ZA200108560B

ZA200108560B - Glucagon antagonists/inverse agonists.

Info

Publication number: ZA200108560B
Application number: ZA200108560A
Authority: ZA
Inventors: Jesper Lau; Peter Madsen; Christian Sams; Carsten Behrens; Josef Vagner; Inge Thoger Christensen; Behrend Frederik Lundt; Ulla Grove Sidelmann; Henning Thogersen; Anthony Ling; Michael Bruno Plewe; Larry Kenneth Truesdale
Original assignee: Novo Nordisk As; Agouron Pharma
Priority date: 1999-05-17
Filing date: 2001-10-18
Publication date: 2002-06-13

Description

GLUCAGON ANTAGONISTS/INVERSE AGONISTS

FIELD OF THE INVENTION

The present invention relates to agents that act to antagonize the action of the glucagon pep- tide hormone. More particularly, it relates to glucagon antagonists or inverse agonists.

BACKGROUND OF THE INVENTION

Glucagon is a key hormonal agent that, in co-operation with insulin, mediates homeostatic regu- lation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of glucagon is opposite to that of insulin, which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both giucagon and insulin are peptide hormones.

Glucagon is produced in the alpha islet cells of the pancreas and insulin in the beta islet cells.

Diabetes mellitus is a common disorder of glucose metabolism. The disease is characterized by hyperglycemia and may be classified as Type 1 diabetes, the insulin-dependent form, or Type 2 diabetes, which is non-insulin-dependent in character. Subjects with Type 1 diabetes are hyper- glycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin. However, in some patients with Type 1 or Type 2 diabetes, absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state. Both in healthy control animals as well as in animal models of Type 1 and Type 2 diabetes, removal of circulating glucagon with selective and specific antibodies has resulted in reduction of the gly- cemic level (Brand et al., Diabetologia 37, 985 (1994); Diabetes 43, [suppl 1], 172A (1994); Am.

J. Physiol. 268, E469-E477 (1995); Diabetes 44 [suppl 1], 134A (1995); Diabetes 45, 1076 (1996)). These studies suggest that glucagon suppression or an action that antagonizes gluca- gon could be a useful adjunct to conventional antihyperglycemia treatment of diabetes. The ac- tion of glucagon can be suppressed by providing an antagonist or an inverse agonist, ie sub- stances that inhibit or prevent glucagon induced responses. The antagonist can be peptidic or non-peptidic in nature. Native glucagon is a 29 amino acid peptide having the sequence:

His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gin-Asp-

Phe-Val-GIn-Trp-Leu-Met-Asn-Thr-NH,.

Glucagon exerts its action by binding to and activating its receptor, which is part of the Glu- cagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family (Jelinek et al., Science 259, 1614, (1993)). The receptor functions by an activation of the adenylyl cy- clase second messenger system and the result is an increase in CAMP levels.

Several publications disclose peptides that are stated to act as glucagon antagonists. Proba- bly, the most thoroughly characterized antagonist is DesHis'[Glu®]-glucagon amide (Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. Natl. Acad. Sci. USA 90, 1662 (1993)). Other antagonists are eg DesHis’,Phe®[Glu®]-glucagon amide (Azizh et al., Bioorganic & Medicinal

Chem. Lett. 16, 1849 (1995)) or NLeu® Ala'"'®-glucagon amide (Unson et al., J. Biol. Chem. 269(17), 12548 (1994)).

Peptide antagonists of peptide hormones are often quite potent; however, they are generally known not to be orally available because of degradation by physiological enzymes, and poor distribution in vivo. Therefore, orally available non-peptide antagonists of the peptide hormones are preferred. Among the non-peptide glucagon antagonists, a quinoxaline derivative, (2-styry}- 3-[3-(dimethylamino)propylmethylamino]-6,7-dichloroquinoxaline was found to displace gluca- gon from the rat liver receptor (Collins, J.L. et al., Bioorganic and Medicinal Chemistry Letters 2(9):915-918 (1992)). West, RR. et al., WO 94/14426 (1994) discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists. Anderson, P.L., US patent No. 4,359,474 discloses the glucagon an- tagonistic properties of 1-pheny! pyrazole derivatives. Barcza, S., U.S. Patent No. 4,374,130, discloses substituted disilacyclohexanes as glucagon antagonists. WO 98/04528 (Bayer Corpo- ration) discloses substituted pyridines and biphenyls as glucagon antagonists. WO 97/16442 and US patent No 5,776,954 (Merck & Co., Inc.) disclose substituted pyridyl pyrroles as gluca- gon antagonists and WO 98/21957, WO 98/22108, WO 98/22109 and US 5,880,139 (Merck &

Co, Inc.) disclose 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. Furthermore, WO 97/16442, US patent Nos 5,837,719 and 5,776,954 (Merck & Co., Inc.) discloses 2,5-substituted aryl pyrroles as glucagon antagonists. WO 98/24780, WO 98/24782, WO 99/24404 and WO 99/32448 (Amgen Inc.) disclose substituted pyrimidinone and pyridone compounds and substi- tuted pyrimidine compounds, respectively, which are stated to posses glucagon antagonistic activity. Madsen et al (J. Med. Chem. 1998 (41) 5151-7) discloses a series of 2-(benzimidazol- 2-yithio)-1-(3,4-dihydroxyphenyl)-1-ethanones as competitive human glucagon receptor antago- nists. WO 99/01423 (Novo Nordisk A/S) discloses a series of acylhydrazones as glucagon an- tagonists/inverse agonists.

I hese known glucagon antagonists differ structurally from the present compounds.

DEFINITIONS

The following is a detailed definition of the terms used to describe the compounds of the inven- tion: “Halogen” designates an atom selected from the group consisting of F, CI, Bror I.

The term “C,¢-alkyl” in the present context designates a branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and the like.

The term "C,¢-alkenyl”" as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups in- clude, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexeny! and the like.

The term "C.e-alkynyl” as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond. Examples of such groups in- clude, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl, 2,4-hexadiyny! and the like.

The term “C,s-alkoxy” as used herein, alone or in combination, refers to the radical -0O-C,s-alkyl where C,.s-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The term “Cie-alkanoyl” as used herein denotes a group -C(O)H or -C(O)-C,.s-alkyl.

Representative examples are formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like.

The term “C, g-cycloalkyl” as used herein represents a carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term “Cas-cycloalkenyl” as used herein represents a carbocyclic group having from 3 to 8 carbon atoms containing a least one double bond. Representative examples are 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1,4-cyclooctadienyl and the like.

The term “C4 s-cycloalkenyl” as used herein represents a carbocyclic group having from 4 to 8 carbon atoms containing a least one doubie bond. Representative examples are 1-cyclo- pentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1,4-cyclooctadienyl and the like.

The term “heterocyclyl” as used herein represents a saturated or partially unsaturated 3 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur.

Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.

The term “aryl” as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydro- genated derivatives are 1,2,3,4-tetrahydronaphthyi, 1,4-dihydronaphthyl and the like.

The term “aryloxy” as used herein denotes a group -O-aryl, wherein aryl is as defined above.

The term “aroy!” as used herein denotes a group -C(O)-aryl, wherein aryl is as defined above.

The term “heteroaryl” as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2.4-triazolyl, pyrany!, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-

thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzothiopheny! (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, 5 carbazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. Non- limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like. “Aryl-C,e-alkyl”, “heteroaryl-C,s-alkyl”, “aryl-C,¢-alkenyl” etc. mean C;s-alkyl or C,¢-alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:

The term “optionally substituted” as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.

Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.

Furthermore, when using the terms “independently are” and “independently selected from” it should be understood that the groups in question may be the same or different.

The present invention is based on the unexpected observation that the compounds of the gen- eral formula (I) disclosed below antagonize the action of glucagon.

DESCRIPTION OF THE INVENTION

Accordingly, the invention is concemed with compounds of the general formula (1):

Y

A yA N D 0) v~ Sy” Sx” pe wherein

V is -C(O)OR?, -C(O)NRR?, -C(O)NR?0OR?, -S(0),0R?,

OH

Oo N. PN

J em . Lo bY rR? ' 0 ’ N N ’ wherein

R? and R® independently are hydrogen or Cys-alky!,

R* is hydrogen, halogen, -CN, -CF3, -OCF3, -NO,, -OR®, -NR°R® or C,.¢-alkyl, wherein R® and R® independently are hydrogen or C¢-alkyl,

Ais

RR RA R RS R° ~~ —(CH,); NR— CH) —NR'— CH) N (CH, VAS NM Lr NM 2) or —£ ) wherein bisQor1, nis0,1,20r3,

,

R’ is hydrogen, C,.¢-alkyl or C,.g-Cycloalkyl-C,.¢-alkyl,

R® and R® independently are hydrogen or C,-alkyl,

Yis-C(O)-, -S(O).-, -O- or a valence bond,

Z is phenylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con- taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R* and R* selected from hydrogen, halogen, -CN, -CF;, -OCF3, -NO,, -OR™, -NR'°R"! and C, ¢-alky!, wherein R' and R'' independently are hydrogen or C,s-alkyl, or -A-Y-Z- together are (@] —onon F- 0

R'is hydrogen or Cqs-alkyl,

Xis 13,14 (CRR™)—(CH,)— (CH )T—=—(CR"R")—(CH)— 0 Q 13,14 $ (CH = N—— (CR"R")—(CH;— = —L—(CR™R™)—(CH)—

R

0 fo S — eH, 0— (ERR ™)= (CH) (CH (CRR™) (CH,

R R

Q Q 13,14 %.° ~ (eH, N—l-N—(cR RCH); — —S—(CR"R"™)—(CH,)— -

R'? R' fo 0 —N—L—CR™R™)~(CH,);- —L0—(CR"R")—(CH,)—

R'? 7 1314 1314 (CH) N—(CR"R")~(CH,)= — CRRO)T(CHI—

R'2 NH rR"? \ —(CHT (CRUR™)~(CH)— —T—N—CR"R")—(CH)—

NH

Q 13,14 0) — (CH )eN— (CR RO-(CH)—0—— . —L—(CH,)- (CR"R™)—O—(CH,)—

R

0 o) o)

A (eH,)—s— CR R)—(CH,);— or (CH) —(CR"™R")~(CH,)— wherein risOor1, g and s independently are 0, 1, 2 or 3,

R™, R', R" and R" independently are hydrogen or C,-alkyl,

Dis w R'® R's \ R'"® R' R'® 4 a! RY” Be 3 R" [ rR" f ¢ RY

I) ’ y R'® $ N R'® ?

RY R'

Rr" 16 Rr" “Oe y

R 7 17 ’ ’ [o] rR" R'®

Rr" R" \ rR R' R'® 0 R' 1] RY rR" o Lo

R" R' ory. he 16 Ww

R wherein

Wis -O-, -S-, -S(0),- or -NR%-,

W' is =CR®- or =N-,

R'®, R", R' and R'® independently are e hydrogen, halogen, -CN, -CH.CN, -CHF,, -CF3, -OCF;, -OCHF,, -OCH,CF;, -OCF,CHF,, -0OS(0),CFs, -SCF3, -NO,, -OR?', -NR?*'R%, -SR?', -NR?¥'S(0),R%, -S(0),NR?*'R%, -S(O)NR?'R%, -S(O)R?', -S(0),R?", -OS(0),R?", -C(O)NR?*'R%, -OC(O)NR?'R?%, -NR?'C(0)R?, -CH,C(O)NR*'R%, -OCH,C(O)NR?'R?, -CH,OR?', -CH,NR?*'R%, -OC(0)R?', -C(O)R?' or -C(O)OR?,

Ld Cie-alkyl, C,s-alkenyl or C.,¢-alkynyl, which may optionally be substituted with one or more substituents selected from -

CHF, -CF,, -OCF,, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF,, -OR?, -NR?'R?, -SR¥, -S(O)R?, -S(0),R?, -C(O)NR*'R*, -OC(O)NR?R%, -NR¥C(O)R?, -OCH,C(O)NR*'R?%, -C(O)R? and -C(O)OR?, e Cjs-cycloalkyl, Cys-cycloalkenyl, heterocyclyl, Css-cycloalkyl-C,s-alkyl, C;s-cyclo- : alkyl-C,¢-alkoxy, Cjs-cycloalkyloxy, Cs s-cycloalkyl-C,¢-alkylthio, C;.s-cycloalkyithio,

