EP1979315A2 - Methods for treating hepatitis c - Google Patents

Methods for treating hepatitis c

Info

Publication number
EP1979315A2
EP1979315A2 EP07716610A EP07716610A EP1979315A2 EP 1979315 A2 EP1979315 A2 EP 1979315A2 EP 07716610 A EP07716610 A EP 07716610A EP 07716610 A EP07716610 A EP 07716610A EP 1979315 A2 EP1979315 A2 EP 1979315A2
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
optionally substituted
hydrogen
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07716610A
Other languages
German (de)
French (fr)
Inventor
Gary Mitchell Karp
Peter Seongwoo Hwang
James Jan Takasugi
Hongyu Ren
Richard Gerald Wilde
Anthony Allan Turpoff
Alexander Arefolov
Guangming Chen
Jeffrey Allen Campbell
Chunshi Li
Xiaoyan Zhang
Steven Paget
Nanjing Zhang
Jin Zhu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PTC Therapeutics Inc
Original Assignee
PTC Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/331,180 external-priority patent/US7868037B2/en
Application filed by PTC Therapeutics Inc filed Critical PTC Therapeutics Inc
Priority claimed from PCT/US2007/000996 external-priority patent/WO2007084435A2/en
Publication of EP1979315A2 publication Critical patent/EP1979315A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.
  • HCV hepatitis C virus
  • hepatitis C virus the causative agent of hepatitis C. Seventy to eighty percent of HCV infections lead to chronic liver infection, which in turn may result in severe liver disease, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (115).
  • HCV constitutes the Hepacivirus genus of the family Flaviviridae (106), and contains a positive-stranded 9.6 kb RNA genome.
  • the features of the HCV genome include a 5'- untranslated region (UTR) that encodes an internal ribosome entry site (IRES) that directs the translation of a single long open reading frame (ORF) encoding a polyprotein of 3,010 amino acids.
  • the HCV ORF is followed by a 3'-UTR of variable length, depending on the HCV variant, that encodes the sequences required for the initiation of antigenomic strand synthesis (79).
  • the HCV IRES and 3'-UTR both encode regions of RNA structures that are required for genome translation and replication.
  • the HCV polyprotein is posttranslationally processed into at least 10 mature viral proteins, including the structural proteins core (putative nucleocapsid), El and E2 and the nonstructural (NS) proteins NS2 to NS5B.
  • structural proteins core putative nucleocapsid
  • El and E2 the structural proteins core
  • NS proteins NS2 to NS5B nonstructural proteins
  • Three distinct elements have been shown to be involved in HCV IRES-mediated translation: (1) integrity of the global structure of HCV HtES, (2) the 3 '-terminal region of the HCV genome; and (3) trans-acting cellular factors that interact with the HCV ERES element and assist in translation initiation (35).
  • the initiation of protein synthesis in eukaryotic cells predominantly follows the 5' cap- dependent, first AUG rule (61).
  • a bicistronic expression system can be used to define and evaluate the function of IRES elements.
  • This test system harbors two different reporter genes in which the 5'-proximal reporter gene is expressed by a cap dependent translation mechanism while the second reporter is expressed only if an upstream sequence inserted in the intergenic space contains an IRES sequence element.
  • a putative IRES in the HCV 5' UTR was unambiguously demonstrated to function as an IRES involved in translational control of viral proteins (133).
  • IRES element 23, 41, 42, 108, 129, 132, 133, 134.
  • HCV IRES guides cellular translation initiation factors to an internal site of the viral RNA (56, 58, 120), thus functionally demonstrating the HCV IRES activity.
  • HCV 5'-UTR contains an IRES element that plays an active and crucial role in the mechanism of internal initiation for HCV protein translation.
  • the IRES is one of the most conserved regions of the HCV genome, reflecting its essential nature for viral replication and protein synthesis (13, 118, 122). Although both 5' and 3' sequences of the IRES appear to play a role in the control of initiation of translation (42, 109, 110, 113, 136), the minimal sequence requirement for HCV IRES function has been mapped to a region between nucleotides 44-354 (40).
  • HCV IRES and its 5' sequence is folded into a distinct structure that consists of four major domains and a pseudoknot (11, 42, 122).
  • Domain I contains a small stem-loop structure that does not appear to be a functional part of the IRES element while domains II, III, and IV contain the HCV ERES activity (43, 111).
  • the relationships between secondary and tertiary structures of the HCV IRES and their function have recently been established (5, 55, 56, 99, 124).
  • domains II and III consist of multiple stems, loops, and bulges and are important for IRES activity (23, 40, 51, 52, 54, 56, 64, 74, 75, 93, 107, 108, 110, 124, 127, 131, 139, 141, 142).
  • Domain II can induce conformational changes on the ribosome that have been implicated in the decoding process (124).
  • Domain III has the highest degree of structural conservation among the different HCV strains. It comprises the core of the flavivirus IRES and has 6 subdomains (40). Various studies have shown that subdomain IHd forms complex secondary/tertiary structures and is critical for initiation activity (55, 56, 57, 124, 129).
  • Domain IV has one stem- loop that spans the initiation codon and is specific for the HCV IRES (41, 122), but the precise role of domain IV in IRES activity remains controversial (41, 112).
  • the role of the HCV IRES is to position the translational machinery near an internal initiator codon in the viral mRNA.
  • the translation initiation mechanism of the HCV and other viral IRES differs significantly from that of 5 '-cap-dependent translation initiation (7, 21, 31, 35, 61, 71, 72, 81, 88, 96, 114, 123).
  • Most cellular capped mRNAs utilize a number of initiation factors (elFs) that are required for the translation initiation process.
  • the initial steps of the process require proteins that interact with the 5' cap structure and recruit the 40S ribosomal subunit to the cap-proximal region of mRNA. This complex then scans 3' of the cap, until reaching an AUG codon at which translation will initiate (21, 114)
  • the IRES functionally replaces the 5' cap structure, allowing the 4OS ribosomal subunit and eIF3 to bind directly to the RNA.
  • Subdomain IIId of the HCV IRES harbors the binding site for the 4OS ribosomal subunit and the only initiation factors required for translation initiation are eEF2, eIF3, and eIF4E (15, 58, 94, 100, 120, 124).
  • the polypyrimidine track-binding protein (PTB) and La autoantigen are noncanonical translation initiation factors that bind to and enhance HCV IRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53).
  • PTB a 57-kDa protein involved in RNA splicing, is also necessary for efficient IRES- mediated translation initiation of picomavirus mRNA, and some cellular mRNAs (10, 11, 36, 53, 59, 89, 92).
  • the La autoantigen a 52 IcDa double-stranded RNA unwinding protein, also increases the activity of poliovirus and cellular IRES (38, 85, 86).
  • HCV IRES-mediated translation initiation Other cellular factors involved in HCV IRES-mediated translation initiation include proteasome ⁇ -subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9 (24, 25, 100), and hnRNPL (33).
  • proteasome ⁇ -subunit PSMA7 62
  • ribosomal protein S5 26
  • ribosomal protein S9 24, 25, 100
  • hnRNPL hnRNPL
  • interferon IFN
  • nucleoside analogue ribavirin in combination, are marketed for the treatment of HCV infection.
  • these two agents are immunomodulators and have limited efficacy, relatively high toxicity, and high cost (80, 83,
  • IFNs are naturally produced in response to virus infection, and cellular exposure to IFN leads to the induced expression of a variety of IFN-stirnulated genes (ISGs), many of which have an antiviral function. ISG action can limit virus replication at multiple points within the replicative cycle.
  • the present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral
  • Figure 1 illustrates the HCV-PV chimera construct.
  • One aspect of the invention relates to a compound of formula I
  • R 8 is: -a Ci to Ce alkyl
  • R x is a Ci to Ce alkyl; -a formyl group;
  • Y is:
  • Ra is a Ci to Ce alkyl or a Cs to Cs aryl
  • R is: -a Ci to C 6 alkyl; -a Ce to Cs aryl optionally substituted with-
  • Rg is hydrogen or a Cj to C ⁇ alkyl and R h is hydrogen or a Ce to Cg aryl optionally substituted with an alkoxy; -a Ci to C 6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
  • Ci to Ce alkyl optionally substituted with a Ce to Cg aryl
  • -a 5 or 6 membered heterocycle optionally substituted with: -a -COOR x group, where R x is as defined above, or -a -NHCOOR x group, where R x is as defined above; -a Ce to Cs aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
  • R k is: -a Ci to C 6 alkyl
  • Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy.
  • Ci to C f alkyl(s), -a nitro group, -a Ci to C O alkyl group, optionally substituted with:
  • R n is: -a -CH 2 CONH 2 , or -a CO to Cs aryl optionally substituted with:
  • Ci to Ce alkyl optionally substituted with: -a halogen
  • R 0 is:
  • Ci to C 6 alkyl optionally substituted with one or more of the following:
  • -a Ce to Cs aryl optionally substituted with a Ci to C$ alkyl or an alkoxy, -an alkyiene, -an alkoxy, -an alkyne, -a halogen, or
  • Ci to C O alkyl optionally substituted with:
  • R z is hydrogen or a Ci to Ce alkyl, optionally substituted with a Ce to Cg aryl, -a -SR x group, where R x is as defined above, -a group, where R 23 is:
  • R bb is:
  • R2 1S -a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
  • R x is as defined above, -a dialkyl-amino optionally substituted with an alkoxy,. -a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl,
  • R3 is:
  • X is:
  • R x is a Cj to CQ alkyl
  • Y is: -a haloalkyl; -a halogen;
  • -an amino optionally substituted with one or more Ci to C O alkyl(s); -a benzofuran; -a benzothiophene; -a dibenzofuran;
  • R b is a hydrogen or a Cj to C 6 alkyl, and n is 0 or 1;
  • R 0 is a hydrogen, a -CONHR x , where R x is as defined above, or an -S ⁇ 2 R x , where R x is as defined above; is a Ci to C 6 alkyl or a C 6 to C 8 aryl; -a -NHCOR c group, where R 0 is: -a Ci to C 6 alkyl;
  • R g is a Ci to C 6 alkyl or a hydrogen and R h is a Ce to Cg aryl optionally substituted with an alkoxy; -a C] to C 6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
  • Ci to C 6 alkyl optionally substituted with a Ce to Cs aryl.
  • -a 5 or 6 membered heterocycle optionally substituted with: -a Ci to C 6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more Ci to C 6 alkyl(s), -a -NR 1 SO 2 R x group, where R x is as defined above and R, is: -a hydrogen, -a Ci to C 6 alkyl,
  • R k is: -a Ci to C 6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Ci to Ce alkyl(s), and R j is:
  • Rj is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more Ci to Ce alkyl(s),
  • Ci to Ce alkyl group optionally substituted with:
  • -an amino optionally substituted with one or more Ci to Ce alkyl(s), -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a Ci to C 6 alkyl, • optionally substituted with a dialkyl-amino, -a -NHR n group, where R n is: -a -CH 2 CONH 2 , or
  • Ci to C O alkyl optionally substituted with: -a halogen, -an alkoxy, or -a Ce to Cs aryl,
  • R 0 is:
  • Ci to Ce alkyl optionally substituted with one or more of the following: -a halogen,
  • Ci2 alkyl optionally substituted with:
  • R x is as defined above, or -a Ci to Ce alkyl, optionally substituted with:
  • Ci to Cg alkyl optionally substituted with:
  • R z is hydrogen or a Ci to Ce alkyl, optionally substituted with a C 5 to Cg aryl, -a -SR x group, where R x is as defined above, -a -SC ⁇ Raa group, where Raa is:
  • R b b is:
  • -a Ce to Cs aryl optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halogen,
  • Ci to CO alkyl optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to Cg alkyl(s), -a -NHPOR x R x , where R x is as defined above,
  • Ci to C 6 alkyl or -a -COR x , where R x is as defined above, -a -NRggCOR hh group, where R hh is: -a hydrogen,
  • Ci Ci to Cs alkyl optionally substituted with: -an alkoxy
  • R gg is: -a hydrogen
  • Ci to C ⁇ alkyl, -a haloalkyl, -a haloalkoxy, or
  • R x is as defined above, and R 1 ;
  • R is a hydrogen, a halogen or an alkoxy
  • Ci to Ce alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
  • R 2 is:
  • -a nitro group -a hydrogen; -a halogen; -a hydroxy group; -a Ci to Cs alkyl group, optionally substituted with one or more halogen(s);
  • R3 is: -a hydrogen
  • R x is as defined above; provided that when X is phenyl substituted with alkoxy, Y is phenyl, R is hydrogen, Ri is a halogen, R 2 is hydrogen, and R 3 is hydrogen, and provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Ri is hydrogen or hydroxy, R 2 is hydrogen or hydroxy, and R 3 is hydrogen, then Z is: -a C 1 to C 6 alkyl substituted with:
  • X is a nitro group or a cyano group, hi other embodiments, X is a cyano group.
  • Y is a C 6 to Cs aryl, optionally substituted with one or more of the following:
  • -a Ci to Ce alkyl optionally substituted with: -a halogen, or -a Cg to Cs aryl, or -a 5 or 6 membered heterocycle, and where R 0 is a hydrogen, -a -NRqCONRqR r group, where Rq is: -a hydrogen, or -a Ci to C 6 alkyl, and where R r is a Cj to Ce alkyl optionally substituted with one or more of the following:
  • R n is: -a C i to C i2 alkyl, optionally substituted with:
  • -a Ce to Cg aryl optionally substituted with a Cj to Ce alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or
  • R v is a hydrogen
  • R w is a Ci to Ce alkyl optionally substituted with a halogen
  • R z is a Ci to Cs alkyl
  • Y is a Ce to Cs aryl substituted with:
  • the Ce to Cs aryl may be substituted at the para, meta and/or ortho position(s).
  • the Ce to C$ aryl is phenyl.
  • the C 6 to Cg aryl is phenyl substituted at the para position.
  • Y is phenyl substituted with a -NRqCONRqR r group at the para position. In other embodiments, Y is phenyl substituted with a -NR t COOR u group at the para position. In yet other embodiments, Y is phenyl substituted with a -NR v S ⁇ 2 R w group at the para position. In yet other embodiments, Y is phenyl substituted with a -NHPO(OR X ) 2 group at the para position.
  • Z is: -a Ci to Cs alkyl optionally substituted with -an alkoxy, or
  • Z is a Ci to Ce alkyl. In yet other embodiments, Z is a a C2 to C5 alkyl. In yet other embodiments, Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.
  • R is hydrogen
  • Ri is:
  • -a hydrogen -an alkoxy group optionally substituted with: -one or more halogen(s), -a Ce to Cg aryl group, or -a 5 or 6 membered heterocycle; or
  • Ra is: -a hydrogen; -a halogen; -a hydroxy group
  • Ci Ci to Cs alkyl group, optionally substituted with one or more halogen(s);
  • R2 joins together with Ri to form:
  • At least one of Ri and R2 is a hydroxy group or an alkoxy group optionally substituted with: -one or more halogen(s),
  • R 2 is a -OCOR x group, a -ORuc group, or an alkoxy group substituted with: -an -OCOR x group,
  • R 2 is a -OR kk group or an alkoxy group optionally substituted with:
  • -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C ⁇ ; alkyl; or -a 5 or 6 membered heteroaryl group.
  • R 2 is a Ci to Ce alkoxy group optionally substituted with:
  • R 3 is a hydrogen
  • X is a cyano group
  • Y is a Ce to Cs aryl substituted with:
  • R is hydrogen; at least one of Ri and R 2 is a hydroxy group or an alkoxy group optionally substituted with: -one or more halogen(s),
  • R 2 is a -OCOR x group, a -OR kk group, or an alkoxy group substituted with: -an -OCOR x group, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a Ci to Ce alkyl; or -a 5 or 6 membered heteroaryl group; and R 3 is hydrogen.
  • Y is a phenyl substituted with a -NR t COOR u group.
  • R t is a hydrogen
  • R u is:
  • R u is a Ci to Ce alkyL
  • Y is a phenyl substituted with a -NR q CONR q R r group.
  • R 3 is a hydrogen and R r is:
  • R r is a a Ci to Cs alkyl.
  • Y is phenyl substituted with a -NR v S ⁇ 2 R w group.
  • R v is a hydrogen, and where R w is -a Ci to Ce alkyl.
