, 2H), 1.01-1.05 (m, 2H). LC-MS: 476 [M+l]⁺.

Example 17

Synthesis of H0847

Step 1:

To a solution of 12b (10.4 g, 25 mmol) and 9b (19.4 g, 50 mmol) in 1,2-dimethoxyethane (1.2 L) were added Pd(PPh3)4 (4.54 g, 3.92 mmol) and Cul (227 mg, 1.19 mmol) at r.t. under N2. The mixture was heated at 90 °C overnight, then cooled, diluted with CH2CI2 (800 mL) and filtered. The filtrate was washed with brine (600 mL) and the organic phase was separated, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc: Petroleum, 1:3) to provide crude compound 15a (10.3 g, ca. 100% yield) as yellow solid. LC-MS: 386 [M+l]⁺.

Step 2:

To a solution of 15a (10.3 g, 26 mmol) in DCM (500 mL) cooled to 0 °C was added TFA (100 mL) dropwise. After the addition was completed, the mixture was stirred for 3 h, then basifîed with saturated NaaCCh solution (400 mL) and extracted with DCM (3x100 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, MeOH : CH2CI2 : NH4OH, 1:20:0.01) to provide 15b (4.1 g, 57% yield) as a red solid. LC-MS: 440 [M+l]⁺¹

Step 3:

To a solution of 15b (2.0 g, 7.1 mmol) and TEA (80 mL) in CH2CI2 (220 mL) was added triphosgene (1.52 g, 5.1 mmol) portion wise at 0 °C. After the addition was completed, the

solution was stirred for 45 min. 2b (2.7 g, 7.1 mmol) was then added to the above solution. The resulting solution was stirred for 2 h, then diluted with CH2CI2 (100 mL) and washed with aqueous Na2CO3 solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purifîed with silica gel column chromatography (silica: CH2CI2 : CH3OH=10/l) to provide H0847 (2.0 g, 65% yield) as white solid. ’H-NMR (CDCI3, 400 MHz): 8.77 (d, 1H), 8.38 (d, 1H), 7.40 (d, 1H), 7.31 (d, 1H), 5.26-5.30 (m, 1H), 4.78 (d, 1H), 4.10-4.00 (m, 1H), 2.79-2.84 (m, 2H), 2.75 (s, 3H), 2.20 (s, 3H), 1.94-2.05 (m, 2H), 1.57-1.69 (m, 2H), 1.47-1.64 (m, 2H), 1.41 (d, 3H). LC-MS: 440 [M+l]⁺. ee%=98.5%. (Chiralpak, 5 pm, 4.6*250mm, Phase: Hex: EtOH: DEA = 90: 10: 0.2), rétention time =12.829 min).

Example 18

Synthesis of H0829 and H0860

16a 16b 16c 16d

Step 1:

To a solution of 16a (100 g, 0.54 mol) in DMF (1400 mL) was added N-chlorosuccinimide (73 g, 0.54 mol) slowly at 0 °C. The resulting mixture was heated at 40 °C for 12 h, then poured into

water (1600 mL). The precipitate was collected by filtration, dissolved in ethyl acetate (1000 mL) and washed with brine (1000 mL). Evaporation of the solvent gave the residue which was re-crystallized in éthanol to give crude 16b (80 g) and it was used directly in next step.

Step 2:

To a well stirred solution of 16b (80 g, 0.365 mol) in dry THF (4 L) was added LÎA1H4 (27.6 g, 0.73 mol) slowly at 0 °C. The mixture was stirred at 0 °C for 2 h. Then ice-water (600 mL) was slowly added at 0 °C and the mixture was filtered. The filtrate was concentrated and the residue was purified by re-crystallization in ethyl acetate/petroleum ether (1:2) to give 16c (39 g, 56% overall yield in two steps) as a light yellow solid. ’H-NMR (CDCh, 400 MHz): <5= 7.15 (d, 1H),

6.68 (d, 1H), 4.68 (d, 2H), 4.12 (br, 2H), 2.03 (br, 1H) LC-MS: 192 [M+l]⁺.

Step 3:

To a mixture of 16c (39 g, 0.2 mol) and ice (450 g) in con. HCl (200 mL) was added a solution of NaNO₂ (21.2 g, 0.3 mol) in water (30 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min, then a solution of Kl (169.4 g, 1.02 mol) in water (400 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 40 min, then ethyl acetate (1000 mL) was added and the organic phase was washed successively with water (500 mL), NaHSCh solution (500 mL) and brine (500 mL). The organic phase was separated, dried with anhydrous Na₂SÛ4 and concentrated. The residue was purified by column chromatography (silica, EA: PE=1:15) to provide 16d (50 g, yield: 81%). ’H-NMR (CDCI3,400 MHz): δ= 7.81 (d, 1H), 7.17 (d, 1H), 4.75 (d, 2H), 2.02 (br, 1H).

Step 4:

To a mixture of 16d (50 g, 166 mmol) and TEA (50 g, 497.0 mmol) in dry CH₂C1₂ (900 mL) was added methanesulfonyl chloride (22.8 g, 199.0 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for another 90 min, then diluted with ethyl acetate (800 mL) and washed with brine (600 mL). The organic phase was separated, dried over anhydrous Na₂SC>4 and concentrated to afford crude 16e (59 g) which was used directly in next step without further purification.

Step 5:

To a solution of crude 16e (59 g, 160 mmol) in EtOH (1200 mL) was added a solution of NaCN (11.4 g, 230.0 mmol) in H2O (250 mL). The resulting mixture was heated under reflux overnight, then cooled and concentrated. The residue was partitioned between ethyl acetate (500 mL) and water (500 mL). The organic phase was separated, washed with brine, dried over anhydrous Na2SÛ4 and concentrated to afford crude 16f (40 g) as a brown solid which was used directly in next step without further purification.

Step 6:

To a solution of 16f (40 g, 129 mmol) in MeOH (360 mL) was added conc. H2SO4 (114 mL) dropwise at 0 °C. The mixture was then heated under reflux overnight, then cooled and concentrated. Aqueous Na2CCh solution (50 mL) was added to the residue at 0 °C and the mixture was adjusted to pH=9-10 with the addition of Na2CCh powder. The mixture was extracted with ethyl acetate (3 x 300 mL) and the combined organic layers were dried over anhydrous Na2SÛ4 and concentrated. The residue was purified by column chromatography (silica, EA: PE =1:20) to 16g (22 g, yield: 70.5%) as a yellow solid. ’H-NMR (CDCh, 400

MHz): <5= 7.75 (d, 1H), 6.93 (d, 1H), 3.78 (s, 2H), 3.72 (s, 3H).

Step 7:

To a solution of 16g (22 g, 32 mmol) in DMF (150 mL) was slowly added NaH (60%, 2.8 g, 2.2 mmol) at 0 °C. The mixture was stirred at r.t. for 30 min and then EtI (10 g, 64 mmol) was added. The mixture was stirred at r.t. for another 1.5 h, then poured into ice water (600 mL). The resulting mixture was extracted with ethyl acetate (3 x 400 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (silica, ethyl acetate: petroleum ether=l:50) to provide 16h (20 g, 84% yield). ’HNMR (CDCh, 400 MHz): <5=7.76 (d, 1H), 7.00 (d, 1H), 4.06 (t, 1H), 3.67 (s, 3H),

2.05-2.12 (m, 1H), 1.75-1.82 (m, 1H), 0.91 (t, 3H).

Step 8:

To a solution of 16h (22 g, 53.7 mmol) and 3b (25.9 g, 69.9 mmol) in 1,2-dimethoxyethane (660 mL) were added Pd(PPh3)4 (15.5 g, 13.4 mmol), LiCl (0.46 g, 13.4 mmol) and Cul (2.06 g, 10.8 mmol) at r.t. under the protection of N2. The mixture was then heated at 105 °C overnight, cooled and concentrated under vacuum. The residue was punfïed with silica gel column chromatography (silica, ethyl acetate: petroleum ether=l:8)to provide 16i (12 mg, 69 % yield) as a yellow solid.

Step 9:

The mixture of 16i (12 g, 37.0 mmol) and L1OHH2O (9.3 g, 22.2 mmol) in MeOH (480 mL) and H2O (120 mL) was stirred at r.t. ovemight, then concentrated under vacuum. The residue was acidifïed with IN HCl to pH=2 which was extracted with dichloromethane (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated to provide 16j (10.8 g, 94% yield) as a white solid. LC-MS: 310 [M-l]’.

Step 10:

The mixture of 16j (10.8 g, 34.8 mmol), 2b (8.6 g, 52 mmol), DPPA (11.5 mg, 41.8 mmol) and TEA (48 mL) in toluene (400 mL) was stirred at 125 °C ovemight, then cooled and concentrated under vacuum. The residue was partitioned between saturated aqueous Na2CO3 solution (150 mL) and dichloromethane (300 mL). The organic phase was separated, washed with brine (200mL), dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was purifîed by column chromatography (silica, MeOH: dichloromethane 1:50, 1% NH4OH) to provide H0829 (6 g, 41% yield) as a white solid. 1H-NMR (CDC13, 400 MHz): δ= 8.91 (d, 1H), 8.68 (d, 1H), 8.59 (d, 1H), 7.45 (d, 1H), 7.34 (d, 1H), 5.17-5.22 (m, 1H), 4.93 (d, 1H), 4.11-4.17 (m, 1H), 2.85-2.92 (m, 2H), 2.82 (s, 3H), 2.27 (s, 3H), 1.58-2.05 (m, 8 H), 1.00 (t, 3H). LC-MS: 436 [M+l]+.

Step 11:

H0860 (2.0, 66.7%) was obtained through the chiral séparation of H0829 (Chiralpak, 5pm, 4.6* 250 mm, Hex:EtOH:DEA=80:20:0.2, rétention time: 10.76 min). 1H-NMR (CDCH, 400 MHz): <5= 8.89 (d, 1H), 8.66 (d, 1H), 8.57 (d, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 5.16-5.21 (m, 1H), 4.92 (d, 1H), 4.11-4.17 (m, 1H), 2.87-2.90 (m, 2H), 2.81 (s, 3H), 2.26 (s, 3H), 1.48-2.01 (m, 8 H), 0.97 (t, 3H). LC-MS: 436 [M+l]+.

Example 19

Synthesis of H0837 and H0862

Boc

17a

MeNH₂, Pd/C, H₂

MeOH

Step 1

The mixture of 17a (5g, 27.0 mmol), 30% of methyl amine in methanol (50 mL) and 5% Pd/C (500 mg) in methanol (50 mL) was heated at 60 °C under H2 (50 psi) ovemight, then cooled and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (methanol:dichloromethane =1:40) to provide 17b (2.8 g, 52 % yield). ’H-NMR (CDCh, 400 MHz): <5= 9.99 (s, 1 H), 3.79 -3.83 (m, 1 H), 3.61-3.72 (m, 3 H), 3.40 (d,

1 H), 2.71 (s, 3 H), 2.33-2.36 (m, 2 H), 1.75 (s, 9 H), LC-MS: 201 [M+l]⁺

Step 2:

To a solution of 12c (300 mg, 1.12 mmol) and TEA (3.6 g, 40.3 mmol) in dichloromethane (20 mL) was added triphosgene (283 mg, 0.95 mmol) at 0 °C. After the addition was finished, the mixture was stirred at room température for 30 min before the addition of 17b (270 mg, 1.35 mmol). The resulting mixture was stirred at room température for 1 h, then concentrated under

vacuum. The residue was partitioned between dichloromethane (50 mL) and saturated NaHCCh solution (50 mL). The organic phase was separated, washed with brine, dried with anhydrous Na2SÛ4 and concentrate under vacuum. The residue was purified with silica gel column chromatography (silica, methanol: dichloromethane 1:40, 1% NH4OH) to provide 17c (330 mg, 60% yield) as a yellow solid. ’H-NMR (CDCh, 400 MHz): <5= 8.82 (s, 1 H), 8.63 (d, 1 H), 8.51 (dd, 1 H), 7.38 (d, 1 H), 7.33 (d, 1 H), 5.23-5.26 (m, 1 H), 4.99 (d, 1 H), 4.80-4.83 (m, 1 H), 3.31-3.32 (m, 2 H), 3.03-3.23 (m, 2 H), 2.80 (s, 3 H), 1.97-2.03 (m, 1 H), 1.76 -1.84 (m, 1 H), 1.64 (s, 9 H), 1.45 (d, 3 H). LC-MS: 494 [M+l]⁺.

Step 3:

To a solution of 17c (330 mg, 0.67 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL) dropwise at 0 °C. The mixture was stirred at room température for 1 h, then concentrated under vacuum. The residue was partitioned between aqueous NaHCCh solution and dichloromethane. The organic layer were dried over anhydrous Na2SÜ4 and concentrated to provide 17d (252 mg, 96% yield) as a yellow solid. LC-MS: 394 [M+l]⁺.

Step 4:

To a mixture of 17d (252 mg, 0.64 mmol) and 37% aqueous HCHO solution (250 mg, 3.1 mmol) in MeOH (15 mL) were added NaOAc (600 mg, 7.3 mmol), AcOH (1 mL, 50 mmol) and NaBHaCN (121 mg, 1.9 mmol) at room température. The mixture was stirred at room température ovemight, and then concentrated under reduced pressure. The residue was partitioned between dichloromethane (50 mL) and saturated NaHCCh solution (50 mL). The organic phase was separated, washed with brine, dried with anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica, methanol: dichloromethane 1:50, 1% NH4OH) to provide H0837 (200 mg, 77% yield) as a white solid. ’H-NMR (CDCh, 400 MHz): <5= 8.82 (d, 1 H), 8.60 (dd, 1 H), 8.50 (d, 1 H), 7.97 (br, 1 H), 7.38 (d, 1 H), 7.28-7.31 (m, 1 H), 5.26-5.31 (m, 1 H), 4.08-4.10 (m, 1 H), 3.03-3.06 (m, 1 H), 2.95-2.99 (m, 2 H), 2.90 (s, 3H), 2.19-2.35 (m, 5 H), 1.94-1.98 (m, 2H), 1.37-1.40 (m, 3 H). LCMS: 408 [M+l]⁺.

Step 5:

H0862 was obtained through the chiral séparation of H0837 (Chiralcel OJ-H, 5pm, 4.6 x 250 mm, Hex:EtOH:DEA=90:10:0.3, rétention time: 11.34 min). ’H-NMR (CDC1₃,400 MHz): 5= 8.82 (d, 1 H), 8.60 (dd, 1 H), 8.51 (d, 1 H), 7.98 (br, 1 H), 7.37 (d, 1 H), 7.30 (d, 1 H), 5.28-5.31 (m, 1 H), 4.07-4.10 (m, 1 H), 3.06-3.10 (m, 1 H), 2.99-3.06 (m, 1 H), 2.90 (s, 3H), 2.20-2.35 (m, 5 H), 1.96-2.05 (m, 2H), 1.38 (d, 3 H). LC-MS: 408 [M+l]⁺.

Example 20

Synthesis of H0900

triphosgene

Step 1:

To a mixture of 16d (32 g, 120 mmol) in dry CH2CI2 (800 mL) was added Dess-Martin peroxide reagent (76 g, 180 mmol) portion-wise at 0 °C. The mixture was stirred at room température for h, then diluted with DCM (800 mL), washed with aqueous NaHCCh solution (300 mL) and brine (300 mL). The organic phase was separated, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to afford crude 18a (31.4 g) which was used directly in the next step without further purification.

Step 2:

To a solution of 18a (12 g, 40 mmol) and 3b (22.2 g, 60 mmol) in DME (560 mL) were added Pd(PPh3)4 (9.25 g, 8 mmol) and Cul (1.52 g, 8 mmol) at room température. The mixture was stirred at 90 °C ovemight, then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica, EA : PE = 1:5) to provide 18b (8.0 g, 79.3%) as a 10 white solid. LC-MS: 253 [M+l]⁺.

Step 3:

To a solution of 18b (7 g, 27.7 mmol) and fS)-tert-butylsulfinamide (7.27 g, 30.56 mmol) in dry THF (200 mL) was added Ti(i-OPr)4 (15.7 g, 55.4 mmol) dropwise at room température. The 15 mixture was stirred at 80 °C ovemight, and then cooled. Ethyl acetate (40 mL) was added, the resulting mixture was filtered and the fîltrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica, EA:PE =1:5) to provide 18c (6.8 g, 69%) as a yellow solid. ’H-NMR (CDCh, 400 MHz): δ= 9.10 (s, 1H), 8.97 (s, 1H), 8.72 (s, 1H), 8.64 (d, 1H),8.12 (d, 1H), 7.59 (d, 1H), 1.30 (s, 9H).LC-MS: 356 [M+l]⁺.

Step 4:

To a stirred solution of 18c (6.8 g, 19 mmol) and Tetrabutylammonium difluorotriphenylsilicate (15.8 g, 29 mmol) in dry THF (250 mL) was added a solution of TMSCF3 (11 g, 77 mmol) in anhydrous THF (50 mL) at -65 °C. The mixture was then stirred at -65 °C for 2 h, and at that 25 point aqueous NH4CI solution (250 mL) was added. The mixture was diluted with ethyl acetate (250 mL), washed with brine (250 mL), dried over anhydrous Na2SÜ4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica, EA : PE=1:2) to provide 18d (4.3 g, 52%) as a yellow solid. LC-MS: 426 [M+l]⁺.

Step 5:

To a stirred solution of 18d (4.3 g, 10.1 mmol) in MeOH (40 mL) was added a solution of

HCl/MeOH (4N, 40 mL) at room température. The mixture was stirred for 1 h, then concentrated under reduced pressure. The residue was triturated with ethyl acetate (40 mL) to afford crude 18e (4.3g) which was directly in the next step without further purification. LC-MS: 322 [M+l]⁺.

Step 6:

To a solution of 18e (2.7 g, 7.1 mmol), 2b (3.4 g, 21.3 mmol) and TEA (80 mL) in DCM (220 mL) was added thiphosgene (3.15 g, 10.6 mmol) in DCM (40 mL) dropwise at 0 °C. The solution was warmed to ambient température and stirred for 1 h, then diluted with DCM (100 mL) and washed with aqueous Na2CC>3 solution (100 mL) and brine (100 mL). The organic layer 10 was separated, dried over anhydrous ISfeSCU and concentrated. The residue was purified with silica gel column chromatography (silica, DCM : CHjOHTIO : 1) to provide crude H0900 (2.13 g, ee%=92.5%) which was further purified through chiral séparation to afford H0900 (1.6 g, 49% yield) as a white solid. (ee%=98.5%, Chiralpak IC 5um, 4.6*250mm, Phase: Hex: EtOH: DEA=90:10:0.2), rétention fine =12.829 min. ’H-NMR (CDCh, 400 MHz): δ= 8.86 (d, 1H),

8.63 (dd, 1H), 8.55 (d, 1H), 7.47 (d, 1H), 7.40 (d, 1H), 6.28 (m, 1H), 5.18 (d, 1H), 4.12 (m, 1H),

2.88 (t, 2H), 2.77 (s, 3H), 2.22 (s, 3H), 2.05 (m, 2H), 2.48 (m, 2H), 1.52 (m, 2H), 1.73-1.49 (m, 4H). LC-MS: 476 [M+l]⁺.

Example A

Calcium FLIPR Assay

The intracellular calcium assay was carried out in a 384-well format FLIPR™ (Molecular Device) HEK293/GHSRla cell line. Cells were seeded 24 hr prior to the experiments at an optimal density per well. Preincubation with selected calcium dye lasted for 30-60 min at room 25 température or 37° C. Test compounds, dissolved in DMSO, were added at the appropriate time and incubated for 15 min followed by the addition of ghrelin with FlexStation or FLIPR. Relative fluorescence was monitored by the FLIPR™ Molecular Device. EC50 and IC50 values were estimated from dose-response data using GraphPad Prism software. To check for GHSR-la agonism the compound was added at t=20 sec. and the calcium response was followed for 2 30 minutes. To check for GHSR-la antagonism the compound and Ghrelin (10 nM) were added to the cells at t=20 sec. and the calcium response was measured for 2 minutes. The potency of the antagonist was calculated by its ability to reduce the ghrelin response. Dose-response curves were made for relevant antagonists.

Example B

Evaluation of GHSRla Antagonists on Food Intake Test in Mouse

Male C57BL/6J mice, 18-22 g body weight, were fasted overnight (16 h before compound administration) and placed in a regular light dark cycle (6:00-18:00 light/18:00-6:00 dark). After 1 wk acclimation, animais were sorted into two groups (n=6 each, 2 per cage) based on body weight. Animais in group one were be treated with vehicle and animais in group 2 were treated with the test agent (n=6 for each group). The cumulative food intake was evaluated at 1, 10 2,4, 8 and 24 hrs after drug or vehicle treatment. Food intake was measured by subtracting uneaten food from the initial premeasured food.

The following table présents représentative compounds of Formula I with biological data including the ghrelin antagonist/agonist activity in vitro (Example A) and mouse food intake results (Example B). The data clearly demonstrates that compounds of Formula I are ghrelin receptor modulators and are useful in preventing and/or treating diseases associated with ghrelin receptor, for example, obesity.

