NZ720467B2 - P-substituted asymmetric ureas and medical uses thereof - Google Patents

P-substituted asymmetric ureas and medical uses thereof Download PDF

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Publication number
NZ720467B2
NZ720467B2 NZ720467A NZ72046715A NZ720467B2 NZ 720467 B2 NZ720467 B2 NZ 720467B2 NZ 720467 A NZ720467 A NZ 720467A NZ 72046715 A NZ72046715 A NZ 72046715A NZ 720467 B2 NZ720467 B2 NZ 720467B2
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New Zealand
Prior art keywords
urea
methyl
dichloro
ethyl
methylpiperidinyl
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NZ720467A
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NZ720467A (en
Inventor
Antoine Daina
Rubio Silvina Garcia
Claudio Giuliano
Angelo Guainazzi
Claudio Pietra
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Helsinn Healthcare Sa
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Priority claimed from PCT/US2015/019112 external-priority patent/WO2015134839A1/en
Publication of NZ720467A publication Critical patent/NZ720467A/en
Publication of NZ720467B2 publication Critical patent/NZ720467B2/en

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    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

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

TITUTED ASYMMETRIC UREAS AND MEDICAL USES F CROSS-REFERENCE TO D APPLICATIONS This application claims priorty to US. Provisional Application Serial No. 61/949/664, filed March 7, 2014, which is herein incorporated by reference in its entirety.
FIELD OF THE INVENTION The present 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 ) regulates a number of physiological processes, including growth hormone (GH) release, metabolism, and appetite. Ghrelin, a circulating e produced predominantly by ine 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). n has been shown to stimulate growth hormone (GH) release and to se 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., Diabetes, 50, 1714-1719, 2001). Ghrelin also appears to play a role in maintaining long term energy balance and appetite tion. Chronic administration of ghrelin in rodents leads to hyperphagia and weight gain that are independent of growth hormone secretion (Tschop et al., , 407, 3, 2000). Circulating ghrelin levels se in response to chronic overfeeding and increase in response to chronic negative energy balance ated with anorexia or exercise. Obese people generally have low plasma ghrelin levels (Tschop et al., Diabetes, 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 n receptor activity have been proposed for preventing and/or treating disorders associated with n receptor physiology. For example, antagonists at ghrelin receptor might one day be developed to reduce appetite, reduce food intake, induce weight loss and treat obesity without ing 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 intestinal motility by increasing the frequency of ctions in the small ine or making them stronger, but without disrupting their rhythm. Gastroprokinetic agents are used to e gastrointestinal symptoms such as abdominal discomfort, bloating, constipation, heart burn, 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, paresis, and functional dyspepsia. Furthermore, compounds that modulate ghrelin receptor activity might also be used to prevent or treat diseases related to substance abuse, for e, alcohol or drug (e. g., amphetamines, barbiturates, benzodiazepines, cocaine, ualone, and opioids) abuse, which refers to a maladaptive pattern of use of a substance that is not ered dependent.
A number of compounds acting on the ghrelin receptor have been reported in the literature. 1, for example, is a small molecule ghrelin receptor antagonist from Bayer that reportedly improves glucose tolerance, suppresses appetite and promotes 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, 5 873-5876); anamorelin is an orally available n receptor small molecule agonist from Helsinn Therapeutics that is in clinical trials for the treatment of anorexia and cachexia in cancer ts. Ghrelin receptor agonists and nists based on asymmetric ureas are disclosed in US 2012/0220629, which is incorporated herein by reference in its entirety. Other small molecule ghrelin receptor modulators can be found in WO 2008/092681, US 2009/0253673, , , US 2007/0270473 and US 2009/0186870.
In view of the above, it is desirable to find new compounds which te ghrelin receptor activity.
SUMMARY The present invention provides compounds of Formula I: with X, Z, Rl-RS, r, s, and n as defined herein, and pharmaceutically acceptable salts thereof.
Compounds of Formula I, also ed to herein as asymmetric ureas, are particularly useful for preventing and/or treating es that are hysiologically related to the ghrelin or 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 t a eutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt 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 ive amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically able excipients.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows Highly Palatable Food (HPF) intake in rats at different times after initial access to HPF. The values shown are the mean :: S.E.M. of HPF intake. Statistical differences 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. Difference 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. ence 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 difference from vehicle-treated rats was not statistically significant.
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. Difference 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. Difference between R + S vehicle and R + S d 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. Difference between R + S e and R + S treated rats: * P <0.05,** P <0.01.
Figure 8 shows the effect of H08 16 (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. Difference between R + S vehicle and R + S treated rats: *P <0.05; **P <0.05.
Figure 9 shows the effect of compound H0847 on l dministration in msP rats.
Figure 10 shows the effect of compound H0860 on alcohol dministration 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.
DETAILED DESCRIPTION Before the present compounds, compositions, articles, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods or specific treatment methods unless otherwise specified, or to particular reagents unless ise 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 ments only and is not ed to be limiting.
In a first principal embodiment, the present invention provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein: a dashed line indicates an optional bond; X is CH or N; z is NR9, CRIOR“, or o; R1 is H, C1_6 alkyl, benzyl, OH, or C1_6 , wherein said C1_6 alkyl, benzyl, or C1_6 alkoxy is optionally substituted with 1-3 substituents selected from halo, OH, C1_6 alkyl, C1_6 alkoxy, C1_6 hydroxyalkyl, CO(C1_6 alkyl), CHO, COzH, _6 alkyl), and C1_6 haloalkyl; R2 is H or C1_6 alkyl; R3 and R4 are each, independently, H, CN, halo, CHO, or COzH, or optionally substituted C1_6 alkyl, C1_6 hydroxyalkyl, C1_6 alkylcycloalkyl, C1_6 kyl, C1_6 alkoxy, CO(C1_6 alkyl), coz(c1_6 alkyl), or CONRIZRB; or R3 and R4 taken together with the C atom to which they are attached form a 3 membered ring; R5 is halo, CN, CHO, COzH, CO(C1_6 alkyl), coz(c1_6 alkyl), NR14R15,NHCONR14R15, CONRMRIS, 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(C1_6 alkyl), _6 , NRMRIS, NHCONRMRIS, CONRMRIS, 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, N02, Si(CH3)4, CH0, and COzH, or optionally substituted 6 alkyl), COZ(C1_6 alkyl), NRMRIS, NHCONRMRIS, CONRMRIS, CH=NOH, C1_6 alkyl, C1_6 , 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; WO 34839 or two R7 can be taken together with the atoms to which they are attached form a 5 memebered ring; or R5 and R7 taken together with the atoms to which they are attached form an optionally substituted 5membered ring; R8 is H or C1_6 alkyl; R9 is H, C1_6 alkyl, CO(C1_6 alkyl), CHO, COZH, or C02(C1_6 alkyl); R10 and R11 are each, independently, H, C1_6 alkyl, or halo; R12 and R13 are each, independently, H or C1_6 alkyl; R14 and R15 are each, independently H, C1_6 alkyl, CO(C1_6 alkyl), eroaryl), heteroaryl, or cycloalkyl; r is l 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 pal embodiments, in one subembodiment, Z is NR9.
In the first, second and third pal embodiments, in one subembodiment, Z is N(C1_6 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 CRIOR“.
In the first, second and third principal embodiments, in one odiment, 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 odiment, said benzyl is optionally substituted with C02(C1_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 pal embodiments, in one subembodiment, R1 is C1_6 alkoxy.
In the first, second and third principal embodiments, in one subembodiment, said C1_6 alkoxy is methoxy, ethoxy or propoxy.
In the first, second and third principal ments, 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 C1_6 alkyl, CN, C1_6 alkylcycloalkyl, C1_6 hydroxyalkyl, _6 alkyl), C1_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 C1 alkylcylopropyl.
In the first, second and third principal embodiments, in one subembodiment, said C1_6 yalkyl is C1 hydroxyalkyl optionally substituted with a substituted or unsubstituted benzyl group.
In the first, second and third principal ments, in one subembodiment, said C02(C1_ 6 alkyl) is COzCH3.
In the first, second and third principal ments, 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 3membered ring.
In the first, second and third pal embodiments, in one subembodiment, R3 and R4 are 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 R4 are 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, c0(c1_6 alkyl), coz(c1_6 alkyl),NR14R15,NHCONR14R15, CONRMRIS, c1_6 alkyl, C1_6 alkoxy, C1_6 haloalkyl, C1_6 hydroxyalkyl, C2_6 l, C2_6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said CO(C1_6 alkyl), _6 alkyl), NRMRIS, NHCONRMRIS, CONRMRIS, c1.6 alkyl, c1.6 alkoxy, c1.6 haloalkyl, c1.6 hydroxyalkyl, c2.6 alkenyl, C2_6 l, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1-3 substituents selected from halo, CN, OH, N02, Si(CH3)4, CH0, and COzH, or optionally substituted CO(C1_6 alkyl), C02(C1_6 alkyl), NRMRIS, NHCONRMRIS, CONRMRIS, , C1_6 alkyl, C1_6 alkoxy, C1_6 kyl, C1_6 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 ments, R5 is not methoxy; In some ments, 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 SOzMe; 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 first, 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 COzH; In the first, second and third pal embodiments, in one subembodiment, R5 is CO(C1_ 6 alkyl); In the first, second and third pal embodiments, in one subembodiment, R5 is C02(C1—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 NHCONRMRfl In the first, second and third principal embodiments, in one odiment, R5 is CONRMRfi In the first, second and third principal embodiments, in one odiment, R5 is C1_6 alkyl; In the first, second and third principal embodiments, in one subembodiment, R5 is C1_6 alkoxy; In the first, second and third principal ments, in one subembodiment, R5 is C1_6 haloalkyl; In the first, second and third principal embodiments, in one subembodiment, R5 is C1_6 hydroxyalkyl; In the first, 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 first, second and third principal embodiments, in one subembodiment, R5 is cycloalkyl; In the first, second and third pal ments, 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 pal embodiments, in one subembodiment, R5 is C1_6 haloalkyl, heteroaryl, aryl, halo, C1_6 alkoxy, C02(C1_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 ments, in one subembodiment, said C1_6 haloalkyl is CHFZ.
In the first, second and third principal embodiments, in one subembodiment, said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl, triazinyl, enyl, pyrazolyl, imidazolyl, lyl, 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 C1 or I.
In the first, second and third principal embodiments, in one subembodiment, said C1_6 alkoxy is methoxy.
In the first, second and third principal embodiments, in one subembodiment, said C02(C1_ 6 alkyl) is COzMe.
In the first, second and third pal 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 odiment, R7 is halo.
In the first, second and third principal embodiments, in one subembodiment, said halo is C1 or F.
In the first, second and third principal embodiments, in one subembodiment, 2 R7 come together to form a phenyl group.
In the first, second and third principal embodiments, in one subembodiment, R5 and R7 come 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 pal 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 ments, in one subembodiment, R10 is C1_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 odiment, 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 C1_6 alkyl; In the first, second and third principal embodiments, in one subembodiment, R13 is H; In the first, second and third pal embodiments, in one odiment, R13 is C1_6 alkyl; In the first, second and third principal embodiments, in one subembodiment, R14 is H; In the first, second and third principal ments, in one subembodiment, R14 is C1_6 alkyl; In the first, second and third pal embodiments, in one subembodiment, R14 is CO(C1_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 pal embodiments, in one subembodiment, R15 is H; In the first, second and third principal embodiments, in one subembodiment, R15 is C1_6 alkyl; In the first, second and third principal embodiments, in one subembodiment, R15 is CO(C1_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 lkyl; 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 odiment, n is 2; In the first, second and third principal embodiments, in one subembodiment, n is 3 In a second pal embodiment, the compounds have the ure of Formula II: R4 R7 x R5 or a pharmaceutically acceptable salt thereof.
In a third principal embodiment, the compounds have the ure of Formula III: R4 R7 or a pharmaceutically acceptable salt thereof.
In fourth and fifth principal embodiments, the compounds have the ure of Formula IIIa or IIIb: WO 34839 SRIZj/R17 Illa IIIb, or a pharmaceutically acceptable salt thereof, wherein: R16 is H, cyclopropyl or thiazolyl; and R17 is H or halo.
In some forms, the nds as tly disclosed are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein the compound of Formula I is a compound selected from the group ting of: Chemical Structure compound Chemical Name N0\ JKO M9 CI 3-(1-(2,3-d1chloro.
H0494 I}! M cyclopropylphenyl)ethyl)methy1(1- Me methylpiperidiny1)urea 3-(1-(2,3-dichloro H0621 '1 fl (difluoromethy1)pheny1)ethyl)hydroxy- 1-(1 -methy1piperidiny1)urea 3-(1-(2,3-dichloro(pyridin N N H0496 Me H y1)pheny1)ethy1)-1 -methy1(1- I methylpiperidiny1)urea 3-(1-(2,3-dichloro(pyridin H0617 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 2015/019112 methyl 4-((3-(1-(2,3-dich10r0(pyridin- H0539 3-y1)pheny1)ethy1)(1-methy1piperidin- reid0)methy1)benzoate 3-(1-(2,3-dich10r0(pyridin ny1)ethy1)-1 -(4- H0546 (hydroxymethy1)benzy1)( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyridin y1)pheny1)ethy1)-1 -methyl(1 - methylpyrrolidin-3 -y1)urea 3-(1-(2,3-dich10r0(pyridin y1)pheny1)ethy1)-1 -(1,3- dimethylpiperidinyl)methy1urea 3-(1-(2,3-dich10r0(pyridin y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyridin y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 - cyclopropylpyridiny1)pheny1)ethy1)-1 - methyl-1 -(1 -methy1piperidiny1)urea 1-methy1(1-methy1piperidiny1)-3 -(1- (4-(pyridiny1)naphthalen y1)ethy1)urea |V'e‘N 0 Me CI NJLN CI 3-(1-(2,3-dichloro(6-meth0xypyridin- H051 1 |\|/|e H 3-y1)pheny1)ethy1)methy1—1-(1- I methylpiperidiny1)urea N/ OMe NERO 0 Me CI NJLN 0' 3-(1-(2,3-dich10r0(6- H0820 |\'/|e H cyclopropylpyridiny1)pheny1)ethy1)-1 - | methyl-1 -( 1 1piperidiny1)urea IV'e‘N 0 Me CI JL Cl N N 3-(1-(2,3-dich10r0(5 -cyan0pyridin H0613 |\l/|e H y1)pheny1)ethy1)-1 -methyl( 1 - \ methylpiperidiny1)urea 2,3-dich10r0(5 -fluor0pyridin-3 - H0614 y1)pheny1)ethy1)-1 -methyl( 1 - piperidiny1)urea methyl 5 -(2,3-dich10r0(1-(3 -methy1—3- H0635 (1 -methy1piperidin y1)ureid0)ethy1)pheny1)nicotinate 3-(1-(2,3-dich10r0(5 - (hydroxymethy1)pyridin-3 - H0636 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 - (difluoromethy1)pyridin-3 - H0637 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 - H0638 I H (fluoromethy1)pyridin-3 -y1)pheny1)ethyl) methyl(1-methy1piperidiny1)urea 3 -(1-(2,3 -dich10r0(5 -methy1pyridin-3 - H0639 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 -f0rmy1pyridin y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(4-(5 -amin0pyridiny1)-2,3- dichloropheny1)ethy1)methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 -(cyclopenteny1)pyridin-3 -y1)pheny1)ethy1)methyl- 1-(1 -methy1piperidiny1)urea 3 -(1-(4-(5 -(1H-pyraz01y1)pyridin-3 -y1)- 2, 3 0r0pheny1)ethyl) -1 -methyl(1 - methylpiperidiny1)urea 3-(1-(4-(5 -(1H-imidaz01y1)pyridin H0711 y1)-2, 3 -dich10r0pheny1)ethy1)-1 l (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(5 -(thiaz01-5 - H0716 y1)pyridin-3 -y1)pheny1)ethy1)-1 l (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(5 -(thi0phen H0717 y1)pyridin-3 -y1)pheny1)ethy1)-1 -methyl (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(5 - H0718 entylpyridiny1)pheny1)ethy1) methyl-1 -( 1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(5 -(pyrr01idin H0719 y1)pyridin-3 -y1)pheny1)ethy1)-1 -methyl (1 -methy1piperidiny1)urea N—(5 -(2, 3 0r0(1-(3-methy1—3 -(1- piperidin H0712 y1)ureid0)ethy1)pheny1)pyridin-3 - y1)acetamide 2,3-dich10r0(5 - (methoxymethy1)pyridin-3 - H0708 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 -(2- H0714 methoxyethy1)pyridiny1)pheny1)ethy1)methyl(1-methy1piperidiny1)urea 3-(1-(2,3-dich10r0(5 -ethy1pyridin H0715 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 -Viny1pyridin H0706 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 -ethyny1pyridin H0710 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(cyan0(2,3 -dich10r0(5-cyan0pyridin- H0666 heny1)methy1)-1 -methyl( 1 - methylpiperidiny1)urea 3 -((4-(5 -(1H-pyrr01—2-y1)pyridin-3 -y1)- H0739 2, 3 -dich10r0pheny1)(cyan0)methy1)-1 - methyl-1 -( 1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(5 -cyan0pyridin H0667 y1)pheny1)ethy1)-1 -hydr0xy-1 -(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 -cyan0(4- methylpiperaziny1)pyridin-3 - H0821 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea (E)-3 -(1-(2,3-dich10r0(5- ((hydroxyimin0)methy1)pyridin-3 - H0646 ny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(2-cyclopr0py1(2,3-dich10r0 H0720 iny1)pheny1)ethy1)-1 -methyl (1 -methy1piperidiny1)urea 3-(1-(4-(5 -amin0pyridiny1)-2,3- H0721 dichlorophenyl)cyclopr0pylethy1) methyl-1 -( 1 -methy1piperidiny1)urea N 0 Me CI JL Cl 3-(1-(2,3-dich10r0(pyrimidin H0516 I H y1)pheny1)ethy1)methy1(1- I piperidiny1)urea Me‘N 0 Me 0 JL 1-methy1(1-methy1piperidiny1)(1- H0579 Elle N D (4-(pyfimidiny1)naphtha1en_1- I y1)ethy1)urea 3-(1-(2,3-dich10r0(2- H0649 methoxypyrimidin-S-y1)pheny1)ethy1)-1 - methyl-1 -(1 -methy1piperidiny1)urea 2,3-dich10r0(2- H0797 hydroxypyrimidin-S-y1)pheny1)ethy1) methyl-1 -(1 -methy1piperidiny1)urea 3-(1-(4-(2-amin0pyrimidiny1)-2,3- H0798 dichloropheny1)ethy1)methyl( 1 - piperidiny1)urea 3-(1-(2,3-dich10r0(2-(4- methylpiperazin-l -y1)pyrimidin-5 - H0799 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(2-flu0r0pyrimidin- H0800 5-y1)pheny1)ethy1)methyl(1 - methylpiperidiny1)urea 3 -(1-(2,3 -dich10r0(2-ch10r0pyrimidin- H0801 5-y1)pheny1)ethy1)methyl(1 - methylpiperidiny1)urea 3 ,3 -dich10r0(2-cyan0pyrimidin- H0802 5-y1)pheny1)ethy1)methyl(1 - methylpiperidiny1)urea 3-(1-(4-(2-(1H-imidaz01—1-y1)pyrimidin- ,3 -dich10r0pheny1)ethyl)- 1 l- 1-(1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(2- (dimethylamin0)pyrimidin-5 - y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(2- (cyclopropylamin0)pyrimidin-5 - y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(2- (methylamin0)pyrimidin-5 - y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea N—(5 -(2, 3 -dich10r0(1-(3-methy1-3 -(1- methylpiperidin y1)ureid0)ethy1)pheny1)pyrimidin y1)cyclopropanecarboxamide 3-(1-(2,3-dich10r0(2- cyclopropylpyrimidin-S-y1)pheny1)ethy1)- 1-methy1-1 -(1-methy1piperidiny1)urea I m 3-(1-(2,3-dich10r0(2-(pyrr01idin H0813 Me \ N y1)pyrimidiny1)pheny1)ethy1)-1 - | methyl-1 -(1 -methy1piperidiny1)urea N No Me‘U 0 Me CI NJLN CI 3-(1-(2,3-dich10r0(2-(4-ethy1—3- H0814 Me erazin-l -y1)pyrimidin-5 - | i y1)pheny1)ethy1)methy1(1- N NV piperidiny1)urea Me‘N 0 Me CN CI CI 3-(1-cyan0(2,3-dichlor0(pyrimidin- N N H0703 Me H 5-y1)pheny1)ethy1)methy1—1-(1- \ N methylpiperidiny1)urea I N/J Me‘N 0 CN Cl AL Cl N N 3-(cyan0(2,3 -dich10r0(pyrimidin-5 - H0709 (I) H y1)pheny1)methyl)-1 -meth0xy-1 -(1- ‘Me \ N methylpiperidiny1)urea I NA 0 Me CI NJLN CI l-cyclohexy1(1-(2,3-dich10r0 H0584 I H (pyrimidin-S-y1)pheny1)ethy1) I methylurea O 0 Me CI NJLN CI 3-(1-(2,3-dich10r0(pyrimidin H0586 I H y1)pheny1)ethy1)-1 -methyl(tetrahydr0- \ N 2H-pyrany1)urea F 0 Me CI NJLN CI 3-(1-(2,3-dich10r0(pyrimidin H0587 “IA H ny1)ethy1)-1 -(4,4- \ N difluorocyclohexy1)methy1urea | N/J Me O 1-(1-acety1piperidiny1)-3 ,3 - H0588 dich10r0(pyrimidiny1)pheny1)ethyl) methy1urea 3-(1-(2,3-dich10r0(2,4- H0663 oxypyrimidin-S-y1)pheny1)ethy1)- 1-methy1-1 -(1-methy1piperidiny1)urea 3-(1-(2,3-dich10r0(pyrimidin y1)pheny1)((3- H0620 (hydroxymethy1)benzy1)0xy)ethy1) methyl-1 -(1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(pyrimidin H0624 y1)pheny1)ethy1)-1 -hydr0xy-1 -(1 - methylpiperidiny1)urea methyl 2-(2,3-dich10r0(pyrimidin-5 - H0662 y1)pheny1)(3-methy1-3 -(1- methylpiperidiny1)ureid0)acetate 3-(1-(2,3-dich10r0(pyrimidin H0670 y1)pheny1)hydr0xyethy1)-1 -methyl (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(pyrimidin H0673 ny1)cyclopr0pyl)-1 -methyl(1 - methylpiperidiny1)urea 2015/019112 3 -(4-(2,3 -dich10r0(pyrimidin-5 - H0727 y1)pheny1)tetrahydr0-2H-pyrany1) methyl-1 -(1 -methy1piperidiny1)urea 3-(cyan0(2,3-dich10r0(pyrimidin-5 - y1)pheny1)methyl)-1 -methy1-1 -( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyrimidin-5 - y1)pheny1)-2,2,2-triflu0roethy1)- 1 l- 1-(1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(pyrimidin y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyrimidin y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3 -(1-(2,3 -dich10r0(6-methy1pyrimidin- 4-y1)pheny1)ethy1)methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyrazin y1)pheny1)ethy1)-1 -methyl(1 - piperidiny1)urea (S)—3-(1-(2,3 -dich10r0(pyrazin H0816 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea (R)(1-(2,3 -dich10r0(pyrazin H0817 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(2-cyclopr0py1(2,3-dich10r0 (pyrazin-Z-y1)pheny1)ethy1)-1 -methyl (1 1piperidiny1)urea 3-(2-cyclopr0py1(2,3-dich10r0 (pyrazin-Z-y1)pheny1)ethy1)-1 -meth0xy (1 -methy1piperidiny1)urea yclopr0py1(2,3-dich10r0 (pyrazin-Z-y1)pheny1)ethy1)-1 -eth0xy (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(pyrazin H0743 y1)pheny1)ethy1)-1 -meth0xy( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyrazin H0750 y1)pheny1)ethy1)-1 y( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyrazin H0756 y1)pheny1)ethy1)-1 -hydr0xy-1 -(1 - methylpiperidiny1)urea Me\ .
