ZA200400240B - Viral polymerase inhibitors. - Google Patents

Viral polymerase inhibitors. Download PDF

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Publication number
ZA200400240B
ZA200400240B ZA200400240A ZA200400240A ZA200400240B ZA 200400240 B ZA200400240 B ZA 200400240B ZA 200400240 A ZA200400240 A ZA 200400240A ZA 200400240 A ZA200400240 A ZA 200400240A ZA 200400240 B ZA200400240 B ZA 200400240B
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South Africa
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alkyl
het
cycloalkyl
aryl
salkyl
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ZA200400240A
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Beaulieu Pierre Louis
Sylvie Goulet
Martin Poirier
Eric Jolicoeur
Marc-Andre Poupart
Gulrez Fazal
George Kukolj
Youla S Tsantrizos
James Gillard
Jean Rancourt
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Boehringer Ingelheim Ca Ltd
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Publication of ZA200400240B publication Critical patent/ZA200400240B/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Description

® } VIRAL POLYMERASE INHIBITORS i TECHNICAL FIELD OF THE INVENTION
The invention relates to inhibitors of RNA dependent RNA polymerases, particularly ; 5 those viral polymerases within the Flaviviridae family, more particularly to HCV polymerase.
BACKGROUND OF THE INVENTION
About 30,000 new cases of hepatitis C virus (HCV) infection are estimated to occur in the United States each year (Kolykhalov, A.A; Mihalik, K.; Feinstone, S.M.; Rice,
C.M.; 2000; J. Virol. 74: 2046-2051). HCV is not easily cleared by the hosts’ ® immunological defences; as many as 85% of the people infected with HCV become chronically infected. Many of these persistent infections result in chronic liver disease, including cirrhosis and hepatocettular carcinoma (Hoofnagle, J.H.; 1997;
Hepatology 26: 15S-20S*). There are an estimated 170 million HCV carriers world- wide, and HCV-associated end-stage liver disease is now the leading cause of liver : transplantation. In the United States alone, hepatitis C is responsible for 8,000 to 10,000 deaths annually. Without effective intervention, the number is expected to triple in the next 10 to 20 years. There is no vaccine to prevent HCV infection.
Prolonged treatment of chronically infected patients with interferon or interferon and ribavirin is the only currently approved therapy, but it achieves a sustained response in fewer than 50% of cases (Lindsay, K.L.; 1997; Hepatology 26: 71S-77S*, and
Reichard, O.; Schvarcz, R.; Weiland, O.; 1997 Hepatology 26: 1085-111S*).
HCV belongs to the family Flaviviridae, genus hepacivirus, which comprises three genera of small enveloped positive-strand RNA viruses (Rice, C.M.; 1996; “Flaviviridae: the viruses and their replication”; pp. 931-960 in Fields Virology, Fields,
B.N.; Knipe, D.M.; Howley, P.M. (eds.); Lippincott-Raven Publishers, Philadelphia
Pa. *). The 9.6 kb genome of HCV consists of a long open reading frame (ORF) - 30 flanked by 5’ and 3' non-transiated regions (NTR's). The HCV 5' NTR is 341 nucleotides in length and functions as an internal ribosome entry site for cap- ) independent translation initiation (Lemon, S.H.; Honda, M.; 1997; Semin. Virol. 8: 274-288). The HCV polyprotein is cleaved co- and post-translationally into at least 10 individual polypeptides (Reed, K.E.; Rice, C.M.; 1999; Curr. Top. Microbiol.
Immunol. 242: 55-84"). The structural proteins result from signal peptidases in the N-
® terminal portion of the polyprotein. Two viral proteases mediate downstream - cleavages to produce non-structural (NS) proteins that function as components of the HCV RNA replicase. The NS2-3 protease spans the C-terminal half of the NS2
Ie and the N-terminal one-third of NS3 and catalyses cis cleavage of the NS2/3 site.
The same portion of NS3 also encodes the catalytic domain of the NS3-4A serine protease that cleaves at four downstream sites. The C-terminal two-thirds of NS3 is highly conserved amongst HCV isolates, with RNA-binding, RNA-stimulated : NTPase, and RNA unwinding activities. Although NS4B and the NS5A phosphoprotein are also likely components of the replicase, their specific roles are unknown. The C-terminal polyprotein cleavage product, NS5B, is the elongation subunit of the HCV replicase possessing RNA-dependent RNA polymerase (RdRp) ( activity (Behrens, S.E.; Tomei, L.; DeFrancesco, R.; 1996; EMBO J. 15: 12-22%; and
Lohmann, V.; Kérner, F.; Herian, U.; Bartenschlager, R.; 1997; J. Virol. 71: 8416- 8428*). It has been recently demonstrated that mutations destroying NS5B activity abolish infectivity of RNA in a chimp mode! (Kolykhalov, A.A.; Mihalik, K.; Feinstone,
S.M.; Rice, C.M.; 2000; J. Virol. 74: 2046-2051%).
The development of new and specific anti-HCV treatments is a high priority, and virus-specific functions essential for replication are the most attractive targets for drug development. The absence of RNA dependent RNA polymerases in mammals, "and the fact that this enzyme appears to be essential to viral replication, would suggest that the NS5B polymerase is an ideal target for anti-HCV therapeutics.
WO 00/06529 reports inhibitors of NS5B which are a, y-diketoacids.
WO 00/13708, WO 00/10573, WO 00/18231, and WO 01/47883 report inhibitors of
NS5B proposed for treatment of HCV.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a novel series of compounds having improved inhibitory activity against HCV polymerase. o» 30
®
In a first aspect of the invention, there is provided an isomer, enantiomer, - diastereoisomer or tautomer of a compound, represented by formula I: y i A eT
A 0 wherein:
Ais O,S, NR’, or CR’, wherein R' is selected from the group consisting of: H, (C1-6)alky! optionally substituted with: -halogen, OR", SR™ or N(R"?),, wherein R'" and each R' is independently ® H, (C1.6)alkyl, (Csz)cycloalkyl, (C1.6)alkyl-(Csr)cycloalkyl, (Cq.)alkyl-aryl or (Cs. e)alkyl-Het, said aryl or Het optionally substituted with R'; or both R'? are covalently bonded together and to the nitrogen to which they are both attached to form a 5, 6 or 7-membered saturated heterocycle; --—- represents either a single or a double bond;
Ris selected from: halogen, R%', OR?!, SR%', COOR?, SO,N(R?)z, N(R**)z, ,
CON(R®),, NR22C(O)R? or NR?2C(O)NR? wherein R*' and each R* is independently H, (C1.s)alkyl, haloalkyl, (Cas)alkenyl, (Ca)cycloalkyl, (Cag)alkynyl, (Cs.
J)cycloalkenyl, 6 or 10-membered aryl or Het, said R*' and R? being optionally substituted with R*®; or both R? are bonded together to form a 5, 6 or 7-membered saturated heterocycle with the nitrogen to which they are attached,
B is NR? or CR®, with the proviso that one of A or B is either CR" or CR?, wherein R? is selected from (Cy.¢)alkyl, haloalkyl, (Ca)cycloalkyl, (Cs)cycloalkenyl, (Ce.1o)bicycloalkyl, (Cs.o)bicycloalkenyl, 6- or 10-membered aryl, Het, (Ci.¢)alkyl-aryl . or (Cie)alkyl-Het, said alkyl, cycloalkyl, cycloakenyl, bicycloalkyl, bicycloalkenyl, aryl, Het, alkyl- - aryl and alkyl-Het being optionally substituted with from 1 to 4 substituents selected from: halogen, or a) (Cy.6)alkyl optionally substituted with: - OR® or SR® wherein R*' is H, (Ci.salkyl), (Cs)cycloalkyl,
® (C1s)alkyl-(Cs7)cycloalkyl, aryl, Het, (Ci.g)alkyl-aryl or (Ci. - g)alkyl-Het; or - N(R®), wherein each R* is independently H, (C+.g)alkyl, (Ca- @ s)cycloalkyl, (Cy.g)alkyl-(Caz)cycloalkyl, aryl, Het, (Cq.q)alkyl-aryl or (C1.)alkyl-Het; or both R*? are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle; b) OR® wherein R® is H, (Cy.g)alky!, (Ca)cycloalkyl or (C1.5)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cyg)alkyl-aryl or (Ci.)alkyl-Het; ¢) SR* wherein R* is H, (Ci.)alkyl, (Caz)cycloalkyl, or (Cy.6)alkyl-(Ca)cycloalkyl, aryl, Het, (Cig)alkyl-aryl or (Cyo)alkyl-Het;
L and d) N(R%*), wherein each R* is independently H, (C,z)alkyl, (Cs7)cycloalkyl, (Cy.5)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.)alkyl-aryl or (C1.¢)alkyl-Het; or both R> are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
K is N or CR*, wherein R* is H, halogen, (Cis)alkyl, haloalkyl, (Cs.7)cycloalkyl or (C:. g)alkyl-(Car)cycloalkyl; or R* is OR™ or SR", COR* or NR*'COR" wherein each R*' is independently H, (Ci.g)alkyl), (Ca7)cycloalkyl or (C4.g)alkyl-(Cs.7)cycloalkyl; or R* is NR*R* wherein R*? and R* are each independently H, (Ci.s)alkyl, (Ca.
J)cycloalkyl, (C+.e)alkyl-(Ca7)cycloalkyl, or both R*? and R* are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
Lis N or CR®, wherein R® has the same definition as R* defined above;
Mis N or CR’, wherein R has the same definition as R* defined above; i 30
Y'isOorS;
Z is OR® wherein R® is C,.qalky! substituted with: - 1 to 4 substituents selected from: OPOsH, NO», cyano, azido, C(=NH)NH,,
¢ C(=NH)NH(C.¢)alkyl or C(=NH)NHCO(C,.¢)alkyl; or - - 1 to 4 substituents selected from: ’ a) (Cy.5) alkyl or haloalkyl, (Cs7)cycloalkyl, Czy spirocycloalkyl optionally # containing 1 or 2 heteroatom, (C,.¢)alkenyl, (Cag)alkynyl, (Cy.) alkyl-(Ca. 5 s)eycloalkyl, all of which optionally substituted with R*®; b) OR™ wherein R'is (C;.salkyl) substituted with R'®, (Cs)cycloalkyl, or (C16)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C,.salkyl)Het, said cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Csalkyl)Het being optionally substituted with R'®; c) OCOR'® wherein R'® is (C,.)alkyl, (Cs.7)cycloalkyl, (C1.)alkyl-(Ca. 7)cycloalkyl, Het, (Ci.salkyl)aryl or (Cq.salkyl)Het, said alkyl, cycloalkyl, aryl, o Het, (C,.salkylaryl or (C,.galkyl)Het being optionally substituted with R™% d) SR'®, SO.H, SON(R'™), or SON(R'®)C(O)R'® wherein each R'® is independently H, (C1.s)alkyl, (Cs7)cycloalkyt or (Ci¢)alkyl-(Car)cycloalkyl, aryl,
Het, (C+.calkyl)aryl or (Cy ealkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,. salkylaryl or (Cyealkyl)Het or heterocycle being optionally substituted with : R's e) NR™R'™ wherein RB" is H, (C1s)alkyl, (Cs7)cycloalkyl or (C+.e)alkyl-(Cs.
J)cycloalkyl, aryl, Het, (Cq.salkyl)aryl or.(Cycalky)Het, and R'is H, CN, (C;. s)alkyl, (Ca7)cycloalkyl or (C1.)alkyl-(Cs.r)cycloalkyl, aryl, Het, (Cy.calkyl)aryl, (C1.calkyl)Het , COOR™ or SOR" wherein R'"® is (C16)alkyl, (Ca. 7)eycloalkyl, or (Cy.¢)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cq.salkyl)aryl or (C;. salkyl)Het, provided that when R™" is H or unsubstituted alkyl, Ris not H or unsubstituted alkyl, or both R"" and R'"2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl, (Cysalkyl)Het, or heterocycle ’ 30 being optionally substituted with R'%%; : : f) NR" COR" wherein R'"® and R'" is each H, (Ci.s)alkyl, (Cs.7)cycloalkyl, ’ (Ci.s)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Cysalkyl)Het, said (C;. s)alkyl, (Caz)cycloalkyl, (Ca-s)alkyl-(Cag)cycloalkyl, aryl, Het, (Cy. salkyl)aryl or (C1salkyl)Het being optionally substituted with R";
@ g) NR''®CONR'R'™, wherein R'", R'"® and R'® is each H, (Ci.¢)alkyl, (Ca - s)eycloalkyl, (Cy.)alkyl-(Caz)cycloalkyl, aryl, Het, (Cq.ealkyl)aryl or (Cs. salkyl)Het, or R™® is covalently bonded to R'"® and to the nitrogen to which “ they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R'"® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C1.e)alkyl-(Ca)cycloalkyl, aryl, Het, (Gisalkyl)aryl or (Cs. salkyl)Het or heterocycle being optionally substituted with R™®, h) NR'?'"COCOR'™ wherein R™' and R'# is each H, (C1.s)alkyl, (Cs. s)eycloalkyl, (Cqe)alkyl-(Caz)cycloalkyl, a 6- or 10-membered aryl, Het, (C4. salkyl)aryl or (C,.salkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, ] (C,.salkyl)aryl or (C1.calkyHet being optionally substituted with R™*’; or RZ is OR or N(R"), wherein R'? and each R'** is independently H, (C1.6alkyl), (Caz)cycloalkyl, or (Cy.)alkyl-(Csz)cycloalkyl, aryl, Het, (C;. salkyl)aryi or (Cy.salkyl)Het, or R'>* is OH or O(Cy.alkyl) or both R'* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C;.salkyl)Het and heterocycle being optionally substituted with R's; i) COR'Z wherein R" is H, (Ci.g)alkyl, (Cs)cycloalkyl or (Cye)alkyl~(Cs. cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (Cqsalkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C.salkyharyl or (C1.salkyl)Het being optionally substituted with R'*;
J) COOR' wherein R'® is (C,.)alkyl substituted with R™°; (Cs7)cycloalkyl, or(C1.¢)alkyl-(Cs-)cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (Cy.salkyl)Het, said (Ca.
Jeycloalkyl, or(C.¢)alkyl-(Cs.y)cycloalkyl, aryl, Het, (Cysalkyl)aryl and (Cs. salkyl)Het being optionally substituted with R'*; k) CONR'®R™ wherein R™ and R'* are independently H, (C1.c)alkyl, (Cs. 7cycloalkyl, (Cy.g)alkyl-(Caz)cycloalkyl, aryl, Het, (Cq.salkyl)aryl or (Ci. salkyl)Het, or both R"® and R**® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cisalkyl)aryl, ; (Cisalkyl)Het and heterocycle being optionally substituted with R'*;
I) aryl, Het, (Cy.calkyl)aryl or (C+.ealkyl)Het, all of which being optionally substituted with R™; wherein R'® is selected from:
J
- 1 to 3 substituents selected from: halogen, NO,, cyano, azido or - - 1 to 3 substituents selected from: a) (C..6) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs.7 spirocycloalkyl “ optionally containing 1 or 2 heteroatom, (Cze)alkenyl, (C+.s) alkyl-(Cs. ;)eycloalkyl, all of which optionally substituted with R™®; b) OR'™ wherein R'™ is H, (Cysalkyl), (Cas)cycloalkyl, or (Cy.s)alkyl- (Cax)cycloalkyl, aryl, Het, (C+.salkyl)aryl or (C,.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Ci.calkyl)Het being optionally substituted with R™%; c) OCOR'® wherein R'® is (Ci.6)alkyl, (Ca7)cycloalkyl, (Cy.c)alkyl-(Cs. ) cycloalkyl, Het, (C4.calkyl)ary! or (Cqealkyl)Het, said alkyl, cycloalkyl, ] aryl, Het, (C.calkyl)aryl or (C,.¢alkyl)Het being optionally substituted with R™; d) SR', SON(R'®), or SO:N(R'®)C(O)R'® wherein each R'* is independently H, (Cy.s)alkyl, (Ca.7)cycloalkyt or (Cy.c)alkyl-(Ca.
J)cycloalkyl, aryl, Het, (Cycalkyl)aryl or (Cq.salkyl)Het or both R™™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C+.calkyl)aryl or (C1.¢alkyl)Het or © 20 heterocycle being optionally substituted with R'®; e) NR"R'? wherein R""" is H, (Cis)alkyl, (Ca.7)cycloalkyl or (Ci. e)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C+.ealkyl)aryl or (Cy.salkyl)Het, and
R"2is H, (C.s)alkyl, (Csz)cycloalkyl or (Cy.6)alkyl-(Cs)cycloalkyl, aryl,
Het, (C1satkylaryl, (Ci.calkyl)Het , COOR™ or SO,R'* wherein R'*® is (C1.)alkyl, (Cs.z)cycloalkyl, or (Ci.s)alkyl-(Csz)cycloalkyl, aryl, Het, (Cirealkyl)aryl or (C,alkyl)Het, or both R*" and R"'? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,.salkyl)Het, or heterocycle ’ 30 being optionally substituted with R'®?; f) NR""®COR""” wherein R"" and R'" is each H, (Ci.s)alkyl, (Cs. ) J)eycloalkyl, (Cye)alkyl-(Csr)cycloalkyl, aryl, Het, (Cr.salkyl)aryl or (C,. salkyl)Het, said (C,.¢)alkyl, (Ca.7)cycloalkyl, (Cq.¢)alkyl-(Csz)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C,.calkyl)Het being optionally substituted
® with R'®; " g) NR'™CONR'R'®, wherein R'"%, R""? and R'? is each H, (Ci. s)alkyl, (Cs~)cycloalkyl, (Ci.)alkyl-(Csz)cycloalkyl, aryl, Het, (C,. “ salkyl)aryl or (C.calkyl)Het, or R'"® and R'° are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C;. s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cy.calkyl)Het or : heterocycle being optionally substituted with R®; h) NR'¥COCOR'? wherein R'?' is H, (Cy.)alkyl optionally substituted with R'®®, and R'is OR"? or N(R'**), wherein R'? and each R'?* is independently H, (Cisalkyl), (Ca)cycloalkyl, or (Cy.g)alkyl- @ (Ca)cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (Cy.calkyl)Het, or R'?* is OH or O(Cy.salkyl) or both R*?* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (C1 5aliyl)aryl or (Cyalkyl)Het and heterocycle being optionally substituted with R"®%; j) tetrazole, COOR'?® wherein R'* is H, (C,.)alkyl, (Ca.7)cycloalkyl, or(C1g)alkyl-(Ca;)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (C.salkyl)Het, said (Cyg)alkyl, (Caz)cycloalkyl, or(C;.s)alkyl-(Csy)cycloalkyl, aryl, Het, (C1salkyl)aryl and (Cy salkyl)Het being optionally substituted with R'®®; and k) CONR'*R"° wherein R'® and R™ are independently H, (C;. e)alkyl, (Cs.7)cycloalkyl, (Ci.g)alkyl-(Cs.z)cycloalkyl, aryl, Het, (C;. calkyharyl or (Cysalkyl)Het, or both R™® and R" are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, atkyl-cycloalkyl, aryl, Het, (Ci.calkyl)aryl, (C4salkyl)Het and heterocycle being optionally substituted with R'®; wherein R'® is defined as 1 or 2 substituents selected from: ’ 30 tetrazole, halogen, CN, Cy.salkyl, haloalkyl, COOR'', SO;H,
SOR, OR, N(R), SOMN(R®),, NR'®2COR?, or
CON(R'%?),, wherein R'"®" and each R'is independently H, (C1-p)alkyl, (Caz)cycloalkyl or (Cy.g)alkyl-(Cav)cycloalkyl; or both
R'®? are covalently bonded together and to the nitrogen to
° ® which they are attached to form a 5, 6 or 7-membered e saturated heterocycle; « or Z is OR® wherein R® is (C,.calkyl)aryl substituted with: - 1 to 4 substituents selected from: OPO3H, azido, C(=NH)NH,,
C(=NH)NH(C.g)alkyl or C(=NH)NHCO(C,.g)alky}; or - 1 to 4 substituents selected from: a) (C1.0)alkyl substituted with R*™, haloalkyl, (Cs7)cycloalkyl, Caz spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cz g)alkenyl, (Co. g)alkynyl, (C,,) alkyl-(Caz)cycloalkyl, said haloalkyl, cycloalkyl, spirocycloalkyl, alkenyl, alkynyl and alkyl-cycloalky! being optionally substituted with R"®, 9 wherein R'5® is the same as R'® but is not COOR"™®, N(R"*™),,
NR'°°C(O)R*", OR'5% SR'5% SO,R™™, SOLN(R™),, wherein R™® is H or unsubstituted C.salkyl; b) OR wherein R'™ is (C,.calkyl) substituted with R'®’, (Cs.7)cycloalkyl, or (Cys)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Ci.salkyl)Het, said cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,.salkyl)Het being optionally substituted with R'®’; ¢) OCOR'® wherein R'® is (C.e)alkyl, (Csr)cycloalkyl, (Ci.6)alkyl-(Cs. 7)cycloalkyl, Het, (Cysalkyl)aryl or (C,.salkyl)Het, said alkyl, cycloalkyl, aryl,
Het, (C1.salkyl)aryl or (C1.calkyhHet being optionally substituted with R'*®; d) SR'®2 SO,N(R™®?), or SO:N(R'®)C(O)R'*® wherein each R'is independently H, (Ci.s)alkyl, (Cs.z)cycloalkyl or (Ci.c)alkyl-(Cs.7)cycloalkyl, aryl,
Het, (C1salkyl)aryl or (Cialkyl)Het or both R'% are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C;. salkyl)aryl or (C,.salkyl)Het or heterocycle being optionally substituted with
R'™, wherein R'is the same as R'® but is not H or unsubstituted C_salkyl; e) NR"™R" wherein R™ is H, (C1.s)alkyl, (Caz)cycloatky! or (Cy.)alkyl-(Ca. ’ 30 cycloalkyl, aryl, Het, (C1.salkyl)aryl or (Ciealkyl)Het, and R™?is H, CN, (C;. s)alkyl, (Ca)cycloalkyl or (Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cyalkyl)aryl, (Cisalkyl)Het , provided that when R"" is H or unsubstituted alkyl, R'* is not
H or unsubstituted alkyl, or BR"? js also COOR'"® or SO,R'*2 wherein R'"® is H, (C,.)alkyl, (Ca.
@ neycloalkyl, or (Cy.s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cy. " salky)Het, and R"'*® is the same as R'"® but is not H or unsubstituted alkyl, or both R"" and R'* are covalently bonded together and to the nitrogen to “ which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cisalkyharyl or (Ci.salkyl)Het, or heterocycle being optionally substituted with R'™"; f) NR"COR"" wherein R'"® and R'" is each (C.)alkyl substituted with
R', (Cs.7)cycloalkyl, (C1.¢)alkyl-(Csz)cycloalkyl, aryl, Het, (Ciealkyl)aryl or (Ci salkyh)Het, said (Cs.7)cycloalkyl, (Cy.)alkyl-(Cs.r)cycloalkyl, aryl, Het, (Ci. salkylary! or (Cycalkyl)Het being optionally substituted with R'*’; g) NR" CONR'R'®, wherein R"'®, R'"® and R'® is each H, (Ci¢)alkyl, (Ca. @ s)eycloalkyl, (C4.)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C,. salkyl)Het, or R''® is covalently bonded to R'® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R"® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C1.¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cisalkyharyl or (Ci. salkyl)Het or heterocycle being optionally substituted with BR’; h) NR'2'COCOR'# wherein R'*' and R"? is each H, (Ci.)alkyl, (Ca 7cycloalkyl, (C4.g)alkyl-(Ca.z)cycloalkyl, a 6- or 10-membered aryl, Het, (Ci. ’ salkyl)aryl or (Cgalkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, : (C1.salkyl)aryl or (C:.calkyl)Het being optionally substituted with R**’; or R'2 is OR" or N(R'?*), wherein R'® and each R'#* is independently H, (C,.calkyl), (Caz)cycloalkyl, or (Cy.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Ci. salkyl)aryl or (C,salkyl)Het, or R'2* is OH or O(Cy.calkyl) or both R'* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyt-cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (C1.salkyl)Het and heterocycle being optionally substituted with BR"; i) COR wherein R'Z" is (Cy.)alkyl substituted with R'°, (Cs.7)cycloalkyl or (C16)alkyl-(Ca.z)cycloalkyl, aryl, Het, (C.calkyl)aryl or (Ci.ealkyl)Het, said . cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cisalkyl)Het being optionally substituted with R'®; j) COOR"® wherein R'? is (C,.¢)alkyl substituted with R'*, (Cs7)cycloalkyl, or(Cy.g)alkyl-(Ca)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cyealkyl)Het, said (Cs.
L
J)eycloalkyl, or(Cy.e)alkyl-(Car)cycloalkyl, aryl, Het, (Cr.salkyl)aryl and (Cy. . salkyl)Het being optionally substituted with R'*’; kK) CONR'R'™ wherein R'*® and R'® are independently H, (Ci.g)alkyl, (Ca. © 7)cycloalkyl, (Ci.a)alkyl-(Car)cycloalkyl, aryl, Het, (Cy.calkyl)aryl or (C+. salkyHet, provided that when R'is H or unsubstituted alkyl, R'is not H or unsubstituted alkyl, or both R*?® and R'* are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C.salkyl)aryl, (Ci ¢alkyl)Het and heterocycle being optionally substituted with R"™; 1) aryl, Het, (Cy.calkyl)aryl or (Calkyl)Het, all of which being optionally @ | substituted with R*°; and wherein R'is : --1 to 3 substituents selected from: halogen, NO,, cyano or azido; - 1 to 3 substituents selected from: : a) (C,.) alkyl or haloalkyl, (Cs)cycloalkyl, Cs; spirocycloalkyl optionally containing 1 or 2 heteroatom, (Ca.g)alkenyl, (Czg)alkynyl, (C1.6) alkyl-(Caz)cycloalkyl, all of which optionally substituted with R'®; b) OR™ wherein R'® is H, (C+.salkyl), (Cs7)cycloalkyl, or (Cie)alkyl- (Car)cycloalkyl, aryl, Het, (Cy.salkylaryl or (Cy.salkyHet, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cialkyl)Het being optionally substituted with R*®°; c) OCOR' wherein R'® is (C1.)alkyl, (Ca.z)cycloalkyl, (C1.g)alkyl-(Cs. 7)cycloalkyl, Het, (Cisalkylaryl or (Cisalkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Ci.alkyl)Het being optionally substituted with R'®’; : d) SR™, SO.N(R'®), or SO,N(R'®)C(O)R'® wherein each R™ is independently H, (Cig)alkyl, (Cs7)cycloalkyl or (Ci.¢)alkyl-{Ca.
J)eycloalkyl, aryl, Het, (C1.calkyl)ary or (C.calkyl)Het or both R'® are ’ 30 covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Ci.¢alkyl)aryl or (Cs.salkyl)Het or heterocycle being optionally substituted with R'™; e) NR'R"? wherein R'is H, (Ci.¢)alkyl, (Ca)cycloalkyl or (Cs.
® s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cy.salkyl)Het, and . R'is H, CN, (Ci)alkyl, (Csz)cycloalkyl or (Cy.g)alkyl-(Cs.r)cycloalkyl, aryl, Het, (C.calkyl)aryl, (Csalkyl)Het , COOR™" or SO,R""® wherein « R'is (Cy.g)alkyl, (Cs)cycloalkyl, or (Cy.e)alkyl-(Car)cycloalkyl, aryl,
Het, (C,.salkyl)aryl or (C,.calkyl)Het, or both R"'" and R'? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C.calkyl)Het, or heterocycle being optionally substituted with R'®%; f) NR'"COR""” wherein R"" and R'" is each H, (C.)alkyl, (Cs. 7)cycloalkyl, (Cy.g)alkyl-(Csz)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,. [ salkyl)Het, said (C.¢)alkyl, (Ca.7)cycloaltkyl, (Ci.6)alkyl-(Cs7)cycloalkyi, ~aryl, Het, (Cy¢alkyl)aryl or (Cy.salkyl)Het being optionally substituted with R'®; g) NR'""®CONR'"R'®’, wherein R"*®, R""? and R"® is each H, (C. s)alkyl, (Cs.z)cycloalkyl, (C.¢)alkyl-(Cs;)cycloalkyl, aryl, Het, (C;. galkyljaryl or (C, salkyl)Het, or R""® and R'® are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 : . or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Ci. g)alkyl-(Csy)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (C4.gatkyl)Het or heterocycle being optionally substituted with R'®®; h) NR'™COCOR'? wherein R'?' is H, (C,.s)alkyl optionally substituted with R'®% and R'? is OR'® or N(R'?*), wherein R'® and each R'is independently H, (Csalkyl), (Ca)cycloalkyl, or (Cy.)alkyl- (Caz)oycloalkyl, aryl, Het, (Cy.calkyl)aryl or (C1salkyl)Het, or R™* is OH or O(C, alkyl) or both R™* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,_salkyl)Het and heterocycle being optionally substituted with R'®’; ’ 30 i) tetrazole, COOR'®® wherein R'? is H, (C1.s)alkyl, (Cs.7)cycloalkyl, . or(C4.)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cgalkyl)aryl or (Cy.ealkyl)Het, said (Cy.g)alkyl, (Ca.7)cycloalkyl, or(C,g)alkyl-(Csr)cycloalkyl, aryl, Het, (Ci.ealkybaryl and (C4 alkyl)Het being optionally substituted with R'6?; and
® k) CONR'®R™ wherein R'? and R'® are independently H, (C1. “ o)alkyl, (Caz)cycloalkyl, (Ci.s)alkyl-(Caz)cycloalkyl, aryl, Het, (Cs. salkyharyl or (C1ealkyl)Het, or both R**® and R'* are covalently © bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C;salkyharyl, (Cisalkyl)Het and heterocycle being optionally substituted with R*; wherein, R'is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, Cy.salkyl, haloalkyl, COOR'™, SO;H,
SO,R™!, OR", N(R'),, SO.N(R'®?),, NR'®*COR'® or ® CON(R®?),, wherein R™" and R'® are as defined above; or Z is OR® wherein R® is, (Ca.s)cycloalkyl, (Cze)alkenyl, 6- or 10-membered aryl, Het, (C1.¢)alkyl-Het, wherein said cycloalkyl, alkenyl, aryl, Het or alkyl-Het, is optionally substituted with R%; or Z is N(R*)R®, wherein R* is H or (Ci.¢alkyl) and
RS is (C1.c)alkyl optionally substituted with: - 4 to 4 substituents selected from: OPO3H, NO;, cyano, azido, C(=NH)NH,,
C(=NH)NH(C.g)alkyl or C(=NH)NHCO(C,.s)alkyt; or - 1 to 4 substituents selected from: a) (C+) alkyl substituted with B'™*2, haloalkyl substituted with R'®°, (Cs. s)cycloalkyl, Ca; spirocycloalkyl optionally containing 1 or 2 heteroatom, (C..6)alkenyl, (Cog)alkynyl, (Ci.6) alkyl-(C.7)cycloalkyl, all of which optionally substituted with R'®, wherein R'** is the same as R'®° but is not halogen,
OH, O(C16alkyl), COOH, COO(C.salkyl), NHz, NH(C1.calkyl) and N(Cy.ealkyl),; b) OR'™ wherein R'is (C.salkyl) substituted with R'®°, (Car)cycloalkyl, or (C1.e)alkyl-(Cs7)cycloalkyl, aryl, Het, (C1calkyhary) or (Cr.calkyl)Het, said cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Cisalky))Het being optionally ’ 30 substituted with R**°; ¢) OCOR' wherein R'® is (Cve)alkyl, (Caz)cycloalkyl, (C1.c)alkyl-(Cs. s)cycloalkyl, Het, (Cyealkyl)aryl or (C,.calkyl)Het, said alkyl, cycloalkyl, aryl,
Het, (C ealkyl)aryl or (Cy.calkyl)Het being optionally substituted with rR" d) SR SOgH, SO:N(R™™), or SON(R'®)C(O)R'™ wherein each R™™ is
® independently H, (C1.g)alkyl, (Ca)cycloalkyl or (Cy.g)alkyl-(Csz)cycloalkyl, aryl, . Het, (C1.salkyl)aryl or (Cisalkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7- « membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,. salkyl)aryl or (Cq.salkyl)Het or heterocycle being optionally substituted with
RS. e) NR"R"2 wherein R'is H, (Cy.)alkyl, (Cs.7)cycloalkyl or (Cy.s)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (Cy.calkyl)aryl or (Ciealkyl)Het, and Ris H, CN, (C+. s)alkyl, (Cs;)cycloalkyl or (Cyg)alkyl-(Csz)cycloalkyl, aryl, Het, (Cisalkyl)aryi, (C,alkyl)Het, COOR'* or SO,R'*® wherein R'"® is (Cy.6)alkyl, (Cs7)cycloalkyl, or (Cy.e)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci.galkyl)aryl or (C,.calkyl)Het, @® provided that when R'is H or unsubstituted alkyl, R'is not H or unsubstituted alkyl, or both R"" and R**? are covalently bonded together and "to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cs.ealkyl)aryl or (Cs. calkyl)Het, or heterocycle being optionally substituted with R'’; f) NR'®COR""” wherein R""® and R'" is each H, (Cy.s)alkyl, (Css)cycloalkyl, + (Cye)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cicalkyl)aryl or (Csalkyl)Het, said (C;. g)alkyl, (Ca)cycloalkyl, (Cy.c)alkyl~(Csy)cycloalkyl, aryl, Het, (Cy salkyl)aryl or (C,.salkyl)Het being optionally substituted with BR’; g) NR'8CONR'*R'®, wherein RB", Rr"? and R'? is each H, (C;.¢)alkyl, (Cs. s)cycloalkyl, (Cy.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cqsalkyl)aryl or (C;. salky)Het, or R'"® is covalently bonded to R'*® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; © 25 or R" and R" are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C1.s)alkyi-(Ca.7)cycloalkyl, aryl, Het, (Cqsalkyl)aryl or (C4. salkyl)Het or heterocycle being optionally substituted with R'®’; h) NR'2'COCOR'2 wherein R™' and R' is each H, (C1.c)alkyl, (Ca. 7)eycloalkyl, (Cq.¢)alkyl-(Ca)cycloalkyl, a 6- or 10-membered aryl, Het, (C4. ) salkyl)aryl or (C.salkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C1ealkyharyl or (C1.calkyhHet being optionally substituted with R**°; or RB? is OR'® or N(R"), wherein R'® and each R'** is independently H, (C1ealkyl), (Ca7)cycloalkyl, or (Cyg)alkyl-(Caz)cycloalkyl, aryl, Het, (Cy.
® salkylaryl or (C1alkyhHet, or R'* is OH or O(C.calkyl) or both R'** are : covalently bonded together to form a 5, 6 or 7-membered saturated : heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.salkylaryl or “ (C1.calkyl)Het and heterocycle being optionally substituted with R™; i) COR" wherein R'¥ is H, (Cis)alkyl, (Cas)cycloalkyl or (Cy.g)alkyl-(Cs. s)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cy salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C+salkyl)Het being optionally substituted with R'*’; j) COOR™ wherein R'?® is (C1.s)alkyl substituted with R'®, (Cy.7)cycloalkyl, or(Cyg)alkyl-(Ca.)cycloalkyl, aryl, Het, (Ci salkyl)ary! or (Cy.salkyl)Het, said (Cs.
Jeycloalkyl, or(Cy.¢)alkyl-(Csy)cycloalkyl, aryl, Het, (Cqsalkyl)aryl and (C,. salkyl)Het being optionally substituted with R'®°; ® k) CONR'R'*® wherein R'? and R™ are independently H, (Cy.q)alkyl, (Ca. s)eycloalkyl, (Ci.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C..salkyl)aryt or (Ci. salkylHet, or both R'* and R'* are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C;.calkyl)aryl, (C1salkyl)Het and heterocycle being optionally substituted with R**’; : aryl, Het, (Ci.salkyl)aryl or (C,salkyl)Het, all of which being optionally substituted with R'*°, wherein R'is selected from: - 1 to 3 substituents selected from: halogen, NO,, cyano, azido or - 1 to 3 substituents selected from: a) (Cy) alkyl or haloalkyl, (Cs.7)cycloalkyl, C57 spirocycloalkyl optionally containing 1 or 2 heteroatom, (C,.)alkenyl, (Ci.¢) alkyl-(Cs. ;)cycloalkyl, all of which optionally substituted with R'®%; b) OR'™ wherein R'is H, (C1alkyl), (Ca)cycloalkyl, or (Cy.e)alkyl- . (Csz)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C4.alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C.salkyl)Het being optionally substituted with R'®?; c) OCOR'® wherein R'® is (Cy.¢)alkyl, (Ca7)cycloalkyl, (Ci.e)alkyl-(C,.
J)eycloalkyl, Het, (C1salkyl)aryl or (C1alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Csalkyl)Het being optionally substituted with R'%; d) SR'®, SON(R'), or SO,N(R'®)C(O)R'® wherein each R'® is independently H, (C4.g)alkyl, (Ca7)cycloalkyl or (C1:s)alkyl-(Cs.
® .
J)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cy.ealkyl)Het or both R'™ are . covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said : alkyl, cycloalkyl, aryl, Het, (C4.alkyl)aryl or (Cysalkyl)Het or heterocycle being optionally substituted with R'®; e) NR"R™ wherein R'is H, (C1.s)alkyl, (Ca7)cycloalkyl or (Ci. e)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C4.¢alkyl)Het, and
R'2is H, (C1.s)alkyl, (Cs)cycloalkyl or (Cy.g)alkyl-(Ca.7)cycloalkyl, aryl,
Het, (Cs.salkylaryl, (Cicalkyl)Het , COOR™ or SO,R""® wherein R'"® is (C1g)alkyl, (Ca7)cycloalkyl, or (Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C1.calikyl)aryl or (Cy.salkyl)Het, or both R'" and R"'® are covalently ® bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, - cycloalkyl, aryl, Het, (Cs.salkyi)aryi or (C,.alkyl)Het, or heterocycle being optionally substituted with R'®°; f) NR'"COR'" wherein R""® and R"" is each H, (C1)alkyl, (Cs. 7)cycloalkyl, (Cie)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Cy. calkyl)Het, said (Cy.c)alkyl, (Cs.y)cycloalkyl, (Cs.c)alkyl-(Caz)cycloalkyl, aryl, Het, (C1.salkyl)aryl or (C;.salkyl)Het being optionally substituted with R'®’; g) NR'®CONR"R'®, wherein R''®, R"® and R'* is each H, (C1. e)alkyl, (Caz)cycloalkyl, (Ci.)alkyl-(Ca7)cycloalkyl, aryl, Het, (Ci. ] salkyharyl or (Cysalkyl)Het, or R'® and R"™ are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Gi. o)alkyl-(C4.)cycloalkyl, aryl, Het, (Cy_salkyl)aryl or (C+.alkyl)Het or heterocycle being optionally substituted with BR"; h) NR'?’COCOR' wherein R'?' is H, (C1.¢)alkyl optionally substituted with R'®®, and R'2 is OR'® or N(R'?*), wherein R'**and each R'is independently H, (Cy.salkyl), (Csz)cycloalkyl, or (C+.g)alkyl- (Cas)cycloalkyl, aryl, Het, (Cy salkylaryl or (Cy.salky))Het, or R'* is OH or O(C.calkyl) or both R'?* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (C1.calkyl)aryl or (C,.salkyl)Het and heterocycle
® ‘being optionally substituted with R'®"; : j) tetrazole, COOR'® wherein R'? is H, (C1.c)alkyl, (Cas)cycloalkyl, or(C4.g)alkyl-(Ca.;)cycloalkyl, aryl, Het, (C+.salkyl)aryl or (Cysalkyl)Het, : said (C1.s)alkyl, (Car)cycloalkyl, or(Ci.s)alkyl-(Cs)cycloalkyl, aryl, Het, (C,salkyl)aryl and (Ci.salkyl)Het being optionally substituted with R'®’; and k) CONR'R'® wherein R'*® and R'® are independently H, (C. e)alkyl, (Caz)cycloalkyl, (C1.)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cy. salkyl)aryl or (C.calkyl)Het, or both R'* and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, ® cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cy.calkyl)aryl, (C1alkyl)Het and heterocycle being optionally substituted with R'®; wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, Cyalkyl, haloalkyl, COOR'™", SOzH,
SO,R™", OR" N(R'2),, SO,N(R'®?),, NR'62COR'®2 or
CON(R"%),, wherein R'®' and R'®*? are as defined above; or Z is N(R**)R® wherein R® is as defined above and R°® is (Ca.)cycloalkyl, (Cie)alkenyl, 6- or 10-membered aryl, Het, (C,.¢)alkyl-aryl, (C1.)alkyl-Het, wherein said alkyl, cycloalkyl, alkenyl, aryl, Het, alkyl-aryl, or alkyl-Het, are all optionally substituted with R®; or Z is OR® or N(R®)R® wherein R*? is as defined above and R® is: . a R? RB’ a \ wherein R” and R® are each independently H, (C4.)alkyl, haloalkyl, (Caz)cycloalkyl, 6- . or 10-membered aryl, Het, (C,.g)alkyl-aryl, (C,.¢)alkyl-Het, wherein said alkyl, cycloalkyl, aryl, Het, (C,.¢)alkyl-aryl, (C;.¢)alkyl-Het are optionally substituted with R™; : or 30. Rand R® are covalently bonded together to form second (Ca.;)cycloalkyl or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; or when Z is N(R*)RS, either of BR” or R® is covalently bonded to R® to form a nitrogen-containing 5-or 6-membered heterocycle;
Y2isOors;
R%is H, (Cy alkyl), (Ca7)cycloalkyl or (C+.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cie)alkyl- aryl or (C,.)alkyl-Het, all of which optionally substituted with R%; or
R? is covalently bonded to either of R’ or R® to form a 5- or 6-membered heterocycle;
Q is a 6- or 10-membered aryl, Het, (C1) alkyl-aryl, (C15) alkyl-Het, (C..¢) alkyl-
CONH-aryl or (Cy.5) alkyl-CONH-Het, all of which being optionally substituted with: ° oor
FL
® pou AA coon [¢] , soon , or R'% or a salt or a derivative thereof; wherein Het is defined as 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, or a 9- or 10-membered heterobicycle having 110 5 heteroatoms selected from O, N and S; and -
R', R?, R® R™, R* and R'” is each defined as: - 1 to 4 substituents selected from: halogen, OPO;H, NO,, cyano, azido,
C(=NH)NH,, C(=NH)NH(C.s)alkyl or C(=NH)NHCO(C.¢)alkyl; or - 1 to 4 substituents selected from: a) (Cy.6) alkyl or haloalkyl, (Cs)cycloalkyl, Caz spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cz)alkenyl, (Cag)alkynyl, (C16) alkyl-(Cs. cycloalkyl, all of which optionally substituted with R'’; b) OR'™ wherein R'is H, (C1calkyl), (Cs)cycloalkyl, or (C.e)alkyl-(Cs. ;)cycloalkyl, aryl, Het, (Ci.salkylaryl or (Cy.calkyl)Het, said alkyl, cycloalkyl, ; aryl, Het, (Ciealkyl)aryl or (C+.calkyl)Het being optionally substituted with
R150: ) c) OCOR'™ wherein R'® is (Ci.¢)alkyl, (Ca7)cycloalkyl, (Gy.e)alkyl-(Cs.
Jeycloalkyl, Het, (Ci.satkyl)aryl or (Cy.calkyl)Het, said alkyl, cycloalkyl, aryl, ;
Het, (Csalkyl)aryl or (Cy.salkyl)Het being optionally substituted with R™’; d) SR, SO:N(R'™), or SO:N(R'®)C(O)R'™ wherein each R'™ is
® independently H, (C,.)alkyl, (Cs.7)cycloalkyl or (Cy.s)alkyl-(Ca)cycloalkyl, aryl, ) Het, (Ci.salkyl)aryl or (Cy.ealkyl)Het or both R' are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7- , membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C. salkyl)aryl or (C,.galkyl)Het or heterocycle being optionally substituted with
R15; : ’ e) NR" R""? wherein R™ is H, (C,.)alkyl, (Cs.7)cycloalkyl or (C.g)alkyl-(Cs. : 7)cycloalkyl, aryl, Het, (Cq.calkyl)aryl or (C;.salkyl)Het, and R'is H, CN, (C1. e)alkyl, (Cs.z)cycloalkyl or (Cy.s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.galkyl)aryl, (C1.salkyl)Het , COOR"* or SOR" wherein R" is (C1.)alkyl, (Ca. 7)cycloalkyl, or (Cy.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Cs. ® calkyl)Het, or both R'""! and R'"? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,salkyl)Het, or heterocycle being optionally substituted with R**; f) NR''°COR""” wherein R'"® and R'" is each H, (Ci.)alkyl, (Cs7)cycloalkyl, (Cig)alkyl-(Ca.z)cycloalkyl, aryl, Het, (Ci.salkylaryl or (C,.salkyl)Het, said (C4. s)alkyl, (Csz)cycloalkyl, (C.g)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cisalkyl)Het being optionally substituted with B'*°; g) NR"'®CONR'®R'®, wherein R'*®, R""® and R' is each H, (Cy.)alkyl, (Ca. 7)cycloalkyl, (Cy.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C4. salkyl)Het, or RB"? is covalently bonded to R'* and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R'"® and R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Cy.s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.zalkyl)aryl or (C,. calkyl)Het or heterocycle being optionally substituted with R'; h) NR'?'COCOR' wherein R'?' and R'? is each H, (Cy.¢)alkyl, (Ca. 7)cycloalkyl, (Cy g)alkyl-(Cs~)cycloalkyl, a 6- or 10-membered aryl, Het, (C,. salkyl)aryl or (C.salkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Crsalkylaryl or (Cysalkyl)Het being optionally substituted with R'*°; or R"? is OR'® or N(R'?*), wherein R'** and each R'* is independently H, (C1.salkyl), (Ca7)cycloalkyl, or (Cy.s)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cs. salkylaryl or (Cy.ealkyl)Het, or R'* is OH or O(C, alkyl) or both R*** are
® covalently bonded together to form a 5, 6 or 7-membered saturated . heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C.salkyl)Het and heterocycle being optionally substituted with R'*°; “ i) COR wherein R'is H, (Cy.)alkyl, (Cs.7)cycloalkyl or (Cy.¢)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cy salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,salkyl)aryl or (C1.salkyl)Het being optionally substituted with R'>’; j) COOR™® wherein R'® is H, (C1.s)alkyl, (Ca7)cycloalkyl, or(C.)alkyl-(Cs. z7)cycloalkyl, aryl, Het, (Ci.salkyl)ary! or (Cy salkyl)Het, said (Ci.s)alkyl, (Ca. z7)cycloalkyl, or(Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cq-salkyharyl and (C;. calkyl)Het being optionally substituted with R'*°;
CL k) CONR'>R™® wherein R'® and R™ are independently H, (Ci.s)alkyl, (Cs. ® 7)cycloalkyl, (C4¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cq.salkyl)aryl or (C,. salkyl)Het, or both R'*® and R**® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated * heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cialkyl)aryl, (Cisalkyl)Het and heterocycle being optionally substituted with R';
I) aryl, Het, (Ci.salkyl)aryl or (Cy.salkyl)Het, all of which being optionally substituted with R'*%; and wherein R'is defined as: - 1 to 3 substituents selected from: halogen, OPOz;H, NO;, cyano, azido, C(=NH)NH,, C(=NH)NH(C,)alkyl or C(=NH)NHCO(C,.)alkyl; or - 1 to 3 substituents selected from: a) (Cy) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs; spirocycloalkyl optionally containing 1 or 2 heteroatom, (Ca.g)alkenyl, (Cs.)alkynyl, (C+.6) alkyl-(Ca.7)cycloalkyl, all of which optionally substituted with R'®°; b) OR wherein R'is H, (Cy.salkyl), (Ca.z)cycloalkyl, or (C1.g)alkyl- (Cs7)cycloalkyl, aryl, Het, (Ci.calkyl)ary! or (Cysalkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cyalkyl)aryl or (C1.calkyl)Het being optionally substituted with R®; c) OCOR'® wherein R'® is (Cy.)alkyl, (Ca7)cycloalkyl, (C.)alkyl-(Ca. 7)cycloalkyl, Het, (Cy.calkyl)aryl or (Cisalkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,.salkyl)Het being optionally substituted with R'®;
® d) SR, SO,N(R'®); or SO,N(R'*)C(O)R'® wherein each R'* is . independently H, (Cys)alkyl, (Cs.7)cycloalkyl or (Ci)alkyl-(Cs. 7)eycloalkyl, aryl, Het, (Ci.calkyl)aryl or (Cy.alkyl)Het or both R'® are : covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Ci¢alkyl)aryl or (Cy.calkyl)Het or heterocycle being optionally substituted with R'®; e) NR"''R"'2 wherein R'" is H, (Cy.¢)alkyl, (Cs)cycloalkyl or (Cs. s)alkyl-(Ca.z)cycloalkyl, aryl, Het, (Cy.calkyl)aryl or (C,.6alkyl)Het, and
R'is H, CN, (C1e)alkyl, (Ca)cycloalkyl or (Cy.e)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C,alkyl)aryl, (Cyealkyl)Het , COOR'"® or SO,R""® wherein ® R'is (Cy.o)alkyl, (Ca.)cycloalkyl, or (C1s)alkyl-(Ca.r)cycloalkyl, aryl,
Het, (C1salkyl)aryi or (C;calkyl)Het, or both R'"! and R**? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cy.alkyl)Het, or heterocycle being optionally substituted with R®’; f) NR"'°COR'"” wherein R'"® and R""” is each H, (Cy.¢)alkyl, (Ca. 7)cycloalkyl, (Ci.e)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cisalkylyaryl or (C,. calkyl)Het, said (C¢)alkyl, (Caz)cycloalkyl, (C1.)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Cisalkyl)Het being optionally substituted with R'®% g) NR''®CONR'"®R'®, wherein R"*%, R'"® and R" is each H, (C:. s)alkyl, (Ca7)cycloalkyl, (Cy.s)alkyl-(Ca.z)cycloalkyl, aryl, Het, (Cs. salkyaryl or (C1.ealkyl)Het, or R""® is covalently bonded to R'"® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, or R''*® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 ’ or 7-membered saturated heterocycle, said alkyl, cycloalkyl, (Ci. s)alkyl-(Css)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (C,.calkyl)Het or heterocycle being optionally substituted with R'®%; h) NR'?’COCOR'? wherein R'?' and R'# is each H, (C,.g)alkyl, (Ca. z7)cycloalkyl, (Ci.)alkyl-(Ca.7)cycloalkyl, a 6- or 10-membered aryl, Het, (Ciealkyl)aryl or (Cy.calkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl,
® aryl, Het, (Cysalkyl)aryl or (C,salkyl)Het being optionally substituted : with R™®, or R'2 is OR"? or N(R"), wherein R'® and each R'** is independently H, (C,.salkyl), (Cs.7)cycloalkyl, or (C1.g)alkyl-(Cs. . J)eycloalkyl, aryl, Het, (Cy.ealkyl)aryl or (Cy.calkyl)Het, or R™* is OH or
O(C1.salkyl) or both R'# are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (C.salkyl)aryl or (Ci.salkyl)Het and heterocycle being optionally substituted with R®’; i) COR wherein R" is H, (C1.g)alkyl, (Ca)cycloalkyl or (Cy.¢)alkyl- (Ca.7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cisalkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cy salkyl)aryl or (C4 alkyl)Het being optionally ® substituted with R*®; j) tetrazole, COOR'® wherein R'? is H, (Cys)alkyl, (Ca.s)cycloalkyl, or(C.¢)alkyl-(Cs.z)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C,.salkyl)Het, said (Cig)alkyl, (Cs.7)cycloalkyl, or(C,s)alkyl-(Cs.7)cycloalkyl, aryl, Het, : (Ci.salkyl)aryl and (Cy.salkyl)Het being optionally substituted with R'®; and k) CONR'R"® wherein R™ and R' are independently H, (Cs. s)alkyl, (Cs7)cycloalkyl, (Cie)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,. salkyl)aryl or (C,.salkyl)Het, or both R™® and R'™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Ci.salkyl)aryl, (C,.salkyl)Het and heterocycle being optionally substituted with R'®°; wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, Cj .salkyl, haloalkyl, COOR™', SO;H, : SR! SOR", OR'™! N(R®2),, SO;N(R'3),, NR'®2COR¢2 or
CON(R'2),, wherein R'®" and each R'*is independently H, (Cig)alkyl, (Caz)cycloalkyl or (Ci.g)alkyl-(Cs7)cycloalkyl; or both ' R™2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered ) saturated heterocycle, or a salt thereof, with the proviso that, when A is CH, R? is phenyl or N-butyl, B is NR?, R* is Me, K is
N
Dm . SN S
CH, Lis CH, Mis CH, Y'is O, and Z is NHR®, then R®is not :
Alternatively, in a first aspect of the invention, there is provided a compound represented by Formula la:
Y
M
A SP .
R— . L =
OK (12) wherein: ® Ais O, S, NR, or CR";
B is NR® or CR?
R' is selected from the group consisting of: H, (C,.e)alkyl, benzyl, (C1. alkyl)-(Cs. jparyl), (Ci. alkyl)-5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, and 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, Nand S, wherein said benzyl and said heteroatom are optionally substituted with from 1 to 4 substituents selected from the group consisting of: COOH, COO(C.¢ alkyl), halogen, and (C1 alkyl);
R? is selected from the group consisting of: H, halogen, (C,.s)alkyl; (Cs.7)cycloaltkyl, phenyl, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O,
N, and S, pyridine-N-oxide , and 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S, said phenyl, heterocycle and heterobicycle being optionally substituted with from 1 to 4 substituents selected from the group consisting of: halogen,
C(halogen)s, (Cyg)alkyl, OH, O(Cis alkyl), NH,, and N(Cy5 alkyl)z;
Ris selected from the group consisting of: 5-, 6- or 7-membered heterocycle having . 1 to 4 heteroatoms selected from O, N, and S, norbornane, (C3 ;)cycloalkyl and (Cs7)cycloalkyl-(Cy.¢ alkyl);
Mis N, CR*, or COR®, wherein R* is selected from the group consisting of: H,
® halogen, and (C+. alkyl); and R® is selected from the group consisting of: H and (Cys alkyl; . Kand Lis Nor CH; ----- represents either a single or a double bond;
YisOorS;
Z is OR® or NR°R®
R®is selected from the group consisting of: H, (Cy.g)alkyl, (Cs.¢)cycloalkyl, o (Cae)eycloalkyl(Cy)alkyl, (Ce-10)aryl, (Csq0)aryl(Cqg)altkyl, (Cae)alkenyl, (Cse)cycloalkyl(Cy.g)alkenyl, (Ce.10)aryl(Ca.s)alkenyl, N{(Ci.s) alkyl}, NHCOO(C,. s)alkyl(Cs.10)aryl, NHCO(Cq.1g)aryl, (Cy.6)alkyl-5- or 8-atom heterocycle, having 1 to 4 heteroatoms selected from O, N and S, and 9- or 10-atom heterobicycle having 1 to 4 heteroatoms selected from O; N and S; wherein said alkyl, cycloalkyl, aryl, alkenyl, heterocycle are all optionally substituted with from 1 to 4 substituents selected from: OH, COOH,
COO(Ci.g)alkyl, (Cie)alkyl, (Cy.g)alkyl-hydroxy, phenyl, benzyloxy, halogen, (Ca.s)alkenyl, (Ca4)alkenyl-(C1.s)alkyl-COOH, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, Nand S, wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle being optionally substituted with from 1 to 4 substituents selected from: (C,, alkyl), CF3, OH, COOH,
NHC(C.salkyl)z, NHCO(C, alkyl), NH», NH(C.¢ alkyl), and
N(C,.s alkyl),; 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O,
N and S, said heterobicycle being optionally substituted with from 1 to 4 , 30 substituents selected from: halogen, OPO3H, sulfonamido, SO3H, SO,CHs, -CONH,, } -COCHy, (C1.9)alkyl, (C.4alkenyl)COOH, tetrazolyl, COOH, -CONH_, triazolyl, OH, NO,, NHj, -O(C.s alkyl) COOH, hydantoin, benzoyleneurea, (C;.4)alkoxy, cyano, azido, -0-(C,.)alkyl COOH, -O-(C,.)alkyl COO-(Cg)alkyl, NHCO(C,.
® 25 ¢ alkyl), -NHCOCOOH, -NHCOCONHOH,-NHCOCONH, ) -NHCOCONHCH;, -NHCO(C1.¢)alkyl-COOH, _NHCOCONH(C;.¢)alkyl-COOH, -NHCO(Ca.7)cycloalkyl- ’ COOH, -NHCONH(C.10)aryl-COOH, - NHCONH(Ce.10)aryl-
COO(C15)alkyl, - NHCONH(C1.6)alkyl-COOH,- NHCONH(C:.- 6)alkyl-COO(C.)alkyl, - NHCONH(C.¢)alkyl-(C.¢)alkenyl-
COOH, - NH(C1.5)alkyl-(Ce.10)aryl-O(C1.g)alkyl COOH, - NH(C+. o)alkyl-(Ce.10)aryl-COOH, -NHCH,COOH, -NHCONH;, -NHCO(C1.5)hydroxyalkyl COOH, -OCO(C;.¢)hydroxyalkyl
COOH, (Cas)cycloalkyl COOH, ° LL 2 g a °c, S$, -NHCN, -NHCHO, -NHSO,CHjs, and -NHSO,CF3; 6- or 10-membered aryl being optionally substituted with from 1to 4 substituents selected from: halogen, OPO3H, sulfonamido, S03H, SO,CHj3, -CONH,, -COCHs, (C1.3)alkyl, (Cz4alkenyl) COOH , tetrazolyl, COOH, . -CONH,, triazolyl, OH, NO,, NH, -O(C1. alkyl) COOH, hydantoin, benzoyleneurea, (C1.s)alkoxy, cyano, azido, -O-(C1.¢)alkyl COOH, -O-(C.)alkyl COO-(C.g)alkyl, NHCO(C.. s alkyl), -NHCOCOOH, -NHCOCONHOH,-NHCOCONH,, -NHCOCONHCHS3;, -NHCO(C,.s)alkyl-COOH, : -NHCOCONH(C1.¢)alkyl-COOH, -NHCO(Cs.7)cycloalkyl-
COOH, -NHCONH(Cg.10)aryl-COOH, - NHCONH(Cs-10)aryl-
COO(C1.6)alkyl, - NHCONH(C¢)alkyl-COOH,- NHCONH(C,. g)alkyl-COO(C,.g)alkyl, - NHCONH(C+.e)alkyl-(Cae)alkenyl- : COOH, - NH(C;.6)alkyl-(Cs-10)aryl-O(Ci.g)alkyl COOH, - NH(C;. 6)alkyl-(Ce.10)aryl-COOH, -NHCH,COOH, -NHCONH,, } -NHCO(C1.¢)hydroxyalkyl COOH, -OCO(C.e)hydroxyalkyl
COOH, (Ca)cycloalkyl COOH, \ OH PL ° S$, -NHCN,. -NHCHO, -NHSO-CHj, and
-NHSO,CFj3; : coumarin, (C.)alkyl-amino, NH(C,.¢ alkyl), C(halogen)s, -NH(C:.4)acyl, -NH(Cs.10)aroyl, -O(C.salkyl)-Het;
R®is H or (Cy alkyl) covalently bonded to either R” or R* to form pyrrolidine; orZis
R® : y 2a oO ® wherein
Wis CR’R® wherein R” and R® are each independently H, (C1 alkyl), (Cs cycloalkyl), (C1. alkyphenyl, (C1. alkyl)-(Ca.7 cycloalkyl), (Caz cycloalkyl)-( C+. alkyl), (Cs. cycloalkyl)-(C2. alkenyl), (Cy. alkyl)-OH, phenyl, CHzbiphenyi, 5- or 6-membered heterocycle having from1 to 4 heteroatoms selected from O, N, and S, 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N, and 8, (Cys alkyl)-5- or 6-membered heterocycle having from1 to 4 heteroatoms selected from O, N, and S, or (Cy alkyl)-9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N, and S, or R’ and R® are covalently bonded together to form (Cs cycloalkyl), 4-, 5- or 6-membered heterocycle having from1 to 4 heteroatoms selected from O, N, and S; or one of R” or R® is covalently bonded to R® to form a pyrrolidine; wherein said alkyl, cycloalkyl, heterocycle, heterobicycle, phenyl are optionally substituted with from 1 to 4 substituents selected from the group consisting of: OH, COOH, (C1. alkyl), (C..+ alkenyl), CONH,, NH,, NH(C,. alkyl), N(C.s alkyl),, NHCOCOOH, NHCOCON(C;.; alkyl), NHCOCONH(C, 4 alkyl), SH, S(C. alkyl), NHC(=NH)NH,, halogen, and COO(C..salkyl); ; R® is H or (C1. alkyl); and ’ Q is selected from the group consisting of: (Cy.salkyl CONHaryl, 6-, 9-, or 10-membered aryl, biphenyl, 5- or 6-atom heterocycle having 1 to 4 heteroatoms selected from O, N and S, 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S;
® wherein said aryl, biphenyl, heterocycle and heterobicycle are all optionally . substituted with from 1 to 4 substituents selected from: OH, COOH,
COO(Cg)alkyl, (Cie)alkyl, (Cie)alkylCOOH, (C1. alkyl)(C24 alkynyl), : (C1.6)alkyl-hydroxy, phenyl, benzyloxy, halogen, (Cz.4)alkenyl, (Cz.4)alkenyl- (C1.6)alkyl-COOH, 5- or 6-membered second heterocycle having 1 to 4 heteroatoms selected from O, N and S, NH-5- or 6- membered second heterocycle having 1 to 4 heteroatoms selected from O, N, and S, wherein said second heterocycle and phenyl being optionally substituted with from 1 to 4 substituents selected from: (Cys alkyl),
CF,, OH, (Cy.¢alkyl) COOH, O(C4.salkyl) COOH, (C1.salkyl) COO(Cs. calkyl), CHaphenyl, COO(C,.s alkyl), (C1.salkyl)O(C+.6alkyl), COOH, ® NCH(C.salkyl)s, NCO(C1 alkyl), NHz, NH(C,. alkyl), halogen, and
N(C1.5 alkyl)s; halogen, OPOgH, benzyl, sulfonamido, SH, SOCH3 SO3H, SO;CHs3, S(Ci5 alkyl)lCOOH, -CONH,, -COCHj, (C1.g)alkyl, (C2.4alkenyhCOOH wherein said alkenyl is optionally substituted with from 1 to 2 (C16 alkyl) substituents, (C..4alkenyl)COO(C,.salkyl), tetrazolyl, COOH, triazolyl, OH, NOx, NH,, , -
O(C1.5 alkyl)COOH, hydantoin, benzoyleneurea, (C..s)alkoxy, (Ci.4)alkoxy(C, alkyl) COOH, cyano, azido, -O-(C.g)alkyl COOH, -O-(C.¢)alkyl
COO0-(C1.g)alkyl, -NHCOCOOH, -NHCOCONHOH,-NHCOCONH,, -NHCOCONHCH;, -NHCO(Cs)alkyl-COOH, -NHCOCONH(C;.s)alkyl-COOH, -NHCO(C3.)cycloalkyl-COOH, -NHCONH(Ce.10)aryl-COOH, - NHCONH(GCe. 10)aryl-COO(Cy.g)alkyl, - NHCONH(C.s)alkyl-COOH,- NHCONH(C.¢)alkyl-
COO(C.¢)alkyl, - NHCONH(C1.g)alkyl-(Co.)alkenyl-COOH, - NH(C.g)alkyl-(Ce. 10)aryl-O(C.g)alkyl COOH, - NH(C.g)alkyl-(Ce.10)aryl-COOH, -NHCH.COOH, -NHCONH;, -NHCO(C1.)hydroxyalkyl COOH, -OCO(C,.)hydroxyalkyl
COOH, (Cs)cycloalkyl COOH, \ OH AX : po C J" “Ore ° 5S “0 _NHCN, -NHCHO, -NHSO,CHj, ’ 30 -NHSO,CF3, coumarin, (Cy.¢)alkyl-amino, NH(C,.salkyl),, C(halogen)s, -NH(Cz.4)acyl, -NH(Cs.10)aroyl, -CONH(C;.galkyl), -CO(C1.s)alkyl-COOH, -CONH(C,.g)alkyl-COOH, -CO-NH-alanyl, -CONH(C,.,)alkyIN(C1.¢alkyl)z, -CONH(C,.4) alkyl-Het,
-CONH(C.4) alkyl-(COOH)-Het -CONH(C,, alkyl) (OH)(C;., alkyl)OH, . -CONH(C,.¢) alkyl-COOH, -CONH(Cq.4; aryl), -CONH-Het, -CONH(Cg.10) aryl-COOH, -CONH(Cq.1o) aryl-COO(Ci.5) alkyl, » -CONH(C.¢) alkyl-COO(C+.g) alkyl, -CONH(Cs.10) aryl-(Ci.¢)alkyl-COOH, and -CONH(Cs.10) aryl-(Co.6)alkenyl-COOH, or a salt thereof.