TABLE 1

Compoun dNo.	Chemical Structure	Activity	Metabolic Stability (H = Human; M = Mouse)	Mouse Food Intake (% Inhibition; Doses as mg/kg i.p.)*
H0494	^Me'N'^xA O Me Cl άα aa·⁰¹	IC₅o= 52 nM EC50 =66 nM Emax ⁼ 2996	Medium H HighM	No Effect
H0621	^Me'N^A O Me Cl °^{H H} AA^f F	IC50A30 \|1M EC50 “2 nM Emax ⁼ 3896	HighH HighM	No Effect
H0496	^MeNA O Me Cl UAW lie ^H LA	IC₅₀= lOnM ECso >30 μΜ	Medium H HighM	NSE (10 mg/kg)

Η06Γ7	0 Me Cl Me ^H AAyïy 4	IC_So=3.4pM EC_So>3OpM	Not done	Not Done
H0539	0 Me Cl A ^hXcc MeO₂C^^ N	IC₅o= 9 nM EC50 >30 μΜ	Not done	Not Done
H0546	^MeN'^> 0 Me Cl îV ^hXXc ηο^Λ>	ICso= 8 nM EC50 >30 μΜ	Medium H Medium M	Not Done
H0526	Λ~-> O Me Cl MeN 1 Il 1 1 _c, ώθ ^H UUy ^hT	IC₅o= 57 nM EC50 >30 μΜ	Not done	Not Done
H0527	Μβ.,,ζχ ^Me„ ,, N y 0 Me Cl lAnAnÂ/L·'	IC₅₀=19nM EC50 >30 μΜ	Medium H Medium M	Not done
H0497	O Me Cl ^A_n^c. lie ^H UU^. AAn	IC_So= 24 nM EC₅o>3O μΜ	Medium H Medium M	NSE (30 mg/kg)
H0650	^Μθ'ΝΆ ^{0 Me cl} Λ H Me nA	IC5o= 4 nM EC50 =9 nM Emax = 2150	Not Done	Not Done
H0849	Μθ'Ν^] 0 Me Cl ^_nA_n^ci ώ. ^H UUy	IC50- 37 nM EC50 =51 nM Emax ⁼ 1383	Not Done	Not Done

H0578	^Μθ'Ν'^^χΊ 0 Me AU) Me ^H Un	ICso=49O nM ECso >30 μ M	Not Done	Not Done
H0511	^MeN'^XU O Me Cl u/AU Me ^H UU^ N OMe	IC₅o= 98 nM ECso>3O μΜ	Medium H Medium M	94% at lh Inhibition up to24h (30 mg/kg))
H0820	“θ'ΝΛ O Me Cl lie UU^ ^ⁿ^\7	ICso= 5.7 nM EC50 =9 nM Emax ” 3955	Not Done	Not Done
H0613	^Me'N^> 0 Me Cl aAu-uv¹ ¹ H Me ⁿ \AUA/^CN	ICso⁼ 20 nM EC50 >30 μΜ	HighH High M	NSE (10 mg/kg) PO: inhibition at lh, up to 2 h IP+ANAM 30 mpk PO: inhibition at lh up to 24h
H0614	0 Me Cl AAkU¹ Me ^H LAy^V	IC₅o= 12 nM EC50 >30 μΜ	HighH High M	No IP done, PO: NSE
H0635	^Me'N·^ 0 Me Cl ¹ H Me k^k^^COaMe	ICso= 1090 nM ECso>3O μΜ	Not Done	Not Done
H0636	Μθ'Ν^'Α O Me Cl U^u-AU_V ^CÎ “ ^H IX^OH >ι\κ	IC₅o= 90 nM ECso>3O μΜ	HighH Medium M	Not Done

H0637	^ΜθΝ^Α O Me Cl ΑΑΑΑ/γ¹ f i H 1 Μ»	IC5o= 85 nM ECso>3O μΜ	Medium H Medium M	Not Done
H0638	0 Me Cl AAAAA-⁰¹ ώ. ^H Ap/.p	IC₅o= 57 nM EC50 >30 μΜ	Not Done	Not Done
H0639	^MeN^A 0 Me Cl ΑΛ\γ Me ^H	IC_So= 48 nM EC5o>3O μΜ	Medium H Medium M	NSE (10 mg/kg)
H0642	^ΜβΑ'Χ O Me Cl LAAA/v⁰¹ Λ ^H ^M° ''ya	IC_S0= 78 nM EC50 >30 μΜ	Very low H Very Low M	Not Done
H0704	^MeN^P 0 Me Cl Onaa° Me ^H ρΛγγΝΗ₂	IC_So=19nM EC50 >30 μΜ	HighH Medium M	32% inhibition at 2 h (10 mg/kg)
H0705	Μθ'Ν'Χ O Me Cl ΑΑΡΡγ' γλ ώβ ^H Αγν	IC₅₀= 53 nM EC5o>30 μΜ	HighH HighM	Not Done
H0707	^MeN^A O Me Cl AVA” _Nώ. ^h ΑΡγΑ/^ΝΗ ^1+	IC₅o=185nM EC₅o>3O μΜ	Not Done	Not Done

H0711	O Me Cl Υ'Λ'Υγ⁰¹ n*=\ ώβ ^H	IC₅(A 1.85μΜ ECso >30 μΜ	Not Done	Not Done
H0716	^N'A 0 Me Cl S'A lùe ^H ΜγγΟ¹	IC₅₀= 15nM EC50 >30 μΜ	LowH Medium M	Not Done
H0717	Μθ'Ν^Α O Me Cl ΑΑ^νΑΛχ¹ ώ. ^H 1-AA	IC_So= 396 nM ECso >30 μΜ	Not Done	Not Done
H0718	^MeN^A O Me Cl A_nA_nÂN_vci Λ h > ^Me ΑΑ/χ/Α	IC₅₀= 499 nM ECso >30 μΜ	Not Done	Not Done
H0719	Πθ'Ν^'Α 0 Me Cl Me ^H	IC₅o= 780 nM EC50 >30 μΜ	Not Done	Not Done
H0712	^M®'N'A 0 Me Cl ^lA_na_naj_vc₁ Me ΑΑΑΆ ΪΎ L o N	IC₅₀= 420 nM EC50 “ 220 nM Emax ⁼ 1962	Not Done	Not Done
H0708	^MeN^A O Me Cl 'AA_Y ^CI ώθ ^H UA^n., Af AL OMe	IC₅o= 1.37μΜ EC_So >30 μΜ	Not Done	Not Done

H0714	0 Me Cl ^L'A_naA'Av^ci ¹ H Me	IC₅o= 453nM > EC50 >30 μΜ	Not Done	Not Done
H0715	^MeN^~A 0 Me Cl LAAAJyCI Me ^H	IC_So= 57 nM EC50 = 42nM E_max = 2479	Not Done	Not Done
H0706	^Μβ'ΝΦ O Me Cl LAAAAa ' H Μθ	IC₅₀=116nM EC₅o= 91 nM E_max = 2111	Not Done	Not Done
H0710	^ΜθΝ^/ΧΑ 0 Me Cl LAAAAa Me ^H	IC₅₀= 275 nM EC50 = 395nM Emax ⁼ 1621	Not Done	Not Done
H0666	O CN Cl EA,A'nAJ_v ^ci i H Me ^hF	IC50 =8 nM EC50 ”21 nM Eæax ~ 4927	Not Done	Not Done
H0739	^Μθ'ΝΦ 0 CN Cl _HN_~ Me ^H UÇ^A?	IC₅₀= 39 nM ECso>30 μΜ	Not Done	Not Done
H0667	^Μθ'Ν^ O Me Cl ’AAAV¹ OH ^H ^bF	IC₅o <1 nM EC50 = 3 nM Emax ⁼ 4887	High H HighM	76% inhibition at lh; activity upto4h(10 mg/kg)

H0821	O Me Cl i H Me CN Α-Μθ	IC₅o= 2.3 μΜ ECso >30 μΜ	Not Done	Not Done
H0646	^MeN^V O Me Cl al_na_nW^ci N'^ohώθ ^H IXyH	IC₅o= 541 nM EC50 >30 μΜ	Not Done	Not Done
H0720	o / ci uaw ^H	IC50” 8 nM EC50 >30 μΜ	Medium H High M	Not Done
H0721	^MeN^A 0 (CI UAW Me ^H	ICso⁼ 20 nM EC50 >30 μΜ	Medium H High M	Not Done
H0516	^Me'N^ 0 Me Cl A_na_naJLci Me ^H 'Ap, V	IC₅₀= 41 nM EC50 >30 μΜ	High H High M	88% inhibition at 1 hour. Activity up to 24 h (30 mg/kg ) PO: no effect
H0579	^M®'nV 0 Me rfA A_na_n-W ώβ ^H LX^_n M	IC₅o=l μΜ ECso >30 μΜ	Not Done	Not Done
H0649	^MeN^A 0 Me Cl - ^H TA_ l A N OMe	IC50= 18nM EC50 = 64 nM Emax ~ 1400	High H High M	48% inhibition at 1 and 2 h (10 mg/kg)

H0797	^Μβ'Ν^/Α O Me Cl AAW - ^H Op l A N OH	IC₅o= 594 nM EC₅o = 1.8 μΜ Emax ⁼ 2879	Not Done	Not Done
H0798	0 Me Cl UAW - ^H l A n nh₂	ICso=162nM EC50 >30 μΜ	Not Done	Not Done
H0799	^Me'N^A 0 Me Cl Awa ώ. ^h ιλ_Γν ^^N'Me	IC₅o= 5.4 nM EC50 =14 nM Emax ~ 503 1	Not Done	Not Done
H0800	^Μθ'Ν^χΑ 0 Me Cl JaAa i H Me	IC50- 1.3 μΜ EC5o>30 μΜ	Not Done	Not Done
H0801	O Me Cl ÜAW λ. ^H UL· kA	IC₅o= 20 nM EC50 = 45 nM Emax = 3915	Not Done	Not Done
H0802	O Me Cl lVav i H M. Ά'όν	IC₅o= 99 nM EC50 =153 nM E_max “ 4149	Not Done	Not Done
H0803	^Me'N^A O Me CI AA-W¹ i H Μθ ^N^O	IC₅₀= 171 nM EC₅₀ = 149 nM Emax ⁼ 2364	Not Done	Not Done

H0804	^MeN^A 0 Me Cl UAW - ^H ^Ν^ΛΝ-^Μβ Me	IC₅o= 375 nM ECso = 263 nM Emax ⁼ 2740	Not Done	Not Done
H0805	O Me Cl I H ^Μβ Ά··< . IL A A N N H	ICso= 4 nM EC50 =9nM Emax ⁼ 5433	Not Done	Not Done
H0806	^MeN^A 0 Me Cl UAW - ^H XX^_NUn* H	IC₅₀= 1.2 nM EC50 ⁼ 6.8 nM Emax ~ 5751	Not Done	Not Done
H0807	^ΜβχΝ'^χΑ 0 Me Cl Me ^H ₀	ICso= 14 nM EC50 ~ 24 nM Emax ⁼ 3669	Not Done	Not Done
H0854	^Me'N^/A 0 Me Cl UAW ώ. ^H ΐΛρ_Ν ^Ν<ίίν	IC5o= 65 nM EC50 ⁼24 nM Emax ⁼ 3246	Not Done	Not Done
H0813	O Me Cl ^ALy^ci Λ ^H ^Me	IC₅o= 644 nM EC50 = 528 nM Emax - 1605	Not Done	Not Done
H0814	^Me'N^xA 0 Me Cl Me ^H LL/^_n	IC₅₀= 926 nM EC₅o= 15 nM Emax ⁼⁼ 1097	Not Done	Not Done

H0703	^Μθ'Ν A O Me CN Çl - ^H 1¼ In*¹	IC₅₀= 695 nM ECso >30 μΜ	Not Done	Not Done
H0709	^Μθ'Ν^> 0 CN Cl à h H 1 'Me N	IC_S0= 676 nM ECso >30 μΜ	Not Done	Not Done
H0584	0 Me Cl AAVy^ci Me ^H Uy>_N N	IC₅₀= 1-1 μΜ ECso >30 μΜ	Not Done	Not Done
H0586	0 Me Cl u/AV Me ^H II	IC₅₀=4.2 μΜ ECso⁼ 63 μΜ	Not Done	Not Done
H0587	O Me Cl WAV Me ^H kÀ_Y^_NV	ICso>3O μΜ ECso >30 μΜ	Not Done	Not Done
H0588	0 0 Me Cl ΆΛΑΜ¹ Me ^H 'A/=>_nV	ICso >30 μΜ ECso >30 μΜ	Not Done	Not Done
H0663	^Μθ'Ν^ O Me Cl _0Me ώ.^H IXx_N 1 A N OMe	ICso” 274 nM ECso >30 μΜ	Not Done	Not Done

H0620	A ^ΜβΝ_Ί o r° ci ^0HA/AA - ^H uç,_N	ICso=32 nM EC50 >30 μΜ	PoorH Poor M	Not Done
H0624	^MeN'^/Xj 0 Me Cl ALAAAa ÔH « IX^_NA	IC₅o= 253 nM EC50 >30 μΜ	Not Done	Not Done
H0662	Me^_kl^\ _ Os .OMe OjXv ό H l 'J N	ICso->l μΜ ECso >30 μΜ	Not Done	Not Done
H0670	^Ms'n^, O r^0H0l ΦΑγ λ. ^H LAp_N V	ICso= 523 μΜ ECso >30 μΜ	Not Done	Not Done
H0673	^M‘O î v ? ό H Me l N	IC5o>l μΜ ECso >30 μΜ	Not Done	Not Done
H0727	o A _Cl - ^H IK_MA	IC₅₀=3.6 μΜ ECso >30 μΜ	Not Done	Not Done
H0631	0 CN Cl AAW¹ Me ^H U.z>_tM	ICso=719 nM ECso >30 μΜ	Not Done	Not Done

H0686	^Μθ'νΎ ο cf3 ci làayçci ώβ^Η UUN Μ	IC₅o= 14 nM EC50 >30 μΜ	Medium H High M	61% inhibition at 2hand4h(10 mg/kg) PO: NSE
H0619	0 Me Cl <A_na_nXA<^ci Me ^H νΆ	IC₅o= 13 nM EC50 = 39 nM	High H High M	34% inhibition at 1 and 2 h (10 mg/kg)
H0768	0 Me Cl Me ^H ΙχΑχχ^Νχ Il	IC₅₀= 279 nM EC5o>3O μΜ	Not Done	Not Done
H0808	^MeN'^xX 0 Me Cl i H Me Me	ICso= 674 nM EC50 “ 90 nM E_max⁼1494	Not Done	Not Done
H0700	^Me'N^X O Me Cl i H Me ⁿ U N	IC₅o= 7 nM EC5o>3O μΜ	High H High M	41% inhibition at 2 h; activity upto4h(10 mg/kg) 71% inhibition at 1 h, activity up to 2 h (Fed, 10 mg/kg) PO SC: inhib at 1,2 h
H0816	^Me'N^X 0 Me Cl ΧιλΧ' i H Me ⁿ \A/% M	ICso=5.1 nM ECso>3O μΜ	Not Done	12% inhib 30 mg/kg PO fasted mice

H0817	^MeN^A 0 Me Cl W/yV¹ Me ^H AA/N. i: N	IC₅o= 94 nM ECso>3O μ M	Not Done	30 mg/kg PO fasted mice NSE
H0722	^ΜθΆ 0 f Cl MAnAA⁰¹Me ^H M	ICso= 13 nM ECso>3O μΜ	HighH High M	90% inhibition at 1 h; activity up to 24 h (10 mg/kg) PO: NSE (30 mg/kg)
H0741	^Me'N^ Ο Λ UA-w ¹ H OMe U N	ICso= 15 nM ECso-^O μΜ	Not Done	Not Done
H0752	^MeN^ 0 /ci AAAy^cl OEt ^H AA/N U N	IC_5o=100nM EC50 >30 μΜ	Not Done	Not Done
H0743	^Μβ'Νυ 0 Me Cl ¹ H OMe ⁿ A^k/%	IC₅o= 94 nM EC50 >30 μΜ	Not Done	Not Done
H0750	^M®N^U O Me Cl cXAnUU⁰¹ OEt ^Π LAX U N	IC₅o= 177 nM EC50 >30 μΜ	Not Done	Not Done
H0756	^Me'N^A O Me Cl ^/_N^n/A^ci ¹ H OH \Ax/ⁿ\ O N	IC₅o= 13 nM ECso= 13 nM E_max=1729	Not Done	Not Done

H0761	^Me'_NQ	OH ^H 1	Cl	IC50” 0.2 nM EC50 — 3 nM Emax “ 2907	High H HighM	63% inhibition at 1 h; activity up to 8h (10 mg/kg) PO: NSE No activity in fed mice PO: 215% FI increase in fed mice. No activity in fasted mice
	_XCI ___N i: N
H0781		OH ^H l (s,R)	Cl 'ί'	_XCI i: N	IC₅o= 95 nM EC50 =420 nM E_max ~ 4210	Not Done	Not Done
	(single enantiomer)
H0782	^Me'rQ	OH ^H l (S,R)	Cl	,ci i: N	ICso= 5 nM EC50 =6 nM E_raax =1923	Not Done	93% inhibition at 1 h, activity up to 24 h (10 mg/kg)
	(single enantiomer)
H0824	^μΆ U	de ^,Me_ O Me Λ H Me <	Cl	_XCI Π A	IC₅o= 3 nM EC50 >30 μΜ	High H Medium M	PO 30 mg/kg + ANA mice: NSE
				1J N
H0890	^M,A A·	de ^x 0 Me Λ H Me <	Cl 'y'	_XCI i: N	IC₅o= 1.6 nM EC50 >30 μΜ	High H HighM	Not Done
H0858	^Μ®'Ν'^ΧχΧ^Μ®Ο <^Me .'. H Me <	Cl ^x	γι h A	ICso= 8 nM ECso>3O μΜ	Medium H Medium M	Not Done
				l J N

H0865	.. ^Me.. Ά'ο cf₃ α τΧυυν Me ^Η Αλ/Ν a : Ν	ICso= 6 nM ECso>3O μΜ	Medium H LowM Medium R	Not Done
H0825	^Μ®'νΑ 0 Me Cl /Αλλα ) ^Η Αλ ο U	IC₅o= lOnM ECso>3O μΜ	Medium H Medium M Medium R	Not Done
H0826	0 Me Cl τΆμΑτΆ⁰¹ _Μτ ^Η ΙΧν	ICso= 5 nM ECso>3O μΜ	HighH HighM HighR Medium D	Not Done
H0889	^MeNA ο Me Cl A_na_nXJLc_I U ^H νφ N	IC₅o= 6 nM EC50 >30 μΜ	HighH HighM	Not Done
H0896	ο Λα U ^H νφ N	ICso” 7 nM EC5o>3O μΜ	Not Done	Not Done
H0827	^Me'N^U 0 Me Cl UAW ^H A Me	ICso= 35 nM ECso>3O μΜ	Not Done	Not Done
H0829	o“S a Φλν i H Me ⁿ 1O N	IC₅o= 3nM ECso>3O μΜ	HighH HighM	PO 10 mg/kg + ANA30 mg/kg mice: NSE

H0859	“'-NY <?··.. Cl ÜaA Me ^H AA/bf Ai N	IC₅₀= 2.2 μΜ ECso >30 μΜ	Not Done	Not Done
H0860	^Me'N^\| <^Ί C! AAv Me ^H AAa	ICso= 3nM ECso >30 μΜ	High H HighM	68% inhib 1 h PO 10 mg/kg ΠΑΝΑ 30 mg/kg mice
H0922	^Me'N Y K‘°Y° d Μθ ^H AA*k A) N	ICso⁼ 2.8 μΜ ECso >30 μΜ	Not Done	Not Done
H0924	Μθχ HO nA 0 > Cl i H ^.3	IC₅₀= 300 nM EC50 >30 μΜ	Not Done	Not Done
H0830	^Me'N^A O CF₃ Ci Aaa Me ^H ^,3	IC₅₀= 3nM ECso >30 μΜ	High H HighM High R Medium D	Not Done TBD
H0899	^MS'nA 0 CF₃ Cl uaâa i H Me ^Π a: N	ICso= 1.6 μΜ ECso >30 μΜ	Medium H HighM	Not Done
H0900	^m®'nA o cf₃ Cl Akw Me ^H A^\/bl ^.3)	ICso⁼ 3nM ECso >30 μΜ	Medium H HighM	60% inhib 1 h PO 10 mg/kg ΠΑΝΑ 30 mg/kg fed mice 91% inhib 1 h PO 30 mg/kg +

				ANA30 mg/kg fed mice 26% inhib 1 h PO 30 mg/kg fasted mice 90% inhib 1 h PO 30 mg/kg fed mice
H0909	^Me'N^/U 0 CF₃ Cl A_nA_n^c, N	IC₅o= 12nM EC50 >30 μΜ	Medium H HighM	Not Done
H0856	0 Me F A_nA_nW I H Me ^Π U N	IC₅o= 339nM ECso>3O μΜ	Not Done	Not Done
H0837	Me ,^N-T 0 Me Cl A a_naï c. Me ^H LAzN. ID N (diasteromeric mixture)	IC50” 2nM EC_So>3O μΜ	HighH HighM HighR High D	180% increase 2 h mice 30 mg/kg PO PO 10 mg/kg + ANA30 mg/kg mice: NSE
H0861	Me N-n 0 Me Cl Me ^H (R/S) Y J N (single diastereoisomer)	IC₅o”189nM EC50 >30 μΜ	Not Done	Not Done
H0862	Me N-i 0 Me Cl Xaw 1 H Me ^π (R/S) Y J N (single diastereoisomer)	IC50” 3nM EC5o>3O μΜ	HighH medium M	PO (10 mg/kg) + ANA: no activity in mice