N 0 CI 3-(2-cyclopr0py1—1-(2,3-d10h10r0 H0761 NJLN CI (pyraz1ny1)ph§nyl)ethyl)hydr0xy | H (1 -methy1p1per1d1ny1)urea OH N Me \ .
N 0 CI 3-(2-cyclopr0py1—1-(2,3-d10h10r0 JL CI (pyraziny1)pheny1)ethyl)hydr0xy H0781 N N . . . . 6H H (1 -methy1p1per1d1ny1)urea (smgle enantiomer) 3-(2-cyclopr0py1—1-(2,3-dich10r0 (pyraziny1)pheny1)ethy1)-1 -hydr0xy H0782 (1 -methy1piperidiny1)urea (single enantiomer) 2,3-dich10r0(pyrazin H0824 y1)pheny1)ethy1)-1 -methyl((R)- 1 , 3 , 3 - trimethylpiperidiny1)urea 3-((S)(2,3 -dich10r0(pyrazin H0890 y1)pheny1)ethy1)-1 -methyl((R)- 1 , 3 , 3 - hylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyrazin H0858 y1)pheny1)pr0py1)methy1—1-((R)-1,3 ,3 - trimethylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyrazin H0865 y1)pheny1)-2,2,2-triflu0roethy1)methyl- -1,3 , 3 -trimethylpiperidiny1)urea 2015/019112 MEN 0 Me CI NJLN CI 1-benzy1(1-(2,3-dich10r0(pyrazin H0825 H N y1)pheny1)ethy1)-1 -(1-methy1piperidin \ 1)urea I y |VIE‘N 0 Me CI 3-(1-(2,3-dich10r0(pyrazin H0826 ny1)ethy1)ethy1(1- methylpiperidiny1)urea (S)—3 -(1-(2,3 -dich10r0(pyrazin H0889 ny1)ethy1)ethy1(1- methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyrazin H0896 y1)pheny1)pr0py1)ethy1(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyrazin H0827 y1)pheny1)ethy1)-1 -(1-methy1piperidin y1)pr0py1urea 3-(1-(2,3-dich10r0(pyrazin H0829 y1)pheny1)pr0py1)methy1(1- methylpiperidiny1)urea (R)(1-(2,3 -dich10r0(pyrazin y1)pheny1)pr0py1)methy1(1- H0859 methylpiperidiny1)urea (single enantiomer) (S)—3-(1-(2,3 -dich10r0(pyrazin y1)pheny1)pr0py1)methy1(1- H0860 methylpiperidiny1)urea (single enantiomer) methyl 2-(2,3-dich10r0(pyrazin H0922 y1)pheny1)(3-methy1-3 -(1- methylpiperidiny1)ureid0)acetate 2,3-dich10r0(pyrazin H0924 y1)pheny1)hydr0xyethy1)-1 l (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(pyrazin H0830 y1)pheny1)-2,2,2-triflu0roethy1)methyl- 1-(1 -methy1piperidiny1)urea (S)—3-(1-(2,3 -dich10r0(pyrazin H0899 y1)pheny1)-2,2,2-triflu0roethy1)methyl- 1-(1 -methy1piperidiny1)urea (R)(1-(2,3 -dich10r0(pyrazin H0900 y1)pheny1)-2,2,2-triflu0roethy1)- 1 l- 1-(1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(pyrazin H0909 y1)pheny1)-2,2,2-triflu0roethy1)-1 -ethy1— 1 - (1 -methy1piperidiny1)urea 3-(1-(3 -ch10r0flu0r0(pyrazin H0856 y1)pheny1)ethy1)-1 l(1 - methylpiperidiny1)urea 3-((S)(2,3 -dich10r0(pyrazin y1)pheny1)ethy1)-1 -methyl(1 - H0837 methylpyrrolidin-3 -y1)urea (diasteromeric mixture) 3-((S)- l -(2,3 -dichlor0(pyrazin yl)phenyl)ethyl)-l -methyl( l - H0861 methylpyrrolidin-3 -yl)urea (single reoisomer) 3-((S)- l -(2,3 -dichlor0(pyrazin yl)phenyl)ethyl)-l -methyl( l - H0862 methylpyrrolidin-3 -yl)urea (single diastereoisomer) 3-(1-(2,3-dichlor0(pyrazin H0857 yl)phenyl)pr0pyl)methyl( l - methylpyrrolidin-3 -yl)urea 3-(1-(2,3-dichlor0(pyrazin yl)phenyl)-2,2,2-triflu0r0ethyl)methyl- l-(l -methylpyrrolidinyl)urea 3-(2-cyclopr0pyl(2,3-dichlor0 in-Z-yl)phenyl)ethyl)-l -methyl (l -methylpyrrolidin-3 -yl)urea N—(l dichlor0(pyrazin yl)phenyl)ethyl)(4-methylpiperazin- l - yl)pr0panamide 3 -(l -(2,3 -dichlor0(6-methylpyrazin yl)phenyl)ethyl)-l -methyl( l - methylpiperidinyl)urea 2015/019112 3 -(1-(2,3 -dich10r0(3 -methy1pyrazin y1)pheny1)ethy1)-1 -methyl(1 - H083 1 methylpiperidiny1)urea 3 -(1-(2,3 -dich10r0(3 -methy1pyrazin y1)pheny1)ethy1)-1 -methy1((R)-1,3 ,3 - trimethylpiperidiny1)urea 3-(2-cyclopr0py1(2,3-dich10r0(3 - methylpyrazin-Z-y1)pheny1)ethy1)-1 - methyl-1 -(1 -methy1piperidiny1)urea 3 -(1-(2,3 -dich10r0(6-meth0xypyrazin- 2-y1)pheny1)ethy1)methyl(1 - methylpiperidiny1)urea 3-(1 -(4-(6-amin0pyraziny1)-2,3 - dichloropheny1)ethy1)- 1 l( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(6- (ch10r0methy1)pyraziny1)pheny1)ethy1)- 1-methy1-1 -(1-methy1piperidiny1)urea 3-(1-(2,3-dich10r0(6-ch10r0pyrazin H0791 y1)pheny1)ethy1)-1 -methy1(1- methylpiperidiny1)urea 3-(1-(2,3-dich10r0(6-flu0r0pyrazin H0795 y1)pheny1)ethy1)-1 1(1- methylpiperidiny1)urea (S)—3-(1-(2,3 -dich10r0(6-flu0r0pyrazin- H0847 2-y1)pheny1)ethy1)methyl(1 - piperidiny1)urea (R)(1-(2,3 -dich10r0(6- H0848 fluoropyrazin-Z-yl)pheny1)ethy1) methyl-1 -(1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(6-flu0r0pyrazin H0863 y1)pheny1)pr0py1)methy1(1- methylpiperidiny1)urea 3-(1-(2,3-dich10r0(6-flu0r0pyrazin H0908 y1)pheny1)-2,2,2-triflu0roethy1)methyl- 1-(1 -methy1piperidiny1)urea 2,3-dich10r0(6-flu0r0pyrazin H0864 y1)pheny1)pr0py1)methy1(1- methylpyrrolidin-3 -y1)urea 3-((S)(2,3 -dich10r0(6-flu0r0pyrazin- H0872 2-y1)pheny1)ethy1)methyl(1 - methylpyrrolidin-3 ea 3-(1-(2,3-dich10r0(3 -flu0r0pyrazin H0840 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(6- (trifluoromethy1)pyrazin H0910 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(6-cyan0pyrazin H0788 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea methyl 6-(2,3-dich10r0(1-(3 -methy1—3- (1 -methy1piperidin y1)ureid0)ethy1)pheny1)pyrazine carboxylate -(2,3-dich10r0(1-(3-methy1(1- methylpiperidin y1)ureid0)ethy1)pheny1)pyrazine carboxamide methyl 5 dich10r0(1-(3 -methy1—3- (1 -methy1piperidin y1)ureid0)ethy1)pheny1)pyrazine carboxylate -(2,3-dich10r0(1-(3-methy1(1- methylpiperidin y1)ureid0)ethy1)pheny1)-N,N- dimethylpyrazine-Z-carboxamide 3-(1-(2,3-dich10r0(5 - (hydroxymethy1)pyrazin y1)pheny1)ethy1)-1 l( 1 - methylpiperidiny1)urea 3 -(1-(2,3 -dich10r0(quin0xa1in H0828 y1)pheny1)ethy1)-1 l( 1 - methylpiperidiny1)urea TFA 3-(1-(2,3-dich10r0(5 -(4- methylpiperazin-l -y1)pyrazin H0822 ny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 1-methy1(1-methy1piperidiny1)-3 -(1- (4-(pyraziny1)naphthalen H0850 y1)urea 3-(1-(4,5-dich10r0(pyrazin y1)pyridin-3 -y1)ethy1)methy1(1- H0881 methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyridazin H0729 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(pyridazin H0783 ny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(1,2,4-triazin H0793 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1 -(2,3-dich10r0(4,6-dim0rph01in0- H0796 1,3,5-triaziny1)pheny1)ethy1)-1 -methy1- 1-(1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(thi0phen-3 - H0498 ny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(thi0phen-3 - H0531 y1)pheny1)ethy1)-1 -methy1(1- methylpyrrolidin-3 -y1)urea 3-(1-(2,3-dich10r0(thi0phen-3 - y1)pheny1)((3- H0594 (hydroxymethy1)benzy1)0xy)ethy1) methyl-1 -(1 1piperidiny1)urea 3-(cyan0(2,3 -dich10r0(thi0phen-3 - H0644 y1)pheny1)methyl)-1 -methy1-1 -( 1 - piperidiny1)urea N JOL Me 0' 3-(1-(2,3-dich10r0(thi0phen H0536 C' N N y1)pheny1)ethy1)methy1(1- Me H methylpiperidiny1)urea Me CI 3-(1-(2,3-dich10r0(thi0phen H0563 “Rim 0 JL CI y1)pheny1)ethy1)methy1(1- N ” methylpiperidiny1)urea (single / enantiomer) S / Me\ 3-(1-(2,3-dich10r0(thi0phen Me CI H0564 U0 y1)pheny1)ethy1)methy1(1- JL CI N N methylpiperidiny1)urea (single |\|/Ie H enantiomer) Me‘N 0 Me CI )L .
CI 3-(1-(2,3-d10h10r0(th10phen.
H0627 N M ny1)ethy1)hydr0xy(1- / methylpiperidiny1)urea methyl -dich10r0(thi0phen H0660 y1)pheny1)(3-methy1—3-( 1 - methylpiperidiny1)ureid0)acetate 3-(1-(2,3-dich10r0(thi0phen H0661 y1)pheny1)hydr0xyethy1)-1 -methyl (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(thi0phen H0672 y1)pheny1)cyclopr0py1)-1 -methyl(1- methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 -f0rmy1thi0phen H0651 y1)pheny1)ethy1)methy1—1-(1- methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5- (hydroxymethy1)thi0phen H0653 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea JL CI 3-(1-(2,3-dich10r0(5- H0668 ” (fluoromethy1)thi0phen 'V'e / y1)pheny1)ethy1)methy1—1-(1- s / methylpiperidiny1)urea Me ‘U 0 Me CI NAN 0' 2,3-dich10r0(5- “be H (difluoromethy1)thi0phen H0654 / / y1)pheny1)ethy1)-1 -methyl( 1 - S methylpiperidiny1)urea 2015/019112 “RU Me CI 3-(1-(4-(5 -acety1thi0pheny1)-2,3- H0655 dichloropheny1)ethy1)methyl( 1 - methylpiperidiny1)urea MeN Me CI -(2,3-dich10r0(1-(3-methy1(1- piperidin H0691 y1)ureid0)ethy1)pheny1)thiophene carboxamide -(2,3 -dich10r0(2-cyclopr0py1(3 - methyl-3 -(1 -methy1piperidin H0728 3% y1)ureid0)ethy1)pheny1)thiophene carboxamide MeNJ\©:§\NMe2Me CI -(2,3-dich10r0(1-(3-methy1(1- methylpiperidin H0726 y1)ureid0)ethy1)pheny1)-N,N- dimethylthiophenecarb0xamide NR06 Me CI -(2,3-dich10r0(1-(3-methy1(1- methylpiperidin H0689 y1)ureid0)ethy1)pheny1)thiophene carboxylic acid |V'e‘N Me CI -(2,3-dich10r0(1-(3-methy1(1- methylpiperidin H0692 y1)ureid0)ethy1)pheny1)-N-meth0xy-N— methylthiophenecarb0xamide N N 3-(1-(2,3-dich10r0(5 -(1- hydroxyethyl)thi0phen H0656 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 -f0rmy1thi0phen H0652 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3 -(1-(2,3 -dich10r0(5 -cyan0thi0phen H0713 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(4-(3 -acety1thi0phenyl)-2,3- H0688 dichloropheny1)ethy1)methyl( 1 - methylpiperidiny1)urea -dich10r0(1-(3-methy1(1- methylpiperidin H0774 y1)ureid0)ethy1)pheny1)thi0phene-3 - amide 3-(1-(2,3-dich10r0(3 - xymethy1)thi0phen H0664 y1)pheny1)ethy1)-1 -methyl(1 - piperidiny1)urea 3-(1-(2,3-dich10r0(1H-pyrrol-Z- H0535 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(1H-pyraz01 H0499 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea Me‘N 0 Me CI NAN 0' 3-(1-(2,3-dich10r0(1-(2-hydr0xyethy1)- H0693 |\'/I e H 1H-pyraz01y1)pheny1)ethy1)-1 -methy1- \ ,N 1-(1 -methy1piperidiny1)urea N OH Me‘N 0 Me CI JL 0' N N 3-(1-(2,3-dich10r0(1-(2-meth0xyethy1)- H0694 “he H 1H-pyraz01y1)pheny1)ethy1)-1 -methy1- \ \,N 1-(1 -methy1piperidiny1)urea 3-(cyan0(2,3 0r0(1H-pyraz01 H0657 y1)pheny1)methyl)-1 -methy1-1 -( 1 - piperidiny1)urea 3-(1-(2,3-dich10r0(1H-pyraz01 y1)pheny1)ethy1)-1 -(4- H0553 (hydroxymethy1)benzy1)( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(1-cyclopr0py1-1H- H0842 1y1)pheny1)ethy1)methy1-1 -(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(1H-imidaz01 H0542 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(thiaz01 H0568 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(4-(2-amin0thiaz01y1)-2,3 - H0794 dichloropheny1)ethy1)methyl( 1 - methylpiperidiny1)urea WO 34839 3-(1-(2,3-dich10r0(2- H0841 cyclopropylthiaz01y1)pheny1)ethyl) -1 - methyl-1 -( 1 -methy1piperidiny1)urea 3-(1-(4-(2-amin0thiaz01—5-y1)-2,3 - H0792 ropheny1)ethy1)methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(0xaz01—4- H0569 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(1H-1,2,3 -triaz01 H0565 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(1H-1,2,3 -triaz01—4- H0604 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(1,3,4-0xadiaz01—2- H0595 y1)pheny1)ethy1)-1 -methyl( 1 - piperidiny1)urea 3-(1-(2,3-dich10r0(3 -methy1-1,2,4- H0596 0xadiaz01-5 -y1)pheny1)ethy1)methyl (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(3 -cyclopr0py1— H0851 1,2,4-0xadiaz01y1)pheny1)ethy1) methyl-1 -( 1 -methy1piperidiny1)urea JL methyl (1-(2,3-dich10r0(1H- H0537 H pyraz01y1)pheny1)ethyl)(1- \ ‘,N piperidin NH yl)ureid0)methy1)benzoate MeOZC 3-(1-(2,3-dich10r0(1H-pyraz01 H0529 . H y1)pheny1)ethy1)-1 l(1 - methylpyrrolidin-3 -y1)urea 3-(1-(2,3-dich10r0(1H-pyraz01 H0528 y1)pheny1)ethy1)-1 -(1, 3 - dimethylpiperidinyl)methy1urea 3-(1-(2,3-dich10r0(1-methy1-1H- H0501 pyraz01y1)pheny1)ethy1)methy1-1 -(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(furan H0507 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(5 -methy1fi1ran H0665 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0-4'—meth0xy-[1,1'- H0508 bipheny1]y1)ethy1)-1 -methy1(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0-[1,1'-bipheny1]—4- H0509 y1)ethy1)-1 -methyl-1 -(1 -methy1piperidin- 4-y1)urea 3-(1-(3'-amin0-2,3-dich10r0-[1,1'- H0510 bipheny1]y1)ethy1)-1 -methy1(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0-3'-meth0xy-[1,1'- H0606 bipheny1]y1)ethy1)methy1—1-(1- piperidiny1)urea 3-(1-(2,3-dich10r0-3'-flu0r0-[1,1'— H0810 bipheny1]y1)ethy1)methy1—1-(1- methylpiperidiny1)urea 3-(1-(2,3-dich10r0-3'-flu0r0-5'— xymethy1)- [ 1 , 1 '-bipheny1] H0696 y1)ethy1)methy1-1 -(1 -methy1piperidin- 4-y1)urea 3-(1-(2,3-dich10r0-3',5'-dimeth0xy-[1,1'— H0611 bipheny1]y1)ethy1)-1 -methy1(1 - methylpiperidiny1)urea dich10r0-4'—(1-(3 -methy1—3 -(1- H0612 methylpiperidiny1)ureid0)ethy1)-[1 , 1 '- bipheny1]carb0xamide N N 2',3'—dich10r0-4'—(1-(3-methy1—3-(1- H0615 |\l/|e H methylpiperidiny1)ureid0)ethyl)-[1,1'— D bipheny1]carb0xamide Me‘U 0 Me Cl NJLN CI 2,3-dich10r0-4'—cyan0-[1,1'- H0809 |\|/Ie H y1]y1)ethy1)methy1—1-(1- O methylpiperidiny1)urea Me‘U 0 Me Cl MJJW 0' 3-(1-(2,3-dich10r0(5- H0699 Me (cyanomethy1)pyridiny1)pheny1)ethy1)- \ CN | 1-methy1—1 -(1-methy1piperidiny1)urea IV'e‘N 0 Me CI JL Cl N N 3-(1-(2,3-dich10r0(5 -meth0xypyridin- H0607 l\l/Ie H 3-y1)pheny1)ethy1)methy1—1-(1- I methylpiperidiny1)urea 3-(1-(4-(5 -br0m0pyridiny1)-2,3 - H0695 dichloropheny1)ethy1)methyl( 1 - methylpiperidiny1)urea methyl 5 -(2,3-dich10r0(1-(3 -methy1—3- (1 -methy1piperidin H0635 y1)ureid0)ethy1)pheny1)nicotinate 3-(1-(4-(5 -acety1pyridin-3 ,3- H0690 dichloropheny1)ethy1)methyl( 1 - methylpiperidiny1)urea Me \ N@NJL CI Nd 3-(1-(2,3-dich10r0(5-(pyrimidin H0735 | N | y1)pyridin-3 -y1)pheny1)ethy1)-1 -methyl \ N (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(5 -(fiJran H0746 y1)pyridin-3 -y1)pheny1)ethy1)-1 -methyl (1 1piperidiny1)urea 3-(1-(2,3-dich10r0(5 -(thi0phen H0747 y1)pyridin-3 -y1)pheny1)ethy1)-1 -methyl (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(5 -(1-methy1—1H- H0748 pyraz01y1)pyridin-3 -y1)pheny1)ethy1)-1 methyl-1 -( 1 1piperidiny1)urea 3-(1-(2,3-dich10r0(5 - H0765 cyclopropylpyridiny1)pheny1)ethy1)-1 - methyl-1 -( 1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(5 -nitr0pyridin ny1)ethy1)-1 -methyl( 1 - H0766 methylpiperidiny1)urea 3-(1-(2,3-dich10r0(6- H0608 isopropoxypyridiny1)pheny1)ethy1) methyl-1 -( 1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(6-cyan0pyridin H0616 y1)pheny1)ethy1)-1 l( 1 - methylpiperidiny1)urea 3-(1 -(2,3-dich10r0(6-flu0r0pyridin-3 - H0618 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(1H-pyraz010[3,4- H0623 b]pyridin-5 -y1)pheny1)ethy1)methyl (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0-3'-cyan0-[1,1'- bipheny1]y1)ethy1)-1 1(1 - methylpiperidiny1)urea 3-(1-(4'-amin0-2,3-dich10r0-[1,1'- bipheny1]y1)ethy1)-1 -methy1(1 - methylpiperidiny1)urea 3 -(1-(2,3 -dich10r0-4'-(dimethy1amin0)- [1,1'-bipheny1]—4-y1)ethy1)methy1—1-(1- methylpiperidiny1)urea 2,3-dich10r0(1-methy1-1H- indaz01y1)pheny1)ethy1)methyl( 1 - methylpiperidiny1)urea 2,3-dich10r0(1H-indaz01 H0513 y1)pheny1)ethy1)methy1—1-(1- methylpiperidiny1)urea 3-(1-(2,3-dich10r0(1H-pyrr010[2,3- H05 14 b]pyridin-5 -y1)pheny1)ethy1)methyl (1 -methy1piperidiny1)urea WO 34839 3-(1-(2,3-dich10r0(1H-indol-S- H0515 y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0-2',3',4',5'-tetrahydr0- [1,1'-bipheny1]—4-y1)ethy1)methy1(1 methylpiperidiny1)urea 3 -(1 -(3 - (cyclopropylamin0)benzo[d] isoxazol y1)ethy1)-1 -methyl-1 -(1 -methy1piperidin- 4-y1)urea 3-(1-(3 -ch10r0flu0r0(thiophen y1)pheny1)ethy1)-1 l(1 - methylpiperidiny1)urea 3-(1-(3-ch10r0flu0r0(1H-pyraz01 y1)pheny1)ethy1)-1 l(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0-3',5'—diflu0r0-[1,1'- bipheny1]y1)ethy1)-1 -methy1(1 - methylpiperidiny1)urea 3 -(1 -(4-br0m0naphthaleny1)ethy1) methyl-1 -(1 -methy1piperidiny1)urea 1-methy1(1-methy1piperidiny1)-3 -(1- (4-(thi0pheny1)naphthalen y1)ethy1)urea 2015/019112 00 M 0 1-methy1(1-methy1piperidiny1)-3 -(1- H0575 ML” 0 I H (4-(thi0pheny1)naphthalen Me S y1)ethy1)urea \ / M\OJM 0 3-(1-(4-(1H-pyraz01y1)naphthalen H0576 MM y1)ethy1)methyl( 1 -methy1piperidin- Me 4-y1)urea \ 3N Mu 1-methy1(1-methy1piperidiny1)-3 -(1- H0577 Me i (4-(pyridiny1)naphthalen y1)ethy1)urea M H 3-(1 -(4-(3 -amin0phenyl)naphthalen-1 - H0591 Me 00 DNH2 y1)ethy1)-1 -methyl-1 -(1 -methy1piperidin- 1-methy1(1-methy1piperidiny1)-3 -(1- H0597 (4-(thiaz01y1)naphthalen-1 - y1)ethy1)urea 3-(1-(4-(furan-3 -y1)naphthalen H0598 y1)ethy1)methyl( 1 -methy1piperidin- 4-y1)urea 3-(1-(4-(1H-imidaz01y1)naphthalen H0599 y1)ethy1)methyl( 1 -methy1piperidin- 4-y1)urea “”0 1 Me 0 H0790 El E D 3 -(1 -(4-cyan0naphthaleny1)ethy1)-1 - 6 methyl-1 -( 1 -methy1piperidiny1)urea 1-methy1(1-methy1piperidiny1)-3 -(1- H0381 (2, 3 ch10r0pheny1)ethy1)urea 3 -(1-(2,3 -dich10r0i0d0pheny1)ethy1) H0519 methyl-1 -( 1 -methy1piperidiny1)urea br0m0ch10r0 H0629 iod0pheny1)(cyano)methy1)-1 -methyl (1 -methy1piperidiny1)urea 3-((3 -br0m0ch10r0 H065 8 methoxyphenyl)(cyan0)methy1)methyl- 1-(1 -methy1piperidiny1)urea 3-(cyan0(2,3 -dich10r0 H0669 ypheny1)methy1)methyl(1 - methylpiperidiny1)urea 3-(1-cyan0(2,3-dich10r0 H0671 methoxypheny1)ethy1)methyl( 1 - methylpiperidiny1)urea 2-(3 -br0m0ch10r0meth0xypheny1)- H0659 2-(3 -methy1—3 -(1-methy1piperidin y1)ureid0)acetamide methyl 2,3-dich10r0( 1 -(3-methy1—3-( 1 - H0521 methylpiperidin y1)ureid0)ethy1)benzoate 3'(1-(2,3-dich10r0-4— H0602 ((trimethylsi1y1)ethyny1)pheny1)ethy1)-1 - methyl-1 -(1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0 H0603 ethynylphenyl)ethyl)methy1(1- methylpiperidiny1)urea 3-(1-(2,3-dich10r0 lphenyl)ethy1)methyl( 1 - methylpiperidiny1)urea (single enantiomer) 3-(1-(2,3-dich10r0 ethynylphenyl)ethy1)- 1 l( 1 - methylpiperidiny1)urea (single omer) 3-(1-(2,3-dich10r0(pr0pyn y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(3 -methy1butyn y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(3 -0x0butyn y1)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea 3-(1-(2,3-dichlor0(3 -hydr0xybut- l -yn- H0733 l -yl)phenyl)ethyl)methyl( l - methylpiperidinyl)urea 3-(1-(2,3-dichlor0(3 -hydr0xypr0p- l - H0755 yn-l -yl)phenyl)ethyl) -1 -methyl(l - methylpiperidinyl)urea 3-(1 dich10r0(3 ,3-dieth0xypr0p- l - H0757 yn-l -yl)phenyl)ethyl) -1 -methyl(l - piperidinyl)urea 3-(1-(2,3-dichlor0(pyridin H0734 ylethynyl)phenyl)ethyl) methyl( l - methylpiperidinyl)urea 3-(1-(2,3-dichlor0(thi0phen H0737 ylethynyl)phenyl)ethyl) methyl( l - methylpiperidinyl)urea 3-(1-(2,3-dichlor0((5- xymethyl)thi0phen H0775 yl)ethynyl)phenyl)ethyl)-l -methyl(l - methylpiperidinyl)urea -((2, 3 -dich10r0( l -(3 -methyl-3 -(l - methylpiperidin H0776 yl)ureid0)ethyl)phenyl)ethynyl)thiophene- 2-carb0xamide IVIe‘N 0 Me CI JL CI methyl 5 -((2,3 -dichlor0(l -(3 -methyl N N . .