In a third aspect of the invention, there is provided a compound of the formula |, or a pharmaceutically acceptable salt thereof, as an inhibitor of RNA dependent RNA polymerase activity of the enzyme NS5B, encoded by HCV. ® In a fourth aspect of the invention, there is provided a compound of the formula I, or a pharmaceutically acceptable salt thereof, as an inhibitor of HCV replication.
In a fifth aspect of the invention, there is provided a method of treating or preventing
HCV infection in a mammal, comprising administering to the mammal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
In a sixth aspect of the invention, there is provided a pharmaceutical composition for the treatment or prevention of HCV infection, comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
According to a specific embodiment, the pharmaceutical compositions of this invention comprise an additional immunomodulatory agent. Examples of additional immunomodulatory agents include but are not limited to, o-, B-, 6- y-, and w- interferons.
According to an alternate embodiment, the pharmaceutical compositions of this . 30 invention may additionally comprise an antiviral agent. Examples of antiviral agents include, ribavirin and amantadine.
According to another alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise other inhibitors of HCV protease.
According to yet another alternate embodiment, the pharmaceutical compositions of - this invention may additionally comprise an inhibitor of other targets in the HCV life cycle, such as helicase, polymerase, metalloprotease or IRES.
Ina seventh aspect of the invention, there is provided a use of a compound of formula 1, for the manufacture of a medicament for the treatment of HCV infection.
In a eighth aspect of the invention, there is provided a use of a compound of formula
I, to prevent HCV infection.
In an ninth aspect of the invention, there is provided a use of a compound of formula
C I, as an HCV polymerase inhibitor.
In a tenth aspect of the invention, there is provided an intermediate of formula (1 a) or (1b): [eo] 0 , or PY one oe
BNA BA ia or 1b wherein A, B, K, L, and M are as described herein and PG is H or a carboxy protecting group.
In a eleventh aspect of the invention, there is provided a process for producing compounds of formula (ii), o] , A me Aor rRR—_
B kt (iii) . wherein A, R?, B, K, L, M, and PG are as described herein, comprising: . 25 a) coupling, in the presence of a metal catalyst (such as, for example, Pd, Ni, Ru,
Cu), a base and an additive (such as a phosphine ligand, Cu salt, Li salt, ammonium salt, CsF) in an appropriate solvent, intermediate (1a)
® : lo) ; TY
Bt ’ 1a with R%-X, wherein R', R®, K, L, M and PG are as described herein and X is (bt not limited to ): Sn(C,alkyl)s, Sn(aryl)a, metal halide, B{(OH),, and B(O(C,.¢)alkyl), to produce compounds of formula (iii).
In an alternative to the eleventh aspect of the invention, there is provided a process ) for producing compounds of formula (iii), 5 ® S00 oPG ‘Bt (1) wherein A, R?, B, K, L, M, and PG are as described herein, comprising: b) coupling, in the presence of a metal catalyst (such as, for example, Pd, Ni, Ru,
Cu), a base and an additive (such as a phosphine ligand, Cu salt, Li salt, ammonium salt, CsF) in an appropriate solvent, intermediate (1b) 0
We a ib with R2-X', wherein X' is halide, OSO,(C;salkyl), OSO.Ar, OSO,CF; and the like, and
M is a metal such as Li, Sn(C,.salkyl)s, Sn(aryl)s, B(OH)., B(OC,.salkyl),, metal halide, to produce compounds of formula (iii).
In an thirteenth aspect of the invention, there is provided an intermediate compound : 20 represented by formula 1c: o pl R®
YY” | :
B® 1c wherein A, R?, B, K, L, M, R” and R® are as defined herein, or a salt, or a derivative thereof.
In an fourteenth aspect of the invention, there is provided a process for producing compounds of formula |, comprising: : 5 a) coupling, in a mixture containing an aprotic solvent, or no solvent, a coupling agent, and at a temperature of about 20 °C to about 170 °C, and intermediate 1c: o pl R® we LTH 1c with amine Q-NH; so as to produce compounds of formula I, wherein A, R?, B, rR’, ® R® Q, K, L, and M are as defined herein.
In an fifteenth aspect of the invention, there is provided an intermediate compound represented by formula 1d:
[0] RX R?
A me As > om
Re 1 © :
B= ~ 7b o id wherein A, R% B, K, L, M, R” and R® are as defined herein or a salt or a derivative thereof.
In a sixteenth aspect of the invention, there is provided a process for producing compounds of formula |, comprising: a) coupling, in a mixture containing an appropriate solvent, or no solvent, a coupling agent, and at a temperature of about 20 °C to about 170 °C, and intermediate 1d: 0 R, R®
A mA por , RE— I x 0
B—~ 2h o id . with amine @-NH; so as to produce compounds of formula |, wherein A, R?, B, rR’,
RS, Q, K, L, and M are as defined herein.
In a seventeenth aspect of the invention, there is provided a method of treating or preventing HCV infection in a mammal, comprising administering to the mammal an - effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in combination with another anti-HCV agent.
DETAILED DESCRIPTION OF THE INVENTION Definitions
The following definitions apply unless otherwise noted:
As used herein,.the terms “(C,.3) alkyl”, “(C.4) alkyl” or “(Cy.¢) alkyl”, either alone or in combination with another radical, are intended to mean acyclic straight or branched chain alkyl radicals containing up to three, four and six carbon atoms respectively.
C Examples of such radicals include methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 1- methylpropyl, 2-methylpropyl, 1,1-dimethylethyl.
As used herein, the term “(C,.6) alkenyl”, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight chain radical containing two to six carbon atoms.
As used herein, the term (C,) alkynyl” either alone or in combination with another group, is intended to mean an unsaturated, acyclic straight chain sp hybridized radical containing 2 to six carbon atoms.
As used herein. the term “(C37) cycloalkyl”, either alone or in combination with } another radical, means a cycloalkyl radical containing from three to seven carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
As used herein, the term *(Cs.7)cycloalkenyl”, either alone or in combination with another radical, means an unsaturated cyclic radical containing five to seven carbon atoms. . 30
As used herein, the term "carboxy protecting group" defines protecting groups that . can be used during coupling and are listed in Greene, “Protective Groups in Organic
Chemistry”, John Wiley & Sons, New York (1981) and “The Peptides: Analysis,
Synthesis, Biology”, Vol. 3, Academic Press, New York (1981), the disclosures of which are hereby incorporated by reference.
® : The a-carboxy! group of the C-terminal residue is usually protected as an ester (CPG) that can be cleaved to give the carboxylic acid. Protecting groups that can be : used include: 1) alkyl esters such as methyl, trimethylsilylethyl and t-butyl, 2) aralkyl esters such as benzyl and substituted benzyl, or 3) esters that can be cleaved by mild base treatment or mild reductive means such as trichloroethyl and phenacyl esters.
As used herein, the term “aryl”, or "6- or 10-membered aryl" either alone or in combination with another radical means aromatic radical containing six or ten carbon ® atoms, for example phenyl or naphthyl.
As used herein the term heteroatom means O, S or N.
As used herein, the term "heterocycle", either alone or in combination with another radical, means a monovalent radical derived by removal of a hydrogen from a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur.
Furthermore, "heterobicyclic" as used herein, means a heterocycle as defined above fused to one or more other cycle, be it a heterocycle or any other cycle. Examples of such heterocycles include, but are not limited to, pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, coumarin, hydantoin, diazepine, 1H-imidazole, isoxazole, thiazole, tetrazole, piperidine, 1,4-dioxane, 4-morpholine, pyridine, pyridine-N-oxide, pyrimidine, thiazolo[4,5-b]-pyridine, quinoline, or indole, or the following heterocycles: . Q
A NH = S nN” N N s— [=o ( \\ J or { 0 s TO , N , N—N ’ As used herein, the term “9- or 10-membered heterobicycle” or “heterobicycle” either alone orin combination with another radical, means a heterocycle as defined above ’ 30 fused to one or more other cycle, be it a heterocycle or any other cycle. Examples of such heterobicycles include, but are not limited to, thiazolo[4,5-b]-pyridine, quinoline, or indole, or the following:
i - 34
AN S o_O o
C0 y >
H
N = 0 Ss 0
Cry C0
N
CO or Ho
As used herein, the term "Het" defines a 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, or a 9- or 10-membered heterobicycle ® having 1 to 5 heteroatoms wherever possible, selected from O, N and S.
As used herein, the term “halo” means a halogen atom and includes fluorine, chlorine, bromine and iodine.
As used herein, the term “haloalkyl” is intended to mean an alkyl that is described above in which each hydrogen atom may be successively replaced by a halogen ’ atom, for example CH,Br or CFs.
As used herein, the term “metal halide” is intended to mean any metal that is bonded to a halogen atom for use in a metal-catalyzed cross-coupling reaction. Examples of such metal halides include, but are not limited to, -MgCl, -CuCl, or -ZnCl and the like.
As used herein, the term “OH” refers to a hydroxyl group. lt is well known to one skilled in the art that hydroxy! groups may be substituted by functional group equivalents. Examples of such functional group equivalents that are contemplated by this invention include, but are not limited to, ethers, sulfhydryls, and primary, secondary or tertiary amines. ’ "05 As used herein, the term “SH” refers to a sulfhydryl group. It is intended within the scope of the present invention that , whenever a "SH" or "SR" group is present, it ) can also be substituted by any other appropriate oxidation state such as SOR, SOR, or SO;R. ltis intended that the term "substituted" when applied in conjunction with a radical
® having more than one moiety such as C;.galkyl-aryl, or C;.salkyl-Het, such . substitution applies to both moieties i.e. both the alkyl and aryl or Het moieties can be substituted with the defined substituents.
As used herein, the term “COOH” refers to a carboxylic acid group. It is well known to one skilled in the art that carboxylic acid groups may be substituted by functional group equivalents. Examples of such functional group equivalents that are contemplated by this invention include, but are not limited to, esters, amides, boronic acids or tetrazole.
As used herein, the term “functional group equivalent’ is intended to mean an o element or a substituted derivative thereof, that is replaceable by another element that has similar electronic, hybridization or bonding properties.
As used herein, the term “metal catalyst” is intended to mean a metal such as palladium (0) or palladium (2) that is bonded to a leaving group for use in a cross- coupling reaction. Examples of such palladium catalysts include, but are not limited to, Pd(Ph3),, Pd/C, Pd(OACc),, PdCl,, and the like. Alternative metals that can catalyze cross-coupling reactions include, but are not limited to: Ni(acac),, Ni(OAc),, or NiCl,.
As used herein, the term “derivative” is intended to mean “detectable label”, “affinity tag” or “photoreactive group”. The term “detectable label" refers to any group that may be linked to the polymerase or to a compound of the present invention such that when the compound is associated with the polymerase target, such label allows recognition either directly or indirectly of the compound such that it can be detected, measured and quantified. Examples of such “labels” are intended to include, but are not limited to, fluorescent labels, chemiluminescent labels, colorimetric labels, enzymatic markers, radioactive isotopes and affinity tags such as biotin. Such labels ; 30 are attached to the compound or to the polymerase by well known methods.
The term “affinity tag” means a ligand (that is linked to the polymerase or to a . compound of the present invention) whose strong affinity for a receptor can be used to extract from a solution the entity to which the ligand is attached. Examples of such ligands include biotin or a derivative thereof, a histidine polypeptide, a polyarginine, an amylose sugar moiety or a defined epitope recognizable by a specific antibody. Such affinity tags are attached to the compound or to the : polymerase by well-known methods. + The term “photoreactive group” means a group that is transformed, upon activation by light, from an inert group to a reactive species, such as a free radical. Examples of such groups include, but are not limited to, benzophenones, azides, and the like.
As used herein, the term “pharmaceutically acceptable salt” includes those derived from pharmaceutically acceptable bases and is non-toxic. Examples of suitable bases include choline, ethanolamine and ethylenediamine. Na*, K*, and Ca™ salts are also contemplated to be within the scope of the invention (also see ® Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19, incorporated herein by reference).
Preferred embodiments
Core: . Preferably, compounds of the present invention have the following formula (il): 0] i
So rz \ A 3
R (i) wherein, preferably, Ais O, S, or NR".
More preferably, A is NR.
Preferably, compounds of the present invention have the following formula (mn: : R! 0] mg, . a2 74 | z zt
K (lr) o5 wherein, preferably, B is NR.
With respect to compounds of formula (11) and (Ili), preferably, M, K and L is CH or
N. More preferably, M, K and L is CH.
More preferably, compounds of the present invention have the following formulae: ’ Lo)
Rl [o] 0
R? * / z \ R®
J N
R i at | lla la i | 0
R\
S \
CE : N z ® 3 SE
Rr’ a lib llc
R! Oo
NN
2 N ~ z.
R \ P 3 or HR ) lid
R’:
Preferably R' is selected from the group consisting of: H or (Cy.¢)alkyl. More preferably, R'is H, CHa, isopropyl, or isobutyl. Even more preferably, R'is H or CHa.
Most preferably, R' is CHa.
R%
Preferably, R? is CON(R?),, wherein each R? is independently H, (C1.e)alkyl, (Cs.
J)cycloalkyl, (Cs)cycloalkenyl, 6 or 10-membered aryl or Het, or both R? are bonded together to form a 5, 6 or 7-membered saturated heterocycle with the nitrogen to ] 20 which they are attached; or BR? is selected from: H, halogen, (C.¢)alkyl, haloalkyl, (C..)alkenyl, (Cs. sycycloaltkenyl, 6 or 10-membered aryl or Het; wherein each of said alkyl, haloalkyl, (Cas)alkenyl, (Cs)cycloalkenyl, aryl or Het is optionally substituted with R*’, wherein
_
R* is defined as: “ - 1 to 4 substituents selected from: halogen, NO,, cyano, azido, C(=NH)NH;,
G(=NH)NH(C.¢)alkyl or C(=NH)NHCO(C.¢)alkyl; or : - 1 to 4 substituents selected from: a) (C1.6) alkyl or haloalkyl, (Cs7)cycloalkyl, (Co.g)alkenyl, (Ca.g)alkynyl, (Cy.6) alkyl-(Cs7)cycloalkyl, all of which optionally substituted with Rr b) OR'™ wherein R'™ is H, (C,salkyl), (Cs )cycloalkyl, or (Cy.g)alkyl-(Ca. z)cycloalkyl, aryl, Het, (Ci-salkyharyl or (Cy .salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C,.calkyl)Het being optionally substituted with rR ¢) OCOR'® wherein R'® is (Ci.5)alkyl, (Caz)cycloalkyl, (Cy.e)alkyl-(Ca. ® z)cycloalkyl, Het, (Cqalkyharyl or (Cyalkyl)Het, said alkyl, cycloalkyl, aryl,
Het, (C,.calkyl)aryl or (C1salky)Het being optionally substituted with R'’; d) SR, SO,N(R'®), or SO,N(R'®)C(0)R® wherein each R'® is independently H, (C.s)alkyl, (Cs-)cycloalkyl or (Ci.s)alkyl-(Cs.7)cycloalkyl, aryl,
Het, (C..salkylaryl or (C,.salkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,. salkyl)aryl or (C1.salkyl)Het or heterocycle being optionally substituted with
R10: e) NR"'R"? wherein R'is H, (Cy.s)alkyl, (Cs.7)cycloalkyl or (Cy.)alkyl-(Ca. cycloalkyl, aryl, Het, (Cqsalkyl)aryl or (C,.ealkyl)Het, and R'*2is H, CN, (C;. s)alkyl, (Ca.7)cycloalkyl or (C4.)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cyealkyl)aryl, (Ci.alkyl)Het , COOR' or SO,R'"® wherein B'*® is (Cy5)alkyl, (Cs. 7)cycloalkyl, or (Cy.s)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cs. salky)Het, or both R'"" and R""? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated . + heterocycle, said alkyl, cycloalkyl, aryl, Het, (Csalkyharyl or (C,galkyl)Het, or heterocycle being optionally substituted with R'®; f) NR''°COR'" wherein R"'® and R'is each H, (Ci.¢)alkyl, (Cs)cycloalkyl, . (Ci-g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Ci.salkyl)Het, said (C;. s)alkyl, (Cs.7)cycloalkyl, (Cy.¢)alkyl-(Ca)cycloalkyl, aryl, Het, (Ciealkyl)aryl or (C;-salkyl)Het being optionally substituted with R'’; g) NR"CONR™R'®, wherein RB", R""® and R'? is each H, (C1c)alkyl, (Ca.
® 7)cycloalkyl, (Cq.6)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cs. . salkyl)Het, or R""® is covalently bonded to R'*® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; * or R" and R'? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C1.s)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cs. salkyl)Het or heterocycle being optionally substituted with R™"; h) NR'?COCOR'? wherein R'?! and R'# is each H, (C1.s)alkyl, (Cs. 7)cycloalkyl, (Cy.s)alkyl-(Caz)cycloalkyl, a 6- or 10-membered aryl, Het, (C. salkyl)aryl or (Cealkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C1.calkyharyt or (Ci.salkyt)Het being optionally substituted with R™; ® or R'2is OR" or N(R"), wherein R'®* and each R'* is independently H, (C16alkyl), (Caz)cycloalkyl, or (Cy.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (C1. salkyharyl or (C1salkyl)Het, or R'?* is OH or O(C1.salkyl) or both R'?* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalky!, aryl, Het, (C,.ealkyharyl or (C1salkyl)Het and heterocycle being optionally substituted with R'*°; i) COR wherein RZ is H, (C,)alkyl, (Cs)cycloalkyl or (Cyg)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (C¢alkyharyl or (C,.calkyl)Het, said alkyl, cycloalkyl, } aryl, Het, (C.calkyl)aryl or (Cy.salkyl)Het being optionally substituted with RB; j) COOR'® wherein R'is H, (Cy.¢)alkyl, (Cs.7)cycloalkyl, or(Cy.¢)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,.¢alkyl)aryl or (Ciealkyl)Het, said (C,.)alkyl, (Cs. 7)cycloalkyl, or(C.g)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cisalkyl)aryt and (C.. calkyl)Het being optionally substituted with R'’; : 25 k) CONR™R™ wherein R'® and R'® are independently H, (Cy.)alkyl, (Ca.
Jeycloalkyl, (Crs)alkyl-(Cs)cycloalkyl, aryl, Het, (Cyealkyllaryl or (C+. calkyl)Het, or both R™® and R'*° are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated } heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.¢alkyl)aryl, (C1.salkyl)Het and heterocycle being optionally substituted with R'®; ] 1) aryl, Het, (C1-6alkyl)aryl or (C1-6alkyl)Het, all of which being optionally substituted with R"™°, wherein R'*° is preferably: - 1 to 3 substituents selected from: halogen, NO,, cyano or azido; or - 1 to 3 substituents selected from:
® a) (C1.¢) alkyl or haloalkyl, (Ca.7)cycloalkyl, (Ca.6)alkenyl, (Ca.g)alkynyl, : (C1.6) alkyl-(Cs)cycloalkyl, all of which optionally substituted with R'% b) OR'"* wherein R'™ is H, (Cysalkyl) or (Cs)cycloalkyl, said alkyl or ' cycloalkyl optionally substituted with R'®; d) SR, SO;H, SO,N(R'®), or SO.N(R'®)C(O)R'® wherein each
R'® is independently H, (C,.6)alkyl, (Cs)cycloalkyl or (Ci.g)alkyl-(Ca. 7)eycloalkyl, aryl, Het, or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het and heterocycle being optionally substituted with R'; e) NR'"R"2 wherein R'is H, (C1.5)alkyl, or (Cs7)cycloatkyl, and R'"? ® is H, (Ci.g)alkyl or (Cs7)cycloalkyl, COOR'* or SO,R"*® wherein R'"® is (Cy.g)alkyl or (Cs7)cycloalkyl, or both R'" and R"*? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R*; f) NR"'°COR'"” wherein R'"® and R’"" is éach H, (Cy.¢)alkyi or. (Ca. 7)cycloalkyl said (C;g)alkyl and (Cs.7)cycloalkyl being optionally substituted with R'®,; g) NR" CONR'"R'®, wherein R"'®, R"® and R'*’ is each H, (C;. e)alkyl or (Ca.7)eycloalkyl, or R''® is covalently bonded to R'® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, or R'*® and R'? are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, and heterocycle being optionally substituted with R®; h) NR'*'COCOR'> wherein R'? is H, (G1.s)alky! or (Ca)cycloalkyl, said alkyl and cycloalkyl being optionally substituted with R'®’; or R'is OR'® or N(R"), wherein R'®and each R'* is independently H, (C.salkyl) or (Cs7)cycloalkyl, or both R' are ] covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R'?; i) COR" wherein R'is H, (C:.s)alkyl or (Cs)cycloalkyl, said alkyl
® and cycloalkyl being optionally substituted with R™®; : | j) COOR'® wherein R'is H, (Cy.)alkyl or (Ca.z)cycloalkyl, said (C1e)alkyl and (Ca.z)cycloalky! being optionally substituted with R'’; ! and k) CONR'* RR" wherein R* and R'™ are independently H, (Cs. e)alkyl or (Ca7)cycloalkyl, or both R*?® and R'*° are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R™; wherein R' is defined as 1 or 2 substituents selected from: halogen, CN, C1.salkyl, haloalkyl, COOR'®', OR™', N(R'%),, ® SO,N(R"2),, NR'®2COR'® or CON(R'®?),, wherein R'®' and each R'® is independently H, (Cy¢)alkyl, (Csz)cycloalkyl or (Ci. s)alkyl-(Cs.7)cycloalkyl; or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle.
More preferably, R? is selected from: aryl or Het, each optionally monosubstituted or disubstituted with substituents selected from the group consisting of: halogen, haloalkyl, Ns, or a) (C1.6)alkyl optionally substituted with OH, O(C1.¢)alkyl or SO»(C+. alkyl); ~ b) (C1-e)alkoxy; e) NR'R'2 wherein both R'" and R""?are independently H, (C,)alkyl, (Ca7)cycloalkyl, or R'*2 is 6- or 10-membered aryl, Het, (Cy.¢)alkyl-aryl or (C1e)alkyl-Het; or both R'"' and R'*? are covalently bonded together and to the nitrogen to which they are attached to form a nitrogen- containing heterocycle, each of said alkyl, cycloalkyl, aryl, Het, alkyl- aryl or alkyl-Het; being optionally substituted with halogen or: - OR?" or N(R®"), , wherein each R*" is independently H, (C;. g)alkyl, or both BR?" are covalently bonded together and to the nitrogen to which they are attached to form a nitrogen- containing heterocycle; f) NHCOR" wherein R'" is (C1.5)alkyl, O(C1.5)alkyl or O(Cs7)cycloalkyl;
® i) CO-aryl; and : kK) CONH,, CONH(C, alkyl), CON(C,.salkyl),, CONH-aryl, or CONHC;. galkyl aryl,
Still, more preferably, R? is aryl or Het, each optionally monosubstituted or disubstituted with substituents selected from the group consisting of: halogen, haloalkyl, or a) (C+.6)alkyl optionally substituted with OH, O(C1.g)alkyl or SO5(C4. salkyl); ~~ b) (C+.6)alkoxy; and e) NR''R"'2 wherein both R""* and R""2 are independently H, (C1.¢)alkyl, ® (Caz)cycloalkyl, or R'? is 6- or 10-membered aryl, Het, (C1.¢)alkyl-aryl or (C,.g)alkyl-Het; or both R""! and R''? are covalently bonded together and to the nitrogen to which they are attached to form a nitrogen- containing heterocycle, each of said alkyl, cycloalkyl, aryl, Het, alkyl- aryl or alkyl-Het; or being optionally substituted with halogen or: - OR* or N(R?"), , wherein each R*" is independently H, (Ci. e)alkyl, or both R™ are covalently bonded together and to the : nitrogen to which they are attached to form a nitrogen- containing heterocycle.
Even more preferably, R? is phenyl or a heterocycle selected from:
SO OD OOO
OO Yon oD o s | H 0) ox
N
SUC ING
= N : Hand S$, all of which optionally substituted as defined above.
Even more preferably, R? is selected from the group consisting of:
H, Br, CONHCHs, CON(CHa),, CONH, CH=CH,
® . ne ne :
SAOGOAG Ino \ i \ y @ ~y" oa J% a x - SN 5 poe oe ae oe
N
A CE GE GW
, Ny ~ & a = s On 0 =N “ De ne oa * oa NN Wa Wa ™ . HN oe / / / ¢
ZN HN BN N ) : 9 A NN an CC) Us i \ . . = a Oe
HN Ss AN 3 p= = % = HN HN Co :
N \ . HN 0 A N~¢
Jo} / / Ao ~ 0 oa ,
SOs
Tw = HN =o 0]
Q . Os NH )— al NH, NH, NO, hi
H,C y CH, ® Sf $i ) pl SoU Io:
HC” 0 CH, > ¥Z Z =
IN IN | SNOT = xX NT
LJ 2 UJ A SN UN NN _
J P cl F CF, Ny NH, NH, NH, OMe ~~ OMe
A XY —
Cr +_0 _N ZN he Na o =~ N oN s -° AM NH, NH, AS av Co
N
© NH © NH -
J Oy g 9g . a "UTD TU ’ , ) , and . . Still more preferably, R? is selected from:
’ NN OY ON NY NN a roo Hoo
A LL a
NT | F NA Nx N J Pa } OH
STN 5 Ty = Mg =
IN HN HN / / HN
NTN N
DL { s —- o) oe SC OO QL ro xn
Oe a. ~N ~N SN SN
HN Ow _NH 7% PZ % =
Ao NH, NH, he , CH, , F OMe CF, ,
CH, -
Je ~N = | = ZZ ~N NN Nx 0] % F cl N, Z NH, ~~ Ome NH, : oa “~ and .
Most preferably, R? is selected from:
EE = oy Tr ~
NTN
\ \ XN =N
N Ny BN Va ® I RN . 0=8=0 don LIS Co
CH,
NN NN NN XN NN y
NY. We, OH OMe Fo ~~ , o, NH,
® a
J, HN
HN / = , / = ©, and . rR:
Preferably, R® is selected from (Cs.7)cycloalkyl, (Ca.7)cycloalkenyl, (Ce-10)bicycloalkyl, (Ce-10)bicycloalkenyl, 6- or 10-membered aryl, or Het. More preferably, R® is (Cs. 7)cycloalkyl. Most preferably, R? is cyclopentyl, or cyclohexyl. ® Y:
Preferably Y' is O.
Preferably, Z is OR® wherein R® is (Cy.salkyl)aryl substituted with: - 1 to 4 substituents selected from: a) (C1)alkyl substituted with R'°%, haloalkyl, (Cs)cycloalkyl, Cs spirocycloalkyl optionally containing 1 or 2 heteroatom, (Coe)alkenyl, (Co. g)alkynyl, (C16) alkyl-(Cs)cycloalkyl, said haloalkyl, cycloalkyl, spirocycloalkyl, alkenyl, alkynyl and alkyl-cycloalkyl being optionally substituted with R'®, wherein R™* is the same as R™ but is not COOR"®, N(R"®),,
NR'®C(O)R'™, OR" SR, SO,R%, SO.N(R®),, wherein R150b is H or unsubstituted Ci.galkyl; b) OR'™ wherein R'is (Cy.salkyl) substituted with R'*°, (Cs)cycloalkyl, or (C1.0)alkyl-(Cas)cycloalkyl, aryl, Het, (Ciealkyl)aryl or (C+.salkyl)Het, said cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,salkyl)Het being optionally substituted with R'*% ‘ 25 d) SR, SO,N(R'®), or SO.N(R'®)C(O)R"® wherein each R'* is independently H, (C1.s)alkyl, (Caz)cycloatky! or (Cyg)alkyi-(Csz)cycloalkyl, aryl, : Het, (Cssalkyl)aryl or (Csalkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cs. calkylaryl or (Ci.salkyl)Het or heterocycle being optionally substituted with
® ' :
R™*°, wherein R'%®? is the same as R'® but is not H or unsubstituted C,salkyl; e) NR'""'R""2 wherein R'is H, (C1.)alkyl, (Cs7)cycloalkyl or (Ci.¢)alkyl-(Ca.
Jeycloalkyl, aryl, Het, (C,galkyl)aryl or (C,.salkyl)Het, and Ris H, CN, (Ci. ’ g)alkyl, (Caz)cycloalkyl or (Cyg)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl, (Cy6alkyl)Het , provided that when R'" is H or unsubstituted alkyl, R'*? is not
H or unsubstituted alkyl, or R"'? is also COOR'® or SO,R"** wherein R'® is
H, (Ci)alkyl, (Csz)cycloalkyl, or (Cy.g)alkyl-(Cs)cycloalkyl, aryl, Het, (C;. salkylaryl or (C,alkyl)Het, and R''** is the same as R""® but is not H or unsubstituted alkyl, or both R*'! and R"*? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cigalkyl)aryl or (C;. ® : salkyl)Het, or heterocycle being optionally substituted with R", f) NR"°COR"" wherein R'® and R'" is each (C,.¢)alkyl substituted with
R™°, (Cs.)cycloalkyl, (C+.¢)alkyl-(Ca.z)cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (C. calkyl)Het, said (Cs.;)cycloalkyl, (Ci¢)alkyl-(Caz)cycloalkyl, aryl, Het, (Cs. calkyaryl or (Cy.ealkyl)Het being optionally substituted with R'; g) NR'™CONR'"R'®, wherein R"'®, R'"? and R'® is each H, (Ci.)alkyl, (Cs.
Jcycloalkyl, (Cs.6)alkyl-(Caz)cycloalkyl, aryl, Het, (C1_salkylyaryl of (C1. calkyl)Het, or R**® is covalently bonded to R'* and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R™® and R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Cy¢)alkyl-(Cs.;)cycloalkyl, aryl, Het, (C1.salkyl)aryl or (C,. calkyl)Het or heterocycle being optionally substituted with BR’; h) NR''COCOR'™ wherein RB"?! is H or C;.¢alkyl and R'? is OR'® or
N(R'?%, wherein R'? and each R'is independently H, (Ci.salkyl), (Ca. 7)cycloalkyl, or (Cy.e)alkyl-(Csz)cycloalkyl, aryl, Het, (C4.calkyharyl or (Cs. salkyl)Het, or R'2* is OH or O(C;.galkyl) or both R'?* are covalently bonded } together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Ci-salkyl)aryl or (Cy.galkyl)Het and . heterocycle being optionally substituted with R'®; j) COOR™ wherein R'is (Cy s)alkyl substituted with R™™, (Cs7)cycloalkyl, or(C.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C+.salkyl)aryl or (C.salkyl)Het, said (Ca. 7)cycloalkyl, or(C.)alkyl-(Cs7)cycloalkyl, aryl, Het, (Csealkyl)aryl and (C;.
® calkyl)Het being optionally substituted with R°; ‘ k) CONR'®R™ wherein R™ and R'® are independently H, (Ci.¢)alkyl, (Cs. s)cycloalkyl, (Cy.6)alkyl-(Ca7)cycloalkyl, aryl, Het, (C.csalkyharyl or (C:. : calkyhHet, provided that when R'? is H or unsubstituted alkyl, R™* is not H or unsubstituted alkyl, or both R'*® and R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,. galkyl)aryl, (Cysalkyl)Het and heterocycle being optionally substituted with
R'% .
I) aryl, Het, (C:alkyl)aryl or (Cy.salkyl)Het, all of which being optionally substituted with R'*®; wherein R'is: ( - 1 to 3 substituents selected from: halogen or azido; or - 1 to 3 substituents selected from: a) (C1) alkyl or haloalkyl, (Cs7)cycloalkyl, Cs. spirocycloalkyl optionally containing 1 or 2 heteroatom, (C,.¢)alkenyl, (C..g)alkynyl, (C1.) alkyl-(Ca.y)cycloalkyl, all of which optionally substituted with R™®; b) OR' wherein R'is H, (Cy.salkyl), (Ca)eycloalkyl, or (Cy.¢)alkyl- (Car)eycloalkyl, aryl, Het, (Ci.calkyl)aryl or (Cy.calkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Ci.salkyl)Het being optionally substituted with R'®; d) SR, SO,N(R'), or SO,N(R'®)C(O)R'® wherein each R'® is independently H, (Cy.)alkyl, (Cs7)cycloalkyl or (Cy.)alkyl-(Cs. scycloalkyl, aryl, Het, (Cy.galkyl)aryl or (C4.salkyl)Het or both R'* are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cqsalkyl)Het or heterocycle being optionally substituted with R'®; e) NR"™MR"'2 wherein R' is H, (C;.5)alkyl, (Cs.s)cycloalkyl or (Cy. s)alkyl-(Cs)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cy.salkyl)Het, and ’ 30 R'2is H, CN, (Cy.g)alkyl, (Ca)cycloalkyl or (Cy.s)alkyl-(Cs7)cycloalkyl, } aryl, Het, (Cqalkyl)aryl, (Ciealkyl)Het , COOR'® or SO,R"** wherein - R"5 is (Cy.p)alkyl, (Ca)cycloalkyl, or (Cye)alkyl-(Cas)cycloalkyl, aryl,
Het, (C+-calkyl)aryl or (C:.alkyhHet, or both R™' and R'" are covalently bonded together and to the nitrogen to which they are
® attached to form a 5, 6 or 7-membered saturated heterocycle, said “ alkyl, cycloalkyl, aryl, Het, (C,.salkyl)ary! or (C,.salkyl)Het, or heterocycle being optionally substituted with R®®; : f) NR'"®*COR""” wherein R'*® and R'" is each H, (C:.¢)alkyl, (Cs. 7)cycloalkyl, (C4.6)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.salkyharyl or (Ci. salkyl)Het, said (C1.s)alkyl, (Cs.7)cycloalkyl, (Ci.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,calkyl)aryl or (Cy.salkyl)Het being optionally substituted with R'®; g) NR"®CONR'R'®, wherein R"*®, R'""® and R'? is each H, (Ci. e)alkyl, (Cs)cycloalkyl, (C4.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cs. salkyharyl or (C,.salkyHet, or R'"® and R™ are covalently bonded
Q together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Ci. e)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.galkyl)aryl or (C,.salkyl)Het or heterocycle being optionally substituted with R'®; h) NR'?’COCOR'® wherein R'® is H, (C,.¢)alkyl and R'?is OR or
N(R"), wherein R'*and each R'is independently H, (Ci.salkyl), {Cy4)cycloalkyl, or (Cig)alkyl-(Cas)cycloalkyl, aryl, Het, (Cy salkyl)aryl or (Cysalkyl)Het, or R'* is OH or O(C;.salkyl) or both R'** are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C;. salkylaryl or (C,¢alkyl)Het and heterocycle being optionally : substituted with R'®;
J) tetrazole, COOR™ wherein R'? is H, (Ci.s)alkyl, (Cs.7)cycloalkyl, or(C.¢)alkyl-(Caz)cycloalkyl, aryl, Het, (C.galkyl)aryl or (C4 salkyl)Het, said (Cy.g)alkyl, (Cas)cycloalkyl, or(Cy.¢)alkyl-(Ca.s)cycloalkyl, aryl, Het, (Ciealkyl)aryl and (Cysalkyl)Het being optionally substituted with R*S°; and k) CONR'*R' wherein R'* and R'® are independently H, (C1. e)alkyl, (Cs7)cycloalkyl, (C4¢)alkyl-(Cs.;)cycloalkyl, aryl, Het, (Cy. salkyaryl or (Ci.calkyl)Het, or both R**® and R'® are covalently : bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C.alkyl)aryl, (C,galkyl)Het and
® heterocycle being optionally substituted with R*®; : wherein, R™ is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C,qalkyl, haloalkyl, COOR™', SOzH, ' SOR", OR, N(R'®),, SO,N(R'"2),, NR'?COR'® or
CON(R™?),, wherein R'® and R'® are as defined above.
More preferably, Z is OR® wherein R® is (C.salkyl)aryl substituted with: - 1 to 4 substituents selected from: a) (Ci¢)alkyl substituted with R**®, haloalkyl, (Cs.7)cycloalkyl, Cs spirocycloalkyl optionally containing 1 or 2 heteroatom, (C..g)alkenvt, (C.- g)alkynyl, (Ci.6) alkyl-(Cs.7)cycloalkyl, said haloalkyl, cycloalkyl, spirocycloatkyl, @ alkenyl, alkynyl and alkyl-cycloalkyl being optionally substituted with R'*°, wherein R™® is the same as R'® but is not COOR"®, N(R"),
NR™®C(O)R™, OR", SR™®, SO,R"*®, SO,N(R'**),, wherein R"" is H or unsubstituted C..galkyl; b) OR'™ wherein R'™ is (C,.salkyl) substituted with R**°, (Cs.7)cycloalkyl, or (Cie)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cigalkyl)aryl or (Ci.salkyl)Het, said cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cisalkyl)Het being optionally substituted with R'*; d) SO;H, SON(R'®?), or SO,N(R")C(O)R' wherein each R*® is independently H, (Ci.¢)alkyl and aryl, said alkyl and aryl being optionally substituted with R'®°, wherein R'®? is the same as R'* but is not H or unsubstituted Cqgalkyl; e) NR'R""? wherein R™ is H, (C.s)alkyl, (Cs7)cycloalkyl or (Cy.)alkyl-(Cs. s)cycloalkyl, aryl, Het, (Cy.calkylaryl or (Cy.salkyl)Het, and R'is H, (Cy.c)alkyl, provided that when R'"" is H or unsubstituted alkyl, R'*? is not H or unsubstituted alkyl, or R'is also COOR""® or SO,R""** wherein R'is H, : (Cie)alkyl or (Cy.satkyl)aryl, and R"*%* is Cysalkyl substituted with R"* or (Ci. calkyharyl, or both R"" and R'"? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (C1ealkyl)Het, or heterocycle being optionally substituted with R™™; f) NR"COR""” wherein R'"® and R""” is each (C.¢)alkyl substituted with
R'®°, (Cs)cycloalkyl, aryl, Het, said (Ca.7)cycloalkyl, aryl, Het being optionally
® substituted with R"®; : a) NRVCONR'"®R'?, wherein R"", R"® and R'®’ is each H, (Ci.)alkyl, aryl,
Het, said alkyl, aryl and Het being optionally substituted with R'": h) NR'2'COCOR'™ wherein R'is H or Cy.alkyl and R'is OR™ or
N(R'?*), wherein R'* and each R'® is independently H, (C+salkyl), aryl or
Het, or R'?* is OH or O(C1.calkyl), said alkyl, aryl and Het being optionally substituted with R'; j) COOR'2 wherein R' is (C1.¢)alkyl substituted with R', k) CONR'™R™ wherein R'*® and R'*° are independently H, (Ci.s)alkyl, aryl or Het, provided that when R'* is H or unsubstituted alkyl, R'is notH or unsubstituted alkyl, said alkyl, aryl and Het being optionally substituted with @ RO ’
I) aryl, Het, (Ci.salkyl)aryl or (Cyealkyl)Het, all of which being optionally substituted with R'®’; wherein R'* is: . 15 - 1 to 3 substituents selected from: halogen or azido; or - 1 to 3 substituents selected from: a) (C1) alkyl or haloalkyl, (C..c)alkenyl, all of which optionally substituted with R'®’; b) OR'™ wherein R'™ is H, (C.calkyl), aryl or Het, said alkyl, aryl and
Het being optionally substituted with R™®; d) SR, SO,N(R'"®), or SON(R'™)C(O)R"*® wherein each R™ is independently H, (C1-s)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R'®; e) NR"R"2 wherein BR" is H, (Cie)alkyl, aryl or Het, and R'is H, (Cr5)alkyl, COOR'* or SOR" wherein R"'® is (C,.s)alkyl, said alkyl, aryl or Het being optionally substituted with R'®’; f) NR'"*COR"” wherein R'® and R'is each H, (Cis)alkyl, aryl or
Het, said alkyl, aryl and Het being optionally substituted with R*®; . g) NR" CONR'"°R'®, wherein BR", R"" and R'** is each H, (C+. ¢)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted : with R'®,; h) NR'?'COCOR'# wherein R'*' is H, (Ci.)alkyl and R'is OR'® or
N(R'*), wherein R*?* and each R'** is independently H, (Cysalkyl), aryl or Het, or R'?* is OH or O(Cy.salkyl), said alkyl, aryl and Het being
® optionally substituted with R'®’; : i) tetrazole, COOR'® wherein R'? is H, (C1.¢)alkyl optionally substituted with R'®%; and ’ k) CONR™R' wherein R'® and R™ are independently H, (C,. e)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R*®; wherein, R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, Cy.salkyl, haloalkyl, COOR'®!, SO;H, : SO,R™', OR™, N(R"), SO,N(R'®),, NR'®**COR"® or
CON(R'%),, wherein R'®' and R'® are as defined above. ® Even more preferably, Z is OR® wherein R® is (C,g)alkenyl, (C,¢)alkyl-Het, wherein said alkenyl or alkyl-Het, is optionally substituted with R®®, wherein preferably R® is: - 1 to 4 substituents selected from: halogen; or - 1 to 4 substituents selected from: a) (C4.¢) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs.; spirocycloalkyl optionally containing 1 or 2 heteroatom, (C..g)alkenyl, (Cog)alkynyl, (Ci.¢) alkyl-(Ca. cycloalkyl, all of which optionally substituted with R'; b) OR wherein R'™ is H, (Cy.salkyl), (Cs)cycloalkyl, or (Ci)alkyl-(Cs. s)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cy.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Cy.salkyl)Het being optionally substituted with : R150; d) SR, SO,N(R'), or SO,N(R'®)C(O)R"® wherein each R'is independently H, (C4.s)alkyl, (Ca7)cycloalkyl or (Cqg)alkyl-(Car)cycloalkyl, aryl,
Het, (C1.calkyl)aryl or (Cy.calkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C1. ’ calkylaryl or (Ci.salkyl)Het or heterocycle being optionally substituted with
R'S% e) NR''R""? wherein R""" is H, (Cy.s)alkyl, (Cs7)cycloalkyl or (Cy.s)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (Cyealkyl)aryl or (Cialky)Het, and Ris H, CN, (Cr. g)alkyl, (Ca.7)cycloalky! or (Cyg)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cisalkyl)aryl, : (Cr.calkyl)Het , COOR'™ or SO,R"*® wherein R'* is (Cy.)alkyl, (Cs. 7)cycloalkyl, or (Cy.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cialkyl)aryl or (Cs.
PS 53 calky)Het, or both R"'" and R"*? are covalently bonded together and to the ’ nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C1salkyl)aryl or (Cy.salkyl)Het, of i heterocycle being optionally substituted with R®’; f) NR'®COR"" wherein R"® and R'" is each (Ci.s)alkyl, (Csz)cycloalkyl, (Cs. e)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C4 salkyl)Het, said (Ci. o)alkyl, (Caz)cycloalkyl, (Ci.g)alkyl-(Car)cycloalkyl, aryl, Het, (Ciealkyl)aryl or (C1salkyl)Het being optionally substituted with R™; g) NR"®CONR'°R'®, wherein R'*®, R"*® and R'is each H, (C1.¢)alkyl, (Cs.
Jeycloalkyl, (C1e)alkyl-(Caz)cycloalkyl, aryl, Het, (Cqgalkylaryl or (Cs. salkyl)Het, or R"® is covalently bonded to R'*® and to the nitrogen to which @ they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R"? and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C;.s)alkyl-(Cas)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C4. salkyl)Het or heterocycle being optionally substituted with R'®; h) NR'2'COCOR'? wherein R'?' is H, (Cs.g)alkyl optionally substituted with
R'™ and R'2 is OR'® or N(R"**), wherein R'* and each R'** is independently H, (C,salkyl), (Ca)cycloalkyl, or (C1.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Ci.calkylaryl or (Csalkyl)Het, or R'** is OH or O(C,.salkyl) or both
R' are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C;.calkyl)aryl or (C,calkyf)Het and heterocycle being optionally substituted with R*’; i) COR" wherein R'¥ is H, (C1g)alkyl, (Ca)cycloalkyl or (Cy.e)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (Crsalkyl)aryl or (C4.calkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryi or (C,salkyl)Het being optionally substituted with RS, i) COOR'?® wherein R'? is H, (Cy.¢)alkyl, (Caz)cycloalkyl, or(Cy.e)alkyl-(Cs. s)cycloalkyl, aryl, Het, (C.salkylaryl or (Cy.calkyl)Het, said (Cyg)alkyl, (Ca. ; s)cycloalkyl, or(C4.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C+salkyl)aryl and (Cs. calkyl)Het being optionally substituted with R™°; . K) CONR'™R™® wherein R'* and R" are independently H, (Cyz)alkyl, (Ca. neycloalkyl, (Cq.6)alkyl-(Cs;)cycloalkyl, aryl, Het, (C.salkyharyl or (Ci. salky)Het, or both R'*® and R'* are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated
® 54 heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Ci.calkyl)aryl, : (C1.calkyl)Het and heterocycle being optionally substituted with R**;
I) aryl, Het, (C.calkyl)aryl or (Ci.salkyl)Het, all of which being optionally ) substituted with R**®, wherein R'is defined as: - 1 to 3 substituents selected from: halogen or azido; or - 1 to 3 substituents selected from: a) (C1.¢) alkyl or haloalkyl, (Cs7)cycloalkyl, Cs; spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cz.)alkenyl, (Cz.g)alkynyl, (C10) alkyl-(Ca7)cycloalkyl, all of which optionally substituted with R™®; b) OR'™ wherein R'is H, (Cy.calkyl), (Ca)cycloalkyl, or (Cq.s)alkyl- (Caz)cycloalkyl, aryl, Het, (Cialkyl)aryl or (Cs.salkyl)Het, said alkyl, @® cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cqcalkyl)Het being optionally substituted with R'®; d) SR, SO,N(R'®), or SO,N(R'*®*)C(O)R"*® wherein each R'is independently H, (C1.)alkyl, (Ca)cycloalkyl or (Ci.e)alky-(Cs. "cycloalkyl, aryl, Het, (C:.calkyl)aryl or (Cysalkyl)Het or both R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cisalkyl)aryl or (C4.salkyl)Het or heterocycle being optionally substituted with R'®’; e) NR"R""2 wherein R'"! is H, (Ci.s)alkyl, (Cs7)cycloalkyl or (Ci. e)alkyl-(Cs7)cycloalkyl, aryl, Het, (C4.calkyl)aryl or (Cealkyl)Het, and
R"2 is H, CN, (C1.g)alkyl, (Caz)cycloalkyl or (Ci¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C1.ealkylaryl, (C1.calkyl)Het , COOR"*® or SOR" wherein
R'* is (C1.0)alkyl, (Caz)cycloalkyl, or (C4.g)alkyl-(Ca)cycloalkyl, aryl,
Het, (C1alkyl)aryl or (C.salkyl)Het, or both R""" and R'™ are covalently bonded together and to the nitrogen to which they are : attached to form a 5, 6 or 7-membered saturated heterocycle, said . alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C4.calkyl)Het, or heterocycle being optionally substituted with B®"; , ] f) NR""® COR" wherein R""® and R'" is each H, (C1.s)alkyl, (Cs. ;)oycloalkyl, (Ci.e)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cy. galkyl)Het, said (Ci)alkyl, (Ca)cycloalkyl, (Cr.s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C1.¢alkyl)aryl or (C,alkyl)Het being optionally substituted
® with R®; , g) NR'®CONR'®R'®, wherein R'*®, R""® and R'® is each H, (Cx. s)alkyl, (Cs.7)cycloalkyl, (Ci.g)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C4. salkylaryl or (Cy alkyl)Het, or R'is covalently bonded to R'"® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, or R**® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, (C;. : s)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C1.salkyharyl or (Cy.salkyl)Het or heterocycle being optionally substituted with R'®; h) NR'>'COCOR'2 wherein R'*' is H or (C,.s)alky! optionally ® substituted with R'®®, and R'# is OR'® or N(R'?*), wherein R'® and each R'?* is independently H, (Cy.¢alkyl), (Cs.7)cycloalkyl, or (C1.e)alkyl- (Car)cycloalkyl, aryl, Het, (C1.salkyl)aryl or (C,.salkyl)Het, or R'?* is OH or O(C4.¢alkyl) or both R'?* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl cycloalkyl, aryl, Het, (Csalkyl)aryl or (C,¢alkyl)Het and heterocycle : being optionally substituted with R'®; j) tetrazole, COOR'™? wherein R'? is H, (Ci.¢)alkyl, (Cs.7)cycloalkyl, or(C.g)alkyl-(Cg.7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,.salkyl)Het, said (Cy.s)alkyl, (Cs.7)cycloalkyl, or(Ci.¢)alkyl-(Ca.;)cycloalkyl, aryl, Het, (C1salkyl)aryl and (C,.calkyl)Het being optionally substituted with R'®%; and k) CONR'*R' wherein R'?® and R'* are independently H, (C1. s)alkyl, (Ca7)cycloalkyl, (C4.¢)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C;. salkyl)aryl or (Cy.salkyl)Het, or both R'?® and R'™° are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Ci.calkyl)aryl, (Cysalkyl)Het and heterocycle being optionally substituted with R'®®; wherein R'is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C, alkyl, haloalkyl, COOR'', SOzH,
SRS! SOR"! OR'®", N(R), SON(R™3),, NR'S2CcOR'62 or
CON(R™),, wherein R'® and each R'is independently H,
® 56 - (Ci.e)alkyl, (Csz)cycloalky! or (C1.¢)alkyl-(Caz)cycloalkyl; or both ’ R'%? are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered ' saturated heterocycle.
Even more preferably, R* is: - 1 to 4 substituents selected from: halogen; or - 1 to 4 substituenis selected from: a) (C1.5) alkyl or haloalkyl, (Cs)cycloalkyl, Cs. spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cas)alkenyl, (Cz g)alkynyl, (C1) alkyl-(Cs.
J)cycloalkyl, all of which optionally substituted with R'; ® b) OR" wherein R'™ is H, (Cy.salkyl), (Csz)cycloalkyl, or (C1.c)alkyl-(Cs. seycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cysalkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.¢alkyl)aryl or (Cisalkyl)Het being optionally substituted with = d) SOzH, SO.N(R'™), or SO,N(R')C(O)R'® wherein each R'® is independently H, (Cy.g)alkyl or aryl, said alkyl and aryl being optionally substituted with R'>’; " &) NR"R"2 wherein R"" is H, (Cy.e)alkyl, (Cs.r)cycloalkyl or (Cq.)alkyl-(Cs.
Jcycloalkyl, aryl, Het, (C1.salkyl)aryl or (Cq.salky)Het, and R'2 is H, (C1.e)alkyl,
COOR" or SO,R""* wherein R'"® is (C1.)alkyl or (Cy.salkyharyl, or both R™ and R""? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Cysalkyl)Het, or heterocycle being optionally substituted with R**°; f) NR" COR" wherein R"*® and R'" is each (Ci.¢)alkyl, (Ca)cycloalkyl, aryl or Het, said (C1.g)alkyl, (Ca)cycloalkyl, aryl or Het being optionally substituted with R"; g) NR'®CONR''’R', wherein R""®, R'"® and R'? is each H, (Ci)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R™, ) h) NR™?’COCOR'2 wherein R'is H or (Cy¢)alkyl, and R'is OR'® or
N(R'?*), wherein R'2 and each R'* is independently H, (C+.calkyl), aryl or
Het, or R'** is OH or O(C1salkyl), said alkyl, aryl and Het being optionally substituted with R'®°;
* j) COOR' wherein R'is H or (C,.s)alkyl optionally substituted with R*®°; : k) CONR'R™ wherein R'?* and R** are independently H, (C,.s)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R*°; 4 1) aryl, Het, (Cisalkyl)aryl or (Cy salkyl)Het, all of which being optionally substituted with R™, wherein R'™ is defined as: - 1 to 3 substituents selected from: halogen; or - 1 to 3 substituents selected from: a) (Cy) alkyl or haloalkyl, (C..s)alkenyl, all of which optionally .substituted with R"®?; b) OR'™ wherein R"™ is H, (Cy alkyl), aryl or Het, said alkyl, aryl and
Het being optionally substituted with R"®’; @ d) SR', SO,N(R'®), or SO,N(R")C(O)R'® wherein each R'® is independently H, (Cy.)alkyl, aryl or Het, said alkyl, aryl and Het being : optionally substituted with R®; e) NR'"'R"* wherein R'""" is H, (C,,)alkyl, aryl or Het, and R'is H, (Cire)alkyl, COOR™® or SO,R""® wherein R"" is (C,.q)alkyl or aryl, said alkyl, aryl and Het being optionally substituted with R*®%; f) NR’ COR” wherein R"'® and R'is each H, (Cy.c)alkyl, aryl or
Het, said alkyl, aryl and Het being optionally substituted with R'®°; g) NR"SCONR"R', wherein R""®, R"* and R'® is each H, (C.. e)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R'®; h) NR'*'COCOR'# wherein R'is H or (Cy.)alkyl optionally substituted with R'*°, and R'?* is OR'® or N(R"®*), wherein B® and each R'* is independently H, (C;.catkyl), aryl or Het, or R'?* is OH or
O(C.galkyl), said alkyl, aryl and Het being optionally substituted with i Re j) tetrazole, COOR'® wherein R'is H or (Cy.¢)alkyl optionally substituted with BR"; and k) CONR'*R™ wherein R'* and R'*° are independently H, (Ci. s)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R*%; wherein R*® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, Cy.salkyl, haloalkyl, COOR'', SO3H,
®
SR, SO,R™" OR" N(R), SO,N(R2),, NR'®2COR"2 or y CON(R'®?),, wherein R"®' and each R**is independently H, (C46)alkyl, (Caz)cycloalkyl or (Cis)alkyl-(Caz)cycloalkyl; or both * R'®2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle.
Most preferably, Z is N(R®*)R® wherein R® is H or C,.salkyl. More preferably, R® is H.
Preferably, R® is (C.)alkenyl, aryl, Het, (Cy.g)alkyl-aryl, (C.¢)alkyl-Het, wherein said alkenyl, aryl, Het, alkyl-aryl or alkyl-Het, are all optionally substituted with: @® - 1 to 4 substituents selected from: halogen, OPO3H, NO,, cyano, azido,
C(=NH)NH,, C(=NH)NH(C.g)alkyl or C(=NH)NHCO(C,.¢)alkyl; or - 1 to 4 substituents selected from: a) (C1.6) alkyl or haloalkyl, (Css)cycloalkyl, Cs. spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cas)alkenyl, (Cag)alkynyl, (Ci) alkyl-(Cas. cycloalkyl, all of which optionally substituted with R*®°; b) OR" wherein R'is H, (Cysalkyl), (Ca)cycloalkyl, or (Cy)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cy.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cisalkyl)aryl or (C;salkyl)Het being optionally substituted with
Rr; d) SR'%, SO,NH(C,.calkyl) or SO,NHC(O)C.salkyl; e) NR'"'R"? wherein R'is H, (C;.¢)alkyl, (Csr)cycloalkyl or (Cy.¢)alkyl-(Cs.
J)cycloalkyl, aryl, Het, (C1salkyf)aryl or (Cq.calky)Het, and R*"? is H, CN, (C,. g)alkyl, (Cs.7)cycloalkyl or (Cy.)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cisalkyl)aryl, (C1.calkyl)Het , COOR" or SO,R""® wherein R'is (Cy.5)alkyl, (Ca. 7)cycloalkyl, or (C4.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cs. calkyl)Het, or both R'" and R'"? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cisalkyl)Het, or heterocycle being optionally substituted with R'*; f) NR""®COR"” wherein R""® and R"" is each H, (C1.¢)alkyl, (Ca7)cycloatkyl, (Ci.e)alkyl-(Cs7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cy.salkyl)Het, said (C1. e)alkyl, (Csz)cycloalkyl, (Cy.g)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or
® } 59 (Cialkyl)Het being optionally substituted with RR’; g) NR¥CONR'"®R'?°, wherein R'", R""® and R'is each H, (Ci.s)alkyl, (Ca. 7)cycloalkyl, (C.¢)alkyl-(Caz)cycloalkyl, aryl, Het, (C,.salkylaryl or (GC. ) salkyhHet, or R**® is covalently bonded to R'* and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R™ and R'# are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C4s)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cssalkyl)aryl or (C4. calkyl)Het or heterocycle being optionally substituted with R'®; h) NR™'COCOR'® wherein R'?! and R"? is each H, (Ci.)alkyl, (Cs. 7)cycloalkyl, (Cy.6)alkyl-(Casz)cycloalkyl, a 6- or 10-membered aryl, Het, (Ci. ® salkyl)aryl or (Cy.salkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C1salkyl)aryl or (C.calkyl)Het being optionally substituted with R™’; or R'2 is OR'® or N(R'?*), wherein R'? and each R'is independently H, ' ~ (Cyealkyl), (Car)cycloalkyl, or (Cy.)alkyl-(Cs7)cycloalkyl, aryl, Het, (Ci. salkyaryl or (Cy.salkyl)Het, or R'** is OH or O(C.alkyl) or both R"** are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,salkyl)aryl or (C1.salkyl)Het and heterocycle being optionally substituted with R™*®; i) COR wherein R'? is H, (C1.s)alkyl, (Cs)cycloalkyl or (Cy.g)alkyl-(Cs. s)eycloalkyl, aryl, Het, (C1.alkyl)aryl or (C,.calkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C1.qalkyl)aryl or (Cysalkyl)Het being optionally substituted with R'*?; i) COOR™® wherein R'? is H, (C1)alkyl, (Caz)cycloalkyl, or(Cy.g)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (C1.galkyl)aryl or (C,salkyl)Het, said (Cys)alkyl, (Cs 7)cycloalkyl, or(C+.e)alkyl-(Cs)cycloalkyl, aryl, Het, (Cisaltkylaryl and (Cy. salkyl)Het being optionally substituted with R*’; k) CONR™R™ wherein R™ and R" are independently H, (Cis)alkyl, (Ca. 7)cycloalkyl, (Ci.g)alkyl-(Cs)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (C;. salky)Het, or both R'® and R*° are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated . heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cisalkyl)aryl, (C1ealkyl)Het and heterocycle being optionally substituted with R'’;
I) aryl, Het, (Cqsalkyl)aryl or (Ci.calkyl)Het, all of which being optionally substituted with R'®°, wherein, preferably, R'* is selected from:
* - 1 to 3 substituents selected from: halogen, NO,, cyano or azido; or ) - 1 to 3 substituents selected from: a) (C.g) alkyl or haloalkyl, (Cs.7)cycloalkyl, Ca. spirocycioalkyl - optionally containing 1 or 2 heteroatom, (Ca.s)alkenyl, (Ca.g)alkynyl, (C1.6) alkyl-(Cs.7)cycloalkyl, all of which optionally substituted with R'®; b) OR wherein R'is H, (Cy.salkyl), (Csz)cycloalkyl, or (C1.)alkyl- (Caz)cycloalkyl, aryl, Het, (Ci.¢alkyl)aryl or (C;.salkyl)Het, said alkyl, : cycloalkyl, aryl, Het, (C,alkyl)ary! or (Cisalkyl)Het being optionally substituted with R'®®; d) SR SO,N(R), or SO,N(R'®)C(0O)R'® wherein each R'® is independently H, (C,.s)alkyl, (Cs7)cycloalkyl or (Ci.)alkyl-(C. ® 7)cycloalkyl, aryl, Het, (Cy.alkyl)aryl or (C.alkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C,salkyl)Het or heterocycle being optionally substituted with R'®; e) NR'"R""2 wherein R'is H, (Cy.¢)alkyl, (Cs.7)cycloalkyl or (Ci. s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,.calkyl)Het, and
R''?is H, CN, (Cy)alkyl, (Ca)cycloalkyl or (Cy.g)alkyl-(Ca7)cycloalkyl, aryl, Het, (C,salkyl)aryl, (Ci.salkyl)Het , COOR'® or SO,R"'* wherein
Ris (Cy0)alkyl, (Cs7)cycloalkyl, or (Cq.)alkyl-(Cs.7)cycloalkyl, aryl,
Het, (C,.salkyl)aryl or (Cysalkyl)Het, or both R*"* and R'? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cicalkyl)aryl or (C,.alkyl)Het, or heterocycle being optionally substituted with R'°; f) NR""®COR'" wherein R'® and R""” is each H, (C;.5)alkyl, (Ca. s)cycloalkyl, (C+.s)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,. calkyl)Het, said (Ci.g)alkyl, (Ca.7)cycloalkyl, (C,.¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,.salkyl)Het being optionally substituted with R'®; g) NR"CONR'R', wherein R™, R"* and R'? is each H, (Cs. s)alkyl, (Cs 7)cycloalkyl, (Cqg)alkyl-(Csz)cycloalkyl, aryl, Het, (C,. calkyl)aryl or (C.calkyl)Het, or RB"? and R'® are covalently bonded
® . together and to the nitrogen to which they are attached to form a 5, 6 . or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C;. g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,.salkyl)Het or : heterocycle being optionally substituted with R'®; h) NR'**'COCOR'? wherein R'?' is H or (Cy.)alkyl optionally substituted with R'®°; and R'is OR'® or N(R'?*), wherein Rand each R'® is independently H, (Cy.salkyl), (Cs.7)cycloalkyl, or (Cy.g)alkyl- (Ca.z)cycloalkyl, aryl, Het, (Cy.calkylaryl or (C,ealkyl)Het, or R'** is OH or O(C,.salkyl) or both R'?* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (Cicalkyl)aryl or (C;.salkyl)Het and heterocycle ® being optionally substituted with R*’; j) tetrazole, COOR'® wherein R'is H, (Ci.¢)alkyl, (Csz)cycloalkyl, or(C1.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C4.calkyl)aryl or (C,.salkyl)Het, said (C1.g)alkyl, (Ca.7)cycloalkyl, or(C.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cs.salkyl)aryl and (C,.salkyl)Het being optionally substituted with R®; and k) CONR'*R™° wherein R'® and R™ are independently H, (C;. s)alkyl, (Cs.7)cycloalkyl, (Cig)alkyl-(Cs7)cycloalkyl, aryl, Het, (C4. salkylaryl or (Cy.salkyl)Het, or both R'* and R**® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.salkyl)aryl, (Ci.calkyl)Het and heterocycle being optionally substituted with R'®; wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C,salkyl, haloalkyl, COOR'®', SOzH,
SO,R™!, OR’! N(R'3),, SO,N(R'?),, NR'®2COR'6? or
CON(R'®),, wherein R'® and each R'®is independently H, (Cy)alkyl, (Cs7)cycloalkyl or (Cy.s)alkyl-(Cay)cycloalkyl; or both
R'®2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle.