H0857	Me N-. 0^Μθ> Cl i H Me ⁿ x: N	IC₅o= 10nM EC50 >30 μΜ	Medium H LowM	Not Done
H0871	Me À o çF_Sçi ΆΑγΑ Me ^H O N	ICso= 9nM EC50 >30 μΜ	Not Done	Not Done
H0874	Me Λ. N-i 0 ( Cl Α'ΆΝ-Μγθ¹ Me ^H AA/N 0 N	IC_5O=115nM ECso>3O μΜ	Not Done	Not Done
H0853	^MeN'^> 0 Me Cl Ox^aJCc! Me ^H 0 N	IC₅₀= 1.5 μΜ ECso>3O μΜ	Not Done	Not Done
H0815	^MeN^> O Me Cl lâ,a_nâJLci Me ^H Me IT N	IC₅o= 176 nM EC50 >30 μΜ	Not Done	Not Done
H0831	0 Me Cl Me ^H JÜ Me^N	IC₅₀= 1.2 μΜ ECso>3O μΜ
H0843	Μθχ.,/χ / „ .. N O Me Cl ΑΑ_ΝΛ_ΝΑΑγι Me ^H xAxx^N.. Me^N	IC₅o= 35 nM EC50 = 51 nM E_max= 1910	Not Done	Not Done

H0844		XV ' H Me	Cl	IC₅o= 705 nM ECso>3O μΜ
û Me'	,CI
H0738	^ΜΌ	O Me Λ ^HMe <	Cl V^CI	N. .OMe T N	IC₅o= 696 nM EC5o>30 μΜ	Not Done	Not Done
H0780	^Μβ 0	0 Me Va i H Me <	Cl A^C1 II	_N NH₂ A	ICso” 63 nM ECso>3O μΜ	Not Done	Not Done
H0786	^ΜΌ	0 Me AA i H Me <	Cl -V^e1	^N'^Î>[A'C\|	IC₅o= 855 nM EC50 = 242 nM E_raax=980	Not Done	Not Done
H0791		> O Me Va ' H Me	Cl V' At N	IC₅₀= 75 nM ECso>30 μΜ	Not Done	Not Done
H0795	Me.ç	> O Me Va ' H Me	Cl A^cl At N	IC₅₀=4nM ECso>30 μΜ	High H High M	PO: NSE PO+ANA: inhib in mice, no activity in rat
H0847		b O Me w Λ H Me	Cl At¹ At N	ICso= 2 nM EC50 >30 μΜ	High H High M	PO 10 mg/kg + ANA30 mg/kg mice: NSE
		(S enantiomer)

H0848	^Me'N^A 0 Me Cl Φαα i H Me ^π F 1T N (R enantiomer)	ICso= 432 nM ECso >30 μΜ	Medium Η HighM	PO 10 mg/kg + ANA30 mg/kg mice: NSE
H0863	0 Et Cl 1 H Me ^π F iy N	IC50— 3 nM ECso >30 μΜ	Medium Η HighM	Not done
H0908	0 CF₃ Cl UAW i H Me ⁿ F IT N	ICso= 8nM ECso >30 μΜ	Medium Η HighM	Not Done
H0864	Me N-i O Et Cl ÛAW' i H Me ⁿ AA/N^F IT N	IC_S0=718nM ECso>30 μΜ	Not Done	Not Done
H0872	Me N-ι O Me Cl ÛAAL· Me ^H	ICso” 6 ηΜ ECso >30 μΜ	HighH medium M	Not Done
H0840	^Me'N'^xA O Me Cl i H Me ⁿ \A\N jD F N	IC₅o= 47 ηΜ ECso >30 μΜ	Not Done	PO 10 mg/kg + ANA30 mg/kg mice: NSE
H0910	^Me'NY 0 Me Cl Me ^H CF₃ V	IC₅o= 125 ηΜ EC_So= 19 ηΜ E_max ⁼ 1359	Not Done	Not Done

H0788	^ΜθΝ^Α 0 Me Cl i H Me ⁿ CN	ICso= 88 nM EC50 ⁼ 20 nM Emax ⁼ 1230	Not Done	Not Done
H0789	0 Me Cl A<_nA_nAX,ci _o Me ^H \A^NxÂ_n.. << OMe	IC₅₀= 284 nM EC50 ⁼ 26 nM Emax =1137	Not Done	Not Done
H0760	^Me'N^x^i O Me Cl Me ^H 0	ICso⁼ 6.2 μΜ ECso>3O μΜ	Not Done	Not Done
H0769	“θ'Ν^ι 0 Me Cl i H Me ⁿ l^OMe O	IC_So=318nM EC50 >30 μΜ	Not Done	Not Done
H0771	O Me Cl AAAAA>^ci Me ^H AAy^ ί_Ν\'^ΝΜβ20	ICso= 9 nM EC50 - 9 nM Emax ⁼ 4662	Not Done	Not Done
H0770	O Me Cl aA_na_naAy^cii H Me ⁿ ^XoH	IC₅o= 700 nM EC50 = 294 nM Emax ⁼ 1783	Not Done	Not Done
H0828	^{0 Me Cl} ΑνΧ° ^H	IC₅o= 376 nM EC5o>3O μΜ	Not Done	Not Done

H0822	Μθ'Ν·''''] Ο Me Cl ^Ν^νΑΛ/⁰¹ TFA Me ^H U^N'Me	IC_So= 1.2μΜ ECso>3O μΜ	Not Done	Not Done
H0850	^MeN^A 0 Me r^ji UAW Me ^H 1O N	IC_So= 1.2 μΜ ECso >30 μΜ	Not Done	Not Done
H0881	^Me'N·^] O Me Cl ^n^nÙA/^ci ^H M	IC₅o=81OnM EC50 >30 μΜ	Not Done	Not Done
H0729	Μθ'Ν'^'Ά 0 Me Cl UAW Me ^H ÇaA_n	IC₅₀= 100 nM EC50 “ 95 nM Emax ⁼ 2818	Not Done	Not Done
H0783	^Me'N^> O Me Cl i H Μβ c	IC₅₀= 681 nM EC50 ⁼ 30 nM	Not Done	Not Done
H0793	^M®N^/U O Me Cl UAW¹ Μθ ^H ί^Λγ%	IC₅₀= 21 nM EC50 ⁼ 22 nM Emax =3501	Not Done	Not Done
H0796	^MeN^/U O Me Cl Me ^H LX^N^N^J ΝγΝ ô O	IC₅₀= 826 nM EC50 = 3 μΜ E_max ⁼ 1671	Not Done	Not Done

H0498		Xa i H Me	Me ]ί	Cl	IC₅o= 29 nM ECso>30 μΜ	Medium H HighM	76% inhibition at Ih, activity up to 24h (30 mg/kg)
Ax xA	Ai Ί	A 'S
H0531		O Me M ' H Me	Cl -A χ^	Z^CI	A		ICso⁼ 4 nM EC50 = 5 nM	Medium H PoorM	Not Done
				\|l__	s⁷
					Ί\|

	Me^_kl/~		I <°	Cl	OH		Poor H
H0594	N					IC₅o= 54 nM	Medium	Not Done
			A	.CI		ECso>3O μΜ	M
		Me ^H	](			A
						s⁷
	Me„
	N	Ί ?	CN	Cl
		i H			,CI	ICso⁼ 6 nM	Medium H
H0644						EC50⁼ 28 nM	Medium	Not Done
		Me				[T\	Emax ⁼ 2822	M
						I 7 ^~S
	Me„
H0536	N	XX' H Me	Me II	Cl Ax,	„CI	J	ICso⁼ 3 nM EC5o>3O μΜ	Medium H Medium M	76% inhibition at lh, activity up to 24 h
					s-		(30 mg/kg)
		(racemic mixture)
	^Me'N^	> O	Me	CI					65%
H0563	X	λ_ΝΑ_Ν- Λ H Me	\|l	Ax, xA	„CI s-	J	IC₅o= 1 nM EC50⁼ 3 nM Emax = 2100	Medium H Medium M	inhibition at 1 h(10 mg/kg)
		(single enantiomer)
	Me^
	N	Xa i ^HMe	Me	Cl	Al		IC_So= 75 nM
H0564	k.	11			EC50 = 124 nM	Not Done	Not Done
		R/S		s-		Emax = 1987
		(single enantiomer)

H0627		A O Me Cl	IC₅o= 4 nM ECso = 1 nM E_max = 5289	HighH High M	Not Done
AX OH ^H	U	.Cl s--^
	Me,, χ	\ _n O.	,OMe
	N	A o A	Cl
	L	A A A	.Cl		IC₅₀= 69 nM
H0660		N N Λ H Me			EC_so=18OnM	Not Done	Not Done
		A			Emax = 2100

	Me,,,/	Αχ I	,OH
	N	Cl	.Cl		ICso⁼ 2 nM
H0661		I H				EC5o=6 nM	Not Done	Not Done
		Me ^M				Emax ” 2280
				s-A
	Me„,,x
	N	l 9 V	7 Cl
	l	A A A	.Cl		1C5o>1 nM
H0672		N N I H	ίΧ		EC50 >30	Not Done	Not Done
		Me		iO		μΜ
	Me,
		Ί O Me	Cl
	A/		iA	Cl		ICso= 4 nM
H0651		J. H Me	AA			EC₅o=llnM Emax = 2300	Not Done	Not Done
				CHO

	AA	O Me A	Cl
	M	V		IC50— 4 nM	Medium H
H0653		J. H Me 't	-, A\			EC50 ~ 9 nM	Medium	Not Done
				sA		t-max ~ 1ÏS15	M
				Aqh

		q O Me	Cl
	A	kAA	îiA	Cl		IC₅o= 8 nM
H0668		Λ ^HMe	AA	'sA^>	F	EC50 = 10 nM Emax = 2168	Not Done	Not Done
	Me. .
	N	η 0 Me	Cl
	A	AAnA		CI
		N N > i H	[ΓΎ			ICîo= 6 nM	HighH
H0654		Me	AA			EC50 = 10 nM	Medium	Not Done
				-F	Emax = 2200	M

				F

H0655	^Me'N^A O Me Cl ΑΛΛΑ/' ώ. ^H (A ^s \ X-Me 0	IC₅₀= 12 nM ECso >30 μΜ	Medium H Medium M	70% Inhibition at 1 h; activity upto4h(10 mg/kg)
H0691	^M®N^XA 0 Me Cl FÀAnÀV⁰¹ ώ. ^H UL· ^s \ y~NH₂o	IC₅o⁼ 5 nM EC50 >30 μΜ	HighH HighM	62% Inhibition at 2 h; activity up to 24 h (10 mg/kg) PO: not active
H0728	^Me'NA 0 < Cl <a_na_naja ώ. ^H ÇL· ^s \ y~NH₂o	ICso= 5 nM ECso >30 μΜ	Medium H Medium M	Not Done
H0726	o Me Cl m· ^H UU ^s \ >- NMe₂ O	IC₅o= 456 nM EC50 >30 μΜ	Not Done	Not Done
H0689	^Me'N^XA 0 Me CI À/AyA ώ, ^H UL ^s \ AoH O	ICso>l μΜ ECso >30 μΜ	Not Done	Not Done
H0692	Μθ'Ν^Α O Me Cl aLaaa<^c' k ^H VU S-A \ OMe /-N ⁰ Me	IC₅o~ 550 nM EC50 >1 μΜ	Not Done	Not Done

H0656	^Μβ'Ν'^ζ^> 0 Me Cl ΆλΑΑ⁰ώ. ^Η ^s \ λ-ΟΗ Me	ICso= 7 nM EC₅₀= 15 nM Emax “ 1350	Medium H Medium M	Not Done
H0652	Ο Me Cl ώ. ^Η ^s \ CHO	IC₅o= 7 nM EC50 - 5 nM Emax = 1500	Not Done	Not Done
H0713	^Me'N^x^> Ο Me CI AAAAAa¹ώ» ^η UA. ^s \ CN	IC_So=187nM EC50 — 29 nM Emax ” 3424	Not Done	Not Done
H0688	^Μθ'Ν^> Ο Me CI ÜAW V ό Η Α—	lCso= 3 nM EC_5o = 12 nM Emax = 3100	Not Done	Not Done
H0774	^ΜθΝ^χΑ Ο Me Cl Me ^Η M'A²	IC₅o= 3.4 μΜ EC₅o >30 μΜ	Not Done	Not Done
H0664	^Μθ'Ν^Α Ο Me Cl r^0H Me ^H UkL	IC₅o= 261 nM EC50 >30 μΜ	Not Done	Not Done
H0535	^MeN'^x^^xi O Me Cl ÜAW «fe ^H UL· HN-zZ	IC₅o= 34 nM EC50⁼ 4 nM	Not Done	Not Done
H0499	Μθ'Ν'Ά O Me Cl lie ^H UL· t N ^NH	IC₅o= 12 nM EC_So>3O μΜ	Medium H Medium M	NSE (30 mg/kg)

H0693	0 Me Cl ÜAW i H Me Y N V^/^OH	ICso= 197 nM EC₅o=lOOnM	Not Done	Not Done
H0694	Ηθ'Ν^ 0 Me Cl YÂV M· ^H U'..^ Y > N__^oMe	IC₅₀= 309 nM EC50 >30 μΜ	Not Done	Not Done
H0657	^MeN^A O CN Cl UAW λ. ^H T> ^NH	IC₅o= 48 nM EC50 >30 μΜ	Medium H PoorM	57% inhibition at 1 h, activity up to 8h (10 mg/kg)
H0553	0 Me Cl iY ^hXXo hîvM Φη	IC₅₀= 7 nM EC50 >30 μΜ	Medium H PoorM	57% inhibition at 1 h, activity upto4h(10 mg/kg)
H0842	^Μθ'Ν*^Α O Me Cl Yav Μθ UL^ Y > N b	IC₅₀= 64 nM EC50 “ 67 nM Emax 1411	Not Done	Not Done
H0542	^MeN'^XA O Me Cl YaAAa Me ^H YyY^-N Y^x> ^~NH	IC₅₀= 18nM EC50 =15 nM	High H HighM	Not Done
H0568	^Me'N-A O Me Cl Yav i H II I Me ^~s	IC50” 9 nM EC50 =4 nM	High H HighM	Not Done
H0794	^Me'N^A 0 Me Cl L-AAnAAa M· Wn y-nh₂ ^L~s^/	ICso⁼ 3 nM ECso=lO nM Emax = 4435	Not Done	Not Done

H0841	^Μθ'Ν'^χχΊ 0 Me Cl dAÀLa Me ^H V>~<i	IC_So=118nM ECso >30 μΜ	Not Done	PO 10 mg/kg + ANAM30 mg/kg mice: NSE
H0792	^Μβ'Ν^Α O Me Cl ^nA^a » ^H UCs Ύ A^NH* ^~Ν	ICso=16nM EC50 ~7 nM Emax ⁼ 1096	Not Done	Not Done
H0569	^MeN'^> O Me Cl H Me ⁿ k^k^N v>	IC₅o= 87 nM ECso>30 μΜ	Medium El Medium M	Not Done
H0565	Μθ'Ν'''^] 0 Me Cl Me ^H ΙΑλ	^5ο⁼28 nM ECso-30 nM	High H High M	Not Done
H0604	^Me'N'A O Me Cl ÜAW λ. ^H UL V NH n=n	ICso=12 nM EC5o=25 nM	High H High M	Not Done
H0595	Μθ'Ν'^ι O Me Cl U/AV Me ^H AA^O A N-n	IC5o⁼28 nM ECso ”43 nM	Not Done	Not Done
H0596	^MeN^x~% 0 Me Cl <AAAA^' ¹ H Me U N Ny Me	ICso“9 nM EC50 “3 nM	High H High M	NSE (10 mg/kg)
H0851	^Me'N^A O Me Cl UAW Me ^H yAx/O 4	ICso=ll nM EC50 “6 nM E_maX“3320	Not Done	Not Done

H0537	^Me'N·^ O Me Cl AAAV A ^H MeO₂cA^ NH	ICso= 13nM ECso>3O μΜ	PoorH PoorM	Not Done
H0529	/—i 0 Me Cl Me'N l H 1 1 ci * W ï N ^~NH	IC₅₀= 12 nM ECso>3O μΜ	Medium H Poor M	Not Done
H0528	Me._N^Me_{Q Μ}θ θ, N N '^Z^^XG^CIMe ^H T N ^NH	IC_So= 34 nM ECso>3O μΜ	Medium H Medium M	Not Done
H0501	0 Me Cl UA-W³ Me VL Y N ^N. Me	IC_So= 13 nM ECso = 22 nM	High H High M	Not Done
H0507	^Me'N·^ 0 Me Cl 5Λ_ΝΑ_ΝΑ±^α ώθ ^H UL^	IC₅(r= 8 nM EC50 “12 nM	High H HighM	Not Done
H0665	^Me'N^V 0 Me Cl Ά-_νΑνΑΑ>:ι lie ^H UU ⁰ \ Me	IC₅o= 4 nM EC50 -8 nM	High H Medium M	Not Done
H0508	^Me'NV ° Me Cl aa\v Λ H 1 Μθ Hx/A ^AcMe	IC₅o= 76 nM ECso>3O μΜ	Medium H HighM	Not Done
H0509	^Me'N'^XX> O Me Cl VAW lie ^H UV	IC₅o= 29 nM EC50 =2 μΜ Emax = 1790	High H High M	66% inhib 1 h; activity up to 2h (10 mg/kg)

H0510	0 Me Cl UAW Me ^H	IC₅o= 14 nM EC5o>3O μΜ	High H HighM	35% inhibition at 4 h, activity up to 24h (30 mg/kg)
H0606	^M®'nA 0 Me Cl A_nA_n^c. ¹ H Me	IC₅₀= 24 nM ECso =31 nM Emax = 2336	Not Done	Not Done
H0810	^M®'nA O Me Cl Aav Me ^H	IC₅₀= 20 nM EC50 =22nM Emax ” 2339	Not Done	Not Done
H0696	^M®'nA 0 Me Cl A_na_naJLc! λ. ^H ΙΛθ/·_ΌΗ F	IC₅₀= 120nM EC50 >30 μΜ	Not Done	Not Done
H0611	^M®'N'^xA 0 Me Cl AAV ¹ h II 1 Me OMe	ICso=2.3 μΜ ECso >30 μΜ	Not Done	Not Done
H0612	^M®'nA O Me Cl A YW' Me ^H AA^^/CONHz	IC₅o= 1.6 μΜ ECso >30 μΜ	Not Done	Not Done
H0615	^M®'nA 0 Me Cl ΑΛΜ/¹ώθ ^H VLy AA_C0NHz	IC_So= 107 nM EC50 >30 μΜ	High H Medium M	Not Done

H0809	^ΜθΝ'^ΧΧ 0 Me Cl ^^CN	IC_S0= 149 nM EC₅o=217 nM E_raax = 2339	Not Done	Not Done
H0699	^Me'N'^xX 0 Me Cl lXn^xnXA<^ciΛ h ^Μβ	IC₅o= 171 nM ECso>3O μΜ	Not Done	Not Done
H0607	^Me'N'^> O Me Cl <ΛΛΑΥ ¹ H Me ’ΥΧ/χ,ΟΜθ	IC5o= 6 nM EC₅o=31 nM Emax ~ 3000	Medium H Medium M	NSE (10 mg/kg)
H0695	^Μθ'Ν'^ζ^^χι O Me Cl OxAVr^cl ¹ H Me	IC₅o= 78 nM EC5o=5 nM	Not Done	Not Done
H0635	^MeN'^XX 0 Me Cl XAAU Me ^H AA/'-îx/COzMe	IC₅o= 1 μΜ EC50 > 30 μΜ	Not Done	Not Done
H0690	0 Me Cl ώ· ^H UL^Am >\| ^γ Me	IC₅o= 980 nM EC50 > 30 μΜ	Not Done	Not Done
H0735	^Me'N^Y O Me Cl XI-My-ci _N<-, Λ. ^H	IC_So=2O9nM EC50 >30 μΜ	Not Done	Not Done

H0746	0 Me Cl LA_NA_NAA,ci _o ώ. ^H IXyU	IC₅₀=216nM EC50 > 30 μΜ	Not Done	Not Done
H0747	Q _{Me C}\| /T^S\ Me ^H	ICso= 84 nM EC50 > 30 μΜ	Not Done	Not Done
H0748	^Me'N'^xU 0 Me Cl A-._nA_nA.A,ci ' ùo ^H UyyU	IC₅₀= 554 nM EC50 > 30 μΜ	Not Done	Not Done
H0765	Μθ'Ν^Α Q _Me ci ΦΑΜ' _λΛ h A Me aAzaU³	IC₅o= 61nM EC₅o=137nM E_max = 2810	Not Done	Not Done
H0766	^Me'N^U O Me Cl UAW i H Me UîAaA/NOz ^isr	IC₅₀= 171nM EC50 > 30 μΜ	Not Done	Not Done
H0608	ΆΑ 0 Me Cl UAW - ” Me IL A a N 0 Me	IC₅o= 69 nM EC50 =422 nM	Not Done	Not Done
H0616	ΆΑ 0 Me Cl UAW lie ^H	ICso= 132 nM EC50 =580 nM	Not Done	Not Done

H0618	^Μ®'νΆ Ο Me Cl A_NA_NAA_rc, Me ^H	ICso=4O nM ECso =130 nM	Not Done	Not Done
H0623	^Μ®Ά O Me Cl A_nA_n^c. ώ. ^H Uy^ A	IC₅o= 71 nM EC50 >30 μΜ	Medium H PoorM	Not Done
H0610	0 Me Cl A^AAV i H Me ^π	ICso= 101 nM EC50 >30 μΜ	Medium H Medium M	Not Done
H0517	^Me'NA 0 Me Cl AAV Me ^H AA_Nh₂	ICso=19nM EC50 >30 μΜ	Not Done	Not Done
H0518	^M®'nA 0 Me Cl Me UA	ICso= 841 nM ECso>3O μΜ	Not Done	Not Done
H0512	^Me'N^xA 0 Me Cl aa A^ci p.N Me ^H ^A^xL/NMe	IC₅o= 495 nM EC50 >30 μΜ	Not Done	Not Done
H0513	^Μ%Α O Me Cl AAA-V _rN Me ^H ALA^NH	ICso= 544 nM ECso >30 μΜ	Not Done	Not Done
H0514	ΆΑ 0 Me Cl A_na_nAV^cilie ^H UAy An	IC₅o= 16nM ECso= 38nM	Medium H Medium M	Not Done