  • Y is phenyl substituted with a -NHP0(OR x ) 2 group. In some embodiments,
  • Y is a phenyl substituted at the para position with: -a -NRqCONRqR r group, -a -NR 1 COOR u group,
  • Z is a Ci to Ce alkyl
  • R 2 is an alkoxy group optionally substituted with:
  • the compound of formula I is not Compound 1.
  • the present invention includes compounds of the following: 1. A compound of formula I
  • X is:
  • R x is a Cj to Q alkyl; -a formyl group;
  • Y is: -a haloalkyl; -a halogen;
  • n 0 or 1 ;
  • R 0 is a hydrogen, a -CONHR x , where R x is as defined above, or an -SChR x , where R x is as defined above;
  • Rd is a C 1 to C 6 alkyl or a Ce to Cg aryl
  • Re is: -a Ci to C 6 alkyl; -a C 6 to C 8 aryl optionally substituted with: -a Ci to C 6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or
  • Rg is hydrogen or a Ci to Ce alkyl and R h is hydrogen or a Ce to Cs aryl optionally substituted with an alkoxy; -a Ci to Ce alkyl; -a 5 or 6 memb ⁇ red heteroaryl, optionally substituted with:
  • Ci Ci to Cs alkyl, optionally substituted with a C 6 to Cs aryl,
  • -a 5 or 6 membered heterocycle optionally substituted with: -a -COOR x group, where R x is as defined above, or -a -NHCOOR x group, where R x is as defined above; -a C 6 to Cg aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
  • -a 5 or 6 membered heterocycle optionally substituted with: -a C, to C 6 alkyl, or
  • R x is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NR j COR k group, where R k is: -a Ci to C 5 alkyl, -a hydrogen, or
  • Rj is: -a hydrogen
  • Ri is a 5 or 6 membered hetero cycle optionally substituted with a hydroxy
  • -an amino optionally substituted with one or more Ci to Ce alkyl(s), -a Ci to Ce alkyl group, optionally substituted with: -a -NHSOaR x group, where R x is as defined above, or
  • -a Ce to Cg aryl optionally substituted with: -an alkyl, -one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NR 0 COR p group, where R p is:
  • Ci to C ⁇ alkyl optionally substituted with: -a halogen, -an alkoxy, or -a Ce to Cs aryl,
  • R 0 is:
  • Ci to Ce alkyl optionally substituted with one or more of the following: -a halogen, -an alkylene, -a Ce to Cg aryl, and/or -a -COOR x group, where R x is as defined above,
  • Ci to Cj 2 alkyl optionally substituted with:
  • R 1 is:
  • R v is: -a hydrogen
  • R x is as defined above, or -a Ci to Ce alkyl, optionally substituted with:
  • R 2 is hydrogen or a Ci to Ce alkyl, optionally substituted with a C f , to Cg aryl, -a -SR x group, where R x is as defined above, -a -SO 2 Ra 3 group, where R 32 is:
  • R 1 * is:
  • -a C 6 to Cg aryl optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halogen,
  • Ci to Ce alkyl optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to Ce alkyl(s), -a -NHPOR X R X , where R x is as defined above,
  • R 1x is a hydrogen or a Ci to Ce alkyl, optionally substituted with a halogen, and R f? is:
  • Ci to C ⁇ alkyl optionally substituted with: -an alkoxy, -a halogen, or
  • Ci Ci to C(, alkyl optionally substituted with: -an alkoxy
  • R is a hydrogen, a halogen or an alkoxy
  • Ci Ci to Cg alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or Ri joins together with R 2 to form:
  • R 2 is:
  • Ci to Ce alkyl group optionally substituted with one or more halogen(s); -an amino group; -an alkoxy group optionally substituted with:
  • R 3 is:
  • R x is as defined above; provided that when X is phenyl substituted with alkoxy, Y is phenyl, R is hydrogen, Ri is a halogen, R 2 is hydrogen, and R3 is hydrogen, and provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Rj is hydrogen or hydroxy, R 2 is hydrogen or hydroxy, and R 3 is hydrogen, then Z is: -a C 1 to C 6 alkyl substituted with: -an alkoxy, -one or more halogen(s), or
  • Y is a Ce to Cs aryl, optionally substituted with one or more of the following: -an amino optionally substituted with one or more Ci to C& alkyl(s), -a Ci to Ce alkyl group, optionally substituted with a -NHSOaR x group, -a -NR 0 COR p group, where R p is: -a Ci to Ce alkyl optionally substituted with:
  • R 0 is a hydrogen, -a -NR q CONRqRr group, where Rq is:
  • R r is a Ci to C ⁇ alkyl optionally substituted with one or more of the following: -a halogen,
  • Ci 2 alkyl optionally substituted with: -a Ce to Cs aryl optionally substituted with a Ci to C& alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or
  • R v is a hydrogen
  • R w is a Cj to C ⁇ alkyl optionally substituted with a halogen
  • R 2 is a Ci to C 6 alkyl
  • R2 is a -OCOR x group, a -OR kk group, or an alkoxy group substituted with: -an -OCOR x group,
  • -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a Ci to Ce alkyl; or -a 5 or 6 membered heteroaryl group.
  • -a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl; or -a 5 or 6 membered heteroaryl group.
  • Y is a C ⁇ 5 to Cs aryl substituted with: -a -NR q CONR ⁇ R r group,
  • Z is: -a Ci to Ce alkyl optionally substituted with -an alkoxy, or -one or more halogen(s), or -a C 2 to Cg alkylene;
  • R is hydrogen; at least one of Rj and R 2 is a hydroxy group or an alkoxy group optionally substituted with:
  • R2 is a -OCOR x group, a -ORkk group, or an alkoxy group substituted with.:
  • R3 is hydrogen
  • R2 is an alkoxy group optionally substituted with:
  • -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C & alkyl; or -a 5 or 6 membered heteroaryl group.
  • R 2 is an alkoxy group optionally substituted with:
  • -a 5 or 6 membered heterocycle group optionally substituted with a C 1 to C 6 alkyl; or -a 5 or 6 membered heteroaryl group.
  • R 2 is an alkoxy group optionally substituted with: -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C 6 alkyl; or
  • Y is:
  • -a 5 or 6 membered heteroaryl optionally substituted with a C 6 to Cs aryl, optionally substituted with -COOR x , where R x is as defined above; -a Cs to Cs aryl, optionally substituted with one or more of the following: -a Ci to Ce alkyl group;
  • R n is: -an amino optionally substituted with one or more Cj to Ce alkyl(s); -a -NR 0 CORp group, where R p is:
  • Ci to Cj 2 alkyl optionally substituted with: -a C 6 to C 8 aryl;
  • Ci Ci to C 6 alkyl
  • dialkyl-amino
  • R 2 is hydrogen or a Ci to Cg alkyl
  • R 33 is: -an amino group; or -an alkyl or dialkyl amino group; -a -NHRbb group, where Rbb is: -a -PO(OR X )2 group, where R x is as defined above;
  • R x is as defined above; R is a hydrogen, Ri is:
  • R 2 is:
  • Ci to Ce alkyl group optionally substituted with one or more halogen(s);
  • -an alkoxy group optionally substituted with: -one or more halogen(s);
  • X is a cyano group
  • Y is:
  • Ci Ci to C 6 alkyl
  • Z is a C] to C 6 alky
  • R is a hydrogen
  • Ri is a hydrogen
  • R 2 is:
  • -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C 6 alkyl; or -a 5 or 6 membered heteroaryl group; or
  • R3 is a hydrogen
  • Y is: -a C ⁇ to Cs aryl substituted with one or more of the following: -a Ci to C 6 alkyl group;
  • R v is hydrogen and where R w is: -a Ci to Ce alkyl; or -an alkyl- or dialkyl-amino; Z is a Ci to Ce alky; R is a hydrogen; Ri is -a hydrogen;
  • R2 is a -OR k ic group, where R 1& is a 5 to 6 membered heteroaryl; R.3 is a hydrogen. 35. The compound of embodiment 32, wherein:
  • X is:
  • Y is:
  • -a Ce to Cg aryl substituted with one or more of the following: -a Ci to C 6 alkyl;
  • R v is hydrogen and where R w is: -a Ci to C 6 alkyl; or
  • Ci to C 6 alkyl Z is: -a C 1 to C 6 alkyl
  • R is:
  • R 2 is:
  • R 3 is:
  • Y is:
  • Ci to C 6 aljkyl Z is: -a C, to C 6 alkyl
  • R is:
  • R 2 is:
  • R kk is a 5 to 6 membered heteroaryl
  • R 3 is:
  • Y is: -a phenyl substituted with a -NR t COOR 1 , group, where R, is hydrogen, and where R u is:a C] to C12 alkyl.
  • X is:
  • Y is:
  • R is:
  • R 1 is:
  • R 2 is:
  • R 3 is:
  • Y is:
  • R is:
  • R 2 is: -a 5 or 6 membered heteroaryl
  • R 3 is: r
  • Y is:
  • Y is: -a C ⁇ to Cz aryl substituted with -a NR q CONRqR r group, where Rq is hydrogen and where R r is a Ci to C ⁇ alkyl.
  • Y is:
  • R is:
  • Ri is:
  • R 2 is:
  • R 3 is:
  • Y is: -a Cg to Cg aryl substituted with one or more of the following:
  • R is:
  • R 2 is: -an alkoxy group
  • R 3 is:
  • Y is:
  • -a Ce to Cs aryl substituted with one or more of the following: -a Ci to Cg alkyl group; -a halogen; -a -NRtCOOR u group, where R t is hydrogen, and where R 11 is:
  • Ci2 alkyl optionally substituted with:
  • R v is hydrogen and where R w is: -a Ci to Ce alkyl; or -an alkyl- or dialkyl-amino;
  • Ci Ci to C 6 alky
  • R is: -a hydrogen
  • Ri is:
  • R 2 is:
  • R 3 is:
  • Y is:
  • R is:
  • R 1 is:
  • R 2 is:
  • R 3 is: -a hydrogen.
  • Y is: -a Ce to Cg aryl, optionally substituted with one or more of the following:
  • R p is: -a C] to C 6 alkyl; and where R 0 is:
  • R 41 is hydrogen and where R 1 is: -a Ci to C 6 alkyl;
  • R 2 is:
  • R 3 is:
  • Y is:
  • Ci to C 12 alkyl optionally substituted with: -a C 6 to Cg aryl; or -a 5 or 6 membered heterocycle;
  • R z is hydrogen or a Ci to Ce alkyl
  • R is:
  • Ri is: -a 5 or 6 membered heterocycle
  • R 2 is: -a hydrogen
  • R 3 is:
  • Ci to Ci 2 alkyl optionally substituted with: -a Ce to Cg aryl; or -a 5 or 6 membered heterocycle;
  • Ri is:
  • R is:
  • R 2 is:
  • X is:
  • R is:
  • Ri is:
  • R 2 is: -a -ORfck group, where Rkk is a 5 to 6 membered heteroaryl;
  • R 3 is:
  • a pharmaceutical composition comprising: (i) a compound of formula I
  • Ci to C 6 alkyl -a Ci to C 6 alkyl, -a Cs to Cg aryl optionally substituted with an alkoxy or one or more halogen(s), or
  • Y is:
  • -a haloalkyl -a halogen; -an amino optionally substituted with one or more Ci to C ⁇ alkyl(s); -a benzofiiran; -a benzothiophene; -a dibenzofuran; -a dibenzothiophene; -a benzothiazole; -a naphthalene; -an indole, optionally substituted on the nitrogen with a C] to Ce alkyl;
  • R t is a hydrogen or a Ci to Ce alkyl, and n is 0 or 1 ;
  • R 0 is a hydrogen, a -CONHR x , where R x is as defined above, or an -SChR x , where R x is as defined above; or
  • -a C 6 to Cs aryl optionally substituted with: -a Ci to C 5 alkyl, -an alkoxy, -a cyano group, -a nitro group, or
  • R g is a C t to C 6 alkyl or a hydrogen and R h is a Cg to Cg aryl optionally substituted with an alkoxy; -a Ci to C 6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
  • -a 5 or 6 membered heterocycle optionally substituted with: -a -COOR x group, where R x is as defined above, or -a -NHCOOR x group, where R x is as defined above; -a C 6 to Cs aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
  • Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy
  • Ci to Ce alkyl group optionally substituted with:
  • Ci to Ce alkyl optionally substituted with: -a halogen, -an alkoxy, or -a Ce to C 8 aryl,
  • R 0 is:
  • R x is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRqCONRqR n group, where R q is:
  • R x is as defined above, and where R r is: -a C ⁇ to Cs aryl optionally substituted with:
  • Ci to Ce alkyl optionally substituted with one or more of the following: -a halogen, -an alkyiene, -a Cg to Cg aryl, and/or -a -COOR x group, where R x is as defined above,
  • Ci to Cn alkyl optionally substituted with:
  • R x is as defined above, or -a Ci to Ce alkyl, optionally substituted with:
  • Ci to Ce alkyl optionally substituted with: -a halogen, -a haloalkyl, -a C 6 to C 8 aryl, or
  • Ci to C 6 alkyl -a 5 or 6 membered heterocycle, or , optionally substituted with a Ci to Cs alkyl, where R y is a
  • R 2 is hydrogen or a Ci to Ce alkyl, optionally substituted with a Ce to C 8 aryl, -a -SR x group, where R x is as defined above, -a -SChRaa group, where R 33 is:
  • -a Ce to Cs aryl optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halogen,
  • Ci to Cs alkyl optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to C$ alkyl(s), -a -NHPOR x R x , where R x is as defined above,
  • Rce is a hydrogen or a Ci to Q alkyl, optionally substituted with a halogen
  • Rfr is: -a hydrogen, -a halo alkyl, -a haloalkoxy
  • -an amino optionally substituted with one or more Ci to Cs alkyl(s), and/or -a -NR 11 SOiR x group, where R x is as defined above, and R n is: -a hydrogen, -a Ci to C 6 alkyl, -a haloalkyl, -a haloalkoxy,
  • Ci to Ce alkyl optionally substituted with: -an alkoxy
  • Ci Ci to C ⁇ alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or Ri joins together with R 2 to form:
  • R 2 is:
  • Ci to Ce alkyl group optionally substituted with one or more halogen(s); -an amino group; -an alkoxy group optionally substituted with:
  • -a 5 or 6 membered heterocycle group optionally substituted with a Ci to Cs alkyl, -a 5 or 6 membered heteroaryl group, or
  • R 3 is:
  • R x is as defined above; provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Ri is hydrogen or hydroxy, R 2 is hydrogen or hydroxy, and R 3 is hydrogen, then Z is:
  • R a is: -a Ci to C 6 alkyl
  • Ci to C 6 alkyl -a Ci to C 6 alkyl, -a C 6 to C 8 aryl optionally substituted with an alkoxy or one or more halogen(s), or
  • Y is:
  • -a haloalkyl -a halogen; -an amino optionally substituted with one or more Ci to C 6 alkyl(s); -a benzofuran; -a benzothiophene; -a dibenzofuran; -a dibenzothiophene; -a benzothiazole; -a naphthalene; -an indole, optionally substituted on the nitrogen with a Ci to C 6 alkyl;
  • R b is a hydrogen or a Ci to Ce alkyl, and n is 0 or 1 ;
  • Rc is a hydrogen, a -CONHR x , where R x is as defined above, or an -SOaR x , where R x is as defined above;
  • Rd is a Ci to C 6 alkyl or a C 6 to Cg aryl; -a -NHCORe group, where R e is: -a Ci to C 6 alkyl; -a Ce to Cs aryl optionally substituted with:
  • -a Ci to C 6 alky -an alkoxy, -a cyano group, -a nitro group, or -a halogen; -a -NHCOOR x group, where R x is as defined above; -a -CH 2 O-R f group, where R f is a C 6 to Cs aryl; -a -NRgRi, group, where R g is a Ci to Ce alkyl or a hydrogen and R h is a C 6 to Cg aryl optionally substituted with an alkoxy; -a Ci to C 6 alkyl;
  • -a 5 or 6 membered heteroaryl optionally substituted with: -a Ci to Ce alkyl, optionally substituted with a C 6 to C 8 aryl,
  • -a 5 or 6 membered heterocycle optionally substituted with: -a -COOR x group, where R x is as defined above, or -a -NHCOOR x group, where R x is as defined above;
  • -a C 6 to C 8 aryl optionally substituted with one or more of the following: -an alkoxy, optionally substituted with: -an alkoxy, -a hydroxy, -one or more halogen(s),
  • R k is: -a C J to C 6 alkyl, -a hydrogen, or
  • R 1 - is:
  • Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more Ci to Cs alkyl(s),
  • Ci to Ce alkyl optionally substituted with: -a halogen, -an alkoxy, or -a Ce to Cg aryl, -a 5 or 6 membered heterocycle,
  • R 0 is:

Abstract

The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.