Css-cycloalkyl-Cos-alkenyl, C;s-cycloalkyl-C,s-alkynyl, Ca s-cycloalkenyl-Cyg-alkyl, Cas- cycloalkenyl-C.¢-alkenyl, Css-cycloalkenyl-C,s-alkynyl, heterocyclyl-C, ¢-alkyl, heterocy- clyl-C,-alkenyl or heterocyclyl-C,¢-alkynyl, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from -CHF,, -CF3, -OCF3, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF3, -OR?, -NR?'R%, -SR?', -5(0)R?, -5(0).R?, -C(O)NR?'R%, -OC(O)NR?'R%, -NR?*'C(O)R%, -OCH,C(O)NR?'R%, -C(0O)R?' and -C(O)OR?,

Cis-alkyl, C,g-alkenyl and C,¢-atkynyl, : which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF;, -OCF3, -OCHF,, -OCH,CF,, -OCF,CHF,, -SCF,, -OR?', -NR?'R%, -SR?, -S(O)R?', -S(0).R?', -C(O)NR?'R%, -OC(OINR?'R%, -NR?'C(O)R?%, -OCH,C(O)NR?*'R%, -C(O)R?' and -C(O)OR?, = aryl, aryloxy, aryloxycarbonyl, aroyl, ary!-C,g-alkoxy, aryl-C,.¢-alkyl, aryl-C,¢-alkenyl, aryl-

C.,e-alkynyl, heteroaryl, heteroaryl-C, ¢-alkyl, heteroaryl-C, ¢-alkenyl or heteroaryi-

C.s-alkynyl, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from

Co _

halogen, -CN, -CH.CN, -CHF,, -CF,, -OCF,, -OCHF,, -OCH.CF,, -OCF,CHF,, -0S(0),CF3, -SCF3, -NO,, -OR?, -NR*'R%, -SR?, -NR?'S(0),R%, -S(0),NR?'R%, -S(O)NR?'R%, -S(O)R?', -S(0),R?', -OS(0),R?', -C(O)NR?'R?, -OC(O)NR?'R?, -NR?'C(0)R?, -CH,C(O)NR?'R%, -OCH,C(O)NR?'R%, -CH,OR?", -CH,NR?'R%, -OC(O)R?, -C(O)R?' and -C(O)OR?,

C¢-alkyl, Ca¢-alkenyl and C,¢-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF3, -OCF,, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF;, -OR?, -NR¥'R%, -SR?', -S(0)R?', -S(0),R?', -C(O)NR?'R?, -OC(O)NR?'R%, -NR?'C(0O)R%, -OCH,C(0)NR?'R%, -C(0)R?' and -C(O)OR?, wherein R?' and R? independently are hydrogen, -CFs, C,-alkyl, tri-C, e-alkylsilyl, Cs.g-cyclo- alkyl, Csg-cycloalkyl-C,s-alkyl, aryl, aryl-C,4-alkyl or heteroaryl, or R”' and R? when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R'® to R'® when placed in adjacent positions together may form a bridge —(CR'®*R"),-O-(CR'"R").-0-, wherein ais 0,1o0r2, cistor2,

R'™, R", R'® and R'? independently are hydrogen, C,-alkyl or halogen,

R” and R* independently are hydrogen, C,s-alkyl, Css-cycloalkyl or C;g-cycloalkyl-C.- alkyl,

E is a 3 to 9 membered mono- or bicyclic ring which may optionally contain one or two dou- ble bonds and which may optionally contain one or two heteroatoms selected from nitrogen, oxygen and sulfur, wherein one or two groups R* and R? may be attached to the same or different ring carbon atoms and wherein a group R*' may be attached to a ring nitrogen atom when present, or

R® rR?

RY RY

Oy N20 NO 0 \ o \ 1) RR R™ (Dw

J , oy 17 ry (CHR ’ rR? * rR? ’ ’ | (J .

Fe

RA R? R% R® 25 ( ER he RY R* a

Nel AG

R (HE Cw o - Ni ! (CH,) !

CHR™) CH [ ** HR

He Ye rR? rR? 34 3s

R*% _R® R* RS R Y" (Br (Be y hd

GH (Gur i (CHR), CH ’ ! 1]

CH I : aH (CHR™),, I (CHR), CH (CHR™),, | he J | CHR) [or

RY g® CH, CH, RR R®

N NH or 1) , 3, ’ " Pe , (HR ) Fo

R% rR?

RY wherein m and p independently are 0, 1, 2, 3 or 4, with the proviso that when both m and p are pre- sent in the same formula at least one of m and p is different from O,

RR a

R? and R?* independently are » hydrogen, -CHF;, -CF3, -OCF3, -OCHF,, -OCH,CF,, -OCF,CHF,, -SCF,, -OR®, -NR*R™, -SR¥, -S(0)R¥®, -S(0);R*, -C(O)NR*R?, -OC(O)NR*R¥, -NR*C(O)RY, -OCH,C(O)NR*R¥, -C(O)R* or -C(O)OR®, » C,s-alkyl, Cos-alkenyl or C,s-alkynyl, which may optionally be substituted with one or more substituents selected from -CHF,, -CF,, -OCF3, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF;, -OR¥*, -NR**R¥, -SR¥®, -S(0)R¥, -S(0),R®, -C(O)NR¥R*’, -OC(O)NR¥R¥, -NR*C(O)RY, -OCH,C(O)NR*R¥, -C(O)R* and -C(O)OR®, eo Cjs-cycloalkyl, C;s-cycloalkylidene, C,s-cycloalkenyl, heterocyclyl, Cs 4-cycloalkyl-

C,.e-alkyl, Ca s-cycloalkyl-C, s-alkenyl, Cs a-cycloalkyl-C, ¢-alkynyl, C,s-cycloatkeny!-

Cis-alkyl, C4g-cycloalkenyl-C,s-alkenyl, C44-cycloalkenyl-C,s-alkynyl, heterocyclyl-

C,s-alkyl, heterocyclyl-C, ¢-alkeny! or heterocyclyl-C,¢-alkynyl, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from -CHF,, -CF;, -OCF3, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF;, -OR%, -NR¥*RY, -SR*, -5(0)R*, -5(0),R®, -C(O)NR*R%", -OC(O)NR¥R¥ -NR*C(O)R¥, -OCH,C(O)NR¥RY, .C(O)R* and -C(O)OR®,

C,s-alkyl, C,s-alkenyl and C,¢-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF,, -OCF;, -OCHF,, -OCH,CF;, -OCF,CHF,, -SCF;, -OR*, -NR*R¥ -SR%* -S(0O)R*, -S(0),R*, -C(O)NR*RY, -OC(O)NR*R¥, -NR*C(0)R¥, -OCH,C(0)NR*R¥ -C(O)R*® and -C(O)OR?®,

e aryl, aryloxy, aroyl, aryl-Cy¢-alkoxy, aryl-C4s-alkyl, aryl-C,s-alkenyl, aryl-C,4-alkynyl, het- eroaryl, heteroaryl-C,¢-alkyl, heteroaryl-C,s-alkeny! or heteroaryl-C,¢-alkynyl, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CH,CN, -CHF,, -CF;, -OCF3, -OCHF,, -OCH,CF3, -OCF,CHF,, -OS(0),CF3, -SCF3, -NO,, -OR*, -NR*RY -SR™*, -NR*S(0),RY, -S(0),NR*R¥, -S(0)NR¥RY, -S(0)R¥, -S(0),R*, -OS(0),R*, -C(O)NR*R¥, -OC(O)NR*R?, -NR*C(O)R¥, -CH,C(O)NR*RY, -CH,C(O)NR*RY, -CH,0OR®, -CH,NR*R*, -OC(O)R*, -C(0)R* and -C(O)OR™,

C,e-alkyl, Cog-alkenyl and C,g-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF3, -OCF,, -OCHF,, ~OCH,CF;, -OCF,CHF,, -SCF,, -OR™®, -NR*R¥, -SR®, -S(0)R*, -S(0),R*, -C(O)NR*R¥, -OC(O)NR*R¥, -NR*C(0)R¥, -OCH,C(O)NR*R¥, -C(O)R* and -C(O)OR*, wherein R*® and RY independently are hydrogen, C,¢-alky! or aryl, of which the ary! moiety optionally may be substituted with one or more substitu- ents selected from halogen, -CN, -CF;, -OCF3, -NO,, -OR*®, -NR*R* and

C..s-alkyl, wherein R* and R¥ independently are hydrogen or C.¢-alkyl, or R* and RY when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or R? and R* when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH)-CR*R*'-(CH,)-O-, -(CH )-CR*R*'-(CH2)- or

-S-(CH,)-CR*R*!-(CH,)-S-, wherein tandlindependently are 0, 1, 2, 3, 4 or 5,

R* and R*' independently are hydrogen or C,s-alkyl,

R* to R* independently are hydrogen, halogen, -CN, -CF3, -NO,, -OR*, -NR*’R*?, C, ¢-alkyl,

Csg-cycloalkyl or Cg-cycloalkenyl, wherein R* and R*® independently are hydrogen or C,¢-alkyl, or

R* and R*’ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,

R*', R¥ and R* independently are hydrogen or C,-alkyl,

R* and R® independently are « hydrogen, C,e-alkyl, C,s-alkoxy, C,s-alkanoyl, -C(O)NR*R* or -S(0),R*, eo aryl, aroyl, aryl-C,s-alkoxy, aryl-C,e-alkanoyl or aryl-C, ¢-aikyl, of which the aryl maieties optionally may be substituted with one or more sub- stituents selected from halogen, -CN, -CF3, -OCF;, -OR*, -NR*R* and C, s-alkyl, wherein R* and R* independently are hydrogen or C,s-alkyl, or

R* and R* when attached to a carbon atom together with the said carbon atom may form a 3 to 8 membered cyclic ring optionally containing one or two heteroatoms selected from ni- — trogen, oxygen or sulfur, and optionally containing one or two double bonds, or

R* and R* when attached to a nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms se- lected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

The compounds according to the invention preferably have an ICs, value of no greater than 5 uM as determined by the Glucagon Binding Assay (I), Glucagon Binding Assay (Il) or

Glucagon Binding Assay (lll) disclosed herein.

More preferably, the compounds according to the invention have a glucagon antagonistic ac- tivity as determined by the Glucagon Binding Assay (!), Glucagon Binding Assay (11) or Giu- cagon Binding Assay (lil) disclosed herein corresponding to an ICs; value of less than 1 uM, preferably of less than 500 nM and even more preferred of less than 100 nM.

The compounds according to the invention are useful for the treatment and/or prevention of an indication selected from the group consisting of hyperglycemia, IGT (impaired glucose tolerance), Type 2 diabetes, Type 1 diabetes and obesity.

In a further aspect the invention relates to compounds of the general formula (1):

E

Al, IN. .D (i voy X :

Tt wherein

Vis -C(O)OR?, -C(O)NR’R?, -C(O)NR?OR?,

OH o N

OE) (ro. Or

RY ’ 0 ' N N B wherein

R? and R® independently are hydrogen or C, -alkyl,

R* is hydrogen, halogen, -CN, -CF3, -OCF3, -NO,, -OR?, -NR°R® or C,¢-alkyl, wherein R® and R® independently are hydrogen or C, s-alkyl;

Ais

RS R® Rr? Rr? R® R° ~

PR VASE I , MCh, — NRT — , “My cry— or — (CH), wherein bis 0or1, nis0, 1, 2o0r 3,

R’ is hydrogen, C,s-alkyl or C;s-cycloalkyl-C,6-alkyl,

R®and R’ independently are hydrogen or C,s-alkyl;

Y is -C(O)-, -S(O).- or -O-;

Z is phenylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con- taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF,, -OCF;, -NO,, -OR™, -NR"R"" and C,s-alkyl, wherein R'" and R"' independently are hydrogen or C,s-alkyl; or -A-Y-Z- together is ~

0 ~onoi{ J 0

R' is hydrogen or C,s-alkyl:

Xis tT 2 13414 (CRR™—(CH)—~ | —E=Cc—(CRPR™)—(CH,)~ 0) 0 S eH N—L— (CR R™)~(CH,) Ll cr®*R"—(CH,)—

R'? 0 0 $ eH )—lo—CR R)=CH)— | (CH) N= (CR RM — (CH) —, rR"? R'2 [@) 0) 0, ,0 — eH) NL N—(CR¥R™)~ (CH, — —SZ(CRPR™)—(CH,)— -

Rr? R'S 0 0 —N— (ROR CH) —0—(CcR"R")—(CH,)—

R'? 0) 13514 (eH, N—(CRR™)- (CH); : — CR RCH

R'? NH

Rr" —(CH,)5 (CR™R")~(CH,)— ' ——N—(CRR™)— (CH); or

NH

0 — (GH) N—(CR™R™)~ (CH )—0—

R'2 ! wherein risOor1,

q and s independently are 0, 1, 2 or 3,

R', R™, R" and R'® independently are hydrogen or Cy ¢-alkyl;

