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WO 2010/015655 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 11 February 2010 (11.02.2010) WO 2010/015655 Al (51) International Patent Classification: sham Research Centre, Wimblehurst Road, Horsham C07C 233/79 (2006.01) C07D 277/42 (2006.01) West Sussex RH 12 5AB (GB). SVIRIDENKO, Lilya C07C 255/58 (2006.01) A61K 31/166 (2006.01) [GB/GB]; Novartis Horsham Research Centre, Wimble C07C 311/39 (2006.01) A61K 31/427 (2006.01) hurst Road, Horsham West Sussex RH 12 5AB (GB). C07D 213/74 (2006.01) A61K 31/44 (2006.01) (74) Agent: VOEGELI-LANGE, Regina; Novartis Pharma C07D 213/75 (2006.01) A61P 1/00 (2006.01) Ag, Patent Department, CH-4002 Basel (CH). C07D 213/84' (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/EP2009/060150 AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) International Filing Date: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 5 August 2009 (05.08.2009) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (25) Filing Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (26) Publication Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (30) Priority Data: SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, 08162006.4 7 August 2008 (07.08.2008) EP TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 09150543.8 14 January 2009 (14.01 .2009) EP 61/205,1 39 14 January 2009 (14.01 .2009) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): NO- GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, VARTIS AG [CH/CH]; Lichtstrasse 35, CH-4056 Basel ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (CH). TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, (72) Inventors; and ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (75) Inventors/Applicants (for US only): BEATTIE, David MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, [GB/GB]; Novartis Horsham Research Centre, Wimble- TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, hurst Road, Horsham West Sussex RH 12 5AB (GB). ML, MR, NE, SN, TD, TG). COLSON, Anny-Odile [US/GB]; Novartis Horsham Re Declarations under Rule 4.17: search Centre, Wimblehurst Road, Horsham West Sussex — as to applicant's entitlement to apply for and be granted RH 12 5AB (GB). CULSHAW, Andrew James [GB/GB]; Novartis Horsham Research Centre, Wimble a patent (Rule 4.1 7(H)) hurst Road, Horsham West Sussex RH 12 5AB (GB). Published: SHARP, Lisa [US/GB]; Novartis Horsham Research (Art. Centre, Wimblehurst Road, Horsham West Sussex RH 12 — with international search report 21(3)) 5AB (GB). STANLEY, Emily [GB/GB]; Novartis Hor (54) Title: CYCLOHEXYL AMIDE DERIVATIVES AND THEIR USE AS CRF-I RECEPTOR ANTAGONISTS (57) Abstract: There are described cyclohexyl amide derivatives useful as corticotropin releasing factor (CRF i) receptor antago nists. CYCLOHEXYL AMIDE DERIVATIVES AND THEIR USE AS CRF-I RECEPTOR ANTAGONISTS FIELD OF THE INVENTION The present invention relates to cyclohexyl amide derivatives, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them. More particularly the present invention relates to their use as corticotropin releasing factor (CRF-1 ) receptor antagonists. SUMMARY OF THE INVENTION In a first aspect of the invention we provide a compound of formula I; 1 x in which R is -(CH 2)n(SO2)mR ; Rx is phenyl, biphenyl, naphthyl or heteroaryl, each of which may be optionally substituted by one or more substituents selected from the group alkyl C 1 to 10, alkoxy C 1 to 10, hydroxyalkyl C 1 to 10, halogen, haloalkyl C 1 to 10, haloalkoxy C 1 to 25 29 30 3 1 32 10, nitrile, -CO 2R , -(CH 2)PNR R , -SO 2NR R , alkoxy(C1 to 6)alkyl(C1 to 6)-, a 5- or 6- membered heterocycle, a 5- or 6- membered heteroaryl, phenyl, phenylalkyl(C1 to 6r aryloxy, each of the 5- or 6- membered heterocycle, 5- or 6- membered heteroaryl, phenyl and aryloxy being optionally substituted by one or more substituents selected from the group, carboxy, alkyl C 1 to 6, halogen and hydroxy; R2 is hydrogen or alkyl C 1 to 6 or R1 and R2, together with the nitrogen to which they are attached, form a 5- or 6- membered heteroaryl containing 2 , 3 or 4 heteroatoms, the heteroaryl being optionally substituted by one or more substituents selected from the group alkyl C 1 to 10, alkoxy C 1 to 10, halogen, haloalkyl C 1 to 10, haloalkoxy C 1 to 10, phenyl or a 5- or 6- membered heterocycle, said heterocycle being optionally substituted by carboxy; R3, R4, R5, R6, R7, R9, R10 , R17 , R22, R25, R29, R30, R3 1 and R32, which may be the same or different, are each hydrogen or alkyl C 1 to 6; R30 is hydrogen, alkyl C 1 to 6 or R33CO-; R33 is alkyl C 1 to 6 ; R8 is phenyl or a heteroaryl, each of which may be optionally substituted by one or more substituents selected from the group alkyl C 1 to 6 , haloalkyl C 1 to 6 , halogen, alkoxy C 1 to 6, nitrile or dialkyl amino C 1 to 6 or two adjacent substituents may together form a saturated or unsaturated carbocyclic or heterocyclic ring; m is an integer 0 or 1; n is an integer, 0 , 1 or 2 ; p is an integer from 0 to 6; and isomers thereof; in free form or in salt form. For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. As used herein, the term "alkyl" refers to a fully saturated, branched or unbranched hydrocarbon moiety, i.e. primary, secondary or tertiary alkyl or, where appropriate, cycloalkyl or alkyl substituted by cycloalkyl, they may also be saturated or unsaturated alkyl groups. Where not otherwise identified, preferably the alkyl comprises 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, /so-propyl, n- butyl, sec-butyl, /so-butyl, te/f-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n- decyl and the like. As used herein, the term "haloalkyl" refers to an alkyl as defined herein, that is substituted by one or more halo groups as defined herein. Preferably the haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Preferably, the polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4 , or 3 , or 2 halo groups. Non- limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms. As used herein, the term "alkoxy" refers to alkyl-O-, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, te/f-butoxy, pentyloxy, hexyloxy, cyclopropyloxy- , cyclohexyloxy- and the like. Preferably, alkoxy groups have about 1-7, more preferably about 1-4 carbons. As used herein, the term "sulphonyl" refers to R-SO2-, wherein R is hydrogen, alkyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl, alkoxy, aryloxy, cycloalkyl, or heterocyclyl. As used herein, the term "heterocyclyl" or "heterocyclo" refers to an optionally substituted, saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states. The heterocyclic group can be attached at a heteroatom or a carbon atom. The heterocyclyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1, 4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3- dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like. The term "heterocyclyl" further refers to heterocyclic groups as defined herein substituted with 1, 2 or 3 substituents selected from the groups consisting of the following: (a) alkyl; (b) hydroxy (or protected hydroxy); (c) halo; (d) haloalkyl; (e) oxo, i.e., =0; (f) amino, alkylamino or dialkylamino; (g) alkoxy; (h) cycloalkyl; (i) carboxyl; (j) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge; (k) alkyl-O-C(O)-; (I) mercapto; (m) nitro; (n) cyano; (o) sulfamoyl or sulfonamido; (P) aryl; (q) alkyl-C(O)-O~; (r) aryl-C(O)-O-; (S) aryl-S-; (t) aryloxy; (U) alkyl-S-; (V) formyl, i.e., HC(O)-; (W) carbamoyl; (X) aryl-alkyl—; and (y) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkyl- C(O)-NH-, alkylamino, dialkylamino or halogen.
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