Description

METHODS FOR TREATING HEPATITIS C
CROSS REFERENCES TO RELATED APPLICATIONS
This application is a continuation-in-part of Application No. 11/331,180, filed January 13, 2006, which is a continuation-in-part of Application No. 11/180,961, filed July 14, 2005, and of International Application No. PCT/US2005/024881, filed July 14, 2005, both of which " applications claim the benefit of U.S. Provisional Application No. 60/587,487, filed July 14, 2004, U.S. Provisional Application No. 60/634,979, filed December 13, 2004, U.S. Provisional Application No. 60/645,586, filed January 24, 2005, U.S. Provisional Application No. 60/665,349, filed March 28, 2005, and U.S. Provisional Application No. 60/675,440, filed April 28, 2005; this application also claims the benefit of U.S. Provisional Application No. 60/758,527, filed January 13, 2006, the entire contents of which applications are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.
BACKGROUND OF THE INVENTION
An estimated 170 million people worldwide are reported to be infected with hepatitis C virus (HCV), the causative agent of hepatitis C. Seventy to eighty percent of HCV infections lead to chronic liver infection, which in turn may result in severe liver disease, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (115).
HCV constitutes the Hepacivirus genus of the family Flaviviridae (106), and contains a positive-stranded 9.6 kb RNA genome. The features of the HCV genome include a 5'- untranslated region (UTR) that encodes an internal ribosome entry site (IRES) that directs the translation of a single long open reading frame (ORF) encoding a polyprotein of 3,010 amino acids. The HCV ORF is followed by a 3'-UTR of variable length, depending on the HCV variant, that encodes the sequences required for the initiation of antigenomic strand synthesis (79).
The HCV IRES and 3'-UTR both encode regions of RNA structures that are required for genome translation and replication. The HCV polyprotein is posttranslationally processed into at least 10 mature viral proteins, including the structural proteins core (putative nucleocapsid), El and E2 and the nonstructural (NS) proteins NS2 to NS5B. Three distinct elements have been shown to be involved in HCV IRES-mediated translation: (1) integrity of the global structure of HCV HtES, (2) the 3 '-terminal region of the HCV genome; and (3) trans-acting cellular factors that interact with the HCV ERES element and assist in translation initiation (35). The initiation of protein synthesis in eukaryotic cells predominantly follows the 5' cap- dependent, first AUG rule (61). However, an increasing number of viral (6, 12, 28, 31a, 50, 95, 97, 98, 105, 128) and cellular mRNAs (18, 39, 45, 78, 91, 130) have been shown to use an IRES element to direct translation initiation. In 1992, an IRES element was reported in the 5' UTR of the HCV RNA genome (129), indicating that synthesis of the viral protein is initiated in a cap-independent fashion.
A bicistronic expression system can be used to define and evaluate the function of IRES elements. This test system harbors two different reporter genes in which the 5'-proximal reporter gene is expressed by a cap dependent translation mechanism while the second reporter is expressed only if an upstream sequence inserted in the intergenic space contains an IRES sequence element. Using this system, a putative IRES in the HCV 5' UTR was unambiguously demonstrated to function as an IRES involved in translational control of viral proteins (133). In vitro translation, RNA transfection, and mutagenesis studies provided further evidence that the HCV 5' UTR contains an IRES element (23, 41, 42, 108, 129, 132, 133, 134). Both in vitro and cell-based studies demonstrated that the HCV IRES guides cellular translation initiation factors to an internal site of the viral RNA (56, 58, 120), thus functionally demonstrating the HCV IRES activity. Taken together, these results demonstrate that the HCV 5'-UTR contains an IRES element that plays an active and crucial role in the mechanism of internal initiation for HCV protein translation.
The IRES is one of the most conserved regions of the HCV genome, reflecting its essential nature for viral replication and protein synthesis (13, 118, 122). Although both 5' and 3' sequences of the IRES appear to play a role in the control of initiation of translation (42, 109, 110, 113, 136), the minimal sequence requirement for HCV IRES function has been mapped to a region between nucleotides 44-354 (40).
Biochemical probing and computer modeling indicate that the HCV IRES and its 5' sequence is folded into a distinct structure that consists of four major domains and a pseudoknot (11, 42, 122). Domain I contains a small stem-loop structure that does not appear to be a functional part of the IRES element while domains II, III, and IV contain the HCV ERES activity (43, 111). The relationships between secondary and tertiary structures of the HCV IRES and their function have recently been established (5, 55, 56, 99, 124). Both domains II and III consist of multiple stems, loops, and bulges and are important for IRES activity (23, 40, 51, 52, 54, 56, 64, 74, 75, 93, 107, 108, 110, 124, 127, 131, 139, 141, 142). Domain II can induce conformational changes on the ribosome that have been implicated in the decoding process (124). Domain III has the highest degree of structural conservation among the different HCV strains. It comprises the core of the flavivirus IRES and has 6 subdomains (40). Various studies have shown that subdomain IHd forms complex secondary/tertiary structures and is critical for initiation activity (55, 56, 57, 124, 129). Domain IV has one stem- loop that spans the initiation codon and is specific for the HCV IRES (41, 122), but the precise role of domain IV in IRES activity remains controversial (41, 112). The role of the HCV IRES is to position the translational machinery near an internal initiator codon in the viral mRNA. The translation initiation mechanism of the HCV and other viral IRES differs significantly from that of 5 '-cap-dependent translation initiation (7, 21, 31, 35, 61, 71, 72, 81, 88, 96, 114, 123). Most cellular capped mRNAs utilize a number of initiation factors (elFs) that are required for the translation initiation process. The initial steps of the process require proteins that interact with the 5' cap structure and recruit the 40S ribosomal subunit to the cap-proximal region of mRNA. This complex then scans 3' of the cap, until reaching an AUG codon at which translation will initiate (21, 114) However, in the case of HCV, the IRES functionally replaces the 5' cap structure, allowing the 4OS ribosomal subunit and eIF3 to bind directly to the RNA. Subdomain IIId of the HCV IRES harbors the binding site for the 4OS ribosomal subunit and the only initiation factors required for translation initiation are eEF2, eIF3, and eIF4E (15, 58, 94, 100, 120, 124).
The polypyrimidine track-binding protein (PTB) and La autoantigen are noncanonical translation initiation factors that bind to and enhance HCV IRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53). PTB, a 57-kDa protein involved in RNA splicing, is also necessary for efficient IRES- mediated translation initiation of picomavirus mRNA, and some cellular mRNAs (10, 11, 36, 53, 59, 89, 92). The La autoantigen, a 52 IcDa double-stranded RNA unwinding protein, also increases the activity of poliovirus and cellular IRES (38, 85, 86). Other cellular factors involved in HCV IRES-mediated translation initiation include proteasome α-subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9 (24, 25, 100), and hnRNPL (33). However, the role of these RNA-binding proteins in HCV IRES-mediated initiation of translation is unclear. Recently, it was reported that the activity of interferon (IFN) α against HCV replication might target HCV IRES-mediated translation initiation by causing a reduction of La protein levels (117) Some HCV proteins, such as NS 5 A, core and NS4A/4B, also reported to be involved in the HCV IRES function (143-146). Thus, an inhibitor that blocks interaction between the IRES and the noncanonical factors might efficiently inhibit HCV replication and lack cytotoxicity.
Currently, only interferon (IFN) α and the nucleoside analogue ribavirin, in combination, are marketed for the treatment of HCV infection. However, these two agents are immunomodulators and have limited efficacy, relatively high toxicity, and high cost (80, 83,
84, 138). Although the treatment outcome is variable among the six major HCV genotypes, only about one-half of all treated patients respond to therapy, suggesting that the virus encodes protein products that may directly or indirectly attenuate the antiviral action of IFN. IFNs are naturally produced in response to virus infection, and cellular exposure to IFN leads to the induced expression of a variety of IFN-stirnulated genes (ISGs), many of which have an antiviral function. ISG action can limit virus replication at multiple points within the replicative cycle.
There remains a need for an alternative means of treating patients afflicted with HCV.
Specifically, a need exists for novel antiviral drugs, for example, that have no cross-resistance with existing treatment modalities, and which demonstrate synergy with other anti-HCV agents.
AU documents referred to herein are incorporated by reference into the present application as though fully set forth herein.
SUMMARY OF THE INVENTION The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral
IRES activity.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 illustrates the HCV-PV chimera construct. The cloverleaf-like RNA structure of PV; an essential czs-acting replication signal ending with the genome-linked protein VPg, is located at the 5' end of the genome. The solid (HCV) and open (PV) boxes depict open reading frames encoding viral polypeptides. The position of the HCV core fragment (the first
123 amino acids) gene is denoted by Δ Core. Overall, the HCV-specific sequence in the HCV-
PV spans from nucleotides 18 to 710 (139). DETAILED DESCRIPTION OF THE INVENTION
A. Compounds of the Invention
One aspect of the invention relates to a compound of formula I
wherein: X is:
-hydrogen; -a nitro group; -a cyano group; -a -COR3 group, where R8 is: -a Ci to Ce alkyl,
-a Ce to Cg aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COORx group, where Rx is a Ci to Ce alkyl; -a formyl group;
-a Cg to Cg aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with: -a Ci to C6 alkyl,
-a Ce to Cs aryl optionally substituted with an. alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl;
Y is:
-a hydrogen; -a haloalkyl; -a halogen; -an amino optionally substituted with one or more Ci to Ce alkyl(s); -a benzofuran; -a benzothiophene; -a dibenzofuran; -a dibenzothiophene;
-a benzothiazole;
-a naphthalene,
-an indole, optionally substituted on the nitrogen with a Ci to Cβ alkyl,
or 1;
above, or an -SOaRx, where Rx is as defined above; or
where Ra is a Ci to Ce alkyl or a Cs to Cs aryl;
-a -NHCORe group, where R» is: -a Ci to C6 alkyl; -a Ce to Cs aryl optionally substituted with-
-a Ci to C6 alkyl, -an alkoxy,
-a cyano group, -a nitro group, or -a halogen;
-a -NHCOORx group, where Rx is as defined above; -a -CHaO-Rf group, where Rf is a Ce to Cg aryl;
-a -NRgRi, group, where Rg is hydrogen or a Cj to C^ alkyl and Rh is hydrogen or a Ce to Cg aryl optionally substituted with an alkoxy; -a Ci to C6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
-a Ci to Ce alkyl, optionally substituted with a Ce to Cg aryl,
-a Cs to Cs aryl, optionally substituted with -COORx, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above, or -a -NHCOORx group, where Rx is as defined above; -a Ce to Cs aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy,
-one or more halogen(s),
-a 5 or 6 membered heterocycle, optionally substituted with: -a Ci to C6 alkyl, or
-a hydroxy,
-an amino group optionally substituted with one or more Ci to Ce alkyl(s), -a -NR1SOaRx group, where Rx is as defined above and R1 is:
-a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy,
-a -NRjCORk group, where Rk is: -a Ci to C6 alkyl,
-a hydrogen, or
-an amino optionally substituted with one or more Ci to Cg alkyl(s),
-a hydrogen, -a Ci to C6 alkyl,
- a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -N=N+=N" group, or
-a -CORi, where Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy.
-an amino optionally substituted with one or more Ci to Cf, alkyl(s), -a nitro group, -a Ci to CO alkyl group, optionally substituted with:
-a -NHSO2RX group, where Rx is as defined above, or -a -NRxSOiRx group, where Rx is as defined above, -a haloalkoxy, -a halogen, -a hydroxy,
-a -COORx group, where Rx is as defined above, -a -CORn, group, where Rn, is:
-an amino optionally substituted with one or more Ci to Ce alkyl(s), where the one or more Ci to Ce alkyl(s) is/are optionally substituted with: -a hydroxy
-a 5 or 6 membered heterocycle,
-an amino optionally substituted with one or more C] to CO alkyl(s), -an alkoxy,
-a 3 to 7 membered heterocycle, optionally substituted with a C] to Cβ alkyl, optionally substituted with a dialkyl-amino,
-a -NHRn group, where Rn is: -a -CH2CONH2, or -a CO to Cs aryl optionally substituted with:
-an alkyl, -one or more halogen(s),
-a nitro group, or -one or more alkoxy(s), -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with: -a halogen,
-an alkoxy, or
-a Ce to C8 aryl,
-a 5 or 6 membered heterocycle, -a Cs to Ce aryl, optionally substituted with a halogen,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyl(s), -a hydrogen,
and where R0 is:
-a hydrogen,
-a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above,
-a haloalkyl, or
-a haloalkoxy, -a -NRqCONRqRr group, where Rq is:
-a hydrogen,
-a Ci to C6 alkyl,
-a haloalkyl,
-a haloalkoxy, or
-a -CORx group, where Rx is as defined above, and where Rr is:
-a C6 to Cs aryl optionally substituted with:
-a Ci to C6 alkyl, -a haloalkyl, -a -ORS group, where Rs is a Cβ to Cg aryl, or -a -COORx group, where Rx is as defined above, -a Ci to Ce alkyl optionally substituted with one or more of the following:
-a halogen, -an alkyiene,
-a Ce to Cs aryl, and/or
-a -COORx group, where Rx is as defined above, -a -COORx group, where Rx is as defined above, -a -NR1COORu group, where Ru is: -a Ci to Ci2 alkyl, optionally substituted with:
-a Ce to Cs aryl optionally substituted with a Ci to C$ alkyl or an alkoxy, -an alkyiene, -an alkoxy, -an alkyne, -a halogen, or
-a 5 or 6 membered heterocycle, -a Ce to Cg aryl, optionally substituted with: -an alkoxy, -a halogen, or -a Ci to C6 alkyl, or
-a 5 or 6 membered heterocycle,
-a hydrogen, -a Ci to C6 alkyl, -a -CORx group, where Rx is as defined above,
-a haloalkyl, or -a haloalkoxy, -a -NRvSθ2Rw group, where Rv is:
-a hydrogen, -a -CORx, where Rx is as defined above, or
-a C i to C^ alkyl, optionally substituted with: -a halogen,
-a -CORx group, where Rx is as defined above, -a -OCORx group, where Rx is as defined above, -a hydroxy, or
-an alkoxy, and where Rw is:
-a Ci to CO alkyl optionally substituted with:
-a halogen,
-a haloalkyl,
-a Ce to Cg aryl, or
-a 5 or 6 membered heterocycle, -a Cj to CO alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl,
-a 5 or 6 membered heterocycle, or
-a 5 optionally substituted with a Ci to C$ alkyl, where Ry is a
Ci to C6 alkyl or hydrogen,
where Rz is hydrogen or a Ci to Ce alkyl, optionally substituted with a Ce to Cg aryl, -a -SRx group, where Rx is as defined above, -a group, where R23 is:
-a Ci to C6 alkyl,
-an amino group,
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -COORx group, where Rx is as defined above,
-a 5 or 6 membered heteroaryl, -a Cg to Cg aryl, and/or -a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or
-a -PO(ORχ)2 group, where Rx is as defined above; ===== F?cc group, where R4x is: -a naphthalene, -a 5 or 6 membered heteroaryl,
-a Ce to Cg aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy,
-a halogen,
-a CJ to Ce alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Cj to Cg alkyls, -a -NHPORXRX, where Rx is as defined above, -a -NReeCONRffRfT group, where Ree is a hydrogen or a Ci to Cg alkyl, optionally substituted with a halogen, and Rff is: -a hydrogen, -a haloalkyl, -a haloalkoxy, -a Ci to C6 alkyl, or
-a -CORx, where Rx is as defined above, -a -NRggCORhh group, where Rhh is: -a hydrogen,
-a Ct to Ce alkyl optionally substituted with: -an alkoxy,
-a halogen, or
-an amino optionally substituted with one or more Ci to Ce alkyls, -an amino optionally substituted with one or more Ci to Ce alkyls, where the alkyls are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl,
-a hydrogen, -a Ci to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORx group, where Rx is as defined above,
-a haloalkyl,
-5 or 6 membered heterocycle groups,
-an amino optionally substituted with one or more Ci to Cg alkyls, and/or -a -NRjjSCbRx group, where Rx is as defined above, and RU is: -a hydrogen,
-a Ci to C6 alkyl, -a haloalkyl, -a haloalkoxy,
-a -CORx group, where Rx is as defined above, Z is:
-a hydrogen;
-a Ct to Cδ alkyl optionally substituted with: -an alkoxy,
-one or more halogen(s), or -a C6 to C8 aryl;
-a Ci to Ce alkylene;
-a Cβ to Cs aryl optionally substituted with an alkoxy or one or more Ci to Ce alkyl(s); -a -COORx group, where Rx is as defined aboye; or
R is a hydrogen, a halogen or an alkoxy; Ri is:
-a hydrogen;
-a hydroxy;
-a halogen; -a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with: -one or more halogen(s),
-a Cs to Cg aryl, or -a 5 or 6 membered heterocycle;
-a Ce to Cg aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above; -a C] to Ce alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
Ri joins together with R2 to form:
R2 1S: -a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
-a C] to Ce alkyl group, optionally substituted with one or more halogen(s); -an amino group;
-an alkoxy group optionally substituted with: -one or more halogen(s),
-an -OCORx group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy,. -a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl,
-a 5 or 6 membered heteroaryl group, or -a CO to C$ aryl group;
-a -COORx group, where Rx is as defined above; -a haloalkyl;
-an amide group optionally substituted with: - a hydroxy group, or
-a C6 to C8 aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORjj group, where K^ is: -an alkoxy, or
-an amino optionally substituted with one or more Ci to Ce aUcyl(s); -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; -a -NHSO2RX group, where Rx is as defined above; or R2 joins together with R] to form:
R3 is:
-a hydrogen; or
-CHaOCORx, and Rx is as defined above; or a pharmaceutically acceptable salt thereof. In some embodiments of formula I,
X is:
-a nitro group;
-a cyano group;
-a -COR3 group, where Ra is* -a Ci to C6 alkyl,
-a Cs to Cg aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COORx group, where Rx is a Cj to CQ alkyl;
-a formyl group; -a C$ to C8 aryl optionally substituted with an alkoxy; or
-a 5 or 6-membered heteroaryl optionally substituted with: -a Ci to C6 alkyl,
-a C6 to Cg aryl optionally substituted with an alkoxy or one or more halogen(s), or
-a 5 to 6 mernbered heteroaryl, Y is: -a haloalkyl; -a halogen;
-an amino optionally substituted with one or more Ci to CO alkyl(s); -a benzofuran; -a benzothiophene; -a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a Ci to C6 alkyl;
, where Rb is a hydrogen or a Cj to C6 alkyl, and n is 0 or 1;
where R0 is a hydrogen, a -CONHRx, where Rx is as defined above, or an -Sθ2Rx, where Rx is as defined above; is a Ci to C6 alkyl or a C6 to C8 aryl; -a -NHCORc group, where R0 is: -a Ci to C6 alkyl;
-a C6 to Cg aryl optionally substituted with: -a C1 to C6 alkyl,
-an alkoxy, -a cyano group, -a nitro group, or -a halogen; -a -NHCOORx group, where Rx is as defined above; -a -CH2θ-Rf group, where Rf is a Ce to Cg aryl;
-a -NRgRh group, where Rg is a Ci to C6 alkyl or a hydrogen and Rh is a Ce to Cg aryl optionally substituted with an alkoxy; -a C] to C6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
-a Ci to C6 alkyl, optionally substituted with a Ce to Cs aryl.