Dis 18 R'® \ pit R'"® R16 &’ a Ber Her C= ; ¢ RY ’ ’ y R'® ' N R'® 4

R'S R'® \ R'S RY w 17 N R'™

R'®

R'¢ R'8 ° Re rR" = J 9) , ~ pron or Y [o] RY wherein

W is -O-, -S- or -NR?%-, wherein R? is hydrogen or C,¢-alkyl,

R’ R'7, R' and R" independently are hydrogen, halogen, -CN, -CH,CN, -CHF,, -CF3, -OCF;, -OCHF,, -OCH,CF3, -OCF,CHF,, -0S(0),CF3,, -SCF3, -NO,, -OR?', -NR?'R?, -SR?', -NR?'S$(0),R%, -S(0),NR?*'R?, -S(O)NR?'RZ% -S(O)R?, -S(0),R?, -OS(0),R?, -C(OINR?'RZ, -OC(O)NR?'RZ, -NR?'C(0)R?%, -CH,C(O)NR?*'R?, -OCH,C(0)NR*'R%, -CH,OR?', -CH,NR?'R?, -OC(O)R?", -C(O)R? or -C(O)OR?,

C,s-atkyl, C,¢-alkenyl or C.s-atkynyl,

which may optionally be substituted with one or more substituents selected from -

CHF,, -CF3, -OCF;, -OCHF,, -OCH,CF3, -OCF,CHF5, -SCF3, -OR?', -NR¥'R%, -SR?, -S(0)R?, -5(0);R?, -C(O)NR?'R?, -OC(O)NR?'R%, -NR?'C(O)RZ, -OCH,C(O)NR?'R%, -C(O)R?' and -C(O)OR?,

Cs g-cycloalkyl, Cs 4-cycloalkenyl, heterocyclyl, Cy g-cycloalkyl-C,¢-alkyl,

Cs s-cycloalkyl-Coe-alkenyl, Ci s-cycloalkyl-C,s-alkynyl, Cas-cycloalkenyl-Cys-alkyl,

Css-cycloalkenyl-C,¢-alkenyl, Cs s-cycloalkenyl-C,¢-alkynyl, heterocyclyi-C,s-alky!, heterocy- clyl-C,¢-alkenyl or heterocyclyl-C,s-alkynyl, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from -CHF,, -CF3, -OCF,, -OCHF,, -OCH,CF3, -OCF.,CHF,, -SCF,, -OR?', -NR?'R%, -SR?', -S(O)R?', -S(0).R?", -C(O)NR?*'R?, -OC(O)NR?'R%, -NR?'C(0)R?, -OCH,C(O)NR?'R?%, -C(O)R?' and -C(O)OR?',

C;¢-alkyl, C,¢-alkenyl and C,g¢-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF3, -OCF3, -OCHF,, -OCH,CF,, -OCF,CHF,, -SCF3, -OR?, -NR?'R?%, -SR?, -S(0)R?, -S(0);R?, -C(O)NR?'R?%, -OC(OINR?'RZ, -NR?'C(0O)R%, -OCH,C(O)NR?'R%, -C(O)R?' and -C(O)OR?, aryl, aryloxy, aroyl, aryl-C,s-atkoxy, aryl-C, g-alkyl, aryl-C,¢-alkenyl, aryl-C,s-alkynyl, het- eroaryl, heteroaryl-C,¢-alkyl, heteroaryl-C,¢-alkenyl or heteroaryl-C,¢-alkynyl, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CH,CN, -CHF,, -CF3, -OCF;, -OCHF,, -OCH,CF;, -OCF,CHF,, -0S(0),CF3, -SCF3, -NO,, -OR*, -NR*R?, -SR?', .NR?'S(0),R%, -S(0),NR?'R%, -S(O)NR¥'R?, -S(O)R?, -S(0O),R*, -0S(0),R?, -C(O)NR?'R%, -OC(O)NR?*'R?, -NR?'C(O)R?%, -CH,C(O)NR?*R?, -OCH,C(O)NR?'R%, -CH,OR?', -CH,NR*'R%, -OC(O)R?, -C(O)R*' and -C(O)OR?,

Cis-alkyl, C,¢-alkenyl and C,¢-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF;, -CF;, -OCF;, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF;, -OR?, -NR?'R?%, -SR?', -S(0)R?', -S(0),R?, -C(O)NR?'RZ, -OC(O)NR?'R%, -NR?'C(0O)R?%, -OCH,C(O)NR?*'R%, -C(O)R?' and -C(0)OR?, wherein R*' and R? independently are hydrogen or C,s-alkyl, or R*' and RZ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R'® to R' when placed in adjacent positions together may form a bridge -OCH,0- or -OCH,CH,0-;

Eis a 3 to 9 membered mono- or bicyclic ring which may optionally contain one or two dou- ble bonds and which may optionally contain one or two heteroatoms selected from nitrogen, oxygen and sulfur, wherein one or two groups R% and R? may be attached to the same or different ring carbon atoms and wherein a group R* may be attached to a ring nitrogen atom when present, or

R® rR?

RY RY

N ro Lr Le ’ H rR? ' R® ’ v his b ’ re 25 I. RrR% 28

R* js) > ” - ]?® R* R®

RY R R N°

R2 R® 23 CH R® R® hr ' TT" bo ! OR dey, Re | 7. 2 CH 2)p CHR®Y i on : — i rR? rR?

Ae N R NY" (Ze | (Gre

CH ” i , GH , Il , (nm Ye or CH cH (CHR), Co CHR, ch (HR Nil Im Err m wherein mand p independently are 0, 1, 2, 3 or 4,

RZ and R* independently are hydrogen, -CHF,, -CFj, -OCFj; -OCHF, -OCH,CF;, -OCF,CHF,, -SCF;, -OR%®, -NR¥*R¥, -SR¥, -S(O)R*, -S(0),R¥, -C(O)NR¥RY, -OC(O)NR*R¥, -NR¥C(O)R¥, -OCH,C(O)NR*RY, -C(O)R* or -C(O)OR¥,

Cis-alkyl, Cog-alkenyi or C,¢-alkynyl, which may optionally be substituted with one or more substituents selected from -

CHF, -CF3, ~OCF3, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF3, -OR®, -NR¥RY, -SR%®, -S(0)R%*, -S(0),R*, -C(O)NR*R™, -OC(O)NR*R¥, -NR*¥C(0)RY, -OCH,C(O)NR¥RY, -C(0)R* and -C(O)ORY,

Cas-cycloalkyl, C;g-cycloalkenyl, heterocyclyl, Cy s-cycloalkyl-C,s-alkyl,

Cas-cycloalkyl-C,¢-alkenyl, Cs g-cycloalkyl-C,s-alkynyl, C;s-cycloalkenyl-Cy¢-alkyl,

Cjzs-cycloalkenyl-C,e-alkenyl, Cis-cycloalkenyl-C,s-alkyny!, heterocyclyl-C, s-alkyl, heterccy clyl-C,¢-alkenyl or heterocyclyl-Cy¢-alkynyl,

of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from -CHF;, -CF3;, -OCF3, -OCHF,, -OCH,CF;, -OCF,CHF,, -SCF;, -OR¥®, -NR¥R¥ -SR¥ -S(0)R*, -S(0),R®, -C(O)NR*R¥, -OC(O)NR¥R¥, -NR¥C(0)R¥, -OCH,C(O)NR¥®RY, -C(O)R* and -C(O)OR%,

Cis-alkyl, C,s-alkenyl and C,g-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF3, -OCF;, -OCHF,, -OCH,CF;, -OCF,CHF,, -SCF,, -OR%®, -NR¥RY -SR*, -§(0)R¥®, -S(0),R*, -C(O)NR*RY, -OC(O)NR*¥R¥, -NR*C(0)RY, -OCH,C(0)NR*R¥, -C(O)R* and -C(O)OR®, aryl, aryloxy, aroyl, aryl-C,s-alkoxy, aryl-Css-alkyl, aryl-C,s-alkenyl, aryl-C,g-alkynyl, het- eroaryl, heteroaryl-C,s-alkyl, heteroaryl-C,¢-alkenyl or heteroaryl-C,s-alkynyl, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CH,CN, -CHF,, -CF;, -OCF;, -OCHF,, -OCH,CF;, -OCF,CHF,, -OS(0),CF3, -SCF;, -NO,, -OR%*, -NR*R¥, -SR*®, -NR*S(0);R”, -S(0),NR*R?, -S(O)NR*RY’, -S(O)R*, -S(0),R*, -OS(0),R*, -C(O)NR*R¥, -OC(O)NR*R¥, -NR*C(0)R¥, -CH,C(O)NR*R™, -CH,C(O)NR*¥R¥, -CH,0R¥, -CH,NR*R¥, -OC(O)R*, -C(O)R* and -C(O)OR,

Cis-alkyl, C,g-alkenyl and C,g-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF,, -OCF;, -OCHF,, -OCH,CF,, -OCF,CHF,, -SCF;, -OR*, -NR*R¥ -SR*, -S(O)R*, -S(0),R*, -C(O)NR*R?¥, -OC(O)NR¥™R¥ -NR*C(O)R¥, -OCH,C(0)NR*R¥, -C(O)R* and -C(O)OR®, wherein R* and R* independently are hydrogen, C,¢-alky! or aryl, _

of which the aryl moiety optionally may be substituted with one or more substitu- ents selected from halogen, -CN, -CF;, -OCF3, -NO,, -OR*, -NR*R>® and

Cis-alkyl, wherein R*® and R* independently are hydrogen or Cy.¢-alkyl, or R* and RY when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or R? and R* when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH,)-CR*R*'-(CH,)-O-, -(CH_)-CR*R*'-(CH,)- or -S-(CH)-CRYR*'-(CH,)-S-, wherein t and | independently are 0, 1, 2, 3, 4 or 5,

R* and R*' independently are hydrogen or C,.s-alkyl,

R® to R¥ independently are hydrogen, halogen, -CN, -CFs, -NO,, -OR*, -NR*R*}, C s-alky! or Cs g-cycloalkyl, wherein R*2 and R*® independently are hydrogen or Cis-alkyl,

R¥, R® and R* independently are hydrogen or C,s-alkyl,

R* and R¥ independently are hydrogen, C;s-alkyl, Cis-alkoxy, Cis-alkanoyl, -C(O)NR*R* or-S(O).R*, aryl, aroyl, aryl-C,s-alkoxy, aryl-C,e-alkanoyl or aryl-C; ¢-alkyl, of which the aryl moieties optionally may be substituted with one or mare sub- stituents selected from halogen, -CN, -CFa, -OCF3, -OR*, -NR*R* and C,¢-alkyl,

wherein R* and R*® independently are hydrogen or C,¢-alkyl, or R* and R* when attached to the carbon atom together with the said carbon atom may form a 3 to 8 membered cyclic ring optionally containing one or two heteroatoms selected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds, or R* and R* when attached to the nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroa- toms selected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds; as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof; having an ICs, value of no greater than 5 uM as determined by the Glucagon Binding Assay (1), Glucagon Binding Assay (ll) or Glucagon Binding Assay (Il) disclosed herein.

By a compound of the general formula (I') having an ICs, value of no greater than 5 uM as de- termined by the Glucagon Binding Assay (1), Glucagon Binding Assay (ll) or Glucagon Binding + Assay {lll} is meant any compound of the defined formula having such activity, without limitation to any utility or usefulness for treating any specific indication.

In a further aspect the invention relates to compounds of the general formula (I"): i rR’ wherein

V is -C(O)OR?, -C(O)NR?R?, -C(O)NR?OR?, -S(0),0R?,

OH o N ~ EN

WOE . TD . rR? ! 0 ! N N ’ wherein

R? and R?® independently are hydrogen or C,¢-alkyl,

R* is hydrogen, halogen, -CN, -CF3, -OCF,, -NO,, -OR®, -NR°R® or C,g-alkyl, wherein R® and R® independently are hydrogen or C, g-alkyl,

Ais

RY R' RR RS R° ~ (CH 5 NR NM (CH) — NR — , VAR or —£N (CH), wherein bisQor1, nis0,1,20r3,

R’ is hydrogen, C,¢-alkyl or Cse-cycloalkyl-C,s-alkyl,

R® and R® independently are hydrogen or C,s-alky!,

Y is -C(O)-, -S(0),-, -O- or a valence bond,

Z is phenylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con- taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be attached to one or two groups R* and R* selected from hydrogen, halogen, -CN, -CFa, “OCF, -NO2, -OR", -NR'’R" and Ce-aikyi,

wherein R'® and R"' independently are hydrogen or C, s-alkyl, or -A-Y-Z- together are 8] —onan | - 0 '

R' is hydrogen or C,s-alkyl,

Xis ? 13,14 0 —L(cR™R™)—(CH,)— — (CH, G=G— (CR R™)— (CH) —

Q Q 1 14 3 ergy CR" er) | Lo eRRY (CH) —

R'"

Q Q 13414 3 13,14 —-(cH,)—N——0—(CR"R™)~(CH,)— | —(cH N(R R“)—(CH)—

R'2 R 0 0 0, ,0

Ler) N—N—(CR RCH) — | —ST(ERER™) (CH) rR" R'S

Q 1314 0 13pm 14 —N—l—(cr R"“~(CH)— —0—(CR"R"—(CH,)—

R'? ? 1314 13514, __ CH.)— —L(eH,)—N—CR"R")~ (CH= —CRUR™)—(CHY—

R'2 NH rR" \ —(CH,)7 (CR"R™)~(CHY— ——N—CR"R")—(CH,)—~ .