H0515	^Me'N'U O Me Cl Ά^ΑΑν H	ICso^- 40 nM EC50 ⁼ 885 nM	Not Done
H0520	^Μθ'ΝΑ 0 Me Cl UZAV ώθ ^H XUy	IC₅o= 202 nM EC50 =394nM	Not Done	Not Done
H0787	^Me'N^A O Me ι H I ,N Me UM HN-^-y	ICso— 12 μΜ EC50 “ 3 μΜ	Not Done	Not Done
H0582	^Me'NU 0 Me F Me ^H	IC₅o= 15 nM EC50 ~ 20 nM Emax 2069	Medium H Medium M
H0571	^Me'NU O Me F UAW ώ_β ^H UL· T N ^~NH	IC₅₍r 154nM EC50 >30 μΜ	Not Done
H0605	^M®N^xXU O Me Cl Λ H Me F	IC₅o=31 nM EC50 “ 96 nM Emax ⁼ 1833	Not Done	Not Done
H0573	^Me'NU O Me pAl • H Me <A_Br	IC50- 36 nM ECso>30 μΜ	HighH Medium M	PO: NSE (30 mg/kg)
H0574	A^_NA_NAAA ' H Me ΧΑγΥ A	IC₅₀=67 nM ECso⁼81 nM Emax ⁼ 2489	Medium H Medium M	Not Done

H0575	^Μ®'νΑ 0 Me AU AaaV Me ^H Αλγ-S	IC₅o= 32 nM EC50 ” 28 nM Emax ⁼ 3533	Medium H Medium M	Not Done
H0576	^'N^A 0 Me AA Me ^H QT N Ah	IC₅₀= 180nM EC50 >30 μΜ	Not Done	Not Done
H0577	^MAA O Me AA AUnUL· Me ^H UÇa	IC₅o= 233 nM ECso>3O μΜ	Not Done	Not Done
H0591	^Me'A ^{0 Me} Ad ¹ H Me ⁿ UA^/^NH2	IC₅o= 11 nM EC50 =126 nM	Medium H Medium M	Not Done
H0597	^Me'N'^zA 0 Me AA ¹ H Me AA ^X/> A	IC50” 24 nM EC5o>3O μΜ	PoorH PoorM	Not Done
H0598	AU 0 Me AA aa-aJU ώβ ^H Αγγ L·	ICso⁼ 63 nM EC50 “271 nM	Not Done	Not Done
H0599	^M®'nX 0 Me AA UA A _Hώθ ^H A ^t/> A	IC₅₀=212nM EC50 =478 nM	Not Done	Not Done

H0790	0 Me /A ' H ^Me 'Vn	IC50” 35 nM EC50 “32 nM Emax “ 2810	Not Done	Not Done
H0381	^MeN^/^i 0 Me Cl AA_nA_nAA,ci ùe ^H LAc	ICso= 12 nM EC50 >30 μΜ	Medium H Medium M	IP: No effect
H0519	^Μβ'Ν^/^Ί O Me Cl LA_nA_nAX,ci ώβ ^H Ux,	IC50” 3 nM EC50 = 6 πΜ	Medium H Medium M
H0629	0 CN Cl ΑΑ_ΝΑ_ΝΑΧχΒΓ ώ. ^H Ux,	IC50” 3 ηΜ EC50 “ 1 ηΜ Emax ” 5075	Not Done	Not Done
H0658	^MeN^U 0 CN Cl LA_NA_NôxA,Br - ^H u_OMe	ICso= 6 ηΜ ECso = 9 ηΜ Emax = 2400	Not Done	Not Done
H0669	^Μθ'Ν^> 0 CN CI Α_Ν^_ΝλΧγ^αώβ ^h IXM OMe	ICso= 1 ηΜ ECso = 5 nM Emax = 4961	Not Done	Not Done
H0671	^ΜθΝ^> O Me CN Çl LA_nA_n>OxxCI ^ώ· ^H u»	ICso= 34 nM ECso = 60 nM Emax — 3748	Not Done	Not Done
H0659	'^-N·'··] o VA V*x_NA_NVA^Br “ ^H V_0Me	ICso=39O nM ECso =353 nM Emax ⁼ 200	Not Done	Not Done
H0521	^M%V O Me Cl ΑΑνΑ,,αα^ - ^H U._C02Me	ICso⁼ 20 nM EC₅₀=19nM	Not Done	Not Done

H0602	^Me'N·^ 0 Me Cl A_nA_nAAci Me ^H U. TMS	ICso⁼8 nM EC50 >30 μΜ	Not Done	Not Done
H0603	^Me'N^A 0 Me Cl AV_NA_NAA/Ci ώ. H	ICso“2 nM ECso>30 μΜ	High H HighM	71% inhibition at 1 h, activity up to 24 h (0.1 mpk), 65% inhibition at 1 h; activity up to 24 hrs (lmpk), 34% inhibition at 1 h, activity up to 4h (lOmpk); Inhibition in fed mice after AN AM POSC NSE
H0677	^M®'nA 0 Me Cl λ. UA R/S AH (single enantiomer)	IC5o=5 nM EC50 >30 μΜ	High H Medium M	Inhib up to 2h(10 mg/kg) PO: NSE
H0678	^MeN^A 0 Me Cl ώβ H IJ R/S VH (single enantiomer)	ICso=55 nM ECso>3O μΜ	Medium H Medium M	78% inhibition at 1 h, activity up to 24h (10 mg/kg). PO: no effect
H0832	^Me'N'^xA O Me Cl ύ,Λ,ΛΑ ώβ ^H UV ^'Me	ICso=llnM ECso>3O μΜ
H0852	^M®'N^xA O Me Cl VA “· ^H LA. ^<^Me Me	ICso-22 nM EC₅o=18nM Emax ⁼ 1683	Not Done	Not Done

H0701	O Me Cl i. ^H LA Me	IC5o=2O nM ECso >30 μΜ	LowH LowM	Not Done
H0733	^MeA^A 0 Me Cl Xlaa ώθ ^H 11 Me	IC₅o= 95 nM ECso>3O μΜ	Not Done	Not Done
H0755	Μθ'Ν^Α O Me Cl AAW 1 H Me AA\ ^A/^0H	IC₅o=12 nM EC5o⁼lOnM Emax “ 2196	Not Done	Not Done
H0757	^Me'N'A O Me Cl Me ^H UL A<,OEt OEt	IC₅o= 159 nM EC50⁼ 654nM Emax ⁼ 2704	Not Done	Not Done
H0734	^M®'nA O Me Cl ώβ ^H VA	IC₅₀= 202 nM EC50 >30 μΜ	Not Done	Not Done
H0737	Μθ'Ν^Α O Me Cl AXA Λ ^H Me AA\ ^A^s	IC₅₀= 13 nM ECso>3O μΜ	High H High M	75% inhibition at 1 h, activity up to 4 h (10 mg/kg) PO: NSE
H0775	“θ'Ν^Α 0 Me Cl ALaâ-a m. ^H LA OH	IC₅o~ 74 nM EC50 >5 μΜ	Not Done	Not Done
H0776	Μθ'Ν'Α 0 Me Cl lAaâv λ. ^H la ^NH₂	IC₅o= 120 nM EC50 >4 μΜ	Not Done	Not Done

138

H0779	^Μθ'Νγ 0 Me Cl Me ^H ΧίΑ. OMe	IC₅₀= 429 nM ECso = 4 μΜ	Not Done	Not Done
H0762	^M®'N^ 0 Me Cl ώθ ^h lui	IC5o= 5 nM ECso >30 μΜ	HighH HighM	93% inhibition at 1 h, activity up to 4 h (10 mg/kg) PO mice and rat: NSEt
H0751	^Me'N^> 0 Me Cl AAYV ό H Me lA	ICso⁼ 6 nM EC50⁼ 62 nM Emax ~ 1267	HighH HighM	91% inhibition at 1 h, activity up to 24 h (10 mg/kg) PO mice and rat (+ANA): no effect
H0763	Μθ'Ν^ 0 Me Cl lùe ^H Uk ^nh N;=y	IC50= 835 nM EC50>30 μΜ	Not Done	Not Done
H0759	“θ'Ν^Ν O Me Cl αΑαααυ Μθ ^H Uk ^S<=N Ks	IC₅₀= 7 nM ECso>3O μΜ	HighH HighM	85% inhibition at 1 hr, activity up to 8 h (10 mg/kg) PO: no effect
H0785	^Μ®'νΎ O Me Cl <Aaaaa Me ^H A*k S-a	ICso⁼ 33 nM EC50 ~ 90 nM Emax “ 2869	Not Done	Not Done
H0754	^Μθ'νΎ O Me Cl Ak_NA_NA^L/Ci Μθ ^H UL	IC₅o“llnM EC50 >30 μΜ	HighH HighM	74% inhibition at 1 h; activity up to 24h (10 mg/kg) PO and PO+ANAM: no effect

H0753		Ί 0 Me Cl Um Λ H Me	.Cl A	l A N	ICso= 60 nM ECso>3O μΜ	Not Done	Not Done
H0609	Ύ	> 0 Me ' H Me <	Cl	.Cl	ICso=517 nM EC50 >30 μΜ	Not Done	Not Done
H0764	^Me'C	A 0 Me i H Me <	Cl V	CI	IC₅o=lO nM EC_So = 14 nM Emax ~ 1352	HighH HighM	91% inhibition at 1 h, activity up to 24 h (10 mg/kg) PO: 70% inhibition at 2 h (30 mg/kg), activity up to 24 h PO+ANAM: inhib up to 24h SC: 53% inhibition at 1 h; (30 mg/kg)
H0818	_Ύ	A O Me i H Me < (S/R)	Cl	.Cl	IC₅₀=1.7nM EC50 = 3.5 nM Emax =1915	Not Done	22% inhib at 4 h, 30 mg/kg PO fasted mice
	(single enantiomer)
	^Μθ'Ν^	A O Me VA i H Me < (S/R)	Cl	-CI
H0819			IC5o=65 nM EC50 =140 nM Emax =1419	Not Done	30 mg/kg PO fasted mice NSE
	(single enantiomer)

H0838	Me N—i 0 Me Cl i H Me (diastereoisomer mixture)	IC5o=4 nM EC50 “21 nM Emax = 1340	Not Done	205% increase at 2h, activity up to 8 h, 30 mg/kg PO mice
H0855	^MeN^U 0 Me F ' H Me	ICso=256 nM ECso>3O μΜ	Not Done	Not Done
H0884	^MeN^U 0 Me Cl üaaa° m» ^H LA ^{N S}K_	IC₅₀= 197 nM EC50 >30 μΜ	Not Done	Not Done
H0811	0 Me Cl UAW i H Me \îA\	IC5o=36 nM EC50 = 95 nM Emax = 1320	Not Done	Not Done
H0812	O Me Cl UAW _u ' H χ^Μ-^Μβ Me UU [ N AuJ	ICso”1.2 μΜ EC50-1.5 μΜ E_max ⁼ 871	Not Done	Not Done
H0740	O f Cl ÜAW ¹ H OMe	IC₅o= Ί nM ECso=1.5nM Ernax ⁼ 3620	Not Done	Not Done
H0742	Μθ'Ν^Α 0 Me Cl OMe ^H	IC₅o= 54 nM ECso>3O μΜ	Not Done	Not Done
H0745	^MeN^U 0 Me Cl ^Λ^ζΜγ^α 6h h	IC₅₀= 57 nM ECso = 97 nM Emax — 2391	Not Done	Not Done

H0749	^Μ®Ν^> 0 Me Cl	IC_So=UlnM ECso⁼397nM Emax ⁼ 1554	Not Done	Not Done
H0744	A_na_nAL^ci ÔEt ^H 11	ICso⁼ 33 nM ECso - 45 nM Emax ” 3536	Not Done	Not Done
H0626	^MeN^/A O Me Cl Aax« ώθ ^H UA	IC5o⁼ 4 nM ECso= 15 nM Emax - 3835	Not Done	Not Done
H0767	O Me Cl Aay lie	IC₅₀= 37 nM ECso>3O μΜ	High H HighM	88% inhibition at 1 h, activity up to 4 h (10 mg/kg) PO: NSE
H0772	^Μθ'Ν^Α 0 Me Cl Α^_ΝΛ_ΝΑγΑα_ο ^H HA	ICso” 3 nM EC50 ⁼ 7 nM Emax = 3569	Not Done	Not Done
H0773	^Me'N'A O Me Cl Ab-Wh Me ^M ΑΑ,Ν S_xS T?	IC₅o= 608 nM EC50 >30 μΜ	Not Done	Not Done
H0784	^Μθ'Ν·Α 0 Me Cl A_N ΑγΑ°' Q r—λ Me ^H TA_nX_nJQ H H	IC₅₀= 529 nM EC50 >30 μΜ	Not Done	Not Done
H0777	^Me'N·^ 0 Me Cl s-» ώ, ^H lÀ_NX> H	IC_So= 715 nM ECso = 600 nM Emax ⁼ 2288	Not Done	Not Done

H0846	^Μ®'Ν'^ΧΧΊ Ο Me Cl ΑΑ_ΝΑ_ΝΛΦγα Me ^Η Η	IC₅o= 170 nM EC50 = 130 nM E_max = 3815	Not Done	Not Done
H0875	^Μ®'Ν^χ^ι Ο Me Cl AALAAa ώ. ^Η LA₀A	IC₅o= 91 nM EC50 = 50 nM Emax = 3751	Not Done	Not Done
H0628	^Me'NU 0 Me Cl Me ^H ΐΥίφ,Μβ	ICso= 59 nM ECso=lOl nM Emax “ 4433	Not Done	Not Done
H0630	0 Me Cl Α^ΑΦΑι Me ^H YaY,CN	ICso⁼ 3 nM EC50 = 9 nM Emax = 4714	HighH High M	Not Done
H0633	^Me'N'^XX> 0 Me Cl AA_N\A^C1 Me ^H φ>φθΗ	IC5o⁼ 3 nM EC50 ” 15 nM	HighH High M	Not Done
H0634	0 Me Cl ΑΆνΑΑαι lie ^H LXch₂F	IC₅o= 13 nM EC50 — 37 nM	Not Done	Not Done
H0640	Μθ'Ν^ O Me Cl LA_nA_nAAæi -^H Vc_HO	IC₅o= 103 nM ECso>3O μΜ	Not done	Not done
H0645	^Me'N-U 0 Me Cl ^YiAnAAy^ci Μθ ^H AAyO □J	IC₅₀= 133 nM EC_S0 = 287 nM Emax = 2761	Not done	Not done
H0641	Μθ'Ν^Α O Me Cl Me ^H AAs^-pn _M CO2M©	IC_So=18nM EC50 ⁼ 35 nM Emax ⁼ 1690	Not Done	Not Done

143

H0702	^Μβ'ΝΑ 0 Me Cl O'N^XN'W^{CI ώθ H} Cl	IC₅₀= 96 nM ECso =1.1 μΜ Emax ” 1940	Not Done	Not Done
H0643	^Me'N'^xA 0 Me Cl Μθ ^H	ICso= 22 nM ECso = 83 nM Emax = 2660	Not done	Not Done
H0522	0 Me Cl Me \A^_c0NH2	ICso=201 nM ECso =200 nM	Not Done	Not Done
H0523	0 Me Cl UA-M/i -^H VL	ICso=668 nM EC5o>30 μΜ	Not Done	Not Done
H0876	^MeN^% O Me Cl A_NVUyCI - ^H VL	ICso=13O nM ECso>3O μΜ	Not Done	Not Done
*N	SE: No significant effect.

Example C

Effect of Ghrelin Antagoniste of Formula I on Binge Eating in Non-Estrous Female Rats

In this Example, the therapeutic potential of compounds were tested for their ability to inhibit binge eating. The animal model used was developed to explore the combination of food restriction and stress. Results disclosed below show that female rats submitted to cycles of food restriction and exposure, the day of the test, to Highly Palatable Food (HPF) for 15 minutes without getting access to it, showed a pronounced and statistically significant increase in HPF intake. Considering the reliability and the robustness of this model, it was adopted to test the inventive compounds. Topiramate, used as reference compound, confîrmed its inhibitoiy effect in this procedure. Moreover, results show that, after acute administration, H0900, H0816, and H0847, reduced binge eating épisodes showed in R + S group. H0860, at the considered doses, did not significantly reduce HPF intake in animais exposed to the same procedure.

Animais and Housing:

144

A total of N = 117, 52-day-oId female Sprague-Dawley rats (175-200 g) were used.

Rats were acclimated in individual cages with metallic walls; the floor and the front wall made of metallic grid. The dimensions of the cage floor being 30 cmx30 cm; the cage is 30 cm high. A front door (30 cm><20 cm) made of metallic grid was positioned in the anterior wall of the cage to gain access to the inside of the cage; the remaining part of the front wall was equipped with a 10 drinking burette.

Rats were kept in a room at constant température (20-22°C) and humidity (45-55%) under a 12-h light/dark cycle (lights on at 08:00 am) with ad lib chow and water.

Ail procedures were conducted in adhérence to the European Community Directive for Care and Use of Laboratory Animais.

Diets:

Rats were offered food pellets, 4RF18, Mucedola, Settimo Milanese, Italy (2.6 kcal/g).

The Highly Palatable Food (HPF) was prepared by mixing:

a) Nutella Ferrero chocolaté cream (5.33 kcal/g; 56%, 31% and 7%, respectively, from 20 carbohydrate, fat and protein): 52 %

b) grounded food pellets 4RF18, Mucedola, Settimo Milanese, Italy: 33 %

c) water: 15 %

Experimental Design:

The rats were weight-matched into one of two groups so there was no significant différence in mean body weight between the groups:

Group 1: non-restricted and not exposed to stress (NR + NS): N = 9

Group 2: restricted and exposed to stress (R + S): N = 108

Once assigned to one of these groups, the rats remained in that group throughout the 30 study. The rats exposed to stress were acclimated in different rooms than the group not exposed to stress.

Rats were exposed to 3 consecutive 8-day cycles followed by the final test on day 25:

a) the control group (NR + NS) had chow ad libitum for 4 days, on days 5-6 it received chow +

HPF for 2 h; on days 7-8 it had chow ad libitum; on day 25 it was not exposed to stress;

145

b) the second group (R + S) had chow restricted to 66% of the normal mtake for 4 days, was offered chow and HPF (2 h) on days 5-6 and only chow on days 7-8; on day 25 it was not exposed to stress.

The 8-day cycle was repeated three times, but in the third cycle the animais did not hâve access to HPF.

By the last day of re-feeding, the body weight and food intake of restricted rats were not statistically different from those of non-restricted rats, thus precluding the potentially confounding effect of hunger or energy déficit.

Body weights and food intake were recorded daily. Food intake is expressed as mean kilocalories per kilogram ingested ± SEM.

On the test day (day 25) the animais were divided in the following groups as shown in Table 2:

Table 2

No. of Animais	Procedure	Treatment
8	NRNS	Vehicle
9	RS	Vehicle
9	RS	H0816 3 mg/kg
9	RS	H0816 30 mg/kg
9	RS	H0860 3 mg/kg
9	RS	H0860 30 mg/kg
9	RS	H0847 3 mg/kg
9	RS	H0847 30 mg/kg
9	RS	H0900 3 mg/kg
9	RS	H0900 30 mg/kg
9	RS	Topiramate 60 mg/kg

It has been reported by Applicants (Micioni Di B et al. 2010) that in the estrous phase of the ovarian cycle, female rats do not exhibit BE in the adopted model; while in ail the other three phase of the ovarian cycle they exhibit BE without significant différences in intensity.

146

Therefore, immediately after the test on day 25, vaginal smears were collected and analyzed under microscope to assess the ovarian phase, and data from rats in the estrous phase were not included in the statistical analysis. Vaginal smears were analyzed by an experienced expérimenter blind to treatment conditions.

The Stress Procedure:

For 15 min, the container (China coffee cup) containing HPF is placed outside the cage; the container handle is hooked to the top wire wall of the cage in the hollow part where food pellets are usually offered. In these conditions, the animal is able to see the cup in which it received HPF on days 5, 6, 13, and 14 of the first two cycles, is able to see in part the HPF itself, 15 and is able to smell its odour. In this 15-min period, the rat engages in repeated movements of the forepaws, head, and trunk aimed at obtaining the HPF, but it is not able to reach it. Rats undergo the stressful procedure between 10.00 and 12.00 am. After 15 min, the cup is placed inside the cage of the rats in the stress group (R + S), so that the HPF became accessible to the rat.

Compound Préparation:

100 mg of each compound (HO816, H0860, H0847 and H0900) was accurately weighed and suspended in 13.33 ml of 0.5% carboxymethyl cellulose sodium sait (CMC, Sigma-Aldrich 25 Cat. C4888, lot 120M0216V) solution. The lower dose solution was prepared by dilution of 30 mg/ml suspension with 0.5% CMC solution. Suspensions were prepared freshly on test day. Vehicle was composed by a solution of 0.5% carboxymethyl cellulose sodium sait and was prepared by dissolving 1 g of CMC in 200 ml of distilled water. 180 mg of Topiramate was accurately weighed and suspended in 12 ml of 0.5% CMC solution. Compounds (vehicle and 30 active principles) were administered by gavage in a volume of 4 ml/kg of body weight one hour before access to HPF.