-a C6 to Cg aryl, optionally substituted with -COORx, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above, or
-a -NHCOORx group, where Rx is as defined above; -a C6 to Cs aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy,
-one or more halogen(s),
-a 5 or 6 membered heterocycle, optionally substituted with: -a Ci to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more Ci to C6 alkyl(s), -a -NR1SO2Rx group, where Rx is as defined above and R, is: -a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or
-a haloalkoxy,
-a -NRjCORk group, where Rk is: -a Ci to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Ci to Ce alkyl(s), and Rj is:
-a hydrogen, -a Ci to C6 alkyl,
- a -CORx group, where Rx is as defined above, -a haloalkyl, or
-a haloalkoxy, -a -N=N+=N" group, or
-a -COR|, where Rj is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more Ci to Ce alkyl(s),
-a Ci to Ce alkyl group, optionally substituted with:
-a -NHSOzRx group, where Rx is as defined above, or -a -NRxSOaRx group, where Rx is as defined above, -a haloalkoxy, -a halogen,
-a hydroxy,
-a -COORx group, where Rx is as defined above, -a -CORπi group, where Rn, is:
-an amino optionally substituted with one or more Ci to Ce alkyl(s), where the one or more Ci to Ce alkyl(s) is/are optionally substituted with:
-a hydroxy
-a 5 or 6 membered heterocycle,
-an amino optionally substituted with one or more Ci to Ce alkyl(s), -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a Ci to C6 alkyl, • optionally substituted with a dialkyl-amino, -a -NHRn group, where Rn is: -a -CH2CONH2, or
-a Ce to Cs aryl optionally substituted with: -an alkyl,
-one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NR0CORp group, where Rp is:
-a Ci to CO alkyl optionally substituted with: -a halogen, -an alkoxy, or -a Ce to Cs aryl,
-a 5 or 6 membered heterocycle, i CO to Cs aryl, optionally substituted with a halogen,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Cg alkyl(s),
-a hydrogen,
and where R0 is:
-a hydrogen,
-a Ci to CO alkyl,
-a -CORx group, where Rx is as defined above,
-a haloalkyl, or
-a haloalkoxy, -a -NRqCONRqRr group, where Rq is:
-a hydrogen,
-a Ci to Ce alky],
-a haloalkyl,
-a haloalkoxy, or -a -CORx group, where Rx is as defined above, and where Rr is:
-a Ce to Cg aryl optionally substituted with:
-a Ci to C6 alkyl,
-a haloalkyl,
-a -ORS group, where Rs is a Cs to Cs aryl, or -a -COORx group, where Rx is as defined above,
-a Ci to Ce alkyl optionally substituted with one or more of the following: -a halogen,
-an alkylene, -a Ce to Cg aryl, and/or
-a -COORx group, where Rx is as defined above, -a -COORx group, where Rx is as defined above, -a -NRtCOORu group, where Ru is:
-a Ci to Ci2 alkyl, optionally substituted with:
-a Ce to C8 aryl optionally substituted with a Ci to Ce alkyl or an alkoxy, " -an alkylene, -an alkoxy, -an alkyne,
-a halogen, or
-a 5 or 6 membered heterocycle, -a Cg to Cs aryl, optionally substituted with:
-an alkoxy, -a halogen, or
-a Ci to Ce alkyl, or -a 5 or 6 membered heterocycle, and Rt is:
-a hydrogen, -a Ci to C6 aϋcyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy,
-a -NRvSOzRw group, where Rv is: -a hydrogen,
-a -CORx, where Rx is as defined above, or -a Ci to Ce alkyl, optionally substituted with:
-a halogen,
-a -CORx group, where Rx is as defined above,
-a -OCORx group, where Rx is as defined above,
-a hydroxy, or
-an alkoxy, and where Rw is:
-a Ci to Cg alkyl optionally substituted with:
-a halogen,
-a haloalkyl,
-a Ce to Cg aryl, or
-a 5 or 6 membered heterocycle, -a C2 to Ce alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl,
-a 5 or 6 membered heterocycle, or
- a } optionally substituted with a Ci to Ce alkyl, where Ry is a
Ci to C6 alkyl or hydrogen,
where Rz is hydrogen or a Ci to Ce alkyl, optionally substituted with a C5 to Cg aryl, -a -SRx group, where Rx is as defined above, -a -SC^Raa group, where Raa is:
-a Ci to Ce alkyl,
-an amino group,
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -COORx group, where Rx is as defined above,
-a 5 or 6 membered heteroaryl, -a Cβ to Cg aryl, and/or -a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or
-a -PO(ORX)2 group, where Rx is as defined above; = R00 group, where R0C is:
-a naphthalene,
-a 5 or 6 membered heteroaryl,
-a Ce to Cs aryl, optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halogen,
-a Ci to CO alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to Cg alkyl(s), -a -NHPORxRx, where Rx is as defined above,
-a -NRsεCONRffRfr group,, where Rse is a hydrogen or a Ci to Ce alkyl, optionally substituted with a halogen, and R^ is:
-a hydrogen,
-a haloalkyl,
-a haloalkoxy,
-a Ci to C6 alkyl, or -a -CORx, where Rx is as defined above, -a -NRggCORhh group, where Rhh is: -a hydrogen,
-a Ci to Cs alkyl optionally substituted with: -an alkoxy,
-a halogen, or
-an amino optionally substituted with one or more Cj to Cs alkyl(s),
-an amino optionally substituted with one or more Ci to Cή alkyl(s), where the one or more Ci to Ce alkyl(s) is/are optionally substituted with a halogen,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and Rgg is: -a hydrogen,
-a Ci to C β alkyl, -a haloalkyl, -a haloalkoxy, or
-a -CORx group, where Rx is as defined above, -a haloalkyl,
-5 or 6 membered heterocycle groups,
-an amino optionally substituted with one or more Ci to Ce alkyl(s), and/or
-a -NRnSChRx group, where Rx is as defined above, and R1; is:
-a hydrogen, -a Ci to C6 alkyl,
-a haloalkyl, -a haloalkoxy,
-a -CORx group, where Rx is as defined above; Z is: -a C] to C6 alkyl optionally substituted with: -an alkoxy,
-one or more halogen(s), or -a Ce to Cs aryl; -a C2 to CO alkylene; -a C$ to Cg aryl optionally substituted with an alkoxy or one or more Ci to Ca alkyl(s); -a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy;
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl; -a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl, or
-a 5 or 6 membered heterocycle;
-a Cs to Cg aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above;
-a Ci to Ce alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
Ri joins together with R2 to form:
R2 is:
-a nitro group; -a hydrogen; -a halogen; -a hydroxy group; -a Ci to Cs alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCORx group, where Rx is as defined above,
-a dialkyl-amino optionally substituted with an alkoxy,
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl,
-a 5 or 6 membered heteroaryl group, or
-a Ce to Cs aryl group; -a -COORx group, where Rx is as defined above; -a haloalkyl; -an amide group optionally substituted with:
- a hydroxy group, or
-a Ce to C8 aryl; -a 5 or 6 membered heteroaryl;
-a -OCORx group, where Rx is as defined above; -a -NHCORJ, group, where R1, is:
-an alkoxy, or
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -a -ORkk group, where R^^ is a 5 to 6 membered heteroaryl; -a -NHSOaRx group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is: -a hydrogen; or
-CH2OCORx, and Rx is as defined above; provided that when X is phenyl substituted with alkoxy, Y is phenyl, R is hydrogen, Ri is a halogen, R2 is hydrogen, and R3 is hydrogen, and provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Ri is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is: -a C1 to C6 alkyl substituted with:
-an alkoxy,
-one or more halogen(s), or
-a C6 to Cg aryl; -a C2 to Ce alkylene;
-a Ce to Cs aryl optionally substituted with an alkoxy or one or more Ci to Ce alkyl(s); -a -COORx group, where Rx is as defined above; or
or a pharmaceutically acceptable salt thereof. In some embodiments, X is a nitro group or a cyano group, hi other embodiments, X is a cyano group.
In some embodiments, Y is a C6 to Cs aryl, optionally substituted with one or more of the following:
-an amino optionally substituted with one or more Ci to C6 alkyl(s), -a Ci to C6 alkyl group, optionally substituted with a -NHSO2Rx group,
-a -MR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with: -a halogen, or -a Cg to Cs aryl, or -a 5 or 6 membered heterocycle, and where R0 is a hydrogen, -a -NRqCONRqRr group, where Rq is: -a hydrogen, or -a Ci to C6 alkyl, and where Rr is a Cj to Ce alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, or -a C6 to C8 aryl, -a -NR,COOR« group, where Rn is: -a C i to C i2 alkyl, optionally substituted with:
-a Ce to Cg aryl optionally substituted with a Cj to Ce alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or
-a 5 or 6 membered heterocycle, -a Ce to Cs aryl, optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle, and where Rt is:
-a hydrogen, or -a Ci to Ce alkyl,
-a -NRvSθ2Rw group, where Rv is a hydrogen, and where Rw is a Ci to Ce alkyl optionally substituted with a halogen;
where Rz is a Ci to Cs alkyl, and/or
-a -NHRbb group, where Rbb is a -PO(ORX)2 group. In further embodiments, Y is a Ce to Cs aryl substituted with:
-a -NRqCONR9R1. group,
-a -NRtCOORu group,
-a -NRvSθ2Rw group, or
-a -NHRbt, group, where Rbb is -a -PO(0Rx)2 group. The Ce to Cs aryl may be substituted at the para, meta and/or ortho position(s). In some embodiments, the Ce to C$ aryl is phenyl. In other embodiments, the C6 to Cg aryl is phenyl substituted at the para position.
In some embodiments, Y is phenyl substituted with a -NRqCONRqRr group at the para position. In other embodiments, Y is phenyl substituted with a -NRtCOORu group at the para position. In yet other embodiments, Y is phenyl substituted with a -NRvSθ2Rw group at the para position. In yet other embodiments, Y is phenyl substituted with a -NHPO(ORX)2 group at the para position.
In some embodiments, Z is: -a Ci to Cs alkyl optionally substituted with -an alkoxy, or
-one or more halogen(s), or -a C2 to Ce alkylene.
In other embodiments, Z is a Ci to Ce alkyl. In yet other embodiments, Z is a a C2 to C5 alkyl. In yet other embodiments, Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.
In some embodiments, R is hydrogen.
In some embodiments, Ri is:
-a hydrogen; -an alkoxy group optionally substituted with: -one or more halogen(s), -a Ce to Cg aryl group, or -a 5 or 6 membered heterocycle; or
Ri joins together with R2 to form:
In some embodiments, Ra is: -a hydrogen; -a halogen; -a hydroxy group;
-a Ci to Cs alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCORx group, where Rx is as defined above,
-a dialkyl-amino optionally substituted with an alkoxy,
-a 5 or 6 membered heterocycle group optionally substituted with, a Ci to C& alkyl,
-a 5 or 6 membered heteroaryl group, or
-a Cβ to Cg aryl group; -a -COORx group; or
R2 joins together with Ri to form:
In other embodiments, at least one of Ri and R2 is a hydroxy group or an alkoxy group optionally substituted with: -one or more halogen(s),
-a Ce to Cg aryl group, or -a 5 or 6 membered heterocycle group; or
R2 is a -OCORx group, a -ORuc group, or an alkoxy group substituted with: -an -OCORx group,
-a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a Cj to Ce alkyl; or -a 5 or 6 membered heteroaryl group. In yet other embodiments, R2 is a -ORkk group or an alkoxy group optionally substituted with:
-a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C<; alkyl; or -a 5 or 6 membered heteroaryl group.
In yet further embodiments, R2 is a Ci to Ce alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to C$ alkyl; or
-a 5 or 6 membered heteroaryl group. In some embodiments, R3 is a hydrogen.
In some embodiments, X is a cyano group; Y is a Ce to Cs aryl substituted with:
-a group, -a -NR1COORU group,
-a -NRvSθ2Rw group, or -a -NHPO(ORX)2 group; Z is:
-a Ci to Ce alkyl optionally substituted with -an alkoxy, or
-one or more halogen(s), or -a C2 to Ce alkylene; R is hydrogen; at least one of Ri and R2 is a hydroxy group or an alkoxy group optionally substituted with: -one or more halogen(s),
-a CQ to Cs aryl group, or -a 5 or 6 membered heterocycle group; or
R2 is a -OCORx group, a -ORkk group, or an alkoxy group substituted with: -an -OCORx group, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a Ci to Ce alkyl; or -a 5 or 6 membered heteroaryl group; and R3 is hydrogen. In some embodiments, Y is a phenyl substituted with a -NRtCOORu group. In further embodiments, Rt is a hydrogen, and Ru is:
-a C] to C]2 alkyl, optionally substituted with one or more groups independently selected from the following:
-a Ce to Cg aryl optionally substituted with halogen, -an alcoxy group optionally substituted with one or more alkoxy groups,
-an amino optionally substituted with one or more Ci to Cs alkyl, -halogen, or
-a 5 or 6 membered heteroaryl, - a C2 to C(, alkylene, -a Ce to Cs aryl, optionally substituted with halogen.