NH fo} fo)

ACH N—CR RY CH—o— | rR 0-H)

R' 0 13,14 9 a 13,14 (CH,)—S—(CR¥R")—(CH);— or (CH, (CRPR™)—(CH)— wherein risOor1, gq and s independently are 0, 1, 2 or 3,

R'2, R"®, R" and R'® independently are hydrogen or Cg-alkyl,

Dis 18 R'® \ 18 R'® R'® w er Ber Mer Sao [ ¢ RY , ’ , rR" ) N R'® !

Rr" R'®

Rr" 16 R'S w [1] 1] ! oO

R™ R'

R' rR" \ R' R'" R'® 6] R'®

N 20 \ ) RY Rr" ' ’ ’ (e] RY rR" } R'®

XS

16 w

R ’ wherein

Wiis -O-, -S-, -S(0),- or -NR¥-,

W' is =CR¥- or =N-,

R® and R® are hydrogen, C,¢-alkyl or Cs4-cycloalkyl-C,s-alkyl,

R'%, RY, R'" and R'® independently are « hydrogen, halogen, -CN, -CH,CN, -CHF,, -CFa, -OCF;, -OCHF,, -OCH,CF3, -OCF,CHF,, -OS(0),CFs, -SCF3, -NO,, -OR?', -NR*'R*, -SR?', -NR?'S(0),R%, -S(0),NR*' RZ, 7 -S(0)NR?*'R%, -S(O)R?, -S(0),R?', -0S(0),R?, -C(O)NR?'R%, -OC(O)NR?'R?,

-NR?'C(O)RZ%, -CH,C(O)NR?'R%, -OCH,C(0)NR?'R%, -CH,0R?', -CH,NR?'R%, -OC(0O)R?, -C(O)R?! or -C(O)OR?, e C,¢-alkyl, Coe-alkenyl or C,g-alkynyl, which may optionally be substituted with one or more substituents selected from -CHF,, -CF3, -OCF;, -OCHF,, -OCH,CF;, -OCF,CHF,, -SCF;, -OR?, -NR¥'R%, -SR?, -S(O)R?, -S(0),R?, -C(O)NR?'R?%, -OC(O)NR?'R%, -NR?' C(O)R%, -OCH,C(O)NR?'R%, -C(O)R?' and -C(O)OR?, » Csg-cycloalkyl, Cys-cycloalkenyl, heterocyclyl, Css-cycloalkyl-C,s-alkyi, Cs g-cyclo- alkyl-C, e-alkoxy, Css-cycloalkyloxy, Cs s-cycloalkyi-C,s-alkylthio, C,s-cycloalkylthio,

Cse-cycloalkyl-Cas-alkenyl, Csg-cycloalkyl-Coe-alkynyl, Cas-cycloalkenyl-C,s-alkyl,

Cag-cycloalkenyl-C,s-alkenyl, Css-cycloatkenyl-C,s-alkynyl, heterocyclyl-C, ¢-alkyl, het- erocyclyl-C,s-alkenyl or heterocyclyl-C,¢-alkynyi, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from -CHF,, -CF;, -OCF3, -OCHF,, -OCH,CF,, -OCF,CHF,, -SCF;, -OR?', -NR¥R?, -SR¥, -S(O)R?, -S(0),R?, -C(O)NR?'R%, -OC(O)NR?'R%, -NR?'C(O)R?, -OCH,C(O)NR?'R%, -C(O)R?' and -C(O)OR?, " Cyg-alkyl, Cos-alkenyl and C,g-alkynyi, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF,, -OCF,, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF3, -OR?, -NR?'R?%, -SR?, -S(0)R?', -S(O),R?', -C(O)NR?*'R?%, -OC(O)NR?¥'R%, -NR¥'C(0)R?%, -OCH,C(O)NR*'R?, -C(0)R?*' and -C(O)OR?, e aryl, aryloxy, aryloxycarbonyl, aroyl, ary!l-C,¢-alkoxy, aryl-C,¢-alkyl, aryl-C,¢-alkenyl, aryl-

C.e-alkynyl, heteroaryl, heteroaryi-C, ¢-alkyl, heteroaryl-C,s-alkenyl or heteroaryl-

C,.¢-alkynyl,

of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CH,CN, -CHF,, -CF;, -OCF3, -OCHF,, -OCH,CF3, -OCF,CHF,, -OS(0),CF3, -SCF3, -NO,, -OR?, -NR?*R%, -SR?', -NR?'S(0),R%, -S(0),NR?'R?, -S(O)NR?'R?, -S(O)R?, -S(0),R?', -OS(0),R?, -C(O)NR?'R%*, -OC(O)NR?'R%, -NR?'C(O)R?%, -CH,C(O)NR*'R?%, -OCH,C(O)NR?*R%, -CH,0R?, -CH,NR?'R%, -OC(0)R?, -C(O)R*' and -C(O)OR?,

C.s-alkyl, C,¢-alkenyl and C,s-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF3, -OCF,, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF;, -OR?, -NR?'R%, -SR?', -S(0)R?, -S(0),R?', -C(O)NR*'RZ, -OC(O)NR?'R%, -NR¥'C(0)R?, -OCH,C(O)NR?'R%, -C(O)R?' and -C(O)OR?', wherein R*' and R% independently are hydrogen, -CF, C,s-alkyl, tri-C, -alkylsilyl, C3¢-cyclo- alkyl, Css-cycloalkyl-C, s-alkyl, aryl, aryl-C,s-alky! or heteroaryl, or R?' and R% when at- tached to the same nitrogen atom together with the said nitrogen atom may forma 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R'® to R' when placed in adjacent positions together may form a bridge —(CR'"R'),-0-(CR"™R").-0-, wherein ais 0,1o0r2, cis 1or2,

R' R', R'® and R" independently are hydrogen, C,s-alkyl or halogen,

E is a 3 to 9 membered mono- or bicyclic ring which may optionally contain one or two dou- ble bonds and which may optionally contain one or two heteroatoms selected from nitrogen, oxygen and sulfur, wherein one or two groups R*® and R* may be attached to the same or different ring carbon atoms and wherein a group R*' may be attached to a ring nitrogen atom when present, or

RE RZ

RY RY

[o} N [o} N lo} Io) A o i} o RA RZ (Bw

Pr 5

RY R2® R R*® 2 2 [ RY (Be RY R™ AALS

RE R® H R? » « rR” dre),

Nk ' I ’ R* RY ' ' {CH ), 2 Hl

CH 2p CHR) c Rr? m y HR™) Gr,

R? R®

RY. _R® rR R® " rR» (Zw (Be ol hd fi" hk i : (CHR™), CH ’ 4 4 I ’

CH (CHR), . | —y CH (CHR), | CHR®)_ lL HR) ! f

RZ RS CH, CH, RA Rr? 24 rR?

R R2 rR? R® rR?

N NH

[] , 3 or x Z ' (HR % Fo , wherein mand p independently are 0, 1, 2, 3 or 4, with the proviso that when both m and p are pre- sent in the same formula at feast one of m and p is different from 0,

R* and R* independently are

* hydrogen, -CHF;, -CF3, -OCF3, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF;, -OR®, -NR¥RY, -SR*, -S(O)R*®, -S(O),R*, -C(ONR¥R¥ -OC(O)NR¥R¥, -N R¥C(O)RY, -OCH,C(O)NR*RY, -C(O)R* or -C(O)OR?, eo Cye-alkyl, Cos-alkenyl or C,s-alkynyl, which may optionally be substituted with one or more substituents selected from -CHF, -CF3, -OCF;, -OCHF,, -OCH,CF, -OCF,CHF,, -SCF3, -OR®, -NR*RY, -SR¥, -S(0)R*, -8(0);R¥, -C(O)NR*R*’, -OC(0)NR¥R¥, -NR*C(O)RY, -OCH,C(O)NR¥*RY, -C(O)R* and -C(O)OR®, » Cyg-cycloalkyl, C;g-cycloalkylidene, C;g-cycloalkenyl, heterocyclyl, Cs ¢-cycloalkyl-

C,6-alkyl, Css-cycloalkyl-C,s-alkenyl, C3s-cycloalkyl-C,s-alkynyl, C3 s-cycloalkenyi-

C,¢-alkyl, Cag-cycloalkenyl-C,s-alkenyl, C, g-cycloalkenyl-C, s-alkynyi, heterocyclyl-

C,e-alkyl, heterocyclyl-C, s-alkenyl or heterocyclyl-C, ¢-alkynyl, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from -CHF,, -CF3, -OCF3,, -OCHF 3, -OCH,CF3, -OCF,CHF,, -SCF3, -OR%, -NR*R?Y, -SR™®, -S(O)R¥®, -S(0),R*, -C(O)NR¥*R*, -OC(O)NR*R¥ -NR¥*C(O)R¥, -OCH,C(O)NR¥*R¥, -C(O)R* and -C(O)OR?,

C,s-alkyl, C,s-alkenyl and C,s-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF3, -OCF;, -OCHF,, -OCH,CF;, -OCF,CHF,, -SCF,, -OR%, -NR*R¥, -SR*, -S(O)R*, -S(0),R*, -C(O)NR¥R?, -OC(O)NR*™R¥, -NR*C(0)RY, -OCH,C(O)NR*R¥ -C(O)R* and -C(O)OR™, e aryl, aryloxy, aroyl, aryl-C,s-alkoxy, aryl-C,s-alkyl, aryl-C,¢-alkenyl, aryl-C,¢-alkynyl, het- eroaryl, heteroaryl-Cs-alkyl, heteroaryl-C,¢-alkenyl or heteroaryl-C,¢-alkynyl, —

of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CH.CN, -CHF, -CF3, -OCF;, -OCHF;, -OCH,CF, -OCF,CHF,, > -08(0);CF3, -8CFs, -NO;, -OR¥, -NR*¥R”, -SR*, -NR*S(0),RY, -S(0),NR*R?, -S(O)NR*RY, -S(0O)R*, -S(O),R*, -0S(0).R*®, -C(O)NR*RY, -OC(O)NR*RY, -NR¥C(0)R¥, -CH,C(O)NR*R¥, -CH,C(O)NR*R¥, -CH,OR?, -CH,NR*R¥, -OC(0)R¥*, -C(O)R*® and -C(O)OR?,

Cis-alkyl, C,s-alkenyl and C,¢-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF3, -OCFj3, -OCHF,, -OCH,CF;, -OCF,CHF,, -SCF3, -OR*, -NR*R¥, -SR®, -3(0)R*, -S(0),R*, -C(O)NR*R?Y, -OC(O)NR*¥R¥, -NR*C(0)R¥, -OCH,C(O)NR*¥R¥, -C(O)R* and -C(O)OR?, wherein R* and R* independently are hydrogen, C,¢-alkyl or aryl, of which the aryl moiety optionally may be substituted with one or more substitu- ents selected from halogen, -CN, -CF3, -OCF;, -NO,, -OR3®, -NR*¥R* and

Cis-alkyl, wherein R* and R* independently are hydrogen or C,-alkyl, or R* and R¥ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or R® and R* when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH.)-CR*R*'-(CH,)-O-, -(CH,)-CR*R*'-(CH,)- or -S-(CH2)-CR*R*'-(CH,);-S-,

wherein ) t and | independently are 0, 1, 2, 3, 4 or 5,

R* and R* independently are hydrogen or C,s-alkyl,

R? to R¥ independently are hydrogen, halogen, -CN, -CF,, -NO,, -OR*, -NR*2R®, C, s-alkyl,

Css-cycloalkyl or C,¢-cycloalkenyl, wherein R* and R* independently are hydrogen or C,4-alkyl, or

R* and R* when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,

R*, R* and R* independently are hydrogen or C,¢-alkyl,

R* and R* independently are e hydrogen, C,s-alkyl, C,s-alkoxy, C,g-alkanoyl, -C(O)NR*R* or -S(0),R*®, » aryl, aroyl, aryl-C, ¢-alkoxy, aryl-C¢-alkanoyl or aryl-C, ¢-alkyl, of which the aryl moieties optionally may be substituted with one or more substi- tuents selected from halogen, -CN, -CF3, -OCF3, -OR*, -NR*R* and C; s-alkyl, wherein R* and R* independently are hydrogen or C,s-alkyl, or

R* and R* when attached to the carbon atom together with the said carbon atom may form a 3 to 8 membered cyclic ring optionally containing one or two heteroatoms selected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds, or

R3* and R* when attached to the nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroa-

toms selected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds, - as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

In a preferred embodiment V is -C(O)OH, -S(0), OH, -C(O)NHOH or 5-tetrazolyl, and more preferred -C(O)OH or 5-tetrazolyl.