Data Analysis:

Ail data are expressed as the mean ± s.e.m. and each value reflects the mean number of 35 animais per group as described in the legends. For data évaluation, the analysis of variance

147 (ANOVA) was used followed by post-hoc (Bonferroni’s) test when appropriate. Statistical signifïcance was set at P < 0.05. The Software used for the Graphs was Origin 7.0. The software for the statistical analysis was SYSTAT 13.0

Binge Eating Model:

The ANOVA revealed a highly significant différence in 2-h HPF intake in the 2 groups of rats following vehicle administration [F(l,12) = 18.9; P < 0.01]. As shown in Figure 1, following vehicle administration HPF intake in the R + S group was markedly higher than that of the control (NR + NS) group. HPF intake of R + S rats was very pronounced in the first 15 min of access to HPF; these animais never engaged in competing behaviours, but continuously remained over the cup containing HPF and focused their attention on the intake. Cumulative HPF intake in the R + S group was significantly higher than in controls up to 120 min after access to HPF.

Effect of Topiramate on Binge Eating:

The ANOVA revealed a significant différence in 2-h HPF intake in the R + S rats treated with Topiramate at the dose of 60 mg/kg [F(l,l 1) = 16.2; P < 0.01]. As shown in Figure 2, posthoc comparisons revealed that the effect of Topiramate was statistically significant at ail time points for the whole period in which BE was exhibited.

Effect of H0816 on Binge Eating:

The ANOVA revealed a significant différence in 2-h HPF intake in the R + S rats treated with H0816 at the doses of 3 and 30 mg/kg [F(2,19) = 3.9; P < 0.05]. As shown in Figure 3, posthoc comparisons revealed that the effect of H0816 (30 mg/kg) was statistically significant (P < 0.05) at 15 min time point. H0816 treatment (both doses) did not affect animais' gross behaviour during the 2-h test.

Effect of H0860 on Binge Eating:

As shown in Figure 4, H0860 at the doses of 3 and 30 mg/kg did not affect HPF intake in the R +S group [F(2,19) = 0.6; P > 0.05].

148

Effect of H0847 on Binge Eating:

The ANOVA revealed a significant différence in 2-h HPF intake in the R + S rats treated with H0847 at the doses of 3 and 30 mg/kg [F(2,19) - 8.7; P < 0.01]. As shown in Figure 5, posthoc comparisons revealed that the effect of H0847 (3 mg/kg) was statistically significant at 15, 30 and 60 min after HPF access. At the dose of 30 mg/kg, H0847 significantly (P < 0.01) 10 reduced HPF intake at ail time points for the whole period in which BE was exhibited. Two animais treated with H0847 (3 mg/kg) and one animal treated with the dose of 30 mg/kg showed a mild sédation during the 2-h test.

Effect ofH0900 on Binge Eating:

The ANOVA revealed a significant différence in 2-h HPF intake in the R + S rats treated with H0900 at the doses of 3 and 30 mg/kg [F(2,18) = 12.2; P < 0.01]. As shown in Figure 6, post-hoc comparisons revealed that the effect of H0900 (30 mg/kg) was statistically significant (P<0 .01) at ali time points for the whole period in which BE was exhibited.

H0900 treatment (both doses) did not affect animais' gross behaviour during the 2-h test.

Effect of Topiramate, H0816, H0860, H0847H0900 and Vehicle on 2-h Chow Food Intake During Binge Eating Test:

Statistical analysis indicated that acute administration of Topiramate [F(l,l 1) = 0.9; P > 25 0.05] or H0816 [F(2,19) = 0.3; P > 0.05] or H0900 [F(2,18) = 2.2; P > 0.05] did not modify 2-h chow intake. As shown in Figure 7 A, the acute administration of H0860 [F(2,19) = 22.9; P < 0.01] and H0847 [F(2,19) = 3.9; P < 0.05] significantly increased 2-h chow food intake.

Statistical analysis indicated that acute administration of Topiramate [F(l,l 1) = 0.00; P > 0.05] or H0816 [F(2,19) = 1.2; P > 0.05] or H0900 [F(2,l8) = 2.7; P > 0.05] did not modify 24-h 30 chow intake.

As shown in Figure 7, the acute administration of H0860 [F(2,19) = 14.2; P < 0.01] and H0847 [F(2,19) = 24.3; P < 0.01] significantly increased 24-h chow food intake.

Effect of H0816 on Binge Eating (Second test):

To confirm the effect of H0816 on BE, a second test was performed after ten days.

Of 117 animais used in this study, 53 (the same 8 rats NR+NS and 45 rats R+S) were used for the second test. After one day off at the end of the first test, these groups of rats received an additional 8-day cycle: NR +NS group had 8 days of chow ad libitum, whereas R + S group had 4 days chow restricted to 66% of the normal intake followed by 4 days of chow ad libitum. In 10 this additional cycle, ail groups did not hâve access to HPF. The following day, R+S group was exposed to stress, while NR +NS group was not. On this day, H0816 (3, 10 and 30 mg/kg) and topiramate (60 mg/kg) or vehicle were administered by gavage 1-h before access to HPF.

The ANOVA revealed a highly significant différence in 2-h HPF intake in the 2 groups of rats following vehicle administration [F(l,12) = 28.1; P < 0.01]. Cumulative HPF intake in the R + S 15 group was significantly higher than in controls up to 120 min after access to it (data not shown).

Statistical analysis showed a significant différence in 2-h HPF intake in the R + S rats treated with Topiramate at the dose of 60 mg/kg [F(l,12) = 47.1; P < 0.01]. Post-hoc comparisons revealed that the effect of Topiramate was statistically significant at ail time points, that is for the whole period in which BE was exhibited (data not shown).

The ANOVA revealed a significant différence in 2-h HPF intake in the R + S rats treated with H0816 at the doses of 3, 10 and 30 mg/kg [F(3,25) = 3.3; P < 0.05]. As shown in Figure 8, post-hoc comparisons revealed that the effect of H0816 (10 mg/kg) was statistically significant (P < 0.05) at 15 min time point and the dose of 30 mg/kg completely blocked (P < 0.01) the BE épisode at 15 min. H0816 treatment (both doses) did not affect animais' gross behaviour during the 2-h test. Statistical analysis indicated that acute administration of Topiramate [F(l, 12) = 2.3;

P > 0.05] or H0816 [F(3,25) = 0.2; P > 0.05] did not modify 2-h and 24-h ([F(l,12) = 0.03; P > 0.05]; [F(3,25) = 0.5; P > 0.05]) chow intake (data not shown).

Topiramate, included in the experimental design as positive control, completely abolished BE épisode at the dose of 60 mg/kg. In the same experiment, H0900, H0816, and H0847 30 significantly reduced BE behaviour in the R + S group, after acute administration, confirming the therapeutic potential of sélective GHS-Rla antagonism in binge eaters.

In a second experiment, H0816 confirmed, dose dependently, its sélective inhibitory effect on BE, with no effect on physiological feeding. Surprisingly, H0847 and H0860 significantly increased 2-h and 24-h chow food intake in the same animais, suggesting a not 3 5 clean profile as GHS-R1 a antagonist.

Example D

Characterizing the Effect of Compounds of Formula (I) on Opérant Ethanol SelfAdministration in Marchigian Sardinian alcohol-preferring (msP) Rats

In this experiment, msP- rats (N=24) were trained to self-administer 10% (v/v) éthanol solution in 30-min daily sessions under a fixed-ratio 1 schedule of reinforcement in which each response resulted in delivery of O.lmL of fluids. Training continued until stable baseline of alcohol responding was achieved. At this point, before initiation of treatments, rats were trained to gavage administration procedures for three consecutive days (pre-treatment phase) during which they received drug vehicle. At this point animais were tested for the effect of ghrelin antagoniste on 10% (v/v) éthanol self-administration. Using a within-subject Latin square design, the first group of msP rats (N=12) was tested for the effect of H0847 (0.0, 1.0 and 3.0 mg/kg), while the second (N=12) was treated with H0816 (0.0, 3.0 and 10.0 mg/kg).

Once the experiment was finished, animais were left in their home cages for several days, in order to wash out the drugs. Then, the same rats were employed to test the remaining ghrelin 20 antagonists compounds H0900 (0.0, 3.0 and 30.0 mg/kg) and H0860 (0.0, 3.0 and 30.0 mg/kg).

Once a stable self-administration baseline was reached, treatments begun according to the same experimental procedures described for the previous drugs tested.

Ail the drugs (or vehicles) were administered orally 1 hour before the beginning of the opérant session. Responses at the lever activated the delivery mechanism but did not resuit in the 25 delivery of alcohol.

Animais and Housing:

Male genetically selected alcohol-preferring Marchigian Sardinian (msP) rats were used (N=24). At the time of the experiments their body weight ranged between 350 and 400 g. They 30 were housed 4 per cages in a room with a reverse 12:12 h light/dark cycle (lights off at 9:30 a.m.), température of20-22°C and humidity of 45-55%. Rats were offered free access to tap water and food pellets (4RF18, Mucedola, Settimo Milanese, Italy). Ail the procedures were conducted in adhérence with the European Community Council Directive for Care and Use of Laboratory Animais and the National Institutes of Health Guide for the Care and Use of

Laboratory Animais.

151

Compound Préparation:

mg of each H0900 and H0860 were accurately weighed and suspended in 10 ml of 0.5% carboxymethyl cellulose sodium sait solution (CMC, Sigma-Aldrich Cat. C4888, lot 120M0216V). The lower dose solution was prepared by dilution of 30 mg/ml suspension with 10 0.5% CMC solution.

37.5 mg of H0816 were accurately weighed and suspended in 15 ml of 0.5% carboxymethyl cellulose sodium sait solution (CMC, Sigma-Aldrich Cat. C4888, lot 120M0216V). The lower dose solution was prepared by dilution of mg/ml suspension with 0.5% CMC solution.

11.25 mg of H0847 were accurately weighed and suspended in 15 ml of 0.5% carboxymethyl cellulose sodium sait solution (CMC, Sigma-Aldrich Cat. C4888, lot 120M0216V). The lower dose solution was prepared by dilution of mg/ml suspension with 0.5% CMC solution.

Suspensions were prepared freshly on test day. Vehicle was composed of a solution of

0.5% carboxymethyl cellulose sodium sait and was prepared by dissolving lg of CMC in 200 ml of distilled water.Vehicle and drugs were administered by gavage in a volume of 4 ml/kg of body weight 1 hour before the access to 10% alcohol solution. 10% (v/v) éthanol solution was prepared every two days by diluting 95% (v/v) éthanol solution (F.L. CARSETTI s.n.c CAMERINO) in drinkable water.

Equipment:

The self-administration stations consisted of opérant conditioning chambers (Med Associate, Inc) enclosed in sound-attenuating, ventilated environmental cubicles. Each chamber was equipped with a drinking réservoir (volume capacity: 0.2 ) positioned 4 cm above the grid 30 floor in the centre of the front panel of the chamber, two rétractable levers located 3 cm (one to the right and the other to the left) of the drinking réceptacle and a white eue light located 6 cm above the lever. An infusion pump was activated by responses on the right, or active lever, while responses on the left or inactive lever were recorded but did not resuit in activation of the pump. Activation of the pump resulted in a delivery of 0.1ml of fluid. If a time out was programmed, 35 lever presses during this period were counted but did not lead to further infusions. An IBM17968

152 compatible computer controlled the delivery of fluids (activation of syringe pump), présentation of visual stimuli and recording of the behavioral data.

Experimental procedures:

Using opérant self-administration chambers (Med Associâtes), msP rats were trained to 10 lever press for 10% alcohol (v/v) until stable baseline of responding were achieved. 16 selfadministration training sessions were carried out to train the animais. Opérant sessions lasted 30 minutes and were conducted once a day during the dark phase of the light dark cycle. Active and inactive (control) lever responding were monitored.

After stable baseline of alcohol self-administration was established, msP rats were 15 administered with vehicle or the inventive compounds at 2 different doses using a within subject design. Active and inactive lever responding was monitored: drugs were injected prior to the beginning of the self-administration session, according to indication.

The reinforcement program was FR1-LITO (Fixed Ratio - 1 Light Time Out). During the 5 seconds time out (following the reinforced RR) a house light was switched on. The tests were 20 conducted according to a within subject design where drug treatment (doses) was treated as repeated factors. Total number of active and inactive lever responding were subjected to statistical évaluation. Drug testing was carried out every four days. For 2 days before each drug test rats were not subjected to alcohol self-administration sessions.

Statistical Analysis:

Data were analyzed by means of a one-factor (treatment) ANOVA for repeated measures. Analysis of variance was followed by the Newman-Keuls test when appropriate. Statistical signifîcance was set at p<0.05.

As shown in Figure 9, H0847 had no effect on opérant responding for alcohol [F(2,11) = 30 0.53; p>0.05]. Responses at the inactive control lever were not modified [F(2,11) = 0.53;

p>0.05J.

As shown in Figure 10, H0860 significantly reduced opérant responding for alcohol [F(2,l 1) = 4.19; p<0.05]. Post hoc analysis revealed a significant réduction of alcohol selfadministration following treatment with the higher dose (30 mg/kg) (*p<0.05). Responses at the 35 inactive control lever were not modified [F(2,11) = 0.15; p>0.05].

As shown in Figure 11, H0816 had no effect on opérant responding for alcohol [F(2,l 1) =

0.75; p>0.05], Responses at the inactive control lever were not modified [F(2,11) = 0.30; p>0.05].

As shown in Figure 12, H0900 signifîcantly reduced opérant responding for alcohol [F(2,ll) = 8.62; p< O.Olj.Post hoc analysis revealed a significant réduction of alcohol self10 administration following treatment with both 3 mg/kg (*p<0.05) and 30 mg/kg (**p<0.01).

Responses at the inactive control lever were not modified [F(2,11) =1.03; p>0.05].

In summary, the data shows that, in msP rats, acute oral administration of both H0900 and H0860 induced a statistically significant decrease in éthanol self-administration. For H0900, the effect was seen for both the doses tested (3 and 30 mg/kg). For H0860, only the higher dose 15 (30 mg/kg) reduced éthanol self-administration. On the contrary, in the same experimental conditions, H0847 (1 or 3 mg/kg) and H0816 (3 or 10 mg/kg) had no effect on éthanol responses.

Claims

1. A compound of Formula I:

or a phannaceutically acceptable sait thereof, wherein:

a dashed line indicates an optional bond;

Xis CH or N;

ZisNR⁹, CR¹⁰Rⁿ, or O;

R¹ is H, Ci-6 alkyl, benzyl, OH, or Ci-6 alkoxy, wherein said Ci-6 alkyl, benzyl, or Ci-6 alkoxy is optionally substituted with 1-3 substituents selected from halo, OH, Ci-6 alkyl, Ci-6 alkoxy, Ci-β hydroxyalkyl, CO(Ci-6 alkyl), CHO, CO2H, CO2(Ci-6 alkyl), and C1-6 haloalkyl;

R² is H or Ci-6 alkyl;

R³ and R⁴ are each, independently, H, CN, halo, CHO, or CO2H, or optionally substituted C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkylcycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, CO(Ci-6 alkyl), CO₂(Ci-₆ alkyl), or CONR¹²R¹³;

R⁵ is halo, CN, CHO, CO2H, CO(Ci-6 alkyl), CO2(CW alkyl), NR¹⁴R¹⁵, NHCONR¹⁴R¹⁵, CONR¹⁴R¹⁵, Ci-6 alkyl, C1-6 alkoxy, Ci-6 haloalkyl, C1-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said CO(Ci-6 alkyl), CO2(Ci-6 alkyl), NR¹⁴R¹⁵, NHCONR¹⁴R¹⁵, CONR¹⁴R¹⁵, Ci-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaiyl, or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halo, CN, OH, NO2, Si(CH3)4, CHO, and CO2H, or optionally substituted CO(Ci-6 alkyl), CO₂(Ci-₆ alkyl), NR¹⁴R¹⁵, NHCONR¹⁴R¹⁵, CONR¹⁴R¹⁵, CH=NOH, Ci-6 alkyl, C1-6 alkoxy, Ci-6 haloalkyl, C1-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;

R⁶ is absent or H;

155

R⁷ is H, CN, or halo;

R⁸ is H or Ci-6 alkyl;

R⁹ is H, Ci-6 alkyl, CO(Ci-₆ alkyl), CHO, CO₂H, or CO₂(Ci_6 alkyl);

R¹⁰ and R¹¹ are each, independently, H, Cj-6 alkyl, or halo;

R¹² and R¹³ are each, independently, H or Ci-6 alkyl;

R¹⁴ and R¹⁵ are each, independently H, Ci-β alkyl, C0(Ci-6 alkyl), CO(heteroaryl), heteroaryl, or cycloalkyl;

r is 1 or 2;

s is 0-4; and n is 0-3.

2. The compound of claim 1, wherein X is CH.

3. The compound of claim 1, wherein X is N.

4. The compound of claim 1, wherein Z is NR⁹.

5. The compound of claim 1, wherein Z is N(Ci-6 alkyl).

6. The compound of claim 1, wherein Z is NCH3.

7. The compound of claim 1, wherein Z is CR¹⁰Rⁿ.

8. The compound of claim 1, wherein Z is CF2

9. The compound of claim 1, wherein Z is O.

10. The compound of claim 1, wherein R¹ is C1-6 alkyl.

11. The compound of claim 1, wherein R¹ is CH3.

12. The compound of claim 1, wherein R¹ is benzyl.

156

13. The compound of claim 12, wherein said benzyl is optionally substituted with CO2(Ci-6 alkyl) or Ci-6 hydroxyalkyl.

14. The compound of claim 1, wherein R¹ is OH.

15. The compound of claim 1, wherein R¹ is Ci-6 alkoxy.

16. The compound of claim 15, wherein said Ci-6 alkoxy is methoxy, ethoxy or propoxy.

17. The compound of claim 1, wherein R² is H.

18. The compound of claim 1, wherein R³ and R⁴ are each, independently selected from Ci-6 alkyl, CN, Ci-6 alkylcycloalkyl, Ci-6 hydroxyalkyl, CO2(Ci-6 alkyl), Ci-6 haloalkyl and CONH2,.

19. The compound of claim 18, wherein said C1-6 alkyl is methyl or ethyl.

20. The compound of claim 18, wherein said C1-6 alkylcycloalkyl is Ci alkylcylopropyl.

21. The compound of claim 18, wherein said Ci-6 hydroxyalkyl is Ci hydroxyalkyl optionally substituted with a substituted or unsubstituted benzyl group.

22. The compound of claim 18, wherein said CO2(Ci-6 alkyl) is CO2CH3.

23. The compound of claim 18, wherein said C1-6 haloalkyl is CF3.

24. The compound of claim 1, wherein R³ and R⁴ taken together with the C atom to which they are attached form a 3-6-membered ring.

25. The compound of claim 24, wherein R³ and R⁴ are taken together with the C atom to which they are attached to form a cyclopropyl ring.

26. The compound of claim 24, wherein R³ and R⁴ are taken together with the C atom to which they are attached form a tetrahydropyranyl ring.

27. The compound of claim 1, wherein R⁵ is Ci-e haloalkyl, heteroaryl, aryl, halo, C1-6 alkoxy, CO2<Ci-6 alkyl), C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, or heterocycloalkyl,

157

28. The compound of claim 27, wherein said cycloalkyl is cyclopropyl, cyclohexanyl or cyclohexenyl.

29. The compound of claim 27, wherein said Ci-6 haloalkyl is CHF2.

30. The compound of claim 27, wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, triazinyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl or furanyl,

31. The compound of claim 27, wherein said aryl is phenyl.

32. The compound of claim 27, wherein said halo is Cl or I.

33. The compound of claim 27, wherein said Ci-6 alkoxy is methoxy.

34. The compound of claim 27, wherein said CO2(Ci-6 alkyl) is CChMe.

35. The compound of claim 27, wherein said C2-6 alkynyl is C2 alkynyl.

36. The compound of claim 27, wherein said C2-6 alkenyl is C2 alkenyl.

37. The compound of claim 1, wherein R⁶ is absent.

38. The compound of claim 1, wherein R⁶ is H.

39. The compound of claim 1, wherein R⁷ is halo.

40. The compound of claim 39 wherein said halo is Cl or F.

41. The compound of claim 1, wherein 2 R⁷ corne together to form a phenyl group.

42. The compound of claim 1, wherein R⁵ and R⁷ corne together to form a 5-membered heterocyclic ring.

43. The compound of claim 1, wherein R⁸ is H.

44. The compound of claim 1, wherein R⁸ is C1-6 alkyl.

45. The compound of claim 1, wherein R⁸ is methyl.

46. A compound of claim 1, having Formula II:

R⁸

II, or a pharmaceutically acceptable sait thereof.

47.

III, or a pharmaceutically acceptable sait thereof.

48. A compound of claim 1, having Formula Ilia or Illb:

IHa

Illb, or a pharmaceutically acceptable sait thereof, wherein: R¹⁶ is H, cyclopropyl or thiazolyl; and R¹⁷ is H or halo.