In yet further embodiments, Ru is a Ci to Ce alkyL
In some embodiments, Y is a phenyl substituted with a -NRqCONRqRr group. In further embodiments, R3 is a hydrogen and Rr is:
-a Cj to Ce alkyl optionally substituted with one or more of the following: -a hydroxy,
-an alkoxy,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a CO to Cg aryl optionally substituted with a halogen, -a C2 to Ce alkylene group,
-a Ci to Cf, alkoxy group, -a 5 or 6 membered heterocycle group. In yet further embodiments, Rr is a a Ci to Cs alkyl.
In some embodiments, Y is phenyl substituted with a -NRvSθ2Rw group. In further embodiments, Rv is a hydrogen, and where Rw is -a Ci to Ce alkyl.
In some embodiments, Y is phenyl substituted with a -NHP0(ORx)2 group. In some embodiments,
Y is a phenyl substituted at the para position with: -a -NRqCONRqRr group, -a -NR1COORu group,
-a -NRvSθ2Rw group, or
-a -NHPO(ORx)2 group; Z is a Ci to Ce alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl; or
-a 5 or 6 membered heteroaryl group.
In some embodiments, the compound of formula I is not Compound 1.
In yet another embodiment, the present invention includes compounds of the following: 1. A compound of formula I
wherein:
X is:
-a nitro group;
-a cyano group;
-a -CORa group, where R3 is:
-a Ci to C5 alkyl,
-a Ce to Cs aryl optionally substituted with an alkoxy or a halogen, or
-a dialkyl-amino;
-a -COORx group, where Rx is a Cj to Q alkyl; -a formyl group;
-a Ce to Cs aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl,
-a Ce to Cg aryl optionally substituted with an alkoxy or one or more halogen(s), or
-a 5 to 6 membered heteroaryl; Y is: -a haloalkyl; -a halogen;
-a benzofύran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with, a Ci to Ce alkyl;
to C^ alkyl, and n is 0 or 1 ;
where R0 is a hydrogen, a -CONHRx, where Rx is as defined above, or an -SChRx, where Rx is as defined above; or
, where Rd is a C1 to C6 alkyl or a Ce to Cg aryl;
-a -NHCORe group, where Re is: -a Ci to C6 alkyl; -a C6 to C8 aryl optionally substituted with: -a Ci to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or
-a halogen;
-a -NHCOORx group, where Rx is as defined above; -a -CHaO-Rf group, where Rf is a C6 to Cs aryl;
-a -NRgRh group, where Rg is hydrogen or a Ci to Ce alkyl and Rh is hydrogen or a Ce to Cs aryl optionally substituted with an alkoxy; -a Ci to Ce alkyl; -a 5 or 6 membβred heteroaryl, optionally substituted with:
-a Ci to Cs alkyl, optionally substituted with a C6 to Cs aryl,
-a C6 to Cg aryl, optionally substituted with -COORx, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above, or -a -NHCOORx group, where Rx is as defined above; -a C6 to Cg aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy,
-one or more halogen(s),
-a 5 or 6 membered heterocycle, optionally substituted with: -a C, to C6 alkyl, or
-a hydroxy,
-an amino group optionally substituted with one or more Ci to Ce alkyl(s), -a -NR;Sθ2Rx group, where Rx is as defined above and Ri is:
-a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRjCORk group, where Rk is: -a Ci to C5 alkyl, -a hydrogen, or
-an amino optionally substituted with one or more Cj to Ce alkyl(s), and Rj is: -a hydrogen,
-a Ci to C5 alkyl,
- a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -N=N+=N" group, or
-a -CORi, where Ri is a 5 or 6 membered hetero cycle optionally substituted with a hydroxy,
-an amino optionally substituted with one or more Ci to Ce alkyl(s), -a Ci to Ce alkyl group, optionally substituted with: -a -NHSOaRx group, where Rx is as defined above, or
-a -NRxSOsRx group, where Rx is as defined above, -a haloalkoxy, -a halogen, -a hydroxy, -a -COORx group, where Rx is as defined above,
-a -CORn, group, where Rm is:
-an amino optionally substituted with one or more C] to Cg alkyl(s), where the one or more Ci to Ce alkyl(s) is/are optionally substituted with:
-a hydroxy -a 5 or 6 membered heterocycle,
-an amino optionally substituted with one or more Ci to Ce alkyl(s), -an alkoxy,
-a 3 to 7 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a dialkyl-amino, -a -NHRn group, where Rn is:
-a -CH2CONH2, or
-a Ce to Cg aryl optionally substituted with: -an alkyl, -one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NR0CORp group, where Rp is:
-a Ci to Cβ alkyl optionally substituted with: -a halogen, -an alkoxy, or -a Ce to Cs aryl,
-a 5 or 6 membered heterocycle, -a Cg to Cs aryl, optionally substituted with a halogen,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyl(s), -a hydrogen,
and where R0 is:
-a hydrogen,
-a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above,
-a haloalkyl, or
-a haloalkoxy, -a -NRqCONRqRr group, where Rq is:
-a hydrogen,
-a Ci to C6 alkyl,
-a haloalkyl,
-a haloalkoxy, or
-a -CORx group, where Rx is as defined above, and where R1- is:
-a Ce to Cs aryl optionally substituted with:
-a Ci to C6 alkyl. -a haloalkyl,
-a -OR8 group, where Rs is a Ce to Cs aryl, or -a -COORx group, where Rx is as defined above,
-a Ci to Ce alkyl optionally substituted with one or more of the following: -a halogen, -an alkylene, -a Ce to Cg aryl, and/or -a -COORx group, where Rx is as defined above,
-a -COORx group, where Rx is as defined above, -a -NRtCOORu group, where Ry is:
-a Ci to Cj 2 alkyl, optionally substituted with:
-a Ce to Cs aryl optionally substituted with a Ci to Cs alkyl or an alkoxy, -an alkylene,
-an alkoxy, -an alkyne, -a halogen, or
-a 5 or 6 membered heterocycle, -a Cβ to Cg aryl, optionally substituted with:
-an alkoxy, -a halogen, or -a Ci to Ce alkyl, or -a 5 or 6 membered heterocycle, and R1 is:
-a hydrogen,
-a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above,
-a haloalkyl, or -a haloalkoxy,
-a -NRvSθ2Rw group, where Rv is: -a hydrogen,
-a -CORx, where Rx is as defined above, or -a Ci to Ce alkyl, optionally substituted with:
-a halogen,
-a -CORx group, where Rx is as defined above,
-a -OCORx group, where Rx is as defined above,
-a hydroxy, or
-an alkoxy, and where Rw is:
-a Ci to C(, alkyl optionally substituted with:
-a halogen,
-a haloalkyl,
-a C& to Cs aryl, or
-a 5 or 6 membered heterocycle, -a C2 to Ce alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl,
-a 5 or 6 membered heterocycle, or
j optionally substituted with a Ci to C6 alkyl, where Ry is a
Ci to C5 alkyl or hydrogen,
where R2 is hydrogen or a Ci to Ce alkyl, optionally substituted with a Cf, to Cg aryl, -a -SRx group, where Rx is as defined above, -a -SO2Ra3 group, where R32 is:
-a Ci to C6 alkyl,
-an amino group,
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -COORx group, where Rx is as defined above,
-a 5 or 6 membered heteroaryl, -a Cs to Cs aryl, and/or -a -NHRbb group, where R1* is:
-a -C(=S)NH2 group, or
-a -PO(ORX)2 group, where Rx is as defined above; = Rco group, where R<;C is:
-a naphthalene,
-a 5 or 6 membered heteroaryl,
-a C6 to Cg aryl, optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halogen,
-a Ci to Ce alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to Ce alkyl(s), -a -NHPORXRX, where Rx is as defined above,
-a -NRccCONRffRff group, where R1x is a hydrogen or a Ci to Ce alkyl, optionally substituted with a halogen, and Rf? is:
-a hydrogen,
-a haloalkyl,
-a haloalkoxy,
-a Ci to Ce alkyl, or
-a -CORx, where Rx is as defined above, -a -NRggCORhh group, where Rhh is:
-a hydrogen,
-a Ci to Cβ alkyl optionally substituted with: -an alkoxy, -a halogen, or
-an amino optionally substituted with one or more Cj to C$ alkyl(s), -an amino optionally substituted with one or more Ci to Cs alkyl(s), where the one or more Ci to Cδ alkyl(s) is/are optionally substituted with a halogen,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and Rgg is:
-a hydrogen, -a Ci to C a alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORx group, where Rx is as defined above,
-a haloalkyl,
-5 or 6 membered heterocycle groups,
-an amino optionally substituted with one or more Ci to Ce alkyl(s), and/or -a -NRnSθ2Rχ group, where Rx is as defined above, and RH is: -a hydrogen,
-a C] to C6 alkyl, -a haloalkyl, -a haloalkoxy,
-a -CORx group, where Rx is as defined above; Z is:
-a Ci to C(, alkyl optionally substituted with: -an alkoxy,
-one or more halogen(s), or -a Cs to Cg aryl; -a C2 to C6 alkylene;
-a Ce to Cs aryl optionally substituted with an alkoxy or one or more Ci to Ce alkyl(s); -a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy;
-a hydrogen; -a hydroxy; -a halogen; -a haloalkyl; -a nitro group;
-a 5 or 6 membered heteroaryl; -a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s),
-a Cs to Cg aryl, or
-a 5 or 6 membered heterocycle; -a Ce to Cs aryl optionally substituted with an alkoxy; -a -CORx group, where Rx is as defined above;
-a Ci to Cg alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or Ri joins together with R2 to form:
R2 is:
-a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
-a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); -an amino group; -an alkoxy group optionally substituted with:
-one or more halogen(s),
-an -OCORx group, where Rx is as defined above,
-a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C6 alkyl,
-a 5 or 6 membered heteroaryl group, or
-a Cβ to Cg aryl group;
-a -COORx group, where Rx is as defined above; -a haloalkyl; -an amide group optionally substituted with:
- a hydroxy group, or
-a Cβ to Cs aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORjj group, where Ry is:
-an alkoxy, or
-an amino optionally substituted with one or more C] to C6 alkyl(s); -a -ORkk group, where Rk^ is a 5 to 6 membered heteroaryl; -a -NHSO2Rx group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is:
-a hydrogen; or
-CH2OCORx, and Rx is as defined above; provided that when X is phenyl substituted with alkoxy, Y is phenyl, R is hydrogen, Ri is a halogen, R2 is hydrogen, and R3 is hydrogen, and provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Rj is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is: -a C 1 to C6 alkyl substituted with: -an alkoxy, -one or more halogen(s), or
-a C6 to C8 aryl; -a C2 to Ce alkylene;
-a Ce to Cg aryl optionally substituted with an alkoxy or one or more C t to C6 alkyl(s); -a -COORx group, where Rx is as defined above; or
or a pharmaceutically acceptable salt thereof.
2. The compound of embodiment 1 , wherein X is a nitro group or a cyano group.
3. The compound of embodiment 1 , wherein X is a cyano group. 4. The compound of embodiment 1, wherein:
Y is a Ce to Cs aryl, optionally substituted with one or more of the following: -an amino optionally substituted with one or more Ci to C& alkyl(s), -a Ci to Ce alkyl group, optionally substituted with a -NHSOaRx group, -a -NR0CORp group, where Rp is: -a Ci to Ce alkyl optionally substituted with:
-a halogen, or -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle, and where R0 is a hydrogen, -a -NRqCONRqRr group, where Rq is:
-a hydrogen, or -a Ci to C6 alkyl, and where Rr is a Ci to Cβ alkyl optionally substituted with one or more of the following: -a halogen,
-an alkylene, or -a C6 to C8 aryl, -a -NRtCOORu group, where Ru is:
-a C] to Ci 2 alkyl, optionally substituted with: -a Ce to Cs aryl optionally substituted with a Ci to C& alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or
-a 5 or 6 membered heterocycle, -a Ce to Cg aryl, optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle, and where Rt is:
-a hydrogen, or -a Ci to Ce alkyl,
-a -N-IvSO2Rw group, where Rv is a hydrogen, and where Rw is a Cj to Cβ alkyl optionally substituted with a halogen;
where R2 is a Ci to C6 alkyl, and/or
-a -NHRbt, group, where Rbb is a -PO(ORX)2 group
5 The compound of embodiment 4, wherein Y is a Ce to C$ aryl substituted with -a -NRqCONRqR1. group,
-a -NR1COOR11 group,
-a -NRVSO2RW group, or
-a -NHRbb group, where Rbb is -a -PO(ORX)2 group.
6 The compound of embodiment 5, wherein the Ce to Cg aryl is phenyl. 7 The compound of embodiment 6, wherein the phenyl is substituted at the para position.
8 The compound of embodiment 7, wherein Y is phenyl substituted with a
-NRqCONRqR- group at the para position.
9. The compound of embodiment 7, wherein Y is phenyl substituted with a -NRiCOORu group at the para position.
10. The compound of embodiment 7, wherein Y is phenyl substituted with a -NRvSOiRw group at the para position.
11. The compound of embodiment 7, wherein Y is phenyl substituted with a -NHPO(ORX)2 group at the para position. 12. The compound of embodiment 1 , wherein Z is:
-a Ci to Cδ alkyl optionally substituted with
-an alkoxy, or
-one or more halogen(s), or -a C2 to Ce alkylene. 13. The compound of embodiment 1, wherein Z is a Ci to Ce alkyl
14. The compound of embodiment 13, wherein Z is a -a C2 to Cs alkyl.
15. The compound of embodiment 14, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl. f 16. The compound of embodiment 1 , wherein R is hydrogen.
17. The compound of embodiment 1 , wherein Rl is: -a hydrogen;
-an alkoxy group optionally substituted with:
-one or more halogen(s),
-a Ce to Cs aryl group, or
-a 5 or 6 membered heterocycle; or Ri joins together with R2 to form:
18. The compound of embodiment 1, wherein R2 is:
-a hydrogen; -a halogen; -a hydroxy group;
-a C] to Cg alkyl group, optionally substituted with one or more halogen(s); -an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s),
-an -OCORx group, where Rx is as defined above,
-a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C& alkyl,
-a 5 or 6 membered heteroaryl group, or
-a Cs to Cg aryl group; -a -COORx group; or R2 joins together with Ri to form:
19. The compound of embodiment 1, wherein: at least one of Ri and R2 is a hydroxy group or an alkoxy group optionally substituted with:
-one or more halogen(s), -a Ce to C8 aryl group, or -a 5 or 6 membered heterocycle group; or
R2 is a -OCORx group, a -ORkk group, or an alkoxy group substituted with: -an -OCORx group,
-a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a Ci to Ce alkyl; or -a 5 or 6 membered heteroaryl group.
20. The compound of embodiment 19, wherein R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C] to Ce alkyl; or -a 5 or 6 membered heteroaryl group.
21. The compound of embodiment 20, wherein R2 is a Ci to C& alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl; or -a 5 or 6 membered heteroaryl group.
22. The compound of embodiment 1, wherein R3 is a hydrogen.
23. The compound of embodiment 1, wherein: X is a cyano group;
Y is a C<5 to Cs aryl substituted with: -a -NRqCONRςRr group,
-a -NR1COORu group, -a -NRvSO2Rw group, or -a -NHPO(ORx)2 group; Z is: -a Ci to Ce alkyl optionally substituted with -an alkoxy, or -one or more halogen(s), or -a C2 to Cg alkylene; R is hydrogen; at least one of Rj and R2 is a hydroxy group or an alkoxy group optionally substituted with:
-one or more halogen(s),
-a Ce to Cs aryl group, or -a 5 or 6 membered heterocycle group; or
R2 is a -OCORx group, a -ORkk group, or an alkoxy group substituted with.:
-an -OCORx group,
-a dialkyl-amino optionally substituted with an alkoxy,
-a 5 or 6 membered heterocycle group substituted with a C] to C6 alkyl; or -a 5 or 6 membered heteroaryl group; and
R3 is hydrogen.