“I" H (l -methylp1per1d1n.
H0779 e \ id0)ethyl)phenyl)ethynyl)thiophene- s OMe I 2-carb0xylate “KO 0 Me Cl NJkN 0' 3-(1-(2,3-dichlor0(furan H0762 |\|/| e H ylethynyl)phenyl)ethyl)-l -methyl-l -(1- § methylpiperidinyl)urea l / MG‘U 0 Me CI NJLN 0' 3-(1-(2,3-dichlor0(thiazol H0751 |\|/|e H ylethynyl)phenyl)ethyl)-l -methyl-l -(1- Q methylpiperidinyl)urea 3-(1-(4-((1H-imidazolyl)ethynyl)-2,3- H0763 dichlorophenyl)ethyl)methyl( l - piperidinyl)urea 3-(1-(2,3-dichlor0(thi0phen-3 - H0759 ylethynyl)phenyl)ethyl) methyl( l - methylpiperidinyl)urea 3-(1-(2,3-dichlor0(3 -(thi0phen H0785 yl)pr0p-l -yn-l -yl)phenyl)ethyl) -l - methyl-l -( l -methylpiperidinyl)urea 3-(1-(2,3-dichlor0(thiazol H0754 ylethynyl)phenyl)ethyl) - 1 l( l - methylpiperidinyl)urea Me\U JOL Me CI I}! N 3-(1-(2,3-dichlor0(pyrimidin H0753 Me ylethynyl)phenyl)ethyl)-l -methyl-l -(1- \ N methylpiperidinyl)urea 2,3-dich10r0 H0609 (phenylethynyl)phenyl)ethyl)-l -methyl (l -methylpiperidinyl)urea 3-(1-(2,3-dich10r0 H0764 (cyclopropylethynyl)phenyl)ethyl)-l - methyl-l -( l -methylpiperidinyl)urea Me CI 3'(1-(2,3-dichlor0-4— (cyclopropylethyny1)pheny1)ethy1) H0818 methyl-l -( l -methylpiperidinyl)urea (SIR) (single enantiomer) Me CI 3'(1-(2,3-dlchlor0-4—. (cyclopropylethynyl)phenyl)ethyl) H0819 methyl-l -( l -methylpiperidinyl)urea (single enantiomer) 3-((S)- l -(2,3 -dichlor0 H083 8 (cyclopropylethynyl)phenyl)ethyl)-l - methyl-l -( l lpyrrolidin-3 ea 3-(1 -(3 -chlor0(cyclopr0pylethynyl) H085 5 fluorophenyl)ethyl) -1 -methyl( l - methylpiperidinyl)urea WO 34839 me‘U 0 Me CI NJLN Cl \ 3-(1-(4,5-dich10r0 H0884 |\|/|e H I (cyclopropylethyny1)pyridin-3 -y1)ethy1)- N § 1-methy1—1 -(1-methy1piperidiny1)urea ME‘U 0 Me CI NAN 0' 3-(1-(2,3-dich10r0 H081 1 |\|/| e H (cyclopentylethyny1)pheny1)ethy1)-1 - Q methyl-1 -( 1 -methy1piperidiny1)urea 2,3-dich10r0(3 -(4- methylpiperazin- 1 0p-1 -yn H0812 y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(2-cyclopr0py1(2,3-dich10r0 H0740 ethynylpheny1)ethy1)meth0xy( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0 H0742 ethynylpheny1)ethy1)meth0xy(1- methylpiperidiny1)urea 3-(1-(2,3-dich10r0 H0745 ethynylpheny1)ethy1)hydr0xy( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0 H0749 ethynylpheny1)ethy1)eth0xy-1 -(1 - methylpiperidiny1)urea 3-(2-cyclopr0py1(2,3-dich10r0 H0744 ethynylpheny1)ethy1)eth0xy-1 -(1 - methylpiperidiny1)urea H0626 3 -(1 -(2,3 0r0Viny1pheny1) ethyl)- . H 1-methy1-1 -(1-methy1piperidiny1)urea (E) -3 -(1-(2, 3 -dich10r0(2-(thi0phen H0767 . M y1)Viny1)pheny1)ethy1)- 1 l(1 - methylpiperidiny1)urea N—(2,3-dich10r0(1-(3-methy1—3 -(1- methylpiperidin H0772 y1)ureid0)ethy1)pheny1)thiophene-Z- carboxamide 2,3-dich10r0(1-(3-methy1—3-(1- H0773 methylpiperidiny1)ureid0)ethyl)-N- (thiophen-Z-yl)benzamide 3-(1-(2,3-dich10r0(3 -(thi0phen H0784 y1)ureid0)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea 3-(1-(2,3-dich10r0(thi0phen H0777 ylamin0)pheny1)ethy1)-1 -methyl(1 - methylpiperidiny1)urea WU JL CI 3-(1-(2,3-dich10r0 N N H0846 we HXCE A (cyclopropylamino)phenyl)ethy1)-1 - methyl-1 -(1 -methy1piperidiny1)urea me‘N 0 Me CI CI 3-(1-(2,3-dich10r0 H0875 NJLN 0e H A cyclopropoxyphenyl)ethy1)-1 -methyl (1 -methy1piperidiny1)urea WO 34839 3 -(1 -(2,3 -dich10r0ethy1pheny1)ethy1)-1 - H0628 methyl-1 -( 1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0 methy1)pheny1)ethy1)-1 -methy1-1 - (1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0 (hydroxymethy1)pheny1)ethy1)methyl- 1-(1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0 (fluoromethy1)pheny1)ethy1)methyl (1 -methy1piperidiny1)urea 3 -(1 -(2,3 -dich10r0f0rmy1pheny1)ethy1)methyl(1-methy1piperidiny1)urea 3-(1-(2,3-dich10r0(1,3-di0x01an y1)pheny1)ethy1)-1 -methyl( 1 - methylpiperidiny1)urea methyl (E)-3 -(2,3-dich10r0(1-(3 - -3 -( 1 -methy1piperidin y1)ureid0)ethy1)pheny1)acry1ate (Z)(1-(2,3-dich10r0(1-ch10r0 H0702 oxobuteny1)pheny1)ethy1)-1 -methy1— 1-(1 -methy1piperidiny1)urea 3-(1-(2,3-dich10r0(3 - H0643 hydroxypropy1)pheny1)ethy1)-1 -methyl (1 -methy1piperidiny1)urea 2,3-dichloro(1-(3-methyl(1- H0522 methylpiperidin yl)ureido)ethy1)benzamide 3 -(1 -(2,3 -dichlorocyanophenyl)ethyl)- 1-methy1-1 -(1 -methy1piperidiny1)urea 1-methy1(1-methy1piperidinyl)-3 -(1- (4, 5 ,6-trichloropyridin-3 -y1)ethy1)urea.
At various places in the present cation, 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 "C1_6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
For compounds of the invention in which a variable appears more than once, each variable can be a different moiety ed from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent ent moieties selected from the Markush group defined for R.
It is further iated that certain features of the invention, which are, for y, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, s features of the invention which are, for y, bed in the context of a single embodiment, can also be provided separately or in any 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 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 carbon- carbon 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 carbon- carbon 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, CClg, CHCIZ, C2CIs, and the like.
As used herein, “hydroxylalkyl” refers to an alkyl group having one or more OH substituents. e hydroxyalkyl groups include CH20H, C2CH4OH, C3H6OH, and the like.
As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic arbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms.
As used herein, "cycloalkyl" refers to non-aromatic carbocycles ing ed alkyl, alkenyl, and alkynyl groups. lkyl groups can include mono- or clic (e. g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, eptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, yl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are es that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of e, pentene, hexane, and the like. In some embodiments, cycloalkyl groups can have from about 3 to about 10, or about 3 to about 7 orming 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 ic (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 WO 34839 atom or heteroatom. In further embodiments, the heteroatom can be oxidized (e.g., have an oxo substituent) or a nitrogen atom can be quaternized. Examples of heterocyclyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3- dihydrobenzofuryl, 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, 3,6- dihydropyridyl, l,2,3,6-tetrahydropyridyl, l,2,5,6-tetrahydropyridyl, piperidonyl, ridonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, imidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, ,5-thia-diazinyl, 1,2,3-thiadiazolyl, l ,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, enyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5- triazolyl, 1,3,4-triazolyl, xanthenyl, octahydro-isoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzo-thiophenyl, azolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, othiazolyl, benzimidazolinyl, methylenedioxyphenyl, morpholinyl, yridinyl, deca-hydroquinolinyl, 2H,6H- l,5,2dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, carbazolyl, 4aH- olyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, olyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl and isoxazolyl.
Further examples of heterocycles include in-l-yl, 2,5-dihydro-lH-pyrrol-l-yl, piperindin- lyl, piperazin-l-yl, pyrrolidin-l-yl, isoquinolyl, pyridin-l-yl, hydropyridin-l-yl, 2,3- dihydroindol-l-yl, 1,3,4,9-tetrahydrocarbolinyl, thieno[2,3-c]pyridinyl, 3,4,10,10a— ydro-lH-pyrazino[l,2-a]indolyl, l,2,4,4a,5,6-hexahydro-pyrazino[l,2-a]quinolinyl, no[l,2-a]quinolinyl, diazepan-l -yl, l ,4,5,6-tetrahydro-2H-benzo[fJisoquinolinyl, l ,4,4a,5,6, l0b-hexahydro-2H-benzo[f]isoquinolinyl, 3,3a,8,8a—tetrahydro- l Haza- enta[a]indenyl, and 2,3,4,7-tetrahydro- l H-azepin- l -yl, - l -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 clic and polycyclic (e. g., having 2, 3 or 4 fused rings) systems. Examples of aryl groups include Without limitation, pyridyl, dinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (furanyl), quinolyl, isoquinolyl, l, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, olyl, 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 aryl group has 1 to about 4, l 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, 2,3- dihydrobenzofuryl, l,3-benzodioxole, benzo- 1,4-dioxane, piperidinyl, pyrrolidinyl, olidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also included in the definition of heterocycloalkyl are es that have 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 derivatives 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, l to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group ns 0 to 3 double bonds. In some ments, the heterocycloalkyl group contains 0 to 2 triple bonds.
As used herein, "halo" or "halogen" includes fluoro, , 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, alkyloxy" refers to -O-cycloalkyl.
As used herein, "aralkyl" refres 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 have 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 centers). 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 all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For e, isotopes of hydrogen include tritium and deuterium.
The phrase "pharmaceutically able" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound l judgment, le for use in contact with the tissues of human beings and animals without ive toxicity, irritation, allergic response, or other problem or complication, commensurate with a able benefit/risk ratio.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used , aceutically able salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically able salts include, but are not limited to, mineral 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 present invention include the conventional xic salts or the quaternary ammonium salts of the parent compound , for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present 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 riate base or acid in water or in an c solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of le 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 ed using known organic synthesis techniques and can be sized according to any of numerous possible tic routes.
The reactions for preparing compounds of the invention can be carried out in le solvents which can be y 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 temperatures at which the reactions are carried out, e. g., temperatures which can range from the solyent's freezing temperature to the solyent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one t. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.
Preparation of compounds of the invention can involve the tion and deprotection of various chemical groups. The need for protection and deprotection, and the selection 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 sis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is orated herein by reference in its ty.
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 resonance spectrometry (e.g., 1H or 13C) infrared spectroscopy, spectrophotometry (e.g., UV- visible), 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 ng a subject are further provided comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt 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 t causing any rable 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 degradation of the active ingredient 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, ably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prevention ed. The active compounds and compositions, for example, can be administered orally, rectally, parenterally, ocularly, inhalationaly, or lly. In ular, administration can be epicutaneous, inhalational, enema, ctival, eye drops, ear drops, alveolar, nasal, asal, vaginal, intravaginal, transvaginal, ocular, cular, transocular, enteral, oral, intraoral, transoral, inal, rectal, intrarectal, transrectal, injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular, erebroventricular, intracardiac, subcutaneous, intraosseous, ermal, intrathecal, eritoneal, intravesical, intracavernosal, intramedullar, intraocular, intracranial, transdermal, transmucosal, transnasal, inhalational, intracisternal, epidural, peridural, intravitreal, etc.
Suitable carriers and their formulations are described in Remington: The e and Practice of Pharmacy (19th ed.) ed. AR. Gennaro, Mack Publishing Company, Easton, Pa., 1995. Oral administration of a solid dose form can be, for example, presented in discrete 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 in a powder or granule form. In some forms, the oral dose form is sub- l, such as, for example, a lozenge. In such solid dosage forms, the nds of Formula I are ordinarily combined with one or more nts. 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 emulsions, solutions, sions, syrups, and elixirs containing inert diluents ly used in the art (e.g., water).
Such compositions also can comprise adjuvants, such as g, emulsifying, ding, flavoring (e. g., sweetening), and/or perfuming agents.
In some forms, the disclosed compositions can comprise a parenteral dose form.
"Parenteral administration" includes, for e, aneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion.
Injectable preparations (e.g., e injectable aqueous or oleaginous suspensions) can be formulated according to the known art using le dispersing, wetting agents, and/or suspending agents. lly, an appropriate amount of a pharmaceutically acceptable carrier is used in the formulation to render the ation isotonic. 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 ermal patches or iontophoresis s, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical ation can include a compound which es absorption or penetration of the active ingredient 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 reservoir 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, fllms, skin s, wafers, implants, sponges, f1bres, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration ers 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 aural administration can be in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and ulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed- linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for e, gelan gum, can be incorporated er with a vative, 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 itions can be prepared by any of the well- known techniques of cy, such as effective ation and administration procedures.
The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in rd textbooks. Formulation of drugs is sed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack hing 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 nds can be used, alone or in combination with other therapeutic agents, in the ent or prevention of various conditions or disease states. The administration of two or more compounds "in combination" means that the two compounds are administered y 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 ion or a pharmaceutically accepted salt thereof; and a pharmaceutically WO 34839 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 tion and treatment of ghrelin receptor associated human diseases such as y and/or metabolic disorders.
Methods All of the methods of the ion 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 tion, reduction, prevention, and/or treatment of diseases which are pathophysiologically modulated by the ghrelin receptor. Accordingly, in some forms, disclosed are methods of preventing and/or treating diseases which are pathophysiologically modulated by the n or, comprising administering to a subject a therapeutically effective amount of a compound of Formula I as disclosed above, or a pharmaceutically acceptable salt thereof.
Suitable subjects can e mammalian subjects. Mammals e, but are not limited to, canine, feline, bovine, caprine, equine, oyine, porcine, rodents, lagomorphs, primates, and the like, and encompass s in utero. In some forms, humans are the ts. 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, diabetes, 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. Metabolic disorders potentially treatable by the instant s include diabetes, Type I es, Type II diabetes, inadequate glucose tolerance, insulin resistance, lycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity, aging, me X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease. Gastric disorders ially treatable by the instant methods include post-operative ileus (POI), diabetic gastroparesis, and opioid induced bowel dysfunction.
Gastrointestinal es potentially treatable by the instant methods include irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia. Substance abuse potentially treatable by the t methods includes alcohol and drug abuse, and said drug includes amphetamines, barbiturates, benzodiazepines, cocaine, methaqualone, and s.
In some embodiments of the invention, the compound of Formula I is useful in the treatment of Prader-Willi me, a genetic disorder usually involving chromosome 15.
Prader-Willi is terized 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 x compulsion to eat.
The eating may be excessive (compulsive over-eating); may include normal eating punctuated with episodes of purging; or may include cycles of ng and purging. The most prevalent over-eating disorder is Bulimia a. Another Widely and rapidly spreading over-eating disorder is sive 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 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 ation, 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 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 salt thereof, is administered by one or more routes selected from the group consisting of rectal, , sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral and topical administration.
In some other methods, administration is lished by administering an oral form of the compound of Formula I or a ceutically acceptable salt thereof.
A therapeutically effective amount may vary Widely depending on the severity of the disease, the age and relative health of the subject, the potency of the nd used and other factors. Therapeutically effective amounts of compounds of Formula I may range from approximately 0.01 microgram per Kg (ug/Kg) body weight per day to about 100 mg/Kg body weight per day, or from about 0.1 day to about 10 mg/Kg/day, or from about 1 ug/Kg/day to about 5 mg/Kg/day, or from about 10 ug/Kg/day to about 5 mg/Kg/day, or from about 100 ug/Kg/day to about 5 mg/Kg/day, or from about 500 ug/Kg/day to about 5 mg/Kg/day.
Definitions of Terms Throughout this application, various publications are nced. The sures of these ations 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 sed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. 1. A, an, the As used in the specification and the appended , the singular forms "a," "an" and "the" include plural referents unless the context y dictates otherwise. Thus, for example, 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 ), "mL" for iters, and "rt" for room temperature, "nm" for nanometers, "M" for molar, and like abbreviations). 3. About The term "about," when used to modify the quantity of an ingredient in a composition, concentrations, volumes, process temperature, 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, concentrates or use formulations; through rtent error in these procedures; through differences in the manufacture, source, or purity of starting materials or ingredients used to carry out the methods; and like erations. The term "abou " also asses amounts that differ due to aging 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 "abou " the claims appended hereto include equivalents to these quantities. 4. Comprise Throughout the description and claims of this specification, the word ise" and variations of the word, such as ising" and "comprises," means "including but not d to," and is not intended to exclude, for example, other additives, components, rs or steps.
. Ghrelin Receptor Agonist A ghrelin receptor t is any molecule that binds to and activates the Ghrelin receptor in the cells. 6. Ghrelin Receptor Antagonist A ghrelin receptor antagonist is any molecule that binds to and inhibits the activity of Ghrelin receptor. 7. Pathophysiologically Mediated by Ghrelin or Something is "pathophysiologically mediated by the ghrelin receptor" if the ghrelin receptor is involved in the functional changes in body associated with or ing from disease or injury. 8. Obesity Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems. Obesity treatment includes inducing weight loss, ng bodyweight, reducing food intake, reducing appetite, increasing metabolic rate, reducing fat intake, reducing carbohydrate craving; or inducing y. The obesity-related disorders herein are ated with, caused by, or result from obesity. Examples of obesity-related disorders include overeating, 2015/019112 binge eating, and bulimia, hypertension, es, elevated plasma insulin concentrations and insulin ance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and mias, myocardial infarction, congestive heart failure, ry heart e, sudden death, stroke, polycystic ovary e, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deflcient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic actiVity or a decrease in resting energy expenditure as a tage of total fat-free mass, e. g, children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic me, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro- esophageal reflux, respiratory disorders, such as y-hypoyentilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, ricaemia, lower back pain, adder disease, gout, and kidney cancer, nicotine addiction, substance addiction and alcoholism. The compositions of the present invention are also useful for reducing the risk of ary 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 diabetes, Type I diabetes, Type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, idemia, obesity, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral vascular disease.
. Congestive Heart Failure Congestive heart failure (CHF) is a ion in which the heart's function as a pump to deliver oxygen rich blood to the body is inadequate 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 ction (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. es 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 ty of the heart may be normal, abnormally high oxygen demand by the body's tissues (for example, with hyperthyroidism) may make it difficult for the heart to supply an adequate blood flow (called high output heart failure). In some patients one or more of these factors can be present to cause congestive heart failure. tive 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 salt m) and water. This diminished kidney function can cause to body to retain more fluid. The lungs may become congested with fluid nary 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. 1 1. m Action Agonism action refers to the g of a molecule to a receptor that leads to the tion of the receptor, thus ring a cellular response r to the cellular response for a known agonist for the receptor. 12. Antagonism Action Antagonism action refers to the binding of a molecule to a receptor that leads to the inhibition of the receptor. 13. Modulate To modulate, or forms f, means either increasing, decreasing, or ining a cellular activity ed h a cellular target. It is understood that Wherever one of these words is used it is also sed 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.
. Or The word "or" or like terms as used herein means any one member of a ular 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 reference into this application in order to more fully describe the state of the art to which this ns. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. 17. Subject As used throughout, by a "subject" is meant an individual. Thus, the "subject" can include, for example, domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, , pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.) mammals, non-human mammals, primates, non-human primates, rodents, birds, reptiles, amphibians, fish, and any other . 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 terms include active ent, that is, treatment ed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal ent, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. These terms can mean that the symptoms of the underlying disease are reduced, and/or that one or more of the underlying cellular, physiological, or biochemical causes or isms 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 lar state of the disease, not just the physiological state of the disease. In certain situations a treatment can rtently 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 ed to minimizing or partially or completely inhibiting the development of the associated e, pathological condition, or disorder; and supportive ent, that is, treatment ed to supplement another specific 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 preventive purpose. The ent can be made either acutely or chronically. It is understood that ent can mean a reduction or one or more symptoms or characteristics by at least 5% 10%, %, 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 sed 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 ve to a control.
These terms do not require that the treatment in fact be effective to produce any of the intended s. 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.
. Toxicity Toxicity is the degree to which a substance, le, is able to damage something, such as a cell, a tissue, an organ, or a whole sm, that has been exposed to the substance or molecule. For example, the liver, or cells in the liver, hepatocytes, can be d by n substances. The methods of the present invention are preferably non-toxic.