In a preferred embodiment A is 7 NT —CHy"NR™ , —(CH);~NR— , —NR— , —(CH)— 0) or —NR—CH,— wherein R’ is as defined for formula (1).

More preferred A is —(CH);~N— —CH;/—N— —N— —N—~CH,— —N —H N or H :

In a preferred embodiment Y is -C(O)-.

In another preferred embodiment Y is a valence bond.

In a preferred embodiment Z is

RS

, wherein R%® and RY arc as defined for formula (1).

More preferably, Z is

In a preferred embodiment R' is hydrogen.

In another preferred embodiment R' is methyl.

In a preferred embodiment X is

Q Q 13514 1314 eH) N—I—0—(CR"R™)~(CH);— | — (CHF (CR"R™)~(CH)—

R'2 9 1314 0 0 4 —N (CR"R™)~(CH,)-0— . —(cR*R™)~(Ch,),, L(CH)——=(cH,);~

R'? 0 R' o R" o cH, — N—(CH)— chp) —Nn—L—(crR"R")— CH)— 0 0 e] —N—eH)— |. —o—(ERURM (cH) |. CHS —CH)— rR" . 0 Oo —=N—(CR"R")—(CH,);- —L (eH, (CRR™)—0—(CH,);— or

R" ro R'?

LL (cH,)—N—(CH)-0— wherein q, r, s, R'2, R™ and R'* are as defined for formula (1).

More preferably, X is

O 0 O —L—cH,)— , —l-c=c— , (CH) N— (CH, (0) O 0] — ern ——er)— (cH, — N—(CH);—0— 0 10] 0 —(CH,)— , eH )—N—-o—(cH)— —N—l— (cH) — 0] Oo —L—(CR™H)—o0—(CH,)— —L—0—(CH,)— or

O

—LLN—(CR"R™),—

H whereingisOor1,risOor1,sis0,1or2, and R'is hydrogen or C,s-alky!.

Even more preferably, X is -C(O)NH-, -C(O)NHCH,-, -C(O)NHCH(CHj,)-, -C(O)NHCH,CH-, -C(O)CHy;-, -C(O)CH=CH-, -(CH,)s-, -C(O)-, -C(O)O- or -NHC(O)-, wherein s is 0 or 1.

Still more preferably, X is -C(O)NH-, -C(O)NHCH,-, -C(O)NHCH(CH;)-, -C(O)NHCH,CH_-, -

C(O)CHz-, -(CH,)-, -C(O)- or -NHC(O)-.

Of these X is preferably -C(O)NH- or -C(O)NHCH(CHa)-.

In a preferred embodiment D is

Rr" RS R" R'® R' fo ’ 4 , rR" RY rR" N rR" 17 '

R Fo}

R' R'® S R'® R' , ’ N ’ [] ; ] H R'® rR" o R'® ? ’ RY No wherein RR", R", R" and R? are as defined for formula (1).

More preferably, D is - 16

R' R' R"® R 2 R' 17 _ p20 S - R , N-R RY 18 W 7 !

R rR" R R 0

R'® 16 s . oR — R or SHR" wh : 16 17 18 20 erein R™, RY, R"™ and R* are as defined for formula (1).

In a preferred embodiment D is

R'S 0] iP [ N-R® rR" ! 0 wherein R'®, R'7 and R® are as defined for formula ().

More preferably, R'® and R'” are both hydrogen and R* is C,-alkyl or Cy s-cycloalkyl-C,s- alkyl. Even more preferably, R* is cyclopropylmethyl, butyl or isopropyl, especially preferred isopropyl.

In another preferred embodiment D is . rR R' % °3 rR" or Rr" wherein R' and R" are as defined for formula (I).

In yet another preferred embodiment D is

RY

=

Rr" wherein R'®, R' and R"® are as defined for formula (1).

Preferably, R'®, R' and R'® are independently hydrogen, halogen, -CN, -NO,, -CF,, -OCF3, hydroxy, -SCF;, C,¢-alkyl, C,¢-alkyl substituted with hydroxy, C,s-alky! substituted with -S(0),R?', C,s-alkoxy, -S-C,s-alkyl, -C(O)OR?, -C(O)R?', -CH,(O)R?, -C(O)NR?¥'R%, -S(O)R?', -S(0),R?, -S(0),CF3, -S(0),NR*'R%,

Cag-cycloalkyl, Cs s-cycloalkyl-C,s-alkoxy, Css-cycloalkyl-C, ¢-alkylthio or Cae-cycloalkylthio, wherein R?' and R? independently are hydrogen, C,-alkyl, tri-C,s-alkylsilyl, Css-cycloalkyl,

Cag-cycloalkyl-C, ¢-alkyl, phenyl, phenyl-C,s-alkyl, 2,3-dihydroindolyl or isoindolyl, or R*' and

R?? together with the nitrogen atom to which they are attached form a piperidine ring, phenoxy, phenoxycarbonyl, phenyl, phenyl-C, s-alkoxy, phenyl-Cq-alkyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring systems optionally may be substituted with halogen, -CN, -CF;, -OCF;, -NO,, -C(0)OR?, -OR?, -NR?'R% or C, ¢-alkyl, wherein R*! and

R? independently are hydrogen or C,s-alkyl, or wherein R'® and R' in adjacent positions form the radical -O-CH,-O-, -CF-O-CF,-O- or -0-CF,-CF0-, and R" is hydrogen.

More preferably, R'®, R' and R'® are independently hydrogen, halogen, -CN, -NO,, -CF3, -OCF,, -SCF,, C,¢-alkyl, C,¢-alkyl substituted with hy- droxy, Cye-alky! substituted with -S(O),R?', C,¢-alkoxy, -S-C,¢-alkyl, -C(O)OR?, -C(O)R?", -CHA(O)R?', -C(O)NR?'RZ, -S(O)R?', -8(0),R?', -S(0),CFs, -S(0);NR?'R?, Cs g-cyclo- alkyl-C,s-alkoxy, C;e-cycloalkyl-C,.e-alkylthio or C;s-cycloalkylthio, wherein R*' and R? independently are hydrogen, Cy ¢-alkyl, tri-C,-alkylsilyl, Cs g-cycloalkyl,

Cs e-cycloalkyl-Cs-alkyl, phenyl or 2,3-dihydroindolyl, or R?' and R? together with the nitro- gen atom to which they are attached form a piperidine ring, ) phenoxy, phenyl, benzyl, furanyl, tetrazoly!, benzoxazolyl or oxadiazolyl, of which the ring sys- tems optionally may be substituted with halogen, -C(O)OR?' or C,¢-alkyl, wherein R?' is hy- drogen or C,s-alkyl, or wherein R'® and R'’ in adjacent positions form the radical -CF,-O-~CF,-O- or -O-CF,-CF,-O-, and R'® is hydrogen.

Even more preferably, R®, R" and R'® independently are hydrogen, halogen, -CN, -NO,, -CF;, -OCF,, -SCF3;, C,g-alkyl, C,s-alkyl substituted with hy- droxy, C,e-alkoxy, -S-Cys-alkyl, -C(O)OR?', -C(O)R?', -CH,(O)R?, -C(O)NR?'R%, -S(0),R?, -(0).CF; or -S(0),NR*'R?%, wherein R?' and R% independently are hydrogen, C,.-alkyl, tri-C,s-alkylsilyl, phenyl or 2,3-dihydroindolyl, phenoxy, phenyl, benzyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring sys- tems optionally may be substituted with halogen, -C(O)OR?' or C, s-alkyl, wherein R?' is hy- _ drogen or C,g-alkyl, or wherein R'® and R'7 in adjacent positions form the radical -CF,-O-CF,-O- or -0-CF;-CF,-O-, and R'® is hydrogen.

Still more preferably, R™, R'” and R" are independently hydrogen, halogen, -CN, -NO,, -CF-

S 3 -OCF,, -SCF,, C,¢-alkyl, C,s-alkoxy, -S-Cy¢-alkyl, -C(0)OC, ¢-alkyl, -5(0).C¢-alkyl , -S(0).LF3, -C(O)N(Cs5-alkyl)(Cys-alkyl), -S(O)N(pheny!)(C,¢-alkyl), -C(=0)C,.¢-alkyl, -CH.OH, -CH,O(tri-C,.¢-alkylsily!), 2,3-dihydroindol-1-ylsutfonyl, phenoxy, phenyl, 4-chloro- phenyl, 1,3,5-trimethylbenzyl, benzoxazolyl, 2-methyltetrazol-5-yl, 2-methyl-3-methoxy- carbonylfuran-5-yl or 3-isopropyl-[1,2,4]Joxadiazol-5-yl).

In a preferred embodiment one of R' to R'® is hydrogen.

In another preferred embodiment two of R' to R'® are hydrogen. 16 In yet another preferred embodiment R'® and R'’ are both hydrogen and R™ is -OCF,, -SCF, -CF3, =S(0),CH;, phenyl, halogen, C,s-alkyl, nitro, -S-C, g-alky! or -S(O),NR?'"R%, wherein

R¥ is C,¢-alkyl and R% is phenyl.

In still another preferred embodiment R'® and R'’ are both hydrogen and Ris -OCF; or halogen.

In a further embodiment R* is hydrogen and R' and R* are both halogen or are both —~CFs.

In yet a further embodiment R'® is hydrogen, R'” is CF, and R™ is halogen, -CN, C.s-alkoxy or -OCF,.

In still a further embodiment R'is hydrogen, R" Is -OCF; and R'® is -S(0),CHs, -CH,0-tri-C;. g-alkylsilyl, benzoxazolyl or -CH,OH.

In another embodiment R'is hydrogen, R" is C,s-alkyl and R' is -S(0),NR?'R%, wherein

R* is C,¢-alkyl and R% is phenyl.

In still another embodiment R'¢, R'” and R'® are selected from hydrogen, -OCFs, -CF, -Br, -F and —Cl.

In a preferred embodiment E is

R2 RY rR: RA RR Rr? R 2 / RY x NR Ey R® ! ! ’ ‘RY ' \ ’ ! 2 2 rR 24 2 2

R R R R R

J] N ) 23 &

R® \.R _R® 3 ( %

RY ! | RZ ’ RZ ’ rR? Ro N

R2*

N

N rR? \ ! R® ' RY ' RE rR ’ R? N ’ rR:

RY RY [ ] ' J ! LT ’ , = RY R® RAR”

A RY RY RY R* RAR pe R™ “Tre las {CHR™), (CHR™ CH I” AS o i | I , R Su RY? , do ,

Pr CHR™) " pa] R32 “N R® “ R® Z RY > rR? (CHR™), CH » CH

I : Tr I or 22 ' CH

Te I ao (CHR™),, _-—

GR, | Gre om pe Rr?

Ce _

wherein m, p and R® to R* are as defined for formula (1).

Preferably, E is

R* 25 Rr? 25 26 s 23

R R R R? R® R rR

R% N N- ) A , , oY" , a , rR? R2

R% R% R® RZ rR? ol) (Se “0G RL RY ’ , RZ RY ' Y (CHR), re (CHa), (CHR®), ’ (CHR™ 2 dn i Im Rn 24

R%. _R® R rR? RA R* R® "ey J ~4 (CHR™), : N , Rr? R ” (CHR™, bik Im (EHR

RA R% rR? 2% CH, CH rR? R 3 3

RA rR? R% R® pe) rR

N NH a ’ > ’ Fo , , (CHR), ’

RZ Rr? R* 27 wherein m, p and R® to R* are as defined for formula (1),

More preferably, E is

R RS R?® Rr? R% i os i. ie i 8) ¢ R® Y , , RS RY , CH,), , (GH), (Heh (CH) 24 . i R% rR A RY R®

RZ:

ROR wherein p, RZ, R*, R®, R®, R?, R*®, R®, R¥, R* and R® are as defined for formula (1).

Even more preferably, E is rR? R%® R® R% 0) “<r rR? {r RZ ~ R?