More preferably, B® is (C,.)alkenyl, aryl, Het, (C,.)alkyl-aryl, (C+.)alkyl-Het, wherein
® said alkenyl, aryl, Het, alkyl-aryl, or alkyl-Het, are all optionally substituted with: . - 1 to 4 substituents selected from: halogen, NO,, cyano, azido; or - 1 to 4 substituents selected from: . a) (C.6) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs; spirocycloatky! optionally containing 1 or 2 heteroatom, (Ca.g)alkenyl, (C,.g)atkynyl, (C.¢) alkyl-(Cs. cycloalkyl, all of which optionally substituted with R'®°; b) OR" wherein R'™ is H, (Ci.salkyl), (Cs-)cycloalkyl, or (Ci.s)alkyl-(Cs. s)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cy.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Ci.salkyl)Het being optionally substituted with
R*®° d) SH, S(Ci.salkyl), SO3H, SONH(C, galkyl) or SO,NHC(O)C4 gatkyl; ® e) NR" R"2 wherein R'" is H, (Cig)alkyl, (Cs7)cycloalkyl or (Cy.6)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,salkyl)aryl or (Cy.salkyl))Het, and R'?is H, CN, (C;. s)alkyl, (Cs)cycloalkyl or (C4s)alkyl-(Ca7)cycloalkyl, aryl, Het, (C,.salkyl)aryl, (C1.ealkyl)Het, COOR™ or SOR" wherein R'*® is (C1.¢)alkyl, or both R*™" and R'"2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cigalkyl)aryl or (C,.calkyl)Het, or heterocycle being optionally substituted with R"°°; f) NR'COR" wherein R'*® and R'" is each H, (C.s)alkyl, (Cs.7)cycloalkyl, said (Cy)alkyl, (Cs)cycloalkyl being optionally substituted with R'®°; g) NR"'®CONR'"R'®, wherein R''®, R'"® and R'is each H, (C1.)alkyl, (Ca. scycloalkyl, or R'*® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl or heterocycle being optionally substituted with R'®; h) NR'*'COCOR' wherein R'™ is H, (C1.)alkyl, (Cs.7)cycloalkyl, said alkyl, cycloalkyl being optionally substituted with R**°, or R'is OR'® or N(R'?%), wherein R'® and each R'* is independently H, (Cyalkyl) or (C,)cycloalkyl, or R'?* is OH or O(C;.salkyl) or both R'®* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R**°; - j) COOR'™® wherein R'? is H, (Cig)alkyl, (Cs;)cycloalkyl, or(C,.g)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (C,.ealkyl)aryl or (Cy.calkyl)Het, said (Cy)alkyl, (Cs.
® 7)eycloalkyl, or (C4.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C.salkyl)aryl and (Ci. ” salky)Het being optionally substituted with R'*°; kK) CONR'R" wherein R'* and R'* are independently H, (Ci.s)alkyl, (Ca. ’ Jeycloalkyl, (Cig)alkyl-(Caz)cycloalkyl, aryl, Het, (Cqsalkylaryl or (Ci. salkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Ci.salkyl)aryl, and (C,.salkyl)Het being optionally substituted with R™;
I) aryl, Het, (Ci.salkyl)aryl or (Cy.salkyl)Het, all of which being optionally substituted with R**°, wherein, preferably, R**° is selected from: - 1 to 3 substituents selected from: halogen, NO,, cyano or azido; or - 1 to 3 substituents selected from: a) (Cy) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs. spirocycloalkyl @® optionally containing 1 or 2 heteroatom, (Ca.g)alkenyl, (Czg)alkynyl, (C46) alkyl-(Ca-7)cycloalkyl, all of which optionally substituted with R®; b) OR'® wherein R'is H, (Cy.6alkyl), (Csz)cycloalkyl, or (Cye)alkyl- (Caz)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Cq.calkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cqsalkyl)aryl or (C,salkyl)Het being optionally substituted with R'®°; d) SH, S(Calkyl), SOsH, SON(R'®), or SO.N(R'®)C(O)R'® wherein each R'® is independently H, (C,.)alkyl, (Ca.7)cycloalkyl or (C1e)alkyl-(Cs7)cycloalkyl, aryl, Het, (C4.salkyl)aryl or (Cy salkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C1. salkyl)Het or heterocycle being optionally substituted with R'®’; . ‘e) NR"'R"2 wherein R'is H, (C1.6)alkyl, (Ca7)cycloalkyl or (C1. e)alkyl-(Cs)cycloalkyl, aryl, Het, (C+.salkyharyl or (Cy.¢alkyl)Het, and
R'is H, CN, (Ci.)alkyl, (Ca)cycloalky! or (C1.6)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci.salkyharyl, (Cy-salkyl)Het , COOR''® or SO,R'*° wherein
R''® is (Cy.6)alkyl, (Caz)cycloalkyl, or (Ci.g)alkyl-(Cs7)cycloalkyl, aryl,
Het, (C1.salkyl)ary! or (Cysalkyl)Het, or both R'"" and R"? are ] covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (CyalkyHet, or heterocycle being optionally substituted with RS?
° 64 f) NR'"*COR""” wherein R'"® and R""” is each H, (C1.¢)alkyl, (Cs. ’ 2eycloalkyl, (C4.g)alkyl-(Cas)cycloalkyl, aryl, Het, (C1.salkyl)aryl or (Ci- calkyHet, said (Ci.g)alkyl, (Cs)cycloalkyl, (Cy.g)alkyl-(Cas)cycloalkyl, "aryl, Het, (Crcalkyaryl or (C1.alkyHet being optionally substituted with R*®; ~ g) NR" CONR'R™, wherein R'® R'® and R" is each H, (C1. s)alkyl, (Csz)cycloalkyl, (Cis)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cs. calkyl)aryl or (C+alkyl)Het, or R*'® and R'* are covalently bonded together and to the nitrogen to which they are attached to form a 5,6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Cs. o)alkyl-(Ca.z)cycloalkyl, aryl, Het, (C¢alkyl)aryl or (C.satky)Het or 9 heterocycle being optionally substituted with R*%; h) NR™'COCOR'? wherein R™ is H, (C1.¢)alkyl optionally substituted with R™®; and R'2 is OR"? or N(R'?*), wherein Rand each R'? is independently H, (Ci.salkyl), (Cs)cycloalkyl, or (C4.g)alkyl- (Caz)cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (C.ealkyl)Het, or R'is OH or O(C1.salkyl) or both R'?* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl cycloalkyl, aryl, Het, (Cy.salkylaryl or (Cisalkyl)Het and heterocycle being optionally substituted with R'®; j) tetrazole, COOR™® wherein R'? is H, (Cyg)alkyl, (Cs7)cycloalkyl, or(C1.g)alkyl-(Ca7)cycloalkyl, aryl, Het, (C;.salkylaryl or (Cysalkyl)Het, said (C1.c)alkyl, (Ca.7)cycloalkyl, or(Ci.e)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cisalkyl)aryl and (Ci.calkyl)Het being optionally substituted with R's. and k) CONR'R'® wherein R'* and R'* are independently H, (C:. g)alkyl, (Cs7)cycloalkyl, (C1.e)alkyl-(Csz)cycloalkyl, aryl, Het, (C4. salkyharyl or (C;alkyl)Het, or both R'? and R™ are covalently ‘ : bonded together and to the nitrogen to which they are attached to - form a 5, 6 or 7-membered saturated heterocycle, said alkyl, . cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cisalkylaryl, (C,¢alkyl)Het and heterocycle being optionally substituted with R'®%; wherein, preferably, R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, Cy.salkyl, haloalkyl,
® 65
COOR™, SO;H, SOR, OR, N(R"?),, SO.N(R'®?),, : NR'2COR"® or CON(R"®?),, wherein R'®' and each R'®is independently H or (Cyg)alkyl.
Most preferably, R® is Caalkenyl, phenyl, (Ci.g)alkyl-aryl, (Cy¢)alkyl-Het, wherein said alkenyl, phenyl and the alkyl portion of said alkyl-aryl, or alkyl-Het, are optionally substituted with 1 to 3 of: a) (C+) alkyl Ca spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cz.)alkenyl, all of which optionally substituted with C4ealkyl or Cy.calkoxy;
NH,, NH(Me) or N(Me). e) NHR"? wherein R"? is aryl, Het, (C,salkyl)aryl, (Cicalkyl)Het, said aryl, ® Het, (C:.salkyl)aryl or (CyalkylHet, being optionally substituted with R™*, j) COOH; kK) CONR'®R'® wherein R'? and R"® are independently H, (Ci)alkyl, (Cs. s)eycloalkyl, (C1.s)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C.salkyl)aryl or (Cs. calkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cealkyl)aryl, and (C,salkyl)Het being optionally substituted with R'"; : © 1) phenyl or Het, both optionally substituted with R', wherein, preferably,
R'is selected from: - 1 or 2 substituents selected from: halogen, NO, cyano or azido; - 1 or 2 substituents selected from: a) (C..s) alkyl or (Cz6)alkenyl, both optionally substituted with COOH or CONH,; ‘b) OR" wherein R'is H or (Cyealkyl) optionally substituted with
COOH; " h) NHCOCOOH,; j) COOH; and : k) CONH,, ' 30 Preferably, Zis . Ox, OH Oxy NH, 'S N A,
A A LA Ho =/ 7" 3 ) 3 ) s J aes
N OH N OH N OH N
Ac \—on
HN HN BN EN
7S Vg N N— n i 7h H 2 NS H =
AA AA HN
> N fost fous = Zz m= °
OH N OH OH
H ’ H ’ © ’ OH ] ° »{ \—OH N oY { “J "= 0 —N
H
2 Tor i == N
HN H
NH HN. SN 74 ® ~~ ° ox o
OH | OH 0” OH 0 /
NT s N : \ a Ns =
N N HN N
—_ —N —N H —N
HN HN HN
4 x A =
OH
A & 0 \ — ~
FA A Yon A, > J N
HN = H " N N HN = — oN ey
IW HN xX 0 . Xx SN X “ ] lo] NH, OH | 0” oH 0 OH 0 NH, i.
Te
HN.
Ju iY + o . fo) OH EY OMe
HN ~~ No ) OMe : ) N S OH iy ~ N 5 N dg H OMe H OMe
® 67 . av + HN COOH in COOH Wo .CONH,
H
=N " SA’ Q face. he
OH , “coon OH , OH and
To
Diamides:
C 5 Most preferably, R® is:
RAR’ il or N-_ a . v2 wherein, preferably, R’ and R® are each independently H, (C1.)alkyl, haloalkyl, (Cs. 7)eycloalkyl, 6- or 10-membered aryl, Het, (Cy.s)alkyl-aryl, (Cis)alkyl-Het, wherein said alkyl, cycloalkyl, aryl, Het, (Cy.¢)alkyl-aryl, (C1¢)alkyl-Het are optionally substituted with RB"; or
R’ and R® are covalently bonded together to form second (Cax)cycloalkyl ora4,5-or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; or when Z is N(R®)R®, either of R or R® is covalently bonded to R* to form a nitrogen-containing 5-or 6-membered heterocycle; wherein, preferably, Ris selected from: - 1 to 4 substituents selected from: halogen, NO, cyano, azido; or - 1 to 4 substituents selected from: a) (C1) alkyl or haloalkyl, (Cs7)cycloalkyl, Ca spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cz.¢)alkenyl, (Czg)alkynyl, (C1.¢) alkyl-(Ca. ‘ 20 J)cycloalkyl, all of which optionally substituted with RB"; b) OR™* wherein R'® is H, (Ci.salkyl), (Csz)cycloalkyl, or (Ci.g)alkyl-(Cs. ) seycloalkyl, aryl, Het, (Ci.galkyl)aryl or (Cq.calkyl)Het, said alkyl, cycloalkyl, : : aryl, Het, (Cy.¢alkylaryl or (C.salky)Het being optionally substituted with
R180 d) SR, SO.N(R'™), or SON(R'®)C(O)R'® wherein each R'* is independently H, (Cy.g)alkyl, (Ca.r)cycloalkyl or (Cq.¢)alkyl-(Ca.7)cycloalkyl, aryl, or Het, (C,.salkyl)aryl or (C,salkyl)Het or both R'® are covalently bonded is together and to the nitrogen to which they are attached to forma 5, 6 or 7- “ membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,. salkyharyl or (C.¢alkyl)Het or heterocycle being optionally substituted with
R15 . e) NR'"""R""2 wherein R"" is H, (C1.6)alkyl, (Cs.7)cycloalkyl or (Ci.¢)alkyl-(Cs. z7)cycloalkyl, aryl, Het, (C;.salkyl)aryl or (Cy.salkyl)Het, and R'is H, CN, (Cs. : s)alkyl, (Ca)cycloalkyl or (Cy.)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci.qalkyl)aryl, (C1.salkyl)Het , COOR™ or SOR" wherein R'*? is (Ci.)alkyl, (Cs. - 7)cycloalkyl, or (Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy alkyl)aryl or (C4. salkyl)Het, or both R'* and R'*? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C,.¢alkyl)Het, or heterocycle being optionally substituted with R'’; f) NR'""COR"” wherein R'"® and Ris each H, (Ci.s)alkyl, (Cs)cycloalkyl, (Cy.6)alkyl-(Csy)cycloalkyl, aryl, Het, (C4.salkyl)aryl or (C1salkyl)Het, said (C+. eyalkyl, (Ca7)cycloalkyl, (Cq.)alkyl-(Cas)cycloalkyl, aryl, Het, (Cqsalkyl)aryl or (C1.salkyl)Het being optionally substituted with R'*’; g) NR"'®CONR"R'®, wherein R"® R' and R' is each H, (C.g)alkyl, (Ca. 7)eycloalkyl, (Ci.6)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,. salkyl)Het, or R""® is covalently bonded to R'"® and to the nitrogen to which ® they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R'"® and R™® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C,.e)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C1.salkyl)aryt or (C.. salkyhHet or heterocycle being optionally substituted with R'®’; h) NR'?'COCOR™ wherein R" is H, (Cys)alkyl, (Caz)cycloalkyl, (C.g)alkyl- . ol (Csz)cycloalkyl, a 6- or 10-membered aryl, Het, (Cysalkyl)aryl or (Cs. : RN 30 calkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cisalkyl)aryl or
A (C,.salkyl)Het being optionally substituted with R'®’, and R*? is OR'® or
N(R"), wherein R'® and each R'* is independently H, (C;.¢alky!), (Cs. 7)cycloalkyl, or (Cy.g)alkyl-(Cas.7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C;. calkyhHet, or R'2* is OH or O(C;salkyl) or both R' are covalently bonded ® together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, p cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C;.calkyl)aryl or (C,.salkyl)Het and : heterocycle being optionally substituted with R'; & i) COR wherein R'# is H, (Cy.g)alkyl, (Csz)cycloalkyl or (Ci)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Ci.calkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Cy.salkyl)Het being optionally substituted with R'*°; j) COOR'® wherein R'# is H, (Cy.¢)alkyl, (Cs.z)cycloalkyl, or(C1.s)alky!-(Cs. zs)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cy.salkyl)Het, said (Cy.)alkyl, (Ca. z)cycloalkyl, or(Cy.¢)alkyl-(Cs.;)cycloalkyl, aryl, Het, (Ci.salkyl)aryl and (C.. salkyl)Het being optionally substituted with R'*°; k) CONR'™R™ wherein R'* and R'® are independently H, (C,.)alkyl, (Ca. 7)cycloalkyl, (Ci.)alkyl-(Cs7)cycloalkyl, aryl, Het, (C.salkyl)aryl or (Cs. ealkyl)Het, or both R'? and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C¢alkyi)aryl, (Cy.salkyl)Het and heterocycle being optionally substituted with R**°; [) aryl, Het, (Cysalkyl)aryl or (C4galkyl)Het, all of which being optionally substituted with R'*?, wherein, preferably, R'® is selected from: - 1 to 3 substituents selected from: halogen, NO, cyano, azido; or - 1 to 3 substituents selected from: a) (C1.¢) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs; spirocycloalkyl optionally containing 1 or 2 heteroatom, (C,.¢)alkenyl, (Cz.g)alkynyl, all ® of which optionally substituted with R'®; b) OR™ wherein R'™ is H, (Cisalkyl) or (Cs)cycloalkyl, said alkyl and cycloalkyl being optionally substituted with R'®%; d) SR'®, SO,N(R'"®), wherein R'® is H, (C,.s)alkyl or (Cs)cycloalkyl, : said alkyl or cycloalkyl being optionally substituted with R*’; e) NR'"R"? wherein R"" is H, (C,.)alkyl or (Cs.)cycloalkyl, and R™*2 is H, (Cy6)alkyl, (Cs;)cycloalkyl or (C.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, ’ 30 (Crsalkylaryl, (C1 ealkyl)Het, COOR™ or SO,R™ wherein Bis (C,. . s)alkyl, (Ca7)cycloalkyl, or (Cy.6)alkyl-(Csr)cycloalkyl, aryl, Het, (C4. salkyharyl or (C,.calkyl)Het, or both R'"" and R'*? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, ® cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Ci.¢alkyl)Het, or heterocycle tr being optionally substituted with R*®°; f) NR""®COR'" wherein R""® and R'" is each H, (Cy.g)alkyl or (Cs. ; 7)cycloalkyl, said (Cq.s)alkyl or (Cs.7)cycloalkyl being optionally substituted with R'®?; g) NR" CONR"R'®, wherein R'"®, R""® and R'is each H, (Cs. ¢)alkyl or (Cs)cycloalkyl; or R'® and R'® are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl or heterocycle being optionally substituted with R'®°; } h) NR'?’COCOR™ wherein R'? is H, (Cy.s)alkyl or (Cs.7)cycloalkyl, said alkyl or cycloalkyl being optionally substituted with R'®’; or R'? is OR" or N(R'%), wherein R'* and each R*** is independently H, (C1.salkyl) or (Cs7)cycloalkyl, or R?* is OH or O(C;. ealkyl) or both R'* are covalently bonded together to form a 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R™®’; j) tetrazole, COOR'® wherein R'? is H, (C1.s)alkyl or (Cs)cycloalkyl, said (C.¢)alkyl and (Cz 7)cycloalkyl being optionally substituted with
RS? and k) CONR'*R"® wherein R'*® and R'* are independently H, (Cs. e)alkyl or (Cs7)cycloalkyl, or both R'® and R™° are covalently bonded @® together and to the nitrogen to which they are attached to form a 5, 6 ~ or 7-membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R'®; wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C,alkyl, haloalkyl, COOR'™, OR",
N(R®?), or CON(R'®?),, wherein R'®' and each R'®is ] independently H or (Cy.g)alkyl. . More preferably, R” and R® are each independently H, (C1.c)alkyl, haloalkyl, (Ca.
Jeycloalkyl, 6- or 10-membered aryl, Het, (Cyg)alkyl-aryl, (C,.s)alkyl-Het, all of which optionally substituted with from 1 to 4 substituents selected from halogen or: a) (Cie)alkyl; and : ® b) N(R®),, COR®, or SO,R*" COOR®, COCOOR®, CON(R*),, r COCON(R®"), wherein each R® or R*™ are independently H, (Ci.e)alkyl, (Csz)cycloalkyl, or (C4.g)alkyl-(Ca7)cycloalkyl; or “ each R® are independently covalently bonded together and to the nitrogen to which they are both bonded to form a 5, 6 or 7- membered saturated heterocycle; or R* is independently (Ci. e)alkyl, (Cs.7)cycloalkyl, or (Ci.g)alkyl-(Ca.7)cycloalkyl. or R” and R® are covalently bonded together to form (Cs.7)cycloalkyl, 4, 5- or 6- membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S.
Most preferably, R” and R® are each independently H, (C.¢)atkyl, haloalkyl, (Cs. : 7)cycloalkyl, 6- or 10-membered aryl, Het, (C4.g)alkyl-aryl, (C+.¢)alkyl-Het; or R’ and
R® are covalently bonded together to form cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran, or pentamethylene sulfide; wherein said alkyl, haloalkyl, (Cs.7)cycioalkyl, 6- or 10-membered aryl, Het, (Cre)alkyl-aryl, (C1.6)alkyl-Het, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidine, : piperidine, tetrahydrofuran, tetrahydropyran, or pentamethylene sulfide are optionally monosubstituted with substituents selected from: a) {Ci.e)alkyl; and
C) NH, N(CH,CH)., COCH;, or SO,CHs.
Even more preferably, R” and R® are selected from: [
NH, § P mY ¢ Se
OH CONH, ( (0 C | ( | )
OH
. = \
XS x
TC , T° , TTT, or TTT .
R” and R® together form: : ®
H 7 ocbso0nd a fs 0
Q NZ H
ST Vo ’ Ss N ss ilsaiciiv]ioie]
Os CH, 0=8S=0 O
LCT 3 J
SIVICIOROICAES) @ and “7.
Most preferably, R” and R® are selected from the group consisting of: lo}
H / Na cod o Or
H | dé 0
N N N J
SHCICIONS ®
ST EE NE and
BX:
Preferably R® is H; or R® is covalently bonded to either of R” or R® to form a 5- or 6- membered heterocycle. More preferably, R® is H. “ 15 Preferably, Q is a 6- or 10-membered aryl, Het, (Ci.salkyl)aryl or (C,salkyl)-Het, all of which being optionally substituted with: 1 OH ° oon
H ) A NN" cooH © , “coo , or R"; ® wherein R'® is: v - 1 to 4 substituents selected from: halogen, NO,, cyano or azido; or . - 1 to 4 substituents selected from: * a) (C16) alkyl or haloalkyl, (Cs7)cycloalkyl, (Co.g)alkenyl, (Cag)alkynyl, (Ci.g) alkyl-(Cs.;)cycloalkyl, all of which optionally substituted with R'%; b) OR™ wherein R' is H, (C,.salkyl), (Cs7)cycloalkyl, or (C1.g)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,¢alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.¢alkyl)aryl or (Cy.salkyl)Het being optionally substituted with
R's. d) SR wherein R'® is H, (Cy.5)alkyl, (Cs5)cycloalkyl or (Cy.g)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (C,.¢salkyl)aryl or (C,.galkyl)Het, all of which being optionally substituted with R"*°; e) NR'R"2 wherein R" is H, (Ci.6)alkyl, (Cs-)cycloalkyl or (Ci.s)alkyl-(Cs. s)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C,¢alkyl)Het, and R'*? is H, CN, (Ci. s)alkyl, (Cs.7)cycloalkyl or (Cy.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C;.salkyharyl, (Ciealkyl)Het , COOR'"S or SO,R""®* wherein R'® is (Cy)alkyl, (Ca. 7)eycloalkyl, or (C4.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C+.salkyl)aryl or (C4. calkyl)Het, or both R'"" and R''? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,ealkyl)aryl or (C;salkyl)Het, or heterocycle being optionally substituted with R'®; f) NR'"®COR""” wherein R"® and R"" is each H, (C1.)alkyl, (Cs)cycloalkyl, @ (Cis)alkyl-(Csy)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cigalkyl)Het, said (Ci. s)alkyl, (Cs7)cycloalkyl, (Cig)alkyl-(Caz)cycloalkyl, aryl, Het, (Cy.calkyl)aryl or (C1.calkyl)Het being optionally substituted with R™, g) NR" CONR'R'®, wherein R'*, R"'® and R'® is each H, (C,.g)alkyl, (Cs. 7)cycloalkyl, (Cy.6)alkyl-(Ca.z)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cs. salky)Het, or R'*® is covalently bonded to R'"® and to the nitrogen to which 3 they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R'"® and R' are covalently bonded together and to the nitrogen to which . they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Ci.¢)alkyl-(Cs7)cycloalkyl, aryl, Het, (C4salkylyaryl or (C.. salkyl)Het or heterocycle being optionally substituted with R'’; h) NR'*COCOR™ wherein R'?' and R'# is each H, (Ci.)alkyl, (Ca. ® s)cycloalkyl, (C1.)alkyl-(Cs)cycloalkyl, a 6- or 10-membered aryl, Het, (C+: v salkyl)aryl or (C4.salkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C1.calkyl)Het being optionally substituted with R®%; : | or R'2 is OR" or N(R'?%), wherein R'? and each R'** is independently H, (C1salkyl), (Caz)cycloalkyl, or (Cq.6)alkyl-(Csz)cycloalkyl, aryl, Het, (C.. calkyaryl or (Crealkyl)Het, or R™* is OH or O(Cy.salkyl) or both R™* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C1.salkyl)Het and heterocycle being optionally substituted with R™?; j) COOR'® wherein R'? is H, (C1.g)alkyl, (Cs7)cycloalkyl, or(Ci.¢)alkyl-(Ca. ;)eycloalkyl, aryl, Het, (C1.calkyl)aryl or (Cy.calkyl)Het, said (C,.)alkyl, (Ca. s)cycloalkyl, or(Cy.6)alkyl-(Caz)cycloalkyl, aryl, Het, (C.calkylaryl and (C+. salkyl)Het being optionally substituted with R®’; k) CONR'?°R™ wherein R'*® and R'*° are independently H, (Ci.c)alkyl, (Cs. ;)eycloalkyl, (Ci.s)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.salkyharyl or (Ci. salkyl)Het, or both R™® and R'* are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, atkyl-cycloalkyl, aryl, Het, (C..salkyl)aryl, (C1salkyHet and heterocycle being optionally substituted with R'*%;
I) aryl, Het, (Cisalkyl)aryl or (Cq.salkyl)Het, all of which being optionally substituted with R"®; wherein R'is selected from: @® - 1 to 3 substituents selected from: halogen, NO, cyano or azido; or - 1 to 3 substituents selected from: a) (C1) alkyl or haloalkyl, (Cs.7)cycloalkyl, Caz spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cz.c)alkenyl, (C2g)alkynyl, (Cy.6) alkyl-(Cs.7)cycloalkyl, all of which optionally substituted with B®; b) OR'™ wherein R'* is H, (Cy.salkyl), (Caz)cycloalkyl, or (C+.c)alkyl- . (Csz)cycloalkyl, aryl, Het, (Cyealkyl)aryl or (Cy.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,ealkyl)aryl or (Cisalkyl)Het being optionally \ substituted with R'®’; d) SR'S, SO.N(R™), or SON(R)C(O)R'® wherein each R'* is independently H, (C1.s)alkyl, (Ca.7)cycloalkyl or (Cq.g)alkyl-(Cs-
Jcycloalkyl, aryl, Het, (C.calkyl)aryl or (Cs.salkyl)Het or both R'* are ® covalently bonded together and to the nitrogen to which they are v attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C4.calkyl)aryl or (Cicalkyl)Het or " heterocycle being optionally substituted with R*®’; e) NR'""'R'"'2 wherein R"" is H, (C1.¢)alkyl, (Cs7)cycloalkyi or (Cs. s)alkyl-(Cs7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cysalkyl)Het, and
R'"2is H, CN, (Cis)alkyl, (Cs.7)cycloalkyl or (Cy.¢)alkyl-(Cs.z)cycloalkyl, aryl, Het, (Ci.calkyaryl, (C1.calkyl)Het or SO,R'" wherein R'* is (Cs. e)alkyl, (Ca7)cycloalkyl, or (Cig)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cs. : galkyl)aryl or (Cy.calkyl)Het, or both R'! and R'*? are covalently bonded together and to the nitrogen to which they are attached to formas, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cygalkylaryl or (Cy.salkyl)Het, or heterocycle being optionally substituted with R'®’; f) NR"COR"" wherein R"*® and R'" is each H, (Ci)alkyl, (Ca. 7)cycloalkyl, (Cq.g)alkyl-(Caz)cycloalkyl, aryl, Het, (Cigalkyl)aryl or (C4. calkyl)Het, said (Ci.g)alkyl, (Ca7)cycloalkyl, (Ci.e)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,salkyl)aryl or (C,salkyl)Het being optionally substituted with R'®%; g) NR" CONR"°R'*°, wherein R"*®, R"' and R" is each H, (C1. s)alkyl, (Cs.7)cycloalkyl, (Cy.¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C. salkylaryl or (Cy.calkyl)Het, or R'*® is covalently bonded to BR" and to ® the nitrogen to which they are attached to form a 5, 6 or 7-membered : saturated heterocycle, or R'*® and R'® are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, (C;. s)alkyl-(Cs7)cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (Ci.salkyl)Het or heterocycle being optionally substituted with R'®’; h) NR'COCOR" wherein R'?' is H, (C+.¢)alkyl optionally ) 30 substituted with RB", and R22 is OR" or N(R"), wherein R'® and . : each R™* is independently H, (C:salkyl), (Cs.z)cycloalkyl, or (Cy.¢)alkyl- (Cax)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cq.salkyl)Het, or Ris OH or O(C,.¢alkyl) or both R*?* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- ® cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C,6alkyl)Het and heterocycle a being optionally substituted with R®; j) tetrazole, COOR'™® wherein R'* is H, (Cre)alkyl, (Caz)cycloalkyl, or(C+.e)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C.ealkyaryl or (Ci.ealkyl)Het, said (C1.¢)alkyl, (Ca.z)cycloalkyl, or(Ci¢)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl and (C,.calkyl)Het being optionally substituted with R™®"; : and k) CONR'™R'® wherein R'® and R™ are independently H, (Cs. e)alkyl, (Cs7)cycloalkyl, (Cyg)alkyl-(Ca7)cycloalkyl, aryl, Het, (C1. salkyl)aryl or (C,.calkyl)Het, or both R'?® and R™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyi-cycloalkyl, aryl, Het, (Cq.salkyl)aryl, (C,.calkyl)Het and heterocycle being optionally substituted with R®; wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C.calkyl, haloalkyl, COOR™' SO4H,
SR, SO,R™', OR, N(R'%),, SO,N(R™2),, NR'®COR" or
CON(R'®%),, wherein R'®' and each R'®?is independently H, (C1)alkyl, (Caz)cycloalkyl or (Cy.g)alkyl-(Cs.7)cycloalkyl; or both
R'®2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle. (
More preferably, Q is a 6- or 10-membered aryl, Het, (C1salkyl)aryl or (Csalkyl)-Het, all of which being optionally substituted with: - 1 to 4 substituents selected from: halogen,NO,, cyano or azido; or - 1 to 4 substituents selected from: a) (C1.¢) alkyl or haloalkyl, (Ca.7)cycloalkyl, (Ca.¢)alkenyl, (C,.g)alkynyl, (C1.6) ] alkyl-(Cs7)cycloalkyl, all of which optionally substituted with RS; : 30 b) OR! wherein R'™ is H, (C1.salkyl), (Caz)cycloalkyl, or (C1.¢)alkyl-(Cs. . 7)eycloalkyl, aryl, Het, (C+salkyl)aryl or (Cq.salkyl)Het, said alkyl, cycloalkyl, - aryl, Het, (Cisalkyl)aryl or (Cisalkyl)Het being optionally substituted with
R's. d) SR, SON(R'®), or SO.N(R'®)C(O)R"® wherein each R'® is ® independently H, (Cy.¢)alkyl, (Ca.z)cycloalkyl or (C1.)alkyl-(Cs7)cycloalkyl, aryl, > Het, (Ci.calkyharyl or (C+calkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7- - membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C;. salkyharyl or (C1salkyl)Het or heterocycle being optionally substituted with
R'®° e) NR'R"2 wherein R'is H, (Ci.¢)alkyl, (Cs7)cycloalkyl or (Cyg)alkyl-(Ca. s)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Ci.¢alkyl)Het, and R'is H, CN, (Cy. alkyl, (Ca)cycloalkyl or (C1.¢)alkyl-(Ca7)cycloalkyl, aryl, Het, (Ci.ealkyl)aryl, (C,salkyl)Het , COOR™® or SO,R'"® wherein R'* is (Cy.¢)alkyl, (Ca. s)eycloalkyl, or (Cy.¢)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Ciealkylaryl or (Cs. salkyl)Het, or both R'! and R*'2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C1.calkyl)aryl or (C;.salkyl)Het, or heterocycle being optionally substituted with R'®; f) NR" COR" wherein R"'® and R""" is each H, (Ci.s)alkyl, (Cs7)cycloalkyl, (C1.s)alkyl-(Ca7)cycloalkyl, aryl, Het, (Ci.¢alkyl)aryl or (C4.salkyl)Het, said (C4. oo ~ oalkyl, (Cs-)cycloalkyl, (Cy.e)alkyl-(Ca)cycloalkyl, aryl, Het, (Cysalkylaryl of (C1salkyl)Het being optionally substituted with R'*°; 'g) NR'CONR'R'®, wherein R"'®, R'"® and R'*° is each H, (Ci.s)alkyl, (Cs. 7)eycloalkyl, (Cq.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,salkyl)aryl or (Cs. salkyhHet, or R'"® and R' are covalently bonded together and to the ® nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C.s)alkyl-(Csz)cycloalkyl, aryl, Het, (Cs. salkyl)aryl or (Cy¢alkyl)Het or heterocycle being optionally substituted with
R's: h) NR'?'COCOR*?? wherein R'® is H, (C1.s)alkyl optionally substituted with
R'®, and R'is OR or N(R"), wherein R'® and each R'* is . independently H, (C;salkyl), (Ca)cycloalkyl, or (C4.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cgalkyhary! or (Ci.calkyl)Het, or R'™* is OH or O(C1.¢alkyl) or both . R'?* are covalently bonded together to form a 5, 6 or 7-membered saturated "heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cisalkylaryl or (C,salkyl)Het and heterocycle being optionally substituted with R**%; j) COOR'® wherein R'? is H, (C1.6)alkyl, (Cs.7)cycloalkyl, or(C1.e)alkyl-(Cs. ®
7)cycloalkyl, aryl, Het, (Cqsalkylaryl or (Cy.¢alkyl)Het, said (Cy.)alkyl, (Cs. » 7)cycloalkyl, or(Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy galkylaryl and (Ci. salkyl)Het being optionally substituted with R®°; . k) CONR™R™° wherein R'® and R"® are independently H, (C1.¢)alky!, (Cs. 7)cycloalkyl, (C4.¢)alkyl-(Csz)cycloalkyl, aryl, Het, (Cy.salkylaryl or (C;. salkyl)Het, or both R™® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cysalkyl)aryl, (C1salkyl)Het and heterocycle being optionally substituted with R'*%; 1) aryl, Het, (C1-6alkyl)aryt or (C1-6alkyl)Het, all of which being optionally substituted with R'*°, wherein R'is preferably selected from: - 1 to 3 substituents selected from: halogen, NO,, cyano or azido; or - 1 to 3 substituents selected from: a) (C+.6) alkyl or haloalkyl, (Cs.7)cycloalkyl, (Ca.¢)alkenyl, (Ca.g)alkynyl, (C1) alkyl-(Ca.7)cycloalkyl, all of which optionally substituted with R*®; b) OR'™* wherein R'™ is H, (C,.salkyl), (Cs)cycloalkyl, or (Ci)alkyl- (Css)cycloalkyl, aryl, Het, said alkyl, cycloalkyl, aryl and Het being optionally substituted with R'®?; c) OCOR'® wherein R'® is (Cy.6)alkyl, (Caz)cycloalkyl, (C1.)alkyl-(Cs. 7)cycloalkyl, Het, (Ci.calkyl)aryl or (Cq.galkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cialkyl)aryl or (Ci.salkyl)Het being optionally substituted } with R'%; ® d) SR, SO,N(R'®), or SO.N(R'"®)C(O)R® wherein each R'® is independently H, (Cy)alkyl, (Cs7)cycloalkyl or both R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl or heterocycle being optionally substituted with R*°; e) NR''R""2 wherein R'is H, (C,s)alkyl, (Caz)cycloalkyl or (Cs. s)alkyl-(Ca.z)cycloalkyl, and R'is H, (C,.¢)alkyl, (Cs.s)cycloalkyl or (C. } 30 g)alkyl-(Ca7)cycloalkyl, COOR'" or SO,R""® wherein R**® is (Cy.)alkyl, ] (Caz)cycloalkyl, or both R"" and R'"2 are covalently bonded together and to the nitrogen to which they are attached to formab, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C. salkylaryl or (Ci.salkyl)Het, or heterocycle being optionally substituted ® with R'®; ‘ f) NR" COR” wherein R"® and R"" is each H, (Ci.)alkyl, (Cs. cycloalkyl, (Cy.g)alkyl-(Caz)cycloalkyl, aryl, Het, (Cy.qalkylaryl or (Ci. salkyl)Het, said (C.¢)alkyl, (Ca-)cycloalkyl, (C1.)alkyl-(Car)cycloalkyl, aryl, Het, (C,calkyl)aryl or (Cisalkyl)Het being optionally substituted with R%; a) NR’ CONR'’R'?, wherein R""®, R""? and R'*" is each H, (C.. e)alkyl, (Caz)cycloalkyl, or R''® and R' are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl or heterocycle being optionally substituted with R®’; h) NR" COCOR'? wherein R'® is H, (C1.)alky) optionally substituted with R'®%; or R'2 is OR'® or N(R"), wherein R'** and each R'is independently H, (C1.salkyl) of (Ca)cycloalkyl, or R'* is
OH or O(C1-calkyl), or both R'?* are covalently bonded together to form . a5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R®’; j) tetrazole, COOR' wherein R'® is H, (C1.)alkyl or (Csz)cycloalkyl, said (Cig)alkyl and (C3s)cycloalkyl being optionally substituted with
R' and k) CONR'?°R™ wherein R' and R'® are independently H, (C;. e)alkyl or (Cs.7)cycloalkyl, or both R'® and R'* are covalently bonded | ® together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R'®’; wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, Cy.galkyl, haloalkyl, COOR'®, SOzH,
SO,R™, OR", N(R2),, SO,N(R™2),, NR'2COR™2 or . CON(R'%),, wherein R'®' and each R'is independently H, (C.g)alkyl, (Caz)cycloalkyl or (Cy.g)alkyl-(Cs)cycloalkyl; or both " R'™2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle. ®
Most preferably, Q is a 6- or 10-membered aryl or Het, both being optionally ‘ substituted with: - 110 3 halogen, NO,, cyano, azido; or : - 1 to 3 substituents selected from: a) first (C,.6) alkyl or haloalkyl, first (Csr)cycloalkyl, (Cag)alkenyl, (Ca.g)alkynyl, (C16) alkyl-(Cs.7)cycloalkyl, all of which are optionally substituted with R**®; b) OR wherein R'is H, (C;alkyl); d) SO,NHR'"® wherein R'® is H or (Cy.¢)alkyl; e) NR"'R""? wherein both R'"! and R'"? are independently H or (Ci¢)alkyl; 10. f) NHCOR'" wherein R''® is H or (Cy.s)alkyl; g) NHCONR'°R'®, wherein R"'® and R'is each independently H or (C;. alkyl; h) NHCOCOR'? wherein R'? is OR'® or N(R'*%), wherein R'® and each
R'* is independently H or (C;.¢alkyl); j) COOR' wherein R'2 is H, (Cy¢)alkyl; k) CONHR™ wherein R'is H, (Ci.¢)alkyl;
I) 6- or 10-membered aryl, Het, (C.galkyl)aryl or (Cy ¢alkyl)Het, said aryl, Het, (Cisalkylaryl or (C1.salkyl)Het being optionally substituted with R'’; and wherein, preferably, R™ is selected from: - 1 to 3 halogens; or - 1 to 3 substituents selected from: a) first (Cy.) alkyl or haloalkyl, first (Cs.7)cycloalkyl, (C,.¢)alkenyl, (Co. ® g)alkynyl, (C1) alkyl-(Cs.7)cycloalkyl, all of which are optionally substituted with tetrazole, OR'"2, COOR'%, wherein R'®is H or (C1.g)alkyl; b) OR™ wherein R'* is H, (Cy.calkyl); d) SO.NHR'® wherein R'® is H or (C1.c)alky}; e) NR'"R'*2 wherein both R'"! and R'"? are independently H or (Ci. . e)alkyl; f) NHCOR"" wherein BR" is H or (Cy.s)alkyl; and h) NHCOCOR'® wherein R'is OR'® or N(R'**), wherein R'* and each R'® is independently H or (Cy. galkyl); oo j) COOR' wherein R'"® is H, (C,,)alkyl; and k) CONHR'™ wherein R'is H, (C,.c)alkyl. ®
’ More preferably Q is selected from:
J / , : CH, / O 4 0 0] i on Ss OH } CH, 0) NH oO NH 0. NH 0x NH ~n [0] ~ 0} — NH, le} H HN O wo” TO N = J SS : ~OH : “NH, ; ~OH : “NH, : ~OH ] ’ 2 2 1 7 ~ «_ CN ~
OH ~_ OH pu of 0” OH o a” oH » ~ ES ES
XN Ny] lo} fo) a
OH OH 0 o o 0 0 lo] NH, OH OH NH, NH,
oh N=
NC 7 { \ 73 Js \_/ = N — } od 74 N "NN on / OH
NH, o” “OH N=" NH, 0 Oo \ / o\ \ / \ /
OH \7/ ad OH ad OH o) _ Hooc—/ 0 0 7 / "Oo sO! ball ci OH Yad on —~ OH N 6) 0) (@) \=/
Ss OH N NH,
OH y
N\ 0 N 0
Jd o cl \ 1 * oH HN
A OH OH
\ s ° BS) o
Ny fo
OH AP
“Crd “0 A a s Yo s H . Lr ° . os : 72 , aga T oO , N=N , OH , SO,NH, , and .
Most preferably, Q is selected from:
® ’ CH, NH
Uo hv: ~ 2 ; o HO 0 OH
HO HO 1S , N lo} OH 0 NH, 0] 7
QS \ J / ( = = = 7 A ol oH OH 0” OH NH, — Io;
A SNA | 0 <
N on NZ nm
[0] 0 H , N=N OH SONH, CONH,, and :
Specific embodiments
Included within the scope of this invention are all compounds of formula | as presented in Tables 1 to 9.
Polymerase activity
The ability of the compounds of formula (1) to inhibit RNA synthesis by the RNA dependent RNA polymerase of HCV can be demonstrated by any assay capable of measuring RNA dependent RNA polymerase activity. A suitable assay is described in the examples.
Specificity for RNA dependent RNA polymerase activity
To demonstrate that the compounds of the invention act by specific inhibition of HCV polymerase, the compounds may be tested for inhibitory activity in a DNA dependent
RNA polymerase assay.
® ¢ When a compound of formula (I), or one of its therapeutically acceptable salts, is employed as an antiviral agent, it is administered orally, topically or systemically to « mammals, e.g. humans, rabbits or mice, in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice.
For oral administration, the compound or a therapeutically acceptable salt thereof can be formulated in unit dosage forms such as capsules or tablets each containing a predetermined amount of the active ingredient, ranging from about 25 to 500 mg,
Qo in a pharmaceutically acceptable carrier.
For topical administration, the compound can be formulated in pharmaceutically accepted vehicles containing 0.1 to 5 percent, preferably 0.5 to 5 percent, of the active agent. Such formulations can be in the form of a solution, cream or lotion.
For parenteral administration, the compound of formula (l) is administered by either intravenous, subcutaneous or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers. For administration by injection, it is preferred to use the compounds in solution in a sterile aqueous vehicle which may also contain other solutes such as buffers or preservatives as well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make the solution isotonic.
Suitable vehicles or carriers for the above noted formulations are described in pharmaceutical texts, e.g. in "Remington's The Science and Practice of Pharmacy", 19th ed., Mack Publishing Company, Easton, Penn., 1995, or in "Pharmaceutical
Dosage Forms And Drugs Delivery Systems”, 6th ed., H.C. Ansel et al., Eds., . 30 Williams & Wilkins, Baltimore, Maryland, 1995. . The dosage of the compound will vary with the form of administration and the particular active agent chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small increments until the optimum effect under the circumstance is reached. In general, the compound of formula | is
® most desirably administered at a concentration level that will generally afford ¢ antivirally effective results without causing any harmful or deleterious side effects. « : For oral administration, the compound or a therapeutically acceptable salt is administered in the range of 10 to 200 mg per kilogram of body weight per day, with a preferred range of 25 to 150 mg per kilogram.
For systemic administration, the compound of formula (1) is administered at a dosage of 10 mg to 150 mg per kilogram of body weight per day, although the aforementioned variations will occur. A dosage level that is in the range of from about 10 mg to 100 mg per kilogram of body weight per day is most desirably @ employed in order to achieve effective results.
When the compositions of this invention comprise a combination of a compound of 156 formula | and one or more additional therapeutic or prophylactic agent, both the compound and the additional agent should be present at dosage levels of between : about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen. * When these compounds or their pharmaceutically acceptable salts are formulated together with a pharmaceutically acceptable carrier, the resulting composition may be administered in vivo to mammals, such as man, to inhibit HCV polymerase orto treat or prevent HCV virus infection. Such treatment may also be achieved using the compounds of this invention in combination with agents which include, but are not limited to: immunomodulatory agents, such as o-, B-, or y-interferons; other antiviral agents such as ribavirin, amantadine; other inhibitors of HCV NS5B polymerase; inhibitors of other targets in the HCV life cycle, which include but not limited to, helicase, NS2/3 protease, NS3 protease, or internal ribosome entry site (IRES); or combinations thereof. The additional agents may be combined with the compounds of this invention to create a single dosage form. Alternatively these additional agents . 30 may be separately administered to a mammal as part of a multiple dosage form. : Methodology and Synthesis
Indole derivatives or analogs according to the present invention can be prepared from known monocyclic aromatic compounds by adapting known literature sequences such as those described by J.W. Ellingboe et al. (Tet. Lett. 1997, 38,
® 7963) and S. Cacchi et al. (Tet. Lett. 1992, 33, 3915). Scheme 1, shown below - wherein R, R?, R%, R®, K, L, and M are as described herein illustrate how these procedures can be adapted to the synthesis of compounds of formula 1 of this ” invention.
Scheme 1
F
" Sh
HN COOMe R® PdCL(PPhy), HN COOMe
SCAN
1 (ii) ] 4 160) R 0) ® Pd(PPhy), / K,CO, H,/ Pd cat. TY
No ) n R' Ii) “ Ral NaOH then ™ Ay H,N-RS coupling
N COOMe
Riv) oman Compound of formula
H,N-RS coupling
In carrying out the route illustrated in Scheme 1, a suitably protected form of 3- trifluoroacetamido-4-iodobenzoic acid ii) is reacted with an alkyne Iii) in the presence of a metal catalyst (e.g. a palladium metal complex such as PdCL(PPhy),, Pd.dbas, Pd(PPhs), and the like), a base (Et;N, DIEA and the like or an inorganic basic salt including metal carbonates, fluorides and phosphates), and optionally in the presence of an additional phosphine ligand (triaryl or heteroaryiphosphine, dppe, dppf, dppp and the like). Suitable solvents for this reaction include DMF, dioxane,
THF, DME, toluene, MeCN, DMA and the like at temperatures ranging from 20 °C to 170 °C, or alternatively without solvent by heating the components together.
Alternatively, the cross-coupling reaction can be carried out on a suitably protected form of 3-amino-4-iodobenzoate and the amino group can be trifluoroacetylated in a the subsequent step as described by J.W. Ellingboe et al. (Tet. Lett. 1997, 38, 7963).
Reaction of the above diarylalkynes iii) with an enol triflate under cross-coupling conditions similar to those described above gives after hydrogenation of the douple bond, indole derivatives I{iv). Enol triflates are known and can be prepared from the corresponding ketones by following known literature methods (for example, cyclohexene triflate can be prepared from cyclohexanone, triflic anhydride and a hindered organic base such as 2,6-di-tert-butyl-4-methylpyridine). The “ hydrogenation of the double bond originally present in R' can be carried out with hydrogen gas or a hydrogen donor (ammonium formate, formic acid and the like) in ° the presence of a metal catalyst (preferably Pd) in a suitable solvent (lower alkyl alcohols, THF etc.).
Finally, following hydrolysis of the ester protecting group in i(iv), the resulting 6- carboxyindole derivative I(v) is converted to compounds of formula 1 by coupling with the appropriate amine of formula H,N-R°®. Condensation of the 6- indolecarboxylic acid with amines H,N-R® can be accomplished using standard amide bond forming reagents such as TBTU,HATU, BOP,BroP, EDAC, DCC, isobutyl chloroformate and the like, or by activation of the carboxyl group by @ conversion to the corresponding acid chloride prior to condensation with an amine.
Any remaining protecting group is removed following this step to give compounds of formula 1.
Alternatively, compounds of formula 1 can be prepared by elaboration from a pre- exisitng indole core by following adaptations of literature procedures as described, for example, by P. Gharagozloo et al. (Tetrahedron 1996, 52, 10185) or K. Freter (J.
Org. Chem. 1975, 40, 2525). Such a methodology is illustrated in Scheme 2:
Scheme 2 fo} y PI] y COOH
COOH Sy 2A)
N ARE CAT
\ NaOMe or H* ) i then H, / Pd cat. R 2(iii) 2() "A RY 1. MeOH / SOC, N COOMe Br, source N COOMe —_— —_—— 3 Br 2. NaH / ix \ \ {for R® not H) . 1 2
RO 20) R ©) 1.Buli/-78°C 2. RSC FBO or ZnCl, RESNRY, . catalyst / base 3 mn
R
. R2.-X R=
ST ee IO catalyst / base
M = R'sSn or ClZn '
R' R I(v) 2(vi)
PY 88
In carrying the route illustrated in Scheme 2, commercially available 6- ’ indolecarboxylic acid 2(i), which can also be prepared according to the method of S.
Kamiya et al. (Chem. Pharm. Bull. 1995, 43, 1692) is used as the starting material. i The indole 2(i) is reacted with a ketone 2(ii) under basic or acidic aidol-type conditions. Suitable conditions to affect this condensation include strong bases such as alkali metal hydroxides, alkoxides and hydrides in solvents such as lower alkyl alcohols (MeOH, EtOH, tertBuOH etc.), THF, dioxane, DMF, DMSO, DMA and the like at reaction temperature ranging from —20 °C to 120 °C. Alternatively, the condensation can be carried out under acid conditions using organic or mineral acids or both. Appropriate conditions include mixtures of ACOH and aqueous phosphoric acid at temperatures ranging from 15°C to 120 °C. @ Following protection of the carboxylic acid group in the form of an ester (usually lower alkyl) using known methods, the indole nitrogen can be alkylated with R® if desired. Reaction conditions to alkylate the nitrogen of an indole derivative are well known to those skilled in the art and include the use of strong bases such as alkali metal hydrides, hydroxides, amides, alkoxides and alkylmetals, in the appropriate solvent (such as THF, dioxane, DME, DMF, MeCN, DMSO, alcohols and the like) at temperatures ranging from —78 °C to 140 °C. An electrophilic form of R® is used for the alkylation of the indole anion. Such electrophilic species include iodides, bromides, chlorides and sulfonate esters (mesylates, tosylate, brosylate or triflate).
Halogenation (usually bromination, but also jodination) of the 2-position of the indole 2(iv) gives 2(v). Suitable halogenating agents include, for example, elemental bromine, N-bromosuccinimide, pyridine tribromide, dibromohydantoin and the corresponding iodo derivatives. Suitable solvents for this reaction are inert to reactive halogenating agents and include for example hydrocarbons, chlorinated hydrocarbons (DCM, CCl,, CHCl), ethers (THF, DME, dioxane), acetic acid, ethyl acetate, IPA, and mixtures of these solvents. Reaction temperature ranges from —40 °C to 100 °C. A method of choice to carry out the bromination ofindoles as shown in
Scheme 2 was described by L. Chu (Tet. Lett. 1997, 38, 3871). i 30
The 2-bromoindole derivatives 2(v) can be converted directly to fully substituted key intermediates iv) through a cross-coupling reaction with aryl or heteroaryl boronic acids, boronate esters or trialkylstannane derivatives. These boron or tin organometallic species are from commercial sources or can be prepared by standard literature procedures. Cross-coupling with organoboron reagents can be
[ carried out by any variations of the Suzuki cross-coupling reaction reported in the . literature. This usually involves the use of a transition metal catalyst (usually Pd°), triaryl or triheteroarylphosphine ligands, an additive such as an inorganic chloride o (e.g. LiCl), and a base (usually an aqueous inorganic base such as sodium or potassium carbonate or phosphate). The reaction is usually carried out in an alcoholic solvent (EtOH), DME, toluene, THF and the like at temperatures ranging from 25 °C to 140 °C. " Cross-coupling with tin reagents can be carried out by any variations of the Stille cross-coupling reaction reported in the literature. This usually involves the use of a transition metal catalyst (usually Pd®), triary! or triheteroaryl phosphine ligands, and an additive such as an inorganic chloride (e.g. LiCl) or iodide (e.g. Cul). Suitable 9 solvents for this reaction include toluene, DMF, THF, DME and the like at temperatures ranging from 25 °C to 140 °C. Intermediate I(v) is then converted to compounds of formula 1 as described for Scheme 1.
Alternatively, the 2-bromoindole intermediate 2(v) can be trans-metallated to an organotin species (or organozinc) and used in Stille-type cross-coupling reactions under conditions described above. In this case, aromatic and heteroaromatic halides (chlorides, bromides, iodides) or triflates are used to introduce R2. The conversion of 2-bromoindole derivatives 2(v) to the corresponding organotin species 2(vi) is carried out via initial low-temperature (usually -78 ° to —30 °C) halogen-metal exchange using an alkyllithium reagent (e.g. nBuli or tert-BuLi) or using lithium metal. The transient 2-lithioindole species is then trapped with a trialkyltin halide (e.g. nBusSnCl or MesSnCl). Alternatively, the lithioindole intermediate can be trapped with zinc chloride to form the corresponding organozincate which can also undergo transition metal-catalyzed: cross-coupling with aromatic and heteroaromatic halides or triflates as described, for example, by M. Rowley (J. Med. Chem. 2001, 44, 1603).
The present invention also encompasses compounds of formula 1 where the . 30 carboxylic group is in the 5-position of the indole system. The synthesis of such compounds is based on adaptation of literature procedures and is depicted in : Scheme 3:
®
Scheme 3 : NHAC IR Po os a(ii) TY
PdACI,(PPh,), / Cul N ‘
COOEt 3(iii) 3(i) os "
RIX COOEt COOH base } N | N 3(iv) Raw)
Qo Bi i Compound of formula I- coupling .
In carrying out the synthetic route illustrated in Scheme 3, ethyl 4-acetamido-3- jodobenzoate 3(i) undergoes metal catalyzed cross-coupling with an alkyne 3(ii) to give a 2,3-disubstituted-5-indolecarboxylate 3(iii) according to an adaptation of a procedure described by A. Bedeschi et al. (Tet. Lett. 1997, 38, 2307). The indole derivative 3(iit) is then alkylated on nitrogen with electrophilic R' groups (halides, sulfonate esters) under the action of a base such as alkali metal hydroxides, fluorides, hydrides amides, alkyllithium, phosphabases and the like, to give 3(iv).
Suitable solvents for this alkylation include DMF, DMA, DMSO, MeCN, THF, dioxane, DME and the like. Following saponification of the ester group with an alkaline solution, the resulting 5-indolecarboxylic acid derivative 3(v) is coupled to
H,N-R°® using an amide bond forming reagent as described previously (Scheme 1), to give compounds of formula I.
EXAMPLES
The present invention is illustrated in further detail by the following non-limiting 20 . examples. All reactions were performed in a nitrogen or argon atmosphere.
Temperatures are given in degrees Celsius. Flash chromatography was performed on silica gel. Solution percentages or ratios express a volume to volume relationship, unless stated otherwise. Mass spectral analyses were recorded using electrospray mass spectrometry. Abbreviations or symbols used herein include:
WQ 63/010141 PCT/CA02/01128
PS 91
DIEA: diisopropylethylamine; : DMAP: 4-(dimethylamino)pyridine;
DMSO: dimethylsulfoxide; : } DMF: N,N-dimethylformamide;
Et: ethyl; :
EtOAc: ethyl acetate;
Et,0: diethyl ether;
HPLC: high performance liquid chromatography;
Pr: isopropyl
Me: methyl;
MeOH: Methanol; ( MeCN: acetonitrile;
Ph: phenyl; -
TBE: tris-borate-EDTA,; TBTU: 2-(71H-benzotriazol-1-yl)-N,N,N’,N"-tetramethyluronium tetrafluoroborate;
TFA: trifluoroacetic acid;
TFAA: trifluoroacetic anhydride;
THF: tetrahydrofuran;
MS (ES): electrospray mass spectrometry;
PFU: plaque forming units;
DEPC: diethyl! pyrocarbonate;
DTT: dithiothreitol
EDTA: ethylenediaminetetraacetate
HATU: O-(7-azabenzotriazol-1-yl)-N, N,N, N'-tetramethyluronium hexafluorophosphate
BOP: benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
EDAC: see ECD
DCC: 1,3-Dicyclohexyl carbodiimide
HOB: 1-Hydroxybenzotriazole
ES": electro spray (positive ionization)
ES": electro spray (negative ionization) ; DCM: dichloromethane
TBME: tert-butylmethyl ether
TLC: thin layer chromatography
AcOH: acetic acid
EtOH: ethanoi : . DBU: 1,8-diazabicyclo[5.4.0]junder-7-ene
BOC: tert-butyloxycarbonyl
Cbz: carbobenzyloxy carbonyt 5 'PrOH: isopropanol
NMP: N-methylpyrrolidone
EDC: 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride
RNAsin: A ribonuclease inhibitor marketed by Promega Corporation
Tris: 2-amino-2-hydroxymethyl-1,3-propanediol
UMP: uridine 5’-monophosphate
UTP: uridine 5'-triphosphate @ IPA: isopropyl acetate
Examples 1-45 illustrate methods of synthesis of representative compounds of this invention.
EXAMPLE 1
F,C.__0O
HN COOH HN COOMe NY ry _— 1 TFAA HN COOMe ——
I MeOH / SOC, I reflux Ir = CF,COHN ° Coole OT} = _
PACL,(PPh,), OC Pd(PPhy),/ K,CO,
Et,N
H . coo
H COOMe N H (OC ) \ 1.H,/Pd cat. , —_—— 2. NaOH then HCI () ; 20
Methyl 3-amino-4-iodobenzoate: 3-Amino-4-iodobenzoic acid (13.35 g, 50.8 mmol) was added to MeOH (150mL) and
SOCI; (4.8 mL, 65.8 mmol, 1.3 equivalent) was added. The mixture was refluxed for
® 3 h and then volatiles were removed under reduced pressure. The residue was co- . evaporated three times with MeOH and dried in vacuo (15.23 g). a Methyl! 3-trifluoroacetamido-4-iodobenzoate:
The aniline derivative from above (14.53 g, 52 mmol) was dissolved in DCM (200 mL) and TFAA (15 mL, 104 mmol) was added. The dark purple solution was refluxed overnight. Volatiles were removed under reduced pressure and the residue was passed through a short pad of silica gel using DCM as eluent. The desired product was obtained as a pink solid (13.81 g). 4-Phenylethynyl-3-(2,2,2-trifluoro-ethanoylamino)-benzoic acid methyl ester: @ The iodide from above (0.742 g, 2 mmol), phenylacetylene (0.37 mL, 3.9 mmol, 1.7 equivalent) and Et;N (6 mL) were charged in a dry flask under argon. PdCL(PPhj), (0.241 g, 0.3 mmol) was added and the mixture was stirred at room temperature until judged complete by HPLC analysis (~5 h). The reaction mixture was concentrated to half volume under reduced pressure and diluted with water (80 mL). The mixture was extracted with EtOAc (3 x 100 mL) and the organic extract washed with 5% HCI (100 mL), after (100 mL) and brine (40 mL). After drying over MgSO, the residue was purified by flash chromatography using 20% EtOAc — hexane as eluent to give the desired cross-coupled alkyne as a tan solid (0.442 g).
Methy! 3-(cyciohexenyl)-2-phenylindole 6-carboxylate:
A flame-dried flask was charged with finely powdered anhydrous K,CO3 (0.153 g, 1.1 mmol) and the alkyne derivative from above (0.390 g, 1.1 mmol). Dry DMF (4 mL) was added and the suspension degassed with a stream of argon. The enol triflate derived from cyclohexanone, prepared following the procedure described by A.G.
Martinez, M. Hanack et al. (J. Heterocyclic Chem. 1988, 25, 1237 or equivalent methods described in the literature, (0.802 g, 3.3 mmol, 3 equivalents) was added followed by Pd(PPhg), (0.086 g, 0.07 mmol) and the mixture was stirred for 8 h at . room temperature. DMF was removed under vacuum and the residue purified by flash chromatography using DCM as eluent (0.260 g).
Methyl 3-cyclohexyl-2-phenylindole-6-carboxylate:
The material from above was hydrogenated (1 atm H, gas) over 20% Pd(OH), in the usual manner, using MeOH as solvent. The desired cyclohexane indole was isolated after filtration of the catalyst. 3-Cylohexyl-2-phenylindole-6-carboxylic acid: ° The methyl ester from above (0.154 g, 0.15 mmol) was refluxed overnight in a mixture of MeOH (10 mL) and 2N NaOH (6 mL) until complete hydrolysis had occurred as shown by HPLC analysis. After cooling to room temperature, 2N HCI (5 mL) was added followed by AcOH to pH 7. MeOH was removed under reduced pressure, water (50 mL) was added and the product extracted with EtOAc. The extract was washed with water an brine, and dried (MgSQ,). Removal of volatiles under reduced pressure gave the title indole carboxylic acid as a light-orange solid (0.149 q).
Following the same procedure but using 2-ethynylpyridine instead of phenylacetylene, 3-cyclohexane-2-(2-pyridyl)indole-6-carboxylic acid was obtained.
EXAMPLE 2: 0 H COOMe
H 1. NaOhe
N COOH 0) MeOH / reflux \ ) + —_— \ 2. MeOH / SOCI, i COOMe H COooMe 1. H, (1 atm) \ pyridine tribromide Br N\ — >= a 20% Pd(OH), - C THF - CHCl, /0 °C
THF - MeOH 2. MeOH/SOCI, } 3-Cyclohexenyl-6-indole carboxylic acid:
A 12 L round-bottomed flask was equipped with a reflux condenser and a mechanical stirrer, and the system was purged with nitrogen gas. 6-Indole carboxylic acid (300.00 g, 1.86 mole, 3 equivalents) was charged into the flask, followed by MeOH (5.5 L). After stirring for 10 min at room temperature, ) cyclohexanone (579 mL, 5.58 mole) was added. Methanolic sodium methoxide (25% wiw, 2.6 L, 11.37 mole, 6.1 equivalents) was added in portions over 10 min.
The mixture was then refluxed for 48 h. After cooling to room temperature, water (4
®
L) was added and methanol removed under reduced pressure. The residual : aqueous phase was acidified to pH 1 with concentrated HCI (~1.2 L). The resulting yellowish precipitate was collected by filtration, washed with water and dried under ¢ vacuum at 50 °C. The desired cyclohexane derivative was obtained as a beige solid (451.09, 100% yield). 3-Cyclohexyl-6-indole carboxylic acid:
The unsaturated derivative from above was hydrogenated for 20 h under 55 psi hydrogen gas pressure over 20% Pd(OH)./C (10.25 g) using 1:1 THF — MeOH (2.5
L) as solvent. After filtration of the catalyst, volatiles were removed under reduced pressure and the residue was triturated with hexane. The beige solid was collected ® by filtration, washed with hexane and dried under vacuum (356.4 g, 78% yield).