24. The compound of embodiment 23, wherein Y is a phenyl substituted with a -NRqCONRqRr group.
25. The compound of embodiment 24, wherein: Z is a C1 to C6 alkyl; and
R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to C& alkyl; or -a 5 or 6 membered heteroaryl group.
26. The compound of embodiment 23, wherein Y is a phenyl substituted with a - NR1COORu group.
27. The compound of embodiment 26, wherein: Z is a C] to C6 alkyl; and
R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group.
28. The compound of embodiment 23, wherein Y is a phenyl substituted with a - NRvSO2Rw group.
29. The compound of embodiment 28, wherein: Z is a Cj to Cg alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C] to C6 alkyl; or -a 5 or 6 membered heteroaryl group. 30. The compound of embodiment 23, wherein Y is -a -NHPO(ORX)2 group.
31. The compound of embodiment 30, wherein: Z is a Cj to CO alkyl; and
R2 is an alkoxy group optionally substituted with: -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C6 alkyl; or
-a 5 or 6 membered heteroaryl group.
32. The compound of embodiment 1 , wherein: X is:
-a cyano group; or -a foπnyl group;
Y is:
-a 5 or 6 membered heteroaryl, optionally substituted with a C6 to Cs aryl, optionally substituted with -COORx, where Rx is as defined above; -a Cs to Cs aryl, optionally substituted with one or more of the following: -a Ci to Ce alkyl group;
-an amino optionally substituted with one or more C] to C6 alkyl(s); -a halogen; -a hydroxy;
-a -CORn, group, where Rn, is: -an amino optionally substituted with one or more Cj to Ce alkyl(s); -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with an alkoxy; and where R0 is: -a hydrogen;
-a -NRqCONRqRr group, where Rq is hydrogen and where Rr is:
-a Ci to C6 alkyl; -a -NRtCOORu group, where R, is hydrogen, and where Rn is:
-a Ci to Cj2 alkyl, optionally substituted with: -a C6 to C8 aryl;
-a halogen; or
-a 5 or 6 membered heterocycle; -a -NRvSO2Rw group, where Rv is hydrogen and where Rw is:
-a Ci to C6 alkyl; or -an alkyl- or dialkyl-amino;
where R2 is hydrogen or a Ci to Cg alkyl;
-a -SC>2Raa group* where R33 is: -an amino group; or -an alkyl or dialkyl amino group; -a -NHRbb group, where Rbb is: -a -PO(ORX)2 group, where Rx is as defined above;
Z is:
-a Ci to CO alky; or
-a -COORx group, where Rx is as defined above; R is a hydrogen, Ri is:
-a hydrogen;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s); or -a 5 or 6 membered heterocycle;
R2 is:
-a hydrogen; -a hydroxy group;
-a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); -an alkoxy group optionally substituted with: -one or more halogen(s);
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to C6 alkyl; or
-a 5 or 6 membered heteroaryl group; -a -COORx group, where Rx is as defined above;
-an amide group; -a 5 or 6 membered heteroaryl; or
-a -ORkk group, where Rtk is a 5 to 6 membered heteroaryl; R3 is a hydrogen. 33. The compound of embodiment 32, wherein:
X is a cyano group;
Y is:
-a CO to Cg aryl substituted with one or more of the folio wing:
-an amino optionally substituted with one or more Ci to Cs alkyl(s); -a -NRqCONRqRr group, where R, is hydrogen and where Rr is:
-a Ci to C6 alkyl;
-a -NRtCOORu group, where Rt is hydrogen, and where R11 is: -a C] to Ci2 alkyl, optionally substituted with:
-a C6 to C8 aryl; -a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is:
-a Ci to C6 alkyl; Z is a C] to C6 alky; R is a hydrogen, Ri is a hydrogen; R2 is:
-an alkoxy group optionally substituted with: -one or more halogen(s);
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to C6 alkyl; or -a 5 or 6 membered heteroaryl group; or
R3 is a hydrogen.
34. The compound of embodiment 32, wherein: X is a cyano group;
Y is: -a Cβ to Cs aryl substituted with one or more of the following: -a Ci to C6 alkyl group;
-an amino optionally substituted with one or more Ci to C6 alkyl(s); -a halogen; -a -NRtCOORu group, where Rt is hydrogen, and where R11 is:
-a Ci to C 12 alkyl;
-a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is: -a Ci to Ce alkyl; or -an alkyl- or dialkyl-amino; Z is a Ci to Ce alky; R is a hydrogen; Ri is -a hydrogen;
R2 is a -ORkic group, where R1& is a 5 to 6 membered heteroaryl; R.3 is a hydrogen. 35. The compound of embodiment 32, wherein:
X is:
-a cyano group; Y is:
-a Ce to Cg aryl substituted with one or more of the following: -a Ci to C6 alkyl;
-a halogen; -a -NRtCOORu group, where Rt is hydrogen, and where Ru is:
-a Ci to C]2 alkyl;
-a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is: -a Ci to C6 alkyl; or
-an alkyl- or dialkyl-amino; or -a -NRqCONRqRr group, where Rq is hydrogen and where Rr is:
-a Ci to C6 alkyl; Z is: -a C1 to C6 alkyl;
R is:
-a hydrogen,
-a hydrogen; R2 is:
-an alkoxy group optionally substituted with:
-one or more halogen(s); -an amide; -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; or
-a 5 or 6 membered heteroaryl; R3 is:
-a hydrogen.
36. The compound of embodiment 35, wherein: X is:
-a cyano group;
Y is:
-a Ce to Cg aryl substituted with one or more of the following:
-a halogen; -a -NR,COORU group, where Rt is hydrogen, and where Ru is:
-a C] to Ci2 alkyl; or -a -NRvSO2Rw group, where Rv is hydrogen and where Rw is:
-a Ci to C6 aljkyl; Z is: -a C, to C6 alkyl;
R is:
-a hydrogen,
-a hydrogen; R2 is:
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; R3 is:
-a hydrogen.
37. The compound of embodiment 36, wherein the C6 to Cs aryl is phenyl. 38. The compound of embodiment 37, wherein the phenyl is substituted at the para position.
39. The compound of embodiment 38, wherein:
Y is: -a phenyl substituted with a -NRtCOOR1, group, where R, is hydrogen, and where Ru is:a C] to C12 alkyl.
40. The compound of embodiment 38, wherein: Y is: -a phenyl substituted with a halogen and a -NRtCOORu group, where Rt is hydrogen, and where Ru is Ci to C12 alkyl.
41. The compound of embodiment 38 , wherein: Y is:
-a phenyl substituted with a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is Ci to C6 alkyl.
42. The compound of embodiment 38, wherein: Y is:
-a phenyl substituted with a Ci to Ce alkyl and a -NRtCOORu group, where Rt is hydrogen, and where Ru is:a Ci to Cj2 alkyl. 43. The compound of embodiment 35, wherein:
X is:
-a cyano group; Y is:
-a Ce to Cs aryl substituted with -NRtCOORu group, where R, is hydrogen, and where Ru is a C1 to Ci 2 alkyl. Z is:
-a Ci to Ce alkyl; R is:
-a hydrogen; R1 is:
-a hydrogen; R2 is:
-an alkoxy group optionally substituted with:
-one or more halogen(s); R3 is:
-a hydrogen.
44. The compound of embodiment 35, wherein R2 is: an alkoxy group substituted with one or more halogens. 45. The compound of embodiment 43, wherein the Cs to Cg aryl is phenyl.
46. The compound of embodiment 45, wherein the phenyl is substituted at the para position.
47. The compound of embodiment 35, wherein: X is:
-a cyano group;
Y is:
-a Cβ to Cg aryl substituted with one or more of the following:
-a -NRtCOORu group, where R, is hydrogen, and where Ru is: -a Ci to Q2 alkyl;
-a -NRqCONRqRr group, where Rq is hydrogen and where Rr is:
-a Ci to C6 alkyl; Z is:
-a Ci to C6 alkyl; R is:
-a hydrogen,
-a hydrogen; R2 is: -a 5 or 6 membered heteroaryl;
R3 is: r
-a hydrogen.
48. The compound of embodiment 47, wherein the Cg to Cg aryl is phenyl.
49. The compound of embodiment 48, wherein the phenyl is substituted at the para position.
50. The compound of embodiment 49, wherein:
Y is:
-a phenyl substituted with a -NRtCOORα group, where Rt is hydrogen, and where R1, is:a Ci to Cn alkyl. 51. The compound of embodiment 49, wherein:
Y is: -a Cδ to Cz aryl substituted with -a NRqCONRqRr group, where Rq is hydrogen and where Rr is a Ci to C^ alkyl.
52. The compound of embodiment 35, wherein: X is: -a cyano group;
Y is:
-a Ce to Cs aryl substituted with a -NRtCOORu group, where Rt is hydrogen, and where Ru is a Ci to Ci2 alkyl; Z is: -a C, to C6 alkyl;
R is:
-a hydrogen, Ri is:
-a hydrogen; R2 is:
-a amide; R3 is:
-a hydrogen.
53. The compound of embodiment 52, wherein the Ce to Cg aryl is phenyl. 54. The compound of embodiment 53, wherein the phenyl is substituted at the para position.
55. The compound of embodiment 35, wherein R2 is: an alkoxy group substituted with one or more halogen(s).
56. The compound of embodiment 35, wherein R2 is: a -ORuc group, where R^c is a 5 to 6 membered heteroaryl.
57. The compound of embodiment 32, wherein X is:
-a formyl group;
Y is: -a Cg to Cg aryl substituted with one or more of the following:
-a -NRtCOORu group, where Rt is hydrogen, and where Ru is: -a Ci to Ci2 alkyl; -a -NRqCONRqRr group, where Rq is hydrogen and where R1- is:
-a Ci to C6 alkyl; Z is:
-a C1 to C6 alky; R is:
-a hydrogen; R] is:
-a hydrogen; R2 is: -an alkoxy group;
R3 is:
-a hydrogen.
58. The compound of embodiment 32, wherein: X is: -a cyano group;
Y is:
-a Ce to Cs aryl substituted with one or more of the following: -a Ci to Cg alkyl group; -a halogen; -a -NRtCOORu group, where Rt is hydrogen, and where R11 is:
-a Ci to Ci2 alkyl, optionally substituted with:
-a Ce to C8 aryl;
-a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is: -a Ci to Ce alkyl; or -an alkyl- or dialkyl-amino;
Z is:
-a Ci to C6 alky; R is: -a hydrogen; Ri is:
-a hydrogen; R2 is:
-an alkoxy group substituted with one or more halogen(s); R3 is:
-a hydrogen.
59. The compound of embodiment 32, wherein: X is:
-a cyano group; Y is:
-a Cβ to Cg aryl, optionally substituted with one or more of the following: -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with an alkoxy; and where R0 is: -a hydrogen;
Z is:
-a Ci to Ce alky; R is:
-a hydrogen; R1 is:
-a hydrogen; R2 is:
-an alkoxy group substituted with a 5 or 6 membered heteroaryl group; R3 is: -a hydrogen.
60. The compound of embodiment 32, wherein: X is:
-a cyano group; Y is: -a Ce to Cg aryl, optionally substituted with one or more of the following:
-a Ci to Cβ alkyl group;
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -a halogen;
-a -NR0CORp group, where Rp is: -a C] to C6 alkyl; and where R0 is:
-a hydrogen;
-a -NR^CONRqR1. group, where R41 is hydrogen and where R1 is: -a Ci to C6 alkyl;
-a -NRtCOORu group, where Rt is hydrogen, and where R11 is:
-a Ci to Ci2 alkyl; -a -NRvSO2Rw group, where Rv is hydrogen and where Rw is:
-a C1 to C6 alkyl; -a -NHRbb group, where Rbb is:
-a -PO(ORX)2 group, where Rx is as defined above; Z is:
-a Ci to C5 alky; R is: -ahydrogen, Ri is:
-ahydrogen; R2 is:
-a 5 or 6 membered heteroaryl; R3 is:
-a hydrogen.
61. The compound of embodiment 32, wherein: X is:
-a cyano group; Y is:
-a Ce to Cg aryl, optionally substituted with one or more of the following: -an amino optionally substituted with one or more Cj to Cg alkyl(s); -a -NRqCONRqRr group, where Rq is hydrogen and where Rr is:
-a Ci to C6 alkyl; -a -NRtCOORu group, where Rt is hydrogen, and where Ru is:
-a Ci to C 12 alkyl, optionally substituted with: -a C6 to Cg aryl; or -a 5 or 6 membered heterocycle;
-a -NRvSOaRw group, where Rv is hydrogen and where Rw is: -a Ci to C6 alkyl;
where Rz is hydrogen or a Ci to Ce alkyl; Z is:
-a Ci to C6 alky; R is:
-a hydrogen, Ri is: -a 5 or 6 membered heterocycle;
-an alkoxy substituted with:
-one or more halogen(s); or -a 5 or 6 membered heterocycle; R2 is: -a hydrogen;
R3 is:
-a hydrogen.
62. The compound of embodiment 61 , wherein R1 is a 5 or 6 membered heterocycle. 63. The compound of embodiment 61, wherein Ri is an alkoxy substitued with one or more halogen.
64. The compound of embodiment 61, wherein" Y is:
-a Ce to Cg aryl substituted with : -a -NRtCOORu group, where Rt is hydrogen, and where R11 is:
-a Ci to Ci2 alkyl, optionally substituted with: -a Ce to Cg aryl; or -a 5 or 6 membered heterocycle; Ri is:
-an alkoxy substitued with one or more halogen. 65. A compound of formula IHa
wherein: X is:
-hydrogen; Y is:
-a C6 to Cg aryl, optionally substituted with one or more of the following: -a -NRqCONRqRr group, where Rq is hydrogen and where Rr is:
-a Ci to C6 alkyl;
-a -NRtCOORu group, where Rt is hydrogen, and where Ru is: -a Ci to Ci2 alkyl;
-a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is:
-a Ci to C6 alkyl; Z is:
-a Ci to C6 alky; R is:
-a hydrogen,
-a hydrogen; R2 is:
-an alkoxy group optionally substituted with:
-one or more halogen(s); or
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; R3 Ϊs: -a hydrogen.
66. The compound of embodiment 65, wherein:
X is:
-hydrogen; Y is:
-a Ce to Cg aryl substituted with a -NRtCOORu group, where Rt is hydrogen, and where Ru is a Ci to Ci2 alkyl; Z is:
-a Ci to Ce alkyl; R is:
-a hydrogen, Ri is:
-a hydrogen; R2 is: -a -ORfck group, where Rkk is a 5 to 6 membered heteroaryl;
R3 is:
-a hydrogen.