CH, (CH,), ) I or pe S GH, : (CHa);

NT rm wherein R%, R*, RR? RZ, R* and R® are as defined for formula (1).

NT

I

When E is , R* and R® are preferably independently C,s-alkyl, hydrogen or

Ci s-alkoxy. More preferably, R* and R* are both C, ¢-alkyl.

In another preferred embodiment E is [ad wherein R? and R* are as defined for formula (I).

Preferably, E is . . wherein R? and R** are as defined for formula (1).

Preferably, RZ and R* are independeritly selected from hydrogen, C,s-alkyl, Cs s-cycloalkyl,

Cse-cycloalkylidene, phenoxy, phenyl, -C(O)NR¥*R* and -OC(O)NH-phenyl, of which the phenyl moiety optionally may be substituted with -OCF;, wherein R* and R* are as defined in claim 1, or R? and R? together form the radical -(CH,)-CR*R*’-(CH,)r, -O-(CH)-CR*R*'- (CH,)-O-, -S{CH)-CR*R"'-(CH,)-S-, wherein t, |, R* and R*' are as defined for formula (1).

More preferably, R* is hydrogen and R* is C,-alkyl such as tert-butyl or Css-cycloalky! such as cyclohexyl, wherein R® and R? are both C,s-alkyl or wherein R® and R* together form the radical —(CH,)s-.

In yet another preferred embodiment E is

RS R% rR? “£3 RY 3 RY o “~£ RY

CH, (CH, ), wherein R®, R* and RY are as defined for formula (1).

Preferably, E is

RZ

£3 wherein R?®, R?® and R? are as defined for formula (I).

Preferably, R®, R? and RY are independently selected from hydrogen, halogen, C,-alkyl,

C,¢-alkoxy, Cas-cycloalkyl, C,s-cycloalkenyl, -CF3, -OCF; or -NR*?R*?, wherein R*? and R* are as defined for formula (1).

More preferably, E is rR? wherein R? is —OCF;, -CF3, Cy.¢-alkyl such as tert-butyl, piperidyl, Cys-cycloalkyl such as cyclohexyl or C, s-cycloalkenyl such as cyclohexenyl.

Claims

1. A compound of the general formula (1): T _A V4 N...D 0) v© YY” ~X he wherein Vis -C(O)OR?, -C(O)NRR?, -C(O)NR?0OR?, -S(0),0R?, OH o N CEES SRI of ) , = o” N=N or 1 A R N ’ H wherein R? and R® independently are hydrogen or C,¢-alkyl, R* is hydrogen, halogen, -CN, -CF3, -OCF3, -NO,, -OR®, -NR°R® or C, g-alkyl, wherein R® and R® independently are hydrogen or C,¢-alkyl, Ais rR R° rR? R° RE R° cry NR Me (cry—NR'— ' BNVARPS. or —£ NT (CH,), wherein bisOor1, nis0,1,2o0r3,

R’ is hydrogen, C,¢-alkyl or Ca g-cycloalkyl-C,.s-alkyl, R® and R® independently are hydrogen or C,¢-alkyl, Yis-C(0O)-, -S(0),, -O- or a valence bond, Z is phenylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con- taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R*¢ and RY selected from hydrogen, halogen, -CN, -CF3, -OCF;, NO, -OR', -NR™R"" and C,¢-alkyl, wherein R' and R"" independently are hydrogen or C,s-alkyl, or -A-Y-Z- together are 0] — CH CH;— CF 0 R'is hydrogen or C,s-alkyl, :

Xis _2 rn 2 1 14 (CRPR™)—(CH,)— —(CH,)—=—(CR"R"),— (CH, — 0 0 S 13,14 “eH ——CRR CH) | (eR RM (OH) R Q i" 13.41 v AL eH )—N—0—(CR"R*)=(CH)— | (CH) N= (CR™R™)—(CH,):—, R'? Rr" 0 0 ie 0, ,0 —ery—N—-N—(cr ROCH)— | —S—(CRR")—(CH,)— R'? R' 0 lo} —N——(CRUR (CH) —0—(CR¥R")—(CH,),— R'? 0 13.14 1314 ——(cH,);-N—(cR R“)-(CH)— —CRROT(CHY— R'2 NH R'? 314 \ —(CH)7 (CRUR™)~(CH)— —T—N—CRR")—(CH)— NH Q 13,14 oO cH) —(CcR RY)(CH);—0—— . —L—(CH,)~(CR"R")—O0—(CH,)— R 0 0 0 LL (CH,)—S—(CR™R™)—(CH)— or (cH) —(CR"R"™)—(CH,)— wherein risQor1, g and s independently are 0, 1, 2 or 3,

R'2, R*™, R" and R'® independently are hydrogen or C,-alkyl, Dis Rr" rR'S \ R® R' R'® w N «3 rR” pa: RY Q A = £5 ’ 4 ’ Rr" ’ N rR" ' R"” R'® R'*® R' rR w ’ ? ! [0] ' R™ R'® rR" R" \ Rr" rR" R" 0 Rr" \ ’ rY R'® ! ’ !

[0] rR" rR": R'® 2% oN 1 w R wherein Wis -O-, -S-, -S(0)- or -NR?-, W' is =CR%- or =N-, R'®, RY, R" and R" independently are e hydrogen, halogen, -CN, -CH,CN, -CHF,, -CF3, -OCF;, -OCHF,, -OCH,CF3, -OCF,CHF,, -OS(0),CF,, -SCF3, -NO,, -OR?, -NR?'R?%, -SR?', -NR?'S(0),R%, -S(O),NR?'R%, -S(O)NR?*'R?%, -S(0)R?, -S(0),R?', -OS(0),R?, -C(O)NR¥'R?, -OC(O)NR?'R%, -NR?'C(O)R%, -CH,C(OINR¥R?, -OCH,C(O)NR?'R%, -CH,0R?', -CH,NR?'R%, -QC(O)R?, -CLORY or -C(O)ORY,

LJ Cie-alkyl, C..s-alkenyl or Czg-alkynyl, which may optionally be substituted with one or more substituents selected from - CHF, -CF3;, -OCF;, -OCHF,, -OCH,CF,, -OCF,CHF,, -SCF3, -OR?', -NR?'R%, -SR?, -§(0)R?, -S(0),R?, -C(O)NR*'R%, -OC(O)NR?'R?, -NR?'C(0O)R?%, -OCH.C(O)NR?'R%, -C(O)R?' and -C(O)OR?, » Cjs-cycloalkyl, C4s-cycloalkenyl, heterocyclyl, C;s-cycloalkyl-C,e-alkyl, Cs s-Cyclo- alkyl-C,s-alkoxy, Cs s-cycloalkyloxy, C;s-cycloalkyl-C,e-alkylthio, Cs s-cycloalkylithio,

Css-cycloalkyl-C,s-alkenyl, Cs g-cycloalkyl-C,s-alkynyl, Cys-cycloalkenyl-C,s-alkyl, Cqs- cycloalkenyl-C,s-alkenyl, C,5-cycloalkenyl-C,s-alkynyl, heterocyclyl-C,s-alky!, heterocy- clyl-C,¢-alkenyl or heterocyclyl-C,e-alkynyl,

of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from -CHF,, -CF,, -OCFj3, -OCHF;, -OCH,CF;, -OCF,CHF,, -SCF3, -OR?, -NR?'R?%, -SR?, -§(0)R?', -S(0),R?, -C(O)NR?*'R%, -OC(O)NR?'R%, -NR?'C(0O)R%, -OCH,C(O)NR?'R?, -C(O)R?*' and -C(O)OR?",

Cis-alkyl, Co¢-alkenyl and Cy¢-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF3, -OCF3, -OCHF,, -OCH,CF,, -OCF,CHF,,

-SCF;, -OR?', -NR?'RZ%, -SR?', -S(0)R?', -S(0),R?', -C(O)NR?'R%,

-OC(O)NR?'R%, -NR?'C(0)R%, -OCH,C(O)NR?R?%, -C(O)R?*' and -C(O)OR?, e aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C¢-alkoxy, aryl-C,s-alkyl, aryl-C,s-alkenyl, aryl-

C,¢-alkynyl, heteroaryl, heteroaryl-C, g-alkyl, heteroaryl-C, -alkenyl or heteroaryl- Ce-alkynyl,

of which the aryl and heteroaryl moieties optionally may be substituted with one = or more substituents selected from halogen, -CN, -CH:CN, -CHF;, -CF3, -OCF;, -OCHF2, -OCH,CF,, -OCF,CHF,, -0S(0),CF3, -SCF3, -NO,, -OR?, -NR?'R%, -SR*", -NR¥'S(0),R?%, -S(0),NR*'R%, -S(O)NR?*'R?%, -S(0)R¥, -S(0),R?, -OS(0),R?, -C(O)NR?'R*, .OC(O)NR?*'RZ, -NR?'C(0)R?%, -CH,C(O)NR?'R%, -OCH,C(0)NR?'R%, -CH,0R?', -CH,NR?'R%, -OC(0)R?, -C(O)R? and -C(O)OR?', Cis-alkyl, C,s-alkenyl and C,¢-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF,, -OCF,, -OCHF,, -OCH,CF,, -OCF,CHF,, -SCF3, -OR?, -NR?'R%, -SR?, -S(0)R?', -S(0),R?', -C(O)NR?*'R?%, -OC(O)NR?'R%, -NR?'C(0)R?%, -OCH,C(O)NR?'R??, -C(O)R?' and -C(O)OR?, wherein R?' and R% independently are hydrogen, -CF;, Cy-alkyl, tri-C, ¢-alkylsilyl, Cas-cyclo- alkyl, Csg-cycloalkyl-C,¢-alkyl, aryl, aryl-C,¢-alkyl or heteroaryl, or R* and R# when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R'® to R* when placed in adjacent positions together may form a bridge —(CR'*R'"),-O-(CR*¥R'®)-0-,

wherein ais 0, 1or2, cistor2, R'®, RY, R"® and R'® independently are hydrogen, C,s-alky! or halogen, R? and R% independently are hydrogen, C,¢-alkyl, Cas-cycloalkyl or Cse-cycloalkyl-Ci.g- alkyl,

E is a 3 to 9 membered mono- or bicyclic ring which may optionally contain one or two dou- ble bonds and which may optionally contain one or two heteroatoms selected from nitrogen, oxygen and sulfur, wherein one or two groups R? and R?* may be attached to the same or different ring carbon atoms and wherein a group R*' may be attached to a ring nitrogen atom when present, or rR? RZ RY rR

[0] N [0] N [eo] fo) A 0 } o ni ut rR I 3). )938 , | 31 , KJ , LJ (Cue } Fe

RE. Rr RR R® 23 yeh Pe : R CHR®), oH . RB Ni ’ | 0 cH), CHR), (CHR™),, JN | " CHR™) rR? rR? wv hd il Nl i (CHR®), CH ’ ! CH ! [ ! cH (CHR), - dr, GH (CHR™), | CHR Jn CHR [i R® RS CH,_ CH, RY R® & LP oe N NH or ’ , » H] pl FZ ’ (GHR % Fo R% pr (Ge wherein F— m and p independently are 0, 1, 2, 3 or 4, with the proviso that when both m and p are pre- sent in the same formula at least one of m and p is different from 0,