The invention will be bed in greater detail by way of specific 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 1k CI CI Me gin—3:» Hjfij— 8 | iPd(OAc)2 DPPP AcHN ACHN ii HCI CI Me i) NaNo2 HCI 0' Me NaOH CI ii) Kl fl 0 —> CI]:CIj;/N:—>NaBH4 (:leOH H2N ' 1f 1h KEEN“ Clj:CIj/Mkel\iphth—>N2H4_2H0 0:]:j/kNH2—>D-Mandelic acidN C' 1i 1]- lntermediate 1k Step 1: To a solution of 1a (100 g, 0.62 mol) in DMF (1.2 L) was added N—bromosuccinimide (110 g, 0.62 mol) at 0 CC. The mixture was stirred at room temperature 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 Na2SO4 and trated under reduced pressure. The residue was triturated with petroleum ether to provide 1b (133.7 g, 89% yield) as a brown solid. 1H- NMR (CDC13, 300 MHz): 5: 7.30 (d, 1 H), 6.59 (d, 1 H), 4.22 (br, 2 H). LC-MS: 241 [M+1]+.
Step 2: To a solution of 1b (133.7 g, 0.55 mol) in dry CH2C12 (1.5 L) was added acetic anhydride (110 g, 0.62 mol) dropwise over a period of 20 minutes at room temperature. The mixture was stirred at room temperature overnight, then diluted with CH2C12 (300 mL) and washed with water (150 mL) and brine (200 mL). The c layer was ted, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was triturated with eum ether (300 mL) to e compound 1c (143.0 g, 91% yield) as a white solid. 1H-NMR (CDC13, 400 MHz): 5: 8.26 (d, 1 H), 7.63 (br, 1 H), 7.54 (d, 1 H), 2.26 (s, 3 H). LC-MS: 280 [M-1]'.
Step 3: A mixture of compound 1c (50.0 g, 0.18 mol), butyl vinyl ether (1d, 89.0 g, 0.89 mol), bis(1,3- diphenylphosphino)propane (DPPP, 22.0 g, 0.053 mol), TEA (100 mL, 0.71 mol) and )2 (6.4 g, 0.027 mol) in DMSO (1.2 L) was heated at 130 CC under N2 overnight. After the reaction was completed, the mixture was cooled to 0 CC and 2N HCl (480 mL) was added dropwise over a period of 30 s. 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=1 :10) to provide 1e (19.5 g, 45% yield) as a yellow solid. 1H-NMR (CDC13, 400 MHz): 5: 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-1]'.
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 temperature. The mixture was heated at 50 CC overnight, then cooled and concentrated under d pressure. The resulting solid was triturated with water (100 mL) for min and filtered to provide If (18.0 g, 98% yield) as a brown solid. 1H-NMR (CDC13, 400 MHz): 5: 7.48 (d, 1 H), 6.68 (d, 1 H), 4.56 (br, 2 H), 2.62 (s, 3 H). LC-MS: 202[M-1]'.
Step 5: To a mixture of compound 1f (18.0 g, 89.2 mmol) and ice (360 g) in conc. HCl (180 mL) was added a on ofNaNOz (9.2 g, 133.7 mmol) in water (20 mL) dropwise over a period of 30 minutes, and the resulting e stirred in an ice bath for 30 min. A solution of K1 (74.0 g, 446 mmol) in water (360 mL) was added dropwise over 45 min at 0 CC. The mixture was d for min and then extracted with EtOAc (3 X 100 mL). The ed organic layers were dried over anhydrous Na2SO4 and concentrated under d pressure. The residue was purified by column chromatography (silica, EtOAc: PE=1:40) to provide 1g (23.9 g, 86% yield) as a yellow solid. 1H-NMR (CDC13, 400 MHz): 5: 7.6 (d, 1 H), 7.06 (d, 1 H), 2.62 (s, 3 H).
Step 6: To a solution of Ig (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 CC. The mixture was stirred at room temperature 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 purified by column chromatography a, EtOAc: PE=1 :10) to provide lb (22.4 g, 93% yield) as a white solid. 1H-NMR (CDCI3, 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 lb (22.4 g, 70.9 mmol), phthalimide (12.5 g, 85.0 mmol) and PPh3 (22.3 g, 85.0 mmol) in dry THF (450 mL) was added DIAD (21.5 g, 106.3 mmol) at room temperature under N2 protection. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc: PE=1:15) to provide 1i (18.5 g, 58% yield) as a white solid. 1H-NMR (CDC13, 400 MHz): 5: 7.78-7.84 (m, 3 H), .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 1i (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 CH2C12 (3 X 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. 1H-NMR (CDCl3, 400 MHz): 5: 7.81 (d, 1 H), 7.25 (d, 1 H), 4.55 (q, 1 H), 1.36-1.38 (d, 3 H). LC-MS: 316 [M+1]+.
Step 9: To a on 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 utyl ether (110 mL) at 45°C. The mixture was stirred at this ature for 30 min then cooled and filtered. White solid obtained was partitioned between 5% NaOH solution (3 00 mL) and methyl tert-butyl ether (3 00 mL). The bi-phases were ted and the aqueous phase was extracted with methyl tert-butyl ether (3 00 mL). The combined organic layer was concentrated to provide Intermediate 1k (12 g, 58.5% yield) as a white solid 8.0%, pak AD-H, 5 um, 4.6*250mm, mobile phase: Hex: EtOH : DEA=80 : 20 : 0.2), retention time = 6.408 min).
Example 2 Synthesis of Compound 2b Me‘IxElO y—bcie/ldHfizwoi Mew psi) ii HCI.dioxane NH'HCI A suspension ofN—methylpiperidone 2a (13.3 g, 58.6 mmol), NH2Me (30% in MeOH, 100 mL) and Pd/C (0.66 g) in MeOH (200 mL) was heated at 60 CC under H2 atmosphere (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. 1H-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), .02 (m, 2 H), LC-MS: 129 [M+1]+.
Example 3 Synthesis of Compound H0603 MexN CI Me CI ‘N 0 Me CI NHHCI + NH2 sgene, TEA NJLN CI Me I | H 2b Compound 1k 38 i) Pd(PPh3)ZC|2/Cu| Me\ N Me CI TMS : JOL 0| —> I?! N ii) MeOH Me H0603 % Step 1: To a solution of 1k (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 CC. 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 CH2C12 (50 mL) and saturated NaHC03 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. 1H-NMR (CDC13, 400 MHZ): 5: 7.74 (d, 1 H), 6.94 (d, 1 H), 5.19- .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), 2.20- 2.27 (m, 2 H), 1.70-1.77 (m, 2 H), 1.45 (d, 3 H). LC-MS: 470 [M+1]+.
Step 2: A mixture of 3a (3 g, 6.38 mmol), Trimethylsilylacetylene (3.1 g, 31.9 mmol), Pd(PPh3)2C12 (210 mg, 0.3 mmol) and CuI (85 mg, 0.45 mmol) in TEA (60 mL) was heated at 80 CC under N2 overnight, then cooled, diluted with CH2C12 (40 mL) and d. The filtrate was concentrated under reduced re 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 e 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 sion of K2C03 (0.75 g, 5.45 mmol) in MeOH (40 mL) and stirred at room temperature for 30 min. The mixture was filtered and concentrated under reduced re and the residue was ioned between EtOAc (40 mL) and water (40 mL). The organic phase was separated, dried with anhydrous Na2SO4 and concentrated under reduced pressure to provide H0603 (1.9 g, 82% yield) as a white powder. 1H-NMR (CDCl3, 400 MHz): 5: 7.43 (d, 1 H), 7.21 (d, 1 H), .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). LC- MS: 368 [M+1]+.
Example 4 Synthesis of Compound H0700 Me0 N \ SnBu3 JOL Me CI 0 Me CI NKCEC' [\ 3b / N Me\r\0\ N NJLN CI I H —> | H Pd(PPh3)4/Cu| Me Compound 3a H0700 l Nj A mixture of 3a (3.0 g, 6.38 mmol), 3b (3.54 g, 9.57 mmol), CuI (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 CC under N2 overnight, then diluted with CH2C12 (100 mL) and filtered. The filtrate was washed with brine (100 mL). The organic phase was separated, dried with anhydrous Na2SO4 and trated under reduced pressure. The residue was purified by column chromatography (silica, MeOH: CH2C12 1:30, 1% NH4OH) to e H0700 (1.3 g, 48% yield) as a white solid. 1H-NMR (CDCl3, 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 (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+1]+.
Example 5 sis of Compound H0722 MeQe 0' DPPA ”CL :1 CI NH“0' M TEA/toluene Me N 2b H0722 N 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 saturated Na2C03 solution (50 mL). The c phase was separated, washed with brine (50 mL), dried with anhydrous Na2S04 and trated under reduced pressure. The e was purified by column chromatography (silica, methanol: romethane 1:40, 1% NH4OH) to provide H0722 (1.03 g, 55% yield) as a white solid. 1H-NMR (CDCl3, 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 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), 1.66- 1.80 (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+1]+.
Example 6 Synthesis of Compound H0751 B’\(\ \ T'V'S % TBAF/THF \ \/S / S 3 3)ZC|2/Cu| N=/ TBME: rt Nt/ TEA/THF 5b 5c Me Ugo \N Me CI JLN“VI. Me\ CL Pd(PPh3)4/Cu| Q TBME/TEA/DMF H0751 / Step 1: The mixture of Sa (5 g, 30.5 mmol), Trimethylsilylacetylene (3.6 g, 36.6 mmol), Pd(PPh3)2C12 (210 mg, 0.3 mmol) and CuI (85 mg, 0.45 mmol) in TEA (150 mL) was heated at 80 CC for 3h WO 34839 under N2, then cooled, diluted with Et20 (100 mL) and washed with brine (100 mL). The organic phase was separated, dried over anhydrous Na2SO4 and trated 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. 1H-NMR (CDClg, 400 MHz): 5: 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 temperature was added Bu4NF (1 M in THF) (22.5 ml, 22.5 mmol). The mixture was stirred at room temperature 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), CuI (180 mg, 0.95 mmol) in DMF (50 ml) and TEA(10 mL).
The mixture was heated at 110 °C under N2 overnight in a sealed tube, then cooled, diluted with CH2C12 (100 mL) and filtered. The filtrate was washed with brine (100 mL) and the organic phase was separated, dried over ous Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (silica, methanol: romethane 1:30, 1% NH4OH) to provide H0751 (1.18 g, 40% yield) as a yellow solid. (CDC13, 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), .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), 1.63- 1.69 (m, 2 H), 1.52-1.62 (m, 2 H), 1.41 (d, 3 H). LC-MS: 451 [M+1]+.
Example 7 Synthesis of Compound H0754 Me (:1 Me‘N 0 Me CI [:/>—Br Pd(PPh3)2012/0111 JL CI TEA 65 c N N Me H H0603 H0754 ‘j 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 CuI (264 mg, 1.38 mmol) in TEA (50 mL) was heated at 65 CC under N2 overnight, then cooled, diluted with CH2C12 (100 mL) and filtered. The filtrate 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 Na2SO4 and concentrated under reduced pressure. The residue was d by column chromatography (silica, methanol: romethane 1:30, 1% NH4OH) to provide H0754 (990 mg, 37% yield) as a white solid. 1H-NMR , 300 MHz): : 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), 1.70- 1.90 (m, 4 H), 1.51 (d, 3 H). LC-MS: 451 [M+1]+.
Example 8 Synthesis of Compound H0761 CI Me\ Me\N CI HO CI DPPA CI + 0\NH O N 1 TEA/toluene EjlxN N . ‘1 o. 4a H0761 1 N/ 7a N/ 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 e (200 mL) was stirred at 110 CC for 2 h, then cooled to room ature and compound 7a (1.75 g, 13.56 mmol) was added. The mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The residue was partitioned n EtOAc (100 mL) and saturated Na2C03 solution (100 mL). The organic phase was separated, washed with brine (100 mL), dried over ous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, methanol: dichloromethane 1:30, 1% NH4OH) to provide H0761 (1.4 g, 48.3% yield) as a white solid. 1H- WO 34839 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), .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), .14(m, 2 H). LC-MS: 464 [M+1]+.
Example 9 sis of Compound H0764 Me Me‘N 0 Me CI ‘N 0 Me CI Pd(PPh3)2C|2/Cu| L CI JL CI % TEA/THF, 80 °c 'P' N N N + —> H Me Q 3a 8b 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)2C12(597 mg, 0.85 mmol) and CuI (220 mg, 1.16 mol) at room temperature under N2. The mixture was heated at 80 CC overnight in a sealed tube, then cooled, d with CH2C12 (50 mL) and filtered. The filtrate was washed with brine (50 mL) and the organic phase was separated, dried over anhydrous Na2SO4 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. 1H- NMR(CDC13, 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), 4.07- 4.14 (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, H), 1.38 (d, 3 H), 0.70-0.90 (m, 4 H). LC-MS: 408 [M+1]+.
Example 10 Synthesis of Compound H0795 N F E jN\ F n BUSSnCLrFBuU,TMP, Bu3Sn THF,-78toO°C / \E j// N ii) -78 to -40 °c, THF N Me Cl Me CI Pd(PPh3)4Cul Oflflmrj/FH0795 Step 1: To a 2.5 M solution of llithium (40 mL, 0.1 mol) in anhydrous THF (250 mL) cooled to — 78 CC 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 CC by replacing the dry ice/acetone bath with an ice bath and stirred for 1.5 h. The mixture was cooled back to —78 CC 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 CC by replacing the dry ice/acetone bath with an dry ice/acetonitrile bath. A solution of 35% HCl, ethanol and THF (1 45) was added. The mixture was warmed to room temperature and washed with saturated NaHC03 solution (100 mL) and extracted with EtOAc (3 X 100 mL). The combined organic layers were dried over ous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc: eum ether=1: 15) to provide 9b (3.4 g, 29% yield) as light yellow oil. 1H-NMR (CDCl3, 300 MHz): 5: 8.41 (d, 1 H), 8.17 (d, 1 H), 18-053 (m, 27 H).
Step 2: To a on of 3a (2.0 g, 4.4 mmol) and 9b (3.4 g, 9.35 mmol) in methoxyethane (200 mL) were added Pd(PPh3)4 (800 mg, 0.69 mmol) and CuI (40 mg, 0.21 mmol) at room ature under N2. The mixture was then heated at 90 CC overnight, then cooled, diluted with CH2C12 (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. 1H-NMR (CDCl3, 400 MHz): : 8.83 (d, 1 H), 8.44 (d, 1 H), 7.46 (d, 1 H), 7.22 (d, 1 H), 5.26-5.30 (m, 1 H), 4.99 (d, 1 H), 4.47-4.60 (m, 1 H), 2.90-2.95 (m, 2 H), 2.83 (s, 3 H), 2.32 (s, 3 H), 2.10-2.17 (m, 2 H), 1.78-1.83 (m, 2 H), .64 (m, 2 H), 1.51 (d, 3 H). LC-MS: 440 [M+1]+.
Example 11 Synthesis of H0816 Me CI Me CI Bu38n\E Me 0' CI Boc O2 CI —b> BocHN H2N BocHN Pd(PPh3)4, Cul I I 1k DME 100°C 10c 10b (1:: MeQNH.HCI Me\ Me CI Me 0' i TFA(HCI) CI ii Nazco3 (aq.) H2N 2b —> QMSLM N N —> \ | ] triphosgene,TEA,DCM H0816 0/]I 10d N/ N Step 1: To a solution of 1k (12.0 g, 38.1 mmol), sat.NaHC03 solution (120 mL) in THF (480 mL), was added (Boc)20 (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 Na2804 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. 1H-NMR (CDClg, 400 MHZ): 5: 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), CuI (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 e which was then filtered. The organic phase was separated, dried over ous Na2804 and concentrated under reduced pressure. The residue was purified by column tography (silica, EA: PE=1: 10) to e compound 10c (3.47 g, 78.5% yield) as yellow solid. 1H-NMR(CDC13, 300 MHz): 5: 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 CC was added TFA (35 mL) dropwise. The e 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 CC. Sat. Na2C03 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 ous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, MeOH : DCM =1:100) to provide 10d (1.7 g, 68.0% yield) as a yellow solid. LC-MS: 268 [M+1]+.
Step 4: To a solution of 10d (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 CC. The solution was then warmed to r.t. and d for 0.5 h. 2b (1.57 g, 9.6 mmol) was added to the above mixture at r.t. The e was then stirred for another 0.5 h, and finally evaporated under d 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 Na2SO4 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. 1H-NMR(CDC13, 400 MHZ): 5: 8.82 (s, 1H), 8.60 (s, 1H), 8.51 (d, 1H), 7.36- 7.38 (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+1]+.
Example 12 Synthesis of H0824 2015/019112 N SnBu3 Me CI CI Me CI Me [ j/ N/ CI CI Boczo, THF 3b CI [BOG Bod-1N NH2 é M —> Pd(PPh3)4, Cul N\ I I TEA,DME I 11_ 11b 11c N/ Me C' Mimi/Y.-K‘ Me\ iTFA,DCM N Me CI .. | CI H2N 119 Me NAE j: || N32003 (aq.) K CI N N Me N\ l triphosgene 11d N/j DCM, TEA | NJ H0824 Step 1: To a solution of lj (2 g, 6.36 mmol) and t-butyl dicarbonate (2.75 g, 12.72 mmol) in THF (30 mL) was added saturated s Na2C03 solution (5 mL) at 0 CC. The mixture was then stirred at room temperature for 1 h, and eventually diluted with ethyl e (40 mL). The resulting mixture was washed with brine (10 mL), dried over anhydrous Na2SO4 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. 1H-NMR (CDCl3, 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+1]+.
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 3)4 (780 mg, 0.67 mmol) and CuI (90 mg, 0.45 mmol) at room temperature under the protection of N2. The mixture was then heated to 90 CC and stirred overnight at this temperature. 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+1]+.
Step 3: To a solution of 11c (600 mg, 1.63 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL) at 0 CC. After the addition, the mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was ioned between saturated aqueous NaHC03 solution (15 mL) and romethane (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 11d (350 mg, 80% yield) as a colorless oil. 1H-NMR (CDCl3, 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+1]+.
Step 4: To a solution of compound 11d (60 mg, 0.225 mmol) and TEA (0.5 mL) in romethane (10 mL) was added triphosgene (46 mg, 0.158 mmol) at 0 CC. The mixture was then stirred at room temperature for 15 min before the on of He (53 mg, 0.337 mmol). Then stirred for another min, diluted with dichloromethane (10 mL), washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica, methanol: romethane 1:40, 1% NH4OH) to provide H0824 (60 mg, 57% yield) as a white solid. 1H-NMR(CDC13, 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+1]+.
Example 13 Synthesis of H0890 (enantiomer of H0824) SnBu3 CI Me CI Me [NNE; Me CI CID)’NH2 B0020 THF CI "’N’BOC BocHN I I Pd(PPh3)4 Cul 1k TEA DME Me CI iTFA/DCM aW CI ii (aq.) C' H2N 11e Me “1*:JLN MeK —, N triphosgene N/j 12c 90M» TEA H0390 |:j Step 1-4: Compound H0890 was synthesized in a similar manner to H0824 (overall yield 31% from 1k). 1H-NMR(CDC13, 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), .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+1] Example 14 sis of H0826 Me CI Me C' Me\ iEtNHg-HCI, Pd/C, MexN H2 (50 psi) @NH.HCI HNKéEE:Nj C' 0 ' _. . n HCI/dloxane triphosgene 13a 13bE ”0826 |j|N DCIVI, TEA N/ Step 1: A mixture of 13a (3g, 26.5 mmol), HCl (11.2 g, 132.7 mmol), TEA (5 ml) and Pd/C (300 mg) in MeOH (50 mL) was heated at 60 CC under H2 (50 psi) overnight, then cooled and d.
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. 1H-NMR (DMSO-d6, 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+1]+ .
Step 2: To a solution of 11d (60 mg, 0.225 mmol) and TEA (0.5 mL) in dichloromethane (5 mL) was added triphosgene (46 mg, 0.158 mmol) at 0 CC. After the addition, the mixture was stirred at room ature for 15 min before the on of 13b (60 mg, 0.337 mmol). The resulting mixture was stirred for another 30 min at room temperature, then diluted with dichloromethane (10 mL), washed with brine (10 mL). The organic layer was separated, dried over anhydrous Na2804 and concentrated under vacuum. The residue was purified with silica gel column chromatography (silica, methanol: dichloromethane 1:40, 1% NH4OH) to provide H0826 (44 mg, 45% yield). 1H-NMR(CDC13, 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+1]+.
Example 15 Synthesis of H0889 (enantiomer of H0826) Me CI o Me CI CI Mew triphosgene H2N DCM, TEA MRUNJLN N NH.HC| I E N I j IIEt 12d 13b I N H0889 /j The synthesis of H0889 (49 mg. 30% yield) is r to that of H0826. 1H-NMR (CDClg, 400 MHz): 5: 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, 1 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+1]+.
Example 16 Synthesis of H0830 CI j/snBU3 Dess MartIn Ion CI [N3b 0/ TII/ISCF3 HO —, 3)4, Cul TBAF | (7:3 | 14a DME 100 °C CFB CI CFa CI 93:3 NaNa MsCI DMSO 100 °c TEA DCM | Nj Me N’ 7:: CFa CI ““0 N O NH. HCI Raney Ni —|\|/I>e2'3 @N HCOZH 20 01:3 triphosgene TEA 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 temperature. The mixture was stirred at room temperature for 2 h, then concentrated under vacuum. The residue was purified by column chromatography (silica, ethyl acetate: petroleum ether=1 :15) to provide 14b (3.05 g, 99% yield) as a light yellow solid. (CDC13, 400 MHZ): 5: 10.40 (s, 1 H), 7.97 (d, 1 H), 7.52 (d, 1 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 CuI (147 mg, 0.76 mmol) at room temperature under the protection of N2. The mixture was heated at 90 CC overnight, and then concentrated under reduced pressure. The residue was purified with silica gel column tography (silica, ethyl acetate: petroleum ether=1 :10) to provide 14c (826 mg, 86% yield) as a light yellow solid. 1H-NMR(CDC13, 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 .
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 CC.
After the mixture was stirred at room temperature 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 Na2SO4 and concentrated reduced pressure. The residue was purified by column chromatography (silica, ethyl acetate: petroleum ether=1 :5) to provide 14d (640 mg, 52 % yield) as a white solid. (CDC13, 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+1]+.
Step 4: To a on 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 mol) at 0 CC. After the addition was ed, the mixture was stirred at room temperature for 20 min, then diluted with romethane (50 mL). The mixture was washed with saturated aqueous NaHC03 solution (40 mL), dried over anhydrous Na2SO4 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. 1H-NMR(CDC13, 400 MHZ): 5: 8.96 (d, 1 H), 8.73 (dd, 1 H), 8.67 (d, 1 H), 7.74 (d, 1 H), 7.64 (d, 1 H), 6.54 (q, 1 H), 3.15(s, 3 H).
Step 5: To a on of compound 14e (910 mg, 2.27 mmol) in DMSO (20 mL) was added NaN3 (296 mg, 4.55 mol) at room ature. The mixture was stirred at 100 CC overnight, 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 Na2SO4 and trated under vacuum. The e was purified by column chromatography (silica, ethyl acetate: petroleum ether=1 :5, v:v) to provide 14f (340 mg, 44% yield) as a yellow oil. 1H-NMR (CDClg, 400 MHZ): : 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 .
Step 6: To a solution of 14f (34.7 mg, 0.1 mmol), HCOOH (46 mg, 1.0 mmol) and N2H4’H20 (50 mg, 1.0 mmol) in EtOH (10 mL) was added Ni (50 mg). The mixture was stirred at room temperature for 1 h, then d and concentrated under vacuum. The residue was diluted with dichloromethane (20 mL), washed with water (15 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to provide 14g (30 mg, 93% yield) as a colorless oil. 1H-NMR (CDClg, 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), .17 (q, 1 H), 1.86 (br, 2 H). LC-MS: 322 [M+1]+.
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 temperature. The resulting mixture was stirred at 35 CC under the protection ofN2 for 2 h, then diluted with dichloromethane (10 mL). The mixture was washed with saturated aqueous Na2C03 solution (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified 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 (CDClg, 400 MHZ): 5: 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), 1.61- 1.66 (m, 2H), 1.01-1.05 (m, 2H). LC-MS: 476 [M+1]+.