49. A compound selected from the group consisting of:

Compound No. Chemical Structure Chemical Name H0494 ^Me'N^ 0 Me Cl rie ^H Ul 3-( 1 -(2,3-dichloro-4cyclopropylphenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0621 0 Me Cl θΗ ^H UÇf F 3-(1-(2,3 -dichloro-4(difluoromethyl)phenyl)ethyl)-1 -hydroxy1 -( 1 -methylpiperidin-4-yl)urea H0496 Μθ'Ν'''^ O Me Cl AVA⁰¹ Me Uy-y 3-( 1 -(2,3 -dichloro-4-(pyridin-3 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0617 “SA 0 Me Cl ÜAW ¹ H Me \ΑγΑ 4 3-(1-(2,3 -dichloro-4-(pyridin-3 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0539 Μθ'Ν^Α 0 Me Cl UAW' & ^hXcc MeOzC'^^ N methyl 4-((3 -( 1 -(2,3 -dichloro-4-(pyridin- 3- yl)phenyl)ethyl)-1 -( 1 -methylpiperidin- 4- yl)ureido)methyl)benzoate H0546 ^Ms'nA 0 Me Cl ÜAW¹ xY ^hOCc hoJV V 3-( 1 -(2,3-dichloro-4-(pyridin-3yl)phenyl)ethyl)-1 -(4(hydroxymethyl)benzyl)-1 -( 1 methylpiperidin-4-yI)urea H0526 /—1 0 Me Cl ^MeAA_NA_NÀAr⁰¹ Me ^H VAy 3-(1-(2,3 -dichloro-4-(pyridin-3 yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpyrrolidin-3-yl)urea H0527 “^e _trr^M'o Me Cl uaw Me ^H UAy 3-(l -(2,3-dichloro-4-(pyridin-3yl)phenyl)ethyl)-1-(1,3dimethylpiperidin-4-yl)-1 -methylurea

H0497 ^Μ®'Ν'^χχΊ 0 Me Cl lie ^H ULy 3-(1-(2,3 -dichloro-4-(pyridin-4yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0650 Μθ'Ν^'Α 0 Me Cl Λ ^H Me W\AV 3-(l -(2,3-dichloro-4-(pyridin-2yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0849 ^Me'N'^> O Me Cl <AVvV lie ^H LAy>s» 3-(1-(2,3-dichloro-4-(5cyclopropylpyridin-2-yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0578 ^MeN'^XV 0 Me ¹ H Me ⁿ WYs U 1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(pyridin-4-yl)naphthalen-1 yl)ethyl)urea H0511 ^Me'N'^V 0 Me Cl üaw ώ. ^H UU^ \Amb 3-( 1 -(2,3-dichloro-4-(6-methoxypyridin3-yl)phenyl)ethyl)-l -methyl-l-( 1 methylpiperidin-4-yl)urea H0820 0 Me Cl kA_NA_NAX,ci ULy ^brV-? 3 -( 1 -(2,3 -dichloro-4-(6cyclopropylpyridin-3 -yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0613 ^Wle'-N'^x> 0 Me Cl UAW ¹ H Me \AV>V^CN ^NT 3-(1-(2,3-dichloro-4-(5-cyanopyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0614 ^Μθ'νΆ ^{0 Me cl} Ia\v ώβ ^H ULy ^FT 3-( 1 -(2,3-dichloro-4-(5-fluoropyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0635 ^Μθ'Ν·^ Ο Me Cl Me ^Η ^ÿAx^x/COzMe methyl 5-(2,3-dichloro-4-(l-(3-methyl-3( 1 -methylpiperidin-4- yl)ureido)ethyl)phenyl)mcotinate H0636 ^Μ%Λ 0 Me Cl 'Α-?γν^α Λ H Μθ Vpp_OH IT 3-(1-(2,3-dichloro-4-(5(hydroxymethyl)pyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0637 ^Μβ'Ν^Ί O Me Cl ΑΛΛΧο _f Λ H I Me ^bF 3-(1-(2,3-dichloro-4-(5(difluoromethyl)pyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0638 0 Me Cl LAAnAAa Λ H M» V.p/-._F Ά 3-( 1 -(2,3-dichloro-4-(5- (fluoromethyl)pyridin-3-yl)phenyl)ethyl)- 1 -methyl-1 -(1 -methylpiperidin-4-yl)urea H0639 ^Μθ'Ν^% O Me Cl CL-AAÂa Me ^H ΑΑγ^Υχ/Μθ ^bF 3-(1-(2,3-dichloro-4-(5-methylpyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0642 ^Μθ'Ν^Α O Me Cl ÜAW' ώ. H lAæ 3-( 1 -(2,3-dichloro-4-(5-formylpyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0704 ^Μθ'Ν^Α O Me Cl UA\V i H Me ^bF 3-( 1 -(4-(5-aminopyridin-3-yl)-2,3dichloropheny l)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0705 ^Me'N^/A O Me Cl Άαααα r\ ^bF 3-( 1 -(2,3 -dichloro-4-(5-(cy clopent-1 -enl-yl)pyridin-3-yl)phenyl)ethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea

H0707 0 Me Cl AA_nA_nAxAci m Me ^H UyX^NH 3-( 1 -(4-(5-( 1 H-pyrazol-4-yl)pyridin-3-yl)- 2,3-dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0711 ^Me'N^A O Me Cl AA_nA_nAxAx^c| _n==xlùe ^H UyY^^NH 3-(1-(4-(5-(1 H-imidazol-4-yl)pyridin-3 yl)-2,3-dichlorophenyl)ethyl)-l-methyI-l( 1 -methylpiperidin-4-yl)urea H0716 ^Me'NA 0 Me Cl Μθ ^H VLyO 3-(1-(2,3 -dichloro-4-(5-(thiazol-5yl)pyridin-3-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0717 ^MeN^xA O Me Cl A^ÂAV st ώ=^H LAA 3-( 1 -(2,3-dichloro-4-(5-(thiophen-2yl)pyridin-3-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0718 ^Μθ'Ν^Α O Me Cl AA-V t 1 H ) Me 3-(1-(2,3-dichloro-4-(5cyclopentylpyridin-3-yl)phenyl)ethyl)-lmethyl-1 -( 1 -methyIpiperidin-4-yl)urea H0719 ^Μθ'ΝΆ 0 Me Cl AAAA^CI tt Me ^H 3-(1-(2,3 -dichloro-4-(5-(pyrrolidin-1 yl)pyridin-3-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0712 ^Me'NA 0 Me Cl ν,λαζ i H H Me ^π Αγ^γ^Νγ^Μβ < f 0 N N-(5-(2,3-dichloro-4-(l-(3-methyl-3-(lmethylpiperidin-4yl)ureido)ethyl)phenyl)pyridin-3yl)acetamide H0708 ^MeN^A 0 Me Cl AAW Λ H Me A^^oMe ^hF 3-( 1 -(2,3-dichloro-4-(5(methoxymethyl)pyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0714 O Me Cl LAAAAa ¹ H Me \^/A/\z°Me ^hF 3-(1-(2,3-dichloro-4-(5-(2- methoxyethyl)pyridin-3-yl)phenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea H0715 ^Μ®ΝΦ 0 Me Cl Me ^H 3-(1-(2,3 -dichloro-4-(5-ethylpyridin-3 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0706 ^MeN^A 0 Me Cl ^ι'/>ΛΑγ^::ΐ ^Me 3 -( 1 -(2,3 -dichloro-4-(5-vinylpyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0710 ^N^A 0 Me Cl 'AAArV lie ^H 3-(1-(2,3-dichloro-4-(5-ethynylpyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0666 ^MeN^A O CN Cl kALW¹ ¹ H Me 3-(cyano(2,3-dichloro-4-(5-cyanopyridm- 3 -yl)phenyl)methyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0739 ^μ®νΛ O CN Cl ALAnAAa hnώθ ^H υφΧ> ^N^ 3-((4-(5-( 1 H-pyrrol-2-yl)pyridin-3 -yl)- 2,3-dichlorophenyl)(cyano)methyl)-l- methyl-1 -( 1 -methylpiperidin-4-yl)urea H0667 Μ'Φ'φ O Me Cl ¹ H oh 3-(1-(2,3-dichloro-4-(5-cyanopyridin-3yl)phenyl)ethyl)-l -hydroxy-1 -( 1 methylpiperidin-4-yl)urea

H0821 AU 0 Me Cl i H Me ^π ^^Ν·Μ. 3-(1-(2,3 -dichloro-4-(5-cyano-6-(4methylpiperazin-l-yl)pyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0646 ^Me'N^U O Me Cl ΛΛ/Χο _n.oh ώ. ^H LA—Xh (E)-3-(l-(2,3-dichloro-4-(5((hydroxyimino)methyl)pyridin-3 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0720 O ( C! Aw ώ. ^H UL· 3-(2-cyclopropyl-1-(2,3 -dichloro-4(pyridin-3-yl)phenyl)ethyl)-l-methyl-l( 1 -methylpiperidin-4-yl)urea H0721 ^Μ'^γ 0 (a i H Me ΑΑχχ/^ΝΗ2 3-( 1 -(4-(5-aminopyridin-3 -yl)-2,3 dichlorophenyl)-2-cyclopropylethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0516 ^Me'A ^{0 Me Cl} Aw ώβ ^H ul_n V 3-(1-(2,3 -dichloro-4-(pyrimidin-5yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0579 ^Μ®'νΑ 0 Me fiA AA Me ^H LT — A 1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(pyrimidin-5-yl)naphthalen-l yl)ethyl)urea H0649 ^Μ®Ά ^{0 Me Cl} Aw -^H A l A N OMe 3-(1-(2,3 -dichloro-4-(2methoxypyrimidin-5-yl)phenyl)ethyl)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea

H0797 O Me Cl ώ. ^H (.Χρ_Ν l A N OH 3-(1-(2,3-dichloro-4-(2hydroxypyrimidin-5-yl)phenyl)ethyl)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea H0798 ^MeN^X 0 Me Cl uaw - ^H νγ_Ν ^rLNH₂ 3 -( 1 -(4-(2-aminopyrimidin-5-yl)-2,3 dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0799 Μθ'Ν·''^ 0 Me Cl ^n^nLV^CI Λ ^H Me ^^N'Me 3-( 1 -(2,3 -dichloro-4-(2-(4methylpiperazin-l-yl)pyrimidin-5yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yI)urea H0800 ^Μθ'Ν^Α 0 Me Cl ώ. ^H ix_rN Lf 3 -( 1 -(2,3-dichloro-4-(2-fluoropyrimidin5-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0801 ^Me'N^/~A O Me Cl kXci 3-(1-(2,3-dichloro-4-(2-chloropyrimidin- 5-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0802 ^ΜβΝΆ O Me Cl ώ. ^H l A N CN 3-( 1 -(2,3 -dichloro-4-(2-cyanopyrimidin5-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0803 0 Me Cl Me ^H IX^_N ^LnAO 3-( 1 -(4-(2-(1 H-imidazol-1 -yl)pyrimidin- 5-yl)-2,3-dichlorophenyl)ethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea

H0804 0 Me Cl ' H ^Me AAp_N A* Me 3-(1-(2,3 -dichloro-4-(2(dimethylamino)pyrimidin-5yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0805 0 Me Cl Uj.,aa,= - ^H ΙΑ _Λ l A A N N H 3-( 1 -(2,3 -dichloro-4-(2(cyclopropylamino)pyrimidin-5 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0806 ^M®'nA 0 Me Cl ' H ^Μβ W* H 3-( 1 -(2,3 -dichloro-4-(2(methylamino)pyrimidin-5yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0807 ^Me'N'A 0 Me Cl ^n^n\V^ci Λ H Me _o N-(5-(2,3-dichloro-4-(l -(3-methyl-3-( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)pyrimidin-2yl)cyclopropanecarboxamide H0854 ^M®'nA 0 Me Cl A_na_n\v - ^H Up Ay 3-(1-(2,3-dichloro-4-(2- cyclopropylpyrimidin-5-yl)phenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea H0813 ^M®'nA 0 Me Cl AXA¹Λ ^H ^Me Ya 3-( 1 -(2,3 -dichloro-4-(2-(pyrrolidin-1 yl)pyrimidin-5-yl)phenyl)ethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0814 ^Me'N”A 0 Me Cl YAAM¹ i H Me <A_t 3-(1-(2,3-dichloro-4-(2-(4-ethyl-3oxopiperazin-l-yl)pyrimidin-5yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

167

H0703 0 Me CN Çl AA-vA/¹ ^Me N 3-(l-cyano-l-(2,3-dichloro-4-(pyrimidin- 5 -yl)phenyl) ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0709 ^M®'N^ 0 CN Cl aa-Vu à ^H |l 1 'Me 13 N 3-(cyano(2,3-dichloro-4-(pyrimidin-5yl)phenyl)methyl)-1 -methoxy-1 -( 1 methylpiperidin-4-yl)urea H0584 0 Me CI V_nAnVy^ci - ^H XX-N X 1 -cyclohexyl-3-( 1 -(2,3 -dichloro-4(pyrimidin-5-yl)phenyl)ethyl)-1 methylurea H0586 0 Me Cl VAAV Μθ Cjx-_S:_NM 3-(1-(2,3 -dichloro-4-(pyrimidin-5yl)phenyl)ethyl)-1 -methyl-1 -(tetrahydro2H-pyran-4-yl)urea H0587 fÀV 0 Me Cl Xaw - ^H UL· V 3-( 1 -(2,3-dichloro-4-(pyrimidin-5yl)phenyl)ethyl)-1 -(4,4difluorocyclohexyl)-l -methylurea H0588 0 j o Me Cl aa\V Me ^H QAx^_nV 1 -( 1 -acetylpiperidin-4-yl)-3-( 1-(2,3dichloro-4-(pyrimidm-5-yl)phenyl)ethyl)- 1-methylurea H0663 Μθ'Ν^ν O Me Cl AA_NX_N AK/^ci _OMeΛ H 1 ^Me XAn ^νΑ)Μθ 3-( 1 -(2,3 -dichloro-4-(2,4dimethoxypyrimidin-5-yl)phenyl)ethyl)1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea

H0620 A ^ω·'_Νγ ο <° « ^OH - ^H vu V 3-(1-(2,3 -dichloro-4-(pyrimidin-5yl)phenyl)-2-((3- (hydroxymethyl)benzyl)oxy)ethyl)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea H0624 0 Me Cl UkW ÔH H UU U 3-( 1 -(2,3-dichloro-4-(pyrimidin-5yl)phenyl)ethyl)-1 -hydroxy-1 -( 1 methylpiperidin-4-yl)urea H0662 „ O-. .OMe WiXt· ώβ H UU_NU methyl 2-(2,3-dichloro-4-(pyrimidin-5yl)phenyl)-2-(3 -methyl-3 -( 1 methylpiperidin-4-yl)ureido)acetate H0670 «•'_N-s o A^H _CI UaW ώθ ^h v U 3-(1-(2,3-dichloro-4-(pyrimidin-5yl)phenyl)-2-hydroxyethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0673 “’O î v ? LA_nA_nXA.ci ώ. ^H UV U 3-( 1 -(2,3-dichloro-4-(pyrimidin-5yl)phenyl)cyclopropyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0727 ^Mev î 0 ? Av_na_n><Ay^ciMe N 3-(4-(2,3-dichloro-4-(pyrimidin-5yl)phenyl)tetrahydro-2H-pyran-4-yl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0631 ^M®nV 0 CN Cl UVU^aώ. ^h uu V 3-(cyano(2,3-dichloro-4-(pyrimidin-5yl)phenyl)methyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

169

H0686 ^MeN^A 0 CF₃ Cl OxAVa ^{ώβ H} ΑΑγχ 1 j N 3-(1-(2,3-dichloro-4-(pyrimidin-5yl)phenyl)-2,2,2-trifluoroethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0619 0 Me Cl AA-W¹ ¹ H Me ⁿ 3 -( 1 -(2,3 -dichloro-4-(pyrimidin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0768 ^M®N^xA 0 Me Cl ÜAW i H Me ^π 3-( 1 -(2,3 -dichloro-4-(pyrimidin-4yl)phenyl)ethyl)-1 -methyl-1 -(1 methylpiperidin-4-yl)urea H0808 ^Μβ'Ν^Α O Me Cl Ά_ΝΑ_ΝΑΑθ· Me ^H XXx/N T 1 Me 3- ( 1 -(2,3 -dichloro-4-(6-methylpyrimidin- 4- yl)phenyl)ethyl)-1 -methyl-1 -(1 methylpiperidin-4-yl)urea H0700 ^MeN^A O Me Cl AAAV Me ^H Xÿ^x/N. 3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0816 Μθ'Ν^Ά O Me Cl Me ^H %^Αχ/^Νχ U N (S)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0817 Μθ'Ν^'Α 0 Me Cl ^„A_NAA_rc Me ^H ^UaL/^Nx O N (R)-3-(l-(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -(1 methylpiperidin-4-yl)urea

H0722 Ο ( Cl AaA* Me ^H wL/N. U N 3 -(2-cyclopropyl-1-(2,3 -dichloro-4(pyrazin-2-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0741 0 [Cl ¹ H OMe ⁿ kAk/^N\ O N 3-(2-cyclopropyl-l-(2,3-dichloro-4(pyrazin-2-yl)phenyl)ethyl)-l-methoxy-l( 1 -methylpiperidin-4-yl)urea H0752 “' n-'', O < Cl ÜAW i H OEt ^Π k^k^N O N 3-(2-cyclopropyl-l-(2,3-dichloro-4(pyrazin-2-yl)phenyl)ethyl)-l -ethoxy-1 ( 1 -methylpiperidin-4-yl)urea H0743 ^Me'N'^^xi 0 Me Cl ÜAW ¹ H OMe ⁿ k^k/% V 3-( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methoxy-1 -( 1 methylpiperidin-4-yl)urea H0750 ^M®'N^X O Me Cl lAanJA i H OEt A^k/^N\ i: N 3-( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -ethoxy-1 -( 1 methylpiperidin-4-yl)urea H0756 ^Me'N^A 0 Me Cl ¹ H OH k^A^N O N 3-(1-(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -hydroxy-1 -(1 methylpiperidin-4-yl)urea H0761 ^Μθ'Ν^> 0 [CI ^νΑΧΑλ Ôh ^H UAn M 3-(2-cyclopropyl-1-(2,3 -dichloro-4(pyrazin-2-yl)phenyl)ethyl)-1 -hydroxy-1 ( 1 -methylpiperidin-4-yl)urea

H0781 0 ( Cl V/AV¹ θ^{Η h} (S,R) P L 3-(2-cyclopropyI-1 -(2,3 -dichloro-4(pyrazin-2-yl)phenyl)ethyl)-1 -hydroxy-1 ( 1 -methylpiperidin-4-yl)urea (single enantiomer) H0782 ^MeN^ o ( Cl ΦΑφ θ^{Η H} ^(S'^R) 5 N 3-(2-cyclopropyl-l-(2,3-dichloro-4(pyrazin-2-yl)phenyl)ethyl)-l-hydroxy-l( 1 -methylpiperidin-4-yl)urea (single enantiomer) H0824 ^ΜβΆ U de ^χΜβΟ Me Cl VAV Me ^H N 3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-l-methyl-l-((R)-l,3,3trimethylpiperidin-4-yl)urea H0890 ^m’'nX U de ^χΜθΟ Me Cl AA-V i H Me ^π lÎ^L^N o N 3-((S)-1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -((R)-1,3,3trimethylpiperidin-4-yl)urea H0858 ^M9'nL U X Aci ^Ln^XnW^ci Me ^H U N 3-(1-(2,3-dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -methyl-1 -((R)-1,3,3trimethylpiperidin-4-yl)urea H0865 ^m»~_nA U CF_S Cl AXa Me ^H V 3-(1-(2,3-dichloro-4-(pyrazin-2- yl)phenyl)-2,2,2-trifluoroethyl)-l-methyl- 1 -((R)-1,3,3-trimethylpiperidin-4-yl)urea H0825 ^Μ®'Νφ 0 Me CI OaAvV A Φ 1 -benzyl-3 -( 1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-l -( 1 -methylpiperidin-4yl)urea

H0826 ^Μθ'Ν^ Ο Me Cl Ν 3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -ethyl-1 -( 1 methylpiperidin-4-yl)urea H0889 0 Me Cl lAiAmYY⁰¹ J ^H ULx Me ^bT (S)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -ethyl-1 -( 1 methylpiperidin-4-yl)urea H0896 “/N-·, 0 Λ, _Mej ^H IXn ^bT 3 -( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -ethyl-1 -(1 methylpiperidin-4-yl)urea H0827 ^Me'N^X 0 Me Cl Me 3 -( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -( 1 -methylpiperidin-4yl)-l-propylurea H0829 ^Me-N-'/ d*S Cl Me ^H CxÀ N 3 -( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0859 ^Me'N^> O^MeA Cl ^^iAn^Ay^ci Me ^H KAx^^Nx N (R)-3-(l-(2,3-dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer) H0860 “θ'Ν^, <?% Cl <ΛΛ_ΝλΧα i H N (S)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer) H0922 o^eV°ci ΧίΑνΧΑ/⁰' Me ^H \Χ·^·Ν. O N methyl 2-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)-2-(3 -methyl-3 -( 1 methylpiperidin-4-yl)ureido)acetate

H0924 Me, HO 0 b Cl Me ^H ΑΑγ/% 3 -( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)-2-hydroxyethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0830 ^MeN^U 0 CF₃ Cl UAW Me ^H U N 3-(1-(2,3 -dich!oro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0899 ^MeN^A O CF₃ Cl A_nA_nAy^ci Me ^H (S)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0900 Μθ'Ν^Α O CF₃ Cl 'Ja-W' Me ^H <R) ΊΟ N (R)-3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0909 ^Me'N'^U O CF₃ Cl CLAW k.^H lX(N N 3-(1-(2,3 -dichloro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-1 -ethyl-1 ( 1 -methylpiperidin-4-yl)urea H0856 ^Me'N^A O Me F Me ^H UAn, U N 3-(1-(3 -chloro-2-fluoro-4-(pyrazin-2yl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0837 Me N-, o Me Cl <\Av Me ^H \A/N, U N 3-((S)-l-(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3 -yl)urea (diasteromeric mixture) H0861 Me N-i 0 Me Cl Aaw Me ^H (R/S) T η N 3-((S)-l-(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3-yl)urea (single diastereoisomer)