R% and R* independently are * hydrogen, -CHF, -CF;, -OCF;, -OCHF,, -OCH,CF;, -OCF,CHF,, -SCF;, -OR, -NR*R?, -SR*, -S(0)R*, -S(0),R*, -C(O)NR*RY, -OC(O)NR*R?, -NR*C(O)R¥, -OCH,C(O)NR*RY, -C(O)R* or -C(O)OR®, eo C,e-alkyl, C,s-alkenyl or C,¢-alkynyl, which may optionally be substituted with one or more substituents selected from -CHF,, -CF3, -OCFj3, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF;, -OR%, -NR*R%, -SR*, -S(O)R¥, -§(0).R*, -C(O)NR¥R¥, -OC(OINR¥R¥, -NR*C(0)R¥, -OCH,C(O)NR*¥R¥, -C(O)R¥ and -C(O)OR®, 15» Csg-cycloalkyl, Cs4-cycloalkylidene, C,q-cycloalkenyl, heterocyclyl, Cs s-cycloalkyl- Ci ¢-alkyl, Ca s-cycloalkyl-C, ¢-alkenyl, Cs g-cycloalkyl-C,e-alkynyl, C4 g-cycloalkenyl- Ci¢-alkyl, C4s-cycloalkenyl-C,¢-alkenyl, C4 q-cycloalkenyl-C,.g-alkynyl, heterocyclyl- Cis-alkyl, heterocyclyi-C,e-alkenyl or heterocyclyl-C, ¢-alkynys, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from -CHF, -CF3, -OCF,, -OCHF,, -OCH,CF3, -OCF,CHF,, -SCF3, -OR®, -NR¥*R¥ -SR¥, -S(0)R¥, -S(0),R¥, -C(O)NR*R¥, -OC(O)NR*R¥, -NR¥C(O)RY, -OCH,C(O)NR¥RY, -C(O)R*® and -C(O)OR®, C,s-alkyl, C,¢-alkenyl and C,¢-alkynyl, which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF,, -OCF,, -OCHF,, -OCH,CF,, -OCF,CHF,, -SCF3, -OR¥®, -NR*R¥, .SR*¥, .5(0)R*, -S(0),R*, -C(O)NR*RY, -OC(O)NR¥R¥ -NR®C(O)R¥, -OCH,C(O)NR*RY, -C(O)R* and -C(O)OR¥,

aryl, aryloxy, aroyl, aryl-C,¢-alkoxy, aryl-C,s-alkyl, aryl-C,s-alkenyl, aryl-C,¢-alkynyl, het- eroaryl, heteroaryl-C,s-alkyl, heteroaryl-C,¢-alkenyl or heteroaryl-C,¢-alkynyl, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen, -CN, -CHZCN, -CHF,, -CF3, -OCF3, -OCHEF,, -OCH.CF;, -OCF.CHF,, -0OS(0),CF3, -SCF3, -NO;, -OR¥*, -NR¥*RY, -SR*, -NR*S(0),R¥, -S(0),NR*R¥, -S(O)NR¥RY, -S(0)R*, -S(0),R*, -OS(0),R*, -C(O)NR¥R¥, -OC(O)NR*R¥,

-NR*C(O)R*, -CH,C(O)NR¥R¥, -CH,C(O)NR¥*R¥, -CH,OR®, -CH,NR*RY, -OC(0)R*, -C(O)R* and -C(O)OR®, Cis-alkyl, Cos-alkenyl and C,¢-alkynyl,

which may optionally be substituted with one or more substituents se- lected from -CHF,, -CF,, -OCF;, -OCHF,, -OCH,CF,, -OCF,CHF,, -SCF;, -OR™*, -NR¥R¥ .SR* -S(O)R¥, -S(0),R*, -C(O)NR*R¥,

-OC(O)NR*R¥, -NR*C(O)RY, -OCH,C(0)NR*R¥, -C(O)R* and -C(O)OR*,

wherein R* and R¥ independently are hydrogen, C,¢-alkyl or aryl, of which the aryl moiety optionally may be substituted with one or more substitu- ents selected from halogen, -CN, -CF3, -OCF;, -NO,, -OR®, -NR*R and Ci¢-alkyl, wherein R* and R* independently are hydrogen or C,¢-alkyl, or R* and R¥ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or R? and R* when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)-CR*R*'-(CH,)--O-, ~(CH,)-CR*R*'-(CH)- or

-S-(CH2)-CR*R*'-(CH,)\-S-, wherein tandlindependently are 0, 1, 2, 3,4 or 5, R* and R*' independently are hydrogen or C,s-alkyl, R* to R* independently are hydrogen, halogen, -CN, -CF3, -NO,, -OR%, -NR2R*| Ci¢-alkyl, Cjs-cycloalkyl or C4s-cycloalkenyl, wherein R* and R*® independently are hydrogen or Cqs-alkyl, or R*? and R* when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, R*, R* and R*® independently are hydrogen or C,¢-alkyl,

R* and R* independently are hydrogen, C,.e-alkyl, Cy¢-alkoxy, C,s-alkanoyl, -C(O)NR*R* or -S(0),R*, e aryl, aroyl, aryl-C,e-alkoxy, aryl-C,s-alkanoyl or aryl-C,¢-alkyl, of which the aryl moieties optionally may be substituted with one or more sub- stituents selected from halogen, -CN, -CF3, -OCF,, -OR*, -NR*R* and C,s-alkyl, wherein R* and R*® independently are hydrogen or Cys-alky!, or R* and R* when attached to a carbon atom together with the said carbon atom may form a 3 to 8 membered cyclic ring optionally containing one or two heteroatoms selected from ni- trogen, oxygen or sulfur, and optionally containing one or two double bonds, or

2. A compound according to claim 1, wherein V is -C(O)OH, -S(O),0H, -C(O)NHOH or 5- tetrazolyl.

3. A compound according to claim 2, wherein V is -C(O)OH.

4. A compound according to claim 2, wherein V is 5-tetrazolyl.

5. A compound according to any one of the claims 1 to 4, wherein A is nN —CH;— NR— » (CH) NR— , —NR— y (CH) ;— ’ —£) —NR™—CH,— wherein R’ is as defined in claim 1.

6. A compound according to claim 5, wherein A is — (CH) N—

7. A compound according to claim 5, wherein A is

8. A compound according to claim 5, wherein A is

8. A compound according to claim 5, wherein A is —N—CH,—

10. A compound according to any one of the claims 1 to 9, wherein Y is -C(O)-.

11. A compound according to any one of the claims 1 to 9, wherein Y is a valence bond.

12. A compound according to any one of the claims 1 to 11, wherein Z is

RY . wherein R* and RY are as defined in claim 1.

13. A compound according to claim 12, wherein Z is

14. A compound according to any one of the claims 1 to 13, wherein R' is hydrogen.

15. A compound according to any one of the claims 1 to 13, wherein R' is methyl.

16. A compound according to any one of the claims 1 to 15, wherein X is o Q 13,14 13,14 —-eHp—n—l—o-(cr R)T(CHY— | — (CH (CR™R™)—(CH)—~ R Q 13514 0 0 —N—L—cr RY~(CH)-0— . —L(cR®R™)~(CH,), . —L—(CH)——(CH)— R'? 12 0 R 0 R™ Io) —cH)N—cH)— —— (cH )—N—IL—(CR¥R™)— (CH) 0 0 0] —N——cH)— —o-crURY)—cH)— |. -cH)—s—eH)— R'? i ail 13,14 —-N—(CR"R")— (CH); (CH) (CR™R™)—0—(CH,);— or R'? 12

2 . (CH); —N—(CH)-0— whereinq, r,s, R'%, R" and R" are as defined in claim 1.

17. A compound according to claim 16, wherein X is 0 0 0) ——cH)— . —le=e— | AeH)N—e)— Oo Oo 0) ey —en— Lenyy—cni—o— Oo 0 oO —(CH)— eH —-0—cH,— Nl e)— 0) 3 0) —L— (CR"*H)—O0—(CH,)— ——0—(CH,)— or 0] —lN—(CR"R"), — H whereingisOor1,risOor1,sis0, 1o0r2, and R'is hydrogen or C,s-alkyl.

18. A compound according to claim 17, wherein X is -C(O)NH-, -C(O)NHCH,-, -C(O)NHCH(CHa)-, -C(O)NHCH,CH,-, -C(O)CH,-, -C(O)CH=CH-, -(CH_);-, -C(O)-, -C(O)O- or -NHC(O)-, wherein sis 0 or 1.

19. A compound according to claim 18, wherein X is ~C(O)NH-, -C(O)NHCH,-, -C(OINHCH(CHa)-, -C(O)NHCH,CH,-, -C(O)CH_-, -CH_-, -C(QO)- or -NHC(O)-.

20. A compound according to claim 19, wherein X is -C(O)NH-.

21. A compound according to claim 19, wherein X is -C(O)NHCH(CH,)-.

22. A compound according to any one of the claims 1 to 21, wherein D is R'® R R' R'® R' 0 18 17 rR" N18 7 R R R R ° R'® R' R' R'® Ss 17 8 1 0 , ’ N ! ’ R" H R" RY fo) R™ ou RY” N RY 21 or KX ZR” 17 N ’ ’ R ‘rR? wherein R'®, R", R"®, R" and R® are as defined in claim 1.

23. A compound according to claim 22, wherein D is N 16 rR RS rR" R o R'"® 17 ’ R'® RY rR" R 0 R'® 18 Ss " oN — R or poy wherein R'®, RY, R'® and R? are as defined in claim 1.

24. A compound according to claim 23, wherein D is R™ 0 rR" h ° wherein R'®, R'” and R” are as defined in claim 1.

25. A compound according to claim 24, wherein R'® and R'” are both hydrogen and R® is C,s-alkyl or C3 g-cycloalkyl-C,.¢-alkyl.

26. A compound according to claim 24 or 25, wherein R? is cyclopropylmethyl, butyl or iso- propyt.

27. A compound according to claim 26, wherein R% is isopropyl.

28. A compound according to claim 23, wherein D is R'" R'® % °3 rR" or rR" wherein R' and R'7 are as defined in claim 1.

29. A compound according to claim 23, wherein D is rR" RY R'® wherein R', R' and R'® are as defined in claim 1.

30. A compound according to any one of the claims 22, 23, 28 or 29, wherein R'®, R'” and R'" independentiy are hydrogen, halogen, -CN, -NO,, -CF3, -OCF,, hydroxy, -SCF,, C,¢-alkyl, C,¢-alkyl substituted with hydroxy, C.s-alkyl substituted with -S(O),R?', C,4-alkoxy, -S-C,¢-alkyl, -C(O)OR?, -C(O)R?, -CH,(O)R?*', -C(O)NR?'R%, -S(O)R?, -S(0),R?, -S(0),CF3, -S(0).NR?'R%, Cse-cycloalkyl, Css-cycloalkyl-Cy¢-alkoxy, Cse-cycloalkyl-C, ¢-alkylthio or C;a-cycloalkyithio, wherein R*' and R% independently are hydrogen, C,¢-alkyl, tri-C,g-alkylsily!, Cs s-cycloalkyl, Cs g-cycloalkyl-C, alkyl, phenyl, phenvl-C, .-alky!, 2,3-dihvdraindalvl or isoindalyl, or R?' and RZ together with the nitrogen atom to which they are attached form a piperidine ring,

phenoxy, phenoxycarbonyl, phenyl, phenyl-C,¢-alkoxy, pheny}l-C,¢-alkyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring systems optionally may be substituted with halogen, -CN, -CF3, -OCF3, -NO,, -C(O)OR?', -OR?, -NR?'R? or C, g-alkyl, wherein R?' and RZ independently are hydrogen or C,.¢-alkyl, or wherein R'® and R"” in adjacent positions form the radical -O-CH,-0-, -CF,-O-CF,-O- or -O-CF,-CF-O-, and R'® is hydrogen.

31. A compound according to claim 30, wherein R'®, R'” and R™ independently are hydrogen, halogen, -CN, -NO,, -CF3, -OCF,, -SCF,, C,s-alkyl, C,s-alkyl substituted with hy- droxy, C,s-alkyl substituted with -S(0),R?', C,s-alkoxy, -S-C,¢-alkyl, -C(O)OR?', -C(O)R?', -CH2(0)R?', -C(O)NR?'R%, -S(O)R?, -S(0),R?, -S(0),CF3, -S(0).NR?'R?, C,4-cyclo- alkyl-C, ¢-alkoxy, C,s-cycloalkyl-C,¢-alkylthio or C;5-cycloalkylthio, wherein R?' and R% independently are hydrogen, C, s-alkyl, tri-C,s-alkylsilyl, C3 s-cycloalkyl, Cass-cycloalkyl-C,s-alkyl, phenyl or 2,3-dihydroindolyl, or R*' and R* together with the nitro- gen atom to which they are attached form a piperidine ring, phenoxy, phenyl, benzyl, furanyi, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring sys- tems optionally may be substituted with halogen, -C(O)OR?' or C, ¢-alkyl, wherein R*' is hy- drogen or C,-alkyl, or wherein R'® and R" in adjacent positions form the radical -CF,-O-CF,-O- or -O-CF,-CF,-O-, and R'® is hydrogen.

32. A compound according to claim 31, wherein R'®, R' and R" independently are hydrogen, halogen, -CN, -NO,, -CF3, -OCF3, -SCF;, Cys-alkyl, Cy¢-alkyl substituted with hy- droxy, C,s-alkoxy, -S-C.-alkyl, -C(O)OR?', -C(O)R?', -CH,(O)R?', -C(O)NR?'R%, -S(0),R?, -(0),CF3 or -S(0),NR*'R%, wherein R?' and R# independently are hydrogen, C, s-alkyl, tri-C, g-alkylsilyl, phenyl or 2,3-dihydroindolyl,

phenoxy, phenyl, benzyl, furanyl, tetrazolyl, benzoxazolyl or oxadiazolyl, of which the ring sys- tems optionally may be substituted with halogen, -C(O)OR*' or C,s-alkyl, wherein R?' is hy- drogen or C,g-alkyl, or wherein R' and R" in adjacent positions form the radical -CF,-O-CF,-O- or -O-CF,-CF,-0O-, and R'® is hydrogen.