Methyl 3-cyclohexyl-6-indole carboxylate:
A 5 L three-necked flask was equipped with a reflux condenser and a mechanical stirrer, and the system was purged with nitrogen gas. The indole carboxylic acid from above (300.00 g, 1.233 mole) was charged into the flask and suspended in
MeOH (2 L). Thionyl chloride ( 5 mL, 0.0685 mole, 0.05 equivalent) was added dropwise and the mixture was refluxed for 48 h. Volatiles were removed under reduced pressure and the residue was triturated with hexane to give a beige solid that was washed with hexane and dried under vacuum (279.6 g, 88% yield).
Methyl-2-bromo-3-cyciohexyl-6-indole carboxylate:
Adapting the procedure of L. Chu (Tet. Lett. 1997, 38, 3871) methyl 3-cyclohexyl-6- indole carboxylate (4.65 g, 18.07 mmol) was dissolved in a mixture of THF (80 mL) and CHCl; (80 mL). The solution was cooled in an ice bath and pyridinium bromide perbromide (pyridine tribromide, 7.22 g, 22.6 mmol, 1.25 equivalent) was added.
After stirring for 1.5 h at 0 °C, the reaction was judged complete by TLC. It was : diluted with CHCl; (200 mL), washed with 1M NaHSO; (2 x 50 mL), saturated . aqueous NaHCO; (2 x 50 mL) and brine (50 mL). After drying over Na,S0O,, the solvent was removed under reduced pressure and the residue crystallized from : TBME — hexane. The desired 2-bromoindole derivative was collected by filtration, washed with hexane and dried (3.45 g). Evaporation of mother liquors gave a red solid that was purified by flash chromatography using 15% EtOAc in hexane yielding an additional 3.62 g of pure material. Total yield was 5.17 g (85% yield).
® . EXAMPLE 3: :
General procedure for the Suzuki cross-coupling of aryl and heteroarylboronic ° acids with 2-bromoindole derivatives:
Cross-coupling of aromatic/heteroaromatic boronic acid or ester derivatives with 2- bromoindoles such as the one described in example 2 can be performed using any variations of the standard metal-catalyzed Suzuki cross-coupling reaction as described in the literature and well known to those skilled in the art. The following example serves to illustrate such a process and is non-limiting. - 3-Cyclohexyl-2-furan-3-yl-1 H-indole-6-carboxylic acid methyl ester: ( 10
IN COOMe pe
The 2-bromoindole of example 2 (8.92 g, 26.5 mmol), 3-furanboronic acid (B.P.
Roques et al. J. Heterocycl. Chem. 1975, 12, 195; 4.45 g, 39.79 mmol, 1.5 equivalent) and LiCl (2.25 g, 53 mmol, 2 equivalents) were dissolved in a mixture of
EtOH (100 mL) and toluene (100 mL). A 1M agueous Na,COj; solution (66 mL, 66 mmol) was added and the mixture was degassed with argon for 45 min. Pd(PPhy), (3.06 g, 2.65 mmol, 0.1 equivalent) was added and the mixture stirred overnight at 75-85 °C under argon. Volatiles were removed under reduced pressure and the residue re-dissolved in EtOAc (500 mL). The solution was washed with water, saturated NaHCO; (100 mL) and brine (100 mL). After drying over a mixture of
MgSO, and decolorizing charcoal, the mixture was filtered and concentrated under reduced pressure. The residual oil was triturated with a mixture of TBME (20 mL) . and hexane (40 mL), cooled in ice and the precipitated solid collected by filtration, washed with cold 25% TBME in hexane, and dried (3.09 g). The filtrate and . washings from the above trituration were combined, concentrated and purified by flash chromatography using 10-25% EtOAc in hexane to give an additional 4.36 g of product. The total yield of the 2-(3-furyl)indole of example 3 was 8.25 g.
® s EXAMPLE 4: .
N Me ¢ COOMe N COOMe
DMF
Me :
N COOMe pyridine tribromide Br \ ® THF - CHC, /0 °C .
Methyl 3-cyclohexyl-1-methyl-6-indole carboxylate:
Methyl 3-cyclohexyl-6-indole carboxylate from example 2 (150.00 g, 0.583 mole) was charged into a 3 L three-necked flask equipped with a mechanical stirrer and purged with nitrogen gas. DMF (1 L) was added and the solution was cooled in an ice-bath.
NaH (60% oil dispersion, 30.35 g, 0.759 mole, 1.3 equivalent) was added in small portions (15 min) and the mixture was stirred for 1 h in the cold. lodomethane (54.5 mL, 0.876 mole, 1.5 equivalent) was added in small portions, maintaining an internal temperature between 5-10 °C. The reaction mixture was then stirred overnight at room temperature. The reaction was quenched by pouring into ice-water (3 L), resulting in the formation of a cream-colored precipitate. The material was collected by filtration, washed with water and dried in vacuum at 45 °C (137.3 g, 86% yield).
Methyi 2-bromo-3-cyciohexyi-1-methyl-6-indole carboxylate:
The 1-methylindole derivative from above (136.40 g, 0.503 mole) was charged into a 5 L three-necked flask equipped with a mechanical stirrer and purged with nitrogen . gas. CHCl; (750 mL) and THF (750 mL) were added and the solution was cooled to 0 °C. Pyridine tribromide (pyridinium bromide perbromide, 185.13 g, 0.579 mole, . 1.15 equivalent) was added in small portions and the mixture was stirred for 1 hat 0 °C. The solvent was removed under reduced pressure at room temperature and the residue dissolved in EtOAc (3 L). The solution was washed with water and brine, dried (decolourising charcoal / MgSO.) and concentrated under reduced pressure.
®
The residue was suspended in TBME and heated to 50 °C. The suspension was : stored overnight in the refrigerator and the cream-coloured crystalline product was collected by filtration. It was washed with TBME and dried in vacuum (134.3 g, 76% o yield).
EXAMPLE 5:
Cyclohexyi-methyi-tributylstannanyl-1H-indole-6-carboxylic acid methyl ester:
Me
N COOMe
Bu,Sn \ . 37
The bromoindole derivative of example 4 (2.70 g, 7.71 mmol) was dissolved in dry
THF (40 mL) and the solution was cooled to —78 °C under an argon atmosphere. A solution of nBulLi in hexane (1.4 M, 6.90 mL, 9.64 mmol, 1.25 equivalent) was added dropwise over 15 min and stirring at low temperature was continued for 75 min. To the resulting suspension was added nBu;SnCl (2.93 mL, 10.8 mmol, 1.4 equivalent) over 5 min. The suspension dissolved and the solution was stirred for 1 h at —=78 °C.
The reaction mixture was warmed to room temperature and THF removed under reduced pressure. The residue was dissolved in TBME (150 mL), washed with 1:1 brine — water and dried over MgSQ,. The material was purified by chromatography on silica gel that was previously deactivated by mixing with a solution of 5% Ei;N in hexane. The same solvent was used as eluent for the chromatography. The title stannane was isolated as a yellow oil (3.42 g, 79 % yield).
EXAMPLE 6:
General procedure for Stille cross-coupling of the 2-stannane indole of . ~ 25 example 5 with aromatic/heteroaromatic halides:
Cross-coupling of aromatic/heteroaromatic halides or pseudohalides (preferably - bromides, iodides and triflates) with the stannane derivative of example 5 can be performed using any variations of the standard metal-catalyzed Stille cross-coupling reaction as described in the literature. The following example serves to illustrate such a process.
> 3-Cyclohexyl-1~-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid methyl ester: ‘ | \ — N COOMe /
EAC
The stannane derivative of example 5 (3.42 g, 6.1 mmol) was dissolved in DMF (10 mL) and Cul (0.116 g, 0.61 mmol, 0.1 equivalent), LiCl (0.517 g, 12.21 mmol, 2 @® equivalent), triphenylphosphine (0.320 g, 1.22 mmol, 0.2 equivalent) and 2- bromopyridine (0.757 mL, 7.94 mmol, 1.3 equivalent) were added. The solution was degassed with a stream of argon (30 min) and Pd(PPhg), (0.352 g, 0.31 mmol, 0.05 equivalent) was added. After purging with argon for an additional 10 min, the solution was heated and stirred at 100 °C overnight under argon. The DMF was then removed under vacuum and the residue dissolved in EtOAc (150 mL). The solution was washed with TN NaOH (25 mL) and brine (25 mL) and dried over
MgSO, The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with CHCl; then 5-10% EtOAc in CHCl; (1.516 g, 71% yield).
EXAMPLE 7:
General procedure for Stille cross-coupling of 2-bromoindoles with aryl or heteroarylstannanes: 3-Cyclohexyl-1-methyl-2-pyridin-2-yi-1H-indole-6-carboxylic acid methyl ester: » COOMe \ COOMe
A Br PACL(PPhy), [| \ (] THF / reflux
The 2-bromoindole derivative of example 4 (0.150 g, 0.428 mmol) and 2- trimethylstannyithiophene (S.F. Thames et al. J. Organometal. Chem. 1972, 38, 29; 0.150 g, 0.61 mmol, 1.4 equivalent) were dissolved in dry THF (7 mL) in a sealed
® tube, and the solution was degassed with a stream or argon for 30 min. - Pd(Cl),(PPh3), (0.018 g, 0.026 mmol, 0.06 equivalent was added and the tube sealed. The solution was heated to 80 °C for 40 h. The reaction mixture was cooled " to room temperature, EtOAc (10 mL) was added and the suspension filtered. After evaporation of the solvent, the residue was re-submitted to the reaction conditions for an additional 20 h, with fresh 2-stannylthiophene (0.150 g, 0.61 mmol) and catalyst (0.020 g). After cooling to room temperature and filtration of solids, the solvent was evaporated and the residue purified by flash chromatography using 15- 100% CHCl; in hexane as eluent (0.133 g, 88% yield).
The same procedure can be used to couple stannane derivatives to the 2- ® bromoindole of Example 2.
EXAMPLE 8:
General procedure for the N-alkylation of 2-aryl and 2-heteroaryl-6-indole carboxylates: 3-Cyclohexyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid methyl ester: \ _ N COOMe
RAS
NaH (60% oil dispersion, 0.186 g, 4.64 mmol, 1.5 equivalent) was washed with hexane (20 mL) to remove the oil and then re-suspended in DMF (5 mL). After cooling to 0 °C in an ice bath, the indole derivative of example 3 (1.000 g, 3.09 mmol) was added dropwise as a solution in DMF (3 mL + 2 mL rinse). After stirring for 15 min, iodomethane (0.385 mL, 6.18 mmol, 2 equivalents) was added in one portion and the mixture was stirred for 2 h in the cold and an additional 2 h at room temperature. The reaction was then quenched by addition of 1N HCl (1 mL) and : diluted with TBME (100 mL). The solution was washed with 1N HCI (25 mL) and dried (MgSO,). After removal of volatiles under reduced pressure, the residue was ’ purified by flash chromatography using 5-10% EtOAc in hexane as eluent to give the title compound as a white solid (0.903 g, 86% Yield).
Other N-alkylindole derivatives within the scope of this invention could be prepared from the appropriate electrophiles (e.g. Etl, iPtl, iBul, BnBr) using a similar procedure.
EXAMPLE 9: * General procedure for the saponification of 6-indolecarboxylates to the corresponding free carboxylic acids:
This procedure applies to both indole and N-methylindole carboxylates. 3-Cyclohexyi-1-methyi-2-pyridin-2-yi-1H-indole-6-carboxylic acid: \ COOH 7 N\ 4 ® =N oo
The 6-indole carboxylate of example 6 (1.517 g, 4.35 mmol) was dissolved in DMSO (8 mL) and 5N NaOH (4.4 mL) was added. The mixture was stirred at 50 °C for 30 min. The solution was then cooled to room temperature and added dropwise to water (15 mL). Insoluble black impurities were removed by filtration and AcOH (2 mL) was added dropwise to the filtrate. The white precipitate that formed was collected by filtration, washed with water and dried (1.37 g, 94% yield).
ExamPLE 10: 1-Cyclohexyl-2-phenyl-1H-indole-5-carboxylic acid:
NH NHAc : Ho I = pp COOEt
EO
2. AcCl/ pyr PACL,(PPh,), / Cul N
COOEt COOE? 1. H,/ OH - CsOH.R,0 asso 20% Pd(OH), OY — —_—
Br N 2. NaOH N 8 _
Ethyl! 4-amino-3-iodobenzoate:
®
Ethyl 4-aminobenzoaie (15.00 g, 91 mmol) and iodine (11.80 g, 46.5 mmol) were ’ mixed with water (80 mL) and chlorobenzene (4.60 g, 41 mmol). The mixture was stirred while the temperature was gradually raised to 90 °C over 30 min. Hydrogen : peroxide (30%, 50 mL) was added over 10 h at 90 °C. After stirring at that temperature for an additional 6 h, the mixture was cooled and the solution decanted from the residual solids. The solids were dissolved in DCM and the solution washed successively with sodium thiosulfate and brine. After drying (MgSQO,), the solvent was removed under reduced pressure and the resulting brown solid was triturated with hexane to remove di-iodinated by-products. The desired compound was obtained as a brown solid (22.85 g, 86% yield). ® Ethyl 4-acetamido-3-iodobenzoate:
The aniline from above (1.00 g, 3.44 mmol) was dissolved in pyridine (5 mL) and the solution was cooled inice. AcCl (0.32 mL, 4.47 mmol, 1.3 equivalent) was added dropwise and the mixture was stirred for 1 h at 0 °C and 2 h at room temperature.
The reaction mixture was then diluted with 1 N HCI and the product was extracted with TBME (100 mL). The organic phase was washed with 1N HCI (50 mL), dried (MgS0O,) and concentrated to give the desired material as a tan-colored solid (1.121 g, 97% yield).
Ethyl 2-phenyl-indole-5-carboxylate:
Following the procedure of A. Bedeschi et al. (Tet. Leit. 1997, 38, 2307), the acetanilide derivative from above (0.900 g, 2.7 mmol) was reacted with phenylacetylene (0.385 mL, 3.5 mmol, 1.3 equivalent) in the presence of PdCl,(PPhg), (10 mole %) and Cul (10 mole %) in a mixture of dioxane (5 mL) and tetramethylguanidine (5 mL). The desired 2-phenylindole (0.589 g, 82% yield) was isolated as a yellow solid after flash chromatography with 15% EtOAc in hexane. 1-Cyclohex-1-enyl-2-phenyl-1H-indole-5-carboxylic acid ethyl ester: ’ The 2-phenylindole derivative from above (0.265 g, 1.0 mmol) was dissolved in DMF (2 mL) and cesium hydroxide monohydrate (0.208 g, 1.2 mmol, 1.2 equivalent) was - added. The solution was cooled in an ice bath and 3-bromocyclohexene (0.193 g, 1.2 mmol, 1.2 equivalent) was added dropwise (5 min) as a solution in DMF (1 mL).
The mixture was stirred for 30 min at 0 °C. The reaction was diluted with water (25 mL), extracted with EtO (2 x 50 mL) and the extract dried over MgSQ,. The solvent
® was evaporated under reduced pressure to give a white foam (0.095 g) that was + used without purification in the next step. 8 1-Cyclohexyl-2-phenyi-1H-indole-5-carboxylic acid:
The crude indole from above was hydrogenated in the usual way (1 atm H, gas) in
EtOH over 20% Pd(OH), on carbon for 20 h at room temperature. After filtration of the catalyst, the EtOH was removed under reduced pressure.
The residue was dissolved in a mixture of MeOH (1 mL) and DMSO (1 mL) and 5N
NaOH (0.5 mL) was added. The mixture was stirred overnight at 50 °C. The reaction mixture was cooled and water (10 mL) was added. After acidification with
IN HCI, the product was extracted into Et,O (70 mL) and the solution dried ® (Na;S0,). Evaporation of the solvent gave a green residue consisting of a 2:1 mixture (85 mg) of the desired 1-cyclohexyl-2-phenylindole-5-carboxylic acid and 1 3-dicyclohexyl-2-phenylindole-5-carboxylic acid.
EXAMPLE 11: 1-Cyclohexyl-3-methyl-2-phenyl-1H-indole-5-carboxylic acid:
NH, @
Cr —== pn wo pp -— +
Pd(OAc), / PPh, N 7 ®
Coogt LiCI/K,CO, N
CSOH.H,0 OY jd PA(OH), coon
Ethyl 2-phenyl-3-methyl-indole-5-carboxylate:
Adapting the procedure of H.-C. Zhang (Tet. Lett. 1997, 38, 2439) ethyl 4-amino-3- . 20 iodobenzoate (from example 10, 0.500 g, 1.72 mmol) was dissolved in DMF (5 mL) and LiCl (0.073 g, 1.72 mmol, 1 equivalent), PPh; (0.090 g, 0.34 mmol, 0.2 equivalent), KoCO; (1.188 g, 8.6 mmol, 5 equivalents) and phenylpropyne (0.645 mL, 5.76 mmol, 3 equivalents) were added. The solution was degassed by purging with argon for 1 h and palladium acetate (0.039 g, 0.17 mmol, 0.1 equivalent) was added.
The mixture was stirred at 80 °C under argon for 20 h. The reaction mixture was
® diluted with water (25 mL) and extracted with EtOAc (50 mL). The extract was ’ washed with brine (3 x 25 mL) and dried (MgSQO,). Concentration under reduced : pressure and purification by flash chromatography with 10-15% EtOAc — hexane ’ gave the desired 2-phenyl-3-methyl indole (0.275 g, least polar component) and the 3-phenyl-2-methyl isomer (0.109 g, more polar component).
Ethyl 1-(3-cyclohexenyl)-3-methyl-2-phenylindole-5-carboxylate:
The less polar isomer from above (0.264 g, 0.95 mmol) was dissolved in DMSO (2 mL) and cesium hydroxide monohydrate (0.191 g, 1.14 mmol, 1.2 equivalent) was added followed by 3-bromocyclohexene (0.183 g, 1.14 mmol, 1.2 equivalent in 0.7 mL of DMSO). The mixture was stirred at room temperature for 30 min. Additional ® CsOH monohydrate (0.400 g, 2.4 equivalents) and 3-bromocyclohexene (0.400 g, 2.4 equivalents) were added and stirring continued for an additional 30 min. Similar amounts of the two reagents were again added and after another 30 min of stirring at room temperature, the reaction was diluted with 1N HCI (6 mL) and water (20 mL).
The product was extracted with TBME (100 mL), dried (MgSO,) and after concentration under reduced pressure, the residue was purified by flash chromatography using 5-10% EtOAc in hexane as eluent. The desired N-alkylated indole was obtained (0.130 g).
Ethyl 1-cyclohexyl-3-methyl-2-phenylindole-5-carboxylate:
The unsaturated product from above was hydrogenated (1 atm H, gas) in the usual way over 20% Pd(OH), in EtOH at room temperature for 3 h. o 1-Cyclohexyi-3-methyl-2-phenyl-1H-indole-5-carboxylic acid: :
The hydrogenated material from above was dissolved in a mixture of DMSO (2 mL) and MeOH (2 mL). 5N NaOH (0.5 mL) was added and the mixture was stirred overnight at 60 °C. After dilution with water (40 mL), the product aqueous phase was washed with a 1:1 mixture of Et,O — hexane (50 mL) and then acidified with IN ~~ . HCl to pH 1. The liberated free acid was extracted with diethyl ether (2 x 50 mL) and the exiract dried over Na,SO,. Removal of the solvent under reduced pressure gave . the desired indole as a light brown solid (0.074 g).
EXAMPLE 12: 2-Bromo-3-cyclopentyl-1-methy!-1H-indole-6-carboxylic acid methyl ester:
LJ
N COOH i COOH boy or be ©, " COOMe Me hed N COOMe —_— —_— Br rt I
A 3 L three-necked flask equipped with a mechanical stirrer was charged with indole 6-carboxylic acid (220 g, 1.365 mole) and KOH pellets (764.45 g, 13.65 mole, 10 equivalents). Water (660 mL) and MeOH (660 mL) were added and the mixture heated to 75 °C. Cyclopentanone (603.7 mL, 6.825 mole, 5 equivalents) was added ® dropwise over 18 h using a pump. The reaction mixture was heated for an additional 3 h (after which the reaction was judged complete by HPLC) and cooled to 0 °C for 1 h. The precipitated potassium salt is collected by filtration, and washed with TBME (2 X 500 mL) to remove cyclopentanone self-condensation products. The brown solid was re-dissolved in water (2.5 L) and the solution washed with TBME (2 X 1 L). ~ Following acidification to pH 3 with conc. HCI (425 mL), the beige precipitate was collected by filtration, washed with water (2 X 1 L) and dried under vacuum at 70 °C.
The crude product weighed 275.9 g (88.9 % mass recovery) and had an homogeneity of 85% (HPLC). 15 .
The crude product from above (159.56 g, 0.70 mole) was dissolved in MeOH (750 mL) and 20% Pd(OH). on charcoal (8.00 g) was added. The mixture was hydrogenated in a Parr apparatus under 50 psi hydrogen gas for 18 h. After completion, the catalyst was removed by filtration through celite and the solvent removed under reduced pressure. The resulting brown solid was dried at 70 °C under vacuum for 12 h. The crude product (153.2 g) was obtained as a brown solid and was 77% homogeneous by HPLC. ’ The crude 3-cyciopentylindole-6-carboxylic acid (74.00 g, 0.323 mole) was charged ina 3 L three-necked flask equipped with a mechanical stirrer and a thermometer. ) The system was purged with nitrogen gas and anhydrous DMF (740 mL) was added.
After dissolution on the starting material, anhydrous potassium carbonate (66.91 g, 0.484 mole, 1.5 equivalent) was added and the mixture stirred for 5 minutes. lodomethane (50 mL, 0.807 mole, 2.5 equivalents) was added and the mixture
® 106 stirred for 5 h after which HPLC analysis of the reaction mixture indicated 97% . conversion to the methyl ester.
The reaction mixture was cooled in an ice bath and sodium hydride (95%, oil-free, 10.10 g, 0.420 mole, 1.3 equivalent) was added in small portions over 3 min . 5 (exothermic: 8 °C to 30 °C internal temperature raise). After stirring for an additional 15 min, the cooling bath was removed and stirring continued for 1.5 h at room temperature after which no further progression was observed (HPLC). Additional
NaH (1.55 g, 65 mmol, 0.2 equivalent) and iodomethane (1.0 mL, 16 mmol, 0.05 equivalent) were added and after stirring for 15 min, the reaction was judged complete by HPLC (96% N-methylated).
The reaction mixture was slowly (2 min) poured into water (4 L) with vigorous stirring ® and after 10 min, acidified to pH <2 with conc. HCI (85 mL). The mixture was stirred for 5 min to allow complete conversion of any remaining potassium carbonate and bicarbonate to the more soluble chloride. The pH was adjusted to ~7 with 4N NaOH (40 mL) and the mixture stirred overnight at room temperature. The precipitated material was collected by filtration, washed with water (600 mL) and dried at 60 °C under vacuum. The crude product (79% homogeneity by HPLC) was obtained as a brown solid (72.9 g).
The crude material from above is triturated with a minimal amount of MeOH to remove a series of minor impurities. The solid was then collected by filtration and dissolved in a minimal amount of hot EtOAc. After cooling to room temperature, hexane was added (5 X volume) and the mixture cooled in ice and filtered. The , filtrate was then evaporated to dryness to give the desired product.
The N-methylindole from above (10.60 g, 41.2 mmol) was dissolved in isopropy! acetate (150 mL) and sodium acetate (5.07 g, 62 mmol, 1.5 equivalent) was added.
The suspension was cooled in an ice bath and bromine (2.217 mL, 43.3 mmol, 1.05 equivalent) was added dropwise over 2 min. The pale amber suspension turned dark red (exotherm from 5 °C to 13 °C). It was stirred for 1 h at 0 °C. The reaction . 30 was completed by adding additional bromine (0.21 mL, 4.2 mmol, 0.10 equivalent) as shown by HPLC analysis. The reaction was then quenched by addition of 10% - aqueous sodium sulfite solution (15 mL), followed by water (50 mL) and K.CO; (10.6 g, 1.8 equivalent) to neutralize HBr. The organic layer was separated, washed with 10% aqueous sodium sulfite and aqueous K,COj; and dried (MgSO). The solvent was removed under reduced pressure and the residue co-evaporated with TBME (75
® mL) to give a beige solid that was dried under vacuum overnight (13.80 g). The - crude material was triturated with boiling MeOH (80 mL) for 30 min, cooled in ice and the beige solid collected by filtration. The product was dried at 60 °C under vacuum - (10.53 g, 76% recovery).
EXAMPLE 13 3-Cyclopentyl-1 -methyl-2-vinyl-1H-indole-6-carboxylic acid: \ 0 \ o \ lo}
N 0” NN o” \_N OH pid hi of @
To the 2-bromoindole derivative of example 12 (2.044 g, 6.08 mmol) in dry dioxane (20 mL) was added vinyltributyltin (1.954 mL, 6.69 mmol). The solution was degassed by bubbling nitrogen for 15 min. Then bis(triphenylphosphine) palladium (I) chloride (213.4 mg, 0.304 mmol) was added and the reaction mixture was heated at 100 °C overnight. The reaction mixture was diluted with ether and successively washed with water and brine. After the usual treatment (MgSO, filtration and concentration) the residue was flash chromatographed (5 cm, 10% AcOEt-hexane) to afford the desired compound (1.32 g, 4.70 mmol, 77 % yield) as a white solid.
To the ester from above (153 mg, 0.54 mmol) in a mixture of THF (2.8 mL) and methanol (1.4 mL) was added an aqueous solution of lithium hydroxide (226.6 mg, 5.40 mmol in 1.6 mL of water). The reaction mixture was stirred at 50 °C for 1.5 h and diluted with water. The aqueous layer was acidified with 1M ag. HCl and extracted three times with CH,Cl,. The combined organic layers were successively washed with water (2X) and brine. After the usual treatment (MgSQ,, filtration and concentration) the desired crude acid was isolated (150 mg).
EXAMPLE 14 » 3-Cyclohexyl-1-methyl-2-oxazol-5-yl-1H-indole-6-carboxylic acid:
® \ [0] \ [0] \ [o]
N oo” NN 0” HO N 0” “ \ ol \ lo] \ 0} oO, MN oo . 0” NAN OH
To the bromide of example 4 (1.00 g, 2.855 mmol) in dry dioxane (10 mL) was added vinyltributyltin (917.8 pL, 3.141 mmol). The solution was degassed by bubbling nitrogen through for 15 min. Then bis(triphenylphosphine) palladium (il) chloride [ (101 mg, 0.144 mmol) was added and the solution was refluxed for 7 hrs. The reaction mixture was diluted with ether and successively washed with water and brine. After the usual treatment (MgSO, filtration and concentration) the residue was flash chromatographed (5 cm, hexane to 2.5% AcOEt to 5% AcOEt to 10% AcOEi- hexane) to afford the desired compound (773 mg, 2.60 mmol, 91 % yield) as a pale yellow solid.
To the olefinic derivative from above (100 mg, 0.336 mmol) in a mixture of acetone (690 pL), tert-butanol (690 pL) and water (690 pL) were successively added N- methylmorpholine N-oxide (NMMO; 48 mg, 0.410 mmol) and a 2.5 % solution of osmium tetroxide in tert-butanol (33 yL). The reaction mixture was stirred at room temperature for three days and then concentrated. The residue was dissolved in
EtOAc and successively washed with water (2X) and brine. After the usual treatment (MgSQ,, filtration and concentration) the crude diol (117 mg) was isolated.
To the crude diol obtained above (ca. 0.336 mmol) in a mixture of THF (3.2 mL) and water (3.2 mL) at 0 °C was added sodium periodate (86.2 mg, 0.403 mmol). The cooling bath was then removed and the reaction mixture was stirred at room i temperature for 1h 45 min, AcOEt was then added. The resulting solution was successively washed with 10% aq. citric acid, water, satd aq. NaHCOj3, water (2X) . and brine. After the usual treatment (MgSO, filtration and concentration) the crude desired aldehyde was isolated (92 mg, 0.307 mmol, 91 % yield).
A mixture of the aldehyde from above (25.8 mg, 0.086 mmol), anhydrous potassium
® 109 carbonate (12.4 mg, 0.090 mmol) and Tosmic (17.57 mg, 0.090 mmol) in absolute ‘ MeOH (500 ul) was refluxed for 2 h. AcOEt was then added and the mixture was successively washed with water (2X) and brine. After the usual treatment (MgSO,,
B filtration and concentration) the crude desired oxazole was isolated (28 mg, 0.083 mmol, 96 % yield).
To the ester from above (28 mg, 0.083 mmol) in a mixture of THF (425 pL), MeOH (210 pL) and water (250 pL) was added lithium hydroxide (34.8 mg, 0.830 mmol).
The reaction mixture was stirred overnight at room temperature, then diluted with water and acidified with a 1N aq. HCI solution. The aqueous layer was extracted with dichloromethane (3X) and successively washed with water (2X) and brine. After the o usual treatment (MgSO, filtration and concentration) the title crude acid was isolated (30 mg).
EXAMPLE 15 : 2-(1 H-Benzimidazol-2-yl)-3-cyclohexyl-1-meth yl-1H-indole-6-carboxylic acid: 0 ht Nadir ve padi’ Shandeds od
To a mixture of the aldehyde from example 14 (28 mg, 0.094 mmol) and 1 2- diaminobenzene (10.9 mg, 0.101 mmol) in acetonitrile (500 pL) and DMF (200 pL) was added chloranil (24.8 mg, 0.101 mmol). The reaction mixture was stirred at room temperature for three days. AcOEt was added and the reaction mixture was successively washed with a 1N ag. NaOH solution (2X), water (4X) and brine. After the usual treatment (MgSO, filtration and concentration) the residue was flash chromatographed (1 cm, 30% AcOEt-hexane) to afford the desired benzimidazole ester derivative (11 mg, 0.028 mmol, 30 % yield). - To the ester from above (11 mg, 0.028 mmol) in a mixture of THF (240 pL), MeOH (120 pL) and water (140 pL) was added lithium hydroxide (11.7 mg, 0.280 mmol). . The reaction mixture was stirred overnight at room temperature, then diluted with water and acidified with a 1N ag. HCI solution. The aqueous layer was extracted with dichloromethane (3X) and successively washed with water (2X) and brine. After the usual treatment (MgSO, filtration and concentration) the title crude acid was isolated
(9 mg, 0.0241 mmol, 86 % yield).
EXAMPLE 16 " 3-Cyclopentyl-1-methyl-1H-indole-2,6-dicarboxylic acid 6-methyl ester: [o] o]
Q \ \ \ N 0” Q, N 0” \ - \
HO
To the 3-cyclopenty! aldehyde prepared in a similar fashion to that described in ) example 15 (20 mg. 0.07 mmol) and 2-methyl-2-butene (541 pL, 5.11 mmol) in tert- butanol (500 pL) at 0 °C was added a freshly prepared solution of sodium chiorite (64.2 mg, 0.711 mmol) in phosphate buffer (98 mg of NaH,PO, in 150 pL of water).
The reaction mixture was stirred for 45 min. at room temperature then brine was added. The aqueous layer was extracted twice with EtOAc. The combined organic layer was successively washed with a 0.5 N ag. HCI solution and brine. After the usual treatment (MgSQ,, filtration and concentration) 23.1 mg of the desired crude acid were isolated as a yellow solid.
EXAMPLE 17 2-Bromo-3-cyclopentyi-benzofuran-6-carbonitrile: fo fo
BrCH,COOEt
Br OH Br OH NaH Br 0 \ coo: [o}
NaOH ro NaOAc CuCN
Br [0] Ac,O N “coor Br ©
NBS-DMF - NT Nar
NC ) NC o . To a solution of 3-bromophenol (10 g, 57.8 mmol) in 1,2-dichloroethane (50 mL) was added AICI; (11.5 g, 86.2 mmol), cautiously, in two equal portions at room temperature. Cyclopentanecarbonyl chioride (7.7 g, 58.1 mmol) was then added dropwise via syringe at room temperature. The reaction solution was then heated to
® reflux under N, for a period of 2 hours. The reaction solution was cooled to room : temperature and carefully poured into 100 mi of 1N HCI ice slush. After a few minutes of gentle stirring, the phases were separated and the aqueous phase was * extracted with 1,2-dichloroethane. The organic phases were combined and washed with water and brine and dried over MgSQO,. The solvent was removed under reduced pressure and the residue was purified ona pad of silica gel by hexanes. 17.2 g (78%) of the product was collected as a yellow liquid / low melting solid.
To a solution of the above phenol (12.2 g, 45.3 mmol) in 80 mL DMF at 0°C was added 60% NaH (2.67 g, 66.7 mmol). The ice bath was removed and the reaction solution was allowed to stir for 30 minutes. Ethyl Bromoacetate (11.4 g, 68.3 mmol) : was then added dropwise via syringe. A mild exotherm (~40 °C) was observed, and ® the reaction solution was allowed to stir at room temperature for 1 hour. The C. reaction mixture was carefully poured into 150 ml of ice water, then acidified to pH 4- 5 with IN HCI. The reaction mixture was then extracted with EtOAc. The phases were separated and the organic fraction was washed with saturated NaHCO, water and brine, then dried over MgSO,. The solvent was removed under reduced : pressure. The crude material was taken to next step as is and treated as theoretical in yield. 16.1 g (45.3 mmol) of the above crude ester was combined with 61 mL of 1N NaOH and 137 mL of THF and stirred at room temperature overnight (additional 1N NaOH may be added if starting material persists.) Upon hydrolysis the THF was stripped off and the agueous phase was extracted with EtOAc, which was discarded. The aqueous phase was then acidified to pH 2-3 with 1N HCI and extracted with EtOAc.
The phases were separated and the organic phase was washed with water and brine, then dried over MgSO,. The solvent was removed under reduced pressure.
The crude material was taken to the next step as is and treated as theoretical in yield. 13.3 g (40.7 mmol) of the crude acid from above was dissolved in 200 mL AcO.
NaOAc (6.7 g, 81.7 mmol) was added and the resulting mixture was refluxed for 5 ; 30 hours under No. The heat was removed and the reaction mixture was allowed to cool to room temperature. The reaction solution was then diluted with 100 mL . toluene and neutralized with ice / 8N NaOH (STRONG EXOTHERM!). The phases : were separated and the aqueous phase was extracted with EtOAc. The organic fractions were combined and washed with water and brine, then dried over MgSO,.
The solvent was removed under reduced pressure and the residue was purified on a
° 112 pad of silica gel by petroleum ether. 7.8 g (72%) of product was collected as a clear ; liquid / low melting solid.
The bromobenzofuran from above (29.6 g, 111.6 mmol) was dissolved in 60 mL g DMF. CuCN (12.0 g, 134.0 mmol) was added and the resulting mixture was refluxed under N, for 7 hours. The heat was removed and the reaction mixture was allowed to cool to room temperature. The reaction solution was poured into 300 mL of 5% aqueous NaCN, and 200 mL of EtOAc was added. The resulting solution was stirred gently until all solids went into solution. The layers were separated and the aqueous fraction was extracted with EtOAc. The organic fractions were combined and washed with 5% aqueous NaCN, water and brine, then dried over MgSO,. The solvent was removed under reduced pressure. The crude brown solid was cleaned @ up on a pad of silica gel by 10% EtOAc / Hexanes, and then purified by recrystallization in hexanes.
A solution of N-bromosuccinimide (5.340 g, 30 mmol) in DMF (20 mL) was added dropwise to a solution of the above benzofuran derivative (2.00 g, 9.47 mmol) in
DMF (20 mL). The mixture was stirred overnight at room temperature after which the bromination was judged complete (HPLC). The reaction mixture was diluted with
EtOAc and washed successively with water (3 X) and brine. After drying (MgSO,), the solvent was removed under reduced pressure and the residue purified by flash chromatography using 3 % EtOAc in hexane to give the title 2-bromobenzofuran derivative as a white solid (1.45 g, 53 % vield).
EXAMPLE 18 : 3-Cyclopentyl-2-pyridin-2-yl-benzofuran-6-carboxylic acid: 0 CN = 0 CN — 0 COOH
The 2-bromobenzofuran derivative of example 17 (0.850 g, 2.93 mmol), 2-tri(n- butyl)stannylpyridine (1.362 g, 3.7 mmol), triphenylphosphine (0.760 g, 2.90 mmol), lithium chloride (0.250 g,.5.9 mmol) and Cul (0.057 g, 0.3 mmol) were dissolved in . DMF (30 mL) and the mixture was degassed by bubbling argon for 30 min. Tetrakis (triphenylphosphine)palladium (0.208 g, 0.18 mmol) was added and the mixture stirred at 100 °C under an argon atmosphere. After 19 h, the reaction was cooled to room temperature, poured into water (70 mL) and extracted with TBME. The organic
® phase was washed with water (2 X) and brine, dried (MgS0O,) and concentrated to . give a residue that was purified by flash chromatography. The desired 2(2- pyridyl)benzofuran derivative (0.536 g, 63 % yield) was obtained as a white solid. . The nitrile from above (0.200 g, 0.694 mmol) was suspended in a mixture of conc.
HoSO0, (5 mL), AcOH (4 mL) and water (2 mL). After refluxing for 1.5 h, TLC showed complete hydrolysis. The mixture was cooled in ice and the 10 N NaOH was added : .- dropwise to pH 9. The aqueous layer was washed with dichloromethane and then acidified to pH 6 with 5 N HCI. The product was extracted with EtOAc, dried (MgSO0,) and solvents removed under reduced pressure. The desired carboxylic acid was obtained as a white solid. ® EXAMPLE 19 2-Bromo-3-cyclopentyl-benzo[b]thiophene-6-carboxylic acid ethyl ester fo o 2 'DABCO 180-190 °C jens
Jeane eGEa LO Br 3 a ar i NaOH ro
KOH . jens EE JO - .
COOE! . COOH
AR - ol i Poe — C oe
Br Ss NG s NC §
EtOH ok “hso, S—pr
Et00C s
To a solution of 3-bromo-6-cyclopentanecarbonylphenol of Example 17 (5.194 g, 19.30 mmol) in DMF (58.0 mL) was added 1,4-diazabicyclo[2.2.2]octane (4.33 g, 38.60 mmol) and dimethyithiocarbamyl chloride (4.77 g, 38.6 mmol) at room ‘ temperature. The mixture was stirred at room temperature for 3 hr. The mixture was acidified with 1 N HCI to pH 3 and then extracted with EtOAc. The organic layers : were combined and washed with brine and dried over MgSO,. The crude mixture was purified through a plug of silica gel with 3%EtOAc/hexanes to provide 6.976 g (100%) of the desired thiocarbamate as a colorless oil.
The neat O-3-bromo-6-cyclopentanecarbonyl N,N-dimethylthiocarbamate from
® above (43.147 g, 121.1 mmol) was heated to internal temperature of 180-190 °C for : 5 hr. TLC (20% EtOAc/hexanes: R; 0.6 (starting material), 0.5 (product) was used to monitor the reaction progress. The crude material was used for the next reaction . without further purification. :
The crude S-3-bromo-6-cyclopentanecarbonyl N,N-dimethylthiocarbamate from above was dissolved in MeOH (600 mL), KOH (40.0 g, 714 mmol) was added and the mixture was heated to reflux for 1.5 h. The mixture was cooled to room temperature and the solvent was removed by rotary evaporation. The residue was dissolved in water and acidified by 6 N HCI to pH 3. It was extracted with EtOAc and the crude product was purified by a silica gel chromatography with 1-5% :
EtOAc/hexanes. 31.3 g (91%) of the desired thiophenol derivative was obtained as a ® yellow oil.
To a solution of the 3-bromo-6-cyclopentanecarbonylthiophenol from above (0.314 g, 1.105 mmol) in acetone (5.0 mL) was added KoCO3 (0.477 g, 3.45 mmol) followed by addition of ethyl bromoacetate (0.221 g, 0.147 mL, 1.33 mmol). The mixture was stirred overnight. The reaction mixture was filtered through filter paper and the filtrate was concentrated. Purification by silica gel with 5% EtOAc/hexanes provided 0.334 g (82%) of the product as a colorless oil. :
The crude ester from above was dissolved in THF (12.0 mL), 1 N NaOH (5.0 mL) was added at room temperature. The mixture was stirred at room temperature for 2- 3 hr, or until TLC indicated complete reaction. The solvent was removed by rotary evaporation. Water was added and the mixture was acidified with 6 N HCI to pH 3 and extracted with EtOAc, washed with brine and dried over MgSO,. The solvent was removed under reduced pressure and the residue was used without further purification.
To the crude acid from above was added acetic anhydride (16.0 mL), and then
NaOAc (0.573 g) and the mixture was heated to reflux overnight. The mixture was cooled to room temperature and poured into a mixture of ice and toluene. 6 N NaOH was added until pH to about 7, and extracted with EtOAc, washed with brine and dried over MgSO,. The solvent was removed by rotary evaporation and the residue was purified by silica gel with hexanes to provide 0.795 g (80%) of 6-bromo-3-
R cyclopentyl benzothiophene as a colorless oil.
A mixture of the 6-bromo-3-cyclopentylbenzothiophene from above (0.723 g, 2.57 mmol), and copper cyanide (0.272 g, 3.04 mmol) in DMF (1.4 mL) was heated to reflux overnight. The mixture was cooled to room temperature and diluted with
° 115
EtOAc. 2N NH,OH was added and the mixture was stirred for 10 minutes and : filtered through Celite. The aqueous layer was extracted with EtOAc. The organic layers were combined and washed with brine, dried over MgSQO,, and the solvent ‘ was removed under reduced pressure. The product was used without further purification. 3-cyclopentyl-6-cyanobenzothiophene (17.65 g, 77.65 mmol) was dissolved in acetic acid (310 mL), bromine (49.64 g, 310.6 mmol) was added at room temperature. The mixture was stirred at room temperature overnight and HPLC was used to monitor the reaction progress. After the reaction was complete, toluene was added to the reaction mixture to remove acetic acid (3 x 100 mL). The crude product was dried under reduced pressure and used without further purification. ® The crude cyano derivative from above was added to ethanol (150 mL, denatured) and conc. H.SO, (45 mL) and the mixture heated to reflux for 1-2 days. After : completion (HPLC) the reaction mixture was cooled to room temperature and poured. into ice-water and extracted with dichloromethane (5 x 100 mL), the organic layers were combined and washed with 5% NaHCO;, and brine. The solvent was removed under reduced pressure and the residue was purified with silica gel by 1%
EtOAc/hexanes. The collected fractions were concentrated and the residue was slurried in methanol. The solid was filtered and washed with ice-cold methanol to provide 15.9 g (58%, two steps) of pure ethyl ester as a slight yellow solid.
EXAMPLE 20 : 3-Cyclopentyl-2-pyridin-2-yl-benzo[b]thiophene-6-carboxylic acid: s COOE! = 5 COOEt — s COOH
The 2-bromobenzothiophene of example 19 (0.354 g, 1.00 mmol), 2-tri(n- butyl)stannylpyridine (0.442 g, 1.2 mmol), triphenylphosphine (0.262 g, 1.00 mmol), lithium chloride (0.085 g, 2.0 mmol) and Cul (0.019 g, 0.1 mmol) were dissolved in
DMF (10 mL) and the mixture was degassed by bubbling argon for 30 min. Tetrakis (triphenylphosphine)palladium (0.069 g, 0.06 mmol) was added and the mixture stirred at 100 °C under an argon atmosphere. After 24 h, the reaction was cooled to room temperature, poured into water (70 mL) and extracted with TBME. The organic phase was washed with water (2 X) and brine, dried (MgSO,) and concentrated to give a residue that was purified by flash chromatography. The desired 2(2- : pyridyl)benzothiophene ester (0.197 g, 56 % yield) was obtained as a pale yellow waxy solid. : The ester from above was hydrolyzed in the usual manner using NaOH, to give the title acid that could be used directly or purified by HPLC and flash chromatography.
The acid could be coupled to amine derivatives following the general procedure described in example 37.
EXAMPLE 21 3-Cyclopentyl-2-furan-3-yl-benzofb]thiophene-6-carboxylic acid:
Ss COOEt — Ss COOEt _ s COOH
The 2-bromobenzothiophene ester of example 19 was coupled to 3-furanboronic acid as described in example 3 to give the desired 2(3-furyl)benzothiophene ester in 85 % vield. Saponification of the ethyl ester was carried out with NaOH at room temperature to give the title carboxylic acid derivative.
EXAMPLE 22 3-Cyclohexyl-1-methyl-2-phenyi-1H-pyrrolo[2,3,b]pyridine-6-carboxylic acid: [+] ’ - ’ O Ron Ron i J LoS
HE VA H, NAS wersa Oo) Me CT)
CI NaOMe Pd{OH), NaH N \ \ \
Ne N._-CN N-._N._COOE! Pyr.Br, NN. _-COOEt
TMSCN had HC! hed —_— Rad
ENC EtOH \
LiCl/ Pd” / Na,CO, h MN ] COOE NaOH 4 4 | com a ug ) 7-Azaindole (15.00 g, .127 mole) was dissolved in MeOH (330 mL) and sodium methoxide (25% w/w in MeOH, 172 mL, 0.753 mole) and cyclohexanone (52.86 mL, 0.51 mole) were added. The mixture was refluxed for 60 h and then concentrated ) under reduced pressure. After cooling in ice-water, the reaction mixture was
® . acidified to pH 8 with 3N HCI and the precipitated solid was collected by filtration. : The product was washed with water, triturated with TBME-hexane and dried by azeotroping with toluene (19.8 g). ‘ The material from above (15.00 g, 75.65 mmol) was dissolved in a mixture of EtOH (130 mi) and THF (30 mL) and 20% Pd{OH), on carbon {1.30 g) was added. The mixture was hydrogenated under 1 atm of H, gas for 24 h, after which point additional catalyst (1.30 g) was added. After stirring under H, gas for an additional 16 h, the catalyst was removed by filtration and the solution evaporated under reduced pressure to give a residue that was triturated with TBME to give an amber solid (13.9 g).
The azaindole derivative from above (7.50 g, 37.45 mmol) was dissolved in DME ] (130 mL) and meta-chloroperbenzoic acid (12.943 g, 60.0 mmol) was added. After stirring for 2 h, volatiles were removed under reduced pressure and the residue suspended in water (100 mL). The mixture was basified to pH 10 by addition of saturated aqueous Na,CO; solution under vigorous stirring. The solid was then collected by filtration, washed with water and a small amount of TBME, and dried (7.90 g).
The crude N-oxide from above (4.00 g, 18.49 mmol) was dissolved in DMF (350 mL) and NaH (60% dispersion, 1.52 g, 38 mmol) was added in small portions over 5 min.
The mixture was stirred for 30 min and iodomethane (1.183 mL, 19 mmol) was added dropwise over 20 min to the suspension. After stirring for 3 h at room temperature, no more progress was measured by HPLC analysis. The reaction mixture was poured into water and extracted 3 times with EtOAc. The extract was washed with brine, dried (MgSO,) and evaporated to give an amber solid (3.65 g, 60% homogeneity by NMR) that was used immediately without purification.
The crude product from above (0.80 g, 3.47 mmol) was dissolved in MeCN (10 mL).
Triethylamine (1.13 mL, 8.1 mmol) was added followed by trimethylsilyl cyanide (2.13 mL, 16 mmol). The solution was then refluxed for 19 h. After cooling to room temperature, the reaction was quenched by slow addition of aqueous NaHCO; and the product extracted with EtOAc. The extract was washed with brine, dried (MgSQ,) and concentrated to a residue that was purified by flash chromatography on silica gel using 15% EtOAc-hexane (0.285 g).
The nitrile (0.300 g, 1.254 mmol) was suspended in EtOH (15 mL) and hydrogen chloride gas was bubbled through for 15 min to give a clear solution. The solution was then refluxed for 1.5 h until TLC showed complete conversion of starting
® 118 material. After cooling to room temperature, volatiles were removed under reduced : pressure and the residue was dissolved in EtOAc. The solution was washed with brine, dried (MgSQ,) and concentrated. The residue was purified by flash ’ chromatography on silica gel (15-20% EtOAc-hexane) to give the desired ethyl ester asapale yellow gum (0.227 g).
The ester from above (0.100 g, 0.35 mmol) was dissolved in THF (4 mL) and } pyridinium hydrobromide perbromide (0.200 g, 0.532 mmol) was added. The mixture was stirred at 65 °C in a sealed vial for 16 h (>80% conversion). The solution was evaporated and the residue taken up into EtOAc. The solution was washed with water and brine, dried (MgSO,) and concentrated. The crude material was purified by flash chromatography on silica gel (15% EtOAc-hexane). ® The bromide from above (0.100 g, 0.274 mmol), phenylboronic acid (0.049 g, 0.4 mmol) and lithium chloride (0.019 g, 0.45 mmol) were dissolved in a mixture of toluene (2 mL), EtOH (2 mL) and 1M Na,COj3 (0.43 mL). The mixture was degassed. by passing argon gas through the solution for 30 min, and tetrakistriphenylphosphine palladium (0.035 g, 0.03 mmol) was added. The mixture was refluxed for 18 h after which point more catalyst (0.035 g, 0.03 mmol) was added. After refluxing for an additional 2 h, the EtOH was removed under reduced pressure. The residue was dissolved in EtOAc and the solution washed with 10% aqueous HCI and brine, and dried (MgS0O,). Removal of volatiles under reduced pressure gave an orange gum that was purified by flash chromatography on silica gel using 20% EtOAc-hexane (0.105 g, crude).
The partially purified ester from above (0.100 g, 0.276 mmol) was dissolved in a mixture of THF (2 mL) and EtOH (2 mL). iN NaOH (2.8 mL) was added and the mixture stirred for 4 h at room temperature. Volatiles were removed under reduced pressure and the residue diluted with 10% aqueous HCI. The product was extracted with EtOAc (3 X), dried (MgSQ,), evaporated and purified by reversed-phase preparative HPLC to give the title compound. : 30 EXAMPLE 23:
General procedure for the preparation of aromatic amide derivatives from o- : monosubstituted N-Boc-amino acids:
® 7/8 . Is + HAO 1. TBTU/DIEA | A
BocHN™ “COOH 2 2. HCI - dioxane HN Q ) cm O
N-Boc protected a-monosubstituted amino acids were coupled to aromatic amine derivatives using standard amide bond coupling reagents. The N-Boc protecting group was then cleaved under acidic conditions and the appropriate amine derivatives were isolated as hydrochloride salts. The following procedure for coupling N-Boc-D-alanine to ethyl 4-aminocinnamate is representative: (R)-1-[4-((E)-2-Ethoxycarbonyl-vinyl)-phenylcarbamoyl]-ethyl-ammonium chloride: ® i H co” © ZCO0Et N-Boc-D-alanine (0.284 g, 1.5 mmol) was dissolved in DMSO (2 mL) and DIEA (1.04 ml, 6 mmol, 4 equivalents) was added. Ethyl 4-aminocinnamate (0.287 g, 1.5 mmol) was added followed by TBTU (0.578 g, 1.80 mmol) and the mixture was stirred for 24 h at room temperature. The reaction mixture was diluted with EtOAc (75 mL) and the solution washed with water (40 mL), 1N NaOH (3 x 25 mL), 1M
KHSO, (2 x 25 mL) and 5% NaHCO; (25 mL). The extract was dried (MgSO,) and concentrated to give the desired N-Boc-protected anilide as a yellow solid (0.411 g).
The material from above was stirred for 1 h with 4N HCl in dioxane (10 mL).
Removal of volatiles under reduced pressure and trituration of the residue with
TBME gave the title hydrochloride salt as a brown solid.
EXAMPLE 24: 4-(4-Amino-phenyl)-thiazole-2-carboxylic acid ethyl ester:
ON ethyl thioxamate bch . H,/Pd(OH), AN
COOEt COOEt 4’-Nitro-2-bromoacetophenone (6.100 g, 25 mmol) and ethyl thioxamate (3.460 g, 26 mmol) were dissolved in MeOH (20 mL) and the solution was refluxed for 1 h. After
® } . cooling to room temperature, the precipitated solid was collected by filtration, : washed with cold MeOH and dried under vacuum (5.15 g, 75% yield).
A suspension of the nitroester from above (2.50 g, 8.98 mmol) and 20% Pd(OH), on ’ carbon (200 mg) in 2:1 EtOH — THF (60 mL) was stirred for 3 h under 1 atm of hydrogen gas. The suspension was filtered to remove the catalyst and volatiles removed under reduced pressure to give the title compound as a reddish foam (2.05 g, 92% yield).
EXAMPLE 25: 4-(4-Ethoxycarbonyi-thiazol-2-yi)-phenyl-ammonium chloride:
HN Boc,0 BocHN 1)CHLI BocHN ¢ a, QQ, EE Ds, 1) PAPPhy), nN oo 4)HCI Na,CO, (210) ° SE . a Gi i. foc ) 2) Hl coe : Hn=( . Ts lemcong CT
NH, Tn, gy CUB: , p-Bromoaniline (13.0 g, 76 mmol) and Boc,O (19.8 g, 91 mmol) were dissolved in toluene (380 mL) and stirred at 70 °C for 15 h. The reaction mixture was cooled to
RT, evaporated to dryness, re-dissolved in EtOAc and washed with 0.1M HCI and brine. The organic solution was dried over anhydrous MgSO, evaporated to dryness and purified by flash column chromatography, using 5% to 10% EtOAc in hexane as the eluent, to obtain the Boc-protected aniline (23 g). The Boc-protected bromoaniline (10.7 g, 39.2 mmol) was dissolved in anhydrous THF (75 mL) in a flask equipped with an overhead stirrer. The solution was cooled to 0 °C and Mel. (1.2 M in Et,0, 33 mL, 39.2 mmol) was added drop wise while maintaining the internal temperature below 7 °C. The reaction mixture was stirred at 0 °C for 15 min and then cooled to —78 °C before N-BuLi (2.4 M in hexane, 17 mL, 39.2 mmol) was added drop wise, maintaining the internal temperature below —70 °C). The reaction ’ 25 mixture was stirred at —78 °C for 1h, B(OEt)s (17 mL, 98 mmol) was added drop wise (internal temperature < -65 °C) and stirring was continued for 45 min at-78°C and at 0 °C for 1 h. The reaction mixture was then treated with 5% aqueous HCI (~100 mL, to pH ~1) for 15 min and NaCl(s) was added to saturate the aqueous layer. The aqueous layer was extracted with 0.5 M NaOH (4 x 100 mL) and the combined
® aqueous layers were acidified with 5% HCI (150 mL, to pH ~1) and extracted with
EO (3 x 200 mL). The combined organic layers were dried over anhydrous MgSOy, filtered and concentrated to give the N-Boc carbamate of 4-aminophenylboronic acid as a solid (7.5 g). Thiourea (7.60 g, 100 mmol) and ethyl bromopyruvate (12.6 mL, 100 mmol) were mixed and heated to 100 °C for 45 min. After cooling of the reaction mixture, the solid obtained was triturated with acetone, filtered and recrystallized from EtOH to obtain the desired aminothiazole product (10.6 g, 40 mmol). The aminothiazole was then added slowly (over a period of 20 min) to a solution of tbutylnitrite (6.2 g, 60 mmol) and CuBr; (10.7 g, 48 mmol) in MeCN (160 mL) at 0°C. The reaction mixture - was allowed to warm-up to RT and to stirred for 2.5 h. The mixture was then added ® to an aqueous HCI solution (20%) and extracted with EO (2 x 400 mL). The organic layer was washed with aqueous HC! (10%), dried over anhydrous MgSO, and evaporated to dryness. The desired bromothiazole product was isolated in ~85% yield (4.3 g) after flash column chromatography using 15% EtOAc in hexane as the eluent.
To a de-gassed solution of the bromothiazole product (230 mg, 0.97 mmol), the boronic acid derivative from above (230 mg, 0.97 mmol) and aqueous Na,CO; (2M, 3 mL) in DME (3mL), a catalytic amount of Pd(PPhs), (56 mg, 0.049 mmol) was added and the reaction mixture was stirred at 80 °C under argon for 20 h. The reaction mixture was then cooled to RT, diluted with EtOAc and extracted with brine, aqueous NaHCOs (2 x) and brine. The organic layer was dried over anhydrous
MgSO, and concentrated to dryness. The carbamate-ester product was isolated after flash column chromatography using 20% to 30% EtOAc in hexane: 180 mg.
The aniline hydrochloride was isolated after removal of the Boc protecting group with 4N HCl in dioxane for 30 min.
EXAMPLE 26: 4-(2-Methoxycarbonyl-4-methyl-thiazol-5-yi)-phenyl-ammonium chloride:
® Br Br ] Br — or, NA H,S0, NL 1) n-Buli “NA
Nx TT Ny cuso, Nx NS : NH, NH,Br NaBr Br 2) COs) CO,CH,
NaNO,
Br DPAPPh),
EY . Ns Na,CO, (2M) 9 Oye coon
B(OH), Seon,” He \
To a solution of 2-amino-4-methylthiazole (7.90 g, 69 mmol) in ELO (70 mL) at 15 °C, Br, was added slowly over a period of 30 min while stirring vigorously. The solid material formed was filtered and recrystallized from EtOH. The crystalline product ® 5 was filtered and dried under vacuum to give the 5-bromo derivative as the HBr salt (10.3 g). This product was then dissolved in a solution of CuSO, (11.4 g) and NaBr (9.9 g) in H,0 (115 mL) and H,SO, (5M, 360 mL) was added at 0 °C. An aqueous solution of NaNO; (6.10 g in 20 mL of H,0) was then added drop wise to the reaction mixture over a period of 25 min, maintaining the temperature below 3°C. The reaction mixture was stirred at 3 °C for 20 min and then at RT for 1 h. The reaction mixture was diluted with brine (280 mL) and extracted with EO (3 x 300 mL). The ether layers were combined, washed with a saturated, aqueous solution of sodium thiosulfate to eliminate any unreacted Br,, dried over anhydrous MgSO, and filtered through a pad of silica gel (~200 mL). The solvent was evaporated and the desired product isolated by distillation (bp = 80-81 °C at 15mm Hg).
A solution of the dibromo intermediate (500 mg, 1.94 mmol) in hexane (5 mL) was added to a cooled solution (-70 °C) of n-BuLi (870 ul of 2.2M in hexane), diluted with 10 mL of hexane. The reaction was stirred at —70 °C for 1 h and then added to
COq(s). The mixture was partitioned between H,O and Et,0. The aqueous layer was acidified with 1N HCI (pH ~2) and extracted with EtOAc (2 x), dried over anhydrous
MgSO, filtered and evaporated to dryness. The residue was re-dissolved in MeOH /
DCM, treated with CH,N, (until the solution remained yellow) and evaporated to . dryness to give the desired 5-bromo-4-methylthiazole-2-carboxylate ester as a yellow solid (230 mg). Suzuki cross-coupling of this product with the N-Boc protected 4- . 25 aminophenylboronic acid, as previously described (example 25), gave the building block 5-(4-amino-phenyl)-4-methyl-thiazole-2-carboxylate methyl ester. This product was treated with 4N HCI in dioxane for 30 min to remove the Boc protecting group and obtain the desired compound.
EXAMPLE 27: (E)-3-(4-Amino-phenyl)-2-methyl-acrylic acid methyl ester: —_— — —
CO,H 2) SnCl,, EtOH co Me ‘5 a-Methyl-4-nitrocinnamic acid (53 mg, 0.25 mmol) was dissolved in EtOAc and
MeOH and a solution of CH:Nz in Et;0 was added until a persistent yellow color was observed. A couple of drops of AcOH were added to destroy the excess CHuN,. The ® - mixture was diluted with EtOAc and the organic layer was washed with H,0O, aqueous NaOH (1N) and brine, dried over anhydrous MgSO, and concentrated to dryness. The residue was re-dissolved in EtOH (2 mL), SnChL2H,0 (289 mg, 1.28 mmol) was added and the reaction mixture was heated to reflux for 1h. The mixture was cooled to RT, diluted with EtOAc and quenched by the addition of aqueous, saturated NaHCO3. The organic layer was separated, washed with brine, dried over anhydrous MgSO, and concentrated to dryness to give the title compound (40 mg) as a yellow solid.
EXAMPLE 28: 4-((E)-2-Methoxycarbonyl-vinyl)-3-methyl-phenyl-ammonium chioride:
Lh 1) Boc,0, NaOH SOc —_— —
CO,H 2) CH,N, CO, ie
HCI H,+N —_— - cl CO,Me : : 20 4-Amino-2-methyl cinnamic acid (0.090 g, 0.51 mmol) and NaOH (1M, 1.1 mL, 1.1 . mmol) were dissolved in dioxane (4 mL), Boc,O (117 mg, 0.53 mmol) was added and the mixture was stirred at RT for 15 h. The reaction mixture was partitioned between EtOAc and H,0, the pH of the aqueous layer was adjusted to be basic using TN NaOH, and extracted with EtOAc (3 x). The aqueous layer was then
® acidified to pH ~2 and extracted with EtOAc (3 x). The new organic layers were » combined, washed with brine, dried over anhydrous MgSO, filtered and concentrated to give an orange gum (118 mg). The crude Boc-protected 4-amino-2- ) methyl cinnamic acid was re-dissolved in EtOAc and a solution of CH,N, in Et,O was added until a persistent yellow color was observed. A few drops of AcOH were added to destroy the excess CH;N; and the reaction mixture was washed with 10% aqueous HCI, saturated NaHCO; and brine, dried over anhydrous MgSO; filtered and concentrated to dryness. Purification by flash column chromatography, using 10% EtOAc in hexane as the eluent, led to the isolation of the Boc-protected methyl ester as a yellow solid (36 mg). Finally, the Boc protecting group was removed after acid treatment with HCI in dioxane (as described previously) to give the title ® compound.
EXAMPLE 29: 5-Amino-1-methyl-1H-indole-2-carboxylic acid ethyl ester
O,N 1) NaH, Met HN \
ToDo — TL oom 2) SnCl,2H,0 \
The ethyl ester of 5-nitroindole-2-carboxylic acid (0.300 g, 1.28 mmol) was dissolved in anhydrous DMF (6 mL) and NaH (0.078 g, 60%, 1.92 mmol) was added. The reaction was stirred at RT for 20 min, then Mel (160 pL, 2.56 mmol) was added and stirring was continued for 3 h. The reaction was quenched with the addition of aqueous NaHCO; (~1%) while stirring vigorously. The brown solid formed (0.096 g) was filtered and dried in air overnight.
The N-methyl nitro derivative (196 mg, 0.79 mmol) was then dissolved in DMF (4 mL), H,O (400 pL) and SnCl,2H,O (888 mg, 3.95 mmol) were added, and the mixture was stirred at 60 °C for 3 h. The mixture was then partitioned between 10% aqueous NaHCO; and EtOAc and stirred vigorously. The aqueous layer was re- . extracted with EtOAc and the combined EtOAc layers were washed with brine, dried over anhydrous MgSO, and concentrated to dryness. The residue was purified by flash column chromatography, using 1:1 ration EtOAc/hexane as the eluent, to obtain the pure 5-aminoindole derivative (118 mg).
* N-Alkylation of 5-nitroindole-2-carboxylate with other alkylating agents (such as Etl, : propargyl bromide, benzyl bromide) under the conditions described above gave the corresponding 5-amino-1-alkyl- 1 H-indole-2-carboxylates.