Example 17 Synthesis of H0847 Me CI Me CI Bugsn \E jN\ F Pd(PPh3)4,Cu| CI CI + BocHN DME,1OO OC BocHN / —> N N F | | 9b 12b /fT/ 15a N Me CI CI 0 Me\ i) TFA H2N NHHCI 0 CI ii) N82003(ag.) N F 2b Me iMe C I \j/ N N I ' Me N F 15b N/ triphosgene,TEA,DCM H0847 j// 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 CuI (227 mg, 1.19 mmol) at r.t. under N2. The e was heated at 90 CC overnight, then cooled, diluted with CH2C12 (800 mL) and filtered.
The filtrate was washed with brine (600 mL) and the organic phase was separated, dried over anhydrous Na2804 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, EtOAc: Petroleum, 1:3) to provide crude nd 15a (10.3 g, ca. 100% yield) as yellow solid. LC-MS: 386 [M+1]+.
Step 2: To a solution of 15a (10.3 g, 26 mmol) in DCM (500 mL) cooled to 0 CC was added TFA (100 mL) dropwise. After the addition was completed, the mixture was d for 3 h, then basified with saturated Na2C03 solution (400 mL) and extracted with DCM (3><100 mL). The combined organic layers were dried over anhydrous Na2804 and trated under d pressure. The residue was purified by column chromatography (silica, MeOH : CH2C12 : NH4OH, 1:20:0.01) to provide 15b (4.1 g, 57% yield) as a red solid. LC-MS: 440 1 Step 3: To a solution of 15b (2.0 g, 7.1 mmol) and TEA (80 mL) in CH2C12 (220 mL) was added triphosgene (1.52 g, 5.1 mmol) portion wise at 0 CC. 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 CH2C12 (100 mL) and washed with aqueous Na2C03 solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and trated. The residue was purified with silica gel column chromatography (silica: CH2C12 : CH30H=10/ 1) to provide H0847 (2.0 g, 65% yield) as white solid. 1H-NMR , 400 MHZ): 5: 8.77 (d, 1H), 8.38 (d, 1H), 7.40 (d, 1H), 7.31 (d, 1H), .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+1]+. ee%=98.5%. (Chiralpak, 5 um, 4.6*250mm, Phase: Hex: EtOH: DEA = 90: 10: 0.2), retention time =12.829 min).
Example 18 Synthesis of H0829 and H0860 “4601??NCS/DMF MeOiEEENIH CI LAH H NaN02 KI HofidI Me | M_S.C' v K—> NC CI MeOH MeO EtOH/HZO NaH, DMF Me N Bus CI E j/Sn MECI M60 0' N/ MeO CI LIOH_ 0 3b I o N\ O 16h Pd(PPha)4,Cul 16i | j 16] l DME,100°C / / ] DPPA/TEA Me~ N O toluene —> Jk CI CI Me\ [)1 N ——separation N H Me iijiNe(SH/R) N NHHCI | 2'0 H0829 Me H0860 N 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 CC. The resulting mixture was heated at 40 CC for 12 h, then poured into water (1600 mL). The precipitate was collected by tion, dissolved in ethyl acetate (1000 mL) and washed with brine (1000 mL). ation of the solvent gave the residue which was re-crystallized in ethanol to give crude 16b (80 g) and it was used ly in next step.
Step 2: To a well stirred solution of 16b (80 g, 0.365 mol) in dry THF (4 L) was added LiAlH4 (27.6 g, 0.73 mol) slowly at 0 CC. The mixture was stirred at 0 °C for 2 h. Then ice-water (600 mL) was slowly added at 0 CC 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. 1H-NMR (CDCl3, 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+1]+.
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 ofNaNOz (21.2 g, 0.3 mol) in water (30 mL) dropwise at 0 CC. The mixture was stirred at 0 CC for 30 min, then a solution of K1 (169.4 g, 1.02 mol) in water (400 mL) was added dropwise at 0 CC. The mixture was stirred at 0 CC for 40 min, then ethyl acetate (1000 mL) was added and the organic phase was washed successively with water (500 mL), NaHS03 solution (500 mL) and brine (500 mL). The organic phase was separated, dried with ous Na2SO4 and concentrated. The residue was purified by column chromatography (silica, EA: PE=1: 15) to provide 16d (50 g, yield: 81%). 1H-NMR(CDC13, 400 MHz): 5: 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 CC. The mixture was d at 0 CC for another 90 min, then diluted with ethyl acetate (800 mL) and washed with brine (600 mL). The organic phase was ted, dried over anhydrous Na2SO4 and concentrated to afford crude 16e (59 g) which was used directly in next step without r purification.
Step 5: To a solution of crude 16e (59 g, 160 mmol) in EtOH (1200 mL) was added a solution ofNaCN (11.4 g, 230.0 mmol) in H20 (250 mL). The resulting mixture was heated under reflux overnight, then cooled and concentrated. The residue was ioned between ethyl acetate (500 mL) and water (500 mL). The organic phase was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated to afford crude 16f (40 g) as a brown solid which was used ly in next step without further purification.
Step 6: To a solution of 16f (40 g, 129 mmol) in MeOH (360 mL) was added conc. H2804 (114 mL) dropwise at 0 CC. The mixture was then heated under reflux overnight, then cooled and concentrated. Aqueous Na2C03 solution (50 mL) was added to the residue at 0 CC and the e was ed to pH=9-10 with the addition ofNa2C03 powder. The mixture was extracted with ethyl acetate (3 x 300 mL) and the combined organic layers were dried over anhydrous Na2SO4 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. 1H-NMR (CDCl3, 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 CC. 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 e was extracted with ethyl acetate (3 x 400 mL). The ed organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (silica, ethyl acetate: petroleum ether=1 :50) to e 16h (20 g, 84% yield). 1H NMR(CDC13, 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 CuI (2.06 g, 10.8 mmol) at r.t. under the protection of N2. The mixture was then heated at 105 CC overnight, cooled and concentrated under vacuum. The residue was purified with silica gel column chromatography (silica, ethyl acetate: petroleum ether=1 :8) to provide 16i (12 mg, 69 % yield) as a yellow solid.
Step 9: The mixture of 16i (12 g, 37.0 mmol) and LiOH‘H20 (9.3 g, 22.2 mmol) in MeOH (480 mL) and H20 (120 mL) was stirred at r.t. overnight, then concentrated under vacuum. The residue was acidified with 1N HCl to pH=2 which was extracted with romethane (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to provide 16j (10.8 g, 94% yield) as a white solid. LC-MS: 310 [M-1]'.
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 CC overnight, then cooled and concentrated under vacuum. The residue was partitioned between ted aqueous Na2C03 solution (150 mL) and dichloromethane (300 mL). The c phase was separated, washed with brine (200mL), dried with anhydrous Na2SO4 and concentrated under vacuum. The e was purified by column chromatography (silica, MeOH: dichloromethane 1:50, 1% NH4OH) to provide H0829 (6 g, 41% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz): 5: 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), .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+1]+.
Step 11: H0860 (2.0, 66.7%) was obtained through the chiral separation of H0829 (Chiralpak, 5um, 46* 250 mm, Hex:EtOH:DEA=80:20:0.2, retention time: 10.76 min). 1H-NMR (CDCl3, 400 MHz): : 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), .17 (m, 1H), .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+1]+.
Example 19 2015/019112 Synthesis of H0837 and H0862 Me CI Me CI 12c IN:IN 300’“ MeNH2, Pd/C, H2 6 JLN CI \ MeOH N ally/I: 1' h TEA BOC \ rlp osgene, 17a 17b HNJ )1 Me CI 0 M iTFA/DCM e CI iiNaHC03(aq.) N N 7:: #Me’NaNJLNHCHO CI —> Me NaBH3CN “he H H0837 | J ‘N 0 Me CI chiral-HPLC QNJLN CI (S/R)|\‘,Ie H ,j\ H0862 | 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 0C under H2 (50 psi) overnight, 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). 1H-NMR(CDC13, 400 MHZ): 5: 9.99 (s, 1 H), 3.79 -3.83 (m, 1 H), .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+1]+ 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 mol) at 0 CC. After the addition was finished, the mixture was stirred at room temperature for 30 min before the on of 17b (270 mg, 1.35 mmol). The resulting mixture was stirred at room temperature for 1 h, then concentrated under vacuum. The residue was partitioned between dichloromethane (50 mL) and saturated NaHC03 solution (50 mL). The organic phase was separated, washed with brine, dried with anhydrous Na2SO4 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. 1H-NMR(CDC13, 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+1]+.
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 CC. The mixture was stirred at room temperature for 1 h, then concentrated under vacuum. The residue was partitioned n aqueous NaHC03 on and dichloromethane. The c layer were dried over anhydrous Na2SO4 and concentrated to provide 17d (252 mg, 96% yield) as a yellow solid. LC-MS: 394 .
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 NaBH3CN (121 mg, 1.9 mmol) at room temperature. The mixture was stirred at room ature overnight, and then concentrated under reduced pressure. The e was partitioned between dichloromethane (50 mL) and saturated NaHC03 solution (50 mL). The organic phase was separated, washed with brine, dried with anhydrous Na2804 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. 1H-NMR(CDC13, 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), .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). LC- MS: 408 [M+1]+.
Step 5: H0862 was obtained through the chiral separation of H0837 (Chiralcel OJ-H, 5um, 4.6 x 250 mm, Hex:EtOH:DEA=90:10:0.3, retention time: 11.34 min). 1H-NMR , 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, H), 1.96-2.05 (m, 2H), 1.38 (d, 3 H). LC-MS: 408 . e 20 Synthesis of H0900 UNanBug 0/ Pd(PPh3)4 CullLiCI/DME 18b (1::ZTi(i-OPr)4 0 CI (IS? CF3 CI CF3 CI HCI/MeOH zWSW, CI TMSCF3 (1:) CI .HCI | :3 | 18c 18e N’J Me—Oi.
MeQF/kjjnfl CF3 CI Mam O CF3 CI b.HCI CI NJL CI Chiral separation N N —> | H | J\ Me N triphosgene crude H0900 | ee%=92.5% N H0900 j Step 1: To a mixture of 16d (32 g, 120 mmol) in dry CH2C12 (800 mL) was added Dess-Martin de reagent (76 g, 180 mmol) portion-wise at 0 CC. The mixture was stirred at room temperature for 1 h, then diluted with DCM (800 mL), washed with aqueous NaHC03 solution (3 00 mL) and brine (3 00 mL). The organic phase was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 1821 (31.4 g) which was used directly in the next step without further purification.
Step 2: To a on 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 CuI (1.52 g, 8 mmol) at room temperature. The mixture was stirred at 90 °C overnight, 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 white solid. LC-MS: 253 [M+1]+.
Step 3: To a solution of 18b (7 g, 27.7 mmol) and (S)-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 temperature. The mixture was stirred at 80 0C overnight, and then cooled. Ethyl acetate (40 mL) was added, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column tography (silica, EA:PE =1 :5) to provide 18c (6.8 g, 69%) as a yellow solid. 1H-NMR (CDC13, 400 MHZ): 5: 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+1]+.
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 CC. The mixture was then d at -65 CC for 2 h, and at that point s NH4Cl solution (250 mL) was added. The mixture was diluted with ethyl acetate (250 mL), washed with brine (250 mL), dried over ous Na2SO4 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+1]+.
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 temperature. The mixture was d for 1 h, then trated 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 t further purification. LC-MS: 322 [M+1]+.
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 CC. The solution was warmed to ambient temperature and stirred for 1 h, then diluted with DCM (100 mL) and washed with aqueous Na2C03 solution (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The residue was purified with silica gel column chromatography (silica, DCM : CH30H=10 : 1) to provide crude H0900 (2.13 g, ee%=92.5%) which was further purified through chiral tion 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), ion tine =12.829 min. 1H-NMR(CDC13, 400 MHZ): 5: 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 . e A Calcium FLIPR Assay The intracellular calcium assay was carried out in a 384-well format FLIPRTM (Molecular Device) HEK293/GHSR1a 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 temperature or 370 C. Test compounds, dissolved in DMSO, were added at the appropriate time and incubated for 15 min followed by the addition of ghrelin with ation or FLIPR.
Relative cence was monitored by the FLIPRTM Molecular . 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 se was followed for 2 minutes. To check for GHSR-la antagonism the nd 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/l 8:00-6:00 dark). After 1 wk acclimation, animals were sorted into two groups (n=6 each, 2 per cage) based on body weight. Animals in group one were be treated with vehicle and animals in group 2 were d with the test agent (n=6 for each group). The cumulative food intake was ted at l, 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 presents entative nds of Formula I with ical data including the ghrelin antagonist/agonist activity in vitro (Example A) and mouse food intake results (Example B). The data clearly trates 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 Metabolic Mouse Food Stability Intake (A)0 Compoun (H = Chemical Structure Activity Inhibition; d No. Human, Doses as mg/kg 1.p.)' * Mouse) NERO 0 Me CI IC50: 52 M1’1 Cl .
H0494 I}! N EC50 =66 nM $16??? H No Effect Me Emax = 2996 Me‘U 0 Me CI Cl IC50 >30 MM .
H0621 'l‘ fl EC50 =2 nM giggfi No Effect 0“ F g Emax = 3896 N )3 Me CI I?! M IC50= 10 nM Medium H NSE (10 H0496 \ EC50 >30 uM High M mg/kg) W0 2015/134839 2015/019112 Me‘N 0 Me CI Jk CI .N 8 Me IC50= 3.4 MM H0617 \ Not done Not Done I EC50 >30 HM lV'e‘N 0 Me CI NAN 0' IC — 9 nM H0539 H Not done Not Done EC50 >30 HM 1 j \ MeOZC N lV'e‘N i Me CI N N IC50= 8 nM Med?“ H Not Done H0546 H Medlum EC >30 M HO N/ 0 Me CI Me’N JL CI N N I H IC50= 57 HM H0526 Me Not done Not Done \ EC50 >30 HM lV'e‘N M31 Me CI CI Medium H H0527 I}! H 13%0—>1390n1\1/{4 Medium Not done Me 50 \ M M Me‘N 0 Me CI NJLN 0' IC50= 24 nM H0497 Egg H NSE (30 Me H EC50 >30 HM mg/kg) \ M |V'e‘N 0 Me CI JL CI IC50= 4 HM H0650 N N EC50 =9 nM Not Done Not Done \ Emax=2150 Me‘U 0 Me CI NJLN 0' IC50= 37 nM H0849 “he H EC50 =51 nM Not Done Not Done l Emax = 1383 W0 2015/134839 2015/019112 0 Me J'L IC50= 490 HM H0578 M O EC50 >30 H Not Done Not Done \ M Me\N Me Cl . 94% at 1h NAN MedlumH Inhibition Up IC50= 98 nM Medium H0511 t024h (30 EC5° >30 “M M mgkg» Me‘O Me CI IC50= 5.7 nM H0820 EC50 =9 nM Not Done Not Done Emax = 3955 MamQ1 NSE(10 Me CI rug/kg) u ii ii1g 1H“iii1 1 Ion a1 Me CN 2 H0613 \ EC” EgonMM High M 111, up t02h l 50 “ / IP+ANAM N 30 mpk PO: inhibition at 1h up to 24h IVIe‘N )1 Me CI CI - H0614 N N IC50= 12 nM EigEIi/i NOIP done, Me F EC50 >30 NM PO:NSE Me\N Me CI CI IC50= 1090 H0635 Not Done Not Done COgMe EC50 >30 NM Me\NQM 0 Me CI H0636 H EC50 >30 11M Medium Not Done \ M W0 2015/134839 PCT/U82015/019112 Me\U 0 Me CI NJLN CI IC50= 85 nM MediumH H0637 M H EC50 >30 HM Medium Not Done \ M Me\U 0 Me CI NJLN CI IC50= 57 nM H0638 M H EC50 >30 HM Not Done Not Done \ F Me\“CL ii Me 0' CI IC50= 48 nM MediumH H0639 I?! ” EC50>30 “M Medium Me Me ESE?g g \ M N 0 Me CI NAN CI IC50= 78 nM Eerylow H0642 I H EC50 >30 HM Not Done Me Very Low \ \O I M Me\U 31 Me 6' CI IC50= 19 nM nghH. . . ..
H0704 [Y] H “ at EC50>30 HM Medium Me NH2 2h(10 \ M l mg/kg) Me\“CL ii Me C' CI IC =53 nM N N 50 nghH.
N )1 Me CI N N N\ IC50=185 nM H0707 NH Me \ EC50>30 HM Not Done Not Done PCT/U82015/019112 N 0 Me CI JL CI N N N§\ IC50=1.8511M H0711 NH Me \ 0 0M Not Done Not Done N JOL Me CI CI IC50= 151’1M LOW H H0716 '1] M S/\\N EC50 >30 11M Medium Not Done Me \ \ M N 0 Me CI NJJxN CI IC50= 396 nM H0717 |\|/| H \ EC50 >30 11M Not Done Not Done e \ N 0 Me CI NJLN CI IC50= 499 nM H0718 |\I/I H EC50 >30 11M Not Done Not Done N 0 Me CI NAN Cl IC50= 780 11M H0719 “IA H D EC50>30 11M Not Done Not Done N 0 Me CI NJJxN CI IC50= 420 nM H0712 “be H H Me Not Done Not Done \ 518150: 220 | Em: 1962 / \101/ N 0 Me CI H0708 |\|/| H EC50 >30 11M Not Done Not Done \ OMe PCT/U82015/019112 N ji Me CI I?! IC50= 453nM H0714 Me 0M9 EC50 >30 11M Not Done Not Done NJLN CI IC50= 57 nM H0715 I H EC50 = 4211M Not Done Not Done Me Et \ Emax = 2479 N 0 Me CI NJLN CI IC50= 116 nM H0706 I H EC50 = 91 nM Not Done Not Done \ \ Emax = 2111 N 0 Me CI NAN CI IC50= 275 nM H0710 I H / EC50 = 395nM Not Done Not Done Me / \ Emax = 1621 N 0 CN CI CI IC50 =8 HM H0666 I H EC50 = 21 nM Not Done Not Done Me CN \ Emax = 4927 N 0 CN CI NAN CI IC50= 39 HM H0739 “IA \ EC50 >30 MM Not Done Not Done e \ Me\U JOL Me CI CI IC50 <1 nM . tion at H0667 '1‘ H EC50 = 3 nM 31:33; 1h; activity OH CN g \ Emax = 4887 up to 4 h (10 l mg/kg) N N Me CN IC50= 2.3 uM H0821 I EC50 >30 uM Not Done Not Done N/ N/fi K/N ‘Me N 0 Me CI NAN CI N,OH mm: 541 nM H0646 I H | EC50 >30 uM Not Done Not Done \ H Cl IC50= 8 nM Medium H H0720 N N Not Done EC50 >30 HM High M Me‘N JOL CI CI IC50= 20 nM Medium H H0721 N N Not Done EC50 >30 HM High M Me \ NH2 Me\U 88% JOL Me 0' inhibition at . 1 hour.
N N I IC50= 41 nM nghH H0516 H Act1V1ty up to. .
\ EC50 >30 HM High M N 24 h I A (30mg/kg) N PO: no effect Me‘N )1 Me O N N IC50=1 “M H0579 I H D N tD0 one N tD0 one Me EC50 >30 MM | NJ MEN 0 Me Cl JL 0 oi 1050—:8 HM HigiH 484)..
N N EC50 — 64 tlon at H0649 H Hi h Mg Me nM 1and2h(10 | Em: 1400 A mg/kg) N OM |VIE‘N0\ JL0 Me CI Cl IC50= 594 HM H0797 me n E5450 2 1'8 Not Done Not Done | Emax = 2879 N OH N N IC50= 162 nM H0798 | H N tD0 one N tD0 one \ N EC50 >30 MM N NH2 Mew 0 Me CI NJLN CI |\|/|e H IC50= 5.4 l’lM H0799 I EC50 =14 nM Not Done Not Done N/ N/fi Emax = 5031 K/N\Me N N IC50= 1.3 11M H0800 |\|/|e H N tD0 one N tD0 one EC50 >30 MM N F @NJLN0 Me CI Cl IC50= 20 HM H0801 I H EC50 = 45 nM Not Done Not Done \ N Emax = 3915 N CI |VIE‘N@NJLN0 Me Cl CI IC50= 99 HM H0802 I H EC50 =153 nM Not Done Not Done \ N Emax = 4149 N CN Me U\ 0 Me CI NJKN Cl IC50= 171 nM H0803 |\|/|e H Eli/1150 = 149 Not Done Not Done I N/)\N/\\ E = 2364 \\/N 2015/019112 MEN@NJLN0 Me Cl Cl IC50= 375 nM H0804 |\|/|e \ N Eli/1150 = 263 Not Done Not Done | NAN E — 2740 M _ 6 max Mew 0 Me CI JL CI N N IC50— 4 HM_ H0805 |\|/|e H EC50 = 9 nM Not Done Not Done | j: Emax = 5433 N/ m” MewCL 1L0 Me CI 6 1650:1264 N fl EC50 = 6.8 H0806 Me Not Done Not Done \ N HM l E = 5751 N/ NMe MEN 0 Me CI JL CI N N IC50= 14 nM H0807 H Me EC50 = 24 nM Not Done Not Done \ N 0 | Emax = 3669 N MW Me‘N 0 Me CI JL CI N N IC50— 65 HM_ H0854 [\l/le H EC50 =24 nM Not Done Not Done l E = 3246 Me O\ 0 Me CI NJLN Cl IC50= 644 nM H0813 |\|/|e \ N Eli/1150 = 528 Not Done Not Done / Emax = 1605 M9 “CL\ '}‘ fl IC50= 926 nM H0814 Me \ N EC50 = 15 nM Not Done Not Done I NAN/Yo Emax = 1097 K/N\Et 2015/019112 IC50= 695 HM H0703 Not Done Not Done EC50 >30 HM 1C”: 676 “M H0709 I H Not Done Not Done O\Me EC50 >30 “M | NA 0 Me CI NJLN CI IC50: 11~ M I M H0584 H Not Done Not Done Me EC50 >30 HM | N) o 0 Me CI N N IC5°='42 M H0586 I “ H NtD0 0116 NtD0 0116 Me EC50=63 MM | N) F 0 Me CI N N IC >30 M H0587 50 H I H Not Done Not Done Me EC50 >30 “M | N) MeJLU JOL Me Cl 0' IC >30 HM H0588 N N 50 N tD0 0116 N tD0 0116 |\|/|e H EC50>30 MM | )N MEN 0 Me Cl NJkN CIOMe IC50——274 nM H0663 |\|/|e H Not Done Not Done EC50 >30 HM | NXOMe WO 34839 Me\ O OH N 0 CI IC50=32 nM PoorH H0620 OxNJLN NOtDone CI EC50>30 MM Poor M I H | NJ Me‘N 0 Me CI H0624 I H EC50 >30 HM Not Done Not Done | N) Me\ O O aM N O NJLN CI IC50= >1 MM H0662 M H EC50 >30 HM Not Done Not Done I N» Me\NQ JL OH 1C”: 523 N N “M H0670 “I” e H N tD0 one N tD0 one EC50 >30 MM N 0 CI NJLN CI 1c50>1 pM H0673 I H EC50 >30 HM Not Done Not Done | N» N 0 JL CI IC50= 3.6 MM H0727 N N EC50 >30 HM Not Done Not Done Me U\ 0 CN CI NJLN CI IC50 = 719 H0631 M H nM Not Done Not Done \N EC50>30 MM | NJ Medium H inhibition at IC = 14 nM H0686 | H High M 2h and 4h (10 Me EC50 >30 “M \ N ) | g PO: NSE Me‘N 0 Me CI I}! N IC50= 13 nM High H inhibition at H0619 Me N\ EC50 = 39 nM High M 1 and 2 h (10 Nl / mg/kg) IV"B‘N 0 Me CI N JLN IC — 279 nM H0768 |\|/|e H Not Done Not Done N\ EC50 >30 HM | W MB‘U 0 Me CI NJLN Cl IC50= 674 HM H0808 Me H N EC5°:19292M Not Done Not Done l H Me\U i 41% Me 0' inhibition at CI 2 h; activity I?! N Me N up to 4h (10 \ mg/kg) / 71% N inhibition at 1C”: 7 “M High H H0700 1113230511” EC50 >30 “M ngh M (Fed, 10 mg/kg) SC: inhib at 1, 2 h N N | H 12% inhib 30 Me = H0816 Not Done | Nj 13%;) >53?) Til/1 rug/kg PO fasted mice 2015/019112 IC50= 94 nM 30 mg/kg PO H0817 EC50 >30 11 Not Done fasted mice M NSE inhibition at 1 h; ”my IC50= 13 nM High H H0722 upt024h EC >30 M Hi h M 50 H g (10 mg/kg) PO: NSE (30 mg/kg) MEN 0 CI | = C H0741 [NAN EEO :SSOHMM Not Done Not Done H 50 H OMe N | J\ Mew 0 CI H0752 NJL” $0130: “11:44 Not Done Not Done ° “ OEt N J\ | Me‘N 0 Me CI NJkN CI IC — 94 11M H0743 | H Not Done Not Done OMe N\ EC50 >30 “M I J Me‘N 0 Me CI NJLN CI IC — 177 nM H0750 (IDEt H Not Done Not Done N\ EC50 >30 HM I J Me‘N 0 Me CI NJLN CI IC50= 13 HM H0756 I H EC50 = 13 nM Not Done Not Done OH N\ Em: 1729 | J inhibition at 1 h; activity CI up to 8h (10 N N OH N IC50= 0.2 nM EngklfiéE I;\ EC50=3nM Hith ‘ H0761 No act1V1ty1n.. .