33. A compound according to claim 32, wherein R', R" and R'® independently are hydro- gen, halogen, -CN, -NO,, -CF3, -OCF,, -SCF;, C,s-alkyl, Cy s-alkoxy, -S-C,6-alkyl, -C(O)OC,g-alkyl, -S(0),Cy5-alkyl, -S(0).CF3, -C(O)N(Cy¢-alkyl)(Cy5-alkyl), -S(0)N(phenyl)(Cys-alkyl), -C(=0)C s-alkyl, -CH,0H, -CH,O(tri-C s-alkylsilyl), 2,3-dihydro- indol-1-yisulfonyl, phenoxy, phenyl, 4-chlorophenyl, 1,3,5-trimethylbenzyl, benzoxazolyl, 2- methyltetrazol-5-yl, 2-methyl-3-methoxycarbonylfuran-5-yl or 3-isopropyl-[1,2,4)oxadiazol-5-

yl).

34. A compound according to any one of the claims 30 to 33, wherein one of R'® to R™ is hy- drogen.

35. A compound according to any one of the claims 30 to 33, wherein two of R'® to R'® are hydrogen.

36. A compound according to claim 30, wherein R'®and R'” are both hydrogen and R" is -OCF;, -SCF; -CF3, —S(0).CH,, phenyl, halogen, C4¢-alkyl, nitro, -S-C,¢-alky! or -S(0).NR*'R?%, wherein R*' is C,¢-alkyl and R22 is phenyl.

37. A compound according to claim 30, wherein R*® and R'” are both hydrogen and R™ is -OCF; or halogen.

38. A compound according to claim 30, wherein R'® is hydrogen and R'” and R'® are both halogen or are both —CF,.

39. A compound according to claim 30, wherein R' is hydrogen, R'is ~CF3 and R'" is halo- gen, -CN, C,¢-alkoxy or —OCF,.

40. A compound according to claim 30, wherein R'®is hydrogen, R'is -OCF; and R" is -S(0),CHg, -CH,0-tri-C, -alkyisilyl, benzoxazoly! or —-CH,0OH.

41. A compound according to claim 30, wherein R'is hydrogen, R' is C,¢-alkyl and R" is -S(0).,NR?'R%, wherein R?' is C,g-alkyl and R% is phenyl.

42. A compound according to claim 30, wherein R'®, R'” and R'® are selected from hydrogen, -OCF,, -CF3, -Br, -F and -Cl.

43. A compound according to any one of the preceding claims, wherein E is RA RH R23 RR rR R? R* 24 Y Rr R N Rr ay rR? ’ ’ ’ ‘R¥ } \ ’ ’ 24 2 R® 2 24 24 R R R R R R® ’ i R 23 , N RY ’ | R rR? ’ R? ’ rR? der , R#

Go. = er Gor (3 N R2 \ ! RB ! Rr? ’ rR? R™ ’ rR? N ’ . rR® rR¥ Rr! 1 1 | | 2 wy or 0s N._.O N.__.O R ' JJ ’ LJ ’ ) 25 26 r® rR? R R ~ (Se Chr RA rR RNR 20 29 al » CH R +1 Je R (CHR), ’ i" ho 4 ’ R (CH,) rR ’ 32 ’ (CHR™), i [= Nia In 'm HR 23 rR? R “Nv R® RA R* RY (Gre (CHR®) Y 1 CH b , i (CHR™), fi or (CHR), CH J tH HRY) ’ GR I m R% R*® Ce wherein m, p and R? to R*® are as defined in claim 1.

44. A compound according to claim 43, wherein E is RY 20 R% R R% rR? R% R® RA oo R™ = ] ’ hd ’ i a ’ R® R® 24 R RZ R® RY rR? oi) EN Ge R* R® In NL Y kk} ’ R 1] (CHR), (He ) CHa), Gr (CHR) 2 I i ), (HR, 24 RM, R¥ R rR? RA R* R® N’ 23 R 7) A ~7n (CHR™) N , rR? ' R (CHR) ’ (CHR) Lon m fone don 26 R® ® R 25 RY R CH, CH, “wy eh . “FF Rr? er NH N a Zz ' Fo : : (CHR, : RS re R74 RY ul or oi) - wherein m, p and R® to R® are as defined in claim 1.

45. A compound according to claim 44, wherein E is R rR rR? RZ rR? “ - R R . oe Ge Y ! ’ ’ R® R¥® ’ CH), (GH), (CHa, (CHa) 24 R rR R® rR? RE KR rR: © ASO wherein p, R%3, R*, R®, R® R?, R%, R®, R¥ R* and R* are as defined in claim 1.

46. A compound according to claim 45, wherein E is R* Rr? RA R™ o£) £3 RY —€ R” —r 7 CH, (CH,), be ’ S ’ CHa ’ (CH, ) of NT ro wherein RZ, R?* R%, R%®, R¥, R* and R* are as defined in claim 1.

47. A compound according to claim 46, wherein R* and R* independently are C,s-alkyl, hy- 4c Neommanm An milrmen, (EV) tugs rw 1EQAINVAY.

48. A compound according to claim 47, wherein R* and R* are both C,-alkyl.

49. A compound according to claim 45, wherein E is R* wherein R? and R* are as defined in claim 1.

50. A compound according to claim 49, wherein E is RA R* wherein R? and R* are as defined in claim 1.

51. A compound according to claim 49 or 50, wherein R* and R** independently are selected from hydrogen, C,s-alkyl, Cs s-cycloalkyl, C,4-cycloalkylidene, phenoxy, phenyl, -C(O)NR¥R¥ and -OC(O)NH-phenyl, of which the phenyl moiety optionally may be substi- tuted with -OCF,, wherein R* and RY are as defined in claim 1, or R? and R* together form the radical -(CH,)-CR*R*'-(CH,)r-, -O-(CH,)-CR*R*-(CH,)-0-, -S-(CH,)-CR*R*'-(CH,)-S-, wherein t, I, R* and R*' are as defined in claim 1.

52. A compound according to claim 51, wherein R? is hydrogen and R?* is C, ¢-alkyl such as tert-butyl or Cs ¢-cycloalkyl such as cyclohexyl, wherein R?® and R?* are both C,s-alkyl or wherein R? and R* together form the radical —(CH,)s-.

53. A compound according to claim 46, wherein E is Rr R% R® i (rs ), wherein R®, R® and R? are as defined in claim 1.

54. A compound according to claim 5§3, wherein E is rR: wherein R%, R%® and R? are as defined in claim 1.

55. A compound according to claim 53 or 54, wherein R”, R?® and R? independently are se- lected from hydrogen, halogen, C,s-alkyl, Cys-alkoxy, Cs s-cycloalkyl, C4q-cycloalkenyl, -CF3, -OCF; or -NR*?R®, wherein R*? and R* are as defined in claim 1.

56. A compound according to claim 55, wherein E is R® wherein R% is ~OCF;, -CF3, Cy¢-alkyl such as tert-butyl, piperidyl, Cs g-cycloalky! such as cyclohexyl or C44-cycloalkenyl such as cyciohexeny!.

57. A compound according to claim 46, wherein E is CH, cH p 5 H,C cH, HC ; x H,Cc._ CHa @ CH, CH, OCF, Cl > on or

58. A compound according to claim 57, wherein E is H,C_-CH, HyC_ Cts @ CH, CH, , C

59. A compound according to claim 1 of the general formula (l,): v 0 RY N D . xX” (1) R 1 R wherein V, A, R*, R*, R', E, X and D are as defined in claim 1 or in any one of the preced- ing claims.

60. A compound according to claim 1 of the general formula (I,): i E Via Ss py Ney-P (1,) 46 R RY R' wherein V, A, R*, RY, R', E, X and D are as defined in claim 1 or in any one of the preced- ing claims.

61. A compound according to claim 1 of the general formula (I): i E Via oO I ; | N<y-D (1) R RY R' wherein V, A, R*, RY, R', E, X and D are as defined in claim 1 or in any one of the preced- ing claims.

62. A compound according to claim 1 of the general formula (l,): Oo Vio ) ; - N<y-P (1) R' wherein V is -C(O)OR?, -C(O)NR?R® or -C(O)NR?OR?, and R', R?, R?, E, X and D are as de- fined in claim 1 or in any one of the preceding claims.

63. A compound according to claim 1 of the general formula (Is): 0 0) R*

N._-D (1) a7 X 5 R R’ wherein R* RY, R', E, X and D are as defined in claim 1 or in any one of the preceding claims.

64. A compound according to claim 1 of the general formula (lg): N= / fo) RY HN, N N E : ND Sx” (lg) R 1 R wherein R*, RY, R', E, X and D are as defined in claim 1 or in any one of the preceding claims.

65. A compound according to claim 1 of the general formula (I). le} RY N ’ N E HN, STN N D N=N = Sx” (,) R' wherein R*, RY, R', E, X and D are as defined in claim 1 or in any one of the preceding claims.

66. A compound according to claim 1 of the general formula (lg): N=N / O R* HN, A ~ N N E H [ 47 Ney-P (Tg) R 4 R wherein R®, RY, R', E, X and D are as defined in claim1 or in any one of the preceding claims.

67. A compound according to claim 1 of the general formula (lp): N=pN / 46 R HN, PY N N E

: N.__D 47 SX” (Ig) R 1 R wherein R*%, RY, R, E, X and D are as defined in claim 1 or in any one of the preceding claims.

68. A compound according to anyone of the claims 59 to 61 or 63 to 67, wherein R* and R*’ are both hydrogen.

69. A compound according to any one of the preceding claims, which has an ICs, value of no greater than 5 uM as determined by the Glucagon Binding Assay (I), Glucagon Binding Assay (ll) or Glucagon Binding Assay (lll) disclosed herein.

70. A compound according to claim 69 characterized by having a glucagon antagonistic ac- tivity as determined by the Glucagon Binding Assay (I), Glucagon Binding Assay (ll) or Glu- cagon Binding Assay (lI) disclosed herein comresponding to an ICs, value of less than 1 uM, preferably of less than 500 nM and even more preferred of less than 100 nM.

1 y oo B oo

71. A compound according to any one of the preceding claims, which is an agent useful for the treatment and/or prevention of an indication selected from the group consisting of hyper- glycemia, IGT, Type 2 diabetes, Type 1 diabetes and obesity.

72. A compound according to any one of the claims 1 to 71 for use as a medicament.

73. A pharmaceutical composition comprising, as an active ingredient, at least one com- pound according to any one of the claims 1 to 71 together with one or more pharmaceutically acceptable carriers or excipients.

74. A pharmaceutical composition according to claim 73 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and espe- cially preferred from about 0.5 mg to about 200 mg of the compound according to any one of the claims 1 to 71.

75. Use of a compound according to any one of the claims 1 to 71 for the preparation of a medicament for the treatment and/or prevention of disorders or diseases, wherein a gluca- gon antagonistic action is beneficial.

76. Use of a compound according to any one of the claims 1 to 71 for the preparation of a medicament for the treatment and/or prevention of glucagon-mediated disorders and dis- eases.

77. Use of a compound according to any one of the claims 1 to 71 for the manufacture of a medicament for the treatment and/or prevention of hyperglycemia.

78. Use of a compound according to any one of the claims 1 to 71 for the manufacture of a medicament for lowering blood glucose in a mammal.

79. Use of a compound according to any one of the claims 1 to 71 for the preparation of a medicament for the treatment and/or prevention of IGT.

80. Use of a compound according to any one of the claims 1 to 71 for the preparation of a medicament for the treatment and/or prevention of Type 2 diabetes.

81. Use according to claim 80 for the preparation of a medicament for the delaying or prevention of the progression from IGT to Type 2 diabetes.

82. Use according to claim 80 for the preparation of a medicament for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.

83. Use of a compound according to any one of the claims 1 to 71 for the preparation of a medicament for the treatment and/or prevention of Type 1 diabetes.

84. Use according to any one of the claims 75 to 83 in a regimen which additionally com- prises treatment with another antidiabetic agent.

85. Use of a compound according to any one of the claims 1 to 71 for the preparation of a medicament for the treatment and/or prevention of obesity.

86. Use of a compound according to any one of the claims 1 to 71 for the preparation of a medicament for the treatment and/or prevention of obesity in a regimen which additionally comprises treatment with another antiobesity agent.

87. A method for the treatment and/or prevention of disorders or diseases mediated by a glu- cagon antagonistic action, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of the claims 1 to 71 or a pharma- ceutical composition according to claim 73 or 74.

88. The method according to claim 87, wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.