EXAMPLE 30: 5-{[1-(4-Amino-1-t-butoxycarbonyl-piperidin-4-yl)-methanoyi]-amino}-1-methyI- 1H-indole-2-carboxylic acid ethyl ester: ~ °° ! Ng 5 J O° ® FmocHN CO.H N
H,N \ HATU, HOA, collidine oF \ 2) piperidine \
A solution of amine from example 29 (70 mg, 0.32 mmol), N-Fmoc-amino-(4-N-Boc- piperidinyl)carboxylic acid (150 mg, 0.32 mmol), HATU (139 mg, 0.35 mmol), HOAt (48 mg, 0.35 mmol) and collidine (155 mg, 1.28 mmol) in DMF (2 mL) was stirred at
RT for 15 h. The reaction mixture was diluted with EtOAc, washed with 1% aqueous . citric acid (2 x), saturated NaHCO; (2 x) and brine, dried over anhydrous MgSO, and concentrated to dryness to give an orange solid (210 mg) which was used in the next reaction without purification. A solution of the crude solid (210 mg) in DMF (3 mL) and piperidine (95 mL, 0.95 mmol) was stirred at RT for 3 h. The reaction mixture was concentrated to dryness and purified by flash column chromatography, using a solvent gradient from 50% EtOAc in hexane to 100% EtOAc as the eluent, to give the compound as a brown solid (110 mg). !
ExAMPLE 31: 5-{[1-(4-Amino-1i-ethyl-piperidin-4-yl)-methanoyl]-amino}-1-methyl-1H-indole-2- ) carboxylic acid ethyl ester: ]
® NBoc » 0)
FmocHN COH ( . HATU, HOA, collidine N
HA 2) 40 % TFA in CH,CL, oF \ 3) CH,CHO, NaCNBH, \ 4) DBU
The 5-aminoindole derivative of example 29 was coupled to N-Fmoc-amino-(4-N-
Boc-piperidinyl)carboxylic acid as described in example 30.
The Boc protecting group was removed with 25% TFA in CH,Cl, in the usual way, ® 5 and the product was then dissolved in EtOH (6 mL). AcOH (133 mg), acetaldehyde (33 mg, 0.74 mmol) and NaCNBH; (23mg, 0.37 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to remove most of the solvent, the residue was re-dissolved in EtOAc and washed with saturated NaHCO; and brine. The organic layer was dried over anhydrous MgSQ, and concentrated to give the N-ethyl derivative as an orange solid.
This solid was dissolved in THF (2.5 mL), DBU (113 mg, 0.74 mmol) was added and the mixture was stirred at room temperature for 30 min. The solvent was evaporated, the remaining residue was dissolved in EtOAc and the organic layer was washed with saturated NaHCO; and brine. The organic layer was further extracted with 1N HCl and H,O (2 x), and the pH of the combined aqueous layers was adjusted to pH ~10 with IN NaOH. The aqueous layer was then extracted with
EtOAc (3 x), the combined organic layers were washed with brine, dried over anhydrous MgSO, and concentrated to dryness to give the title amine derivative (44 mg).
EXAMPLE 32: ’ : (E)-3-(4-{[1-(3-Amino-piperidin-3-yl)-methanoyl]-amino}-phenyi)-acrylic acid ethyl ester: . } . CI
N et |OUR © = “COOEt
® : Following a similar procedure to that described in example 31, commercially available N-Fmoc-amino-(3-N-Boc-piperidinyl)carboxylic acid was coupled to the » ethyl ester of 4-aminocinnamic acid and the Fmoc protecting group was removed to give the title compound of example 32 in racemic form.
The racemic starting material, N-Fmoc-amino-(3-N-Boc-piperidinyl)carboxylic acid, could also be resolved into its two enantiomers by preparative HPLC on a chiral support (Chiralcel OD, 10 micron, 2.00 cm 1.D. x 25 cm), using 35% H,O in MeCN as the eluent. )
EXAMPLE 33: ® General procedure for coupling o,o-disubstituted amino acids to aromatic amines: (E)-3-[4-(2-Amino-2-methyl-propanoylamino)-phenyl]-acrylic acid eth yl ester: o_o HN
H coon SY X RS | whey z PCI, Nar” coat pyridine Z™Co0Et
Adapting the procedure described by E. S. Uffelman et al. (Org. Lett. 1999, 1, 1157), 2-aminoisobutyric acid was converted to the corresponding amino acid chloride hydrochloride: 2-oxazolidinone (12.30 g, 0.141 mole) was dissolved in MeCN (150 mL) and phosphorous pentachloride (49.02 g, 0.235 mole, 1.7 equivalent) was added in one portion. The homogeneous mixture was stirred for 24 h at room temperature. 2-Aminoisobutyric acid (14.55 g, 0.141 mole) was added and the suspension was stirred for 48 h at room temperature. The desired acid chloride hydrochloride was collected by filtration, washed with MeCN and dried under vacuum.
The acid chloride (12.778 g, 80 mmol, 1.4 equivalent) was suspended in DCM (200 mL) and ethyl 4-aminocinnamate (11.045 g, 57.7 mmol, 1 equivalent) was added.
Pyridine (7.01 mL, 86.6 mmol, 1.5 equivalent) was added drop wise and the mixture was stirred for 3.5 h atroom temperature. The reaction was then poured into a . mixture of 1N NaOH (25 mL) and saturated aqueous NaHCO; (100 mL) and extracted with EtOAc. The organic phase was washed with aqueous NaHCO3, water and brine, and dried over MgSO,. Removal of solvent under reduced pressure gave the title compound as a white solid (15.96 g, 101% yield).
@® . EXAMPLE 34: (E)-3-(4-{[1-(1-Amino-cyclobutyl)-methanoyl]-amino}-phenyl)-acrylic acid ethyl » ester:
Q KOH 9% 1.DPPA/ELN 3.
Etooc” "cooer EtOH Hooc” “coogt 2. TMSE-OH Me, Si” 0 H
NaOH 3. ethyl 4-aminocinnamate ne :
MeSi~— 0 H HATU / DIEA 0 Th.
COOEt
Diethyl 1,1-cyclobutanedicarboxylate (20.00 g, 100 mmol) and KOH (6.60 g, 100 ® mmol) were refluxed in EtOH (100 mL) for 2 h. After cooling to room temperature, volatiles were removed under reduced pressure and the residue partitioned between
E10 and 4N HCI. The organic extract was washed with water and brine, and dried over MgSO,. Removal of the solvent under reduced pressure gave the monoester as a clear oil (14.45 g, 84% yield).
The monoester from above (14.45 g, 84 mmol), Et;N (14.1 mL, 100 mmol) and diphenylphosphoryl azide (24.05 g, 87.4 mmol) were dissolved in dry toluene (114 mL) and the mixture heated at 80 °C for 1 h and 110 °C for an additional hour.
Trimethylsilylethanol (9.94 g, 100 mmol) was added in one portion and the mixture refluxed for 48 h. Toluene was then removed under reduced pressure and the residue dissolved in DCM. The solution was washed with water and brine and dried over MgSO,. Concentration under reduced pressure gave a dark oil which was purified by passage through a pad of silica gel using 30% EtOAc in hexane as eluent. The desired carbamate was obtained as a clear yellow liquid (21.0 g).
The carbamate from above (1.50 g, 5.22 mmol) was dissolved in THF (5 mL) and 2N
NaOH (5 mL) was added. The mixture was stirred at 70 °C for 1 h. Following dilution with water, the aqueous phase was washed with Et,O to remove unreacted starting material. The aqueous phase was then acidified with KHSO, and the . ) 25 product extracted with EtOAc. The desired free carboxylic acid was obtained as an oil (1.25 g).
The acid from above (0.519 g, 2.0 mmol) was dissolved in DCM (10 mL). DIEA (1.39 mL, 8.0 mmol, 4 equivalents) was added, followed by ethyl 4-aminocinnamate (0.5739, 3.0 mmol, 1.5 equivalent) and HATU (1.143 g, 3.0 mmol, 1.5 equivalents).
® The mixture was stirred at room temperature for 3 days. The reaction was poured . into TBME (100 mL) and the solution washed successively with 10% aqueous citric acid (2 x 25 mL) and saturated aqueous NaHCO; (25 mL), and dried over MgSO..
N The solvent was removed under reduced pressure and the residue stirred with TFA (10 mL) for 30 min. Volatiles were then removed under reduced pressure and the residue was co-evaporated twice with hexane. The crude product was dissolved in
TBME (60 mL) and the solution washed with 1N NaOH (2 x 25 mL). After drying (NaxS0,), volatiles were removed in vacuum to give the title compound as a light brown solid (0.500 g).
EXAMPLE 35:
Carbonic acid 3-[(S)-2-tert-butoxycarbonylamino-2-(2-amino-thiazol-4-yl)- ® ethyl]-1H-indol-5-yl ester tert-butyl ester:
OH OBoc OBoc
HN —> HN__ —_—> & : H,N OH BocHN OH BocHN CHN,
Fe) 0 [o}
OBoc OBoc = a 5
BocHN Br BocHN™ g 0 N=(
NH, (S)-5-Hydroxytryptophan was converted to the bis-Boc derivative by the method of V.
F. Pozdnev, Chem. Nat. Compd. (Engl. Transl.) 1982, 18 (1), 125) which was isolated as the free carboxylic acid. This material (1.0377 g, 2.47 mmol) was dissolved in THF (5 mL), DIEA (0.645 mL, 3.7 mmol) was added and the mixture cooled in ice. Isobutyl chloroformate (0.384 mL, 2.96 mmol) was added and the mixture stirred at 0-5 °C for 18 h. Excess diazomethane in Et,O (0.6 M, 15 mL) was . then added and the mixture stirred for 1 h. Another portion of diazomethane (10 mL) was added and after 40 min, the reaction was diluted with ELO (75 mL). The solution was washed successively with 10% aqueous citric acid (25 mL) and saturated aqueous NaHCO; (25 mL), and dried (MgS0.). Volatiles were removed under reduced pressure and the residue purified by flash chromatography with 40%
EtOAc / hexane. The diazomethylketone was obtained as a yellow foam (0.783 g).
®
The diazomethylketone from above was dissolved in EtOAc (10 mL) and the solution . cooled to ~30 °C. A solution of HBr in AcOH (48% w/w, 0.384 mL) was added dropwise over 60 min. The cold reaction mixture was then diluted with ELO (100 . mL) and washed successively with 10% aqueous citric acid (2 X 25 mL) and saturated aqueous NaHCO, (25 mL), and dried (MgSQ.). Volatiles were removed under reduced pressure and the residue coevaporated with hexane to give the bromomethylketone as a white foam (0.870 g).
The bromomethylketone from above was reacted with thiourea (2 equivalents) in
MeCN at room temperature for 18 h. The solvent was then removed under reduced pressure and the residue dissolved in minimal DMSO. This solution was added dropwise with stirring to a mixture of water (15 mL) and DIEA (0.2 mL). The ® precipitate that formed was collected by filtration, washed with water and dried to give the title compound.
This method is general and can be applied to the preparation of other 2-alky! and 2- alkylaminothiazole derivatives by reacting the appropriate thioamide or thiourea derivative with the bromomethylketone compound described above.
EXAMPLE 36:
Carbonic acid 3-((S)-2-tert-butoxycarbonylamino-2-thiazol-4-yi-ethyl)-1H-indol- 5-yl ester tert-butyl! ester:
S
BocHN .
OBoc
To a stirred suspension of PSs (0.89 g, 2.0 mmol) in dry dioxane (5 mL) was added dry formamide (433 pL, 10.9 mmol). The mixture was heated at 90°C for 2.5 h (to maintain a free suspension occasional trituration was needed). The suspension was allowed to cool to room temperature, the solid filtered off and the bromoketone from example 29 (0.5 mmol) was added to the filtrate. The solution was heated to 80°C . 25 for 2 h then diluted with EtOAC (25 mL), washed with 5% aqueous citric acid (2 X 20 mL), 5% aqueous sodium bicarbonate (2 X 20 mL) and brine. After drying (MgSOQ,) and removal of the solvent under reduced pressure, the title compound was obtained.
1 EXAMPLE 37 (ENTRY 2050):
General procedure for coupling 5- or 6-indolecarboxylic acids to o,c- ~ disubstituted amino amides: (E)-3-[4-(2-{[1-(3-Cyclohexyl-2-furan-3-yl-1H-indol-6-yl)-methanoyl]-amino}-2- methyl-propanoylamino)-phenyl]-acrylic acid: 0 " a
J : Tl. ° ) ° “coon
The indole carboxylic acid derived from the methyl ester of example 3 (0.050 g, 0.16 mmol), the amino amide derivative of example 33 (0.053 g, 0.019 mmol, 1.2 equivalent) and HATU (0.122 g, 0.32 mmol, 2 equivalents) were dissolved in DMSO (1 mL). DIEA (0:14 mL, 0.8 mmol, 5 equivalents) was added. The mixture was stirred for 1 h at room temperature then treated with 2.5N NaOH (0.3 mL) for 1 h at 50 °C to affect hydrolysis of the cinnamate ester function. The mixture was then acidified to pH 1 with TFA and the title compound was isolated by preparative reversed-phase HPLC (0.033 g).
EXAMPLE 38 (ENTRY 1010):
General procedure for coupling thiazole derivatives (Examples 35, 36) to 6- indolecarboxyilic acids:
HA : s . NJ)
H : = N N
MN
. H
The thiazole derivative of example 35 was deprotected by stirring with 4 N HCI in dioxane and coupled to the 6-indole carboxylic acid derived from the methyl ester of example 3 using TBTU/DIEA in DMSO as described in example 37. Following . coupling, the title compound was isolated directly by preparative reversed-phase
HPLC. v
EXAMPLE 39 : 3-Cyclohexyl-1-methyl-2-pyridin-2-yi-1H-indole-6-carboxylic acid [1-(4-amino- phenylcarbamoyl)-1-methyl-ethyl]-amide (Entry 2072): \ COOH \ j MA / N couplin: N N i» ) + whey —— - } "oo JO o nad oO or o ® J} pe
H, ! 10% Pd/C 7 \ N
EE =p \ o QL,
The amino amide derivative prepared from a-aminoisobutyryl chloride and 4- nitroaniline following the procedure of example 33 was coupled in the usual way (example 37) to the indole derivative of example 9.
The nitro derivative was hydrogenolyzed (1 atm H, gas, 10% Pd/C) in MeOH for 5 h to give the title compound after purification by preparative reversed-phase HPLC.
EXAMPLE 40 (E)-3-(4-{[1-(1-{[1-(2-Carbamoyi-3-cyclopentyl-1-methyi-1H-indol-6-yI)- methanoyl]-amino}-cyclopentyl)-methanoyl]-amino}-phenyl)-acrylic acid: [o] } * \ H \ o, N i
A Q o So —_— \ He 0 |CPy 0 o) o ©
[0] 0, \ A: eo} \ So —_— A\ H o —_— \ H 0 } HO lo HN lot w 0 [eo] [eo] oN Sx —_— \ H go
HN ©, [o] )
® . To a mixture of the acid aldehyde, derived by saponification of the ester aldehyde of example 16, (50 mg, 0.184 mmol) and an amine, prepared adapting the procedure
J described in example 33, (55.7 mg, 0.184 mmol) in CH,Cl, were successively added
HATU (84 mg, 0.221 mmol) and DIEA (128 pL, 0.736 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in EtOAc and successively washed with a 10 % ag. citric acid solution (2X), a satd aq. NaHCO; solution, water and then with brine. After the usual treatment (MgSO, filtration and concentration) the residue was flash chromatographed (2 cm, 35 % AcOEt-hexane) to afford the desired amide-aldehyde derivative (83.5 mg, 0.150 mmol, 81.5 % yield). ® To the aldehyde from above (87 mg, 0.157 mmol) in a mixture of tert-butanol (2 mL) and 2-methyl-2-butene (1.2 mL) at 0 °C was added a freshly prepared solution of sodium chlorite (141.6 mg, 1.57 mmol) in phosphate buffer (216 mg of NaH,PO,, 1.57 mmol, in 600 pL of water). The reaction mixture was stirred for 10 min. at room temperature then brine was added. The mixture was extracted with EtOAc (2X) and the combined organic layers were successively washed with a 0.5 N ag. solution and brine. After the usual treatment (MgSO, filtration and concentration) the crude desired acid was isolated as a white solid (82.6 mg, 92.3 % yield).
To the acid (15 mg, 0.0275 mmol) in DMF at 0 °C were successively added DIEA (7.2 ul, 0.0413 mmol) and isobutyl chioroformate (10.7 pL, 0.0413 mmol). The reaction mixture was stirred for 30 min at this temperature then ammonium hydroxide (7.5 pL, 0.056 mmol) was added. After the addition the mixture was slowly } allowed to warm to room temperature and stirred overnight. 1N ag. NaOH was added (275 ul, 0.275 mmol) and the reaction mixture was heated at 60 °C for 1.5 h.
Glacial acetic acid was finally added to destroy the excess hydroxide and the mixture was HPLC purified. After lyophilization the desired amide was isolated (2.6 mg, 0.005 mmol, 18 % yield) as a white solid.
Other 2-carboxamide derivatives were prepared in a similar fashion by replacing . 30 ammonia with the desired amine. * EXAMPLE 41 (E)-3-[4-((E)-3-{[1-(3-Cyclopentyl-i-methyl-2-pyridin-2-yi-1H-indol-6-yl)- methanoylj-aminoj}-3-methyl-but-1-enyl)-phenyl]-acrylic acid:
PY 134 1) HATU / DIPEA : SA lon Sh Als 2) Dess-Martin H
J
1) CH,N, | o .
TQ. 2) NBS/ AIBN De
Scop 3) (EtO)P ° “cocH, 1) NaH ° gM
H 2) NaOH _
CoH 3-Cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid (0.100 g, 0.31 mmol), 2-amino-2-methyi-1-propanol (0.028 g, 0.31 mmol) and HATU (0.154 g, 0.41 mmol) were dissolved in DMSO (5 mL). To this mixture, DIEA (0.22 mL, 1.2 mmol) was added and the solution was stirred at room temperature for 3 h. The reaction mixture was poured into EtOAc (100 mL) and the solution washed successively with saturated aqueous NaHCO; (2 x 25 mL) and brine (25 mL), and dried over anhydrous MgSO,. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (using 60-70% EtOAc in hexane) to give the primary alcohol intermediate as a yellow oil (0.048 g). This product was dissolved in CHCl, (2 mL), Dess-Martin periodinane (0.063 g, 0.15 mmol) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with CHCl, (100 mL), the organic layer was dried over anhydrous MgSO, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (using 60% EtOAc in hexane) to give the aldehyde intermediate (0.011 g). ’ Diazomethane was slowly added to a solution of 4-methylcinnamic acid (3.0 g, 18.5 mmol) in CHsOH/CH,Cl, (5 mL/15 mL) until the yellow color persisted, indicating the presence of excess diazomethane. The solution was evaporated to dryness under reduced pressure and the residue was re-dissolved in CCl, (15 mL). N-
Bromosuccinimide (3.62 g, 20.4 mmol) and AIBN (0.304 g, 1.85 mmol) were added
® and the mixture was stirred at reflux for 3 hours. The solution was then cooled to y room temperature and filtered. The organic layer was washed with aqueous NaOH (0.5 N, 2 x 50 mL) and water (50 mL), dried over anhydrous MgSO, and filtered. The v solvent was removed under vacuum and the residue was purified by flash column chromatography (0-40% EtOAc in hexane) to obtain the bromide intermediate as a white solid (2.4 g). This product was dissolved in (EtO)sP (37.7 mL, 220 mmol) and heated to reflux at 160 °C. The ethyl bromide formed was collected in a Dean-Stark distillation apparatus over a period of 2.5 hours. The reaction mixture was condensed under vacuum to a yellow solid, which was then purified by flash column chromatography (70-100% EtOAc in hexane) to give the phosphonate as a white solid (1.9 g). ( A solution of phosphonate (20 mg, 0.06 mmol) and NaH (60%, 3.5 mg, 0.087 mmol) in anhydrous THF (300 pL) was stirred at RT for 30 min. A solution of the aldehyde intermediate (11 mg, 0.029 mmol) in THF was added and stirring was continued for 4 hours. After that period, aqueous NaOH (2.5 N, 50 pL) was added and the mixture was stirred at 40 °C for 15 hours. The mixture was acidified with glacial acetic acid (~1 mL), concentrated and purified by reversed HPLC to obtain the title compound (3.7 mg) as a yellow solid.
EXAMPLE 42: (Z)-3-[2-(1-Amino-cyciopentyl)-1 H-benzoimidazol-5-yij-acrylic acid methyl ester: 1) HATU / DIPEA : cl 1)CHN, HN Lo 9% > BocHN 4 we LO LOE £7 LS
Diazomethane was slowly added to a solution of 4-chloro-3-nitrocinnamic acid in
CH3OH/CH,CI, until the yellow color persisted, indicating the presence of excess diazomethane. The solution was evaporated to dryness under reduced pressure ’ and the residue was dissolved in DMSO. The solution was heated to 140 °C and ‘ ammonia gas was bubbled through for a period of 4 hours. The mixture was cooled to room temperature and degassed with N,, and poured onto ice. The precipitate formed was filtered, washed with cold water and dried under vacuum for 16 hours to 30° give the crude 4-amino-3-nitrocinnamic ester as a yellow solid (2.05 g). The solid
@ was dissolved in ethanol (40 mL), SnCl,.dihydrate (9.91 g, 43.9 mmol) was added » and the reaction mixture was heated to reflux for 4 hours. The solution was % ( concentrated to remove most of the ethanol, diluted with EtOAc and saturated ia aqueous NaHCO; was added slowly. The mixture was stirred for 20 min, the organic layer was extracted with brine, dried over anhydrous Na,SO, and evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (using 50% to 70% EtOAc in hexane) to give the diamino : intermediate as a yellow solid (1.03 g).
A portion of the 3,4-diaminocinnamate ester (186 mg, 0.970 mmol) and N-Boc-1- aminocyclopentane-1-carboxylic acid (222 mg, 0.970 mmol) were coupled in the ~ presence of HATU / DIEA (in the usual way) and the amide product formed was
C dehydrated by heating at 65 °C in a solution of acetic acid (4 mL). The reaction residue was purified by reversed HPLC to give the N-Boc protected (2)-3-[2-(1- amino-cyclopentyl)-1H-benzoimidazol-5-yi]-acrylic acid ethyl ester.
The Boc protecting group was removed with 4N HCI in dioxane in the usual way to give (Z)-3-[2-(1-amino-cyclopentyl)-1H-benzoimidazol-5-yl)-acrylic acid ethyl ester as yellow foam (200 mg).
EXAMPLE 43: 2-Amino-3H-benzoimidazole-5-carboxylic acid:
H,N : N 2 TL BrCN HN JZ TL
H,N CO,CH, N CO,CH,
A solution of cyanogen bromide (5M, 1.44 mL, 7.22 mmol) was slowly added to a suspension of 3,4-diaminobenzoate (1.0 g, 6.02 mmol) in water (10 mL). The mixture was stirred at room temperature for 24 hours. An aqueous solution of
Na,CO; (10%) was added slowly until the product had precipitated as a brown solid (890 mg). “ 30 EXAMPLE 44: / 5-Amino-3-iodo-1H-indole-2-carboxylic acid ethyl ester:
I
O,N 1), KOH HN . TD -co mon, RU N—co,cH,cH, i 2) snCl, N o Ethyl 5-nitroindole-2-carboxylate (1.00 g, 4.27 mmol) was dissolved in DMF (15 mL),
KOH (0.84 g, 14.9 mmol) was added and the mixture was stirred at room temperature for 10 min. lodine (1.084 g, 4.27 mmol) was added and stirring was continued for 3 hours. The reaction mixture was poured into a solution of water (150 mL) containing NaHSO; (1 g) and concentrated NH,OH (2.5 mL). The precipitate formed was filtered, washed with water and dried to give the 3-iodo intermediate as a beige solid (1.49 g). A portion of this solid (503 mg, ~1.4 mmol) was dissolved in ethanol (15 mL), SnCl,.dihydrate (1.58 g, 6.99 mmol) was added and the reaction
Qo 10 mixture was heated to reflux for 4 hours. The solution was concentrated to remove most of the ethanol, diluted with EtOAc and saturated aqueous NaHCO; was added slowly to pH=8-9. The mixture was stirred for 20 min, the organic layer was extracted with brine, dried over anhydrous Na,SO, and evaporated to dryness under reduced pressure. The residue (431 mg of brown solid) contained the desired product 5-amino-3-iodo-1H-indole-2-carboxylic acid ethyl ester in reasonable purity to be used in the synthesis of inhibitors without further purification.
EXAMPLE 45: (E)-3-(4-{[1-((S)-3-{[1-(3-Cyclopentyl-1-methyi-2-pyridin-2-yi-1H-indol-6-yl)- methanoyl]-aminoj}-1-methyi-pyrrolidin-3-yi)-methanoyl]-amino}-phenyi)-acrylic acid: 1) HATU/ BLN \
[0] } py . ’
BS TA
‘a NaBH,;CN N N ‘ey, H “, H ——— 74 \ y
HN N 4) NaOH —/ \ 0 _ o = . € COOEt “ 3-Cyclopentyl-1-methyl-2-pyridin-2-yl-1H-indole-6-carboxylic acid (0.197 mg, 0.589 mmol), the appropriate amine (0.170 g, 0.420 mmol) and HATU (0.320 g, 0.840 mmol) were dissolved in DMSO (4 mL). To this mixture, EN (0.300 mL, 2.15 mmol) was added and the solution was stirred at room temperature for 5 hours. The
® reaction mixture was poured into EtOAc (100 mL) and the solution washed - successively with 1% aqueous citric acid (2 x 25 mL), saturated aqueous NaHCO; (2
X25 mL) and brine (25 mL), and dried over anhydrous MgSO,. The solvent was bo removed under reduced pressure and the residue was purified by flash column chromatography (using hexane/EtOAc in 1:1 ratio) to give the intermediate product as a slightly colored foam (280 mg). This product was stirred in 4N HCI in dioxane (3.0 mL) for 1 hour (to remove the Boc protecting group) and then all volatile components were removed under reduced pressure.
A portion of the residue (41 mg, 0.060 mmol) was dissolved in ethanol (2 mL), acetic acid (31 mg, 0.530 mmol) was added, 37% aqueous formaldehyde (15 ul, ~0.2 mmol) and NaBH3;CN (5.6 mg, 0.090 mmol) and the mixture was stirred at room { J temperature for 30 min. The solvent was removed under reduced pressure and the residue was re-dissolved in DMSO (1 mL), aqueous NaOH (2.5 N, 230 uL, 0.58 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified by the addition of acetic acid (~1 mL) and purified by
C18 reversed phase preparative HPLC to give the final product as a light yellow solid (11 mg).
EXAMPLE 46: INHIBITION OF NS58 RNA DEPENDENT RNA POLYMERASE ACTIVITY
The compounds of the invention were tested for inhibitory activity against the hepatitis C virus RNA dependant polymerase (NS5B), according to the following assay:
The substrates are: a 12 nucleotide RNA oligo-uridylate (or oligo-uridine-monophosphate) (oligo-U) primer modified with biotin at the free 5°C position; a complementary poly-adenylate (or adenosine monophospahte) (polyA) template of heterogeneous length (1000-10000 nucleotides); and
UTP-[5,6 *HI. :
Polymerase activity is measured as the incorporation of UMP-[5,6 3H] into the chain - 30 elongated from the oligo-U primer. The *H-labelled reaction product is captured by
SPA-beads coated with streptavidin and quantified on the TopCount. to .
All solutions were made from DEPC treated MilliQ water [2 ml of DEPC is added to 1
L of MilliQ water; the mixture is shaken vigorously to dissolve the DEPC, then autoclaved at 121°C for 30 minutes].
C
. Enzyme: The full length HCV NS5B (SEQ ID NO.1) was purified as an N-terminal hexa-histidine fusion protein from baculovirus infected insect cells. The enzyme can “ be stored at —20°C in storage buffer (see below). Under these conditions, it was found to maintain activity for at least 6 months.
Substrates: The biotinylated oligo-U;, primer, the Poly(A) template, and the UTP- [5,6 *H] were dissolved in water. The solutions can be stored at —8C°C.
Assay buffer: 20 mM Tris-HCI pH 7.5 5 mM MgCl, 25 mM KCI @ 1 mM EDTA 1mM DTT NS5B storage buffer: 0.1.uM NS5B 25 mM Tris-HCI pH 7.5 : 300 mM NaCl 5mM DTT 1 mM EDTA 0.1 % n-Dodecyl maltoside 30 % glycerol
Test compound cocktail: Just prior to assay, test compounds of the invention were dissolved in assay buffer containing 15% DMSO.
Substrate cocktail: Just prior to assay, the substrates were mixed in assay buffer to the following concentrations: - Component Concentration in Final substrate cocktail Concentration in 6 : assay
® _
I EE EE
UTP-[5,6-°H] 35 0.025 pCi/ pb. 0.0083 pCi/ pL
BC El
A CT BTL
\
Enzyme cocktail: Just prior to assay, the RNA polymerase (NS5B) cocktail was prepared in assay buffer to the following specifications: *
Protocol:
The assay reaction was performed in a Microfluor™ white “U” bottom plate (Dynatech™ #7105), by successively adding: 20 pL of test compound cocktail; 20 pl of substrate cocktail; and 20 pb of enzyme cocktail (final [NS5B] in assay = 10 nM; final [n-dodecy! maltoside] in assay = 0.33%; final
DMSO in assay = 5%).
The reaction was incubated at room temperature for 1.5 hours. STOP solution (20 pl; 0.5 M EDTA, 150 ng/ ul tRNA) was added, followed by 30 pl streptavidin coated . PVT beads (8mg/ml in 20 mM Tris-HCI, pH 7.5, 25 mM KCI, 0.025% NaNj). The plate was then shaken for 30 minutes. A solution of CsCl was added (70 pL, 5 M), to “ bring the CsCl concentration to 1.95 M. The mixture was then allowed to stand for 1 hour. The beads were then counted on a Hewlett Packard TopCount™ instrument using the following protocol:
Data mode: counts per minute
® Scintillator: lig/plast ) . Energy range: low
Efficiency mode: normal " Region: 0-50
Countdelay: 5 minutes
Count time: 1 minute
Expected results: 6000 cpm/well 200 cpm/well no enzyme control.
Based on the results at ten different concentrations of test compound, standard concentration-% inhibition curves were plotted and analysed to determine ICsy’s for. o the compounds of the invention. For some compounds the ICs, was estimated from two points.
EXAMPLE 47: SPECIFICITY OF NS5B RNA DEPENDENT RNA POLYMERASE INHIBITION + The compounds of the invention were tested for inhibitory activity against polio virus
RNA dependent RNA polymerase and calf thymus DNA dependent RNA polymerase
It in the format that is described for the HCV polymerase with the exception that another polymerase was used in place of the HCV NS5B polymerase.
EXAMPLE 48: CELL BASED HCV RNA REPLICATION ASSAY
Cell Culture
Huh? cells that stably maintain a subgenomic HCV replicon were established as previously described (Lohman et al., 1999. Science 285: 110-113) and designated asthe 522.3 cell-line. $22.3 cells are maintained in Dulbecco's Modified Earle
Medium (DMEM) supplemented with 10% FBS and 1mg/mL neomycin (Standard
Medium). During the assay, DMEM medium supplemented with 10% FBS, containing 0.5% DMSO and lacking neomycin was used (Assay Medium). 16 hours prior to compound addition, $22.3 cells are trypsinized and diluted to 50 000 cells/ml - 30 in Standard Medium. 200uL (10 000 cells) are distributed into each well of a 96-well plate. The plate was then incubated at 37°C with 5% C0, until the next day. &
Reagents and Materials:
®
Product Company | Catalog # Storage
Deep-Well Titer Plate .
Preparation of Test Compound ; : 10pL of test compound (in 100% DMSO) was added to 2 mi of Assay Medium for a final DMSO concentration of 0.5% and the solution was sonicated for 15 min and filtered through a 0.22uM Millipore Filter Unit. 900ul was transfered into row A of a
Polypropylene Deep-Well Titer Plate. Rows B to H, contain 400pL aliquots of Assay
Medium (containing 0.5% DMSO), and are used to prepare serial dilutions (1/2) by transferring 400p! from row to row (no compound was included in row H).
Application of test compound to cells
Cell culture medium was aspirated from the 96-well plate containing the $22.3 cells. 175pL of assay medium with the appropriate dilution of test compound was transferred from each well of the compound plate to the corresponding well of the cell culture plate (row H was used as the "No inhibition control"). The cell culture plate was incubated at 37°C with 5% CO, for 72 hours.
Extraction of Total Cellular RNA
Following the 72 hour incubation period, the total cellular RNA was extracted from © the $22.3 cells of the 96-well plate using the RNeasy 96 kit Qiagen®, RNeasy
Handbook. 1999.). Briefly, assay medium was completely removed from cells and “ 100 pL of RLT buffer (Qiagen®) containing 143 mM B-mercaptoethanol was added to each well of the 96-well cell-culture plate. The microplate was gently shaken for 20 sec. 100 pL of 70% ethanol was then added to each microplate well, and mixed by
® pipetting. The lysate was removed and applied to the wells of a RNeasy 96 . (Qiagen®) plate that was placed on top of a Qiagen® Square-Well Block. The
RNeasy 96 plate was sealed with tape and the Square-Well Block with the RNeasy © 96 plate was loaded into the holder and placed in a rotor bucket of a 4K15C
S centrifuge. The sample was centrifuged at 6000 rpm (~5600 x g) for 4 min at room temperature. The tape was removed from the plate and 0.8 mi of Buffer RW1 (Qiagen® RNeasy 96 kit) was added to each well of the RNeasy 96 plate. The
RNeasy 96 plate was sealed with a new piece of tape and centrifuged at 6000 rpm for 4 min at room temperature. The RNeasy 96 plate was placed on top of another clean Square-Well Block, the tape removed and 0.8 m! of Buffer RPE (Qiagen®
RNeasy 96 kit) was added to each well of the RNeasy 96 plate. The RNeasy 96 ( plate was sealed with a new piece of tape and centrifuged at 6000 rpm for 4 min at room temperature. The tape was removed and another 0.8 ml of Buffer RPE (Qiagen® RNeasy 96 kit) was added to each well of the RNeasy 96 plate. The
RNeasy 96 plate was sealed with a new piece of tape and centrifuged at 6000 rpm for 10 min at room temperature. Tape was removed, the RNeasy 96 plate was placed on top of a rack containing 1.2-mL collection microtubes. The RNA was eluted by adding 50 pL of RNase-free water to each well, sealing plate with a new piece of tape and incubated for 1 min at room temperature. The plate was then centrifuged at 6000 rpm for 4 min at room temperature. The elution step was repeated with a second volume of 50 ul RNase-free water. The microtubes with total cellular RNA are stored at =70°C.
Quantification of Total Cellular RNA
RANA was quantified on the STORM® system (Molecular Dynamics®) using the
RiboGreen® RNA Quantification Kit (Molecular Probes®). Briefly, the RiboGreen reagent was diluted 200-fold in TE (10mM Tris-HCI pH =7.5, 1mM EDTA). Generally, 50pL of reagent was diluted in 10mL TE. A Standard Curve of ribosomal RNA was diluted in TE to 2ug/mL and pre-determined amounts (100, 50, 40, 20, 10, 5, 2 and - 30 OuL) of the ribosomal RNA solution are then transferred in a new 96-well plate (COSTAR # 3997) and the volume was completed to 100uL with TE. Generally, . column 1 of the 96-well plate was used for the standard curve and the other wells are used for the RNA samples to be quantified. 10pL of each RNA sample that was to be quantified, was transferred to the corresponding well of the 96-well plate and 90pL of TE was added. One volume (100pL) of diluted RiboGreen reagent was added to each well of the 96-well plate and incubated for 2 to 5 minutes at room - temperature, protected from light (a 10 uL RNA sample in a 200 uL final volume generates a 20 X dilution). The fluorescence intensity of each well was measured on the STORM® system (Molecular Dynamics®). A standard curve was created on the basis of the known quantities of the ribosomal RNA and the resulting fluorescent intensities. The RNA concentration in the experimental samples was determined from the standard curve and corrected for the 20X dilution.
Reagents and Materials: ~~ Product Company | Catalog # | Storage ®
Real-Time RT-PCR
The Real-Time RT-PCR was performed on the ABI Prism 7700 Sequence Detection
System using the TagMan EZ RT-PCR Kit from (Perkin-Elmer Applied
Biosystems®). RT-PCR was optimized for the quantification of the 5' IRES of HCV
RNA by using the Tagman technology (Roche Molecular Diagnostics Systems) similar to the technique previoulsy described (Martell et al., 1999. J. Clin. Microbiol. 37: 327-332). The system exploits the 5'-3' nucleolytic activity of AmpliTag DNA polymerase. Briefly, the method utilizes a dual-labeled fluorogenic hybridization probe (PUTR Probe) that specifically anneals to the template between the PCR ’ primers (primers 8125 and 7028). The 5' end of the probe contains a fluorescent reporter (6-carboxyfluorescein [FAM]) and the 3' end contains a fluorescent quencher " (6-carboxytetramethylrhodamine [TAMRA]). The FAM reporter's emission spectrum was suppressed by the quencher on the intact hybridization probe. Nuclease degradation of the hybridization probe releases the reporter, resulting in an increase
® in fluorescence emission. The ABI Prism 7700 sequence detector measures the ‘ increase in fluorescence emission continuously during the PCR amplification such that the amplified product was directly proportion to the signal. The amplification plot . @ was analysed early in the reaction at a point thatrepresents the logarithmic phase of
S product accumulation. A point representing a defined detection threshold of the increase in the fluorescent signal associated with the exponential growth of the PCR product for the sequence detector was defined as the cycle threshold (C7). Cr values are inversely proportional to the quantity of input HCV RNA; such that under identical
PCR conditions, the larger the starting concentration of HCV RNA, the lower the Cr.
A standard curve was created automatically by the ABI Prism 7700 detection system by plotting the Cr against each standard dilution of known HCV RNA concentration. @ Reference samples for the standard curve are included on each RT-PCR plate. HCV
Replicon RNA was synthesized (by T7 transcription) in vitro, purified and quantified by OD. Considering that 1pg of this RNA = 2.15 X 10'' RNA copies, dilutions are made in order to have 10° 107, 10° 10°, 10“, 10° or 10? genomic RNA copies / 5pL.
Total cellular Huh-7 RNA was also incorporated with each dilution (50ng / 5uL). 5uL of each reference standard (HCV Replicon + Huh-7 RNA) was combined with 45uL of Reagent Mix, and used in the Real-Time RT-PCR reaction.
The Real-Time RT-PCR reaction was set-up for the experimental samples that were purified on RNeasy 96 —well plates by combining 5pl of each total cellular RNA sample with 45pL of Reagent Mix.
Reagents and Materials:
Product | Company Catalog #
MicroAmp Optical 96-
PE Applied Biosystems | N801-0560 RT
Re Ce I - 25 Reagent Mix preparation:
Volume for | Volume for One Plate . © Component one sample | (pl) (971 samples + Final ’ (uL) Dead Volume) cone.
Feeteower | wes | wer
®
ILC I I NL ovarian om | 1 | sawn _
Fevers Primer (Oy || sao rTth DNA polymerase 2 196 0.1 U/uL
Su +l IE I ®
TomlVoume [ 45 [ a0] ‘Forward Primer Sequence (SEQ ID. 2): 5 - ACG CAG AAA GCG TCT AGC CAT
GGC GTT AGT -3
Reverse Primer Sequence (SEQ ID NO. 3): 5'- TCC CGG GGC ACT CGC AAG
CAC CCT ATC AGG - 3'
Note: Those primers amplify a region of 256-nt present within the 5' untranslated region of HCV. :
PUTR Probe Sequence (SEQ ID NO. 4): -TGG TCT GCG GAA CCG GTG
AGT ACA CC -
No Template Controls (NTC): On each plate, 4 wells are used as "NTC". For these controls, 5pl of water are added to the well in place of RNA. . Thermal Cycling Conditions: : 50°C 2 min - 60°C 30 min 95°C 5 min 95°C 15sec } for 2 cycles
® 60°C 1 min 90°C 15sec . 60°C 1 min } for 40 cycles
Following the termination of the RT-PCR reaction the data analysis requires setting of threshold fluorescence signal for the PCR plate and a standard curve was constructed by plotting the Ct value versus RNA copy number used in each reference reaction. The Ct values obtained for the assay samples are used to interpolate an RNA copy number based on the standard curve.
Finally, the RNA copy number was normalized (based on the RiboGreen RNA ® quantification of the total RNA extracted from the cell culture well) and expressed as genome equivalents / ug of total RNA [ge/ug].
The RNA copy number [g.e./ug] from each well of the cell culture plate was a measure of the amount of replicating HCV RNA in the presence of various concentrations of inhibitor. The % inhibition was calculated with the following equation: 100 - [(g.e./ug inh)/( g.e./jug ct))x 100].
A non-linear curve fit with the Hill model was applied to the inhibition-concentration data, and the 50% effective concentration (ECs) was calculated by the use of SAS software (Statistical Software System; SAS Institute, Inc. Cary, N.C.).
In Tables 1 to 9 below, the following ranges apply:
ICso: A = 10puM-1uM; B = 1pM-500nM; and C<500niM.
Ecso: A = 5uM-500nM; and B = <500nM ‘
TABLE 1 0 [A A
RZ
\
R®
EAL
#4 rb (MH) 1001 | NH S A 561.2
LL : ® ; ~
N OH
1002 | NH NH C 522.2 a :
Zi . A OH 1003 | NH 7s A A | 5622
NJ
NN :
Ay =
N OH
1004 | NH HN 566.2 ha 1 N P 0 H
A :
N
=
N OH
1005 | NH =< A 546.3 \ i) ’ 2
B [s)
lI A ll I Lia ka . SS DN NS NN IN MN (2M 1006 | NMe BY Cc 648.3
H 0 OH ’ HN = o
Ny ace 1007 Q 0 A 808.3 \—O0H .
NF
®, A “nN H aR : 0]
E HN
$ ; ° ® "J 1008 NMe <0 Oy—on 815.3 0 N { (M-H)
NH
3 4 . [o] oO 0 ® Re 1009 | NMe Le EN A 818.1 0) 0 NH Hh ]
J 1
OH
(e} ® ) 1010 Nie = yon C 636.3
NT NS pz = u HN__~ 3 ~~ o ~¢° a OH 1%” : ) pW ; . H (o} (0) ® ~°
OH
Cpd. ICs ECs m/z . BL NN A EN EY NS SUN (| :] o) 1012 | NMe Je O8—oH C 699.3
NF
» NN | _—
HN
(0) 0 °
OH
1013 | NMe Te Sn C 636.3 ) i [o]
J
S oH ® : 1014 | NMe C 574.4 py EE <
N N
{ H H—nN x he of TOH 1015 | NMe os : C 560.3 =~ N N _ ~ 74
OH lo) 1016 | NiMe w C 534.2
ZN NNT
' xX 4
OH lo) : 1017 {| NMe A C A 534.3
ZN a =N . x HN ) SS 0” OH :
dN a dca
NL EE A I I (LM 1018 | NMe A 2 C 534.3
N— :
ZN HON
’ x J Rs
Se fo) OH 1019 NH OMe A 470.3 . p ~S Ck
N H OMe xn 1020 | NMe Nd C 603.4 ° “3 < . a N N
HN
' SN 0” “OH 1021 AE C 533.4
N— = H
N en
NS HN
) 07 NH, 1022 S Q C 3.3
N N on > \ H o
HN
0 “po
OH
1023 | NMe A C C 560.4 : ZN N ) xn HN = ) : lo) oH
. Cpd. ICs, ECs m/z . #4 (Me) 1024 | © A C | A |5683 . \ N o H he OH 1025 | NMe \— C A 591.4
ZN — g 5 had =N
HN
® > 0 OH 1026 {| NMe x ’ 473.3 : ZN Bg
GP =N : SA
OH
1027 | NMe X . C 559.4
N
ZN H
NY | HN = =N 07 NH, 1028 | Nivie Nn Cc 589.4 a HN:
SP =N
HN
=
OH
: 0 1029 | NMe x 486.4
ZN N o ~ ] ~N (®] H
AA lo}
kl I I hid sl oo TT ey 1030 | NMe T 530.4 yz N ) SN ! oN
Le H = Ny
Ir
Oo 1031 | NMe x C 604.5
N =
MN Ea 0 . 2 a ® _ 1032 A C C | 5755
Q rs
NY HN
= COOH 1033] NMe — 561.3 “3 & ae x HN = COOH
. : TABLE 2 1 O 47 8 ) R\ R R H
N ~
RZ N Q
NN fo) # Hy (M+H)* ht o 2001 | H [| — 1% | -w~ | B | B |53a2]
OF ha 07 on 2002 H x 9 576.2 0 OH ) 2003 H Br A A 578.6 (MH")/ 580 ¥ (MH)
Sy o OH 2004 | H X CH, 526.2
NN :
LJ
SN
: 07 oH
Cpd. RY R? ICs, ECs m/z # DX (M+H)" : HE I ht I 2005 H ’ 580.3 . \ AN _ ; v : Na
I) OH 2006 ‘ 580.3 \ N ° X
Na ® an ] 2008 H A 593.2 1 N ° Y \ // coon 2009 | H & CH, A | 5272
SN :
ZN
Ld | ~
Nl o OH 2010 H A 589.3 { N . o Y ~_ CN o OH 2011 H A CH, A 579.3 - N H
Ld | 9 . : Vand oH
# Hy (MH)* “ i, 2012 | H | & cH, [| B | A |5772]
PY AN 2 .
Ly | YF rr y 2013 H 630.2
MN o ¥
Cl OH
Q
) 2014 H CH, A A | 591.3 . NN = ¢ , NY 4 aly 2015 H XL CH, 567.2
NN T
LJ YN, — OH [e} 2016 H x ] A 594.2 la]
NN 0 . o Y J h=/ 2017 H >< 597.2 » ¥
Q sg” TN : = on 0 2018 H . >< : 607.2
Ss SN . = on
Cpd. RY RB ICs ECs m/z . # ON (MH) 2019 | H | | Sap | B | A e131
S s TN = on
To lo] 2020 Et : >< 578.2 ® | = 07 oH 2021 Is 2X A 596.4
Ly | MY [o]
Sn ’ 0 OH 2022 he ; KX A 592.3 — 0” oH 2023 Me H >< A 488.2 =~ 07 oH
Cpd. rR R° ICs ECs m/z # ON (M+H)* "2024 | H |__| TT = | B | B |5%3 ‘ N » ¥
Xx
N\ d bs
NH, 2025 | H 5 596.3
N (M-H) ’ ¥ @® _ 0 OH 2026 >< 594.4 ’ AS 1) ¥
NH, - : ’ o OH 2027 < 579.3
SN
[ ¥ . J o OH 2028 < | A 579.3
NN
$ ¥ ’ ~~ . 0” OH 2029 >< 635.3 4 _ oF “oH
® 159
Cpd. rR AR’ ICso ECs m/z # > (M+H)* _ EE RC I EE NE A 2030 >< Cc 565.3
Ir | Nl YY er”
AO No . o OH 2031 >< C 595.3
B ¥
N . ® D o OH 2032 | Me >< 608.4 : N Y
Z } .
AN So o OH 2033 H 577.2
SN
= o OH 2034 ® & ; Cc 590.2
B o OH 2035 H . 8 Cc 576.2 ) . No o OH
Cpd. R RY R® ICs, | ECs | m/z # PV (M+H)*
SE RE A HS A RN NE RE
2036 H C 566.3 -“ 1D 0 XY ~~ o OH 2037 H Da C 566.2
Oo = ® Py 2038 H : C 582.2 \ NN : ¢ ae 0 OH 2039 H C 593.3 \_/ 4 OH o 2040 A C 656.3
N b \ J 3 ¥
Ra . oF on : 2041 580.3 \ N . p ¥ o OH
Cpd. rR R° ICs ECs m/z # DX (M+H)*
SN I RE SSE A NU SR A
2042 H Ot C 582.3 . d
Ny o” “OH 2043 Ng Cc 657.3
A
© ¥
Sa @® Han 2044 H C 621.2
AN , :
[0]
SN
= on lo} 2045 H \. C 742.3 ° N 9 (o] y/
N
: ¥ / OH o 2046 H C 610.2
AN ; ) \ 0 Y \_/
OH lo) 2047 H A CH, C 553.2
NN Z
Ly | OF
SRY / . 4 OH lo]
® 162
Cpd. rR, R° ICs ECs m/z } # Pp (M+H)*
EE I RE RCT
2048 H BN Cc 606.2 . A ° ¥
A
O
OH
2049 H Cc A | 620.3
AN N (M-H) (o}
J
N
@® 5d / OH [o) 2050 H >< C 5403 ® rd [oe]
Sa o OH } 2051 >< C 554.3
LS ¥ [o] nN o OH 2052 H C 505.4
AN N
\ [o] : Sa o OH 2053 H >< C 580.2
B® Yo [o} 0 x
OH
Cpd. R\_ R® ICs, ECs m/z # > (M+H)*
I A ER NL ER EE _ 2054 Et >< Cc 568.2 “ 1 Nt Y [o]
Sy . : . 0 on : 2055 H N C 623.2 \ b N o] ® & Rh o OH 2056 H Cc 580.2
N ) : 0 XY ~~ 0 OH 2057 H C 552.2
MN
S ¥
Na o OH 2058 H . xX , C 550.2 ~ k o OH 2059 1 H >< C 556.2 \ N v . S
SN oF oH
® 164
Cpd. rR R° IC; ECso m/z # > (M+H)* aT a 2060 H ~~ | C | 565.2 . A ° XY
Sy of TNH, 2061 H >< C A 597.1
OY ¥ {0} , ~~ ® NL . O
OH
2062 . >< J C 564.2
B o OH 2063 | O=© >< C 674.3 » 3 . (e]
J o OH 2064 H hy NH, C 555.2
XN
= £ , Sa o” “oH . 2065 H N J C 611.3
LS N
- {s) £ D ¥ 0 OH
Cpd. rR R° ICs ECs m/z # Pe (M+H)*
I SN FN NS. IN I NR A 2066 | Me N Cc 570.2 0 + s YY hy o OH 2067 | H - | GC A | 666.2 » N J
J
ES
Ni N @ | Cl 0
OH
2068 KX Cc 565.3 7 ¥ x oN
SN o OH 2069 H A 0] C 582.3 : N =
I) OH 2070 Me x C 605.2 x 0 [ 0
OH
Cpd. R’ rR R® ICs | ECs | m/z 3. Xy (MaH)* “ i | ] I BN I { 2071 IE >< Cc 622.2 oy ~~ N rd nn
NT TS oO
OH
2072 >< C 510.2
NY
® NH, 2073 >< C 604.2
NY
0 SN
O
NH, 2074 >< C 621.2 z N ¥ 1
NS
NT TS ol
NH, 2075 ad C 591.3
NX ) \ / NH,
A [o)
® 167
Cpd. NGL ICs, ECs m/z . # D& (M+H)* 2076 | Me | Tv OX I = 1 Cc | B [5053
I" = N Ng
NY
0... NH ) H 2077 KX C 581.3
NY
@® ad
HN 0 2078 H r C A 608.4 \ h N
[0]
LJ Se ¥ 07 TNH, 2079 | H - C A [6114
LS N
&J o OH 2080 X< C 580.3 “3 ¥ xe UN
NH, 0 OH s 2081 A >< C 581.3 = ¥ he
NH, - 0 QH
® 168
Crd. SV ICs ECs a . +
EE A EE NS E _ 2082 xX C B | 615.3 3 N . ® ¥
Ny o OH 2084 H N Cc A 608.2
AN
\ [o] ¥ / OH ® é 2086 H C 623.3 i N hd [o] &J a o OH : 2087 Me >< C 565.2
NS
= o OH 2088 H - Cc 609.3 ® ~~ _N 0 9) S o OH - 2089 H x Cc 551.2 3) ¥ ) J. o” “OH
® 169
Cpd. rR R° ICs ECs miz : ; Pa (M+) 00 1 Me 1 + 1 ~~ | + | C | B 577.2 . A ~
Sy o OH 2091 | Me xX XK C 566.3 “7 ¥
NaN o ~ 0 OH 2002 7 - C 661.3
PW
N
= / \ : Cd / OH
YY J
2093 2K C 592.3 = )
N
/ on [o} 2094 >< C A | 582.2
NS ad
Ho” © 2095 XK C 597.3
NS
° yd
HO 0
N
Cpd. R’ RR ICs | ECso | m/z # ON (M+H)" [2006 | Me | 1 | Sab | ¢ | B | 5803] x NH,
Na o OH 2097 | Me C A | 581.3
A 0 a “ ® D o OH 2098 | Me C 579.3
A | 2%
SL
= ’ o OH 2099 4 - C 678.4
Zn
N
Jn \_/
OH
¥ § 2100 H - A 610.4 9 N
Gd ¥ jp 2101 | Me - C 685.4 = h N . x 9 ¥ 7
Na o7 “OH
© [Cpd. | R RA ICso | ECs | miz # HX (M+H)* ’ I 1 lL | NS 2102 Me . J C 609.3
NO,
SS o OH : 2103 Me C 608.3 7 7
Na 0]
NH, ® D 0” oH oy — o OH 2105 Q C 648.3 oy PN x a o OH 2106 0 C 634.3 = N = ) 5 ¥ ~ oF oH 2107 C 648.2
So | WS ~ } SN o7 on
- Cpd. R RY R° ICs ECs, m/z # Xy (M+H)*
I IR I RS NE RE
N
2108 Dy C 555.4 @ ° =~ oZ oH
N
H
@ py oF “OH } 2110 robs 7 C 745.2
UN -
LZ
HN 2 I
Hoo 0 2111 “ey C 621.3
XN
P < sf 0
HO
2112 Me “re C 620.3 0)
Z ¥ ass : 0)
HN
2113 Me --- 600.5
Bi . Z ¥ . \ ad
NH,
Cpd. RX Rr’ ICsq ECs m/z . # > (M+H)* yy = oy — xia — | = 2114 | Cc 620.3 @ pn ’ ’ =~ 0 OH 2115 H C 592.3
Fo) [ = J: ® ~ o OH 2116 7 C 606.3
Syl) = o OH 2117 H C 592.3
BE
. Fr “.,
So o OH 2118 | Me \ C
ON
AN
5% = “a,
Sy o OH
PS 174
TABLE 3
RY DR R
_ N as
O V/ \ O = OH 3 .
R le)
R' Ne ICs ECs m/z (M+H)*
HE HT A BE
MEE B
BEE
} CIE }
TABLE 4 1 O RR?! R8
R R\ R H
N N
(OTT WT o
N = H 3
R 0) cpd. RY R® iCso ECs m/z # > (MH) ow 4002 H Q 576.3 ¥
- : TABLE 5 o (fr ! Bl
N
R? \ H O \ OH
R® 0) :
ENS LaEA LILI #0 (MH) ® 5001 1 A 538.2
NN
[¢]
° 177 : TABLE 6
A O RZ Re H
N N
N
R \ H 0 = OH 0
OE ICs ECs m/z
M+H)* ® BE aN 6001 | CH, Oy C | B | 6343 7 N N
N 8 6002 | CHa 9 ~C 634.3
NP
= N
Se ¥ 6003 | CH, ; HC. CH C 634.2 87 3 3
SN
SZ
N
6004 | CH | H.C. CH 648.2
STN 3 3 ) —~N
H
6005 CHs H,C ’N " C 621.3
HN ¥ " EN 6006 | CH, HC >, C 633.3 . _ ® ¢ hoo
(M+H) oN 6007 | CHs ~ [Ho CH | C 670.3
WN Oo ( tr 6008 | CHa a OG C 614.3 . Va . ¥
EN
6009 | CH, a OG C 586.3 a ¥ ® 6010 | CH, a Eo C 600.3 ia 6011 | CHa a ES Cc 634.3 \ vl ) NED - 6013 | CH; a Eo C 649.3
Va ¥ “7 x UN 6013 | CH, a Eo C 628.3 ’ : 6014 | CH a OG C 614.3
SY ICs ECs m/z (M+H)* : I EE I AT. RR NE RE 6015 | CH, a Th 649.3
Wa ¥ = N - 6016 CH; a YG C 640.4 of ' 6017 CH ies WG C 614.3 ® es ¥ 6018 CH; TH H.C CH, Cc 654.3 . TY ~~ )
S
6019 CH; TY H,C._ CHa 639.3 s Ve \_/ 6020 | CH, a OT C 630.3 a / oO / 6021 CHs TH OG Cc 656.4
Wa ¥ § 0 6022 | CHg a Gt 649.3
Wa ¥
O) =N epg. R' S¢ ICso ECs m/z . M+H)*
SR RE p 6023 | CH, oe WO C | B | 6834 d ¥ @ 6024 | CH, oe OSC Cc 649.3 0=5=0 o 6025 | CH; TN Ee C 685.4 g ¥
N
; 6026 | CH, a OC Cc 587.3
OH
6027 | CH, a OC C 642.3 a ¥ = 6028 | CH, a OC Cc 658.3
Na ¥
Jo 8 6029 | CH, oe Th C 656.4 = ¥ a
E ICso | ECs m/z (M+H)" > he HE 6030 CH, oh 684.4
Wa ¥ )~o ls 6031 CH; a oh 642.4 ys ¥
J ) BE - a \ . N— / 6033 CH; | De koh 640.4
We ¥ 6034 CH; ho C 628.4 « 6035 | CH, a Eo C 643.4 ¥ \ / 6036 CHa 2X Cc 549.3 ~N & ¥ . pz 6037 CHs; 2X C 564.3 o SN .
Ct ¥
NH,
Se ICsp | ECs m/z } (M+H)" ’ LE EN NE [6038 | CH; T Cc 564.3 . SN K
NA ¥ 6039 CH; C 563.3
ES
- ¥ 6040 CHaj C 568.3 - \ ANY g ) ’ 6041 | CH, c 631.3 ® ~N = : .
CF, 6042 CHg C 645.3
Ty 2 ¥
CF, 6043 CH; C 593.3 == OMe ¥ 6044 CH, C 607.3 ) 5
Z OMe ¥ 6045 CH, ; §% 596.3 : cl 6046 | CH, ~ Cc 500.2 / > 6047 | CH; C 285.2 oN OX
Ci
R? rR R° ICso | ECs m/z >< (M+H)* [3 “a, 1 6048 | CH; Cc 597/2 pz cl 6049 CHa; - C 611.2
AY
P <
Cl 6050 CH, CH, C 640.3 ® ~
Cl YY 6051 | CH, T C 583.3
STN N
\/ ¥ 6052 CHs > & C 591.3 “NH, ¥ 6053 CH, ; : & C 591.3
NH, 6054 | CHs CH, C 620.4
N
6055 CH, C 582.3 \ N s ¥ 6056 CH, CH, C 611.3
NN N
9 s
WQ 03/010141 PCT/CA02/01128 °® 184 oy ICs ECs m/z . (M+H)*
SE RCN EE RE RR
6057 CH; C 591.4 a ¥ 6058 CH, ¢Ha C 620.4
Cr " = CH, 9 6059 | CH; CH, Cc 621.4
Cr " » L., 9 6060 CH, C 591.4 oN
Z ¥
CH, 6061 CH, CH, C 591.3
NN . = 6062 CH; CH, ¢Hs C 620.4 0d 6063 CHs . C 578.3 [oN
NA ¥ 6064 CHa, C 563.3
BB K
° _ Y 6065 | CH, OH, C A | 607.3
A !
I 6
R' rR R° ICso | ECs | miz
Dv (MH) (6066 | CH, | + | ,— | C | B | 5773 >
N , 6067 CH, £2 A A 605.4
IN
& ¥
N
6068 CHa, Hs C A 634.4
N
IAN ps 6069 CHa, SN C 577.3
WP
. 6070 CH, C 569.2
I
LI ¥ 6071 CH; ' C 626.2
O = ju Hs b ¥
N
H
6072 CHj3 C 598.3 pa XY ~N
H
6073 CHj C 612.3 0 | &
S
\_, ¥
H } 6074 CHa oN C 584.3 . NTN
S
HN
: 6075 CHs C 583.3 : oN
° 186
DE, ICs ECs, m/z (M+H)* “ | KK } I 6076 CH, C 626.3 oR ae / ~~ N : 6077 CHg; ’ C 642.3 oR
Ag ¥ oH 6078 CH; C 695.4
Ton | R ® Mg ¥ ) 6079 CH; C 654.3
BN
~ J 3 ,
N oH 6080 | CHa c 682.4 2
Ag ; ’
N oH 6081 CH; C 668.4
A a ‘ ’
N
0 H 6082 CH; C 655.4 oR
Ms ¥ )
N-— : / . 6083 CHs ¢ C 553.3
A
R’ 5 ICs, | ECso | m/z . M+H)* — — - ji — NE S—— RE I— |! od 6084 | CHa Bi C 512.3 } = h% 8085 | CHa T C 583.3
NTN
Ly & 2 6086 | CHa C 640.3 pa ¥ (e} H ( 6087 | CHa c 612.3
S
— ¥
H
6088 | CHa T C 626.3
NN
\_ As 0
N
H
6089 | CHa C 508.3
S
H,N ¥ 6090 | CHa C 597.3 oN 8091 | CHa Cc 640.4 pa ¥ —N 6092 | CH, C 656.4
NN
Js ¥ oh
® 188
OG, ICs ECso m/z . (M+H)*
I A RE RCA RR RU
6093 CH, C 700.4 “ © s
O
6094 CH; C 668.4
Ss pe ¢ ® a: 6095 CHj C 696.4
Ss \ ¥ oH 6096 CH; C 682.4 <1y | & s \ ¥ oH 6097 CH; |] 669.4
AIIN
Ss p ¥
N— / 6098 CH; C 567.3 x (I ¥ 6099 CH; I < 9] 526.4 g
CH; ’ De C 541.3
NTN
. Lg
PN 189
R' RY R® ICs ECs m/z. . SO (M+H) (6101 | CH, | | — 1 ©CcH, | C | B | 6123 . = ® 0.165 6102 | CH, | cH, c 620.4
N
6103 | CH; OH, C 620.4 [ ~N N 6 ) 6105 | CH, ~~ C 620.4
J oo ST oo SLT 6110 | CH, T A 633.3 6111 | CH; T C 564.3 : N™ SN §% ' J ’ ¥ 6112 | CH; T 593.3
R' ICso | ECs | mlz . (M+H)"
I EE EE I
8114 | CH, % C 606.3 ' [7] i 6115 | CH, C 606.3
S [7 i Ne
WA, ® 6116 | CHg J Cc 606.3
NX / N
Re 6117 | CH, J C 607.3
HN No 6118 | CH, % 9) 593.3
NT /N\
Es
P ,
C&T - - HEE B 6121 H 549.3
Bi
P ¥ 6122 | CHa C 581.3
AS K
. 3 XY
RY R® ICs ECs m/z (M+H)*
A
6123 | CH, | 1 | _~ 1 C | B | 5034 w NT XX KL _ Ni
OMe 6124 | CH, oO. , | C 656.4
Sa
NN IN Ne) 6125 CH; C 670.4
O=3=0 @® SN N = Cd
TABLE 7 ®) 8 ne NER
N
; Sy - \ 0)
E ICso ECs m/z
M+H)* ® % 7001 $ Cc 577.3
NTR lL Y CL o 0 7002 ® 7 A | A | 5523
NTR
0 7003 A A 551.3
NTR l ’ . OH 0] 7004 ® 619.2
NT
$ , Cs = / eo} 7005 C 577.3
NT
0 ’ 7006 oH C 577.2
C goss . 7007 « onl © 627.2
NS
S , Co
Cl
> 193
SY ICs | ECso| m/z . (M+H)* 2 7008 T OH Cc 596.2 \—/ N 0] 7009 C 603.3
OL | Ppp 4
J
: le] 7010 Cc 617.3
Soa... y ¥ [ ) |) @ 7011 C 577.3 > ! PP S ,
OH
0 7012 OH Cc 590.3
O&K |Top lL No 7013 & Cc 631.3 o © a. ¥ Cy 0 7014 : ® C 591.3
NH, YY
OH o} 7015 g OH Cc 604.3 ;
NH, » ¢ N fo} 7016 Cc 617.3 &, o OH /
NH, ©
® 194 pe ICs ECs m/z (M+H)* hs 7017 C 631.3 o, OH ¥ (I
NH, 7018 C 591.4 a,
NH, lo} 7019 C 608.3 ¢ |S Cy, d ¥ 0) OH
J fo) 7020 C 617.3 =N 9 , o OH fo 7021 C 631.3 : | NN 5 o OH
FZ ¥ | / 0 7022 C 591.3 () X
OH
(o} 7023 “Co Lc 604.4
PE ¥ N le] 7024 C 618.3 . SN
Z NH ¥ 0 OH ? / eo} 7025 C 632.3 . Pi N 5 0 OH : ¥ WW; le}
® 195 :
DE ICsp ECs m/z . M+H)*
Ny (M+H) 7026 : Cc 592.3 i | SN
ZS Nr, ¥
OH lo] 7027 OH C 605.3
AY A\
Z NH, ¥ \ o} 7028 Cc 617.3 ~N .