E = 2907 High M N max fed mice PO: 215% FI increase in fed miceNo ty in fasted mice Mew 0 Cl NJLN CI IC50= 95 nM H0781 5... H N $501231“ Not Done Not Done <s,R) \ max— (single enantiomer) Me U\ 0 Cl NJLN 930/0 C' ECG”—361%_ inhibition at H0782 5... H N E 50:1923 Not Done 1h, activity (SR) max I j up to 24h N/ (10 mg/kg) (single enantiomer) Me H\ M'31 Me CI v. CI High H P0 30 mg/kg H0824 IN fl E50 >333MM= Medium +ANA mice: Me N\ 50 II M NSE I J Me \ M NK v :(1 Me Cl \‘ N N IC=16M50 . H H'hH1g H0890 Not Done “I” H EC50 >30 HM HighM e N\ I J Malt Mejji Me CI MediumH H0858 IN fl EC” :33MM Medium Not Done Me N\ 50 II M I J W0 2015/134839 Me\ Me N o CF3 CI .
K JJ\ H H0865 N N IC =6nM50 LowM Not Done Me H EC50>30 MM MedlumR.
| J Me\U JOL Me 0' MediumH CI Eedlum- N N IC5°=10nM H0825 H N tD0 one N EC50>30 MM MedlumR. \ Me U\ )1 Me Cl Hith )N _ HighM H0826 N Not Done N ;%°_:33MM HighR 50 H Me j MediumD Me \ N 0 Me CI NJLN 6 H0889 Me) H IC50= 6 nM High H NOtDone EC50>30 HM HighM | Nj Me‘N JOL CI J fl E502 H0896 Not Done Not Done N >733N£LM 50 Me \ N N IC50= 35 nM H0827 H H Not Done Not Done N\ EC50 >30 HM I N; IVI‘B‘N 0Me CI NJkN Cl P0 10 mg/kg “he H N IC50= 3nM Hith H0829 LA£A310~06' | j EC50>30 HM HighM NEE}; WO 34839 IC50= 2.2 M H0859 Not Done Not Done EC50 >30 HM Me‘N 0Me Cl JL CI 68% inhib 1 [T] m h P0 10 Me N IC50= 3nM High H H0860 \ . mg/kg + | J EC50 >30 HM ngh M ANA 30 N mg/kg mice |VIE‘N MeO 0 o CI NJLN Cl IC - 2 8 M H0922 50— ~ |\|/|e H Not Done Not Done N EC50 >30 HM I J MEN HO 0 Cl NAN Cl IC - 300 nM H0924 |\|/|e H Not Done Not Done N EC50 >30 HM I J Me \ N o CF3 CI JL .
CI ngh H N N High M | H IC50= 3nM . Not Done H0830 Me N High R I j EC50 >30 MM Medium N/ D IC50= 1.6 “M Medium H H0899 Not Done EC50 >30 HM High M 60% inhib 1 h P0 10 rug/kg + ANA 30 IC50= 3nM Medium H mg/kg fed H0900 EC50 >30 HM HighM mice 91% inhib 1 h P0 30 rug/kg + ANA 30 mg/kg fed mice 26% inhib 1 h P0 30 mg/kg fasted mice 90% inhib 1 h P0 30 mg/kg fed mice N N IC50= 12nM Medium H H0909 k H Not Done N EC50 >30 HM HighM I j/ N 0 Me F NJLN CI 1C — 339nM H0856 |\|/|e H Not Done Not Done N\ EC50 >30 HM I J Me\ 180% u i Me CI increaseZh CI . mice 30 H0837 Me N . P0 10 mg/kg \ EC50 >30 HM HighR | + ANA 30 / High D .
N mg/kg mice. (diasteromeric mixture) a; 1 Me 0' '1] N 1C — 189 M H0861 Me N\ EEO—>30 “M Not Done Not Done I j 50 H (R/S) (single diastereoisomer) Q JL0 Me CI Cl P0 (10 N N | mg/kg) + H $50 :31 M= H0862 Me N\ 316%; M ANA: n0 (R/S) | j 50 H ty in N/ mice (single diastereoisomer) W0 34839 u If I Cl IC =10nM MediumH N N 50 H0857 Not Done I H EC50 >30 HM LOWM Me N\ I J Cl IC =9nM N N 50 H0871 Not Done Not Done I H EC50 >30 HM Me N I J u i C.
CI 1C”= “SHM H0874 N N Not Done Not Done | H EC50 >30 MM Me N I J Me N/fi\ 0 Me CI K/NWAN CI H IC50= 1.5 MM H0853 Me N\ Not Done Not Done EC50 >30 HM I J Mew 0 Me CI NJkN CI 1C50—-176 nM H0815 I H Not Done Not Done Me N\ Me EC50 >30 “M N N I H IC50= 1.2 MM H0831 Me N\ EC50>30 MM I 2 Me N Me \ N 0 Me Cl K“‘ NJLN CI IC50= 35 HM H0843 I H EC50=51nM Not Done Not Done Me N\ Emax=1910 I J Me N W0 2015/134839 Mew 0 CI NJLN CI IC50——705 nM H0844 I H Me N\ EC50 >30 “M I 3 Me N MEN 0 Me CI NJLN CI IC — 696 nM H0738 |\|/|e H Not Done Not Done N\ OMe EC50 >30 HM Me‘N 0 Me CI NJLN CI IC — 63 nM H0780 |\|/|e H Not Done Not Done N\ NHZ EC50 >30 HM Mew 0 Me CI JL CI IC50= 855 nM H0786 |'\\H/|e N Not Done Not Done N ERG/150:2” \ 0' | Em=980 Me‘N 0 Me CI NAN CI IC50——75 nM H0791 |\|/|e H Not Done Not Done N\ CI EC50 >30 HM Me \ N 0 Me CI JL PO:NSE N N PO+ANA2 Me N F IC50=4nM Hith inhib in mice, H0795 l j/ EC50 >30 MM High M no ty in N/ rat Me‘N 0 Me CI NJLN Cl P0 10 mg/kg | H . +ANA 30 H0847 N\ F IC5°=2 “M 14?th mg/kg mice | I EC50>30 HM ngh M (S enantiomer) WO 34839 P0 10 mg/kg IC50= 432 nM Medium H + ANA 30 H0848 EC50 >30 HM High M mg/kg mice: Me \ N 0 Et CI NJLN CI IC50: 3 nM Me 1umd‘ H H0863 l\|/|e H Not done N\ F EC50 >30 HM HighM N O CF3 CI NJLN CI IC50: 8nM Me 1umd' H H0908 |\|/|e H Not Done N F EC50 >30 HM High M a; i E‘ 0' N 1C”2 718 “M H0864 I}! Not Done Not Done H EC50 >30 MM Me N F u 1 Me 0' 0' IC = 6 nM Hi h H H0872 N N 50 g Not Done |\|/|e H N F EC50 >30 HM medium M N 0 Me CI JJ\ P0 10 mg/kg N N IC50= 47 nM + ANA 30 H0840 |\|/|e H NOt Done N EC50 >30 MM mg/kg mice: | NSE F N N 0 Me Cl NAN Cl IC50= 125 nM H0910 I H EC50 = 19 nM Not Done Not Done Emax = 1359 IVI‘B‘N Me Cl IC50= 88 HM H0788 CIIZj/CN EC50 = 20 nM Not Done Not Done Emax = 1230 Me‘N Me CI IC50= 284 nM H0789 Cll:j)kOMe EC50 = 26 nM Not Done Not Done Emax = 1137 Me‘N Me CI IC50= 6.2 MM H0760 fifi Not Done Not Done EC50 >30 HM )\fi:[[Me CI IC50= 318 nM H0769 Not Done Not Done EC50 >30 MM Me‘N Me CI IC50= 9 HM H0771 EC50 = 9 nM Not Done Not Done Emax = 4662 NMe2 Mew Me CI IC50= 700 HM H0770 ERG/[5° = 294 Not Done Not Done Emax = 1783 Me‘N Me CI IC50= 376 HM H0828 m Not Done Not Done EC50 >30 HM WO 34839 Me U\ 0 Me CI H0822 Me IC50= 1.2},LM Not Done Not Done | 1 EC50 >30 HM K/N‘Me Me U\ :1 Me 0 N N o | H IC50= 1.2 MM H0850 Me N\ Not Done Not Done EC50 >30 HM I J N N \ | H | IC50= 810 nM H0881 Me N/ Not Done Not Done EC50 >30 HM I Nj IC50= 100 nM H0729 EC50 = 95 nM Not Done Not Done Emax = 2818 IC50= 681 nM H0783 EC50 = 30 nM Not Done Not Done IC50= 21 HM H0793 EC50 = 22 nM Not Done Not Done Emax = 3501 IC50= 826 nM H0796 EC50 = 3 “M Not Done Not Done Emax = 1671 N i Me CI '}‘ M IC50= 29 nM Medium H lnhlbltior} at H0498 Me 1h, act1V1ty EC50 >30 HM Hi h Mg \ \ up to 24h s (30 mg/kg) 0 Me CI Me’N )L CI Medium H N N ICW 4 “M_ H0531 |\|/|e H Poor M Not Done EC50 = 5 HM Poor H Me\ O OH N@NJLN0 CI IC50= 54 nM Medium H0594 Not Done CI EC50 >30 HM M I H N 0 CN CI JL CI IC50= 6 nM Medium H N N H0644 I H EC50 = 28 nM Medium Not Done Me Emax = 2822 M lV'e‘N 0 Me CI 76 A)0 A CI Medium. . h'1b1t10n at. . [i] N in IC50= 3 nM H H0536 H . .
Me 1h, act1V1ty / EC50 >30 HM Medium up to 24 h / M S (30 mg/kg) (racemic mixture) Me\r\O\ i Me CI 65% 0' Medium tion at N N IC50=1nM H 1h (10 H0563 M H e EC50 = 3 nM Medium. / mg/kg) Emax — 2100_ / M (single enantiomer) Me\U it Me 0' IC50= 75 nM H0564 N N EC50 = 124 Not Done Not Done ' H nM / _ R/S Emax — 1987 S / (single enantiomer) W0 2015/134839 2015/019112 Me‘U 0 Me Cl C] IC50= 4 HM 311:3 1:4. H0627 N M EC50 = 1 nM Not Done / Emax = 5289 Me\N O O 0M8 )L CI IC50= 69 nM H0660 N n EC50=180 nM Not Done Not Done / 13max = 2100 S / N O OHCI )L CI IC50= 2 nM H0661 N n EC50=6 nM Not Done Not Done / 13max = 2280 S / N 0 )L CI 1C50 >1 nM H0672 N n EC50 >30 Not Done Not Done / MM 3 / Me‘U 0 Me CI JJ\ 0' N N IC50= 4 nM H0651 |\|/|e H EC50 = 11 nM Not Done Not Done / Emax = 2300 s / Me‘U 0 Me CI NA” CI IC50= 4 nM Medium H H0653 Me EC50 = 9 nM Medium Not Done Emax = 1815 M Me‘U 0 Me CI JL CI N N IC50— 8 HM_ H0668 [\I/le H EC50 = 10 nM Not Done Not Done Emax = 2168 S / Me‘N 0 Me CI JL CI N n IC50= 6 nM High H H0654 Me / EC50 = 10 nM Medium Not Done S / Emax = 2200 M 2015/019112 Me‘U Me CI 1C”: 12 “M Medium H I7r(1)hi)bition at H0655 EC50 >30 Medium 1 h, act1V1ty. .
“M M up to 4 h (10 mg/kg) MaU 62% Me 0' Inhibition at 2 h‘ activity IC50= 5 HM , H0691 EC50 >30 Htgh H Up to 24 h High M (10 mg/kg) HM PO: not active MaU Medium H IC50= 5 nM . Not Done H0728 Medium EC50 >30 HM Me‘N Me CI IC50= 456 nM H0726 EC50 >30 Not Done Not Done NM92 Me‘N Me CI 1C50 >1 0M H0689 EC50 >30 Not Done Not Done |V'e‘N Me CI IC50= 550 nM H0692 % Not Done Not Done EC50 >1 HM W0 34839 Me‘N 0 Me CI JL c1 '?‘ H IC50= 7 nM Medium H H0656 Me / EC50= 15 HM Medium Not Done 8 / Emax = 13 50 M Me‘U 0 Me CI NJLN CI IC50= 7 HM H0652 Me H EC50 = 5 nM Not Done Not Done Em: 1500 Me‘U 0 Me CI NAN 0' IC50= 187 HM H0713 Me H EC50 = 29 nM Not Done Not Done / Emax = 3424 s / Me‘N 0 Me CI JL c1 0 1C50= 3 nM H0688 'fl fl EC50= 12 HM Not Done Not Done / 13max = 3100 s / |V'e‘N 0 Me CI JL CI 0 IC50= 34 MM H0774 I}! m EC50 >30 Not Done Not Done Me 2 / MM 8 / Me‘N 0 Me CI JL CI IC50= 261 HM H0664 N g EC50 >30 Not Done Not Done / MM 3 / N JOL Me CI N N 2 H0535 I 1C” H _34 “M Not Done Not Done Me EC50 — 4 HM HN / Me\0 0 Me CI Med1um. NJLN Cl 1C”: 12 “M H H0499 SSS/1]: ()30 “he H g g EC50>30 HM Medium \ ‘,N M MUJOL Me 0' N N 2 H0693 |\|/|e Fifi? £2150 $950:th Not Done Not Done \ 50 _ \ IN NUOH lV'e‘N i Me CI N N 2 H0694 “he H $50 Not Done Not Done 50 33009 34/1 WOMe MG3‘N JOK CN CI 57% Medium H tion at H0657 'T‘ fl ;%°_:380“MM Poor M 1 h, activity Me 50 H up to 8h (10 mg/kg) Me‘N )1 Me CI 57% Medium H inhibition at N N = H0553 vE)2 H EC” >733MM PoorM 1h, activity 50 “ up to 4h (10 HO mg/kg) Me‘N JoL Me CI 'fl fl IC50= 64 nM H0842 Me EC50 = 67 nM Not Done Not Done Emax = 1411 lVIe‘N 0 Me CI N N IC50= 18 nM High H H0542 Me H EC50 =15 nM High M Not Done \ \> Mew 0 Me CI N N IC50= 9 nM High H H0568 Not Done I\I/|e H EC50 24 nM High M \ ‘> Me‘N 0 Me CI JL CI IC50= 3 HM H0794 'T‘ fl EC50 =10 nM Not Done Not Done “'9 Emax = 4435 \ \>’NH2 W0 34839 PCT/U82015/019112 Me\U :1 Me 0' P0 10 mg/kg IC5°=118nM H0841 '?‘ H Not Done +ANAM. 39 Me N EC50 >30 MM mg/kg mlce.
\ M NSE |V'e‘N 0 Me CI JL CI IC50= 16 l’lM H0792 El fl EC50 =7 nM Not Done Not Done 6 3 EM: 1096 \ />’NH2 |V'e‘N i Me CI CI MediumH 1C”= 87 “M H0569 '3 N Medium Not Done Me N EC50 >30 “M \ ‘> Me‘N JOL Me Cl 0' IC50=28 nM Hi hH N N g H0565 Not Done Me (Kg EC50=30 HM High M N’ o \§/N Me‘N JOL Me CI CI .
N N IC50=12 nM ngh H H0604 [\l/Ie H Not Done EC50 =25 nM High M N=NI Me‘N 0 Me CI NJLN CI IC 28 M I 50: n H0595 H Not Done Not Done Me EC50 =43 nM \ O) N~N/ Me‘N 0 Me CI JL CI '?‘ IC50=9 nM Hith NSE(10 H0596 M ““9 \QN Ecjo=3 nM High M mg/kg) [T] ” IC50=11 l’lM H0851 Me 0‘ EC50 =6 nM Not Done Not Done \ N Emax=3320 W0 2015/134839 2015/019112 Me\“CL )1 Me 6' N H Q) 1C”: ”HM Poor H H0537 Not Done \ EC50 >30 HM Poor M \ N MeOZC 3 )1 Me CI Me’ CI N N IC50= 12 nM Medium H.
H0529 NI/Ie H Not Done EC50 >30 HM Poor M \ \N Mew Meo Me CI CI Medium H '3 M 1C”2 34 “M H0528 Medium Not Done Me EC50 >30 HM \ \N lV'e‘N 0 Me CI N N | IC50= 13 l’lM ngh H H0501 H Me Not Done \ EC50 = 22 nM High M \ N |V'e‘N 0 Me CI N N IC50= 8 HM ngh H.
H0507 Me H Not Done EC50 =12 nM High M N 0 Me CI NAN CI High H IC = 4 nM I Medium H0665 H 50 Me Not Done EC50 =8 nM M CI Medium H N N IC50= 76 HM H0508 .
Me H O ngh M Not Done EC50 >30 HM N i Me CI 66% inhib 1 CI IC50= 29 nM . h; activity up H0509 '3 N O EC50 =2 MM Egg; t0 2h Me g O Emax = 1790 (10 mg/kg) \V()2015n34839 PC17U82015flH9112 Me‘T:::1\ ,fiL Me CI 35%fi. . 1nh1b1t10n at H0510 I?! M 1(:50: 14 HM Egg £14 4 h, ty Me 0Nrb Ecg0>30 061 upt024h(30 mg/kg) Me‘T:::l\ /fi\ Me CI Cl IC =24nM N N 50 Not Done Not Done H0606 M H O EC50 :31 nM 9 OM D e Emax = 2336 CI IC50= 20 nM N N O Not Done Not Done H0810 EC50 =22nM Me F O Emax = 2339 Me‘N 0 Me CI NJLN e | H Ill: IC50= 120 nM Not Done Not Done H0669 M6 0 0H EC50 >30 MM Me‘N 0 Me CI NJLN C' 1c50: 2 3~ MM H0611 Me H O N“ Done NOt Done 0 EC50 > 30 Me‘N 0 Me CI JL CI N m IC50= 1.6 MM H0612 Me CONH2 EC50 > 30 Not Done Not Done 0 1M Me‘N /fi\ Me CI M N IC50= 107 nM High H H0615 Me EC50 > 30 Medium Not Done 0 M M CONH2 Me‘N Me CI CI IC50= 149 nM H0809 NO ° 2217 Not Done Not Done 0 Emax = 23 39 Me‘N Me Cl IC50= 171 HM H0699 EC50 > 30 Not Done Not Done Me\@N/Ieo Me CI Medium JLN CI IC50= 6 nM H H0607 EC50 =31 nM Medium ES/igog g Emax = 3000 M IV'eN Me Cl IC50= 78 HM H0695 my Not Done Not DOUG EC50 =5 nM lV'e‘N@N/EHKCEENj/COZMeMe CI IC50= 1 MM H0635 Not Done Not Done EC50 > 30 MM |V'e‘N Me CI IC50= 980 HM H0690 fifj/K Not Done Not Done EC50 > 30 MM Me‘N Me Cl IC50= 209 nM H0735 :Nilj EC50 > 30 Not Done Not Done 2015/019112 MOLE” 0' 0 IC50= 216 nM H0746 I Not Done Not Done / EC50 > 30 MM H0747 M0351” IC50= 84 nM I / Not Done Not Done EC50 > 30 MM N\ IC50= 554 nM H0748 MMMCLILJOLN I N Not Done Not Done / EC50 > 30 MM CI IC50= 61HM H0765 EC50 =137 nM Not Done Not Done \ Emax = 2810 IC50= 171nM H0766 \ NO2 Not Done Not Done EC50 > 30 MM Me‘@kfiLm Me CI 1C”: 69 “M H0608 Not Done Not Done EC50 =422 nM / Le N 0 Me Me‘OkfiL” Me CI 1C”: 132 “M H0616 Not Done Not Done EC50 =580 nM N CN WO 34839 lVIe‘N Me CI IC50= 40 HM H0618 Not Done Not Done EC50 2130 nM |V'e‘N Me CI IC50= 71 nM Medium H H0623 Not Done EC50 >30 HM Poor M JK CI 0 Medium H IC50= 101 nM H0610 .
CN EC50 >30 HM fiedmm Not Done lV'e‘N Me CI IC50= 19 HM H0517 Not Done Me O Not Done I EC50 >30 HM N N IC50= 841 nM H0518 O Not Done Not Done EC50 >30 HM NM92 N Me CI JL CI H0512 ‘ 50: 495 M1’1 Me 0 Not Done Not Done NMe EC50 >30 HM Me‘N Me CI JL CI O ’N IC50: 544 Mn H0513 \ Not Done Not Done Me NH EC50 >30 HM N Me Cl Medium H IC50= 16 HM H0514 .
Me Medlum Not Done \ EC50 2 38nM | \ M WO 34839 lVIe‘N Me CI IC50= 40 HM H0515 EC50 = 885 Not Done 0\ nM lV'e‘N Me CI IC50= 202 nM H0520 Not Done Not Done Me O EC50 =394nM WU JLN IC50= 12 MM H0787 Not Done Not Done EC50 2 3 HM HN\q N Me JL IC50= 15 nM Medium H H0582 EC50 = 20 nM Medium Me Emax = 2069 M \ / N Me IC50= 154 nM H0571 Not Done Me EC50 >30 HM M6 ”CL\ N IC50= 31 HM H0605 Me F EC50 = 96 nM Not Done Not Done 0 Emax = 1833 N Me JL ICso= 36 nM 31:31:11 PO: NSE (30 H0573 N O u EC50 >30 uM mg/kg) N Me JL IC50=67 nM Medium H H0574 O EC50 =81 nM Medium Not Done Me Emax = 2489 M WO 34839 PCT/U82015/019112 IC50= 32 nM Medium H H0575 we EC50 = 28 nM Medium Not Done 8 Emax = 3533 M \ / NJL “”0 IC50= 180 l’lM H0576 le NO Not Done Not Done EC50 >30 HM \ 3N MG‘NCLFAEON “”0 IC50= 233 nM H0577 NO Not Done Not Done \ EC50 >30 HM WQE: NNIeO Medium H IC50= 11 HM H0591 ONH2 EC50 =126 nM fiedium. Not Done Me\”CL ii Me 0 N N IC =24nM PoorH I 50 H0597 H O N“ Done Me s EC50 >30 uM Poor M \ /> Me\0 ii Me O N N IC50= 63 nM H0598 |\I/|e H O Not Done Not Done EC50 2271 nM Me\0 ii Me O N N IC50= 212 nM H0599 |\I/|e H O H Not Done Not Done EC50 =478 nM \ /> WO 34839 N 0 Me JL IC50= 35 HM N N H0790 M H O EC50 =32 nM Not Done Not Done CN Emax = 2810 NQ JLO M9 CI 1050: 12 nM Medium H H0381 N EC50 >30 Medium IF: NO effect ' H Me NJfiC' MM M Me U\ jji Me CI M6 mmd’ H CI IC50= 3 HM H0519 .