67. The compound of embodiment 65, wherein the Cg to Cg aryl is phenyl.
68. The compound of embodiment 65, wherein the phenyl is substituted at the para position.
69. A pharmaceutical composition comprising: (i) a compound of formula I
wherein: X is:
-a nitro group; -a cyano group; -a -COR3 group, where Ra is:
-a Ci to C6 alkyl,
-a Cβ to Cg aryl optionally substituted with an alkoxy or a halogen, or
-a dialkyl-amino; -a -COORx group, where Rx is a Ci to Ce alkyl; -a formyl group;
-a CO to Cs aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl, -a Cs to Cg aryl optionally substituted with an alkoxy or one or more halogen(s), or
-a 5 to 6 membered heteroaryl; Y is:
-a haloalkyl; -a halogen; -an amino optionally substituted with one or more Ci to Cβ alkyl(s); -a benzofiiran; -a benzothiophene; -a dibenzofuran; -a dibenzothiophene; -a benzothiazole; -a naphthalene; -an indole, optionally substituted on the nitrogen with a C] to Ce alkyl;
where Rt, is a hydrogen or a Ci to Ce alkyl, and n is 0 or 1 ;
, where R0 is a hydrogen, a -CONHRx, where Rx is as defined above, or an -SChRx, where Rx is as defined above; or
Ci to C6 alkyl or a Ce to Cs aryl; -a -NHCORe group, where R- is: -a Ci to C6 alkyl;
-a C6 to Cs aryl optionally substituted with: -a Ci to C5 alkyl, -an alkoxy, -a cyano group, -a nitro group, or
-a halogen;
-a -NHCOORx group, where Rx is as defined above; -a -CH2O-Rf group, where Rf is a C6 to C8 aryl;
-a -NRgRh group, where Rg is a Ct to C6 alkyl or a hydrogen and Rh is a Cg to Cg aryl optionally substituted with an alkoxy; -a Ci to C6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
-a Cj to C6 alkyl, optionally substituted with a C6 to Cs aryl,
-a Ce to Cs aryl, optionally substituted with -COORx, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above, or -a -NHCOORx group, where Rx is as defined above; -a C6 to Cs aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy,
-one or more halogen(s),
-a 5 or 6 membered heterocycle, optionally substituted with:
-a Cj to Cg alkyl, or -a hydroxy,
-an amino group optionally substituted with one or more Ci to Cg alkyl(s), -a -NRJSO2RX group, where Rx is as defined above and Ri is: -a hydrogen, -a Ci to C6 alkyl, -a -CORx group, where Rx is as defined above,
-a haloalkyl, or -a haloalkoxy, -a -NRjCORk group, where Rk is:
-a Ci to Ce alkyl, -a hydrogen, or
-an amino optionally substituted with one or more Ci to Ce alkyl(s), and Rj is:
-a hydrogen, -a Ci to C6 alkyl, - a -CORx group, where Rx is as defined above,
-a haloalkyl, or -a haloalkoxy, -a -N=N+=N" group, or
-a -CORi, where Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
-an amino optionally substituted with one or more Ci to Ce alkyl(s),
-a nitro group,
-a Ci to Ce alkyl group, optionally substituted with:
-a -NHSO2RX group, where Rx is as defined above, or -a -NRxSOzRx group, where Rx is as defined above,
-a haloalkoxy, -a halogen, -a hydroxy, -a -COORx group, where Rx is as defined above, -a -CORn, group, where Rm is:
-an amino optionally substituted with one or more C1 to C6 alkyl(s), where the Ci to Ce alkyls are optionally substituted with: -a hydroxy
-a 5 or 6 membered heterocycle,
-an amino optionally substituted with one or more Ci to Ce alkyl(s), -an alkoxy,
-a 3 to 7 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a dialkyl-amino, -a -NHRn group, where Rn is: -a -CH2CONH2, or
-a Ce to Cs aryl optionally substituted with: -an alkyl,
-one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with: -a halogen, -an alkoxy, or -a Ce to C8 aryl,
-a 5 or 6 membered heterocycle, -a CO to C% aryl, optionally substituted with a halogen,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyl(s), -a hydrogen,
and where R0 is:
-a hydrogen,
-a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRqCONRqRn group, where Rq is:
-a hydrogen, -a Ci to C6 alkyl,
-a haloalkyl, -a haloalkoxy, or
-a -CORx group, where Rx is as defined above, and where Rr is: -a Cδ to Cs aryl optionally substituted with:
-a Ci to C6 alkyl, -a haloalkyl,
-a -OR5 group, where Rs is a Ce to Cs aryl, or -a -COORx group, where Rx is as defined above,
-a Ci to Ce alkyl optionally substituted with one or more of the following: -a halogen, -an alkyiene, -a Cg to Cg aryl, and/or -a -COORx group, where Rx is as defined above,
-a -COORx group, where Rx is as defined above, -a -NRtCOORu group, where Ru is:
-a Ci to Cn alkyl, optionally substituted with:
-a Cs to Cs aryl optionally substituted with a Ci to C6 alkyl or an alkoxy, -an alkyiene,
-an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a Ce to Cs aryl, optionally substituted with: -an alkoxy, -a halogen, or -a Ci to Cf, alkyl, or -a 5 or 6 membered heterocycle, and R1 is:
-a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or
-a haloalkoxy,
-a -NRySChRw group, where Rv is: -a hydrogen,
-a -CORx, where Rx is as defined above, or -a Ci to Ce alkyl, optionally substituted with:
-a halogen,
-a -CORx group, where Rx is as defined above, -a -OCORx group, where Rx is as defined above, -a hydroxy, or -an alkoxy, and where Rw is:
-a Ci to Ce alkyl optionally substituted with: -a halogen, -a haloalkyl, -a C6 to C8 aryl, or
-a 5 or 6 membered heterocycle, -a C2 to Ce alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl, -a 5 or 6 membered heterocycle, or , optionally substituted with a Ci to Cs alkyl, where Ry is a
Ci to Ce alkyl or hydrogen,
where R2 is hydrogen or a Ci to Ce alkyl, optionally substituted with a Ce to C8 aryl, -a -SRx group, where Rx is as defined above, -a -SChRaa group, where R33 is:
-a Ci to C6 alkyl,
-an amino group,
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -COORx group, where Rx is as defined above,
-a 5 or 6 membered heteroaryl, -a Ce to Cg aryl, and/or -a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or
-a -PO(ORX)2 group, where Rx is as defined above; = Rcc group, where R00 is:
-a naphthalene,
-a 5 or 6 membered heteroaryl,
-a Ce to Cs aryl, optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halogen,
-a Ci to Cs alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to C$ alkyl(s), -a -NHPORxRx, where Rx is as defined above,
-a -NReeCONRffRff group, where Rce is a hydrogen or a Ci to Q alkyl, optionally substituted with a halogen, and Rfr is: -a hydrogen, -a halo alkyl, -a haloalkoxy,
-a C) to Ce alkyl, or
-a -CORx, where Rx is as defined above, -a -NRggCORhh group, where Rhh is:
-a hydrogen, -a Ci to C(, alkyl optionally substituted with:
-an alkoxy, -a halogen, or
-an amino optionally substituted with one or more C1 to Ce alkyl(s), -an amino optionally substituted with one or more Ci to Cβ alkyl(s), where the alkyls are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and Rgg is: -a hydrogen,
-a Ci to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or
-a -CORx group, where Rx is as defined above, -a haloalkyl,
-5 or 6 membered heterocycle groups,
-an amino optionally substituted with one or more Ci to Cs alkyl(s), and/or -a -NR11SOiRx group, where Rx is as defined above, and Rn is: -a hydrogen, -a Ci to C6 alkyl, -a haloalkyl, -a haloalkoxy,
-a -CORx group, where Rx is as defined above; Z is:
-a Ci to Ce alkyl optionally substituted with: -an alkoxy,
-one or more halogen(s), or -a Ce to Cg aryl; -a C2 to C6 alkylene;
-a Cs to Cs aryl optionally substituted with an alkoxy or one or more Ci to C6 alkyl(s); -a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy; Ri is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl; -a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl, or
-a 5 or 6 membered heterocycle;
-a C6 to Cs aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above;
-a Ci to Cβ alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or Ri joins together with R2 to form:
R2 is:
-a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
-a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); -an amino group; -an alkoxy group optionally substituted with:
-one or more halogen(s),
-an -OCORx group, where Rx is as defined above,
-a dialkyl-amino optionally substituted with an alkoxy,
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Cs alkyl, -a 5 or 6 membered heteroaryl group, or
-a Ce to Ci aryl group;
-a -COORx group, where Rx is as defined above; -a haloalkyl;
-an amide group optionally substituted with: - a hydroxy group, or
-a Ce to Cg aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORj, group, where Rjj is: -an alkoxy, or
-an amino optionally substituted with one or more C\ to Cg alkyl(s); -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; -a -NHSOiRx group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is:
-a hydrogen; or
-CHaOCORx, and Rx is as defined above; provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Ri is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is:
-a Ci to CO alkyl substituted with:
-an alkoxy,
-one or more halogen(s), or
-a C6 to C8 aryl; -a C2 to Ce alkylene;
-a Ce to Cs aryl optionally substituted with an alkoxy or one or more Ci to Ce alkyl(s); -a -COORx group, where Rx is as defined above; or
or one or more pharmaceutically acceptable salt(s) thereof; and (ii) one or more pharmaceutically acceptable excipient(s).
70. A method for treating an infection by a virus in a subject in need thereof, wherein the virus contains an internal ribosome entry site (IRES), comprising administering to the subject one or more compound(s) of formula I or a pharmaceutical composition comprising one or more comρound(s) of formula I wherein: X is:
-a nitro group; -a cyano group;
-a -CORa group, where Ra is: -a Ci to C6 alkyl,
-a C6 to Cs aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino; -a -COORx group, where Rx is a Ci to C6 alkyl; -a formyl group;
-a C6 to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s), or
-a 5 to 6 membered heteroaryl; Y is:
-a haloalkyl; -a halogen; -an amino optionally substituted with one or more Ci to C6 alkyl(s); -a benzofuran; -a benzothiophene; -a dibenzofuran; -a dibenzothiophene; -a benzothiazole; -a naphthalene; -an indole, optionally substituted on the nitrogen with a Ci to C6 alkyl;
where Rb is a hydrogen or a Ci to Ce alkyl, and n is 0 or 1 ;
, where Rc is a hydrogen, a -CONHRx, where Rx is as defined above, or an -SOaRx, where Rx is as defined above; or
, where Rd is a Ci to C6 alkyl or a C6 to Cg aryl; -a -NHCORe group, where Re is: -a Ci to C6 alkyl; -a Ce to Cs aryl optionally substituted with:
-a Ci to C6 alky], -an alkoxy, -a cyano group, -a nitro group, or -a halogen; -a -NHCOORx group, where Rx is as defined above; -a -CH2O-Rf group, where Rf is a C6 to Cs aryl; -a -NRgRi, group, where Rg is a Ci to Ce alkyl or a hydrogen and Rh is a C6 to Cg aryl optionally substituted with an alkoxy; -a Ci to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with: -a Ci to Ce alkyl, optionally substituted with a C6 to C8 aryl,
-a C6 to Cs aryl, optionally substituted with -COORx, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above, or -a -NHCOORx group, where Rx is as defined above;
-a C6 to C8 aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with: -an alkoxy, -a hydroxy, -one or more halogen(s),
-a 5 or 6 membered heterocycle, optionally substituted with: -a C] to C6 alkyl, or -a hydroxy,
-an amino group optionally substituted with one or more Ci to C6 alkyl(s), -a -NRjSθ2Rx group, where Rx is as defined above and Ri is:
-a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy,
-a -NRjCORk group, where Rk is: -a CJ to C6 alkyl, -a hydrogen, or
-an amino optionally substituted with one or more Ci to C6 alkyl(s), and R1- is:
-a hydrogen,
-a Ci to C6 alkyl,
- a -CORx group, where Rx is as defined above,
-a haloalkyl, or -a haloalkoxy, -a -N=N+=N" group, or
-a -CORi, where Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more Ci to Cs alkyl(s),
-a nitro group, -a Ci to Ce alkyl group, optionally substituted with:
-a -NHSC^Rx group, where Rx is as defined above, or -a -NRxSOaRx group, where Rx is as defined above, -a haloalkoxy,
-a halogen, -a hydroxy,
-a -COORx group, where Rx is as defined above, -a -CORm group, where Rm is: -an amino optionally substituted with one or more Ci to Cδ alkyl(s), where the one or more Cj to Ce alkyl(s) is/are optionally substituted with: -a hydroxy
-a 5 or 6 membered heterocycle,
-an amino optionally substituted with one or more Ci to Ce alkyls, and/or -an alkoxy,
-a 3 to 7 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a dialkyl-amino, -a -NHRn group, where Rn is:
-a -CH2CONH2, or -a Cβ to Cs aryl optionally substituted with:
-an alkyl,
-one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with: -a halogen, -an alkoxy, or -a Ce to Cg aryl, -a 5 or 6 membered heterocycle,
-a CU to Cs aryl, optionally substituted with a halogen,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyl(s),
-a hydrogen,
and where R0 is:
-a hydrogen,
-a C, to C6 alkyl,
-a -CORx group, where Rx is as defined above,
-a haloalkyl, or
-a haloalkoxy, -a -NRqCONRqRr group, where Rq is:
-a hydrogen,
-a Ci to C6 alkyl,
-a haloalkyl,
-a haloalkoxy, or
-a -CORx group, where Rx is as defined above, and where Rr is:
-a C6 to Cg aryl optionally substituted with:
-a Ci to C6 alkyl, -a haloalkyl,
-a -ORs group, where Rs is a Ce to Cs aryl, or -a -COORx group, where Rx is as defined above, -a Ci to C6 alkyl optionally substituted with one or more of the following: -a halogen, -an alkylene, -a Ce to Cs aryl, and/or
-a -COORx group, where Rx is as defined above, -a -COORx group, where Rx is as defined above,
-a -NR(COORu group, where R11 is:
-a Ci to Ca alkyl, optionally substituted with:
-a Ce to Cg aryl optionally substituted with a C] to Cή alkyl or an alkoxy, -an alkylene, -an alkoxy,
-an alkyne, -a halogen, or
-a 5 or 6 membered heterocycle, -a Ce to Cs aryl, optionally substituted with: -an alkoxy,
-a halogen, or -a Ci to Ce alkyl, or -a 5 or 6 membered heterocycle, and Rt is: -a hydrogen,
-a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRvSθ2Rw group, where Rv is:
-a hydrogen,
-a -CORx, where Rx is as defined above, or -a Ci to Ce alkyl, optionally substituted with:
-a halogen, -a -CORx group, where Rx is as defined above,
-a -OCORx group, where Rx is as defined above, -a hydroxy, or -an alkoxy, and where Rw is: -a Ci to Cβ alkyl optionally substituted with:
-a halogen,
-a haloalkyi,
-a Cg to Cs aryl, or
-a 5 or 6 membered heterocycle, -a C2 to Ce alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl,
-a 5 or 6 membered heterocycle, or
-a , optionally substituted with a Ci to C$ alkyl, where Ry is a
Ci to CO alkyl or hydrogen,
where R2 is hydrogen or a Ci to Ce alkyl, optionally substituted with a Ce to Cg aryl, -a -SRx group, where Rx is as defined above, -a -SO2Raa group, where R23 is:
-a Ci to C6 alkyl,
-an amino group,
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -COORx group, where Rx is as defined above,
-a 5 or 6 membered heteroaryl, -a Ce to C8 aryl, and/or -a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or
-a -PO(ORX)2 group, where Rx is as defined above; == Rcc group, where Rc0 is: -a naphthalene,
-a 5 or 6 membered heteroaryl,
-a Cg to Cs aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy,
-a halogen,
-a C| to CO alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to C& alkyl(s), -a -NHPORxRx, where Rx is as defined above, -a -NReeCONRffRfr group, where Ree is a hydrogen or a Ci to C^ alkyl, optionally substituted with a halogen, and Rff is: -a hydrogen, -a haloalkyl, -a haloalkoxy, -a C1 to C6 alkyl, or
-a -CORx, where Rx is as defined above, -a -NRggCORhh group, where Rhh is: -a hydrogen,
-a Ci to Ce alkyl optionally substituted with: -an alkoxy,
-a halogen, or
-an amino optionally substituted with one or more Ci to Ce alkyl(s), -an amino optionally substituted with one or more Cj to Ce alkyl(s), where the alkyls are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and Rgg is:
-a hydrogen, -a Ci to Cs alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORx group, where Rx is as defined above,
-a haloalkyl,
-5 or 6 membered heterocycle groups,
-an amino optionally substituted with one or more Cj to C6 alkyl(s), and/or -a -NRϋSθ2Rx group, where Rx is as defined above, and RU is: -a hydrogen,
-a Ci to C6 alkyl, -a haloalkyl, -a haloalkoxy,
-a -CORx group, where Rx is as defined above; Z is:
-a Ci to Ce alkyl optionally substituted with: -an alkoxy,
-one or more halogen(s), or -a Cs to Cg aryl; -a C2 to C6 alkylene;
-a Cs to Ci aryl optionally substituted with an. alkoxy or one or more Ci to Ce alkyl(s); -a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy; Ri is: -a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl; -a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl, or
-a 5 or 6 membered heterocycle;
-a Ce to Cs aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above;
-a Ci to Cβ alkyl optionally substituted with a diaUcyl-amino or a 5 or 6 membered heterocycle; or
Ri joins together with R2 to form:
R2 is:
-a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
-a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); -an amino group; -an alkoxy group optionally substituted with: -one or more halogen(s),
-an -OCORx group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy,
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl, -a 5 or 6 membered heteroaryl group, or
-a Ce to Cs aryl group; -a -COORx group, where Rx is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or
-a C6 to C8 aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORjj group, where Rjj is:
-an alkoxy, or
-an amino optionally substituted with one or more Ci to C* alkyl(s); -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; -a -NHSO2Rx group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is:
-a hydrogen; or
-CHaOCORx, and Rx is as defined above; or one or more pharmaceutically acceptable salt(s) thereof.