H0862 Me N-, O Me Cl Me ^H AaA/^N\, ^(R/S) ί J N 3-((S)-l-(2,3-dichloro-4-(pyrazm-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3-yl)urea (single diastereoisomer) H0857 Me A °^MA ^cl Me ^H IAs-N. ad N 3-( 1 -(2,3 -dichloro-4-(pyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpyrrolidin-3-yl)urea H0871 Me À » Î^F’Î' ΑΛΛΑ¹ Me ^H IzAn. U N 3 -( 1 -(2,3-dichloro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-1 -methyl- 1 -(1 -methylpyrrolidin-3-yl)urea H0874 Μβ_χ ,^N~~i O ( Cl A_na_nXJLci Me ^H A?A/^N U N 3-(2-cyclopropyl-1 -(2,3 -dichloro-4(pyrazin-2-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methyl pyrrolidin-3-yl)urea H0853 ^M®'N^A 0 Me Cl uJaL·' Me ^H U N N-(l -(2,3-dichloro-4-(pyrazin-2yl)phenyl)ethyl)-2-(4-methylpiperazin-1 yl)propanamide H0815 ^M®'nA O Me Cl Aaaaa i H Me Me IT N 3-(l-(2,3-dichloro-4-(6-methylpyrazin-2yl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0831 ^M®N^xA ° ^{Me Cl} ΑααΑ¹ i H Me ⁿ jO Me^N 3-(1-(2,3-dichloro-4-(3-methylpyrazin-2yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0843 0 Me Cl AAAAAx¹ Me ^H OAAn Me^N 3-(1-(2,3-dichloro-4-(3-methylpyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -((R)-1,3,3trimethylpiperidin-4-yl)urea H0844 “'ίι', 0 < Cl χχνΑ Me ^H JO Me^N 3 -(2-cyclopropyl-1 -(2,3 -dichloro-4-(3methylpyrazin-2-yl)phenyl)ethyI)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea H0738 ^Me'N^O O Me Cl Μθ ^H Αγ^Νυ^Μθ IX N 3-( 1 -(2,3 -dichloro-4-(6-methoxypyrazin2-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0780 ^MeN^X O Me Cl i H Me AAA/^N\z^NH2 IX N 3-( 1 -(4-(6-aminopyrazin-2-yl)-2,3 dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0786 ^Me'N'X O Me Cl Ο^,α,λΧο. ώθ ^H Μγγ_α 3-(1-(2,3 -dichloro-4-(6- (chloromethyl)pyrazin-2-yl)phenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea H0791 Μθ'Ν'Χ O Me Cl Xav Me ^H ΑίΑγΧγθΙ ^bT 3-(1-(2,3 -dichloro-4-(6-chloropyrazin-2yl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0795 ^ΜβΝ·χ O Me Cl Me ^H LA/N^-F IX N 3 -( 1 -(2,3 -dichloro-4-(6-fluoropyrazin-2yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0847 ^MeNX 0 Me Cl ^^nAAA/^CI i H Me ^π F IX N (S)-3-(l-(2,3-dichloro-4-(6-fluoropyrazin2-yl)phenyl) ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

176

H0848 ^Μθ'Ν^> 0 Me Cl AaXA¹ 1 H Me ^π k^k^N F 17 N (R)-3-(l-(2,3-dichloro-4-(6fluoropyrazin-2-yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0863 ^Μβ'Ν^> 0 Et Cl UA-Y i H Me ⁿ F 3-( 1 -(2,3 -dichloro-4-(6-fluoropyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0908 O CF₃ Cl ÜAW l H Me ⁿ F IT N 3-( 1 -(2,3 -dichloro-4-(6-fluoropyrazin-2yI)phenyl)-2,2,2-trifluoroethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0864 Me Ν-η O Et Cl ÛAW i H Me ⁿ k-Ax/^Nx/F IX N 3-( 1 -(2,3 -dichloro-4-(6-fluoropyrazin-2yl)phenyl)propyl)-1 -methyl-1 -( 1 methylpyrrolidin-3 -yl)urea H0872 Me N-i 0 Me Cl Ua_n<Y=i Me ^H LA-N F IX N 3 -((S)-1 -(2,3 -dichloro-4-(6-fluoropyrazin2-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3 -yl)urea H0840 ^M®'nY 0 Me Cl Aava 1 H Me k<A\/N^ I/i F N 3-(1-(2,3-dichloro-4-(3-fluoropyrazin-2yl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0910 Μθ'Ν'Ύ O Me Cl Aiv Me ^H AAn CF₃ U N 3-(1-(2,3 -dichloro-4-(6(trifluoromethyl)pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0788 ^Me'NY 0 Me Cl Ανγ Me ^H ΑΑ/^Νχ/°^Ν M 3-(l -(2,3-dichloro-4-(6-cyanopyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0789 0 Me Cl Me ^H Y OMe methyl 6-(2,3 -dichloro-4-( 1 -(3 -methyl-3 ( 1 -methylpiperidin-4yl)ureido)ethyl)phenyl)pyrazine-2carboxylate H0760 ^Me'N^xU 0 Me Cl <A_NA_NA_rÇ^c| Me ^H U_y ^nh’ 0 5-(2,3-dichloro-4-( l-(3-methyl-3-( 1 - methylpiperidin-4- yl)ureido)ethyl)phenyl)pyrazine-2carboxamide H0769 ^MeN^> 0 Me Cl Me ^H ΥίΥ/Ν. l^CM. 0 methyl 5-(2,3-dichloro-4-(l-(3-methyl-3( 1 -methylpiperidin-4- yl)ureido)ethyl)phenyl)pyrazine-2carboxylate H0771 ^Me'N^> O Me Cl Me ^H KAA'U ΑΑγ^ΝΜθ2 O 5-(2,3 -dichloro-4-( 1 -(3 -methyl-3 -( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)-N,Ndimethylpyrazine-2-carboxamide H0770 ^MeN^xU 0 Me Cl ÙW/ Me ^H AA/^N\ ΦφθΗ 3-( 1 -(2,3-dichloro-4-(5(hydroxymethyl)pyrazin-2yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0828 ^MeN^% 0 Me Cl UAW i H Me ^H 3 -( 1 -(2,3 -dichloro-4-(quinoxalin-2yl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0822 ^Me'N'U 0 Me Cl ΧΥν^νΑΆ⁰¹ TFA Me ^H AA/N υφ Φ-Me 3-(1-(2,3 -dichloro-4-(5-(4methylpiperazin-1 -yl)pyrazin-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

178

H0850 O Me λΑκ-ΧΑζ ¹ Η Me ^Π 1D Ν 1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(pyrazin-2-yl)naphthalen-l yl)ethyl)urea H0881 ^ΜθΝΑ ° ^{Me Cl} Me ^Η A A ^Ν υ Ν 3-( 1 -(4,5-dichloro-6-(pyrazin-2y l)pyridin-3 -yl) ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0729 ^Μ®Ά 0 Me Cl <Α_ΝΛ_ΝΑΑχ ι Η Me ^π 3-( 1 -(2,3 -dichloro-4-(pyridazin-3 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0783 ^Μθ'νΑ ^{0 Me 01} Ά_ΝΑ_ΝΑΑ/>! ώβ ^Η UL· A 3 -( 1 -(2,3 -dichloro-4-(pyridazin-4yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0793 ^Μ®'νΑ 0 Me Cl Aw Μθ ^H AA^N'm Ύ ΐ Μ 3-( 1 -(2,3 -dichloro-4-( 1,2,4-triazin-3yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0796 ^'NU O Me Cl λΤ_ΝΑ_ΝΑΑ^θι ^Me AyUⁿX Il Ί ΝγΝ ô 0 3-( 1 -(2,3 -dichloro-4-(4,6-dimorpholinol,3,5-triazin-2-yl)phenyl)ethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0498 ^Me'NU 0 Me Cl aLAnÙX⁰m. ^H LT— ^-~s 3-(1-(2,3-dichloro-4-(thiophen-3yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0531 /—| 0 Me Cl Me ^H ΤΤγγ 3-(1-(2,3 -dichloro-4-(thiophen-3yl)phenyl)ethyl)-1 -methyl-1 -(1 methylpyrrolidin-3-yl)urea

H0594 A ^Μθ'Ν^ O <° Cl °^H <A^ân-Vy^ci Me ^H a 3-(1-(2,3-dichloro-4-(thiophen-3yl)phenyl)-2-((3- (hydroxymethyl)benzyl)oxy)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0644 0 CN Cl U-VW¹ ' H Me ΑΑγλ 3-(cyano(2,3-dichloro-4-(thiophen-3yl)phenyl)methyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0536 ^Me'NU 0 Me Cl Α^ΑΑ/γ⁰¹ Me ^H UL· s—7 3-(1-(2,3 -dichloro-4-(thiophen-2yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0563 ^MeN^> 0 Me Cl UAÂA ώθ ^H LU R/S \ /) SA 3-(1-(2,3 -dichloro-4-(thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer) H0564 ^MeN'^U O Me Cl Λ H Me R/S V z> SA 3-(1-(2,3 -dichloro-4-(thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer) H0627 ^Μ®'νΑ O Me Cl ÜAW ÔH ^H (A sa 3-( 1 -(2,3-dichloro-4-(thiophen-2yl)phenyl)ethyl)-l -hydroxy-1 -(1 methylpiperidin-4-yl)urea H0660 Me^_11X-\ _ Ο^,ΟΜβ QAXV ώ. ^H IA SA methyl 2-(2,3-dichloro-4-(thiophen-2yl)phenyl)-2-(3 -methyl-3-( 1 methylpiperidin-4-yl)ureido)acetate H0661 0 A. aaUaa a. ^H IJL. sA 3 -( 1 -(2,3 -dichloro-4-(thiophen-2yl)phenyl)-2-hydroxyethyl)-l -methyl-1 ( 1 -methylpiperidin-4-yl)urea

H0672 ^ΜβΌ ϊ ν ? lie ^Η 3-( 1 -(2,3 -dichloro-4-(thiophen-2yl)phenyl)cyclopropyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0651 ^Μθ'Ν^ 0 Me Cl ώ. « w ^s \ CHO 3-(1-(2,3-dichloro-4-(5-formylthiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0653 ^M®'nA 0 Me Cl Aw >i. » (A ^s \ X-OH 3-(1-(2,3-dichloro-4-(5(hydroxymethyl)thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0668 “®'nA O Me Cl Φ-ΑΜ ώβ ^H UL· ^s \ F 3-(1-(2,3-dichloro-4-(5(fluoromethyl)thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0654 ^M6'nA O Me Cl Aav λ. ^H UU ^s \ )—F F 3-( 1 -(2,3-dichloro-4-(5(difluoromethyl)thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0655 “SA O Me Cl A_nA_n^ci M* UL· ^s \ X-Me O 3-( 1 -(4-(5-acetylthiophen-2-yl)-2,3dichlorophenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0691 “SA o Me Cl Auvau ώ. ^h VL. ^s \ y~NH₂o 5-(2,3-dichloro-4-( 1 -(3-methyl-3-( 1 - methylpiperidin-4- yl)ureido)ethyl)phenyl)thiophene-2carboxamide

H0728 O (Cl a/av lie ^H ÇL· ^s \ Anh₂ O 5-(2,3-dichloro-4-(2-cyclopropyl-l-(3methyl-3 -( 1 -methylpiperidin-4yl)ureido)ethyl)phenyl)thiophene-2carboxamide H0726 ^Me'N'^> O Me Cl aaav lie ^H ^s \ X-NMe₂0 5-(2,3 -dichloro-4-( 1 -(3-methyl-3-( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)-N,Ndimethylthiophene-2-carboxamide H0689 ^M®N^A O Me Cl kArAW' Me ^H ^s \ #~OH 0 5-(2,3-dichloro-4-(l-(3-methyl-3-(lmethylpiperidin-4- yl)ureido)ethyl)phenyl)thiophene-2carboxylic acid H0692 ^MeN'^xx> O Me Cl AAAA/¹ώ. ^H IJL· s~# \ _zOMe An ° Me 5-(2,3-dichloro-4-( 1 -(3-methyl-3-( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)-N-methoxy-Nmethylthiophene-2-carboxamide H0656 0 Me Cl UAV' lie ^H UL· ^s \ Aoh Me 3 -(1 -(2,3 -dichIoro-4-(5-( 1 hydroxyethyl)thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0652 ^Μ®Ά 0 Me Cl A_nA_n^ci Me ^H ^S \ CHO 3-( 1 -(2,3 -dichloro-4-(5-formylthiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0713 ^M®'nV O Me Cl UAW lie UL· ^s \ CN 3-(1-(2,3-dichloro-4-(5-cyanothiophen-2yl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea

H0688 ^Me'N^A 0 Me Cl UAW V Λ h A- 3-(1 -(4-(3 -acetylthiophen-2-yl)-2,3 dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0774 O Me Cl φχν 1 Λ· ^H U'À¹ 2-(2,3-dichloro-4-( 1 -(3-methyl-3-( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)thiophene-3carboxamide H0664 0 Me Cl ¹Ά_να_νλj, ci _oh ^H UU 3-(1-(2,3 -dichloro-4-(3(hydroxymethyl)thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0535 ^Me'N^XA 0 Me Cl A/AA ώθ ^H UL· hnY 3-( 1 -(2,3 -dichloro-4-( 1 H-pyrrol-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea ’ H0499 ^MeN'^xA O Me Cl U/Âv ώθ ^H UL· T N Ah 3-( 1 -(2,3 -dichloro-4-( 1 H-pyrazol-4yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0693 ^Μ®'νΑ 0 Me Cl OxA_NAAr^clώ« UU Y N N__/OH 3-( 1 -(2,3 -dichloro-4-( 1 -(2-hydroxyethyl)- 1 H-pyrazol-4-yl)phenyl)ethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0694 ^Μθ'Ν^Α O Me Cl Α_νΑ_νΑΧχι Λ H Me Y N N__/OMe 3-( 1 -(2,3 -dichloro-4-( 1 -(2-methoxyethyl)- 1 H-pyrazol-4-yl)phenyl)ethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0657 ^Μβ'Ν'Α O CN Cl Φλμ lie UL· YN *~~ΝΗ 3-(cyano(2,3-dichloro-4-(lH-pyrazol-4yl)phenyl)methyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0553 ^Me'N'^xV 0 Me Cl %'_H 3-(1-(2,3 -dichloro-4-( 1 H-pyrazol-4yl)phenyl)ethyl)-1 -(4(hydroxymethyl)benzyl)-1 -( 1 methylpiperidin-4-yl)urea H0842 ^MeN^A O Me Cl Me ^H W. Y N ‘N L 3-(1-(2,3 -dichloro-4-( 1 -cyclopropyl-1Hpyrazol-4-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0542 Μθ'Ν'Ύ O Me Cl Me ^H AA-N v> Ah 3 -( 1 -(2,3-dichloro-4-( 1 H-imidazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0568 Μθ'Ν-Ύ 0 Me Cl ν_ΝΛ_ΝΑ±γ! i H Me ^π v> 3-(1-(2,3 -dichloro-4-(thiazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0794 ^Me'N^xV 0 Me Cl An^nAy^CI Μθ VO y y-NH₂ X 3 -( 1 -(4-(2-aminothiazol-4-yl)-2,3dichlorophenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0841 ^Me'NY 0 Me Cl ώ. ^H UCn . 3-(1-(2,3-dichloro-4-(2cyclopropylthiazol-4-yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0792 ^Me'N^xV 0 Me Cl UA<V Y /X^NH2 3-( 1 -(4-(2-aminothiazol-5-yl)-2,3 dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0569 ^M6'nV 0 Me Cl X/a^ci ¹ h II 1 Me \v\/N ^v> 3-(1-(2,3 -dichloro-4-(oxazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0565 Μθ'Ν'-'Α 0 Me Cl A>_NA_NA^L/Ci Me ^H U=/^N 3-( 1 -(2,3 -dichloro-4-( 1 H-l ,2,3 -triazol-1 yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0604 ^MeN^xA 0 Me Cl AAAV lie ^H LA V NH n=n 3 -( 1 -(2,3-dichloro-4-( 1 H-1,2,3 -triazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0595 O Me Cl aIAnAA-⁰¹ Me ^H VaA-0 y ⁿ~n 3-(1-(2,3 -dichloro-4-( 1,3,4-oxadiazol-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0596 0 Me Cl Xaw ¹ H Me U 'n N~Me 3 -( 1 -(2,3-dichloro-4-(3 -methyl-1,2,4oxadiazol-5 -yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0851 “θ'ΝΑ 0 Me Cl A_na_nAA^c' ¹ H Me Y 'n t 3-( 1 -(2,3-dichloro-4-(3-cyclopropyl- 1,2,4-oxadiazol-5-yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0537 ^Me'N''A O Me Cl Xaw A MeO₂C'^ⁱ^ ^NH methyl 4-((3-( 1 -(2,3 -dichloro-4-( 1Hpyrazol-4-yl)phenyl)ethyl)-1 -( 1 methylpiperidin-4yl)ureido)methyl)benzoate H0529 Λ-ι 0 Me Cl ^Me'^NAA_N\V Me ^H UL T N Ah 3-(1-(2,3 -dichloro-4-(l H-pyrazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpyrrolidin-3-yl)urea H0528 ^Me'N^r^MeO Me Cl Xa\v » ^H uu T N Ah 3-(1-(2,3 -dichloro-4-( 1 H-pyrazol-4yl)phenyl)ethyl)-1-(1,3dimethylpiperidin-4-yl)-1 -methylurea

H0501 0 Me Cl lie ^H UL-. T N Me 3-(1-(2,3 -dïchloro-4-( 1 -methyl-1Hpyrazol-4-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0507 ^ΜθΝ'φ 0 Me Cl ÜA\V lie ^H UL· 3-( 1 -(2,3 -dichloro-4-(furan-3 yl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0665 ^Μ®'νΦ 0 Me Cl ΑΑΑΑΑγ⁰¹lie ^H Ιφ ⁰ \ Me 3-(1-(2,3 -dichloro-4-(5-methylfuran-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0508 ^Μβ'Νφ O Me Cl ΦΑ¥ lie ^H 3 -( 1 -(2,3 -dichloro-4'-methoxy-[ 1,1'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0509 ^'Ν'φ 0 Me Cl ΦΑΑ« lie ^H 3- (1-(2,3 -dichloro-[ 1,1 '-biphenyl]-4yl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea H0510 ^Ν'Φ 0 Me Cl AAYV Me ^H ΥΛθζΝ^Η ₂ 3 -( 1 -(3 '-amino-2,3 -dichloro-[l, 1 'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0606 ^Μ®Νφ 0 Me Cl ΦνΑΦΦ Me H 3-( 1 -(2,3-dichloro-3'-methoxy-[l, 1 'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0810 ^Me'N^A ^{0 Me cl} Φαααα W¹, H _c Me 3-( 1 -(2,3 -dichloro-3'-fluoro-[ 1,1'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0696 ^ΜθΝ^Χ O Me Cl Μ» ^H F 3- (1 -(2,3 -dichloro-3 '-fluoro-5'(hydroxymethyl)-[ 1,1 '-biphenyl]-4yl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea H0611 ^Me'N'^xX 0 Me Cl ¹ H Me A^X^x^/OMe OMe 3-( 1 -(2,3 -dichloro-3 ',5'-dimethoxy-[ 1,1'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0612 0 Me Cl Xaw Me ^H X^Lx^/CONH₂ 2',3 '-dichloro-4'-( 1 -(3-methyl-3 -( 1 methylpiperidin-4-yl)ureido)ethyl)-[ 1,1'biphenyl]-3-carboxamide H0615 ^Me'N-X 0 Me Cl UAAV¹ώβ ^H LA^ ^xonh₂ 2',3 '-dichloro-4'-( 1 -(3-methyl-3 -( 1 methylpiperidin-4-yl)ureido)ethyl)-[ 1,1'biphenyl]-4-carboxamide H0809 '^θ'Ν^'Α 0 Me Cl UAvvA ώ. ^H UL^ U'-CN 3-( 1 -(2,3-dichloro-4'-cyano-[l, 1 'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0699 ^MeN^U O Me Cl <Λαα·Λα ώ. ^H lXp^_CN 3-( 1 -(2,3 -dichloro-4-(5- (cyanomethyl)pyridin-3-yl)phenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea H0607 ^Me'N'^xA O Me Cl i H Me ΑΑγΆζθΜβ 3-(1-(2,3 -dichloro-4-(5-methoxypyridin- 3 -yl)phenyl) ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0695 ^Me'N^X O Me Cl Οφ,Ϋ Me H 3-(l-(4-(5-bromopyridin-3-yl)-2,3dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0635 ^MeN'^XX> 0 Me Cl AAW¹ Me ^H AA\/^/CO₂Me methyl 5-(2,3-dichloro-4-( 1 -(3-methyl-3( 1 -methylpiperidin-4- yl)ureido)ethyl)phenyl)nicotinate H0690 Μθ'Ν'^ν 0 Me Cl Μθ ^H UCaAm >| Me 3-( 1 -(4-(5-acetylpyridin-3-yl)-2,3dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0735 ^Me'N^> O Me Cl Λ H I Me 3-(1-(2,3-dichloro-4-(5-(pyrimidin-2yl)pyridin-3 -yl)phenyl)ethyl)-l -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0746 ^MeN^V 0 Me Cl FA_nL_nAA^ci _o ώ= ^H UyyU 3-(1-(2,3-dichloro-4-(5-(furan-3yl)pyridin-3 -yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0747 ^Me'N^/x> 0 Me Cl ^AW¹ _rs ώθ ^H AA^JA 3-( 1 -(2,3-dichloro-4-(5-(thiophen-3yl)pyridin-3-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0748 ^M®'N'^xx> O Me Cl ALAAjAy⁰¹ _rN m· ^H LUX 3-( 1 -(2,3 -dichloro-4-(5-( 1 -methyl-1Hpyrazol-4-yl)pyridin-3-yl)phenyl)ethyl)-lmethyl-1 -(1 -methylpiperidin-4-yl)urea H0765 ^Μβ,'Ν'φ O Me Cl -/,ΛΑ λ 3-(1-(2,3 -dichloro-4-(5cyclopropylpyridin-3-yl)phenyl)ethyl)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea

H0766 ^M®'nA 0 Me Cl AXA ¹ H Me Α^Αθ² 3-( 1 -(2,3-dichIoro-4-(5-nitropyridin-3yl)phenyl)ethyl)-1 -methyl-1 -(1 methylpiperidin-4-yl)urea H0608 ^Me'NA 0 Me Cl ώ. ^H UA >| Me ^N^O^Me 3-(1-(2,3 -dichloro-4-(6isopropoxypyridin-3-yl)phenyl)ethyl)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea H0616 0 Me Cl AAAV lie ^H 3-(1-(2,3 -dichloro-4-(6-cyanopyridin-3 yl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0618 ^M®'nA 0 Me Cl UAW¹lie ^H LXp 3-(1-(2,3 -dichloro-4-(6-fluoropyridin-3yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0623 ^Μ®Ά 0 Me Cl X-ALV¹ lie ^H ¹ H 3-(1-(2,3 -dichloro-4-( 1 H-pyrazolo [3,4b]pyridin-5-yl)phenyl)ethyl)-l-methyl-l( 1 -methylpiperidin-4-yl)urea H0610 ^M®'nA 0 Me Cl AXA i H Me ⁿ 3-(1-(2,3 -dichloro-3 -cyano-[ 1,1 'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0517 ^MeN'A ^{0 Me cl} AXA lie ^H Άγρ Α_Νη₂ 3-( 1 -(4'-amino-2,3-dichloro-[l, 1 'biphenyl]-4-yl)ethyl)-l-methyl-l-(lmethylpiperidin-4-yl)urea H0518 ^μ®'νΑ ^{0 Me Cl} A»w lie ^H Uyp ΑΑ_ΝΜθ₂ 3-(1-(2,3 -dichloro-4'-(dimethylamino)[1,1 '-biphenyl]-4-yl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0512 ^{0 Me Cl} ^'N'^'nXV⁰¹ g=n Me ^H UKA/^NMe 3-( 1 -(2,3-dichloro-4-( 1 -methyl-1Hindazol-4-yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0513 ^M®'nA O Me Cl Me ^H ΙΑΧ^ΝΗ 3 -( 1 -(2,3 -dichloro-4-( 1 H-indazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0514 ^M6snA 0 Me Cl Aw ώθ ^H ^N H 3-( 1 -(2,3 -dichloro-4-( 1 H-pyrrolo[2,3 b]pyridin-5-yl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0515 ^ΜθΆ 0 Me Cl AMA¹lie ^H UAr H 3-(1-(2,3 -dichloro-4-( 1 H-indol-5yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0520 ^Μ®Ά 0 Me Cl AAW lie ^H UA 3-(1-(2,3-dichloro-2', 3', 4', 5'-tetrahydro[1,1 '-biphenyl]-4-yl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0787 ^MeN^A 0 Me X'N^N^/\^ZY°'m Me ^H V/ HN—^y 3- (1-(3- (cyclopropylamino)benzo[d]isoxazol-6yl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea H0582 ^M6'nA 0 Me F UAW ¹ H Me \AxS 3-( 1 -(3 -chloro-2-fluoro-4-(thiophen-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0571 ^Me'N'^xA 0 Me F ÜAW Me ^H UL-. T N ^•NH 3-( 1 -(3-chloro-2-fluoro-4-( 1 H-pyrazol-4yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0605 0 Me Cl UAW' Λ H Me A^y^x^F F 3-(1-(2,3 -dichloro-3 ',5'-difluoro-[ 1,1 'biphenyl]-4-yl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0573 Me ^H UL Br 3-( 1 -(4-bromonaphthalen-l -yl)ethyl)-l methyl-1 -( 1 -methylpiperidin-4-yl)urea H0574 ^MeN^/^| 0 Me Me ^H ULy 1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(thiophen-3 -yl)naphthalen-1 yl)ethyl)urea H0575 ^Me'N^y 0 Me Ay i H Me ^π 1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(thiophen-2-yl)naphthalen-l yl)ethyl)urea H0576 o Me Ay ώθ ^H Ux^ T N ^NH 3 -( 1 -(4-( 1 H-pyrazol-4-yl)naphthalen-1 yl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin4-yl)urea H0577 ^Me'N'^Xy O Me Ay ώθ ^H ULy ^isr 1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(pyridin-3-yl)naphthalen-l yl)ethyl)urea

191

H0591 0 Me AU ¹ H Me ⁿ UAyvNHj 3- (1-(4-(3 -aminophenyl)naphthalen-1 yl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea H0597 0 Me AU Me ^H T/> 1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4-(thiazol-5-yl)naphthalen-lyl)ethyl)urea H0598 0 Me AU UAW ώ. ^H UU ^-0 3- ( 1 -(4-(furan-3 -yl)naphthalen-1 yl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea H0599 O Me AU Me ^H AaU/N T /> 3- ( 1 -(4-( 1 H-imidazol-5-yl)naphthalen-1 yl)ethyl)-1 -methyl-1 -( 1 -methylpiperidin- 4- yl)urea H0790 ^^S^N^U O Me AA i H ^Μθ ^-CN 3 -( 1 -(4-cyanonaphthalen-1 -yl) ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0381 ^Μ®νΦ 0 Me Cl U-VU^ci- ^H Φ_α 1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3-( 1 (2,3,4-trichlorophenyl)ethyl)urea H0519 ^ΜΘ'νΦ 0 Me Cl A>AAUy^ciώθ ^H Uk, 3-( 1 -(2,3 -dichloro-4-iodophenyl)ethyl)-l methyl-1 -( 1 -methylpiperidin-4-yl)urea H0629 ^MeTU 0 CN Cl la_nAnUU^bi· ώ.^H u, 3-((3-bromo-2-chloro-4iodophenyl)(cyano)methyl)-l -methyl-1 ( 1 -methylpiperidin-4-yl)urea

H0658 ^Me'N^X O CN Cl VA/vL-A ώ.^H UL, OMe 3-((3-bromo-2-chloro-4- methoxyphenyl)(cyano)methyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0669 ^Me'N^X 0 CN Cl V>AAA/^CI ^H UL, OMe 3-(cyano(2,3-dichloro-4- methoxyphenyl)methyl)-1 -methyl-1 -( 1 methylpiperidin-4-yI)urea H0671 ^MeN^X 0 Me CN Çl aX_na_nxJVci - ^H u,_Me 3 -( 1 -cyano-1 -(2,3 -dichloro-4methoxyphenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0659 ^Me'N^ O VA LU-_nA_nA A .^Br- ^H u_OMe 2-(3-bromo-2-chloro-4-methoxyphenyl)2-(3-methyl-3 -( 1 -methylpiperidin-4- . yl)ureido)acetamide H0521 ^MeN^Y 0 Me Cl A-_NL/A/' - ^H IXco₂Me methyl 2,3 -dichloro-4-( 1 -(3 -methyl-3 -( 1 methylpiperidin-4yl)ureido)ethyl)benzoate H0602 ^Me'N'^/X 0 Me Cl X^ANMr^clώβ ^H VL ^χ TMS 3-(1-(2,3 -dichloro-4((trimethylsilyl)ethynyl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0603 ^MeN^Y O Me Cl ^Α_Νλ_ΝΑΑψ“ - ^H 3-(1-(2,3-dichloro-4ethynylphenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0677 ^MeN·^ O Me Cl LW W^aώ. H îi R/S ^CH 3-( 1 -(2,3-dichloro-4ethynylphenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer) H0678 ^M®N^XX 0 Me Cl /AAW λ. » UL R/S ^CH 3-(l -(2,3-dichloro-4ethynylphenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea (single enantiomer)

H0832 ^MeN^> 0 Me Cl UAAnAA-⁰¹lie ^H LA Me 3-(1-(2,3 -dichloro-4-(prop-1 -yn-1 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0852 O Me Cl uAaàAa le ^H IA X</Me Me 3 -( 1 -(2,3 -dichloro-4-(3 -methylbut-1 -yn-1 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0701 ^Me’'N^A 0 Me Cl UAW' Λ H Me AÿA\ Χ,ο Me 3-(1-(2,3-dichloro-4-(3-oxobut-l-yn-lyl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0733 Μθ'Ν^'Α O Me Cl üaw lie ^H LA Χ<.°^Η Me 3 -( 1 -(2,3 -dichloro-4-(3-hydroxybut-l -ynl-yl)phenyl)ethyl)-l-methyl-l-(lmethylpiperidin-4-yl)urea H0755 “S'A O Me Cl ÜAW Λ H Me 3 -( 1 -(2,3 -dichloro-4-(3 -hy droxyprop-1 yn-1 -yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0757 ^M®N'X 0 Me Cl ÜAAV I H Me XAx. ^\/^OEÎ OEt 3-( 1 -(2,3 -dichloro-4-(3,3 -diethoxyprop-1 yn-1 -yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0734 ^MeN'X 0 Me Cl <Vxv Me ^H AA. 3-( 1 -(2,3 -dichloro-4-(pyridin-2ylethynyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0737 ^ΜθΝ^Α 0 Me Cl Λ ^H l Me AA 3-( 1 -(2,3 -dichloro-4-(thiophen-2ylethynyl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0775 ^Me'N^A 0 Me CI ÜAA» i ^HMe xA. A\_-S OH 3-( 1 -(2,3 -dichloro-4-((5 (hydroxymethyl)thiophen-2yl)ethynyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0776 ^Me'NA 0 Me Cl ^AA/y^cl Me ^H Ul ^0 /^NHz 5-((2,3 -dichloro-4-( 1 -(3 -methyl-3-( 1 methylpiperidin-4yl)ureido)ethyl)phenyl)ethynyl)thiophene2-carboxamide H0779 O Me Cl UAW Λ H Me OMe methyl 5-((2,3-dichloro-4-(l-(3-methyl-3( 1 -methylpiperidin-4yl)ureido)ethyl)phenyl)ethynyl)thiophene2-carboxylate H0762 “θ'Ν'Α 0 Me Cl UAW Λ H Me 3-( 1 -(2,3 -dichloro-4-(furan-2ylethynyl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0751 ^MeN^A 0 Me Cl Aaay* ώβ ^h UL N^/^S 3-( 1 -(2,3 -dichloro-4-(thiazol-4ylethynyl)phenyl)ethyl)-l -methyl-1 -(1 methylpiperidin-4-yl)urea H0763 ^Μβ'Ν^Ί 0 Me Cl 'Uu-lAz' Λ H Me JA ^nh NY 3-( 1 -(4-(( 1 H-imidazol-4-yl)ethynyl)-2,3dichlorophenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0759 ^Μ®·'Ν'^χΥ 0 Me Cl YAY/ ώβ ^H ΙΥ |Ys 3-(1-(2,3-dichloro-4-(thiophen-3ylethynyl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0785 ^M®'nY 0 Me Cl WVyV Me ^H xkk S-a 3-(1-(2,3 -dichloro-4-(3-(thiophen-2yl)prop-1 -yn-1 -yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0754 ^M®'N^Y 0 Me Cl ΑΥΥΥ^αώθ » ιγ ^^Y-^s N A 3-( 1 -(2,3-dichloro-4-(thiazol-2ylethynyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0753 ^M®'N^Y O Me Cl AAYYY^CIώθ » ιγ Y 3-( 1 -(2,3-dichloro-4-(pyrimidin-5ylethynyl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0609 ^M®'N'^xY 0 Me Cl A/AY lie ^H ILY An 3-( 1 -(2,3 -dichloro-4- (phenylethynyl)phenyl)ethyl)-l-methyl-l- ( 1 -methylpiperidin-4-yl)urea H0764 0 Me Cl Λ h Me Αγ 3-(1-(2,3 -dichloro-4(cyclopropylethynyl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0818 ^M®'N^xY O Me Cl <Ληγγ Λ H Me (S/R) ^Y—, 3-( 1 -(2,3 -dichloro-4(cyclopropylethynyl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea (single enantiomer)

H0819 ^ΜθΝ^Α O Me Cl 'UkAU' ^H VU (S/R) 3-(1-(2,3 -dichloro-4(cyclopropylethynyl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea (single enantiomer) H0838 Me ,^Ν~η 0 Me Cl LUA_NAyU^C' ' H Me 3-((S)-l-(2,3-dichloro-4- (cyclopropylethynyl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpyrrolidin-3 -yl)urea H0855 ^Μθ'Ν^> O Me F ÜAW Me ^H 3-( 1 -(3 -chloro-4-(cyclopropylethynyl)-2fluorophenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0884 ^Me'N^xA O Me Cl UAW -^H VL 3 -( 1 -(4,5-dichloro-6- (cyclopropylethynyl)pyridin-3-yl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea H0811 ^Me'N^ O Me Cl UUUU_r ^clώθ ^h Uk a_a 3 -( 1 -(2,3 -dichloro-4(cyclopentylethynyl)phenyl)ethyl)-lmethyl-1 -( 1 -methylpiperidin-4-yl)urea H0812 ^Me'N^U 0 Me Cl Me ^H LA n 3-( 1 -(2,3-dichloro-4-(3-(4methylpiperazin-1 -yl)prop-1 -yn-1 yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0740 ^MeN^/V O ( Cl VaW OMe^H 3-(2-cyclopropyl-1-(2,3 -dichloro-4ethynylphenyl)ethyl)-1 -methoxy-1 -( 1 methylpiperidin-4-yl)urea H0742 ^MeN-^V 0 Me Cl Α^ΑΛα¹ομθ^η 3-(1-(2,3 -dichloro-4ethynylphenyl)ethyl)-1 -methoxy-1 -( 1 methylpiperidin-4-yl)urea

H0745 TU 0 Me Cl “^H x 3-( 1 -(2,3 -dichloro-4ethynylphenyl)ethyl)-1 -hydroxy-1 -( 1 methylpiperidin-4-yl)urea H0749 0 Me Cl LA_nA_nA-U^ci te υγ 3-(1-(2,3 -dichloro-4ethynylphenyl)ethyl)-1 -ethoxy-1 -( 1 methylpiperidin-4-yI)urea H0744 ^Μθ'νΛ o / ci ^•rW¹ ÔEi^H LA A 3-(2-cyclopropyl-1 -(2,3-dichloro-4ethynylphenyl)ethyl)-1 -ethoxy-1 -( 1 methylpiperidin-4-yl)urea H0626 TU O Me Cl V_na_naJLci ώ. ^H UU 3-(1-(2,3-dichloro-4-vinylphenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea H0767 ^Me'N^V 0 Me Cl UVyV i H Me Χ-ΑΑγδ (E)-3-(l-(2,3-dichloro-4-(2-(thiophen-2yl)vinyl)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0772 O Me Cl Me « N-(2,3-dichloro-4-(l-(3-methyl-3-(lmethylpiperidin-4yl)ureido)ethyl)phenyl)thiophene-2carboxamide H0773 Μθ'Ν^χ O Me Cl VVXV'h Me 2,3-dichloro-4-( 1 -(3-methy 1-3-( 1 methylpiperidin-4-yl)ureido)ethyl)-N(thiophen-2-yl)benzamide H0784 ^Me+U O Me Cl Va H H 3-( 1 -(2,3-dichloro-4-(3-(thiophen-2yl)ureido)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea H0777 O Me Cl LA_nA_nAA.ci ώβ ^H W H 3-( 1 -(2,3 -dichloro-4-(thiophen-2ylamino)phenyl)ethyl)-l -methyl-1 -( 1 methylpiperidin-4-yl)urea

H0846 ^ΜθΝ^Τ 0 Me Cl ώ- ^h U/ H 3-( 1 -(2,3 -dichloro-4(cyclopropylamino)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea H0875 ^Me'N^U O Me Cl Λ. ^H lJ..₀X 3-(1-(2,3 -dichloro-4cyclopropoxyphenyl)ethyl)-l -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0628 ^M®'nA 0 Me Cl λΑ^χΛΑγΟί Me ^H Ax^Me 3-( 1 -(2,3-dichloro-4-ethylphenyl)ethyl)-l methyl-1 -( 1 -methyIpiperidin-4-yl)urea H0630 0 Me Cl λλ_ΝΑ_ΝΑΑγθΐ Me ^H UX/CN 3-( 1 -(2,3 -dichloro-4(cyanomethyl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0633 0 Me Cl λΑ_ΝΛ_ΝΑΑ/ΰΐ Me ^H UX/OH 3-( 1 -(2,3 -dichloro-4- (hydroxymethyl)phenyl)ethyl)-l-methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0634 ^MfA ^{0 Me Cl} *· ^H LA_c„_2F 3-( 1 -(2,3 -dichloro-4(fluoromethyl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0640 ^MeN^U 0 Me Cl LsAAA/¹ - ^H u._CHO 3-(1-(2,3-dichloro-4-formylphenyl)ethyl)- 1 -methyl-1 -(1 -methylpiperidm-4-yl)urea H0645 ^M®N^U O Me Cl λΑ_ΝΑ_ΝΑΑ^οι Μθ ^H ΧΧγΟ O-J 3-( 1 -(2,3-dichloro-4-( 1,3 -dioxolan-2yl)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0641 ^M®'N^U O Me Cl AW lie ^H m^_COîMe methyl (E)-3-(2,3-dichloro-4-(l-(3methyl-3 -( 1 -methylpiperidin-4yl)ureido)ethyl)phenyl)acrylate

H0702 0 Me Cl Me ^H γ^ΟΟΜβ Cl (Z)-3 -( 1 -(2,3-dichloro-4-( 1 -chloro-3 oxobut-1 -en-1 -yl)phenyl)ethyl)-1 -methyl1 -( 1 -methylpiperidin-4-yl)urea H0643 ^MeN^A O Me Cl Μθ ^H 3-(1-(2,3 -dichloro-4-(3 hydroxypropyl)phenyl)ethyl)-1 -methyl-1 ( 1 -methylpiperidin-4-yl)urea H0522 ^MeN^xA 0 Me Cl ^H vC_C0NH2 2,3-dichloro-4-( 1 -(3 -methyl-3 -( 1 methylpiperidin-4yl)ureido)ethyl)benzamide H0523 ^Me'N'^xA 0 Me Cl Me ^H LA_cn 3-(1-(2,3 -dichloro-4-cyanophenyl)ethyl)- 1 -methyl-1 -( 1 -methylpiperidin-4-yl)urea H0876 ^ΜθΝ·^> 0 Me Cl - ^H Vc, 1 -methyl-1 -( 1 -methylpiperidin-4-yl)-3 -( 1 (4,5,6-trichloropyridin-3-yl)ethyl)urea.

or a pharmaceutically acceptable sait thereof.

50. A compound selected from the group consisting of:

H0816 ^Me'N^j 0 Me Cl XaaV- i H Me ⁿ Ai N (S)-3-(l-(2,3-dichloro-4-(pyrazin-2y l)phenyl)ethyl)-1 -methyl-1 -( 1 methylpiperidin-4-yl)urea H0900 0 CF₃ Cl uaw i H Me aC N (R)-3-(l-(2,3-dichloro-4-(pyrazin-2yl)phenyl)-2,2,2-trifluoroethyl)-1 -methyl- 1 -( 1 -methylpiperidin-4-yl)urea H0847 O Me Cl Me ^H My%zF M (S)-3-( 1 -(2,3-dichloro-4-(6fluoropyrazin-2-yl)phenyl)ethyl)-1 methyl-1 -( 1 -methylpiperidin-4-yl)urea

or a pharmaceutically acceptable sait thereof.

51. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, and one or more pharmaceutically acceptable excipients.

52. A compound of any of daims 1 to 50 for use in modulating ghrelin receptor activity in a human subject.

53. A compound of any of daims 1 to 50 for use in treating a disease associated with expression or activity of a ghrelin receptor in a human subject.

54. The compound for use of claim 53, wherein said disease is obesity, overweight, eating disorder, diabètes, metabolic syndrome, cachexia resulting from cancer, congestive heart failure, wasting due to ageing or AIDS, chronic liver failure, chronic obstructive pulmonary disease, gastrointestinal disease, gastric disorder or substance abuse.

55. The compound for use of claim 54, wherein said metabolic syndrome is selected from the group consisting of diabètes, Type I diabètes, Type II diabètes, inadéquate glucose tolérance, insulin résistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease.

56. The compound for use of claim 54, wherein said gastric disorder is selected from the group consisting of Post-operative iléus (POI), diabetic gastroparesis, and opioid induced bowel dysfonction.

201

57. The compound for use of claim 54, wherein said gastrointestinal disease is selected from the group consisting of irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia.

58. The compound for use of claim 54, wherein said substance abuse is alcohol or drug abuse.

59. The compound for use of claim 58, wherein said drug is selected from the group consisting of amphétamines, barbiturates, benzodiazépines, cocaïne, methaqualone, and opioids.

60. The compound for use of claim 53, whrein said disease is selected from the group consisting of Prader-Willi Syndrome, Binge Eating Disorder, Parkinson-induced constipation and gastric dysmotility, chemotherapy-induced nausea and vomiting, inflammation, pain, and motion sickness.

61. The compound for use of claim 53, wherein said disease is Binge Eating Disorder.

62. Use of a compound as claimed in any of claims 1 to 50 for the manufacture of a pharmaceutical composition.