N N EC50 2 6 nM fiedlum Me \ N 0 CN CI JL IC50= 3 HM H0629 N N EC50 = 1 nM Not Done Not Done ' H Emax = 5075 N 0 CN CI JL IC50= 6 HM H0658 r N N EC50 = 9 nM Not Done Not Done Me H Emax = 2400 N 0 CN CI JL IC50= 1 HM H0669 N N EC50 = 5 nM Not Done Not Done Me H Emax = 4961 Me\U IC50= 34 nM H0671 iMe CN CI CI N N EC50 = 60 nM Not Done Not Done Me H Emax = 3748 Me\ O NH2 N O 0' IC50=390 nM H0659 NJLN Br EC50 =353 nM Not Done Not Done M H Emax = 200 H0521 CI IC50= 20 HM N N Not Done Not Done EC50 2 19 nM cone 2015/019112 Mxemf]: Me CI H0602 w IC50=8 HM Not Done Not Done Me EC50 >30 MM inhibition at 1 h, activity up to 24 h (0.1mpk), inhibition at 1 h; activity IC50=2 HM High H up to 24 hrs H0603 EC50 >30 HM High M (lmpk), 34% inhibition at 1 h, activity up to 4h (10mpk); Inhibition in fed mice after ANAM PO- SC NSE Inhib up to High H IC50=5 HM 2h (10 H0677 Medium \ EC50 >30 MM mg/kg) R/S \CH PO: NSE (single omer) CI inhibition at N N Medium H IC50=55 HM 1 h, activity H0678 MeH| Medium EC50 >30 “M up to 24h (10 \ CH R/S mg/kg).
PO: no effect (single enantiomer) Me‘U 0 Me CI H0832 NJL IC50=11 HM .u EC50 >30 HM IC50=22 HM H0852 EC50 =18 HM Not Done Not Done Emax = 1683 WO 34839 Me‘U Me CI IC50=20 nM Low H H0701 qfimo Not Done EC50 >30 HM LOW M Me N\ Me CI IC50= 95 HM H0733 m Not Done Not Done EC50 >30 HM Me‘N Me CI IC50=12 HM H0755 EC50 =10 nM Not Done Not Done Emax = 2196 IV'e‘N Me CI IC50= 159 nM EC” = H0757 Not Done Not Done 654nM Emax = 2704 lV'e‘N Me CI IC50= 202 nM H0734 K Not Done Not Done EC50 >30 HM Me‘N Me CI 75% inhibition at IC50= 13 nM High H 1 h, activity H0737 EC50 >30 MM High M up to 4 h (10 mg/kg) PO: NSE |VIe\N Me CI IC50= 74 HM H0775 % Not Done Not Done EC50 >5 HM lV'e‘N Me CI IC50= 120 nM H0776 % Not Done Not Done EC50 >4 HM MG‘U Me CI 1C50= 429 nM H0779 Not Done Not Done EC50 2 4 HM Mam 93% M9 0' inhibition at 1C50= 5 nM ngh H. ’ activity H0762 . up to 4 h (10 EC50 >30 HM H1 h Mg mg/kg) PO mice and rat: NSEt MeN 91% Me CI inhibition at 1 Elisa?" 1050: 6 nM High H H0751 EC50 = 62 nM High M (10 mg/kg) E = 1267 max PO mice and rat (+ANA): no effect IV'e‘N Me CI 1C50= 835 H0763 N0t Done N0t Done EC50 >30 Me\l\O\ Me CI 85% inhibition at 1C50= 7 nM . 1 hr, activity H0759 EC50 >30 HM 3gb H up to 8 h (10 1gh M mg/kg) PO: no effect IVIe‘N 0 Me CI NJLN CI 1C50= 33 nM H0785 |\|/|e H EC50 = 90 nM Not Done Not Done § \ Emax = 2869 |V'e‘N 0 Me CI 74%. .
JJ\ 1nh1b1t10n at 'i“ M 1 h; activity Me 1C50= 11 nM . up to 24h (10 H0754 % S EC50 >30 HM 31gb H ) | 1gh M P0 d an N / PO+ANAM: no effect Mam i Me Cl N N I H IC50= 60 nM H0753 Me Not Done Not Done % EC50 >30 HM | N/) N JOL Me CI N N H0609 the H O 1C”2517 “M Not Done Not Done % EC50 >30 MM Me\O 91% JOL Me C' inhibition at Cl 1 h, activity N N ' H up to 24 h % (10 mg/kg) P0: 70% inhibition at 2 h (30 _ rug/kg), 0 HM High H. . . act1V1ty up to H0764 EC50 = 14 nM HighM 24h E 21352 max PO+ANAM: inhib up to SC: 53% inhibition at 1h; (30 mg/kg) CI 0 . .
H0818 Me EC50 = 3.5 nM Not Done ’ g g § PO fasted E = 1915 (SIR) max mice sin1e enantiomer) Me‘N 0 Me CI JL on N N IC50=65 nM 30 mg/kg PO H0819 Me EC50 =140 nM Not Done fasted mice \ Emax = 141 9 N ES (SIR) (single enantiomer) W0 2015/134839 {11 0 Me Cl 205% NJLN Cl increase at IC5°=4 “M 2h activity H0838 M H EC50 =21 nM Not Done ’ e upt08h,30 \ E 21340 \ max mg/kg PO mice (diastereoisomer e) Me \ N 0 Me F NJJ\N CI IC50:256 Mn H0855 I H Not Done Not Done Me EC50 >30 HM Me \ N 0 Me CI NJLN CI \ IC 197 M l 50: n H0884 I H Not Done Not Done Me N/ \ EC50 >30 HM Me‘U 0 Me CI N JJ\N IC50=36 nM H0811 |\|/|e H EC50 = 95 nM Not Done Not Done § Emax = 1320 Me‘U 0 Me c1 NJKN 0' IC50=1.2 11M H0812 “he H (\N'Me EC50 =1.5 11M Not Done Not Done % Nd Emax = 871 Mew 0 CI 1050: 7 nM H0740 JL CI EC50 = 1.5 nM Not Done Not Done '1‘ N Emax = 3620 Me‘N 0 Me CI H0742 NJLN Cl 1C”: 54 “M Not Done Not Done (5M6 H EC50 >30 MM Me‘N 0 Me CI JL IC50= 57 HM H0745 N N EC50 = 97 nM Not Done Not Done (5H H Emax = 2391 Me\U i Me CI IC50= 111 nM CI EC50 = H0749 N M Not Done Not Done 39711M OEt Emax = 1554 Me \ N 0 CI 1050: 33 nM H0744 JL CI EC50 = 45 nM Not Done Not Done N fl Emax = 3536 N 0 Me CI )L CI IC50= 4 nM H0626 I}! N EC50 = 15 nM Not Done Not Done Me / Emax = 3835 Me‘N 0 0 Me CI 384’. . i t10n at N N . 1 h activity ’ . H IC50= 37 nM ngh H H0767 Me / s up to 4 h (10 EC50 >30 HM High M \ / rug/kg) PO: NSE Mew 0 Me CI NJLN CI IC50= 3 nM H0772 l\|/Ie H EC50 = 7 nM Not Done Not Done N Emax = 3569 H \ / N N IC50= 608 l’lM H0773 |\|/|e H H Not Done N0t Done S EC50 >30 HM lV'e‘N 0 Me CI NANJUCI 0 IC — 529 nM \ 50— H0784 | H Me NJLNQ Not Done Not Done EC50 >30 HM H H NQJOL M6 CI IC50= 715 nM I?! M S EC50 = 600 H0777 \ Not Done Not Done Me \ N Emax = 2288 W0 34839 PCT/U82015/019112 N@JOL M6 CI IC50= 170 nM H0846 N N 518150: 130 Not Done Not Done Me A N Emax=3815 N 0 Me CI )L Cl IC50= 91 nM H0875 N N EC50=50 nM Not Done Not Done Me o/A Em=3751 N i Me 0' IC50= 5911M C I EC” 2 101 H0628 I}! N Not Done Not Done H HM Me Me Emax=4433 Me\N )1 Me CI IC =3nM Cl 50 .
H0630 N N EC50=9nM 311831114 Not Done Me CN Emax=4714 N )1 Me CI CI IC50= 3 HM ngh H H0633 N] M Not Done EC50=15 nM High M Me OH CI IC50= 13 l’lM H0634 [T] N Not Done Not Done EC50=37 nM CH2F Me e N Me CI H0640 )3 IC =103nM CI 50 Not done Not done IT] ”Av EC50 >30 HM N it 'V'e 0' IC50=133 nM C I EC” 2 287 H0645 N M Not done Not done Me HM Emax=2761 N :1 'V'e 0' IC50= 18 nM H0641 N Mm EC50=35 nM Not Done Not Done ' H Me / Em: 1690 COZMe 2015/019112 Me\U JOL Me CI IC50= 96nM CI EC” = 1'1 H0702 N m Not Done Not Done COMe Emax = 1940 Me\U 0 Me Cl IC50= 22 nM H0643 NJLN Cl EC50 = 83 nM Not done Not Done “l” H Emax = 2660 e OH Me\Q30 Me 0' JLN IC50=201 nM H0522 mm EC50 =200 Not Done Not Done CON H2 Me\@ZMO Me Cl H0523 JLNHm IC50=668 nM N tD0 one N tD0 one EC50 >30 MM CI IC50=130 nM H0876 Ii] M \ N tD0 one N tD0 one I EC50>30 MM *1\ SE: No significant effect.
Example C Effect of Ghrelin nists 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 . The animal model used was developed to explore the combination of food restriction and stress. Results sed below show that female rats ted 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, confirmed its inhibitory effect in this procedure. Moreover, results show that, after acute administration, H0900, H0816, and H0847, reduced binge eating es showed in R + S group. H0860, at the considered doses, did not significantly reduce HPF intake in animals exposed to the same procedure.
Animals and Housing: A total ofN = 117, 52-day-old 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 cm><30 cm; the cage is 30 cm high. A front door (30 cm><20 cm) made of metallic grid was oned 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 ng e.
Rats were kept in a room at constant temperature °C) and humidity (45-55%) under a 12-h light/dark cycle (lights on at 08:00 am) with ad lib chow and water.
All procedures were conducted in adherence to the European Community Directive for Care and Use of Laboratory Animals.
Diets: Rats were offered food pellets, 4RF18, Mucedola, Settimo Milanese, Italy (2.6 kcal/g).
The Highly Palatable Food (HPF) was prepared by : a) Nutella Ferrero chocolate cream (5.33 kcal/g; 56%, 31% and 7%, respectively, from carbohydrate, fat and protein): 52 % b) grounded food pellets 4RF18, Mucedola, o Milanese, Italy: 33 % c) water: 15 % Experimental : The rats were weight-matched into one of two groups so there was no significant difference 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 hout the 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; b) the second group (R + S) had chow restricted to 66% of the normal intake for 4 days, was d 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 s did not have 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 deficit.
Body weights and food intake were recorded daily. Food intake is expressed as mean lories per kilogram ingested :: SEM.
On the test day (day 25) the animals were diVided in the following groups as shown in Table 2: Table 2 N0. of Animals Procedure Treatment 8 NR NS Vehicle 9 R S Vehicle 9 R S H0816 3 mg/kg 9 R S H0816 30 mg/kg 9 R S H0860 3 mg/kg 9 R S H0860 30 mg/kg 9 R S H0847 3 mg/kg 9 H0847 30 mg/kg 9 H0900 3 mg/kg 9 H0900 30 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 all the other three phase of the ovarian cycle they t BE without significant differences in intensity.
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 experimenter 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 y 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, and is able to smell its odour. In this 15-min period, the rat engages in repeated nts of the forepaws, head, and trunk aimed at obtaining the HPF, but it is not able to reach it. Rats undergo the ful procedure n 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 Preparation: 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 salt (CMC, Sigma-Aldrich 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. e was composed by a solution of 0.5% ymethyl cellulose sodium salt and was ed 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 active principles) were stered by gayage in a volume of 4 ml/kg of body weight one hour before access to HPF.
Data Analysis: All data are expressed as the mean :: s.e.m. and each value reflects the mean number of animals per group as described in the legends. For data evaluation, the analysis of variance WO 34839 (ANOVA) was used followed by post-hoc (Bonferroni’s) test when appropriate. Statistical significance 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 difference in 2-h HPF intake in the 2 groups of rats ing vehicle administration [F(1,12) = 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 l (NR + NS) group. HPF intake of R + S rats was very pronounced in the first 15 min of access to HPF; these animals never engaged in competing behaviours, but continuously remained over the cup ning 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 difference in 2-h HPF intake in the R + S rats treated with Topiramate at the dose of 60 mg/kg [F(1,11) = 16.2; P < 0.01]. As shown in Figure 2, post- hoc isons revealed that the effect of Topiramate was tically significant at all time points for the whole period in which BE was exhibited.
Effect of H0816 on Binge Eating: The ANOVA revealed a significant difference in 2-h HPF intake in the R + S rats treated with H0816 at the doses of3 and 30 mg/kg [F(2,19) = 3.9; P < 0.05]. As shown in Figure 3, post- hoc 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 animals' 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].
Effect of H0847 0n Binge Eating: The ANOVA revealed a significant ence in 2-h HPF intake in the R + S rats treated with H0847 at the doses of3 and 30 mg/kg [F(2,19) = 8.7; P < 0.01]. As shown in Figure 5, post- hoc comparisons revealed that the effect of H0847 (3 mg/kg) was statistically significant at 15, and 60 min after HPF access. At the dose of 30 mg/kg, H0847 significantly (P < 0.01) reduced HPF intake at all time points for the whole period in which BE was exhibited. Two animals treated with H0847 (3 mg/kg) and one animal treated with the dose of 30 mg/kg showed a mild sedation during the 2-h test.
Effect of H0900 0n Binge : The ANOVA revealed a significant difference 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 all time points for the whole period in which BE was exhibited.
H0900 treatment (both doses) did not affect animals' gross behaviour during the 2-h test.
Effect of Topiramate, H0816, H0860, H0847H0900 and Vehicle 0n 2-h Chow Food Intake During Binge Eating Test: Statistical analysis ted that acute administration of Topiramate [F(1,11) = 0.9; P > 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 . 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 stration of Topiramate [F(1,11) = 0.00; P > 0.05] or H0816 [F(2,19) = 1.2; P > 0.05] or H0900 [F(2,18) = 2.7; P > 0.05] did not modify 24-h 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 .
Effect of H0816 on Binge Eating (Second test): To confirm the effect of H0816 on BE, a second test was med after ten days.
Of 117 animals 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, s R + S group had 4 days chow restricted to 66% of the normal intake followed by 4 days of chow ad libitum. In this additional cycle, all groups did not have 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 e were administered by gavage 1-h before access to HPF.
The ANOVA revealed a highly significant difference in 2-h HPF intake in the 2 groups of rats following vehicle administration [F(1,12) = 28.1; P < 0.01]. Cumulative HPF intake in the R + S group was icantly higher than in controls up to 120 min after access to it (data not shown).
Statistical analysis showed a significant difference in 2-h HPF intake in the R + S rats treated with Topiramate at the dose of 60 mg/kg [F(1,12) = 47.1; P < 0.01]. Post-hoc comparisons revealed that the effect of Topiramate was statistically significant at all time points, that is for the whole period in which BE was exhibited (data not shown).
The ANOVA revealed a cant difference 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 cant (P < 0.05) at 15 min time point and the dose of 30 mg/kg completely blocked (P < 0.01) the BE episode at 15 min. H0816 treatment (both doses) did not affect animals' gross behaviour during the 2-h test. Statistical analysis indicated that acute administration of Topiramate 2) = 2.3; P > 0.05] or H0816 [F(3,25) = 0.2; P > 0.05] did not modify 2-h and 24-h ([F(1,12) = 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 episode at the dose of 60 mg/kg. In the same experiment, H0900, H0816, and H0847 significantly reduced BE behaviour in the R + S group, after acute administration, confirming the therapeutic potential of ive GHS-Rla antagonism in binge eaters.
In a second experiment, H0816 conf1rmed, dose dependently, its selective 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 animals, suggesting a not clean e as GHS-Rla antagonist.
Example D Characterizing the Effect of Compounds of Formula (I) on Operant Ethanol Self- Administration in Marchigian Sardinian alcohol-preferring (msP) Rats In this experiment, msP- rats (N=24) were trained to self-administer 10% (v/v) ethanol solution in 30-min daily sessions under a fixed-ratio 1 schedule of reinforcement in which each response resulted in delivery of 0.1mL 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 ures for three consecutive days (pre-treatment phase) during which they received drug vehicle. At this point animals were tested for the effect of ghrelin nists on 10% (v/v) l 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, animals were left in their home cages for several days, in order to wash out the drugs. Then, the same rats were ed to test the remaining ghrelin 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 mental procedures described for the previous drugs .
All the drugs (or vehicles) were administered orally 1 hour before the beginning of the operant session. Responses at the lever activated the delivery mechanism but did not result in the delivery of alcohol.
Animals and Housing: Male genetically selected l-preferring Marchigian ian (msP) rats were used (N=24). At the time of the experiments their body weight ranged between 350 and 400 g. They were housed 4 per cages in a room with a reverse 12:12 h light/dark cycle (lights off at 9:30 am), temperature of 20-220C and humidity of 45 -55%. Rats were offered free access to tap water and food pellets (4RF18, Mucedola, Settimo Milanese, Italy). All the procedures were conducted in nce with the European Community Council Directive for Care and Use of Laboratory Animals and the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Compound Preparation: 75 mg of each H0900 and H0860 were accurately weighed and suspended in 10 ml of 0.5% carboxymethyl cellulose sodium salt solution (CMC, Sigma-Aldrich Cat. C4888, lot 120M0216V). The lower dose solution was prepared by dilution of 30 mg/ml suspension with 0.5% CMC solution. 37.5 mg of H0816 were accurately weighed and suspended in 15 ml of 0.5% carboxymethyl cellulose sodium salt solution (CMC, Sigma-Aldrich Cat. C4888, lot 16V). The lower dose on was prepared by dilution of mg/ml sion with 0.5% CMC solution. 11.25 mg of H0847 were accurately weighed and ded in 15 ml of 0.5% ymethyl cellulose sodium salt solution (CMC, Sigma-Aldrich Cat. C4888, lot 16V). The lower dose on 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 salt and was prepared by dissolving 1 g 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) ethanol solution was prepared every two days by diluting 95% (v/v) ethanol solution (F.L. CARSETTI s.n.c - CAMERINO) in drinkable water.
Equipment: The self-administration stations consisted of operant ioning chambers (Med Associate, Inc) enclosed in sound-attenuating, ated environmental cubicles. Each chamber was equipped with a drinking reservoir (volume capacity: 0.2 ) positioned 4 cm above the grid floor in the centre of the front panel of the chamber, two retractable levers located 3 cm (one to the right and the other to the left) of the drinking receptacle and a white cue 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 result in activation of the pump.
Activation of the pump resulted in a delivery of 0.1ml of fluid. If a time out was programmed, lever presses during this period were d but did not lead to further infusions. An IBM- 2015/019112 compatible computer controlled the delivery of fluids (activation of syringe pump), presentation of Visual stimuli and ing of the behavioral data.
Experimental procedures: Using operant self-administration chambers (Med Associates), msP rats were trained to lever press for 10% alcohol (V/V) until stable baseline of responding were achieved. 16 self- administration training sessions were carried out to train the animals. Operant 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 red.
After stable baseline of alcohol self-administration was established, msP rats were administered with e or the inventive compounds at 2 different doses using a within subject design. Active and inactive lever ding was monitored: drugs were injected prior to the beginning of the self-administration session, ing to indication.
The reinforcement program was FR1-LITO (Fixed Ratio - 1 Light Time Out). During the seconds time out (following the rced RR) a house light was switched on. The tests were conducted according to a within subject design where drug ent (doses) was treated as ed factors. Total number of active and inactive lever responding were ted to statistical evaluation. 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. tical significance was set at p<0.05.
As shown in Figure 9, H0847 had no effect on operant responding for alcohol [F(2,11) = 0.53; p>0.05]. Responses at the inactive control lever were not modified [F(2,11) = 0.53; p>0.05].
As shown in Figure 10, H0860 significantly d operant responding for alcohol [F(2,11) = 4.19; p<0.05]. Post hoc analysis revealed a cant reduction of alcohol self- administration following treatment with the higher dose (30 mg/kg) (*p<0.05). Responses at the inactive control lever were not modified [F(2,11) = 0.15; p>0.05].
As shown in Figure 11, H0816 had no effect on operant responding for alcohol [F(2,11) = 0.75; p>0.05]. Responses at the ve control lever were not d [F(2,11) = 0.30; p>0.05].
As shown in Figure 12, H0900 cantly reduced operant responding for alcohol [F(2,11) = 8.62; p< 0.01].Post hoc analysis revealed a significant reduction of alcohol self- 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 stration of both H0900 and H0860 induced a statistically significant decrease in l self-administration. For H0900, the effect was seen for both the doses tested (3 and 30 mg/kg). For H0860, only the higher dose (30 mg/kg) reduced ethanol 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 ethanol responses.

Claims (26)

1. A compound of Formula I: (R8)s O R3 R4 Z (R7)n r N N R1 R2 X R5 5 I, or a pharmaceutically acceptable salt thereof, wherein: a dashed line indicates an optional bond; X is CH; Z is NR9; 10 R1 is H, C1-6 alkyl, benzyl, OH, or C1-6 alkoxy, wherein said C1-6 alkyl, , or C1-6 alkoxy is not substituted or substituted with 1-3 substituents selected from halo, OH, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, CO(C1-6 alkyl), CHO, CO2H, CO2(C1-6 , and C1-6 haloalkyl; R2 is H; 15 R3 and R4 are each, ndently, H, CN, halo, CHO, CO2H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkylcycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, CO(C1-6 alkyl), CO2(C1-6 alkyl), or CONR12R13; or R3 and R4 taken together with the C atom to which they are attached form a 3 membered ring; 20 R5 is pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl or C2-6 alkynyl, each not substituted or substituted with 1-3 substituents selected from halo, CN, OH, NO2, Si(CH3)4, CHO, and CO2H, or 6 alkyl), CO2(C1-6 alkyl), 5, NHCONR14R15, CONR14R15, CH=NOH, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-6 l, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; 25 R6 is H; R7 is halo; R8 is methyl; R9 is H, C1-6 alkyl, CO(C1-6 , CHO, CO2H, or CO2(C1-6 ; R12 and R13 are each, independently, H or C1-6 alkyl; R14 and R15 are each, ndently H, C1-6 alkyl, CO(C1-6 , CO(heteroaryl), 5 heteroaryl, or cycloalkyl; r is 2; s is 0-4; and n is 0-3. 10
2. The compound of claim 1, wherein Z is N(C1-6 alkyl).
3. The compound of claim 1, n Z is NCH3.
4. The compound of claim 1, wherein R1 is CH3, methoxy, ethoxy or propoxy; or R1 benzyl optionally substituted with CO2(C1-6 alkyl) or C1-6 hydroxyalkyl. 15
5. The compound of claim 1, wherein R3 and R4 are each, independently selected from C1-6 alkyl, CN, C1-6 alkylcycloalkyl, C1-6 hydroxyalkyl, CO2(C1-6 alkyl), C1-6 haloalkyl and CONH2.
6. The compound of claim 5, wherein said C1-6 alkyl is methyl or ethyl.
7. The compound of claim 5, wherein said C1-6 alkylcycloalkyl is C1 alkylcylopropyl. 20
8. The compound of claim 5, wherein said C1-6 hydroxyalkyl is C1 hydroxyalkyl optionally substituted with a substituted or unsubstituted benzyl group.