Fo | N N 2 0 OH ® = ¥ | » o) 7029 C 631.3 :
SN
_ 0 OH ; , ® o) 7030 $ C 591.4
OH
(0) 7031 OH C 604.3 7) ; = ¥ \ 0 7032 C 617.3 > \ $ 2 0 OH ~N Y p o) 7033 C 631.4 . AS y Oo, OH
ZN Y | p : fo)
: nL ICs | ECsp m/z (M+H)" ’ a, 7034 C 591.4 ® X
ZN ¥
OH fo) 7035 ToL C 604.3
PN \ o) 7036 A C 604.3 “3 ~ @® J S 2, o oH
No =~ | Pp: 0 7037 A C 618.3
NI
J) & 0 OH
N= XY p o 7038 $ -C 578.3
A
OH
0 7039 x 8% CO C 613.3
A ¥ N © 7040 C 603.3
A ’ y &
N | Y 5 7041 C 617.3
A © on
Ne , Wa 7042 5 A | A | 6313 7) 2
PZ 0 OH
Cs
® 197 cpd # RY R® ICso ECs m/z - SN (M+H)* 7043 A A | 6454 * NN
P/E < ¢ oH
[0] 7044 A A | 605.4
NN
9 ¥
OH
. 0] 7045 on | A A | 618.4
LC) = ¥ \ 0 7046 0 C 650.2 ~N S ¥ EN = OH
S [e] 7047 T C 609.3
ON oO OH = ’ . y 7048 T C 623.3
S NN es YY o_ PH
J
[eo] 7049 T C 583.3 a S 2,
OH
(e} 7050 : C 617.4 ' \ 2 fo) OH
N ¥ Cs,
TE, ICso | ECs m/z . (M+H)* he 7051 OH Cc 604.4
N 0 ¥ \
NH, 7052 C 622.3
LS 5 o on s ¥ [) [e] 7053 Cc 582.3
N o HS
OH
(o] 7054 ol © 595.3
DAR Ye Cr g Y N lo) 7055 A | 571.3 0) KL
PZ NN
¥ | J
N
7056 LH o | A 647.4 ’ “4 [oN a gm g ®! 7057 C 636.3
N OH siEsAnesS = “, Ss 0) 7058 J C 592.4
Oy) g Nee
OH
[23 oO
J rR R° ICso | ECsp m/z
ON (M+H)* 7059 H C A 601.4 = p SN } Pun 7060 \ C 620.5
Bi N ~, OH ¥ J ® 7061 J C 637.3 oo Sel \ “Crd
NA Se s lo} 7062 N o | C 577.4 - “7
P YY N OH
7063 Ny 592.4
NN
P ¥ N\ s 7064 C 607.3 | . 7) 5% “oid yy XY 5 fo) 7065 A 586.4 =N
P S 2, NY a — 7066 N A A 634.4
OH
S pe to) 7067 % Cc 615.4 : SN a N = , NN
Pn,
DE, ICs ECs m/z
M+H)* . (M+H) 7068 C 572.4 ] , 4 Oo oY
Ne le] 7069 C 600.4 /N
Qi Cy x I 7 7070 518.4 ® ZN > ’ Q, x | N 7071 on C 509.3 = N S , § _ 7072 C 509.4 = : ¢ C oH
NS . 7073 493.4 = h S , OD : NS 7075 C 620.5 / A
Jv | Ty
A N=.
NH, . 7076 C 536.4
Xx | ©
RY Rr’ ICso | ECsp m/z & ey (M+H)* 7077 C | B | 5324 = N ¥ X
Xn 7078 575.3 = nl Y xy ™ 7079 C 561.3 ° L&C,
Ww
XX
7080 P= C | A | 5085 es “ 7081 y; | C | A | 5223
N
]
Xx 7082 PE ° C 504.2
X \ = N ge OH .
XX
7083 “01 C 537.3 ~~ ’ y COOH
Xn
® 202
TABLE 8
N
\ A oS . R \ H 0) = OH 0
SY ICso ECs m/z } (M+H)" @® I EE I A TL. NS A 8001 S A A 566.3 = N S$ ,
AN
8002 S < A A 554.3 = °N
NN
8003 S 555.3
AS
J : ’ 8004 S al Cc 543.3
N .
A
0] 8005 A 550.3
NS
=~ °N . “~ {
® . 203
TABLE 9
H.C VRC RH
Wg \
N N N
N Wr
R—Q\ H = oO = OH 0 cpd. RL R® (Cs ECs m/z # > M+H)* ® HE EE S.A I I i : Cc 567 4
AS ¥ o)

Claims (1)

  1. CLAIMS . 1. An isomer, enantiomer, diastereoisomer, or tautomer of a compound, » represented by formula |: / v' M A So R— : L B = K om wherein: Ais O, S, NR, or CR’, wherein R' is selected from the group consisting of: H, ® (Ci.s)alkyl optionally substituted with: -halogen, OR", SR" or N(R"), wherein R'' and each R'is independently H, (Ci.e)alkyl, (Cas)cycloalkyl, (Cy.)alkyl-(Cay)cycloalkyl, (Cy.g)alkyl-aryl or (Cy. c)alkyl-Het, said aryl or Het optionally substituted with R'®; or both R'?are covalently bonded together and to the nitrogen to which they are both attached to form a 5, 6 or 7-membered saturated heterocycle; a represents either a single or a double bond; R2is selected from: halogen, R*, OR, SR*', COOR?, SO.N(R?),, N(R®),, , CON(R?),, NR**C(O)R? or NR”C(O)NR? wherein R?' and each R*® is independently H, (Ci.g)alkyl, haloalkyl, (Ca.¢)alkenyl, (Cs7)cycloalkyl, (Co.g)alkynyl, (Cs. s)cycloalkenyl, 6 or 10-membered aryl or Het, said R*' and BR? being optionally substituted with BR’; or both R* are bonded together to form a 5, 6 or 7-membered saturated heterocycle with the nitrogen to which they are attached; B is NR® or CR®, with the proviso that one of A or B is either CR or CR®, — wherein R® is selected from (Cy.g)alkyl, haloalkyl, (Cs5)cycloalkyl, (Cs)cycloalkenyl, (Ce.10)bicycloalkyl, (Ce.1o)bicycloalkenyl, 6- or 10-membered aryl, Het, (Cy.)alkyl-aryl ” or (Ci.s)alkyl-Het, said alkyl, cycloalkyl, cycloakenyl, bicycloalkyl, bicycloalkenyl, aryl, Het, alkyl- aryl and alkyl-Het being optionally substituted with from 1 to 4 substituents selected from: halogen, or
    ® 205 a) (C,.¢)alky! optionally substituted with: - - OR* or SR® wherein R®' is H, (C1.salkyl), (Ca.7)cycloalkyl, (Cy-0)alkyl-(Ca)cycloalkyl, aryl, Het, (C1.e)alkyl-aryl or (Gi. 4 s)alkyl-Het; or - N(R%), wherein each R* is independently H, (C.g)alkyl, (Ca. z)cycloalkyl, (Cq.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.¢)alkyl-aryl or (Cy.¢)alkyl-Het; or both R* are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle;
    b) OR* wherein R* is H, (Cy.¢)alkyl, (Ca7)cycloalkyl or
    (Ci6)alkyl-(Cs7)cycloalkyl, aryl, Het, (C1.¢)alkyl-aryl or (C¢)alkyl-Het;
    ® c) SR* wherein R* is H, (Cre)alkyl, (Car)cycloalkyl, or (C1)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.)alkyl-aryl or (Cy.¢)alkyl-Het; and d) N(R*), wherein each R* is independently H, (C,.)alkyl,
    : (Ca7)cycloalkyl, (Cy.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.)alkyl-aryl or (C,6)alkyl-Het; or both R* are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
    Kis N or CR? wherein R* is H, halogen, (C1.¢)alkyl, haloalkyl, (Cs.7)cycloalkyl or (C;.
    s)alkyl-(Caz)cycloalkyl; or R* is OR*' or SR*', COR" or NR*'COR*" wherein each R* is independently H, (C,s¢)alkyl), (Cs.7)cycloalkyl or (Cy.¢)alkyl-(Cs.7)cycloalkyl; or R* is NR*R*® wherein R* and R* are each independently H, (C;.¢)alkyl, (Ca.
    ;)cycloalkyl, (Cy.g)alkyl-(Cs7)cycloalkyl, or both R*? and R* are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle;
    L is N or CR®, wherein R® has the same definition as R* defined above; ’ 30 ) M is N or CR’, wherein R” has the same definition as R* defined above; Y'is O or S;
    ® Z is OR® wherein R® is C,.galkyl substituted with: a - 1 to 4 substituents selected from: OPO,H, NO, cyano, azido, C(=NH)NH;, C(=NH)NH(C.¢)alkyl or C(=NH)NHCO(C;_g)alkyl; or 4 - 1 to 4 substituents selected from: a) (C1.6) alkyl or haloalkyl, (Ca.7)cycloalkyl, Cs; spirocycloalkyl optionally containing 1 or 2 heteroatom, (C.s)alkenyl, (Cz.g)alkynyl, (C1.¢) alkyi-(Cs. 7)cycloalkyl, all of which optionally substituted with R*%: b) OR wherein R'is (C,.salkyl) substituted with R'™®, (C;.)cycloalkyl, or (C16)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cigalkyl)aryl or (Cy.¢alkyl)Het, said cycloalkyl, aryl, Het, (Cycalkyl)aryl or (C,¢alkyl)Het being optionally substituted with R'*’; L c) OCOR™™ wherein R'® is (Cy.)alkyl, (C3.)cycloalkyl, (C1e)alkyl-(Ca. 7)cycloalkyl, Het, (Cysalkyl)aryl or (Cyealkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C.calkyharyl or (Cs.alkyl)Het being optionally substituted with R'®; d) SR, SOsH, SO;N(R'™), or SO,N(R"®)C(O)R"® wherein each R'™ is independently H, (Cy¢)alkyl, (Caz)cycloalkyl or (Ci.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Csealkyl)Het or both R* are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7- : membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C;. salkyl)aryl or (Cysalkyl)Het or heterocycle being optionally substituted with Rs e) NR''R'™ wherein R""" is H, (Ci.¢)alkyl, (Cs7)cycloalkyl or (Cy.)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (Cy alkylaryl or (Cy.calkyl)Het, and R" is H, CN, (Cy. s)alkyl, (Cs7)cycloalkyl or (Cy. )alkyl-(Cs7)cycloalkyl, aryl, Het, (Cyealkyh)aryl, (Cicalkyl)Het , COOR™ or SOR" wherein R'"® is (C.¢)alkyl, (Ca. 7)cycloalkyl, or (C.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Crsalkylaryl or (C4. salkyl)Het, provided that when R'" is H or unsubstituted alkyl, R"2 is not H or unsubstituted alkyl, or both R''-and R'"? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered ’ 30 saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cysalkyl)aryl, (C;. ) salkyl)Het, or heterocycle being optionally substituted with R'*°; ’ f) NR"™COR™ wherein BR" and R™" is each H, (Cr.¢)alkyl, (Cs7)cycloalkyl (C1-e)alkyl-(Caz)cycloalkyl, aryl, Het, (C,salkyl)aryl or (Ci-salkyl)Het, said (C,. e)alkyl, (Cs7)cycloalkyl, (Cy.¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy-alkyl)aryl or
    ® 207
    (C.salkyl)Het being optionally substituted with R"; r g) NR" CONR'®R'®, wherein R""®, R"" and R'? is each H, (Ci.)alkyl, (Ca 7)cycloalkyl, (C16)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Cs. ’ salkyHet, or R""® is covalently bonded to R'° and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; : or R'® and R™° are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C16)alkyl-(Cs7)cycloalkyl, aryl, Het, (C1.salkylaryl or (Ci- salkyl)Het or heterocycle being optionally substituted with R'®; h) NR'2'COCOR' wherein R™' and R™ is each H, (Ci.¢)alkyl, (Ca. s)eycloalkyl, (Ca.s)alkyl-(Ca)cycloalkyl, a 6- or 10-membered aryl, Het, (C4. @® salkyl)aryl or (C.salkyhHet, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cysalkyl)aryi or (C1.salky)Het being optionally substituted with R', or RZ is” OR'?® or N(R'?), wherein R*? and each R'** is independently H, (Cigalkyl), (Csy)cycloalkyl, or (C1.6)alkyl-(Cs7)cycloalkyl, aryl, Het, (C1.¢alkyharyl or (Cs. salkyhHet, or R'** is OH or O(Cy.salkyl) or both R'?* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C1.calkyl)aryl or (Ci.salkyl)Het and heterocycle being optionally substituted with Rr"; i) COR'Z wherein R'¥ is H, (C1.s)alkyl, (Ca7)cycloalkyl or (C1.0)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Cyealkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cycalkyl)aryl or (Ci.salkyl)Het being optionally substituted with R',; j) COOR'™® wherein R'? is (C+ .)alkyl substituted with R**°, (Cs5)cycloalkyl, or(C1.)alkyl-(Cs)cycloalkyl, aryl, Het, (Cygalkyl)aryl or (Cy.alkyl)Het, said (Cs. 7)cycloatkyl, or(C1.g)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cisalkyl)aryl and (Cs. salkyhHet being optionally substituted with R'%; k) CONR'®R™ wherein R'*® and R'*’ are independently H, (Ci.)alkyl, (Ca ;)cycloalkyl, (Ci.)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cysalkyharyl or (C+. . salkyl)Het, or both BR"? and R™° are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated . heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Crsalkyl)aryl,
    (C+.calkyl)Het and heterocycle being optionally substituted with R*°; I) aryl, Het, (Cisalkyl)aryl or (Ci.calkyl)Het, all of which being optionally substituted with R'®°, wherein R'®’ is selected from:
    ® - 1 to 3 substituents selected from: halogen, NO,, cyano, azido or ” - 1 to 3 substituents selected from: a) (Cy.6) alkyl or haloalkyl, (Cs)cycloalkyl, Cs spirocycloalkyl 0 optionally containing 1 or 2 heteroatom, (Co.s)alkenyl, (C1.¢) alkyl-(Cs. s)cycloalkyl, all of which optionally substituted with R'®’; b) OR wherein R'™ is H, (Cysalkyl), (Csz)cycloalkyl, or (C1.s)alkyl- (Ca7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cy.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cs.calkyl)Het being optionally . substituted with R'®; ¢) OCOR™ wherein R'is (Cy.g)alkyl, (Ca)cycloalkyl, (Ci.q)alkyl-(Cs. 7)cycloalkyl, Het, (Cyalkyl)aryl or (Cy.calkyl)Het, said alkyl, cycloalkyl, ® aryl, Het, (Cy.calkyharyl or (Cialkyl)Het being optionally substituted with R™; d) SR SO,N(R'), or SO.N(R'®)C(O)R'® wherein each R'is independently H, (C.)alkyl, (Cs.7)cycloalkyl or (Ci.¢)alkyl-(Cs. 7)cycloalkyl, aryl, Het; (Cisalkyl)aryl or (Cy.salkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Calkyl)aryl or (C,.¢alkyl)Het or heterocycle being optionally substituted with R*®: e) NR"'R" wherein R""" is H, (C.)alkyl, (Cs.7)cycloalkyl or (Cy. s)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.calkyl)aryl or (C,.salkyl)Het, and R"2is H, (Cie)alkyl, (Csz)cycloalkyl or (Cy.g)alkyl-(C3.)cycloalkyl, aryl, Het, (C..calkylaryl, (Cisalkyl)Het , COOR'® or SO,R'"® wherein R''® is (C1.g)alkyl, (Caz)cycloalkyl, or (Cy.g)alkyl-(Cs5)cycloalkyl, aryl, Het,
    (C1.calkyharyl or (Cyealkyl)Het, or both R'" and R™2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C1.alkyl)Het, or heterocycle : 30 being optionally substituted with R'®; f) NR"'®*COR" wherein R""® and RB" is each H, (Cy.)alkyl, (Cs. ’ 7)cycloalkyl, (C,.s)alkyl-(Cs)cycloalkyl, aryl, Het, (C1.salkyl)aryl or (C,. salkyl)Het, said (C+.¢)alkyl, (Cs.7)cycloalkyl, (Cy.¢)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci¢alkylaryl or (C,.salkyl)Het being optionally substituted
    ® 209 with R'%% ; g) NR"™CONR™R™, wherein R™™, R™® and R™ is each H, (C+. slalkyl, (Ca7)cycloalkyl, (Ci.c)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C1. 6 salkyharyl or (C,.calkyl)Het, or R""? and R'?° are covalently bonded together and to the nitrogen. to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Gh slalkyl-(Cs)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C,.salkyl)Het or heterocycle being optionally substituted with R?: h) NR''COCOR'? wherein R™' is H, (C,.)alkyl optionally substituted with R'™, and R'is OR'® or N(R'?*), wherein R'? and each R'is independently H, (C1.calkyl), (Cs7)cycloalkyl, or (Cy.e)alkyl- ® (Cs.7)cycloalkyl, aryl, Het, (C4.salkyl)aryl or (Cq.salky))Het, or R** is OH or O(C;.calkyl) or both R'** are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (Cisalkyl)aryl or (C.salkyl)Het and heterocycle being optionally substituted with R'°; j) tetrazole, COOR™® wherein R'?® is H, (Cys)alkyl, (Caz)cycloalkyl, or(C.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.galkylary! or {Cisalkyl)Het, said (Cy.g)alkyl, (Csz)cycloalkyl, or(Ci.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Ciealkylaryl and (C.salkyl)Het being optionally substituted with R®°; and k) CONR'°R'™ wherein R™ and R™ are independently H, (C.. slalkyl, (Cs7)cycloalkyl, (Ci.¢)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cs. salkyl)aryl or (Cssalkyl)Het, or both R™® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cysalkyl)aryl, (Cy.salkyl)Het and heterocycle being optionally substituted with R°; wherein R' is defined as 1 or 2 substituents selected from: ’ 30 tetrazole, halogen, CN, C1.salkyl, haloalkyl, COOR'™', SOsH, SOR, OR, N(R"), SON(R'®),, NR™2COR?, or ) CON(R'®),, wherein BR" and each R'2is independently H, (Cie)alkyl, (Ca.7)cycloalkyt or (Cy.6)alkyl-(C3.7)cycloalkyl; or both R'®* are covalently bonded together and to the nitrogen to
    * which they are attached to form a 5, 6 or 7-membered . saturated heterocycle; y or Z is OR® wherein R® is (Cyealkyl)aryl substituted with: - 1 to 4 substituents selected from: OPO;H, azido, C(=NH)NH,,
    C(=NH)NH(C.s)alkyl or C(=NH)NHCO(C,.)alkyl; or - 1 to 4 substituents selected from: a) (Ci.e)alky! substituted with R®*, haloalkyl, (Cs.;)cycloalkyl, Ca.7 spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cog)alkenyl, (Ca.
    s)alkynyl, (C1) alkyl-(Cs)cycloalkyl, said haloalkyl, cycloalkyl, spirocycloalkyl, alkenyl, alkynyl and alkyl-cycloalkyl being optionally substituted with R'°,
    ® wherein R'** is the same as R' but is not COOR™*®, N(R5),, NR™®C(O)R™®, OR™™, SR™®, SOR", SON(R'*),, wherein R'is H or unsubstituted C.salkyl;
    b) OR wherein R'™ is (C;.galkyl) substituted with R'®, (Cs7)cycloalkyl, or (Cre)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cyealkylaryl or (C,.salkyl)Het, said cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Ci.calkyl)Het being optionally substituted with R'%°;
    c) OCOR'® wherein R'* is (C,.)alkyl, (Ca7)cycloalkyl, (C1.e)alkyl-(Cs.
    7)cycloalkyl, Het, (Cyalkyl)aryl or (Cqsalkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cisalkyharyl or (C4 salkyl)Het being optionally substituted with R*®;
    d) SR, SO,N(R"*), or SO,N(R'*®)C(O)R'® wherein each R'® is independently H, (Ci.)alkyl, (Caz)cycloalkyl or (Ci)alkyl-(Csz)cycloalkyl, aryl, Het, (Cs.salkylaryl or (C;.¢alkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,. salkylaryl or (C,.salkyl)Het or heterocycle being optionally substituted with R'°, wherein R'°® is the same as R'® but is not H or unsubstituted Cr.salkyl; e) NR'R""? wherein B'" is H, (C.)alkyl, (Cs)cycloalkyl or (C,.g)alkyl-(Ca.
    a 30 7)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Cy calkyl)Het, and R'is H, CN, (C.. s)alkyl, (Caz)cycloalkyl or (Cyg)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cigalkylaryl,
    ) (Crealkyl)Het , provided that when R'" is H or unsubstituted alkyl, R'*2 is not H or unsubstituted alkyl, or R'is also COOR'" or SOR "52 wherein R'is H, (Ci)alkyl, (Cs.7)cycloalkyl, or (Cy.¢)alkyl-(Cs;)cycloalkyl, aryl, Het, (C,.
    ® salkyl)aryl or (C1.¢alkyl)Het, and R'**? is the same as R'"® but is not H or . unsubstituted alkyl, or both R'"" and R'"2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryi or (C.. salkyl)Het, or heterocycle being optionally substituted with R**% f) NR'"®*COR™” wherein R"'® and R"" is each (C,.)alkyl substituted with R™, (Cs)cycloalkyl, (Cy)alkyl-(Ca)cycloalkyl, aryl, Het, (Cy.calkyharyl or (Cs. salkyl)Het, said (Ca.s)cycloalkyl, (C1.s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,. salkyl)aryl or (C+.calkyl)Het being optionally substituted with R'*: g) NR'CONR'R', wherein R""®, R" and R'is each H, (Cy.¢)alkyl, (Ca. 7)cycloalkyl, (C1.¢)alkyl-(C.7)cycloalkyl, aryl, Het, (Cy.galkyaryl or (C+. ® salkyhHet, or R"® is covalently bonded to R'® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R'"® and R™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Cy.¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (C;. salkyl)Het or heterocycle being optionally substituted with R'%: h) NR'?'COCOR'? wherein R'' and R™ is each H, (C.¢)alkyl, (Cs. rcycloalkyl, (Cy.s)alkyl-(Csz)cycloalkyl, a 6- or 10-membered aryl, Het, (C.. salkyl)aryl or (Ci.calkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Ciealkyl)aryl or (C,.calkyl)Het being optionally substituted with R'*; or R'is OR™ or N(R"), wherein R'®and each R'* is independently H, (Crealkyl), (Car)cycloalkyl, or (Cy.g)alkyl-(Ca.z)cycloalkyl, aryl, Het, (Cs. salkyl)aryl or (Cy.calkyl)Het, or R'* is OH or O(C, alkyl) or both R'** are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C.calkyl)ary! or (Crsalkyl)Het and heterocycle being optionally substituted with R*™; i) COR™ wherein R' is (Cy.c)alkyl substituted with R'®, (C,.7)cycloalkyl or
    (Ci.e)alkyl-(Csz)cycloalkyl, aryl, Het, (C,.alkyl)aryl or (C,ealkyl)Het, said ’ 30 cycloalkyl, aryl, Het, (C+.salkyl)aryl or (C,calkyl)Het being optionally ) substituted with R'°; j) COOR™® wherein R' is (Cy.¢)alkyl substituted with R'®, (Cs.)cycloalkyl, or(Ci.¢)alkyl-(Cs7)cycloalkyl, aryl, Het, (C;.salkyl)aryl or (C;alkyl)Het, said (Ca. 7)cycloalkyl, or(Cy.s)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl and (Cy-
    ® salkyl)Het being optionally substituted with R'®; o k) CONR'?*R'™ wherein R'™ and R' are independently H, (Ci.)alkyl, (Ca. 7)cycloalkyl, (Cyg)alkyl-(Cs)cycloalkyl, aryl, Het, (Cy.calkylaryl or (Cs.
    Eg salkyl)Het, provided that when R'? is H or unsubstituted alkyl, R™ is not H or unsubstituted alkyl, or both R™® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C;. salkyl)aryl, (C.salkyl)Het and heterocycle being optionally substituted with R50: I) aryl, Het, (Cy.calkyl)aryl or (C1.ealkyl)Het, all of which being optionally substituted with R'*°, wherein R'is: ® - 1 to 3 substituents selected from: halogen, NO,, cyano or azido; or . -1 to 3 substituents selected from: a) (C.) alkyl or haloalkyl, (Cs7)cycloalkyl, Cs; spirocycloalkyl optionally containing 1 or 2 heteroatom, (C..s)alkenyl, (C,.g)alkynyl, (C16) alkyl-(Cs.7)cycloalkyl, all of which optionally substituted with R'®: b) OR™ wherein R'™ is H, (Cy.salkyl), (Ca7)cycloalkyl, or (C4.)alkyl- (Cax)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cy salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C.alkyl)aryl or (Ci.calkyl)Het being optionally substituted with R'®°;
    c) OCOR™ wherein R'® is (C;.)alkyl, (Car)cycloalkyl, (Cs.e)alkyl-(Cs. 7)cycloalkyl, Het, (C;galkyl)aryl or (Cy alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C4_salkyl)aryl or (Cysalkyl)Het being optionally substituted
    - with R"™;
    d) SR, SON(R'®), or SO.N(R"™)C(O)R® wherein each R'® is independently H, (Cy4)alkyl, (Cs7)cycloalkyi or (Cy¢)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (Cy.alkyl)aryl or (C,.galkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said } 30 alkyl, cycloalkyl, aryl, Het, (C;.alkyl)aryl or (C;.calkyl)Het or heterocycle being optionally substituted with R'®%; ’ e) NR"'R" wherein R™ is H, (Cy.s)alkyl, (Cs-)cycloalkyl or (Cr. s)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cy.galky)Het, and R'2is H, CN, (Cy.¢)alkyl, (Cs.s)cycloalkyl or (C1.)alkyl-(Ca7)cycloalkyl,
    ° 213 aryl, Het, (Cialkylaryl, (Csalkyl)Het , COOR'"® or SO,R"*° wherein “ R'8 is (Cy.g)alkyl, (Ca)cycloalkyl, or (Cy.)alkyl-(Caz)cycloalkyl, aryl, Het, (C:.calkyl)aryl or (Ciealkyl)Het, or both R'" and R"? are * covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said atkyl, cycloalkyl, aryl, Het, (C1.satkyl)aryl or (Cysalkyl)Het, or heterocycle being optionally substituted with R'®, f) NR"®COR'"” wherein R™™® and R" is each H, (Cxs)alkyl, (Ca. s)cycloalkyl, (Cyg)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy salkyl)aryl or (C4- salkyl)Het, said (Ci.)alkyl, (Ca)cycloalkyl, (Cig)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,salkyl)aryl or (C4.¢alkyl)Het being optionally substituted ® with R"®; g) NR'™CONR''*R'®, wherein R"®, R""? and R'® is each H, (C1. s)alkyl, (Cs.s)cycloalkyl, (Ci.s)alkyl-(Ca7)cycloalkyl, aryl, Het, (C;. salkyl)aryl or (Cialkyl)Het, or R'*® and R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Cr. g)alkyl-(Cs7)cycloalkyl, aryl, Het, (C1.calkyl)aryl or (C4.salkyl)Het or heterocycle being optionally substituted with R'®; h) NR'™COCOR" wherein R*?! is H, (Cy)alkyl optionally substituted with R'®%; and R*?? is OR or N(R'**), wherein R'® and each R'?* is independently H, (Cy.salkyl), (Css)cycloalkyl, or (Ci.g)alkyl-
    (Ca.z)cycloalkyl, aryl, Het, (C1.calkyl)aryl or (C,.¢alkyl)Het, or R™*is OH or O(Cy.salkyl) or both R'** are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Ci.calkyl)Het and heterocycle being optionally substituted with R'®; J) tetrazole, COOR'? wherein R'® is H, (Cy.)alkyl, (Cs.s)cycloalkyl, ] or(C1.g)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Ci¢alkyl)Het, said (Cy.s)alkyl, (Caz)cycloalkyl, or(C.)alkyl-(Cs7)cycloalkyl, aryl, Het, } (C1-salkyl)aryl and (Cy.galkyl)Het being optionally substituted with R80. and k) CONR'*R' wherein R'*® and R™° are independently H, (Ci. s)alkyl, (Cs)cycloalkyl, (C1.g)alkyl-(Cs7)cycloatkyl, aryl, Het, (Ca.
    ® 214 salkyl)aryl or (Cysalkyl)Het, or both R'® and R'° are covalently - bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, : cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.salkylaryl, (C.alkyl)Het and heterocycle being optionally substituted with R*®; wherein, R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C,.salkyl, haloalkyl, COOR™', SO;H, SO,R™!. OR™" N(R"2),, SO,N(R2),, NR'62COR™2 or CON(R"?),, wherein R'®' and R'®? are as defined above; ‘ or Z is OR® wherein R® is, (Cs.c)cycloalkyl, (Co.¢)alkenyl, 6- or 10-membered aryl, Het, ® (C1.6)alkyl-Het, wherein said cycloalkyl, alkenyl, aryl, Het or alkyl-Het, is optionally substituted with R®®; orZis N(R®)R®, wherein R® is H or (C,salkyl) and RC is (Ci.)alkyl optionally substituted with: - 1 to 4 substituents selected from: OPO3;H, NO,, cyano, azido, C(=NH)NH,, C(=NH)NH(C,.¢)alkyl or C(=NH)NHCO(C,.¢)alkyl; or " -1 to 4 substituents selected from: + a) (Cy) alkyl substituted with R'*®, haloalkyl substituted with R**®, (Cs. 7)cycloalkyl, C57 spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cze)alkenyl, (Ca.g)alkynyl, (Cy.6) alkyl-(Cs7)cycloalkyl, all of which optionally substituted with R'*, wherein R'** is the same as R"* but is not halogen, OH, O(C alkyl), COOH, COO(C1.salkyl), NH,, NH(C, alkyl) and N(Cyealkyl),; b) OR wherein R'™ is (Cgalkyl) substituted with R'*°, (C;)cycloalkyl, or (C1-s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Ci.salkyhary! or (Cy.salkyl)Het, said cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C,.salkyl)Het being optionally substituted with R'>°; c) OCOR' wherein R'is (Cy.¢)alkyl, (Cs7)cycloalkyl, (C1.)alkyl-(Ca. i 30 7)cycloalkyl, Het, (C,.qalkyl)aryl or (C+.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Ci-salkyl)aryl or (C,calkyl)Het being optionally substituted with R'*’; d) SR, SOzH, SON(R'®), or SO.N(R'®)C(O)R*® wherein each R'is independently H, (C.s)alkyl, (Cs.7)cycloalkyl or (C1-6)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C+.salkyl)aryl or (C.salkyl)Het or both R'® are covalently bonded
    ® together and to the nitrogen to which they are attached to form a 5, 6 or 7- e membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C;. salkylaryl or (C.salkyl)Het or heterocycle being optionally substituted with . RS e) NR"'R"? wherein R'"" is H, (C,.)alkyl, {Csz)cycloalkyl or (Cy.)alkyl-(Cs. 7)cycloalky), aryl, Het, (C,.salkyharyi or (Cy.salky))Het, and R"*? is H, CN, (Ci. s)alkyl, (Csz)cycloalkyl or (C4.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cysalkyl)aryl, (Crsalkyl)Het, COOR™"® or SO,R'"® wherein R'** is (C1.c)alkyl, (Cs.7)cycloalkyl, or (Cyg)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C4 alkyl)Het,
    provided that when R""" is H or unsubstituted alkyl, R'* is not H or unsubstituted alkyl, or both R'"" and R'*? are covalently bonded together and ® to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryi or (C;. calkyl)Het, or heterocycle being optionally substituted with R'*’;
    f) NR'"®COR'"” wherein R"'® and R""" is each H, (Ci.¢)alkyl, (Cs.7)cycloalkyl, (C1e)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cyalkyl)aryl or (Cy.salkyl)Het, said (Cy. s)alkyl, (Ca7)cycloalkyl, (Cy.g)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (C1salkyl)Het being optionally substituted with R'°?;
    g) NR'"'®CONR'"R"'®, wherein R""®, R™" and R'® is each H, (C1.)alkyl, (Ca.
    z7)cycloalkyl, (Cy.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cs.salkyl)aryl or (C;. salkyl)Het, or R"® is covalently bonded to R'*® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R""® and R™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C1.g)alkyl-(Ca7)cycloalkyl, aryl, Het, (C,salkyl)aryl or (C,. salkyl)Het or heterocycle being optionally substituted with R'*°,
    h) NR'2'COCOR'® wherein R'*' and R'? is each H, (C1.g)alkyl, (Ca.
    z7)cycloalkyl, (Cy.¢)alkyl-(Cs.7)cycloalkyl, a 6- or 10-membered aryl, Het, (C.
    salkylary! or (C4.salkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, } 30 (Crsalkyl)aryl or (C.alkyl)Het being optionally substituted with R'°;
    or R'# is OR'® or N(R'**), wherein R'? and each R'# is independently H, (Cy .salkyl), (Csz)cycloalkyl, or (Cy.g)alkyl-(Csz)cycloalkyl, aryl, Het, (C,.
    salkylary! or (Cy¢alkyl)Het, or R'** is OH or O(C,.qalkyl) or both R'* are covalently bonded together to form a 5, 6 or 7-membered saturated
    [ . heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.salkyl)aryl or “ (C1salkyl)Het and heterocycle being optionally substituted with R'; i) COR wherein R™ is H, (Cy.¢)alkyl, (Ca)cycloalkyl or (C1.c)alkyl-(Ca.
    . 7)cycloalkyl, aryl, Het, (C,.qalkyl)aryl or (C,.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C,alkyl)Het being optionally substituted with R'’; j) COOR™® wherein R'? is (C1.g)alkyl substituted with R'®, (C;)cycloalkyl, or(C4.¢)alkyl-(Css)cycloalkyl, aryl, Het, (Cy alkyl)aryl or (Cysalky)Het, said (Cs. 7)cycloalkyl, or(C,.s)alkyl-(Cy.7)cycloalkyl, aryl, Het, (C.salkyl)aryl and (C.. salkyl)Het being optionally substituted with R'*°; k) CONR'¥R™ wherein R'? and R' are independently H, (C:.s)alkyl, (Cs. 7)cycloalkyl, (Cq.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.salkylaryl or (C,. ® _ salky)Het, or both R'?® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.¢alkyl)aryl, (Cysalkyl)Het and heterocycle being optionally substituted with R0; I) aryl, Het, (Cy.calkyl)aryl or (Ci.calkyl)Het, all of which being optionally substituted with R'*°, wherein R'® is selected from: - 1 to 3 substituents selected from: halogen, NO,, cyano, azido or - 1 to 3 substituents selected from: a) (C1.) alkyl or haloalkyl, (Ca.s)cycloalkyl, Cs; spirocycloalkyl optionally containing 1 or 2 heteroatom, (C..¢)alkenyl, (Ci.¢) alkyl-(Cs. 7)cycloalkyl, all of which optionally substituted with R'®°; b) OR wherein R'™ is H, (C,.calkyl), (Cs)cycloalkyl, or (Cy.c)alkyl- (Cax)cycloalkyl, aryl, Het, (Cq.calkyl)aryl or (C,.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C1.calkyl)aryl or (Ci.salkyl)Het being optionally : substituted with R™; c) OCOR' wherein R'® is (C,.)alkyl, (Cs7)cycloalkyl, (Cy.q)alkyl-(Ca. 7)cycloalkyl, Het, (C,.calkyl)aryl or (C,.calkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,salkyl)Het being optionally substituted ) 30 with R'®; d) SR'® SO,N(R"), or SO,N(R'**)C(O)R"™® wherein each R'® is independently H, (C1.)alkyl, (Cs5)cycloalkyl or (Cyg)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C.alkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are
    ® 217 attached to form a 5, 6 or 7-membered saturated heterocycle, said “ alkyl, cycloalkyl, aryl, Het, (Cisalkyl)ary! or (C4.calkyl)Het or heterocycle being optionally substituted with R'?; : e) NR'R""2 wherein R'" is H, (Ci.c)alkyl, (Ca.r)cycloalkyl or (Cy. s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,salkyl)aryl or (C.salkyl)Het, and R'is H, (Ci.6)alkyl, (Ca.z)cycloalkyl or (Cy.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl, (Cisalkyl)Het , COOR'® or SO,R'"®* wherein R'"* is (Ci6)alkyl, (Cs 7)cycloalkyl, or (Cy.¢)alkyl-(Csz)cycloalkyl, aryl, Het,
    (Cy.salkyharyl or (Cysalkyl)Het, or both R'" and R'"? are covalently bonded together and to the nitrogen to which they are attached to ~~ form a5, 6 or 7-membered saturated heterocycle, said alkyl, ® cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Ci.salkyl)Het, or heterocycle being optionally substituted with R'®; f) NR'"°COR'"” wherein R''® and R""" is each H, (Cy.)alkyl, (Cs. z)cycloalkyl, (C.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cq.salkyl)aryl or (C,. salkyl)Het, said (C1.)alkyl, (Cs7)cycloaikyl, (Cy.¢)alkyl-(Cs7)cycloalkyl, aryl, Het; (Cy.qalkyl)aryl or (Ci.salkyl)Het being optionally substituted with R'®%; g) NR CONR'"R'®, wherein R"®, R'*® and R'* is each H, (C.. s)alkyl, (Cs.z)cycloalkyl, (Ci.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,. salkyl)aryl or (Cy.calkyl)Het, or R""® and R'?° are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Ci. slalkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.galkyl)aryl or (C4 salkyl)Het or heterocycle being optionally substituted with R'®’; h) NR''COCOR' wherein R'?' is H, (C.¢)alkyl optionally substituted with R'®, and R'?? is OR'® or N(R'?%), wherein R'* and each R™* is independently H, (Cy.salkyl), (Caz)cycloalkyl, or (Cy s)alkyi- ) (Cs)cycloalkyl, aryl, Het, (Cy.salkylaryl or (Cy.¢alkyl)Het, or R'* is OH or O(Cy.¢alkyl) or both R'* are covalently bonded together to form a 5, A 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alky!- cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (CssalkyhHet and heterocycle being optionally substituted with R™®; j) tetrazole, COOR'® wherein R'2 is H, (C.s)alkyl, (Ca)cycloalkyl,
    ® | | 218 or(Cy.s)alkyl-(Cs)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cyealkyl)Het, ‘ said (C+.g)alkyl, (Ca.7)cycloalkyl, or(C4.q)alkyl-(Ca7)cycloalkyl, aryl, Het, (C1ealkyl)aryl and (C,.¢alkyl)Het being optionally substituted with R®": gE and k) CONR'R'® wherein R™ and R'® are independently H, (C;. s)alkyl, (Csz)cycloalkyl, (Cy.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Ci. salkylaryl or (Cyealkyl)Het, or both R'® and R™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C4salkyl)aryl, (C,salkyl)Het and heterocycle being optionally substituted with R'®; ® wherein R" is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C;alkyl, haloalkyl, COOR'®!, SO,H, SOR", OR! N(R'6?),, SO,N(R'2),, NR'2COR'®2 or CON(R'®),, wherein R'® and Rare as defined above: or Z is N(R®)R® wherein R* is as defined above and R® is (Cag)cycloalkyl, (Cag)alkenyl, 6- or 10-membered aryl, Het, (C+.o)alkyl-aryl, (Ci.s)alkyl-Het, wherein said alkyl, cycloalkyl, alkenyl, aryl, Het, alkyl-aryl, or alkyl-Het, are all optionally substituted with R®; or Z is OR® or N(R®*)R® wherein R®® is as defined above and R® is:
    NV. Cr " vy? wherein R” and R® are each independently H, (C1.s)alkyl, haloalkyl, (Ca)cycloalkyl, 6- or 10-membered aryl, Het, (Cy.c)alkyl-aryl, (C1.¢)alkyl-Het, wherein said alkyl, cycloalkyl, aryl, Het, (C,.¢)alkyl-aryl, (C,)alkyl-Het are optionally substituted with rR" . or R” and R® are covalently bonded together to form second (Cs:y)cycloalkyl or a 4, 5- or - 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; ‘orwhen Zis N(R®)R®, either of R” or R? is covalently bonded to R® to form a nitrogen-containing 5-or 6-membered heterocycle;
    ® 219 Y2isOorS; R® is H, (Cy. alkyl), (Ca7)cycloalkyl or (C16)alkyl-(Ca.z)cycloalkyl, aryl, Het, (C,.¢)alkyl- aryl or (Ci.g)alkyl-Het, all of which optionally substituted with R*’; or Ris covalently bonded to either of R” or R® to form a 5- or 6-membered heterocycle; Q is a 6- or 10-membered aryl, Het, (C5) alkyl-aryl, (C1.) alkyl-Het, (C,.) alkyl- CONH-aryl or (C+) alkyl-CONH-Het, all of which being optionally substituted with: . Jr. o 00H A o AP oon 0 COOH or RR: ® 10 ora salt or a derivative thereof; : wherein Het is defined as 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, or a 9- or 10-membered heterobicycle having 1 to 5 heteroatoms selected from O, N and S; and
    R', R%, R°®R", R% and R'” is each defined as: - 1 to 4 substituents selected from: halogen, OPOsH, NO,, cyano, azido, C(=NH)NH,, C(=NH)NH(C)alkyl or C(=NH)NHCO(C,_g)alkyl; or - 1 to 4 substituents selected from: a) (C.6) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs. spirocycloalkyl optionally containing 1 or 2 heteroatom, (Ca.¢)alkenyl, (C..g)alkynyl, (C1.6) alkyl-(Ca. 2)cycloalkyl, all of which optionally substituted with R'*’; b) OR™ wherein R'is H, (C,salkyl), (Caz)cycloalkyl, or (Cyg)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C,.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,¢alkyl)aryl or {Ci.salkyl)Het being optionally substituted with RS: c) OCOR'® wherein R'™ is (C1.e)alkyl, (Cs.7)cycloalkyl, (Cis)alkyl-(Cs. 7)cycloalkyl, Het, (Cy.salkyl)aryl or (Cy.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C1salkyl)ary! or (C.alkyl)Het being optionally substituted with R'®; d) SR'®, SO.N(R'®), or SO.N(R)C(O)R"® wherein each R'® is independently H, (Cy.¢)alkyl, (Caz)cycloalkyl or (Cig)alkyl-(Car)cycloalkyl, aryl, Het, (C1.salkyl)aryl or (C1.salkyl)Het or both R'® are covalently bonded
    ® 220 together and to the nitrogen to which they are attached to forma 5, 6 or 7- - membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C.. calkylaryl or (C.ealkyl)Het or heterocycle being optionally substituted with . RS; e) NR'""'R""? wherein R"" is H, (C1.5)alkyl, (Cs)cycloalkyl or (Cy.)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (C;.calkyl)aryl or (Cs.salkyl)Het, and R'is H, CN, (C:. s)alkyl, (Cs7)cycloalkyl or (C.)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cisalkyl)aryl, (Cysalkyl)Het , COOR'™ or SO,R""* wherein R''® is (Cy.s)alkyl, (Ca. s)eycloalkyl, or (C1.s)alkyl-(Cs;)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cs. calkyl)Het, or both R"" and R**? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated @ heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cicalkyl)aryl or (Cisalkyl)Het, or heterocycle being optionally substituted with R'; f) NR''®COR"” wherein R*'® and R'" is each H, (Cy.)alkyl, (Ca.7)cycloalkyl,
    (C1.6)alkyl-(Css) cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,.alkyl)Het, said (C;. s)alkyl, (Ca.y)cycloalkyl, (Ci¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or
    (Cr.salkyl)Het being optionally substituted with R'>’; g) NR'®CONR'"*R'?, wherein R"'?, R""® and R'is each H, (C1s)alkyl, (Ca. s)eycloalkyl, (Ci.g)alkyl-(Cs7)cycloalkyl, ary, Het, (Cisalkyl)aryl or (C4. calkyl)Het, or R"*® is covalently bonded to R'**'and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R"™® and R'™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Cy.¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cisalkyharyl or (C;. salkyl)Het or heterocycle being optionally substituted with R'™; h) NR''COCOR'® wherein R'?' and R'? is each H, (Cy.s)alkyl, (Ca J)eycloalkyl, (C1.6)alkyl-(Car)cycloalkyl, a 6- or 10-membered aryl, Het, (C;. calkyharyl or (C1.calkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C1salkyl)aryl or (C1.salkyl)Het being optionally substituted with RB’; or R'2is OR™ or N(R"), wherein R'*® and each R'?* is independently H,
    (C.alkyl), (Caz)cycloalkyl, or (Cy.c)alkyl-(Car)cycloalkyl, aryl, Het, (Ci. salkyharyl or (Cysalkyl)Het, or R'?* is OH or O(C,.6alkyl) or both R™* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C1.salkyl)aryl or
    ® 221
    (Cy.6alkyl)Het and heterocycle being optionally substituted with R'% : i) COR™ wherein R™ is H, (C-.¢)alkyl, (Ca7)cycloalkyl or (Cy.)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cy alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,salkylaryl or (C+.salkyl)Het being optionally substituted with R'; ) COOR™® wherein R'is H, (Cy.)alkyl, (Ca)cycloalkyl, or(Cre)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cyalkyl)Het, said (C1.¢)alkyl, (Cs. 7)cycloalkyl, or(Cy.)alkyl-(Cs7)cycloalkyl, aryl, Het, (C.salkyl)aryl and (Cy. salkyl)Het being optionally substituted with R*°; k) CONR'®R™ wherein R'*® and R'® are independently H, (C,.c)alkyl, (Ca. 7)cycloalkyl, (C1g)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,.¢alkyl)aryl or (C,. : salkyl)Het, or both R™ and R' are covalently bonded together and to the @ nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C;.salkyl)aryl,
    (C1.salkyl)Het and heterocycle being optionally substituted with R'*°; I) aryl, Het, (Cy.calkyl)aryl or (Cisalkyl)Het, all of which being optionally substituted with R's wherein R'® is defined as: - 1 to 3 substituents selected from: halogen, OPO3;H, NO,, cyano, azido, G(=NH)NH,, C(=NH)NH(C;_)alkyl or C(=NH)NHCO(C.¢)alkyl; or - 1 to 3 substituents selected from: a) (C1.6) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs; spirocycloalkyl ' optionally containing 1 or 2 heteroatom, (Cz.g)alkenyl, (C.s)alkynyl,
    (C1.6) alkyl-(Cs7)cycloalkyl, all of which optionally substituted with R'®°: b) OR wherein R'™ is H, (C,salkyl), (Cs7)cycloalkyl, or (C4.)alkyl- (Cas)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Cy salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,galkylaryl or (C1.calkyl)Het being optionally substituted with R*®°; c) OCOR'® wherein R'® is (Cy.)alkyl, (Cs.z)cycloalkyl, (C1.)alkyl-(Cs. 7)cycloalkyl, Het, (C.galkyl)aryl or (C,.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cyalkyl)aryl or (C1.calkyl)Het being optionally substituted with R"™®; d) SR'®, SO.N(R'™), or SON(R'*)C(O)R'™ wherein each R'® is independently H, (C,.6)alkyl, (Cs.7)cycloalky! or (Cy.)alkyi-(Cs. 7)cycloalkyl, aryl, Het, (C4.salkyl)aryl or (Cyalkyl)Het or both R'% are
    J covalently bonded together and to the nitrogen to which they are > attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C.salkyl)aryl or (Cyealkyl)Het or : heterocycle being optionally substituted with R'%; e) NR''R""2 wherein R'is H, (C1.s)alkyl, (Cs.7)cycloalkyl or (Ci. s)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C,.salkyl)Het, and R"'2is H, CN, (Cy.e)alkyl, (Ca7)cycloalkyl or (C1.)alkyl-(Ca7)cycloalkyl, aryl, Het, (Ci.calkylaryl, (C;salkyl)Het , COOR" or SO,R'*® wherein R'is (Cy.¢)alkyl, (Cs.7)cycloalkyl, or (C1.6)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cysalkyl)Het, or both R""! and R'* are covalently bonded together and to the nitrogen to which they are ® attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cy.alkyl)aryl or (C,.salkyl)Het, or heterocycle being optionally substituted with R*®°: f) NR" COR" wherein R""® and R"" is each H, (Cy.)alkyl, (Cs. 7)cycloalkyl, (Cy.¢)alkyl-(Cs.s)cycloalkyl, aryl, Het; (C1salkylaryl or (C;. salkyl)Het, said (Ci.g)alkyl, (Csz)cycloalkyl, (Cy.6)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,.¢alkyl)aryl or (C,salkyl)Het being optionally substituted with R'®; g) NR" CONR'"°R'®, wherein R"'®, R™ and R'® is each H, (Cs. s)alkyl, (Cs7)cycloalkyl, (Cy.6)alkyl-(Ca)cycloalkyl, aryl, Het, (C,. salkylaryl or (C,.salkyl)Het, or R'is covalently bonded to R'* and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, or R'"® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5,6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, (C;. s)alkyl-(Caz)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Ci.salkyl)Het or heterocycle being optionally substituted with R'°; : h) NR™'COCOR'™ wherein R™' and R'is each H, (C,s)alkyl, (Cs r)cycloalkyl, (Cy.¢)alkyl-(Cs.7)cycloalkyl, a 6- or 10-membered aryl, Het, } (Ci.salkyharyl or (Cy.qalkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.qalkyl)aryl or (Cy.salkyl)Het being optionally substituted with R™®, or R'2 js OR'® or N(R'%), wherein B'® and each R'?* is independently H, (C.salkyl), (Cs.7)cycloalkyl, or (Cy.g)alkyl-(Cs.
    ® 223 7)cycloalkyl, aryl, Het, (C1.salkylaryl or (C,.alkyl)Het, or R'* is OH or : O(C1.alkyl) or both R** are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- : cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cy salkyl)Het and heterocycle - being optionally substituted with R'®°; i) COR™ wherein R'is H, (Cy.s)alkyl, (Ca)cycloalkyl or (C1e)alkyl- (Cay)cycloalkyl, aryl, Het, (C.calkyl)aryl or (Ci.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C..galkyl)aryl or (Cealkyl)Het being optionally substituted with R'®: j) tetrazole, COOR'® wherein R'® is H, (Cy.¢)alkyl, (Caz)cycloalkyl, or(C.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,salkyl)aryl or (C,salkyl)Het, ® said (Ci.g)alkyl, (Cs.7)cycloalkyl, or(Ci.g)alkyl-(Cs7)cycloalkyl, aryl, Het,
    (Cy.calkyl)aryl and (Cy.ealkyl)Het being optionally substituted with R*®; and k) CONR'™R"™® wherein R*?*® and R™ are independently H, (Cs. s)alkyl, (Cs.7)cycloalkyl, (Ci6)alkyl-(Cs7)cycloalkyl, aryl, Het, (Ci. calkylaryl or (C,¢alkyl)Het, or both R'® and R'° are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C1.salkyl)aryl, (Ci.salkyl)Het and heterocycle being optionally substituted with R'®®; and wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C,.alkyl, haloalkyl, COOR'®, SOsH, SR", SO,R™", OR, N(R 2), SO.N(R"®?),, NR'®2COR152 or CON(R'?),, wherein R'®' and each R'*is independently H, (C16)alkyl, (Csz)cycloalkyl or (Cqg)alkyl-(Ca7)cycloalkyl; or both R'®2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, ora salt thereof, with the proviso that, when A is CH, R? is phenyl or N-butyl, B is NR? Ris Me, Kis we CH, Lis CH, Mis CH, ¥' is O, and Z is NHR®, then R®is not ~ ° :
    . 2. A compound of formula (il):
    0] . Mm , A | So R N\ Pe 3 R 0) wherein, Ais O, S, or NR! and R', R2, R®, K, L, M and Z are as defined in claim 1.
    3. The compound according to claim 2, wherein A is NR.
    o 4. ° The compound according to claim 2, wherein M, Kand Lis CHorN.
    5. The compound according to claim 4, wherein M, K and L is CH.
    6. A compound of formula (Il): Rl (0 EN B zt K (ill) wherein, B is NR® and R', R? R®, K, L, M and Z are as defined in claim 1.
    A
    7. The compound according to claim 6, wherein M, K and L is CH or N.
    8. The compound according to claim 7, wherein M, K and L is CH.
    9. A compound of the formula: ? 0 1 o R . 2 2 2 LY TY 3 R® , J lla a
    . [0] o rR! s ] \ R? \ 2 z
    FN . [TE , od Ib lic : Rl 0] Men R2 | ‘ \ or R® . ® Id - 5 wherein R', R%, R® and Z are as defined in claim 1.
    10. The compound according to claim 1, wherein R! is selected from: H or (Cre)alkyl. :
    11. The compound according to claim 10, wherein R" is H, CHa, isopropyl, or isobutyl.
    12. The compound according to claim 11, wherein R' is H or CHs.
    13. The compound according to claim 12, wherein R' is CH.
    14. The compound according to claim 1, wherein R? is CON(R??),, wherein each R* is independently H, (Cy.g)alkyl, (Cas)cycloalkyl, (Csz)cycloalkenyl, 6 or 10- membered aryl or Het, or both R* are bonded together to form a 5, 6 or 7- membered saturated heterocycle with the nitrogen to which they are attached; or R? is selected from: H, halogen, (Cy.g)alkyl, haloalkyl, {Cs.¢)alkenyl, (Cs. 7)cycloalkenyl, 6 or 10-membered aryl or Het; wherein each of said alkyl, haloalkyl,
    (Ca.s)alkenyl, (Cs)cycloalkenyl, aryl or Het is optionally substituted with R?, wherein } R* is defined as: - 1 to 4 substituents selected from: halogen, NO,, cyano, azido, C(=NH)NH,, C(=NH)NH(C1)alkyl or C(=NH)NHCO(C.)alkyl; or - 1 to 4 substituents selected from:
    ® 226 a) (Cy) alkyl or haloalkyl, (Cs.7)cycloalkyl, (C..)alkenyl, (Ca.g)alkynyl, (C1.s) : -alkyl-(Ca.7)cycloalkyl, all of which optionally substituted with R'; b) OR' wherein R'is H, (C,.calkyl), (Cs)cycloalkyl, or (Ci.s)alkyl-(Ca. ’ : z7)cycloalkyl, aryl, Het, (Ci.galkyl)aryl or (C,salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Cq.salkyl)Het being optionally substituted with : R's : ¢) OCOR'® wherein R'® is (Cy.s)alkyl, (Cs)cycloalkyl, (C1.¢)alkyl-(Cas. 7)cycloalkyl, Het, (Ci.qalkyl)aryl or (Cisalkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,.¢alkyl)Het being optionally substituted with R'®; d) SR, SO:N(R'), or SON(R'®)C(O)R'® wherein each R'® is independently H, (Cy¢)alkyl, (Cs7)cycloalkyl or (Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, ® Het, (C.salkyharyl or (Cysalkyl)Het or both R*® are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C;. salkyl)aryl or (Cq.salkyl)Het or heterocycle being optionally substituted with RO e) NR'"'R"'? wherein R"" is H, (C;.s)alkyl, (Cs7)cycloalkyl or (Cy.)alkyl-(Ca. s)cycloalkyl, aryl, Het, (Cqealkyl)aryl or (C,salkyl)Het, and R'is H, CN, (C;. s)alkyl, (Csz)cycloalkyl or (Ci.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl, (C1ealkyl)Het , COOR™* or SO,R'"® wherein R'"® is (Cyg)alkyl, (Ca. z7)cycloalkyl, or (Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cs. salkyl)Het, or both R™ and R'"? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated : heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,alkyl)aryl or (C,.calkyl)Het, or heterocycle being optionally substituted with R"*°; f) NR" COR" wherein R''® and R" is each H, (Ci.e)alkyl, (Cs.7)cycloalkyl,
    (Cy.s)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci.calkyl)aryl or (Cysalkyl)Het, said (C4. e)alkyl, (Caz)cycloalkyl, (Ci¢)alkyl-(Cs.s)cycloalkyl, aryl, Het, (Cisalkyl)aryl or
    (C1.salkyl)Het being optionally substituted with R'°,; g) NR" CONR'®R™, wherein R""®, R"'® and R'® is each H, (Cy.s)alkyl, (Ca. . 7)cycloalkyl, (C+.¢)alkyl-(Cs,)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C4. salkyl)Het, or R''® is covalently bonded to R'*® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R""® and BR are covalently bonded together and to the nitrogen to which
    ® they are attached to form a 5, 6 or 7-membered saturated heterocycle; . said alkyl, cycloalkyl, (Ci.¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cisalkyharyl or (Cs. salkyl)Het or heterocycle being optionally substituted with R'®; . h) NR'*’COCOR' wherein R'' and R'? is each H, (Cye)alkyl, (Cs. 7)cycloalkyl, (C1.)alkyl-(Ca.7)cycloalkyl, a 6- or 10-membered aryl, Het, (Cy. salkyl)aryl or (Cssalkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Ciealkyl)aryl or (Cy.salkyl)Het being optionally substituted with R*5%: or R™2 is OR™ or N(R"™%, wherein R' and each R™* is independently H,
    (Cy.salkyl), (Cs7)cycloalkyl, or (Cre)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,. salkylaryl or (C,.galkyl)Het, or R'?* is OH or O(C.¢alkyl) or both R'?* are covalently bonded together to form a 5, 6 or 7-membered saturated @ heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cyalkyl)aryl or : (C1.salkyl)Het and heterocycle being optionally substituted with R'%°; i) COR wherein R' is H, (Cy.s)alkyl, (Cs)cycloalkyl or (Cy.q)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,.qalkyl)aryl or (Cy.calkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cycalkylaryl or (Cycalkyl)Het being optionally substituted with R'®°; j) COOR™ wherein R'is H, (Cy.)alkyl, (Ca)cycloalkyl, or(C1.g)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,alkyl)ary! or (Cy.salkyl)Het, said (Cie)alkyt, (Ca. 7)cycloalkyl, or(C.g)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cy6alkyharyl and (C;. salkyl)Het being optionally substituted with R'®°; k) CONR™R"™ wherein R'® and R'™ are independently H, (Cys)alkyl, (Cs. 7)cycloalkyl, (Cy.)alkyl-(Cs.;)cycloalkyl, aryl, Het, (Csalkyl)aryl or (Cy: salkyl)Het, or both R'* and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Crealkylaryl, (C1-6alkyl)Het and heterocycle being optionally substituted with R'; 1) aryl, Het, (C1-6alkyl)aryl or (C1-6alkyl)Het, all of which being optionally substituted with R'*°; wherein R'™ is: - 1 to 3 substituents selected from: halogen, NO, cyano or azido; or - 1 to 3 substituents selected from: a) (C1.¢) alkyl or haloalkyl, (C35)cycloalkyl, (C..¢)alkenyl, (Cog)alkynyl, (C16) alkyl-(Cas)cycloalkyl, all of which optionally substituted with R™®; b) OR wherein R"* is H, (C1.salkyl) or (Cs7)cycloalkyl, said alkyl or cycloalkyl optionally substituted with R€°:
    ® d) SR, SO3H, SO.N(R"®), or SO,N(R'"®)C(O)R"® wherein each R™ is independently H, (Cy.s)alkyl, (Cs-)cycloalkyl of (Cr.e)alkyl-(Ca. 7)cycloalkyl, aryl, Het, or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het and heterocycle being optionally substituted with R'°: e) NR''R" wherein R'is H, (Cy4)alkyl, or (Cs7)cycloalkyl, and R'" is H, (Cys)alkyl or (Ca.7)cycloalkyl, COOR or SOR" wherein R'"® is (Crg)alkyl or (Cs.7)cycloalkyl, or both R' and R'"2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, @ cycloalkyl and heterocycle being optionally substituted with R*®°; f) NR"'®COR" wherein R"'® and R"" is each H, (C.¢)alkyl or (Ca. z)cycloalkyl said (Ci.)alky! and (Cs7)cycloalkyl being optionally substituted with R'°; : g) NR"CONR'"R™, wherein R"", R""® and R'is each H, (Cx. e)alkyl or (Cs)cycloalkyl, or R'is covalently bonded to R'*® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, or R'"® and R" are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, and heterocycle being optionally substituted with R°: h) NR™'COCOR' wherein R'?' is H, (Cy.s)alkyl or (Csz)cycloalkyl, said alky! and cycloalkyl being optionally substituted with R'®; or R'is OR'® or N(R'?*), wherein R'? and each R'?* is independently H, (C,.calkyl) or (Cs)cycloalkyl, or both R'* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R*°; ’ 30 i) COR™ wherein R'is H, (Cy.)alkyl or (Ca7)cycloalkyl, said alkyl and cycloalkyl being optionally substituted with R'%%: j) COOR™® wherein R'is H, (Cy.)alkyl or (Ca7)cycloalkyl, said
    (Cr.e)alkyl and (Cs7)cycloalkyl being optionally substituted with RS; and
    ® : 229 k) CONR™R™ wherein R'* and R' are independently H, (C1. : g)alkyl or (Ca)cycloalkyl, or both R'?® and R'™° are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 : or 7-membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R'?; wherein R'® is defined as 1 or 2 substituents selected from: halogen, CN, C,.salkyl, haloalkyl, COOR®', OR™, N(R®?),,
    SO.N(R™),, NR'2COR'® or CON(R"?),, wherein R'* and each R'is independently H, (C1.)alkyl, (Ca)cycloalkyl or (Cs. s)alkyl-(Ca7)cycloalkyl; or both R'®? are covalently bonded together and to the nitrogen to which they are attached to form . C a 5, 6 or 7-membered saturated heterocycle. :
    15. The compound according to claim 14, wherein R? is selected from: aryl or Het, each optionally monosubstituted or disubstituted with substituents selected from the group consisting of: halogen, haloalkyl, Ns, or a) (C1.6)alkyl optionally substituted with OH, O(C,)alkyl or SO,(C1.4 alkyl); b) (Cy.6)alkoxy; i e) NR"'"R"*? wherein both R""* and R'™ are independently H, (C1.)alkyl, (Cs)cycloalkyl, or R'is 6- or 10-membered aryl, Het, (Ci¢)alkyl-aryl or (Ci.¢)alkyl-Het; or both R'"" and R''2 are covalently bonded together and to the nitrogen to which they are attached to form a nitrogen- containing heterocycle, each of said alkyl, cycloalkyl, aryl, Het, alkyl- aryl or alkyl-Het; being optionally substituted with halogen or: - OR? or N(R™), , wherein each R? is independently H, (C,. e)alkyl, or both R*" are covalently bonded together and to the nitrogen to which they are attached to form a nitrogen- containing heterocycle; . i f) NHCOR"” wherein R'is (C1.e)alkyl, O(C1.s)alkyl or O(Cs7)cycloalkyl: i) CO-aryl; and k) CONH,, CONH(C.salkyl), CON(C.¢alkyl),, CONH-aryl, or CONHC,. salkyl aryl.
    16. The compound according to claim 15, wherein R? is aryl or Het, each . optionally monosubstituted or disubstituted with substituents selected from the group consisting of: halogen, haloalkyl, or . a) (Cig)alkyl optionally substituted with OH, O(C.g)alkyl or SO,(C;. alkyl); : b) (Cy5)alkoxy; and e) NR'R'"? wherein both R""" and R""2are independently H, (C,q)alkyl, (Cs)cycloalkyl, or R''2 is 6- or 10-membered aryl, Het, (Cy)alkyl-ary! or (Cy.g)alkyl-Het; or both R""" and R''? are covalently bonded together and to the nitrogen to which they are attached to form a nitrogen- containing heterocycle, each of said alkyl, cycloalkyl, aryl, Het, alkyl- 9 aryl or alkyl-Het; or being optionally substituted with halogen or: - OR™ or N(R™), , wherein each R*" is independently H, (C;. e)alkyl, or both R*" are covalently bonded together and to the nitrogen to which they are attached to form a nitrogen- containing heterocycle.
    17. The compound according to claim 16, wherein R? is phenyl or a heterocycle selected from: NY TY sey NY SN TN \ \ N yh UN | YZ NA NaN 0 Hi S Hi H ? — bl 1S bl b Hi x s N M N ® CO) ) ¥% N s H and , all of which optionally substituted as defined in claim 16.
    18. The compound according to claim 17, wherein R? is selected from the group consisting of: H, Br, CONHCH; CON(CHs),, CONH,, CH=CHj,
    Ro .. . N Or q OOo r ° 4 o 1) S I Ss H y \ H
    ® . FEE ordo, ad CC ddoduddlooy Sg Go Od ] A i A NN aN oo EN 8 pee hoe jos pea pea ID A EG GN.
    Gh Ls Ny —N =n a J) S a io! =N aR oe ie J ba "e d LA CE A A AN A= k, (Y SS om oe 0 0 hea poe pe N HN N : he | py | = {° ( AO
    % ie N= p= HN HN =o
    O._ _NH = , Cl NH, - NH, NO, he HC 5 Tr NY , HC” 0 X CH, = J CH, ’ y } XN | XN | XN ~N \ A = xX , ©, FF CF aN N NH, NH, NH, ome l sYoY ele o A N° Q Y | ahd ome © AN NH, NH, xX N OSNH NH OAR OER , , and .
    19. The compound according to claim 18, wherein R? is selected from: : NTN FOO eels " Z 1] ° ’ © EH S ’ S Le Lg =
    ] 8 N 8 CQ Las SS XN EN NTN ‘ | J PS N N \ a —g=0 . NT | = NA NaN J Js OH °=9 NA oN oa p= SEEN SE = A HN HN / / HN NTN % / Yok yd Ss HN 0 AN . @ °° “x Os NH ~ Z = NF - 0 , NH, NH, he xX CH, F OMe CH, NN IN XN y RN An o Jo. ~~ UE ty ee CF, , F , Z , Cl Ny = NH, OMe - Xx NH, , and .
    20. The compound according to claim 19, wherein R? is selected from: : a Soro lao0 ke J ! J Lg F NA OH CH, SN SN RN SN ON ALO PEPE QF NH, | NH, NX CH; OMe F Z cl
    ® 234 NA Lg HN HN % i NH; x AT ne .
    21. The compound according to claim 1, wherein R? is selected from (Csz)eycloalkyl, (Ca7)cycloalkenyl, (Ce.1o)bicycloalkyl, (Cs.10)bicycloalkenyl, 6- or 10- membered aryl, or Het. ) 22, The compound according to claim 21, wherein R® is (C;.)cycloalkyl.
    23. The compound according to claim 22, wherein R? is cyclopentyl, or cyclohexyl.
    24. The compound according to claim 1, wherein Y' is O.
    25. The compound according to claim 1, wherein Z is OR® wherein R® is (C;. salkylaryl substituted with 1 to 4 substituents selected from: a) (Ci.e)alkyl substituted with R'%?, haloalkyl, (Ca.7)cycloalkyl, Cs. spirocycloalkyl optionally containing 1 or 2 heteroatom, (C..g)alkenyl, (C,. s)alkynyl, (Ci.s) alkyl-(Css)cycloalkyl, said haloalkyl, cycloalkyl, spirocycloalkyl, alkenyl, alkynyl and alkyl-cycloalkyl being optionally substituted with R'*°, wherein R'** is the same as R'® but is not COOR™, N(R"), NR®C(O)RS®, ORS SRS SO,R'S%® SO,N(R'%),, wherein R™® is H or unsubstituted C,_galkyl; b) OR wherein R'™ is (C,.salkyl) substituted with R'™, (C,)cycloalkyl, or (C1s)alkyl-(Cas)cycloalkyl, aryl, Het, (Csalkyl)aryl or (C,.salkyl)Het, said i cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C4alkyl)Het being optionally substituted with R'% . d) SR'™2, SON(R™®2), or SO,N(R'*)C(O)R'® wherein each R'® is independently H, (C,.g)alkyl, (Cs.;)cycloalkyl or (C.)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C1.salkyl)Het or both R'®® are covalently bonded : together and to the nitrogen to which they are attached to form a 5, 6 or 7-
    ® membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C;. : salkyl)aryl or (C+.calkyl)Het or heterocycle being optionally substituted with R', wherein R'* is the same as R'® but is not H or unsubstituted C; alkyl; - e) NR''R"? wherein R'is H, (C1.6)alkyl, (Cs7)cycloalkyl or (Cy.¢)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (Cy .salkyl)aryl or (Cy.alkyl)Het, and R'2is H, CN, (C. s)alkyl, (Caz)cycloalkyl or (C,.g)alkyl-(Cs)cycloalkyl, aryl, Het, (Cisalkyharyl, (Ciealkyl)Het , provided that when R'is H or unsubstituted alkyl, R'? is not H or unsubstituted alkyl, or R""? is also COOR"® or SO,R'*** wherein R'"® is H, (Cie)alkyl, (Car)cycloalkyl, or (Cyg)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cs. 0 salkyl)aryl or (Cy.salkyl)Het, and R''* is the same as R'"® but is not H or unsubstituted alkyl, or both R""" and R™ are covalently bonded together and ® to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Cs. salkyl)Het, or heterocycle being optionally substituted with R*®"; f) NR"COR"" wherein R""® and R'"” is each (Cy.c)alkyl substituted with R™, (Ca)cycloalkyl, (C1-c)alkyl-(Cs 7)cycloalkyl, aryl, Het, (Cs.calkyl)aryl or (Cy. salkyl)Het, said (Cs )cycloalkyl, (Cy.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,. salkylaryl or (C,.¢alkyl)Het being optionally substituted with R'*%: g) NR" CONR'R", wherein B''®, R™ and BR"? is each H, (C.¢)alkyl, (Cs. 7)cycloalkyl, (Cy.s)alkyl-(Cy.7)cycloalkyl, aryl, Het, (Cqealkyl)aryl or (C;. salkyl)Het, or R'"® is covalently bonded to R'*® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R"™ and R'™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C16)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,.salkyaryl or (Cs. salkyl)Het or heterocycle being optionally substituted with R'5°; h) NR'?'COCOR™ wherein R'* is H or C,¢alkyl and R'? is OR" or N(R"™*), wherein R'? and each R' is independently H, (C,.salkyl), (Cs. 7)cycloalkyl, or (C,.g)alkyl-(Ca)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,. salky)Het, or R** is OH or O(C.galkyl) or both R'?* are covalently bonded i together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,salkyharyl or (Ciealkyl)Het and heterocycle being optionally substituted with R*®®; J) COOR™ wherein R'is (C;.c)alkyl substituted with R"™®, (Ca.7)cycloalkyl,
    ® or(Ci.¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.alkyl)aryl or (C4.salkyl)Het, said (Ca. : ~ 7)cycloalkyl, or(Cy.g)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C1salkylaryl and (Cs. salkyl)Het being optionally substituted with R'®’; : k) CONR'R™ wherein R'® and R"° are independently H, (C.s)alkyl, (Cs. 7)cycloalkyl, (Ci.g)alkyl-(Csr)cycloalkyl, aryl, Het, (C¢alkyl)aryl or (C;. salkyl)Het, provided that when R'® is H or unsubstituted alkyl, R™° is not H or unsubstituted alkyl, or both R™® and R*™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C4. salkylaryl, (Cigalkyl)Het and heterocycle being optionally substituted with RC, ® I) aryl, Het, (Ciealkyl)aryl or (C,.salkyl)Het, all of which being optionally substituted with R**, wherein R'is: - 1 to 3 substituents selected from: halogen or azido; or - 1 to 3 substituents selected from: a) (C4.6) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs.7 spirocycloalkyl optionally containing 1 or 2 heteroatom, (C..¢)alkenyl, (C,.g)alkynyl,
    (Cy.6) alkyl-(Caz)cycloalkyl, all of which optionally substituted with R'?; b) OR'™ wherein R'is H, (Cysalkyl), (Cs.r)cycloalkyl, or (C1.¢)alkyl- (Cs7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,.salkyl)Het being optionally substituted with R'®%; ~~ d) SR'®, SO,N(R'®), or SO,N(R'"®)C(O)R'® wherein each R'® is independently H, (C1)alkyl, (Cs7)cycloalkyl or (C1.6)alkyl-(Ca. scycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cysalkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,.salkyl)Het or heterocycle being optionally substituted with R'®; e) NR"R" wherein R'is H, (Cy.)alkyl, (Cs7)cycloalkyl or (Ci. s)alkyl-(Ca.7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,¢alky)Het, and R'is H, CN, (C,.¢)alkyl, (Cas)cycloalkyl or (Cy.s)alkyl-(Cs7)cycloalkyl, “aryl, Het, (C,.salkylaryl, (Ci-salkyl)Het , COOR''® or SO,R'"® wherein R''® is (Cy.s)alkyl, (Caz)cycloalkyl, or (Cy.e)alkyl-(Cs7)cycloalkyl, aryl,
    ® Het, (Ci.salkyl)aryl or (C,alkyl)Het, or both R'"" and R"? are ‘ covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said . alkyl, cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C,.salkyl)Het, or heterocycle being optionally substituted with R'®%: f) NR"®COR""” wherein R"® and R'" is each H, (Css)alkyl, (Cs. 7)cycloalkyl, (Cq.e)alkyl-(Csr)cycloalkyl, aryl, Het, (C.galkyl)aryl or (C1. salkyl)Het, said (C1)alkyl, (Ca)cycloalkyl, (Cys)alkyl-(Ca.z)cycloalkyl, aryl, Het, (Cy.alkyl)aryl or (Cy.salkyl)Het being optionally substituted with R°%; g) NR'®CONR'"R'®, wherein R"®, R""® and R'® is each H, (C;. ® e)alkyl, (Ca7)cycloalkyl, (Cy.¢)alkyl-(Cs)cycloalkyl, aryl, Het, (C,. ealkyl)aryl or (Cy.salkyl)Het, or R''® and R'® are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C.. s)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Cyalkyl)Het or heterocycle being optionally substituted with R®%: fh) NR'?’COCOR™ wherein R'?' is H, (C,5)alkyl and R'2 is OR or N(R"), wherein R'* and each R'** is independently H, (C; alkyl), (Caz)cycloalkyl, or (Cyg)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cssalkylaryl : or (C+.alkyl)Het, or R'* is OH or O(C,alkyl) or both R' are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C;. salkylaryl or (C1salkyl)Het and heterocycle being optionally substituted with R'®?; j) tetrazole, COOR™® wherein R'% is H, (C,.g)alkyl, (Ca.)cycloalkyl, or(Cy.s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C4.calkyl)aryl or (C,.calkyl)Het, said (Ci.¢)alkyl, (Cs7)cycloalkyl, or(Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cq-6alkyharyl and (C.salkyl)Het being optionally substituted with R'®: and k) CONR™R™ wherein R'® and R'® are independently H, (C;. s)atkyl, (Caz)cycloalkyl, (C1.6)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,. salkyharyl or (Cy.salkyl)Het, or both R'*® and R**° are covalently bonded together and to the nitrogen to which they are attached to
    ® form a 5, 6 or 7-membered saturated heterocycle, said alkyl, : cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cisalkyl)aryl, (Ci.salkyl)Het and heterocycle being optionally substituted with R'®?; - wherein, R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, Cysalkyl, haloalkyl, COOR™!, SO;H, SO,R™", OR'™" N(R), SO.N(R'2),, NRCOR"2 or CON(R"?),, wherein R'® and R'®? are as defined above.
    26. The compound according to claim 25, wherein Z is OR® wherein R® is (C;. salkyl)aryl substituted with 1 to 4 substituents selected from: a) (Ci.s)alkyl substituted with R'%%, haloalkyl, (Cs)cycloalkyl, Cs. Q® 10 spirocycloalkyl optionally containing 1 or 2 heteroatom, (C.¢)alkenyl, (C.. g)alkynyl, (C1.6) alkyl-(Cs7)cycloalkyl, said haloalkyl, cycloalkyl, spirocycloalkyl, alkenyl, alkynyl and alkyl-cycloalkyi being optionally substituted with R'®°, wherein R'is the same as R™ but is not COOR'®®, N(R*®"),, NR'C(O)R, OR™%, SR SO,R™%, SON(R™%),, wherein R15% is H or unsubstituted Csalkyl; b) OR' wherein R'™ is (Ccalkyl) substituted with R'®°, (C,)cycloalkyl, or
    (C1.s)alkyl~(Car)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Cy.calkyl)Het, said cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C+salky)Het being optionally substituted with R: d) SOzH, SON(R'2), or SO,N(R'®)C(O)R'® wherein each R'® is independently H, (C,.¢)alkyl and aryl, said alkyl and aryl being optionally substituted with R'®®, wherein R'%® is the same as R'® but is not H or unsubstituted Ci.salkyl; e) NR'R"™ wherein R""" is H, (C.s)alkyl, (Cs-)cycloalkyl or (Cirs)alkyl~(Cs. 7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cygalkyl)Het, and R'is H, (Cy.5)alkyl, provided that when R'is H or unsubstituted alkyl, R"*? is not H or unsubstituted alkyl, or R'is also COOR'*® or SO,R"'** wherein R"® is H, (Crealkyl or (Crealkyl)aryl, and R'is C1.alkyl substituted with R' or (CG. salkylaryl, or both R'"" and R**? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C+.calkyl)aryl or (C1-salkyl)Het, or heterocycle being optionally substituted with R'®;
    ® f) NR''°COR™” wherein R""® and R'" is each (C,.)alkyl substituted with : R™, (Ca)cycloalkyl, aryl, Het, said (Ca)cycloalkyl, aryl, Het being optionally substituted with R'®% 9) NR'™CONR'"R'®, wherein R'*®, R"" and R'? is each H, (Ci.s)alky!, aryl, Het, said alkyl, aryl and Het being optionally substituted with R**°; h) NR'*’COCOR' wherein R'®' is H or C,alkyl and R'? is OR"? or N(R"), wherein R'* and each R'** is independently H, (C1.calkyl), aryl or Het, or R'is OH or O(C.alkyl), said alkyl, aryl and Het being optionally substituted with R'®°; : : j) COOR'* wherein R'? is (Cy.s)alkyl substituted with R'; oo k) CONR'*R™ wherein R'*® and R'® are independently H, (C;.s)alkyl, aryl ® or Het, provided that when R'is H or unsubstituted alkyl, R'* is not H or unsubstituted alkyl, said alkyl, aryl and Het being optionally substituted with R'%: . I) aryl, Het, (C,ealkyl)aryl or (Cysalkyl)Het, all of which being optionally substituted with R"®°, wherein R'®° is: - 1 to 3 substituents selected from: halogen or azido; or - 1 to 3 substituents selected from: a) (C1.¢) alkyl or haloalkyl, (C,.s)alkenyl, all of which optionally substituted with R®°; b) OR wherein R'™ is H, (Cs.salkyl), aryl or Het, said alkyl, aryl and Het being optionally substituted with R'®°: d) SR'®, SON(R'®), or SO,N(R'®)C(O)R'® wherein each R'® is independently H, (Cy.¢)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R'°?; e) NR''R"? wherein R™ is H, (C,.5)alkyl, aryl or Het, and R"2is H,
    (Ci.e)alkyl, COOR™® or SO,R""* wherein R'is (C,.)alkyl, said alkyl, cycloalkyl, aryl or Het being optionally substituted with RB; ] f) NR'"®COR" wherein R"'® and R"" is each H, (C+)alkyl, aryl or : Het, said alkyl, aryl and Het being optionally substituted with R®; } g) NR"®CONR'®R'™, wherein R"®, R""® and R'? is each H, (C;. s)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R'®; h) NR'?'COCOR™ wherein R'' is H, (C1¢)alkyl and R'2 is OR or
    ® 240 : N(R"), wherein R'® and each R'® is independently H, (Cy.salkyl), ¥ : . aryl or Het, or R'is OH or O(C, alkyl), said alkyl, aryl and Het being optionally substituted with R'®; ’ j) tetrazole, COOR'® wherein R'is H, (C1.¢)alkyl optionally substituted with R'®®; and k) CONR'™R™° wherein R'?® and R™” are independently H, (C.. g)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R"®; and wherein R'is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C;.salkyl, haloalkyl, COOR'®', SO;H, SOR", OR" N(R"), SO.N(R?),, NR'$2COR52 or ® CON(R"®?),, wherein R'® and R'® are as defined above.
    27. The compound according to claim 1, wherein Z is OR® wherein R® is (Cos)alkenyl, (Cqg)alkyl-Het, wherein said alkenyl or alkyl-Het, is optionally substituted with R®, wherein R® is: - 1 to 4 substituents selected from: halogen; or - 1 to 4 substituents selected from: a) (C1.6) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs; spirocycloalkyl optionally containing 1 or 2 heteroatom, (Ca.¢)alkenyl, (C,.g)alkynyl, (C.) alkyl-(Cs. 7)cycloalkyl, all of which optionally substituted with R'%%; b) OR wherein R'™ is H, (C;.¢alkyl), (Cs.)cycloalkyl, or (C1.)alkyl-(Cs. z7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C,.calkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C4 salkyl)aryl or (C,ealkyl)Het being optionally substituted with R150. . d) SR, SO,N(R'®), or SO,N(R'"®)C(O)R'"® wherein each R'*® is independently H, (Ci.s)alkyl, (Cs.7)cycloalkyl or (Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.salkylaryl or (C,.salkyl)Het or both R'® are covalently bonded ) together and to the nitrogen to which they are attached to forma 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,. ] salkyl)aryl or (C4 salkyl)Het or heterocycle being optionally substituted with R150. e) NR"R"? wherein R"" is H, (C1.s)alkyl, (Ca)cycloalkyl or (C.s)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Cy.salkyl)Het, and R''?is H, CN, (C;.
    ® 241 s)alkyl, (Caz)cycloalkyl or (Cy.s)alkyl-(Cas)cycloalkyl, aryl, Het, (C4.calkyl)aryl, oe (Cyealkyl)Het , COOR™ or SO,R"'*®* wherein R'"® is (C1¢)alkyl, (Ca. 7)cycloalkyl, or (Cy.¢)alkyl-(Cs7)cycloalkyl, aryl, Het, (Ciealkyl)aryl or (C,. : salkyhHet, or both R™! and R'"? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,salkyl)aryl or (Cy.calkyl)Het, or heterocycle being optionally substituted with R'*’; f) NR"'®COR"" wherein R'"® and R'is each (C,.¢)alkyl, (Cs)cycloalkyl, (Ci. s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,alkyl)Het, said (C4. s)alkyl, (Css)cycloalkyl, (Cq.g)alkyl-(Cs)cycloalkyl, aryl, Het, (C4 satkyl)aryl or
    (C.salkyhHet being optionally substituted with R**"; ® g) NRCONR'"R'®, wherein R"*®, R'"® and R'® is each H, (C1.¢)alkyl, (Cs. 7)cycloalkyl, (Cq.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cy. salkyl)Het, or R'"® is covalently bonded to R'"® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; : or R""® and R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C1.e)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,. salkyl)Het or heterocycle being optionally substituted with R'*°; h) NR'>'COCOR' wherein R'?! is H, (Ci.¢)alkyl optionally substituted with R™° and R'? is OR'® or N(R"**), wherein R'® and each R'is independently H, (C,.salkyl), (Ci.7)cycloalkyl, or (Ci.¢)alkyl-(Cs7)cycloalkyi, aryl, Het, (Csalkyl)aryl or (C,.calkyl)Het, or R'** is OH or O(C;.salkyl) or both R'®* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C1salkyl)Het and heterocycle being optionally substituted with R's; i) COR'? wherein R'¥ is H, (Cy.6)alkyl, (Cs7)cycloalkyl or (C1.)alkyl~(Cs. 7)cycloalkyl, aryl, Het, (C.salkyl)aryl or (C,salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Csalkyl)aryl or (Cs.salkyl)Het being optionally substituted with R'*: j) COOR"™® wherein R'? is H, (C1.s)alkyl, (Cs.7)cycloalkyl, or(C.c)alkyl-(Ca. i 7ycycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Cy calkyl)Het, said (C;.g)alkyl, (Ca. z)cycloalkyl, or{C.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cysalkyl)aryl and (C.. salkyl)Het being optionally substituted with R**; k) CONR'*R'® wherein R*?® and R'*° are independently H, (C1.)alkyl, (Cs.
    ® 7)cycloalkyl, (Cy.6)alkyl-(Caz)cycloalkyl, aryl, Het, (Cqsalkyharyl or (Cs. , salkyl)Het, or both R™ and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated . heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cygalkyl)aryl,
    (C.salkyl)Het and heterocycle being optionally substituted with R'>°; I) aryl, Het, (Cisalkyl)aryl or (Cysalkyl)Het, all of which being optionally substituted with R™*®; wherein R™ is defined as: - 1 to 3 substituents selected from: halogen or azido; or - 1 to 3 substituents selected from: + a) (C1) alkyl or haloalkyl, (Cs-7)cycloalkyl, C4; spirocycloalkyl optionally containing 1 or 2 heteroatom, (C.¢)alkenyl, (C.g)alkynyl, ® (C1.6) alkyl-(C3.7)cycloalkyl, all of which optionally substituted with R*®°; b) OR" wherein R'® is H, (Cysalkyl), (C3)cycloalkyl, or (Cy.c)alkyi- " (Csy)cycloalkyl, aryl, Het, (C,.calkyl)ary! or (C;.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.alkyl)aryl or (C,.salkyl)Het being optionally substituted with R'°; d) SR, SO,N(R'™), or SO,N(R'*®)C(O)R'® wherein each R'® is independently H, (C,.g)alkyl, (Ca)cycloalkyl or (Cyg)atkyl-(Cs. 7)cycloalkyl, aryl, Het, (Cysalkyl)ary! or (C4ealkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,salkyl)aryl or (Cisalkyl)Het or heterocycle being optionally substituted with RR: e) NR"'R""? wherein R'is H, (Cy.c)alkyl, (Car)cycloalkyl or (C,. slalkyl-(Cs7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cy.qalkyl)Het, and R"2is H, CN, (Cy.)alkyl, (Caz)cycloalkyl or (C1-6)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cysalkyl)aryl, (Cysalkyl)Het , COOR'" or SO,R"'® wherein R'is (Cye)alkyl, (Caz)cycloalkyl, or (C16)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C,.¢alkyl)Het, or both R"" and R'*? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,.alkyl)Het, or heterocycle being optionally substituted with RT: f) NR"SCOR™ wherein BR" and R"" is each H, (C+.¢)alkyl, (Ca.
    ® 7)cycloalkyl, (C1.)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cy.salkyharyl or (Cs. . salkyl)Het, said (Cy¢)alkyl, (Cs.7)cycloalkyl, (Cy.¢)alkyl-(Ca)cycloalkyl, aryl, Het, (C,.salkyl)ary! or (C,.salkyl)Het being optionally substituted : with RT; g) NR'®CONR"®R'®, wherein R""®, R" and R'is each H, (C,. s)alkyl, (Cs7)cycloalkyl, (C,.g)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci. salkyl)aryl or (C,.¢alkyl)Het, or R'*® is covalently bonded to R'"® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, or R'"® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, (C,. ® e)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cy.salkyl)aryi or (Cy.salkyl)Het or heterocycle being optionally substituted with R'®°; oo h) NR™!'COCOR"? wherein R'is H or (C1.)alkyl optionally substituted with R'®, and R'?? is OR"? or N(R"?%), wherein R'® and each R'* is independently H, (C1.alkyl), (C.7)cycloalkyl, or (Cy.g)alkyi- (Caz)cycloalkyl, aryl, Het, (Cy.calkyl)aryl or (C,_galkyl)Het, or R'is OH or O(C.calkyl) or both R'™* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Ci.salkyl)Het and heterocycle being optionally substituted with R®°; j) tetrazole, COOR™ wherein R'® is H, (Cy.6)alkyl, (Cs.7)cycloalkyl, or(C1.s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C.alkyl)aryl or (Ci.salkyl)Het, said (Cy.s)alkyl, (Cs7)cycloalkyl, or(Ci.s)alkyl-(Caz)cycloalkyl, aryl, Het,
    25 . (Cyealkyharyl and (Cy.calkyl)Het being optionally substituted with R16: and k) CONR'®R™® wherein R'* and R™ are independently H, (C.. s)alkyl, (Cs 7)cycloalkyl, (C1.)alkyl-(Cs)cycloalkyl, aryl, Het, (Ci. salkylaryl or (C;.salkyl)Het, or both R'® and R'* are covalently bonded together and to the nitrogen to which they are attached to ) form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.salkylaryl, (C,alkyl)Het and heterocycle being optionally substituted with R*®°; wherein R'® is defined as 1 or 2 substituents selected from:
    ° 244 tetrazole, halogen, CN, Cyalkyl, haloalkyl, COOR"®, SOzH, - SRS", SOR", OR", N(R"%2),, SO,N(R3),, NR'S2COR152 or CON(R'®?),, wherein R'®" and each R'*is independently H, ; (Cq-g)alkyl, (Ca7)cycloalkyl or (Cy.)alkyl-(Cs.7)cycloalkyl; or both R'2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle.
    28. The compound according to claim 27, wherein R* is: - 1 to 4 substituents selected from: halogen; or - 1 {0 4 substituents selected from: ® a) (C6) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs.; spirocycloalkyl optionally containing 1 or 2 heteroatom, {C.¢)alkenyl, (Cag)alkynyl, (Ci.6) alkyl-(Cs. 7)eycloalkyl, all of which optionally substituted with R**; b) OR' wherein R'is H, (Cysalkyl), (Cs.7)cycloalkyl, or (Cy.)alkyl-(Ca. z)cycloalkyl, aryl, Het, (Cy.¢alkyl)aryl or (C,.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cisalkyl)Het being optionally substituted with R'%: d) SO3H, SO.N(R'®), or SON(R'®)C(O)R'® wherein each R'® is independently H, (C.¢)alky! or aryl, said alkyl and aryl being optionally substituted with R™; e) NR'"R'"'2 wherein R'is H, (C,.s)alkyl, (Csz)cycloalkyl or (C1¢)alkyl-(Cs. syeycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cqsalkyl)Het, and R''2 is H, (C;.6)alkyl, COOR' or SOR" wherein R'*® is (C1.)alkyl or (Cy.salkyl)aryl, or both R'" and R'" are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.galkyl)aryl or (C¢alkyl)Het, or heterocycle being optionally substituted with R'*®; f) NR''°COR'"” wherein R'*® and R'" is each (C+.¢)alkyl, (Caz)cycloalkyl, aryl or Het, said (C:)alkyl, (Cs.7)cycloalkyl, aryl or Het being optionally substituted } 30 with R; g) NR'®CONR'"’R'®, wherein R"%, R""® and R'is each H, (Ci.s)alkyl, ary! : or Het, said alkyl, aryl and Het being optionally substituted with R'*°; h) NR'*COCOR'? wherein R'?' is H or (C.¢)alkyl, and R*? is OR'® or
    ¢ | N(R'*%), wherein R'® and each R™ is independently H, (C1.calkyl), aryl or
    “ Het, or R™*is OH or O(C.calkyl), said alkyl, aryl and Het being optionally substituted with R™°;
    j) COOR™® wherein R'is H or (Cy)alkyl optionally substituted with R'’;
    k) CONR'R'® wherein R'™ and R™ are independently H, (Cy.)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R"* I) aryl, Het, (Cy.salkyl)aryl or (C,.salkyl)Het, all of which being optionally substituted with R'*"; wherein R is defined as: - 1 to 3 substituents selected from: halogen; or
    - 1 to 3 substituents selected from:
    a) (C1) alkyl or haloalkyl, (C..s)alkenyl, all of which optionally
    ® substituted with R'; b) OR wherein R'™ is H, (Cy.alkyl), aryl or Het, said alkyl, aryl and Het being optionally substituted with R*®":
    d) SR', SO,N(R'), or SO,N(R')C(O)R'® wherein each R'® is independently H, (C+.)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R'°;
    e) NR™'R""2 wherein R'is H, (C1)alkyl, aryl or Het, and R"*? is H, (C1-s)alkyl, COOR'™ or SO,R"** wherein R"*® is (C;.s)alkyl or aryl, said alkyl, aryl and Het being optionally substituted with R'®;
    f) NR"®COR™ wherein R™® and R™ is each H, (C,.s)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R'®:
    g) NR’ CONR'"*R'™, wherein R'"®, R""® and R'? is each H, (Cs. s)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted with R'®,
    h) NR™*'COCOR'™ wherein R™?' is H or (C:.)alkyl optionally substituted with R'®°, and R'* is OR or N(R"?*), wherein R'®and each R'is independently H, (C,.alkyl), aryl or Het, or R™* is OH or O(C;.salkyl), said alkyl, aryl and Het being optionally substituted with R'™; J) tetrazole, COOR' wherein R™ is H or (Cy.s)alkyl optionally substituted with R'®%; and k) CONR'R'* wherein R' and R* are independently H, (C,. s)alkyl, aryl or Het, said alkyl, aryl and Het being optionally substituted
    ® with R'®; - wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C,.salkyl, haloalkyl, COOR'®', SOgH, . SR", SO,R'! OR" N(R™2),, SO.N(R62),, NR'2COR'™2 or CON(R"®),, wherein R'' and each R'®is independently H,
    (Cy.e)alkyl, (Ca7)cycloalkyl or (Cig)alkyl-(Csz)cycloalkyl; or both R™2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered : saturated heterocycle.
    29. The compound according to claim 1, wherein Z is N(R**)R® wherein R*® is H [ or Cysalkyl and R® is (C,¢)alkenyl, aryl, Het, (C1.¢)alkyl-aryl, (Ci.s)alkyl-Het, wherein said alkenyl, aryl, Het, alkyl-aryl or alkyl-Het, are all optionally substituted with: - 1 to 4 substituents selected from: halogen, OPOsH, NO,, cyano, azido, C(=NH)NH,, C(=NH)NH(C1.s)alkyl or C(=NH)NHCO(C,)alkyl; or - 1 to 4 substituents selected from: . a) (C1) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs.7 spirocycloalkyl optionally : containing 1 or 2 heteroatom, (C..g)alkenyl, (C,.g)alkynyl, (C4.¢) alkyl-(Cs. 7)cycloalkyl, all of which optionally substituted with R'>®; b) OR™ wherein R'™ is H, (C1.¢alkyl), (Cs.s)cycloalkyl, or (C4.e)alkyl-(Ca. z7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C,.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Cialkyl)aryl or (Cy.calkyl)Het being optionally substituted with R'%% d) SR'®, SO,NH(C, alkyl) or SO.NHC(O)C1salkyl; : e) NR''R"? wherein R""" is H, (C1.s)alkyl, (Ca7)cycloalkyl or (Cy.e)alkyl-(Cs. s)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Csalky)Het, and R'is H, CN, (C,. s)alkyl, (Cs7)cycloalkyl or (C,.¢)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cy.qalkyl)aryl, (Cisalkyl)Het , COOR"® or SO,R** wherein R'is (C,¢)alkyl, (Cs. z)cycloalkyl, or (Cy.g)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cs. salkyl)Het, or both R'"" and R""? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cssalkyl)aryl or (Ci.calkyl)Het, or heterocycle being optionally substituted with R*; f) NR"'SCOR" wherein R"*® and R""" is each H, (C)alkyl, (Cas)cycloalkyl,
    ® (Ci-s)alkyl-(Caz)cycloalkyl, aryl, Het, (Cy.salkyl)aryi or (Cy.salkyhHet, said (C1. : s)alkyl, (Cs7)cycloalkyl, (Cys)alkyl~(Cs-)cycloalkyl, aryl, Het, (Cy.¢alkyl)aryl or (C1salkyl)Het being optionally substituted with R*%: ‘ g) NR’ CONR'R", wherein R''3, R" and R'? is each H, (Cy.e)alkyl, (Cs. z)cycloalkyl, (C4.)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.galkyl)aryl or (C,. salkyl)Het, or R'"® is covalently bonded to R'*® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; ~ orR" and R™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C;.s)alkyl-(Cz7)cycloalkyl, aryl, Het, (Cy-salkyaryl or (Cy. salkyl)Het or heterocycle being optionally substituted with R'°;
    ( h) NR''COCOR'® wherein R™' and R'? is each H, (C,s)alkyl, (Cs. 7)cycloalkyl, (C,.s)alkyl-(Cs.7)cycloalkyl, a 6- or 10-membered aryl, Het, (Ca- salkyl)aryl or (Ci.calkyl)Het, said alkyl, cycloalkyl, alkyl-cycioalkyl, aryl, Het,
    (Cisalkyt)aryl or (Cy.calkyl)Het being optionally substituted with R'®’; or R" is OR" or N(R"), wherein R® and each R™* is independently H, (Cirsalkyl), (Car)cycloalkyl, or (Cy. g)alkyl-(Caz)cycloalkyl, aryl, Het, (C,.
    salkyl)aryl or (C;.calkyl)Het, or R'** is OH or O(C,alkyl) or both R'* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C1salkyl)Het and heterocycle being optionally substituted with R'%: i) COR wherein R' is H, (Ci¢)alkyl, (Cas)cycloalkyl or (Cy.g)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,salkyl)aryl or (Cisalkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryt or (Cysalkyl)Het being optionally substituted with RS’:
    j) COOR™® wherein R'? is H, (C1.g)alkyl, (Ca.7)cycioalkyl, or(C1.e)alkyl-(Cs. z)cycloalkyl, aryl, Het, (C:calkybaryl or (Cyealkyl)Het, said (Ci)alkyl, (Cs. 7)cycloalkyl, or(C,.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,salkyl)aryl and (C,. calkyl)Het being optionally substituted with R**°: k) CONR'™R™ wherein R'* and R**° are independently H, (Cy.)alkyl, (Cs.
    7)cycloalkyl, (Cy.6)alkyl-(Caz)cycloalkyl, aryl, Het, (Crealkyl)aryt or (Cy. ealkyl)Het, or both R'® and R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cysalkyl)aryl, (C1-ealkyl)Het and heterocycle being optionally substituted with R**°: : :
    ® I) aryl, Het, (C.salkyl)aryl or (Cisalkyl)Het, all of which being optionally . substituted with R**%;wherein, R'is selected from: i - 1 to 3 substituents selected from: halogen, NO;, cyano or azido; or ; - 1 to 3 substituents selected from: a) (C1.) alkyl or haloalkyl, (Cs7)cycloalkyl, Cs. spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cs.s)alkenyl, (Cz.g)alkynyl, (C46) alkyl-(Cs.7)cycloalkyl, all of which optionally substituted with R'®; b) OR™ wherein R'™ is H, (C,.galkyl), (Cs)cycloalkyl, or (Cy.s)alkyl- (Ca)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Cq.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C1.salkyl)aryl or (C.salkyl)Het being optionally substituted with R'°°: @ d) SR'®, SO.N(R'®), or SO,N(R'®)C(O)R'® wherein each R™® is independently H, (C,)alkyl, (Cs.7)cycloalkyl or (Cy.¢)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (Cy.¢alkyl)aryl or (C,.calkyl)Het or both R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.galkyl)aryl or (Cqsalkyl)Het or heterocycle being optionally substituted with R'®°: e) NR''R"? wherein R"" is H, (C)alkyl, (Cs-)cycloalkyl or (C. s)alkyl-(Csz)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C,.calkyl)Het, and R"is H, CN, (Ci.s)alkyl, (Cas)cycloalkyl or (Cy.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cysalkyl)aryl, (Cysalkyl)Het , COOR" or SO,R""® wherein R'is (Cy.g)alkyl, (Ca)cycloalkyl, or (Cy.6)alkyl-(Cyr)cycloalkyl, aryl, : Het, (C,.salkyl)aryl or (Cysalkyl)Het, or both BR and R'*2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C.alkyl)aryl or (Cy.salkyl)Het, or heterocycle being optionally substituted with R'®°; f) NR" COR" wherein R""® and R'"" is each H, (Cy.¢)alkyl, (Cs. 7)cycloalkyl, (Cy.e)alkyl-(Csz)cycloalkyl, aryl, Het, (Cs.salkylaryl or (C,. esalkyl)Het, said (C.s)alkyl, (Cs.7)cycloalkyl, (Ci.p)alkyl-(Cs)cycloalkyl, aryl, Het, (Cyalkyl)aryl or (C..salkyl)Het being optionally substituted with R'6; 9) NR'CONR'"*R™, wherein R*'®, B® and R'® is each H, (C;.
    ® s)alkyl, (Czz)cycloalkyl, (Cy.g)alkyl-(Ca.r)cycloalkyl, aryl, Het, (C.
    . salkylaryl or (Cq.calkyl)Het, or R'"® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6
    . or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Ci. s)alkyl-(Csz)cycloalkyl, aryl, Het, (C,.¢alkyl)aryl or (C,.salkyl)Het or heterocycle being optionally substituted with R*®°; h) NR™'COCOR' wherein R™' is H or (C,.s)alkyl optionally substituted with R'®; and R'2 is OR"? or N(R"), wherein R'® and each R'* is independently H, (C,.alkyl), (Cs)cycloalkyl, or (Cye)alkyl- (Car)cycloalkyl, aryl, Het, (C.salkyl)aryl or (C,.calkyl)Het, or R'? is OH or O(C.calkyl) or bath R'** are covalently bonded together to form a 5, L 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C1.alkyl)Het and heterocycle being optionally substituted with R®: j) tetrazole, COOR™® wherein R'is H, (C1.)alkyl, (Caz)cycloalkyl, or(C1.s)alkyl-(Caz)cycloalkyl, aryl, Het, (Cy.calkyl)aryl or (Cisalkyl)Het, said (Ci.g)alkyl, (Cs7)cycloalkyl, or(Ci.g)alkyl-(Ca5)cycloalkyl, aryl, Het,
    (Ci.calkylaryl and (Cq.salkyl)Het being optionally substituted with R'6: and k) CONR™R' wherein R™ and R™ are independently H, (C;. s)alkyl, (Caz)cycloalkyl, (Ci.)alkyl-(Caz)cycloalkyl, aryl, Het, (C. salkyl)aryl or (C1.calkyl)Het, or both R'* and R'™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.salkyl)aryl, (Ci.salkyl)Het and heterocycle being optionally substituted with R": wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, Cy.galkyl, haloalkyl, COOR'®', SO;H, SO,R™! OR’, N(R"), SO,N(R2),, NR'™2COR'2 or CON(R'),, wherein R'®' and each R'®?is independently H, (Cie)alkyl, (Ca.)cycloalkyl or (Crs)alkyl-(C,7)cycloalkyt; or bath ) " R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle.
    @ u 30. The compound-according to claim 29, wherein R® is H.
    . 31. The compound according to claim 29, wherein R® is (Cog)alkenyl, aryl, Het, (C1g)alkyl-aryl, (C,.6)alkyl-Het, wherein said alkenyl, aryl, Het, alkyl-aryl, or alkyl-Het, are all optionally substituted with: - 1 to 4 substituents selected from: halogen, NO,, cyano, azido; or - 1 to 4 substituents selected from: a) (C4.¢) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cz.g)alkenyl, (C,.g)alkynyl, (C1.c) alkyl-(Cs. 7)cycloalkyl, all of which optionally substituted with R'®°; ® b) OR wherein R™ is H, (Cy.¢alkyl), (Cs)cycloalkyl, or (C1.c)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C.ealkyl)aryl or (Cy.calkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C.salkyl)aryl or (Cy.salkyl)Het being optionally substituted with R'% d) SH, 5(Cy.6alkyl), SO3H, SO,NH(C1.salkyl) or SO,NHC(O)C1.galkyl; e) NR''R"2 wherein R""" is H, (Cy.)alkyl, (Cs7)cycloalkyl or (Cy.)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (Cy.calkyl)aryl or (Cy.salkyl)Het, and R"*2 is H, CN, (C;. s)alkyl, (Cs7)cycloalkyl or (Cy.g)alkyl-(Ca.7)cycloalkyl, aryl, Het, (Cysalkylaryl, (Cisalkyl)Het, COOR™* or SO,R'* wherein R"*® is (C;.¢)alky), or both RB" and R'™ are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,alkyl)aryl or (Cysalkyl)Het, or heterocycle being optionally substituted with R'%; f) NR'™COR'"” wherein R"® and R'is each H, (C1.)alkyl, (Ca)cycloalkyl, said (Cy.)alkyl, (Ca7)cycloalkyl being optionally substituted with R'™; g) NR"CONR'R"', wherein R'"®, R""® and R'® is each H, (Cic)alkyl, (Cs. 7)cycloalkyl, or R'™ and R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl or heterocycle being optionally substituted with R™; } ] h) NR™'COCOR™ wherein R™' is H, (Cyg)alkyl, (Cs-)cycloalkyl, said alkyl, ) cycloalkyl being optionally substituted with B®: or R'is OR or N(R'*), wherein Rand each R'is independently H, (C16alkyl) or (Ca7)cycloalkyl, or R'** is OH or O(C alkyl) or both R*?* are
    ® covalently bonded together to form a 5, 6 or 7-membered saturated s heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R"™; . j) COOR™ wherein R'? is H, (Cy5)alkyl, (Ca-)cycloalkyl, or(Cy.s)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Cy.calkyl)Het, said (Cy.¢)alkyl, (Ca. 7)cycloalkyl, or (Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cq.salkyl)aryl and (C;. salkyl)Het being optionally substituted with R'®; k) CONR'?R™ wherein R'® and R™ are independently H, (C1.)alkyl, (Cs. 7)cycloalkyl, (C.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Cs. salkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C+.salkyl)aryl, and (C-salkyl)Het being optionally substituted with R'’; o 1) aryl, Het, (Cysalkyl)aryl or (Cy.salkyl)Het, all of which being optionally substituted with R'*®; and wherein R'° is selected from: - 1 to 3 substituents selected from: halogen, NO,, cyano or azido; - 1 to 3 substituents selected from: a) (C+) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs; spirocycloalkyl optionally containing 1 or 2 heteroatom, (C..g)alkenyl, (C,.g)alkynyl,
    (C1.6) alkyl-(C47)cycloalkyl, all of which optionally substituted with R®%; b) OR'™ wherein R'* is H, (C,salkyl), (Cs7)cycloalkyl, or (Ci.g)alkyl- (Ca)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (Cy.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,salkyl)aryl or (Cysalkyl)Het being optionally substituted with R"®; d) SH, S(C1.salkyl), SOzH, SO.N(R®), or SO,N(R'*®)C(O)R"*® wherein each R'® is independently H, (C;.¢)alkyl, (Car)cycloalkyl or
    (C1.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,.alkyharyl or (C1.salkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cs. salky) Het or heterocycle being optionally substituted with B®; e) NR'"'R"2 wherein R"" is H, (C1.)alkyl, (Ca7)cycloalkyl or (Ci. s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Cy.salkyl)Het, and R'is H, CN, (C1e)alkyl, (Csr)cycloalkyl or (C,.c)alkyl-(Cs)cycioalkyl, aryl, Het, (C,salkyl)aryl, (Cisalkyl)Het , COOR™'® or SO,R'*® wherein
    ® R'is (Cy.6)alkyl, (Ca)cycloalkyl, or (C.s)alkyl-(Ca.z)cycloalkyl, aryl, : Het, (Ci.salkyl)aryl or (Cy.salkyl)Het, or both R'"" and R"*2 are covalently bonded together and to the nitrogen to which they are . attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C,salkyl)Het, or heterocycle being optionally substituted with B®: f) NR"™COR"” wherein R"® and R" is each H, (Cy.)alkyl, (Cs. 7)cycloalkyl, (Cy.e)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cq.calkyl)aryl or (C:. salkyl)Het, said (C.)alkyl, (Cs7)cycloalkyl, (Cys)alkyl-(Cs)cycloalkyl, aryl, Het, (Ccalkyl)aryl or (C,.salkyl)Het being optionally substituted with R'®°; ® g) NR""CONR'*R', wherein R'", R""® and R'? is each H, (C:. s)alkyl, (Cs7)cycloalkyl, (C1.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cj. salkyl)aryl or (Cy.ealkyl)Het, or R""® and R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (C.. e)alkyl-(Csz)cycloalkyl, aryl, Het, (C;.salkyl)aryl or (Cygalkyl)Het or heterocycle being optionally substituted with R*®°; h) NR'*'COCOR™ wherein R"™! is H, (Cy.)alkyl optionally substituted with R**’; and R'? is OR'® or N(R'?*), wherein R'® and each R'is independently H, (Cysalkyl), (Cs)cycloalkyl, or (Cy.c)alkyl- (Cs7)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C,salkyl)Het, or R'* is OH or O(C,.salkyl) or both R'* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (C4.calkyl)aryl or (Csalkyl)Het and heterocycle being optionally substituted with R®;
    J) tetrazole, COOR™® wherein R'*® is H, (Cy.s)alkyl, (C.)cycloalkyl, or(C,.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.calkyl)aryl or (C,calkyl)Het, said (C+.g)alkyl, (Cs.7)cycloalkyl, or(C,.)alkyl-(C;.7)cycloalkyl, aryl, Het,
    (Crsalkylaryl and (Cy ealkyl)Het being optionally substituted with R®; and ) k) CONR'®R™ wherein R' and R'™® are independently H, (C;. syalkyl, (C.7)cycloalkyl, (C+.e)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C;. salkyl)aryi or (Cygalky)Het, or both R™° and R™ are covalently
    * bonded together and to the nitrogen to which they are attached to : form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C.alkyi)aryl, (Ci.¢alkyl)Het and heterocycle being optionally substituted with R'®°; So wherein R'is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C,alkyl, haloalkyl, COOR'®", SOzH, SOR, OR™, N(R"?),, SO.N(R'®),, NR'*COR'® or CON(R'®),, wherein R'' and each R'®2is independently H or (Cys)alkyi. :
    32. The compound according to claim 31, wherein R® is Co.alkenyl, phenyl, (C+. ® s)alkyl-aryl, (Cy.¢)alkyl-Het, wherein said alkenyl, phenyl and the alkyl portion of said alkyl-aryl or alkyl-Het, are optionally substituted with 1 to 3 substituents selected from: a) (C16) alkyl Cy. spirocycloalkyl optionally containing 1 or 2 heteroatom, : (Cae)alkenyl, all of which optionally substituted with C4.salkyl or C1salkoxy, NH, NH(Me) or N(Me)s; e) NHR"? wherein R'is aryl, Het, (C1.alkyl)aryl, (C.calkyl)Het, said aryl, Het, (C,.salkylaryl or (C;.salkyl)Het, being optionally substituted with R*®; j) COOH; k) CONR'?’R* wherein R™ and R'® are independently H, (Cy.¢)alkyl, (Cs. 7)cycloalkyl, (Cqe)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Cs. salkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cysalkyl)aryl, and (C,alkyl)Het being optionally substituted with R**°; I) phenyl or Het, both optionally substituted with R'*° and wherein R'is selected from: - 1 or 2 substituents selected from: halogen, NO,, cyano or azido; - 1 or 2 substituents selected from: a) (Cy.6) alkyl or (C..g)alkenyl, both optionally substituted with COOH or CONHy; b) OR" wherein R'is H or (C:.alkyl) optionally substituted with } COOH; kh) NHCOCOOH; j) COOH; and k) CONH,,
    33. The compound according to claim 32, wherein Z is selected from: IS } 78 Og, OH Og NH, NA N A H 3 H S OH Ay A LA yo =/ = 7 7 1 OH N OH OH H bl : b H ’ H y Ae - oH H,N HN Ny Xf TS V3 : NA NA HN AA A HN ® SU = = —_— [% OH N OH OH H ’ : H] 0 I] OH ’ 0 »( \—OH N <, H 0 + H \_ =N " << You HN HN H Loe 0 = $ o OH OH | OH o oH o , : / “\ A ay < H H N = Ho = Ho den HN HN HN 4 x EN x OH o , 0% oH 07 “OH o”7 “OH Ae Q \ A " ~ on A3N ~ SN N = H $ =N : HN : = N 2 NEAT bs HN N 7 Xn SY XN be 0” "NH, oH | 0% 0H 0? “oH 0” "NH,
    : Te SN HN re pae i" o} OH OMe H OMe . ~~ 3 SERCO GS \ & H OMe H OMe oh COOH 1 °F
    BY . HN.__. COOH HN._CONH, H =N CA \_cooH OH | “coon OH , OH and
    I. N=\ Hobs OH
    34. The compound according to claim 29, wherein R® is: 9 8 R R\ R ) ~~ Or Q 2 Y wherein R” and R® are each independently H, (C1.)alkyl, haloalkyl, (Cs7)cycloalkyl, 6- or 10-membered aryl, Het, (Cq¢)alkyl-aryl, (C1¢)alkyl-Het, wherein said alkyl, - cycloalkyl, aryl, Het, (Cy.q)alkyl-aryl, (Cis)alkyl-Het are optionally substituted with R™®; or Rand R® are covalently bonded together to form second (Csz)cycloalkyt or a 4, 5- or 6-membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S; or when Z is N(R®¥)R®, either of R” or R® is covalently bonded to R® to form a nitrogen-containing 5-or 6-membered heterocycle; wherein BR” is selected from: ' 15 - 1 to 4 substituents selected from: halogen, NO,, cyano, azido; or - 1 to 4 substituents selected from: . ? a) (C1) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs.; spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cz.e)alkenyl, (C.g)alkynyl, (C1) alkyl-(Cs. 7)cycloalkyl, all of which optionally substituted with R'®%
    256 oo ® b) OR™ wherein R'™ is H, (C;alkyl), (Ca.r)cycloalkyl, or (Cy.g)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C,.alkyl)Het, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (Csalkyl)Het being optionally substituted with R'®, 5 d) SR'®, SO,N(R'®), or SO,N(R'*®)C(O)R"*® wherein each R'® is independently H, (Ci.g)alkyl, (Cs.7)cycloalkyl or (C1.c)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,salkyl)aryl or (C4.salkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C:. ealkyl)aryl or (Crealkyl)Het or heterocycle being optionally substituted with
    R15. ® e) NR'"R"" wherein R'is H, (Cy.¢)alkyl, (Cs.7)cycloalkyl or (Cy.¢)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,.ealkyl)ary! or (Cialkyl)Het, and R'is H, CN, (C;. s)alkyl, (Ca.7)cycloalkyl or (C.s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.calkylaryl, (Crealkyl)Het , COOR'"® or SO,R"** wherein R' is (C1.c)alkyl, (Cs. 7)cycloalkyl, or (Cy¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cy.alkyl)aryl or (C;. salkyl)Het, or both R'"" and R'*? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C.salkyl)aryl or (C,.salkyl)Het, or heterocycle being optionally substituted with R**; f) NR'"®COR""” wherein R'"® and R'"" is each H, (C1.)alkyl, (Cs)cycloalkyl, (Cre)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cysalkyl)Het, said (C;. slalkyl, (Ca7)cycloalkyl, (Cy.)alkyl-(Cs7)cycloalkyl, aryl, Het, (C+.calkyl)aryl or (C1salkyl)Het being optionally substituted with R'®°; g) NR"™CONR™®R'®, wherein R"®, B""® and R™’ is each H, (C1.)alkyl, (Ca. 7)cycloalkyl, (Cy.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cyeatkylaryl or (C;. salkyl)Het, or R'is covalently bonded to R'® and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R"® and R' are covalently bonded together and to the nitrogen to which ’ 30 they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Cy.s)alkyl-(Cs7)cycloalkyl, aryl, Het, (C4.calkylaryl or (Cs. salkyl)Het or heterocycle being optionally substituted with R'*°; h) NR™'COCOR™ wherein R™' is H, (Cy.)alkyl, (Ca)cycloalkyl, (C1.c)alkyl- (Ca)cycloalkyl, a 6- or 10-membered aryl, Het, (Cq-6alkyl)aryl or (C;.
    e salkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Ci.salkyl)aryl or : (C1.salkyl)Het being optionally substituted with R™°, and R'?? is OR" or N(R'®"), wherein R'® and each R'** is independently H, (C1salkyl), (Ca. ; 7)cycloalkyl, or (Cy.5)alkyl-(Cs)cycloalkyl, aryl, Het, (Cy.calkyl)ary! or (C,.
    salkyl)Het, or R™* is OH or O(C;.ealkyl) or both R'?* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cy.salkyl)Het and oo heterocycle being optionally substituted with R'®; i) COR wherein R" is H, (Cy)alkyl, (Csz)cycloalkyl or (C1.e)alkyl-(Cs. : z)cycloalkyl, aryl, Het, (C1salkyl)aryl or (Cycalkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,alkyharyl or (C,.alkyl)Het being optionally substituted with R'®’; ® j) COOR™® wherein R'? is H, (Cy¢)alkyl, (Caz)cycloalkyl, or(Cy.g)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,.salkyl)Het, said (C,.)alkyl, (Ca. z)cycloalkyl, or(C1.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C,salkyl)aryl and (Ci. salkyl)Het being optionally substituted with R'*°; k) CONR'R™ wherein R'?® and R** are independently H, (Cy.c)alkyl, (Cs. 7)cycloalkyl, (C4.g)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (Cs. salkyl)Het, or both R™ and R™® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.salkylaryl, (C1salkyl)Het and heterocycle being optionally substituted with R'®; I) aryl, Het, (Ci.salkyl)aryl or (C1.calkyl)Het, all of which being optionally substituted with R'®°, wherein, R'is selected from: ~~ 1 to 3 substituents selected from: halogen, NO,, cyano, azido; or - 1 to 3 substituents selected from:
    : a) (C1.6) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs; spirocycloalkyl optionally containing 1 or 2 heteroatom, (Cag)alkenyl, (Ca.g)alkynyl, all of which optionally substituted with R'®’;
    b) OR wherein R'is H, (C1.salkyl) or (Cs.7)cycloalkyl, said alkyl and cycloalkyl being optionally substituted with R'®’; d) SR'®, SO,N(R'®), wherein R'® is H, (C1.)alkyl or (Cs)cycloalkyl, said alkyl or cycloalky! being optionally substituted with B®: e) NR'''R""? wherein R'is H, (Cy)alkyl or (Cas)cycloalkyl, and R*'2 is H, (Cye)alkyl, (Css)cycloalkyl or (Ci.e)alkyl-(Cs.7)cycioalkyl, aryl, Het,
    ® (Cysalkyl)aryl, (Cialkyl)Het, COOR'® or SO,R"* wherein R'® is (Cy. - e)alkyl, (Cs7)cycloalkyl, or (Cqg)alkyl-(Cs)cycloalkyl, aryl, Het, (C:. salkyl)aryl or (C,.ealkyl)Het, or both R'" and R'"? are covalently ' bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (Cisalkyl)Het, or heterocycle being optionally substituted with R*®°; f) NR""® COR"? wherein R'*® and R'"" is each H, (C1.s)alkyi or (Cs. 7)eycloalkyl, said (C4.g)alkyl or (Cs.7)cycloalkyl being optionally substituted with R'®; : g) NR" CONR"'’R'®, wherein R'"'®, R'"® and R'® is each H, (Ci. ® e)alkyl or (C.7)cycloalkyl; or R™® and R'? are covalently bonded : together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl or heterocycle being optionally substituted with R'®; h) NR''COCOR" wherein R'is H, (C,.s)alkyl or (Cs.s)cycloalkyl, said alkyl or cycloalkyl being optionally substituted with R"®’; or R'2 is OR? or N(R'®), wherein R'? and each R'is independently H, (Ci.satkyl) or (Cs.7)cycloalkyl, or R'is OH or O(C. salkyl) or both R*?* are covalently bonded together to form a 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R'®; j) tetrazole, COOR' wherein R'?® is H, (C1.)alkyl or (Csz)cycloalkyl, said (C.g)alkyl and (Cs.7)cycloalkyl being optionally substituted with R'%% and k) CONR'R"® wherein R'*® and R'® are independently H, (C. e)alkyl or (Csz)cycloalkyl, or both R'? and R'* are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl and ) 30 heterocycle being optionally substituted with R'®; wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C, alkyl, haloalkyl, COOR™', OR™®", N(R'2), or CON(R'®?),, wherein R'®' and each R'®is independently H or (C,.¢)alkyl.
    [ : 35. The compound according to claim 34, wherein R” and R® are each independently H, (Cy¢)alkyl, haloalkyl, (Cs7)cycloalkyl, 6- or 10-membered aryl, Het, ’ (Cig)alkyl-aryl, (Cy.)alkyl-Het, all of which optionally substituted with from 1 to 4 substituents selected from halogen or: : a) (Cie)alkyl; and b) N(R®"),, COR®, or SO,R*" COOR®:, COCOOR®?, CON(R™), COCON(R™), wherein each R® or R® are independently H, (Ci. s)alkyl, (Cs.sr)cycloalkyl, or (Cis)alkyl-(Csz)cycloalkyl; or each R® are independently covalently bonded together and to the nitrogen to which they are both bonded to form a 5, 6 or 7-membered saturated ® heterocycle; or R* is independently (Ci.)alkyl, (Cs)cycloalkyl, or (Ci. g)alkyl-(Cs7)cycloalkyl. or R” and R?® are covalently bonded together to form (Cs.)cycloalkyl, 4, 5- or 6- membered heterocycle having from 1 to 3 heteroatom selected from O, N, and S.
    36. The compound according to claim 35, wherein R” and R® are each independently H, (Cig)alkyl, haloalkyl, (Cs7)cycloalkyl, 6- or 10-membered aryl, Het, (Cire)alkyl-aryl, (Cyg)alkyl-Het; or R” and R® are covalently bonded together to form cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidine, piperidine, tetrahydrofuran, tetrahydropyran, or pentamethylene sulfide; wherein said alkyl, haloalkyl, (Cs.7)cycloalkyl, 6- or 10-membered aryl, Het, (C1s)alkyl-aryl, (C46)alkyl-Het, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidine, _ piperidine, tetrahydrofuran, tetrahydropyran, or pentamethylene sulfide are optionally monosubstituted with substituents selected from: a) (Ci.6)alkyl; and b) NHz, N(CH,CH),, COCHs, or SO,CHs.
    37. The compound according to claim 36, wherein R” and R® are selected from: wn LJ Corry All my
    OH CONH, : ¢ [a ( | [ | J OH — N wt LD H ~~ rT , TT , 7, and “7°77 or R” and R® together form: H / odhsoooda , YS 2 2h NR SS ® 0] 0 J NI H ST J JEN N sists aivlode] : 0 CH, Be WS SICICIONOIG ING @ and >
    38. The compound according to claim 37, wherein R” and R® are selected from: . (@] ) H / ST N N N = NH UROEOES ESIGN ’ ° ’ TT , UT ’ UT H oT ’ TT i ° - ’ H | dé 2 O00 or . oT 1 TT I tT 3 TT b] and TT -
    e 38. The compound according to claim 34, wherein R® is H, or R® is covalently : bonded to either of R” or R® to form a 5- or 6-membered heterocycle. . 40. The compound according to claim 39, wherein R® is H.
    41. The compound according to claim 34, wherein Q is a 6- or 10-membered aryl, Het, (Cs.salkyl)aryl or (C,.salkyl)-Het, all of which being optionally substituted with: ot OH o oo A A I 0 , COOH | or R10 ® wherein R'® is: - 1 to 4 substituents selected from: halogen, NO,, cyano or azido; or - 1 to 4 substituents selected from: : a) (C16) alkyl or haloalkyl, (Cs7)cycloalkyl, (C..¢)alkenyl, (Ca.g)alkynyl, (Cig) alkyl-(Cs7)cycloalkyl, all of which optionally substituted with R'%: b) OR wherein R™ is H, (Cy.salkyl), (Ca)cycloalkyl, or (Cy.5)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (Cyealkyl)aryl or (Cy.ealkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,salkyl)aryl or (Cyalkyl)Het being optionally substituted with R15: ’ d) SR" wherein R'® is H, (C.)alkyl, (Csz)cycloalkyl or (Cq.q)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C4.qalkyl)aryl or (Cy.calkyl)Het, all of which being optionally substituted with R'®; e) NR'"'R""? wherein R™" is H, (C.s)alkyl, (Cs7)cycloalkyl or (C.)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,.qalkyl)aryl or (Ci.calkyl)Het, and R"'? is H, CN, (C,. slalkyl, (Ca7)cycloalkyl or (Cy.g)alkyl-(Cg.7)cycloalkyl, aryl, Het, (Ciealkyharyl, (C1calkyl)Het , COOR'" or SO,R""® wherein R™ is (C,.)alkyl, (Cs. 7)cycloalkyl, or (Cq.g)alkyl-(Ca;)cycloalkyl, aryl, Het, (C,alkyl)aryl or (C,. salkyl)Het, or both R™" and R'* are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated . heterocycle, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C4.¢alkyl)Het, or heterocycle being optionally substituted with B®"; f) NR"COR™" wherein R"* and R"" is each H, (Cy.)alkyl, (Cs-)cycloalkyl, (Cis)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl or (C1ealkyl)Het, said (C,.