9. The compound of claim 5, wherein said CO2(C1-6 alkyl) is CO2CH3.
10. The compound of claim 5, wherein said C1-6 haloalkyl is CF3.
11. The compound of claim 1, wherein R3 and R4 are taken together with the C atom to 25 which they are attached to form a ropyl ring or a tetrahydropyranyl ring.
12. The compound of claim 1 wherein R7 is Cl or F.
13. A compound of claim 1, having Formula II or III: O R3 R4 R7 r N N R1 H X R5 5 or a pharmaceutically acceptable salt thereof, N O R3 R4 R7 N N R1 H or a pharmaceutically acceptable salt thereof. 10
14. A compound of claim 1, selected from the group consisting of: Compound al Structure No.14 and Chemical Name N O Me Cl Cl 3-(1-(2,3-dichloro(pyridin N N H0496 H nyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N methyl 4-((3-(1-(2,3-dichloro(pyridin- H0539 H 3-yl)phenyl)ethyl)(1-methylpiperidin- 4-yl)ureido)methyl)benzoate MeO2C N N O Me Cl 3-(1-(2,3-dichloro(pyridin N N yl)phenyl)ethyl)(4- H0546 H (hydroxymethyl)benzyl)(1- methylpiperidinyl)urea Me Me N O Me Cl Cl 3-(1-(2,3-dichloro(pyridin N N H0527 H nyl)ethyl)(1,3- dimethylpiperidinyl)methylurea N O Me Cl Cl 3-(1-(2,3-dichloro(pyridin H0497 N N H yl)phenyl)ethyl)methyl(1- Me methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(pyridin H0650 N N H yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(5- H0849 H Me cyclopropylpyridinyl)phenyl)ethyl) methyl(1-methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(6-methoxypyridin- N N H0511 H 3-yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N OMe N O Me Cl N N 3-(1-(2,3-dichloro(6- H0820 H Me cyclopropylpyridinyl)phenyl)ethyl) methyl(1-methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(5-cyanopyridin N N H0613 H yl)phenyl)ethyl)methyl(1- Me CN methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(5-fluoropyridin N N H0614 H yl)phenyl)ethyl)methyl(1- Me F methylpiperidinyl)urea N O Me Cl Cl methyl 5-(2,3-dichloro(1-(3-methyl N N H0635 H (1-methylpiperidin Me CO2Me yl)ureido)ethyl)phenyl)nicotinate N O Me Cl 3-(1-(2,3-dichloro(5- N N (hydroxymethyl)pyridin H0636 H Me yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl 3-(1-(2,3-dichloro(5- N N F oromethyl)pyridin H0637 H Me yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(5- H0638 H Me (fluoromethyl)pyridinyl)phenyl)ethyl)- F yl(1-methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(5-methylpyridin H0639 H yl)phenyl)ethyl)methyl(1- Me Me methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(5-formylpyridin H0642 H yl)phenyl)ethyl)methyl(1- O methylpiperidinyl)urea N O Me Cl Cl 3-(1-(4-(5-aminopyridinyl)-2,3- N N H0704 H dichlorophenyl)ethyl)methyl(1- Me NH2 methylpiperidinyl)urea N O Me Cl N N 3-(1-(4-(5-(1H-pyrazolyl)pyridinyl)- H0707 H 2,3-dichlorophenyl)ethyl)methyl(1- Me NH methylpiperidinyl)urea N O Me Cl Cl 3-(1-(4-(5-(1H-imidazolyl)pyridin N N N H0711 H Me NH yl)-2,3-dichlorophenyl)ethyl)methyl (1-methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(5-(thiazol N N S H0716 H yl)pyridinyl)phenyl)ethyl)methyl Me N hylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(5-(thiophen N N S H0717 H idinyl)phenyl)ethyl)methyl (1-methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(5- N N H0718 H cyclopentylpyridinyl)phenyl)ethyl) methyl(1-methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(5-(pyrrolidin N N H0719 H yl)pyridinyl)phenyl)ethyl)methyl Me N (1-methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(5-ethylpyridin H0715 H yl)phenyl)ethyl)methyl(1- Me Et methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(5-vinylpyridin H0706 H yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(5-ethynylpyridin H0710 H yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O CN Cl N N 3-(cyano(2,3-dichloro(5-cyanopyridin- H0666 H 3-yl)phenyl)methyl)methyl(1- Me CN methylpiperidinyl)urea N O CN Cl N N 3-((4-(5-(1H-pyrrolyl)pyridinyl)- H0739 H chlorophenyl)(cyano)methyl) methyl(1-methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(5-cyanopyridin H0667 H yl)phenyl)ethyl)hydroxy(1- OH CN methylpiperidinyl)urea N O Me Cl (E)(1-(2,3-dichloro(5- Cl OH N N N ((hydroxyimino)methyl)pyridin H0646 H H yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(pyrimidin N N H0516 H yl)phenyl)ethyl)methyl(1- N methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(2- H0649 H methoxypyrimidinyl)phenyl)ethyl) N methyl(1-methylpiperidinyl)urea N OMe N O Me Cl N N 3-(1-(2,3-dichloro(2- H0797 H hydroxypyrimidinyl)phenyl)ethyl) N methyl(1-methylpiperidinyl)urea N OH N O Me Cl N N 3-(1-(4-(2-aminopyrimidinyl)-2,3- H0798 H Me dichlorophenyl)ethyl)methyl(1- N methylpiperidinyl)urea N NH2 N O Me Cl N N 3-(1-(2,3-dichloro(2-fluoropyrimidin- H0800 H 5-yl)phenyl)ethyl)methyl(1- N methylpiperidinyl)urea N F N O Me Cl N N 3-(1-(2,3-dichloro(2-chloropyrimidin- H0801 H 5-yl)phenyl)ethyl)methyl(1- N piperidinyl)urea N Cl N O Me Cl N N 3-(1-(2,3-dichloro(2-cyanopyrimidin- H0802 H Me 5-yl)phenyl)ethyl)methyl(1- N methylpiperidinyl)urea N CN N O Me Cl N N 4-(2-(1H-imidazolyl)pyrimidin- H0803 Me N 5-yl)-2,3-dichlorophenyl)ethyl)methyl- 1-(1-methylpiperidinyl)urea N N N N O Me Cl N N 2,3-dichloro(2- H0804 Me (dimethylamino)pyrimidin N yl)phenyl)ethyl)methyl(1- Me methylpiperidinyl)urea N N N O Me Cl Cl 3-(1-(2,3-dichloro(2- N N H0805 H (cyclopropylamino)pyrimidin N yl)phenyl)ethyl)methyl(1- piperidinyl)urea N N N O Me Cl Cl 3-(1-(2,3-dichloro(2- N N H (methylamino)pyrimidin H0806 Me N yl)phenyl)ethyl)methyl(1- Me methylpiperidinyl)urea N N N O Me Cl N N 3-(1-(2,3-dichloro(2- H0854 H Me cyclopropylpyrimidinyl)phenyl)ethyl)- N 1-methyl(1-methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(2-(pyrrolidin H0813 Me N yl)pyrimidinyl)phenyl)ethyl) methyl(1-methylpiperidinyl)urea N N N O Me CN Cl N N 3-(1-cyano(2,3-dichloro(pyrimidin- H0703 H Me 5-yl)phenyl)ethyl)methyl(1- N methylpiperidinyl)urea N O CN Cl N N 3-(cyano(2,3-dichloro(pyrimidin H0709 H yl)phenyl)methyl)methoxy(1- Me N methylpiperidinyl)urea N O Me Cl N N OMe 3-(1-(2,3-dichloro(2,4- H0663 H dimethoxypyrimidinyl)phenyl)ethyl)- N 1-methyl(1-methylpiperidinyl)urea N OMe N O Me Cl Cl 3-(1-(2,3-dichloro(pyrimidin N N H0624 H yl)phenyl)ethyl)hydroxy(1- N methylpiperidinyl)urea Me O OMe N O Cl N N methyl 2-(2,3-dichloro(pyrimidin H0662 H nyl)(3-methyl(1- N methylpiperidinyl)ureido)acetate Me OH N O Cl N N 3-(1-(2,3-dichloro(pyrimidin H0670 H yl)phenyl)hydroxyethyl)methyl N hylpiperidinyl)urea N O Cl N N 3-(1-(2,3-dichloro(pyrimidin H0673 H yl)phenyl)cyclopropyl)methyl(1- N methylpiperidinyl)urea N O CN Cl Cl 3-(cyano(2,3-dichloro(pyrimidin N N H0631 H yl)phenyl)methyl)methyl(1- N methylpiperidinyl)urea N O CF3 Cl N N 3-(1-(2,3-dichloro(pyrimidin H0686 H yl)phenyl)-2,2,2-trifluoroethyl)methyl- N 1-(1-methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(pyrimidin N N H0619 H yl)phenyl)ethyl)methyl(1- Me N piperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyrimidin H0768 H yl)phenyl)ethyl)methyl(1- Me N methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(6-methylpyrimidin- H0808 Me N 4-yl)phenyl)ethyl)methyl(1- piperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyrazin H0700 H Me yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N (S)(1-(2,3-dichloro(pyrazin H0816 H Me N yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N (R)(1-(2,3-dichloro(pyrazin H0817 H yl)phenyl)ethyl)methyl(1- Me N methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyrazin H0743 H yl)phenyl)ethyl)methoxy(1- OMe N methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyrazin H0750 H N yl)phenyl)ethyl)ethoxy(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyrazin H0756 H yl)phenyl)ethyl)hydroxy(1- OH N methylpiperidinyl)urea Me Me N O Me Cl Cl 3-(1-(2,3-dichloro(pyrazin H0824 N N H nyl)ethyl)methyl((R)-1,3,3- Me N trimethylpiperidinyl)urea Me Me N O Me Cl Cl 3-((S)(2,3-dichloro(pyrazin H0890 N N H yl)phenyl)ethyl)methyl((R)-1,3,3- Me N trimethylpiperidinyl)urea Me Me Me N O Cl Cl 3-(1-(2,3-dichloro(pyrazin H0858 N N H yl)phenyl)propyl)methyl((R)-1,3,3- Me N trimethylpiperidinyl)urea Me Me N O CF3 Cl Cl 3-(1-(2,3-dichloro(pyrazin H0865 N N H nyl)-2,2,2-trifluoroethyl)methyl- Me N 1-((R)-1,3,3-trimethylpiperidinyl)urea N O Me Cl N N 1-benzyl(1-(2,3-dichloro(pyrazin H0825 H N yl)phenyl)ethyl)(1-methylpiperidin yl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyrazin H0826 H yl)phenyl)ethyl)ethyl(1- Me methylpiperidinyl)urea N O Me Cl N N (S)(1-(2,3-dichloro(pyrazin H0889 H yl)phenyl)ethyl)ethyl(1- Me methylpiperidinyl)urea Me Me N O Cl Cl 3-(1-(2,3-dichloro(pyrazin H0896 N N H yl)phenyl)propyl)ethyl(1- Me methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyrazin H0827 H yl)phenyl)ethyl)(1-methylpiperidin yl)propylurea Me Me N O Cl N N 3-(1-(2,3-dichloro(pyrazin H0829 H yl)phenyl)propyl)methyl(1- Me N methylpiperidinyl)urea Me Me N O Cl (R)(1-(2,3-dichloro(pyrazin N N yl)phenyl)propyl)methyl(1- H0859 H methylpiperidinyl)urea Me N (single enantiomer) Me Me N O Cl Cl (S)(1-(2,3-dichloro(pyrazin N N nyl)propyl)methyl(1- H0860 H Me N piperidinyl)urea (single enantiomer) Me MeO O N O Cl Cl methyl 2-(2,3-dichloro(pyrazin N N H0922 H yl)phenyl)(3-methyl(1- Me N methylpiperidinyl)ureido)acetate Me HO N O Cl Cl 3-(1-(2,3-dichloro(pyrazin N N H0924 H yl)phenyl)hydroxyethyl)methyl Me N (1-methylpiperidinyl)urea N O CF3 Cl N N 3-(1-(2,3-dichloro(pyrazin H0830 H yl)phenyl)-2,2,2-trifluoroethyl)methyl- Me N 1-(1-methylpiperidinyl)urea N O CF3 Cl N N (S)(1-(2,3-dichloro(pyrazin H0899 H yl)phenyl)-2,2,2-trifluoroethyl)methyl- Me N 1-(1-methylpiperidinyl)urea N O CF3 Cl N N (R)(1-(2,3-dichloro(pyrazin H0900 H yl)phenyl)-2,2,2-trifluoroethyl)methyl- Me N 1-(1-methylpiperidinyl)urea N O CF3 Cl N N 2,3-dichloro(pyrazin H0909 H yl)phenyl)-2,2,2-trifluoroethyl)ethyl Me (1-methylpiperidinyl)urea N O Me F N N 3-chlorofluoro(pyrazin H0856 H yl)phenyl)ethyl)methyl(1- Me N methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(6-methylpyrazin H0815 H yl)phenyl)ethyl)methyl(1- Me N Me methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(3-methylpyrazin N N yl)phenyl)ethyl)methyl(1- H0831 H Me N methylpiperidinyl)urea Me N N O Me Cl Cl 3-(1-(2,3-dichloro(3-methylpyrazin N N H0843 H nyl)ethyl)methyl((R)-1,3,3- Me N trimethylpiperidinyl)urea Me N N O Me Cl N N 3-(1-(2,3-dichloro(6-methoxypyrazin- H0738 H 2-yl)phenyl)ethyl)methyl(1- Me N OMe methylpiperidinyl)urea N O Me Cl N N 3-(1-(4-(6-aminopyrazinyl)-2,3- H0780 H dichlorophenyl)ethyl)methyl(1- Me N NH2 methylpiperidinyl)urea N O Me Cl N N 2,3-dichloro(6- H0786 H Me N (chloromethyl)pyrazinyl)phenyl)ethyl)- Cl 1-methyl(1-methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(6-chloropyrazin H0791 H Me N yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(6-fluoropyrazin H0795 H yl)phenyl)ethyl)methyl(1- Me N F methylpiperidinyl)urea N O Me Cl N N (S)(1-(2,3-dichloro(6-fluoropyrazin- H0847 H 2-yl)phenyl)ethyl)methyl(1- Me N F piperidinyl)urea N O Me Cl N N (R)(1-(2,3-dichloro(6- H0848 H Me N F fluoropyrazinyl)phenyl)ethyl) methyl(1-methylpiperidinyl)urea N O Et Cl N N 3-(1-(2,3-dichloro(6-fluoropyrazin H0863 H yl)phenyl)propyl)methyl(1- Me N F methylpiperidinyl)urea N O CF3 Cl N N 3-(1-(2,3-dichloro(6-fluoropyrazin H0908 H yl)phenyl)-2,2,2-trifluoroethyl)methyl- Me N F 1-(1-methylpiperidinyl)urea N O Me Cl N N 2,3-dichloro(3-fluoropyrazin H0840 H Me N yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea F N N O Me Cl Cl 3-(1-(2,3-dichloro(6- N N (trifluoromethyl)pyrazin H0910 H Me N CF3 yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(6-cyanopyrazin H0788 H yl)phenyl)ethyl)methyl(1- Me N CN methylpiperidinyl)urea N O Me Cl Cl methyl 6-(2,3-dichloro(1-(3-methyl N N O (1-methylpiperidin H0789 H Me N yl)ureido)ethyl)phenyl)pyrazine carboxylate N O Me Cl N N 5-(2,3-dichloro(1-(3-methyl(1- H0760 Me N methylpiperidin yl)ureido)ethyl)phenyl)pyrazine NH2 carboxamide N O Me Cl N N methyl 5-(2,3-dichloro(1-(3-methyl H (1-methylpiperidin H0769 Me N yl)ureido)ethyl)phenyl)pyrazine OMe carboxylate N O Me Cl Cl 5-(2,3-dichloro(1-(3-methyl(1- N N H piperidin H0771 Me N yl)ureido)ethyl)phenyl)-N,N- NMe2 N dimethylpyrazinecarboxamide N O Me Cl Cl 3-(1-(2,3-dichloro(5- N N (hydroxymethyl)pyrazin H0770 H Me N yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyridazin H0729 H nyl)ethyl)methyl(1- Me N N methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyridazin H0783 H nyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(5-methoxypyridin- N N H0607 H 3-yl)phenyl)ethyl)methyl(1- Me OMe piperidinyl)urea N O Me Cl N N 3-(1-(4-(5-bromopyridinyl)-2,3- H0695 H Me dichlorophenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl methyl 5-(2,3-dichloro(1-(3-methyl Cl (1-methylpiperidin N N H0635 H yl)ureido)ethyl)phenyl)nicotinate Me CO2Me N O Me Cl N N O 3-(1-(4-(5-acetylpyridinyl)-2,3- H0690 H Me dichlorophenyl)ethyl)methyl(1- Me methylpiperidinyl)urea N O Me Cl N N N 3-(1-(2,3-dichloro(5-(pyrimidin H0735 H Me yl)pyridinyl)phenyl)ethyl)methyl N (1-methylpiperidinyl)urea N O Me Cl N N O 3-(1-(2,3-dichloro(5-(furan H0746 H Me yl)pyridinyl)phenyl)ethyl)methyl (1-methylpiperidinyl)urea N O Me Cl N S 3-(1-(2,3-dichloro(5-(thiophen H0747 H Me yl)pyridinyl)phenyl)ethyl)methyl (1-methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(5- H0765 H Me cyclopropylpyridinyl)phenyl)ethyl) methyl(1-methylpiperidinyl)urea N O Me Cl 3-(1-(2,3-dichloro(5-nitropyridin N N nyl)ethyl)methyl(1- H0766 H methylpiperidinyl)urea Me NO2 N O Me Cl Cl 3-(1-(2,3-dichloro(6- N N H0608 H isopropoxypyridinyl)phenyl)ethyl) Me methyl(1-methylpiperidinyl)urea N O Me N O Me Cl Cl 3-(1-(2,3-dichloro(6-cyanopyridin N N H0616 H yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N CN N O Me Cl Cl 3-(1-(2,3-dichloro(6-fluoropyridin N N H0618 H yl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N F N O Me Cl N N 3-(1-(2,3-dichloro H0602 H Me ((trimethylsilyl)ethynyl)phenyl)ethyl) methyl(1-methylpiperidinyl)urea N O Me Cl Cl 2,3-dichloro H0603 N N H ethynylphenyl)ethyl)methyl(1- Me methylpiperidinyl)urea N O Me Cl 3-(1-(2,3-dichloro(propyn H0832 Cl yl)phenyl)ethyl)methyl(1- N N H methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(3-methylbutyn H0852 N N H yl)phenyl)ethyl)methyl(1- Me methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(3-oxobutyn H0701 H Me nyl)ethyl)methyl(1- O methylpiperidinyl)urea N O Me Cl N N 2,3-dichloro(3-hydroxybutyn- H0733 H Me 1-yl)phenyl)ethyl)methyl(1- OH methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(3-hydroxyprop H0755 N N H ynyl)phenyl)ethyl)methyl(1- Me methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(3,3-diethoxyprop H0757 H Me ynyl)phenyl)ethyl)methyl(1- OEt methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyridin H0734 H Me ylethynyl)phenyl)ethyl)methyl(1- N methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(thiophen H0737 H Me ylethynyl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(furan H0762 H Me ylethynyl)phenyl)ethyl)methyl(1- O methylpiperidinyl)urea N O Me Cl N N 2,3-dichloro(thiazol H0751 H Me ylethynyl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(4-((1H-imidazolyl)ethynyl)-2,3- H0763 H Me rophenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(thiophen H0759 H Me ylethynyl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro(3-(thiophen H0785 N N H yl)propynyl)phenyl)ethyl) Me S methyl(1-methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(thiazol H0754 H Me ylethynyl)phenyl)ethyl)methyl(1- S methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro(pyrimidin H0753 Me ylethynyl)phenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro H0609 H Me (phenylethynyl)phenyl)ethyl)methyl (1-methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro H0764 H Me (cyclopropylethynyl)phenyl)ethyl) methyl(1-methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro N N H (cyclopropylethynyl)phenyl)ethyl) H0818 Me methyl(1-methylpiperidinyl)urea (S/R) (single enantiomer) N O Me Cl Cl 3-(1-(2,3-dichloro N N H0819 H (cyclopropylethynyl)phenyl)ethyl) Me methyl(1-methylpiperidinyl)urea (S/R) (single omer) N O Me F N N 3-(1-(3-chloro(cyclopropylethynyl) H0855 H Me fluorophenyl)ethyl)methyl(1- methylpiperidinyl)urea N O Me Cl N N 3-(1-(2,3-dichloro H0811 H Me (cyclopentylethynyl)phenyl)ethyl) methyl(1-methylpiperidinyl)urea N O Me Cl Cl 3-(1-(2,3-dichloro H0742 N N ethynylphenyl)ethyl)methoxy(1- OMe methylpiperidinyl)urea N O Me Cl 3-(1-(2,3-dichloro H0745 N N ethynylphenyl)ethyl)hydroxy(1- OH methylpiperidinyl)urea N O Me Cl 3-(1-(2,3-dichloro H0749 N N ethynylphenyl)ethyl)ethoxy(1- OEt methylpiperidinyl)urea or a pharmaceutically able salt thereof. 5
15. A compound according to claim 1, selected from the group ting of: N O Me Cl N N (S)(1-(2,3-dichloro(pyrazin H0816 H yl)phenyl)ethyl)methyl(1- Me N methylpiperidinyl)urea N O CF3 Cl N N (R)(1-(2,3-dichloro(pyrazin H0900 H yl)phenyl)-2,2,2-trifluoroethyl)methyl- Me N 1-(1-methylpiperidinyl)urea N O Me Cl N N (S)(1-(2,3-dichloro(6- H0847 H fluoropyrazinyl)phenyl)ethyl) Me N F methyl(1-methylpiperidinyl)urea Me Me N O Cl N N (S)(1-(2,3-dichloro(pyrazin H0860 H yl)phenyl)propyl)methyl(1- Me N piperidinyl)urea or a pharmaceutically able salt thereof.
16. A pharmaceutical composition comprising a therapeutically ive amount of a compound of any one of claims 1 to 15, and one or more pharmaceutically acceptable 5 excipients.
17. Use of a compound of any one of claims 1-15 in the preparation of a medicament for modulating ghrelin receptor activity in a human subject. 10
18. Use of a compound of any one of claims 1-15 in the preparation of a medicament for treating a disease associated with expression or activity of a ghrelin receptor in a human subject.
19. The use of claim 18, wherein said disease is y, overweight, eating disorder, 15 diabetes, 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.
20. The use of claim 19, n said metabolic syndrome is selected from the group 20 consisting of diabetes, Type I diabetes, Type II diabetes, inadequate glucose tolerance, n resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, riglyceridemia, hypercholesterolemia, dyslipidemia, y, aging, Syndrome X, atherosclerosis, heart disease, stroke, hypertension and peripheral ar disease. 25
21. The use of claim 19, wherein said gastric disorder is selected from the group consisting of Post-operative ileus (POI), diabetic gastroparesis, and opioid induced bowel dysfunction.
22. The use of claim 19, wherein said gastrointestinal disease is selected from the group consisting of ble bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia.
23. The use of claim 19, wherein said substance abuse is alcohol or drug abuse.
24. The use of claim 23, wherein said drug is selected from the group consisting of amphetamines, urates, benzodiazepines, cocaine, methaqualone, and opioids.
25. The use of claim 18, wherein said disease is selected from the group consisting of Prader-Willi Syndrome, Binge Eating Disorder, Parkinson-induced constipation and gastric dysmotility, herapy-induced nausea and vomiting, mation, pain, and motion sickness.
26. The use of claim 18, wherein said disease is Binge Eating Disorder.
NZ720467A 2014-03-07 2015-03-06 P-substituted asymmetric ureas and medical uses thereof NZ720467B2 (en)

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