    ® s)alkyl, (Cs.7)cycloalkyl, (C1.g)alkyl-(Csz)cycloalkyl, aryl, Het, (C,.calkyl)aryt or " (C1.salkyl)Het being optionally substituted with R'®°,; g) NR" CONR"R™, wherein R'*®, R'"® and R'is each H, (Cy.g)alkyl, (Cs. : 7)cycloalkyl, (Cy.e)alkyl-(Cs7)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Cs. salkyl)Het, or R""® is covalently bonded to R'* and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; or R'® and R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl, (Cy.)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cisalkyl)aryl or (C4. salkyl)Het or heterocycle being optionally substituted with R'; h) NR'*’COCOR' wherein R'' and R'is each H, (C,.s)alkyl, (Cs. ® : 7)cycloalkyl, (Cq¢)alkyl-(Cs.7)cycloalkyl, a 6- or 10-membered aryl, Het, (C. salkyl)aryl or (C,.alkyl)Het, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cy-salkyl)aryl or (Cy.salkyl)Het being optionally substituted with R'®; : or R'#is OR'® or N(R'*), wherein R?* and each R'?* is independently H, (C-salkyl), (Cs7)cycloalkyl, or (Cy.g)alkyl-(Csz)cycloalkyl, aryl, Het, (Cs. salkyharyl or (Cy.salkyl)Het, or R'** is OH or O(C1.salkyl) or both R'®* are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cysalkyl)aryl or
    (C1.salky)Het and heterocycle being optionally substituted with RS? j) COOR'® wherein R" is H, (C1s)alkyl, (Caz)cycloalkyl, or(Cy.e)alkyl-(Ca. 7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C,.calkyl)Het, said (C1.¢)alkyl, (Cs. : 7)cycloalkyl, or(Cq.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cq¢alkyl)aryl and (C;. calkyl)Het being optionally substituted with R'°; k) CONR™R™ wherein R' and R" are independently H, (Cy.c)alky!, (Cs. 7)cycloalkyl, (Cy.¢)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C.¢alkyharyl or (C. calkyl)Het, or both R'?® and R'®° are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (Cialkyl)aryl,
    (C1.salkyl)Het and heterocycle being optionally substituted with R'*°; I) aryl, Het, (C,.¢alkyl)aryl or (Cycalkyl)Het, all of which being optionally substituted with R'*; wherein RB" is selected from: - 1 to 3 substituents selected from: halogen, NO,, cyano or azido; or - 1 to 3 substituents selected from:
    ® a) (Cy) alkyl or haloalkyl, (Cs.7)cycloalkyl, Cs; spirocycloalkyl » optionally containing 1 or 2 heteroatom, (Co¢)alkenyl, (Cog)alkynyl,
    (C+.6) alkyl-(Ca.7)cycloalkyl, all of which optionally substituted with R'®; . b) OR wherein R'™ is H, (Cy.salkyl), (Cs)cycloalkyl, or (C1.e)alkyl- (Cs7)cycloalkyl, aryl, Het, (C4.qalkylyaryl or (C,.salkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C;.alkyl)aryl or (Ciealkyl)Het being optionally substituted with R™®; d) SR'®, SO,N(R®), or SO.N(R'®®)C(O)R'® wherein each R'® is independently H, (Cy.¢)alkyl, (Cs.7)cycloalkyl or (C;.¢)alkyl-(Cs. 7¥cycloalkyl, aryl, Het, (Cy.salkylaryl or (C4alkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are ® attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Ci.salkyl)aryl or (C,.salkyl)Het or heterocycle being optionally substituted with R'°: e) NR''R""? wherein R'"" is H, (C.s)alkyl, (Cs.7)cycloalkyl or (Cs. s)alkyl-(Cs.7)cycloalkyl, aryl, Het, (C.salkyl)aryl or (Cy.salkyl)Het, and R'is H, CN, (C)alkyl, (Ca)cycloalkyl or (C1.g)alkyl-(Car)cycloalkyl, aryl, Het, (C,.salkylaryl, (C,salkyl)Het or SO,R'""® wherein R'is (C,. s)alkyl, (Ca.s)cycloalkyl, or (C.g)alkyl-(Cs.r)cycloalkyl, aryl, Het, (C. salkylaryl or (C1ealkyl)Het, or both R*'* and R**? are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (Cisalkyl)aryl or (Cysalkyl)Het, or heterocycle being optionally substituted with R'°°; f) NR'™COR"" wherein R"*® and R'is each H, (Cy.s)alkyl, (Cs. 7)cycloalkyl, (C1.g)alkyl-(Csz)cycloalkyl, aryl, Het, (C,.calkylary! or (C.. salkyl)Het, said (Cy.g)alkyl, (Cas)cycloalkyl, (Cy.)alkyl-(Car)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (C;salkyl)Het being optionally substituted with R'®; g) NR"CONR'R'™, wherein R""®, R"® and R'is each H, (Cy. s)alkyl, (Cs 7)cycloalkyl, (C1.e)alkyl-(Cs7)cycloalkyl, aryl, Het, (C. salkylaryl or (Cy alkyl)Het, or R'is covalently bonded to R'' and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, or R'*® and R'®® are covalently bonded
    ® together and to the nitrogen to which they. are attached to form a 5, 6 . or 7-membered saturated heterocycle, said alkyl, cycloalkyl, (C;. s)alkyl-(Cs)cycloalkyl, aryl, Het, (C,calkyl)aryl or (Cqealkyl)Het or , heterocycle being optionally substituted with R'®°; h) NR™?'COCOR™ wherein R'*' is H, (C.s)alkyl optionally substituted with R'®®, and R'? is OR'® or N(R*?*), wherein R'® and each R'is independently H, (Cy.salkyl), (Cs7)cycloalkyl, or (Cy.q)alkyl- (Cs)eycloalkyl, aryl, Het, (Cyealkyl)aryl or (C,.salkyl)Het, or R'is OH or O(Cy.galkyl) or both R'** are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl- cycloalkyl, aryl, Het, (C_salkyl)aryl or (C,.¢alkyl)Het and heterocycle ® being optionally substituted with R®°; j) tetrazole, COOR'® wherein R'® is H, (Cy.¢)alkyl, (Ca.s)cycloalkyl, or(Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cygalkyl)aryl or (Cipalkyl)Het, said (Cy.¢)alkyl, (Cj.7)cycloalkyl, or(Cy.g)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cisalkyharyl and (C.salkyl)Het being optionally substituted with R'®; and k) CONR™R™ wherein R'* and R™ are independently H, (C.. e)alkyl, (Caz)cycloalkyl, (C1.6)atkyl-(Cs.7)cycloalkyl, aryl, Het, (Ci. salkyharyl or (C,.salkyl)Het, or both R'* and R™ are covalently . bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, : cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C.calkyl)aryl, (C;.¢alkyl)Het and heterocycle being optionally substituted with R*®: wherein R'® is defined as 1 or 2 substituents selected from: tetrazole, halogen, CN, C.salkyl, haloalkyl, COOR'!, SO,H, SR", SO,R™!, OR™' N(R), SO,N(R),, NR'2COR 62 or CON(R®%),, wherein R"® and each R'is independently H,- (C1-e)alkyl, (Cs.7)cycloalkyl or (Cy.g)alkyl-(Cs7)cycloalkyl; or both R'™® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered ’ saturated heterocycle.
    42. The compound according to claim 41, wherein Q is a 6- or 10-membered
    ® aryl, Het, (Cy.salkyl)aryl or (C,.calkyl)-Het, all of which being optionally substituted - p with: - 1 to 4 substituents selected from: halogen,NO,, cyano or azido; or . - 1 to 4 substituents selected from: a) (C1.6) alkyl or haloalkyl, (Cs7)cycloalkyl, (Co.g)alkenyl, (Co.g)alkynyl, (Cie) alkyl-(Cs.7)cycloalkyl, all of which optionally substituted with R*®: b) OR wherein R'is H, (C.salkyl), (Ca)cycloalkyl, or (Cs.s)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (C,.salkyl)ary! or (Cysalkyl)Het, said alkyl, cycloalkyl, - aryl, Het, (Cyalkyl)aryl or (C,.calkyl)Het being optionally substituted with R10: d) SR'®, SO.N(R'®), or SO.N(R'*®)C(O)R'® wherein each R™ is ® 10 independently H, (C,.)alkyl, (Cs.s)cycloalkyl or (Ci)alkyl-(Cs7)cycloalkyi, aryl, Het, (C,calkylaryl or (Cyealkyl)Het or both R'® are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,. salkyl)aryl or (Cy.alkyl)Het or heterocycle being optionally substituted with R'%; e) NR™R"™ wherein R"" is H, (Cy.6)alkyl, (Caz)cycloalkyl or (Cy.s)alkyl-(Cs. 7)cycloalkyl, aryl, Het, (Cyealkylaryl or (Cysalkyl)Het, and R'is H, CN, (C. g)alkyl, (Cs.7)cycloalkyl or (Cie)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cy.salkyl)aryl, (Crealkyl)Het , COOR™ or SO,R""® wherein R"*® is (C1.)alkyl, (Cs. 7)cycloalkyl, or (C,.g)alkyl-(Caz)cycloalkyl, aryl, Het, (Ci.ealkyl)aryl or (Cy. salkyl)Het, or both R'"" and R'"? are covalently bonded together and to the nitrogen to-which they are attached to form a's, 6 or 7-membered saturated : heterocycle, said alkyl, cycloalkyl, aryl, Het, (C,salkyl)aryl or (Cisalkyl)Het, or heterocycle being optionally substituted with R'®°; f) NR" COR" wherein R''® and R""" is each H, (Cy.s)alkyl, (Cs)cycloalkyl, (C1-6)alkyl-(Cs7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C1-salkyl)Het, said (C;. s)alkyl, (Caz)cycloalkyl, (C1.e)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cy.calkyharyl or
    (C1.salkyl)Het being optionally substituted with R'*°; g) NR'CONR™R™, wherein R"™, R"*® and R™2 is each H, (C,s)alkyl, (Cs. 7)cycloalkyl, (Cy.q)alkyl-(Cs7)cycloalkyl, aryl, Het, (Ci.ealkylaryl or (C4. salkyl)Het, or R'"® and R'2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated
    ® heterocycle; said alkyl, cycloalkyl, (Ci.¢)alkyl-(Cs)cycloalkyl, aryl, Het, (C,. 2 salkyl)aryl or (C.alkyl)Het or heterocycle being optionally substituted with rR
    . h) NR™!'COCOR™ wherein R™' is H, (C,.¢)alkyl optionally substituted with R'®, and R'* is OR or N(R"), wherein R' and each R'® is independently H, (Cy.salkyl), (Cs.7)cycloalkyl, or (Cs.¢)alkyl-(Cs)cycloalkyl, aryl, Het, (Cy.salkyl)ary! or (C.salkyl)Het, or R'is OH or O(C;.alkyl) or both R' are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Csalkyl)Het and heterocycle being optionally substituted with R'5%: j) COOR' wherein R™ is H, (Ci.s)alkyl, (Cs)cycloalkyl, or(C.¢)alkyl-(Cs. ® 7)cycloalkyl, aryl, Het, (C,.calkyl)aryl or (Cysalkyl)Het, said (Cig)alkyl, (Ca. : 7)cycloalkyl, or(C+.¢)alkyl-(Cg.7)cycloalkyl, aryl, Het, (C,.calkylaryl and (C;. salkyl)Het being optionally substituted with R'*: k) CONR™R™ wherein R'*® and R™ are independently H, (Cis)alkyl, (Cs. 7)cycloalkyl, (C1.e)alkyl-(Ca7)cycloalkyl, aryl, Het, (Cysalkyl)aryl or (C;. salkyl)Het, or both R'® and R' are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl, alkyl-cycloalkyl, aryl, Het, (C.calkyl)aryl, (C1salkyl)Het and heterocycle being optionally substituted with B'5%: [) aryl, Het, (C1-Balkyl)aryl or (C1-6alkyl)Het, all of which being optionally substituted with R'*®; wherein R'is selected from: - 1 to 3 substituents selected from: halogen, NO,, cyano or azido; or - 1 to 3 substituents selected from: a) (C16) alkyl or haloalkyl, (Cs.7)cycloalkyl, (Co.g)alkenyl, (Cog)alkynyl, (C16) alkyl-(Cs)cycloalky, all of which optionally substituted with R*®: b) OR wherein R'™ is H, (C; alkyl), (Cs.)cycloalkyl, or (Cy.)alkyl- (Caz)cycloalkyl, aryl, Het, said alkyl, cycloalkyl, aryl and Het being ’ optionally substituted with R'®%; : c) OCOR™® wherein R'is (C1)alkyl, (Cs-)cycloalkyl, (Cy.q)alkyl-(Cs. ] 7)cycloalkyl, Het, (C,.salkyl)aryl or (C,.calkyl)Het, said alkyl, cycloalkyl, aryl, Het, (C,.salkyl)aryl or (C,salkyl)Het being optionally substituted with B®; d) SR'®, SO,N(R'®), or SO,N(R*®)C(O)R"® wherein each R'® js
    ® independently H, (Cs.g)alkyl, (Ca7)cycloalkyl or both R'® are covalently i bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, : cycloalkyl or heterocycle being optionally substituted with R*®;
    e) NR''R'"2 wherein R™" is H, (C;.¢)alkyl, (Ca7)cycloalkyl or (Ch. e)alkyl-(Cs.7)cycloalkyl, and R"? is H, (Cys)alkyl, (Caz)cycloalkyl or (Ci. e)alkyl-(C3)cycloalkyl, COOR™ or SO,R"'® wherein R™ is (C1.g)alkyl, (Ca)cycloalkyl, or both R'" and R'"? are covalently bonded together and to the nitrogen to which they are attached to forma 5, 6 or 7- membered saturated heterocycle, said alkyl, cycloalkyl, aryl, Het, (C+. salkylaryl or (C,galkyl)Het, or heterocycle being optionally substituted ® with R'®; f) NR'SCOR"" wherein R"® and R"" is each H, (Ci.¢)alkyl, (Cs. s)eycloalkyl, (Cy.6)alkyl-(Cs.7)cycloalkyl, aryl, Het, (Cqsalkyl)aryl or (Cy. salkyl)Het, said (Cy.¢)alkyl, (Ca.7)cycloalkyl, (Ci.¢)alkyl-(Cs.s)cycloalkyl, : aryl, Het, (C,.salkyl)aryl or (Ci.salkyl)Het being optionally substituted with R%°; g) NR"®CONR'"R'®, wherein R'*, R"'® and R'*’ is each H, (Cs. s)alkyl, (Cs7)cycloalkyl, or R''? and R'*® are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle; said alkyl, cycloalkyl or heterocycle being optionally substituted with R'’; h) NR'™*'COCOR'® wherein R'? is H, (Ci.c)alkyl optionally substituted with R*®°, or R'2 is OR'® or N(R"), wherein R*** and each R'is independently H, (C,.salkyl) or (Caz)cycloalkyt, or R'* is OH or O(C1.salkyl), or both R'** are covalently bonded together to form a 5, 6 or 7-membered saturated heterocycle, said alkyl, cycloalkyl and heterocycle being optionally substituted with R'®; j) tetrazole, COOR™® wherein R™ is H, (C1.¢)alkyl or (Cs7)cycloalkyl, said (Cy.¢)alkyl and (Caz.7)cycloalkyl being optionally substituted with . R' and k) CONR'®R™ wherein R'*® and R'* are independently H, (Cs. o)alkyl or (Cs)cycloalkyl, or both R'° and R™° are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6
    ® or 7-membered saturated heterocycle, said alkyl, cycloalkyl and 2 heterocycle being optionally substituted with R'®%; wherein R'® is defined as 1 or 2 substituents selected from: > tetrazole, halogen, CN, C;qalkyl, haloalkyl, COOR'™! SO;H, SO,R'", OR™', N(R'®?),, SO.N(R'®),, NR'®2 COR? or CON(R™?),, wherein R'® and each R'®is independently H, (Cis)alkyl, (Ca7)cycloalkyl or (Cy.g)alkyl-(Ca.7)cycloalkyl; or both R'%2 are covalently bonded together and to the nitrogen to which they are attached to form a 5, 6 or 7-membered saturated heterocycle. ® 43. The compound according to claim 42, wherein Q is a 6- or 10-membered aryl or Het, both being optionally substituted with: - 1 to 3 halogen, NO,, cyano, azido; or - 1 to 3 substituents selected from: a) (Ci.¢) alkyl or haloalkyl, first (Cs.7)cycloalkyl, (Cz.¢)alkenyl, (Cag)alkynyl, (C4. 6) alkyl-(Cs)cycloalkyl, all of which are optionally substituted with R'®?; b) OR' wherein R'™ is H, (C;alkyl); d) SONHR'*® wherein R'% is H or (C,.g)alkyt; e) NR" R"'2 wherein both R'" and R™™ are independently H or (C,¢)alkyl; f) NHCOR" wherein R'is H or (Cyg)alkyl; : g) NHCONR'"'’R™®, wherein R'® and R'® is each independently H or (C;. s)alkyl; h) NHCOCOR'? wherein R'is OR'® or N(R"?%), wherein R'®and each . R'is independently H or (Cy.calkyl); j) COOR™® wherein R22 is H, (Cie)alkyl; - k) CONHR"™ wherein R™ is H, (C,.)alky); I) 6- or 10-membered aryl, Het, (C,.salkyl)aryl or (C,salkyl)Het, said aryl, Het,
    (Cr.ealkyl)aryl or (C1.salkyl)Het being optionally substituted with R'°; wherein R'is selected from: - 1 to 3 halogens; or ’ 30 - 1 to 3 substituents selected from: . a) first (Cig) alkyl or haloalkyl, first (Cz.7)cycloalkyl, (Cas)alkenyl, (Co. g)alkynyl, (C1.6) alkyl-(C3.;)cycloalkyl, all of which are optionally substituted with tetrazole, OR'2, COOR"®, wherein R'is H or , (Cio)alkyl; b) OR'* wherein R'is H, (C.calkyl); * d) SONHR'" wherein R'® is H or (C,.¢)alkyl; e) NR"'R""2 wherein both R'" and R**? are independently H or (C:- g)alkyl; f) NHCOR" wherein R"* is H or (Cy.g)alkyl; and "h) NHCOCOR'® wherein R'# is OR or N(R'?*), wherein R"* and each R'? is independently H or (Cygalkyl); j) COOR' wherein R'is H, (C1¢)alkyl; and k) CONHR" wherein R'™* is H, (C1.)alkyl.
    44. The compound according to claim 43, wherein Q is selected from: J B . I oh, B 0] ! o 0) N or s on 2 OM og NH ’ 0s NH \ OH 1 pe Ss NH, lo) N HN Ho” © H ) I~ = SN g Ton : NH, 4 oH . TNH : oH i 74 N \ ad goon i» OH ZZ OH 0 0” OH lo] 0” OH
    Y . 1] XN N XX XX 0 ~~ & Ss BD \ 3 N\ 4 Q — OH OH go o ° o oO 0 NH, OH OH NH, NH, 7 N= 72 NP Ne \ 72 \ 8 \ y/ N _ ® 0 74 WN “WW oH / OH NH, 0” “oH N=/ NH, 0 0 > ( pi ~~ ( ~~ { OH OH OH N 0) HooCc—/ 4 lo) 7 0 Ss ) HO ° I" / N r a OH Vad on ~~ OH N Oo [e] 0 =" NH S OH 2 OH / OA N\ o N 0 O 0 , Cl , \ x1 OH HN . * N OH OH $ \ , S fo] S le) No N [0] OH ] ges Sdaseiatan © ON OH : s o s ~~ H ,
    « a Ie) bo Jp d -—fe = I) v S NZ TNH } = , on SONH, | and .
    45. The compound according to claim 44, wherein Q is selected from: NH J Th aM ° ~ ~ / ® ° TL HO 0 OH ; [0] ~ ) nd Ho © N 0” oH of TNO = / o N=( 7 Ny OH ol oH OH o7 Ton NH, N=" o 0 OH AA h N OH NT as 0] 0 H . N=N OH SO,NH, CONH, and
    46. A compound represented by Formula la: » } Y i A So a— ” “2 7K (1a) wherein: Ais O, S, NR', or CR;
    ® Bis NR? or CR? R' is selected from the group consisting of: H, (Cy.¢)alkyl, benzyl, (C,.; alkyl)-(Cs. i amyl), (Cy. alkyl)-5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, and 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N and S, wherein said benzyl and said heteroatom are optionally substituted with from 1 to 4 substituents selected from the group consisting of: COOH, COO(C;.¢ alkyl), halogen, and (C.¢ alkyl); .
    R? is selected from the group consisting of: H, halogen, (C,.g)alkyl, (C,)cycloalkyl, @® phenyl, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from 0, N, and S, pyridine-N-oxide , and 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S, said phenyl, heterocycle and heterobicycle being optionally substituted with from 1 to 4 substituents selected from the group consisting of: halogen, C(halogen)s, (Ci.s)alkyl, OH, O(Cy.s alkyl), NH,, and N(C alkyl); Ris selected from the group consisting of: 5-, 6- or 7-membered heterocycle having 1 1to 4 heteroatoms selected from O, N, and S, norbornane, (Ca7)cycloalkyl and (Cs)cycloalkyl-(Cy5 alkyl); Mis N, CR, or COR®, wherein R* is selected from the group consisting of: H, halogen, and (C.s alkyl); and R® is selected from the group consisting of: H and (Cy alkyl); KandL is N or CH; ----- represents either a single or a double bond; - 30 Yis OorS; : Z is OR® or NR°R* R® is selected from the group consisting of: H, (Cy.g)alkyl, (Ca.s)cycloalkyl, (Cas)cycloalkyl(Crg)alkyl, (Ceo)aryl, (Ce-10)aryl(Cg)alkyl, (Czp)alkenyl,
    WQO 03/010141 PCT/CA02/01128 ® (Cs)cycloalkyl(Cs.g)alkenyl, (Cs.10)aryl(Caog)alkenyl, N{(C,.s) alkyl}s, NHCOO(C;. . s)alkyl(Cs.10)aryl, NHCO(Cg.10)aryl, (Cy.¢)alkyl-5- or 6-atom heterocycle, having 1 to 4 heteroatoms selected from O, N and S, and 9- or 10-atom heterobicycle having 1 to * 4 heteroatoms selected from O, N and S; wherein said alkyl, cycloalkyl, aryl, alkenyl, heterocycle are all optionally substituted with from 1 to 4 substituents selected from: OH, COOH, COO(C.g)altkyl, (Cie)alkyl, (Ci.g)alkyl-hydroxy, phenyl, benzyloxy, halogen, (Caa)alkenyl, (Cz4)alkenyl-(Cq)alkyl-COOH, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, Nand S, wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle being optionally substituted with from 1 to 4 substituents
    @® . selected from: (C5 alkyl), CF3, OH, COOH, NHC(C1.salkyl),, NHCO(C. alkyl), NH,, NH(C1.¢ alkyl), and N(C1s alkyl): 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S, said heterobicycle being optionally substituted with from 1 to 4 substituents selected from: halogen, OPO3H, sulfonamido, SO3H, SO,CHj, -CONH,, -COCHg3, (C1.3)alkyl, (Cs.4alkenyl) COOH, tetrazolyl, COOH, -CONH,, triazolyl, OH, NO,, NH,, -O(C1.s alky)COOH, hydantoin, benzoyleneurea, (C,.4)alkoxy, cyano, azido, -0-(C,.g)alkyl COOH, -O-(C;.g)alkyl COO-(C4.g)alkyl, NHCO(C;. 6 alkyl), -NHCOCOOH, -NHCOCONHOH,-NHCOCONH,, “NHCOCONHCH;, -NHCO(C,.¢)alkyl-COOH, -NHCOCONH(C.s)alkyl-COOH, -NHCO(Cs.7)cycloalkyl- COOH, -NHCONH(Cs.10)aryl-COOH, - NHCONH(Cg.1o)aryl- COO(Cg)alkyl, - NHCONH(C,¢)alkyl-COOH,- NHCONH(C,. g)alkyl-COO(C1¢)alkyl, - NHCONH(C.g)alkyl-(C..c)alkenyl- . 30 COOH, - NH(C.g)alkyl-(Cg.10)aryl-O(C1.s)alkyl COOH, - NH(C;. s)alkyl-(Cg.10)aryl-COOH, -NHCH,COOH, -NHCONH,, " -NHCO(C,.g)hydroxyalkyl COOH, -OCO(C;.¢)hydroxyalky! COOH, (C3.g)cycloalkyl COOH,
    ® 274 \ OH A ° S| -NHCN, -NHCHO, -NHSO,CHj, and : -NHSO,CF3; 6- or 10-membered aryl being optionally substituted with from 1 to 4 substituents selected from: halogen, OPO;zH, sulfonamido, SOzH, SO,CHj;, -CONH,, -COCHj, (Ci.g)alkyl, (Co4alkenyl)COOH , tetrazolyt, COOH, -CONH_, triazolyl, OH, NO,, NH, -O(C.5 alkyl) COOH, hydantoin, benzoyleneurea, (C,.)alkoxy, cyano, azido, -O-(C+.)alkyl COOH, -O-(C4.g)alkyl COO-(C.g)alkyl, NHCO(C;. [ 10 6 alkyl), -NHCOCOOH, -NHCOCONHOH,-NHCOCONH;, -NHCOCONHCHs3;, -NHCO(C.5)alkyl-COOH, -NHCOCONH(C,.¢)alkyl-COOH, -NHCO(C3.;)cycloalkyi- COOH, -NHCONH(Cq.10)aryl-COOH, - NHCONH(Cq.10)aryl- COO(C1g)alkyl, - NHCONH(C.¢)alkyl-COOH,- NHCONH(C,. 6)alkyl-COO(C.s)alkyl, - NHCONH(C1.)alkyl-(Ca.c)alkenyl- COOH, - NH(C.)alkyl-(Cs.10)aryl-O(Cy.¢)alkyl COOH, - NH(C;. s)alkyl-(Ce.10)aryl-COOH, -NHCH,COOH, -NHCONH,, -NHCO(C.s)hydroxyalkyl COOH, -OCO(C.¢)hydroxyalkyl COOH, (Cs¢)cycloatkyl COOH, \ oH ~A ~, CQ °c S , -NHCN, -NHCHO, -NHSO,CHs, and -NHSO,CF3; coumarin, (Ci.g)alkyl-amino, NH(C, alkyl), C(halogen)s, -NH(Cz.4)acyl, -NH(Cg.10)aroyl, -O(C,.galkyl)-Het; Ris H or (Cy, alkyl) covalently bonded to either R or R® to form pyrrolidine; ‘ orZis : R° ’ y 2a lo) :
    ® wherein . W is CR'R® wherein R” and R® are each independently H, (C1 alkyl), (Caz cycloalkyl), (C1. alkyl)phenyl, (Ci. alkyl)-(Cs.7 cycloalkyl), (Cs. cycloalkyl)-( Cy. alkyl), (Ca cycloalkyl)-(C..4 alkenyl), (C1. alkyl)-OH, phenyl, CH biphenyl, 5- or 6-membered heterocycle having from1 to 4 heteroatoms selected from O, N, and S, 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N, and S, (C15 alkyl)-5- or 6-membered heterocycle having from1 to 4 heteroatoms selected from O, N, and S, or (C, alkyl)-9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N, and S, orR’and R%are covalently bonded together to form (Cs. cycloalkyl), 4-, 5- or 6-membered heterocycle having from1 to 4 heteroatoms selected from O, N, and S; @ or one of R” or R® is covalently bonded to R® to form a pyrrolidine; wherein said alkyl, cycloalkyl, heterocycle, heterobicycle, phenyl are optionally substituted with from 1 to 4 substituents selected from the group consisting of: OH, COOH, (C46 alkyl), (C,.4 alkenyl), CONH,, NH, NH(C 1.4 alkyl), N(C.¢ alkyl), NHCOCOOH, NHCOCON(C;. alkyl),, NHCOCONH(C.¢ alkyl), SH, S(C1. alkyl), NHC(=NH)NH,, halogen, and COO(C.salkyl); R? is H or (Ci alkyl); and : Q is selected from the group consisting of: (C;_salkyl) CONHaryi, 6-, 9-, or 10-membered aryl, biphenyl, 5- or 6-atom heterocycle having 1 to 4 heteroatoms selected from O, N and S, 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S; wherein said aryl, biphenyl, heterocycle and heterobicycle are all optionally substituted with from 1 to 4 substituents selected from: OH, COOH, COO(C.g)alkyl, (Cye)alkyl, (Cy6)alkylCOOH, (Cy. alkyl)(Ca4 alkynyl), (Cre)alkyl-hydroxy, phenyl, benzyloxy, halogen, (Ca.)alkenyl, (C..4)alkenyi-
    (Cy.6)alkyl-COGH, 5--or 6-membered second heterocycle having 1 to 4 I 30 heteroatoms selected from O, N and S, NH-5- or 6- membered second heterocycle having 1 to 4 heteroatoms selected from O, N, and S, 2 wherein said second heterocycle and phenyl being optionally substituted with from 1 to 4 substituents selected from: (Cy. alkyl), CFs, OH, (Cisalkyl) COOH, O(C,.salkyl) COOH, (C1.6alkyl) COO(C;. salkyl), CHzphenyl, COO(C.¢ alkyl), (C1.6alkyl)O(C1.salkyl), COOH,
    ® NCH(C1.salkyl)2, NCO(C1.5 alkyl), NH,, NH(C alkyl), halogen, and . N(C+.5 alkyl); halogen, OPO3H, benzyl, sulfonamido, SH, SOCHS3, SO3H, SO,CH3, S(Cyg w alkyl)COOH, -CONH,, -COCHjs, (Cy.3)alkyl, (Cs.salkenyl) COOH wherein said alkenyl is optionally substituted with from 1 to 2
    (C1.6 alkyl) substituents,
    (Cz.4alkenyl)COO(C1.salkyl), tetrazolyl, COOH, triazolyl, OH, NO, NH, , - O(C1.6 alkyl) COOH, hydantoin, benzoyleneurea, (Ci.s)alkoxy, (Cy4)alkoxy(Cie alkyl)COOH, cyano, azido, -O-(C.¢)alkyl COOH, -O-(Cy.g)alkyl COO-(Ci.g)alkyl, -NHCOCOOH, -NHCOCONHOH,-NHCOCONH,, -NHCOCONHCHj, -NHCO(C.6)alkyl-COOH, -NHCOCONH(C;.¢)alkyl-COOH, ® -NHCO(C3 )cycloalkyl-COOH, -NHCONH(Cs.1p)aryl-COOH, - NHCONH(Ce. 10)aryl-COO(Cy.g)alkyl, - NHCONH(C.¢)alkyl-COOH, - NHCONH(C,)alkyl- COO(C1.6)alkyl, - NHCONH(C.¢)alkyl-(Cy.s)alkenyl-COOH, - NH(C,.¢)alkyl-(Cs. 10)aryl-O(C,.g)alkyl COOH, - NH(C.¢)alkyl-(Cs.10)aryl-COOH, -NHCH,COOH, -NHCONH,, -NHCO(C,.¢)hydroxyalkyl COOH, -OCO(C¢)hydroxyalkyl COOH, (Cs¢)cycloalkyl COOH, \ OH AA A > L( ; “O° °c s, ©, -NHCN, -NHCHO, -NHSO,CHj, -NHSO,CF3, coumarin, (C4.¢)alkyl-amino, NH(C;.salkyl),, C(halogen)s, -NH(C2.4)acyl, -NH(Cs o)aroyl, -CONH(C,.galkyl), -CO(C.5)alkyl-COOH, -CONH(C.)alkyl-COOH, -CO-NH-alanyl, -CONH(C;.4)alkylN(C+.calkyl)z, -CONH(C,.s) alkyl-Het, -CONH(C.,) alkyl-(COOH)-Het -CONH(C., alkyl) (OH)(C1. alkyl)OH, ~-CONH(C1.6) alkyl-COOH, -CONH(Cq.10 aryl), -CONH-Het, -CONH(Ce.10) aryl-COOH, -CONH(Cs.10) aryl-COO(Ch.q) alkyl, -CONH(C,.¢) alkyl-COO(C;.6) atkyl, -CONH(Cq.10) aryl-(C)alkyl-COOH, and -CONH(Ce.10) aryl-(C,¢)alkenyl-COOH, ” or a salt thereof,
    47. A compound of the formula: . 0 A z @ R2 S Rr? wherein A, R?, R® and Z are defined as follows:
    Cpd. #] A [R° RR | Z q001 | NH |v Ts 001 NH | J p= _Hon 1002 | NH | Oxy ; A : N 7 i ox 1003 | NH | 73 ; SN NA LC a's N OH 1004 | NH HN ; ESI Foo 7 ! AA N Zz N OH 1005 | NH | = ; Ny i) \_/ i i [8] 1006 NMe | AY ; HN No he ace
    Cpd.#| A R R® V4 , 1007 | © UE EE EN : 9, | \ "Da N ON i “ [eo] . ; | _ HN $ | \ ~¢° OH 1008 | NMe | EN ; LO RNG oH ® C . 1009 | NMe | Oo ; oy < } OH OH ie 0 070 | Nive | 0 . < F PONS N l _ lh i N, Ue ~¢ —— | OH : 1011 | NMe | O\—on ; . <, R i ) H Fe to 2 Ae) Bias » ¢ ‘ OH
    Ccpd. #] A [R? “R° y2 ee MSR SSS ESS SE - 1012 NMe 2 oH ’ ZN N { “ Ng! = HN Ie) 0 ! I) { pe 1013 | NMe | Tw ; SN put NH LC ; ) S OH — IRR NES SS Q 1014 | NMe | ; =~ N N . | i Ho =n x hy oo I ul 1015 | NMe | | oC ; PN N ne OH : o ! 1016 | NMe |! = : = “N N _ CN ) OH o 1017 | NMe | =< ; © : N or hy al N HN . . i i i ! SN . ! le} OH
    Cpd.#] A |R? R® z : 1018 | NMe | ™ [++ (= + |; N ~ = H ) Ps ~ fe) OH 1019 NH | OMe ; ! N H OMe 1020 | NMe | | J ; = ™N ® ne k H : . i =N HN oon 1021 | NMe | EE i =z N CC "de N HN i | 07 Nh, 1022 S | QA ; A Mon ’ me h _ HN oo OH 1023 | NMe | A ; . | Za \| N - NN HN . S 0” “oH
    Cpd.#] A |[R® Rr’ TZ . 1024 | § | 1 | y Ho : ; aE \ N . 0 H ] N NS OH T 1025 | NMe | No : Na ~~ CN NY i =N i ~ ® fo) OH 1026 | NMe | | : LPN 2 : : “ | —N OA EE EE RE oH 1027 | NMe | ~ ; Ne as xn HN < 07 NH, 1028 | NMe | RD ; Va N HN CN a lo) ! 1029 | NMe | x ; Na : H
    Cpd.#| A [R® R® Z - 171030 | NMe | T% ES ay oO ; HN ZN BY “ | x ! o N OH 1031 NMe | =% a ; PN o i N= ® SN ER — _ 1032 | NMe | = ; = N 5 and \ HN - ceo 1033 | NMe -~ ; ZN A GG HN
    48. A compound of the formula: a\ O RX R° H N Se re \ 0 wherein R', R?, BR’, R® and Q are defined-as follows:
    Cpd. | R' | RZ | Rm | Q "A CX e ¥
    Wo tson PCT/CA02/01128
    Cpd. | BR | RT| RA 5 * > Ne EU VOU | SS ) : i ! ! } i SN ; | i i ! o OH 2002 | H ® : 2004 | H | Tv | cH | 0 I 2005 | H IIo o I i : ! AN I od | o OH 2006 | Me I I EE _ : | | oF oH
    ® 284
    Cpd. | R' "R? | rR. RA | Q - # > I A | I 2008 | H ) PSS 2 o | Y a. | NO va COOH 2009 | H | & | CH ; ; i i H CY WS LATN o OY le \ ! i Co | oF oH : 2010 | H | : Co 0 ll 2011 | H | Ll | : Lg | wo ¥ RY ad OH { : d i le] 2012 H | & | CH, | ; WY 6 2013 | H | A ; ! : ! ° | ; . Cs cl OH é
    © WO 03/010141 PCT/CA02/01128
    Cpd. | R' | RZ | R(_F Q . # | | SN 2014 | H | { Bl CH, | IE 2 Na z \ J | OY Co | va 2015 [ H | | CH, H H H < i nN LAY i | i ! WY, ad OH : Lo ES 2016 | H | | ; i | N Hoo @® | Rea RS San 0 H H H ¥ oo 2017 | H | T° | xX | ; ° eh = on = on © SERENE ; EEE ORE { : $ i | 0 2020 TET | ~¢ 1 T ; Yo ! i i = i o OH
    Crd. | R ESA ; > SY 2021 ~ | >< | ; oN ¥ : | o i g7 Ton 2022 | i >< ;
    ¥
    I. a | IN 2023 | We | H >< | : I | | ES I lL IS Ss 2024 | H | | x ; re A | ¥ : i o | : : Co | IN NS NH, Toe Wn 2025 | H | EN I ! ‘ N i CY 6d __oTn 2026 | Me Ded | ; CY Xo : i ZN { I A A I 2 | | SN IEE \
    Cpd. | R | R? RL RA’ | Q ¢ > he ] Lo _ 2027 | Me | | >< | : . SN Z| ¥ i ! : ! ! I A I = = oo o” oH 2028 | Me | >< SY I ¥ ! : = i i ; ; | = @® 2029 | Me | | >< | : No Cs 2030 | Me | TT | >< | : i i SN Cl | Fo CNY 0” OH 2031 | Me | | ; _ C0) ve TE ! : A ; i i ! ! SN Co 0” oH 2032 | Me | ; CY Te a aL 0” OH no PCT/CA02/01128
    Cpd. | R' | TIRE Q ’ oN oo i, 2033 | H CO 5 = CY 0” “OH 2035 | H 2036 | H TaN 2037 TH TAL HE I Eh ] i i | oF “OH 2038 | H . 0 | 5 EE a Co | AS Fo) OH cpd. | RR | RT | ’U A | aQ # ON 2039 | H | EYE ; 1 : | nd 5 Co YIN H i ! N D7 oH 0 2040 | ; ! | | RS Co 2041 1 Me | PPT — |v ; = a __o7 2042 | H PH | ; 0” OH 2043 | MN | | ; EERO RIN Coe ¥ EES 2044 | H | | 1 Heo IRAN 2, ° §' ON : | \= Lo | I.
    HE
    N
    Cpd. | R' | RR | RA Q 2045 RTT TT HE [5 0 [| N H i \ J | LJ } ! 0 | | ) ! i CN : ¥ Ed OH J IS NE 2046 | H | | : o Co EY on ISN SS RS EN I A. ® 2047 | H | A | CH | bo j NN : { : i { 7 OH 2048 | H rs a 5 oY j — oH 2049 | H i i BONN I bo 7 od 2050 | H | | >< : BOE : °c AS : : o” oH
    Cpd. | R' R? RR Q « # > : Ki ES : 2051 | Me | >< | ; @ NN } ¥ °o ~~ oon 2052 | H | | | : CS oN Ld o7 "oH 2053 | H | ; BORA Co = 0 _ OH 2054 | Et | | Nad ° 2055 | H | N° BON LC IAAP . 0 © [2056 H | ; re : A 5 Lo = I | oo oe | R RE ’ ON I I LR I 2057 | H & | | CS w ANN N % 0 nN LO oF 2058 | H | x : CY Co EAS 2059 | H | X< | ; BORA i s | i = 0” oH 2060 | H | os Rol 2061 | H | & | Na ; ! I : i ERO Ly < Vd o BN | | OH 2062 | Me | | X ; . I IR LS I oZ on
    ®
    Cpd. | FR R® SC a # ha : BB “7 2063 | © oH xX | ; ne: ¥ ¢ A BEAN : i : : oo” oH 2064 H | | NH, | : re YN I | EEN ® Zon 2065 H J L | : CW NT LC EN : { ¥ 0” "OH 2086 | Me | Om | XK | ; s YY : 0” oH 2067 | H | - ny» | No Pod i { ! N Co | CN lo oH
    Cpd. | RT | R? RR | Q # > i KI 2068 | Me | >< ; ! i NG \ u 2069 | H | | @) | ; Cg | H H : | i i 2070 | Me | ; N 9 = OH 2071 | Me | | ; OH 2072 | Me | | x ¥ ] IX i i ! !
    cpd. | R R® R_ RB Q ; > A I 2073 | Me | | | ; EE Rv CN a. I X : Co | CO 2074 [LK ; : Cy EY H 1 NS ! i E ® Co NT$ ae EER ; AN Y i i i i NY NO) Poon = I: 2076 | Me | >< ; OEY DX ! ] - | |. ox MH 2077 | Me | >< ; OY a uo : | | | oO 5 L
    Cpd. | R' R® = A | Q # Pe IRC 2078 | H | | ; | { ° ] | ¥ | 0” "NH, 2079 | H | | ~ ; Po UY N ! ! 0 ! ! ® a | | on we | Me | < ; Nan ¥o NN Me RS _o” © 2081 | Me | ps | >< | ; ENG ER HG OY 2082 | Me | Dad | ; i i Ni lo Cx) = ¥ oo | CS 2084 | H | CR ;
    CY . | ¥ | " OH : i 0
    Cpd. |. R* | R® | rR A Q ¥ Pa Ny CC . 2086 H | ~ ; : | LD | N 0 i i : i SS Co IA 2087 | Me | ; PN Dad ] ! N ! ENGR aN- ® | | | | 0” OH 2088 | H | - YN 2089 | H | 7 DN oZ om 2090 | Me | | ; Nan LS o” OH 2091 | Me | x 2X | ; YY REL lo | | Pon
    Cpd. | R R® | RA Q # ON I EAA ad Me | ; . ZN i ey A xX i /
    nw. ] IAS NE 2093 | Me a 5 CC) YY CN he {ON 7 on SUS ES EU SU SN - CAN jo ¥ - wo” © 2095 | Me | To | ; A RS Ox NH : : : i Ho< 1 2096 | Me | | x ; EY o” oH 2097 | Me | | ; re ihad NS I ; Pom
    Cpd. R' R? RL A’ Q # yy . lL ny 2098 | Me ENLN ! | | 0” OH 2099 | Me | - Z BORNE FX : Co i | OH ® SN ES I EE CH] - : CY oN i i o 0” NH, 2101 | Me | © IE ; CC onl I BRE EEg NS 2102 | Me a. Ea Ss a 0? oH 2103 | Me | | ; ALYY ES of ] i
    Cpd. | R R® R_ FR" Qa # pa I 2104 | Me | ; IS ! { OQ NH CY NS 2105 | Me | | | ; PI CCN PN : ! ! LS 2106 | Me | Q ; IS a CN) A 2107 | Me | ! I ; I 2 i | = 0 OH 2108 | Me | 0D, | | ; RN Ton] 2109 | Me | NC ; CY i ! No A i . LS lo Zo
    HIF REINS] # 2110 Me | 5 | 5 ; & NY] H &J Z HN #7 : 2111 | Me | | FT Ean {ho ® 2112 | Me | CT ; i | aN 2113 | Me | EE ; Co | ae 2114 | Me | | Cs NA oh Y NE HAN ) | | o7 “OH 2115 | Me | | qo ; “ | NG I EN 07 “oH
    Cpd. | R' R? RC RAR |] Q - ’ > SCT 2116 Me | J ; " SS / ! = Co oF oH 2117 | Me | CH Ny | / and ! | = 2118 | Me | EAN | .
    Cl . i ‘ | | | oF oH
    43. A compound of the formula: 1 O 47 8 R\ R R H H 0 \ o) _~_ OH 3 R fo) wherein R", R®, R” and R® are defined as follows:
    cpd. T ) RT OR oo ICN re i C# | 2X ’ | _ re I 3001 I H : SS NE AE NN
    ° 303 : E 057TH . 1 ee T = ¥ I i 3003 Me ;
    a. | CC) and i H : ! { i Co %¥ 3004 Me | EER va
    I. \/ : Xo ) 50. A compound of the formula: 1 0 Rr’ 8 R R\ R H N 74 N H O OH N = R® 0 wherein BR, R%, R” and R® are defined as follows: Tepd. | RY. BR TRC RY] : 4001 Me | a Lo : | 99 | and ; ! i 4002 H i Eo ; ¥
    ® 304
    51. A compound of the formula: o ((h H ro N R? \ H 0 \ OH R’ 0 wherein R?, R® and n are defined as follows: _cpd# | RR | Rn 5001 | Tr re ® FUP SE Ba I
    52. A compound of the formula: R\ O RX Re H N N 2 N R \ H oO AZ OH 1 ! O wherein R', R?, R’ and R® are defined as follows: Cond # I T mm T we : 6001 © CH | a | Ox_-CH, ZN AN GP | &J i i i i SE A I NE , 6002 | CH; | | 1 (I CL YY
    PA 305 cpd. # | “RT RY RR ]
    i I. ! ! ! Cd LE X o POU (I a et a [SU — 1 . =N ¥ == Cl PN : TN 6004 | CH; NS THC CH (Ny No VY A RE N00 NES NE Co 6005 | CH; | H.C >. GE ; SE a. I 3
    ® a. neo ERE Ee raaian a 6007 | CH; | , | HC. CH: NAS | oe ] o S ; : 6008 ' CHj | a ‘HC CH: WS 6009 | CH; | a WG Ls a | ¥ ] 6010 CH Os H,C CH, ; IEE EES Ea ! 7 I TN HES A 6011 | CH, | a GY ; . | ; ~ ¥ ! LA : I TS A 6012 | CH; | TH | H,C CFy'| ; : I
    FHT RT TRE 1 I SR EN BN 6013 | CH; | Se | Hc CH . | I Co WS a. we EY HE I LA - a0 5 on i TR Free EE oo : ! ® Ee AON LU 6016 | CH3 | a CHC. CH; EE SS Vay \ we ER es eo ~ : 6018 | CH3 | a THC CH ol BY a : ! 7 © 78019 1 CHy | Koa RT CH, to; J | Co Fe sed sores mem] meant sms rmiraramrar rns noms em rma ren
    ® 307 Fry TROT RTT TR Co OY : | 6020 | CHa | a ooh tog “ | ' | t ’ I Cw | ¥ Lo P : SS SUPE EU AU SE © 6021 | CHs | TH {H.C CH i ! = | J i HN : ® | © : oe ni -r coms ram = JE — - — — orm a rm se YE . } A EE EY AS TN] ©6023 | CH; a | Hc CH, |; , ! 1 HN | : N i] RO eo] © 6024 | CH; | a He.
    CH; 1; : ; ! ! { 0=9=0 : i ee eae 6025 CHs oe 5 3 . l i | H CN ¥ ! : ; : { ; j ] | 1 ! ] / CD USS SUR SONU N—— . | 6026 CHs | Oa | So | ; I EN NR - EO NE
    ® | 308 ed FR TRE — . KF -1 6027 CHs; | a | H,C CH, : . | | bo 2S : | | = | ¥ ] pM 6028 | CH; | a HC.
    CH, )=~o ; : : ; : 0 i N ® | 6029 | CH; | a | HC CH, : | HN : j 6030 | CH; | a i HC CH: i = ' 2S =o : NT 6031 CH; Das | posh Lo : ; : . bo EES SL Co ¥ : : : | ; ! CW YY FUR SU TU SUNS
    ® 309 CE wo6034 CH; |! a | HC CH, | ; = NY FN60385 CH; | Koa HC. CHa CL NS I I t= AN SU ® 6036 | CH; | XK BE DE ¥ ! Z 6037 | CHs | oY ; 6038 | CH : ! i : : CL IL. » / madi: A SELF LI : i I PZ ] : : eb No : 6040 + Chg A 0% Lo SE yo YY a aT Co I | Po % EE ; I A I.) BAS 6042 | CH; | | I a. HE I FEY 6043 CHy | Lo EE K oo Powe | EF
    I a RE - i 6044 | CH; | a Lo Lo
    : Cy IR a NT © 6045 CH; | Ros Lo I EA © 6046 | CHs | | Lo SE DN SE NA 6047 | CHs | Co 6048 | CH, | Lo ! ! Z cl 6049 | CH; | ; : 3 Po | AY 5 6050 | CH; | AN SE : = ; | Cl ! Y HE i . i : i a rma creme. sme eee mmm.
    Se mem 2 5. rd 6051 CH; | T Loy $7 IE a I
    A | SOSUSES [SUSY URRY NES
    "6052 | CH; I
    : i { i 0 we EF
    ; | 6053 | CH; | Los i i i i ! ¥ SNS SN FURL SU EA :
    Il
    ] opd. # | a R' fa I TT i -C ns T " Na } ! ] i . i { : ! 6054" CH; | CCH - ! | CNG ; ! | ‘ : f T6055 CH, TTT ee mn, mm, ome tt eet mee, TTT J ! : . © 6056 | CH, | CH, 1; : i l i i : i ! i i ; : [I ! N i N : i | \ 0d © 6057 | CH, | Lo IE PS 5 TE ET a NB 6058 T rs Hy | Ee : TCH, . = — : 6059 | CH; | TTT CH IRE ; ~ ¥ oo Bo TORT Te ry 5 : | : = | ¥ ch, a or " : H H | ; : ON 5 i : ; : : i i i 1 Lo | ZY
    FRC TTR TRE CO 6062 |" CH | CH, GH, 1 z 9 ! ! 76063 | CH; | X : SR Nc : 2 6064 | CHy | TT 0TH ® oy 8065 | CH; | TT CH, EEE AY : N ~~) Cd ; "6066 T = CHs A crv—— a a——— v—— 1 mv 8 F BS i . = Y “6067 | “CH; r ma iss a mae neers + amo El a——— ro FE i N i aos | To TS SH CNG ; ! x » A A SN Nk N I NE A BU 6070 | CH; | Fo N° § ! i iY : ¥ wd ERT R TITRE i SN DU FOU JN — 6071 | CH; Ce TY i | Dy ox 6072 | CH; I OA EE EE Ee ES SS REN; NESS NE . 6073 | CH iN 0% Lo i : i ; ! NTR : \ ® SE Se EY 176074 | CH; | : LN TR 6075 | CH; Co NTN : A yoo ET = Ne Ny, = ¥ Co —N i “qo TT iy | = Po | RN 24 = ¥o oH Ri a x TT : { i NTN ; i Me ; yoo ! om ! No 6079 | CHa ; Tv | Lo oo | NS N lr... oH ed ERT TRE TRE 6080 | CH; | bos MY i N ; A VN UN.
    SLL RRS SU 6081 | CH; | ! Po : : : | NY : SN EE Na I ep OCH] . 6082 | CH; | 5 : Co : NN K j \ ] ; : i S : i ® CL we YY ! | % j ! JUS SU BAT SE 6083 | CH; | IN : LJ SU OU p , . 6084 | CH; | bo ae aE ESR : : N° § 6086 | CH; | Lo Cs 0 EW ! 6087 , CH; | Lo a Jd Y —N : SOS EE FL FE Co | NY 5 : CE YY US EN SL FS
    _ CeRdH RR A 6089 | CH; | EE : | | i» | 5 Co ; | HN S | ¥ i bese rrr —t ee Ei RN VU SN i 6090 CH; | Eo 6091 | CH; | BN Co FR SL NE
    ® 6092 | CH, Co | MY : | | oN TE SS A RE
    © 6093 | CH; | Pos ; ! } | i ; s ; :
    - 6094 TCH; a. es mt a1 rte orm pet hmAor rman mote 7 [EU — 1 : ! | 5. ¥ ' [SSSR Ec ILL RR
    ; 6095 © CH; | ; Py YY 5 Lo | Wa BRERA AN RR SUL - SU BR DE 6096 | CH, I : Lo NN | 5 IS NN EL < SL BSS RA
    ER BE a EE OY . : ! : ! : 76097 | “CH; | hy |; 0 ; i | NTN : ! \ : ! i s ! ow | ¥ i ! | Ne IE —— E—— J —t Ba a errr . 6098 | CH; | Po : ! ; 1 H "6009 "CH; | TTT
    ® a. a | 5 6100 | CH; | 1 So BR 6101 | CH; | NN CCH, J i i ] ! ; P 6102 | "CHj; Ne CH 1 : PLN A SE NR SS 6103 | CH, CH, 7; : Sn I ! : ! ; ! Z : | N i ! : i : | C0 5 . ! | { ZZ “ : i i : | - 6106 | CH; | CONHCHs | ~~ ! Yo LS EU A NAN
    ° 317 oh | ET Rr 6107 | CH, | CON(CHs). | | ; 6110 | CHa | T Fo; wo 5 I SU NS ST "6111 | CHy | T Co SE Ee TE * ® EE RE B.C Uh.
    A 6112 1 CH; | T T6113 CH; | CONH, T >< BE 6114 | CH; | ; J i Co oy £ ESSE FOE SOL SN NU . 6115 | CH; | so No : = y SE FRU JI: SUA A SN mr ee res ata 6116 © CH, ARE ; ! : i N on ; i N oN | a A NN BE 6117 | CH; | Jo N OTA > Lo I EC I SA SOV 76118; CH; | | RE yy oy oo LT ee : I | ; eT rep FH 7 ree ee TRE 1 : 6119 | CH; | H | bos i H ! “ i | i { ; | i HN ¥ 16120 | CH, | Br 0% ls I NN NS A. Tez TH : FH oN OO NSU SOUS SOU e122 CH, xX | = ) Co NE 2 \ 6123 | CH; | Lo ZEN ! 6124 | CH; | O, , ';and : : : Ss. |! : : ES : NA g | va : = Ny 61 25 | CH; | ~~ =m | qo. EN = 9 : ; AR
    53. A compound of the formula: 9) 8 HQ RX R H : R? " N a \ 0} wherein R?, R”, R® and Q are defined as follows:
    Co wr mg nN . i 7001 | | bs : NY XL Bi : | A OHI EES USS NN SE A I 1 7002 ; | IP bo Eo EEE RL ¥ | TO - = : I RS NE 7005 | IE CL | ¥ oo _OH ® A UN RE NR - {7004 | Lo Co | ¢ 0 EEE EN | s. oH A ¥ > ER NS SA I 00 Ls ; ! H : i PNT ; UY as SS SS SS Il : ! : HERS. °°
    = . — JOU S— gl rasta ne EE rom ts re + ——— NS © 13 vemrmet corvette RE . 7007, KX | s. OH, ’ NTN p i 008 FT oN Te TTT Con | ; CY \ oo ry ENO To ; ] ; ! ‘ : CNTY EAE KL o_ oH] ENF ¥ ! | 4 I EE DA 17010] | | I; : | i i . NY : Bl y ¥ I. o_ OH ] ; an :
    EH RR TE lo | Dy 17017] 1
    P. i i ; i \ lo OH ES I EU A «J 17012, | onl ISIN assty i H i N 0 NE ¥o \ CET Ce I i Oo Ok : NH, H : @® | | ? ¥ 1 ! : ! lo} H ! H 3 TE I Sa HEA ¥ OH ; 8 Es OR FOU oA 17015] Ls Lo | K | Cr Ce, ¥ N © OR FE SE SUS [7016 ! ry _
    a. bo | i oA - | | 7 ! NH, 1 | © I [ : i be ee ee 17017 | 4 7 = i ] : : 0 OH Lo ¥ peuy Lo] | | ol. i NH, | i i OE EOS UO. 17018 | | | RE ) | ; i : i i i i i i : Ce | oi I A :
    opd # B RE T FR —— a J 7 7019] | : CN _d ! S , ! 0 oH Co | Va 0! 7020 SU TT J ~t 1 et tte + eens, cmon 2 — : i aN 2 ; oO. OHI RN ¥ | J bo 0 17021 Po : | ; o FH @ BEEN ¥o Pat NE SU EU SA 17022 Ls LU yo I OH 17023 . ] ! “Co bo i i i : y ! IRI 2 | > AI Y Le aT ~ eT T/T re "I ; i Al : ! ! ; INP : ’ ROH IE | | Lo AE EE 7% I SE [7025 : TL CTT TTT Co EY 7% NS PRUNES Sr, SSS _o [7026 i [ Ie I
    ¥ a. | | oH i i. SU RE SE NN 0 1 [7027 | onl ON EE WE 2 | ROR LTT ¥ | N° aE RT 2 “ETT . i i | : [7028 | | | ; Ba S , | 0 on NFL ¥ |) LT | ° KZ MAN ; EGR - | _ A : ¥ lL ! © RS EN RE $7030 | | Po; ® RN ¥ oo Lo oH ! : : i ; I TS AE - 17037 | onl LS ¥ No od i : ! \ EEE LI NE {7032 | | Lo : = Po, L o OHI : ZN ¥ ; | / i ‘ : o ! SS ELE FU SSR 1 7033! : CSN ¥ {4 ° I H H H : 3 Cry 5% on ¥ a. | oH ] ‘a 1 Jo— . er — he — I | ’ 17035 | 1 ! i | ; IRR REA \ ©] SR ANSI HE
    RE Ta i i A LI RF — ly | bY | 0 onl INS TY oC Co TY AR AU DE EE 7037 | | Lo 19s N > | o om ] o) Co | bo A Ga NS YE Kad | | Worl Co EELS Noo h | N : 2 ¥ Cp J LA ER EE 7041 LW ¥ a LS fo i : SN i ! o_O b% ; 2 o OH! TT EN REY WSS FN NUN FE 17043 | 0 BE CL Ay ) i J o OH : Lo | Fo Ua I SS ESN INA 7044 | | ;
    a.0 KL, _ Co | | OH RN BIN cpd # CR - | nL Ta OH } | i I i Ed A A [7046 | | I ; ; CTY KL | HN LNA ¥ CO : ! ! ; i TTT Ls sy . 9 o onl @ SUA EE FS EN ros” . | ¥ (a) | ¥ | o_ PH ; | 7 Ni ] 7049 = T I mrt v rmanen era. 13 te 7 emt mm mam eve nn —— on : } | | i ; Ls 8% i — 1 H i ; OH Il | 1 R | 0 OH ; : NE ¥ : | / ; o y 7051 | 8% | To< ; | : i ; i : N ! ] ¥ © i Ld wm I 17052" Lo : CY & 0 OH _— | A pai ar TR - -r Er i Pe 17053" & | | : A 4 | i ! ; i a. | OH 7054 | j Co Pos : | Na CO RON Los ; N © } 7085 = NE rN . mT mc ota ml rm asm © ir reer B ® CA ; y | >) : { 7056 | | De aN o ; EN a : RN 3 SES DS SS 7057 | | a : or OY N ! NA | sol i . ! i { . SE SC SS 17058 | ! | i EN j ] | ; OH Lo LE S ON SO —..e 0 4 , 7059) a Lo IZ y ; >N Co | | LL _ N NH, ! : | 7060 | \ } ; i i ! i i . " CONF IRENE HN ES ¥ IN SR -
    Cr T&T a 7061 | | a ol , i | : oN [ 3 NS oe | so, i i | i : SE UR UU.
    NE 7062 | A o 7063 : Ns Aw | No j : { ERE a a FA I EEN ¥ oo Se ! | Pa.
    N™ "NH, oes” hs BR ESN : a Cl | N 5. OH, I Ea ¥o Ya bob ee 0 7067 | 2 N NE oN : | B.
    Co ! | NN 7068 | 3 BN L ! | J rN EY rl : 0 \ Ne | >] : SS WR SE HE 7069 | J i EEC NN A I | NT
    ° | 327 oa F A T RTT ET = Cy I ES ICT FS 17670 “o. | ; I ¥ I EE | " 7071 | on 1 J ! EN OY I]! 170727 =n | arn so 2 4 mt 1 er ena marmrd AAatnt hena ens + TT . Lo 9 RS
    ® I. y OY on I : ! | ! i IR | | i 17073 Ls [ J rr N y ’ i JT [——— J mr ants enn eae at ary i rs an rs oe ey temme § 7075 | No Ls - Lo VAST I 2 i ; } { RX! N== Na | “a 678 ATT 2 - } : i : 1 { : i } ea fey 7077 ; —— SUVA immense rs ee be 8ebEth bn i Pa— a a pr a $s —— to —— ——— CLR rN ¥o No EEE UPR SN UN SSO 17078 | ro 1 | a, : rr N ri SW I NI ond? i WTR Thu : Lo | §% | Cu Il! ¥ \ Na | NN ER FN SI } ; ! H Ios 7686. CN “0 co { : xX | ! . RS SUNS NU: FS [7081 | a I ; | aL “0 . i : i i ! ES SN SS FN 7082 | j 0 o ';and : { CI : yo xX 7083! Ia 02 CO. : : ! EN Y SU SN NU A
    54. A compound of the formula: 0 RY R® H A Re RZ \ H Oo = OH 0] wherein A, RB? R’ and R® are defined as follows: . " cpd. #] A ¥ TTR TTT Sa I A SA NS
    Ccpd.# | A | RYT EH , 8001 | S | Lo. i ’ Cr YY ; EE EEN FE SOU NN NR 8002 | S| J l FON - “5505 —5 —— — iy Ea ana I ® ] | Lg : ¥ goog §T me + . =< 1. ES RES NN - SUR SU 1 8005 ; O | | | ; and a. foe 78006" To l aw JENS BE AN A I NG
    55. A compound of the formula: HQ O RY R® H Co : N N N 2 ~ N R \ H ZZ Oo = OH 0] wherein R?, BR” and R® are defined as follows:
    Cepd# | TRE TT mE PC ! i : : 1 I NS e001 | ! | ; and - | | ¥ — Co Ea ee en Na SR L ; i Ny, L Co I RR. SS
    56. A compound of the formula | according to claim 1, or a pharmaceutically ® acceptable salt thereof, as an inhibitor of RNA dependent RNA polymerase activity of the enzyme NS5B, encoded by HCV.
    57. A compound of the formula | according to claim 1, or a pharmaceutically acceptable salt thereof, as an inhibitor of HCV replication.
    58. A pharmaceutical composition for the treatment or prevention of HCV + infection, comprising an effective amount of a compound of formula | according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
    59. A composition according to claim 58, further comprising an immunomodulatory agent. 5
    60. A composition according to claim 59, wherein said immunomodulatory agents is selected from: a-, B-, 8- v-, and w-interferon.
    61. A composition according to claim 58, further comprising another antiviral " agent. : 62. A composition according to claim 61, wherein said antiviral agent is selected from: ribavirin and amantadine.
    ® 331
    63. A composition according to claim 58, further comprising another inhibitor of b HCV polymerase. ’ 64. A composition according to claim 58, further comprising an inhibitor of: HCV helicase, HCV protease, HCV metalloprotease or HCV IRES.
    65. Use of a compound of formula | according to claim 1, for the manufacture of a medicament for the treatment of HCV infection.
    66. An intermediate compound represented by formula 1c: 0 gl RA ® spy RE 1 H B—~ el 0 1c wherein A, R?, B, K, L, M, R” and R® are as defined in claim 1, or a salt, or a derivative thereof.
    67. A process for producing compounds of formula |, comprising: a) coupling, in a mixture containing an aprotic solvent, or no solvent, a coupling agent, and at a temperature of about 20 °C to about 170 °C, and intermediate 1c: } oR, R® RE I H B—~g2k 0 ic with amine Q-NH, so as to produce compounds of formula I, wherein A, R?, B, R, R® Q, K, L, M and Q are as defined in claim 1.
    68. An intermediate compound represented by formula 1d: ‘ o RA Rr® ’ A ug AN X on RE I So . B kt 0 1d © 15 wherein A, R?, B, K, L, M, R” and R® are as defined in claim 1, or a salt or a derivative thereof.
    69. A process for producing compounds of formula I, comprising: a) coupling, in a mixture containing an appropriate solvent, or no solvent, a coupling ‘ agent, and at a temperature of about 20 °C to about 170 °C, and intermediate 1d: . oR gs A mg 3 on RE 1 = 0 Bel o 1d 5 with amine Q-NH, so as to produce compounds of formula |, wherein A, rR? B,R’, R® Q, K, L, and M are as defined in claim 1.
ZA200400240A 2001-07-25 2004-01-13 Viral polymerase inhibitors. ZA200400240B (en)

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