71. A method for treating a Hepatitis C viral (HCV) infection in a subject in need thereof, comprising administering to the subject one or more compound(s) of formula I or a pharmaceutical composition comprising one or more compound(s) of formula I
wherein:
X is:
-a nitro group; -a cyano group; -a -CORa group, where Ra is: -a Ci to C6 alkyl,
-a C6 to Cs aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COORx group, where Rx is a Ci to Cs alkyl; -a formyl group;
-a C6 to Cs aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with: -a Ci to C6 alkyl,
-a C6 to C% aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl; Y is:
-a haloalkyl; -a halogen;
-an amino optionally substituted with one or more C] to C6 alkyl(s); -a benzofuran; -a benzothiophene; -a dibenzofuran; -a dibenzothiophene; -a benzothiazole; -a naphthalene; -an indole, optionally substituted on the nitrogen with a Ci to C6 alkyl;
Rb , where Rb is a hydrogen or a Ci to C6 alkyl, and n is 0 or 1; , where R0 is a hydrogen, a -CONHRx, where Rx is as defined above, or an -S ChRx, where Rx is as defined above; or
where Ra is a Ci to CO alkyl or a Ce to Cg aryl; -a -NHCORc group, where R8 is: -a Ci to Ce alkyl;
-a Cg to Cs aryl optionally substituted with: -a Ci to C6 alkyl, -an alkoxy, -a cyano group,
-a nitro group, or -a halogen;
-a -NHCOORx group, where Rx is as defined above; -a -CH2O-Rf group, where Rf is a C6 to C8 aryl; -a -NRgRh group, where Rg is a C) to Cg alkyl or a hydrogen and Rh is a Ce to Cg aryl optionally substituted with an alkoxy; -a Ci to C6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
-a Ci to Ce alkyl, optionally substituted with a Cβ to Cg aryl, -a C6 to Cs aryl, optionally substituted with -COORx, where Rx is as defined above, or
-an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above, or -a -NHCOORx group, where Rx is as defined above; -a Ce to C8 aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with: -an alkoxy, -a hydroxy, -one or more halogen(s),
-a 5 or 6 membered heterocycle, optionally substituted with: -a Ci to Ce alkyl, or -a hydroxy,
-an amino group optionally substituted with one or more Cj to Cg alkyl(s), -a -NR1SO2Rx group, where Rx is as defined above and Rj is:
-a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy,
-a -NRjCORk group, where Rk is: -a Ci to C6 alkyl, -a hydrogen, or
-an amino optionally substituted with one or more Q to Ce alkyl(s), and Rj is:
-a hydrogen, -a C1 to C6 alkyl,
- a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy,
-a -N=N+=N' group, or
-a -CORi, where Rj is a 5 or 6 membered heterocycle optionally substituted with a hydroxy,
-an amino optionally substituted with one or more Ci to Ce alkyl(s), -a nitro group,
-a Ci to Ce alkyl group, optionally substituted with:
-a -NHSO2RX group, where Rx is as defined above, or -a -NRxSθ2Rx group, where Rx is as defined above, -a haloalkoxy, -a halogen,
-a hydroxy,
-a -COORx group, where Rx is as defined above,
-a -CORm group, where Rm is:
-an amino optionally substituted with one or more Ci to Ce alkyl(s), where the one or more Ci to Ce alkyl(s) is/are optionally substituted with: -a hydroxy
-a 5 or 6 membered heterocycle,
-an amino optionally substituted with one or more Ci to Cg alkyl(s), -an alkoxy,
-a 3 to 7 membered heterocycle, optionally substituted with a C] to Cβ alkyl, optionally substituted with a dialkyl-amino, -a -NHRn group, where Rn is: -a -CH2CONH2, or
-a Cs to Cs aryl optionally substituted with: -an alkyl,
-one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NR0CORp group, where Rp is:
-a Ci to Cs alkyl optionally substituted with: -a halogen, -an alkoxy, or -a Ce to Cg aryl,
-a 5 or 6 membered heterocycle, -a Cs to Cs aryl, optionally substituted with a halogen,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyl(s), -a hydrogen,
and where R0 is: -a hydrogen,
-a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above,
-a haloalkyl, or -a haloalkoxy,
-a -NRqCONRqRr group, where Rq is:
-a hydrogen,
-a Ci to C6 alky],
-a haloalkyl, -a haloalkoxy, or
-a -CORx group, where Rx is as defined above, and where Rr is:
-a Ce to Cs aryl optionally substituted with:
-a Ci to C6 alkyl,
-a haloalkyl,
-a -OR5 group, where R5 is a Cg to Cg aryl, or
-a -COORx group, where Rx is as defined above,
-a Ci to Ce alkyl optionally substituted with one or more of the following: -a halogen,
-an alkylene,
-a Ce to Cs aryl, and/or
-a -COORx group, where Rx is as defined above, -a -COORx group, where Rx is as defined above, -a -NRtCOORu group, where Ru is:
-a Ci to Cn alkyl, optionally substituted with:
-a Ce to C8 aryl optionally substituted with a Cj to Ce aUcyl or an alkoxy,
-an alkylene,
-an alkoxy, -an alkyne, -a halogen, or
-a 5 or 6 membered heterocycle, -a Ce to Cz aryl, optionally substituted with: -an alkoxy,
-a halogen, or -a Ci to Ce alkyl, or -a 5 or 6 membered heterocycle, and R, is: -a hydrogen,
-a Cj to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, N -a -NRvSθ2Rw group, where Rv is:
-a hydrogen,
-a -CORx, where Rx is as defined above, or -a Ci to Ce alkyl, optionally substituted with:
-a halogen, -a -CORx group, where Rx is as defined above,
-a -OCORx group, where Rx is as defined above, -a hydroxy, or -an alkoxy, and where Rw is: -a Ci to CO alkyl optionally substituted with:
-a halogen, -a haloalkyl, -a Ce to Cs aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with: -a Ci to C5 alkyl, -a 5 or 6 metnbered heterocycle, or
, optionally substituted with a Cj to Ce alkyl, where Ry is a
Ci to Cβ alkyl or hydrogen,
where R∑ is hydrogen or a Ci to Ce alkyl, optionally substituted with a CQ to Cs aryl, -a -SRx group, where Rx is as defined above, -a -Sθ2Raa group, where Raa is:
-a Ci to C6 alkyl,
-an amino group,
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -COORx group, where Rx is as defined above,
-a 5 or 6 membered heteroaryl, -a Ce to Cg aryl, and/or -a -NHRbb group, where Rj,b is:
-a -C(=S)NH2 group, or
-a -PO(ORX)2 group, where Rx is as defined above; = Rcc group, where RcC is:
-a naphthalene,
-a 5 or 6 membered heteroaryl,
-a Ce to Cg aryl, optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halogen,
-a Ci to Ce alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to Cs alkyl(s), -a -NHPORxRx, where Rx is as defined above,
-a -NReeCONRfiRfF group, where Ree is a hydrogen or a Ci to Ce alkyl, optionally substituted with a halogen, and Rffis: -a hydrogen, -a haloalkyl, -a haloalkoxy,
-a Ci to Ce alkyl, or
-a -CORx, where Rx is as defined above, -a -NRggCORhh group, where Rhh is:
-a hydrogen, -a Ci to Ce alkyl optionally substituted with:
-an alkoxy, -a halogen, or
-an amino optionally substituted with one or more Ci to Ce alkyl(s), -an amino optionally substituted with one or more Ci to Ce alkyl(s), where the one or more Ci to Ce alkyl(s) is/are optionally substituted with a halogen,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl,
-a hydrogen, -a Ci to C & alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORx group, where Rx is as defined above,
-a haloalkyl,
-5 or 6 membered heterocycle groups,
-an amino optionally substituted with one or more Ci to Ce alkyl(s), and/or -a -NRUSO2RX group, where Rx is as defined above, and R11 is: -a hydrogen, -a Ci to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -CORx group, where Rx is as defined above;
Z is:
-a Ci to Ce alkyl optionally substituted with: -an alkoxy,
-one or more halogen(s), or -a C6 to C8 aryl;
-a C2 to C6 alkylene;
-a Ce to Cs aryl optionally substituted with an alkoxy or one or more Ci to C6 alkyl(s); -a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy;
-a hydrogen;
-a hydroxy;
-a halogen; -a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with: -one or more halogen(s),
-a C^ to Cs aryl, or -a 5 or 6 membered heterocycle;
-a C6 to Cg aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above; -a Ci to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
Rι joins together with R2 to form:
R2 is:
-a nitro group; -a hydrogen; -a halogen; -a hydroxy group; -a Ci to Cs alkyl group, optionally substituted with one or more halogen(s); -an amino group;
-an alkoxy group optionally substituted with: -one or more halogen(s),
-an -OCORx group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy,
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl, -a 5 or 6 membered heteroaryl group, or -a CO to Cg aryl group;
-a -COORx group, where Rx is as defined above; -a haloalkyl;
-an amide group optionally substituted with: - a hydroxy group, or -a C6 to Cs aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORy group, where Rjj- is: -an alkoxy, or
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -a -ORkic group, where Rkk is a 5 to 6 membered heteroaryl; -a -NHSOzRx group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is:
-a hydrogen; or
-CHzOCORx, and Rx is as defined above; or one or more pharmaceutically acceptable salt(s) thereof.
72. A compound of formula HIb
wherein: X is: -hydrogen;
Y is:
-a 5 or 6 membered heteroaryl, optionally substituted with a CO to Cs aryl, optionally substituted with -COORx, where Rx is as defined above; -a Ce to Cs aryl, optionally substituted with one or more of the following: -an amino optionally substituted with one or more Ci to Ce alkyl(s); -a halogen; -a hydroxy; -a -CORm group, where Rn, is:
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with an alkoxy; and where R0 is:
-a hydrogen;
-a -NRqCONRqRr group, where Rq is hydrogen and where Rr is: -a Ci to C6 alkyl;
-a -NRtCOORu group, where R, is hydrogen, and where Ru is: -a Ci to Cj2 alkyl, optionally substituted with: -a C6 to Cg aryl; -a halogen; or
-a 5 or 6 membered heterocycle;
-a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is: -a Ci to Ce alkyl; or
-an alkyl- or dialkyl-amino;
where R2 is hydrogen or a Ci to Cβ alkyl; -a -SOiRaa group, where Raa is:
-an amino group; or
-an alkyl- or dialkyl-amino group; -a -NHRbb group, where Rbb is:
-a -PO(ORX)2 group, where Rx is as defined above;
Z is:
-a Ci to Cβ alky; or -a -COORx group, where Rx is as defined above; R is:
-a hydrogen, Ri is: -a hydrogen; -a 5 or 6 membered heterocycle; -an alkoxy optionally substituted with: -one or more halogen(s); or -a 5 or 6 membered heterocycle; R2 is:
-a hydrogen; -a hydroxy group;
-a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); -an alkoxy group optionally substituted with: -one or more halogen(s);
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl;
-a 5 or 6 membered heteroaryl group; or -a -COORx group, where Rx is as defined above; -an amide group;
-a 5 or 6 membered heteroaryl; or
-a -ORidc group, where Rkt is a 5 to 6 membered heteroaryl; R3 is:
-a hydrogen. 73. The compound of embodiment 72, wherein:
X is:
-hydrogen; Y is:
-a Cs to Cs aryl, substituted with -NRtCOORu group, where Rt is hydrogen, and where Ru is a Ci to Ci2 alkyl;
Z is:
-a Ci to C6 alky; R is:
-a hydrogen; R, is:
-a hydrogen; R2 is:
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; R3 is: -a hydrogen.
74. A compound which is selected from the compound range: 866-1329, 1484-2127, 2129-2545.
75. The compound of embodiment 74 selected from:
As used herein, the term "aLkyl" generally refers to saturated hydrocarbyl radicals of straight, branched or cyclic configuration, or combinations of cyclic and branched or straight, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n- hexyl, cyclohexyl, n-heptyl, octyl, n-octyl, and the like. In some embodiments, alkyl substituents may be C] to C12, or Ci to Cg or Ci to Ce alkyl groups.
As used herein, "alkylene" generally refers to linear, branched or cyclic alkene radicals having one or more carbon-carbon double bonds, such as C2 to Ce alkylene groups including 3- propenyl.
As used herein, "aryl" refers to a carbocyclic aromatic ring structure. Included in the scope of aryl groups are aromatic rings having from five to twenty carbon atoms. Aryl ring structures include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Examples of aryl groups that include phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl (i.e., phenanthrene), and napthyl {i.e., napthalene) ring structures. In certain embodiments, the aryl group may be optionally substituted. As used herein, "heteroaryl" refers to cyclic aromatic ring structures in which one or more atoms in the ring, the heteroatora(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heteroaryl, and independently selectable, are O, N, and S heteroaryl ring structures. The ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. In some embodiments, the heteroaryl groups may be selected from heteroaryl groups that contain two or more heteroatoms, three or more heteroatoms, or four or more heteroatoms. Heteroaryl ring structures may be selected from those that contain five or more atoms, six or more atoms, or eight or more atoms. Examples of heteroaryl ring structures include: acridine, benzimidazole, benzoxazole, benzodioxole, benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-diazanaphthalene, furan, fixrazan, imidazole, indole, isoxazole, isoquinoline, isothiazole, oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazole and quinazoline. As used herein, "heterocycle" refers to cyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heterocycle, and independently selectable, are O, N, and S heterocycle ring structures. The ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Example of heterocyclo groups include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl or tetrahydrothiopyranyl and the like. In certain embodiments, the heterocycle may optionally be substituted. As used herein, "alkoxy" generally refers to a group with the structure -O-R, where R is an alkyl group as defined above.
For the purposes of this invention, halo substituents may be independently selected from the halogens such as fluorine, chlorine, bromine, iodine, and astatine. A haloalkyl is an alkyl group, as defined above, substituted with one or more halogens. A haloalkoxy is an alkoxy group, as defined above, substituted with one or more halogens.
For the purposes of this invention, where one or more functionalities encompassing X, Y, Z, R, R], R2, and R3, are incorporated into a molecule of formula I, each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently substituted. Further, where a more generic substituent is set forth for any position in the molecules of the present invention, it is understood that the generic substituent may be replaced with more specific substituents, and the resulting molecules are within the scope of the molecules of the present invention.
By "substituted" or "optionally substituted" it is meant that the particular substituent may be substituted with a chemical group known to one of skill in the art to be appropriate for the referred-to substituent, unless a chemical group is specifically mentioned.
In some embodiments, X is selected from the X substituents of compounds 866-1329, 1484-2127, 2129-2545. Nonlimiting examples of X substituents include the following, where the * indicates the bond of attachment of the scaffold molecule:
In some embodiments, the X substituent is hydrogen; a cyano group; or a -COR3 group, where R3 is a Cj to Ce alkyl, or a dialkyl-amino.
In other embodiments, the X substituent is selected from the following:
In yet other embodiments, the X substituent is selected from the following:
In some embodiments, Y is selected from the Y substituents of compounds 866-1329, 1484-2127, 2129-2545.
Nonlimiting examples of Y substituents include the following:
In. some embodiments, the Y substituent is selected from the following:
In other embodiments, the Y substituent is selected from the following:
In some embodiments, Z is selected from the Z substituents of compounds 866-1329, 1484-2127, 2129-2545.
Nonlimiting examples of Z substituents include the following:
In some embodiments, the Z substituent is a hydrogen; a Cj to Ce alkyl optionally substituted with an alkoxy, one or more halogens, or a Ce to Cj aryl; a C2 to Ce alkylene; or a Ce to Cg aryl optionally substituted with an alkoxy. In other embodiments, the Z substituent is selected from the following:
<z
In yet other embodiments, the Z substituent is a hydrogen; a Ci to Cg alkyl optionally substituted with: -a Ce to Cs aryl; -a C2 to Cβ alkylene; and -a Cβ to Cs aryl optionally substituted with an alkoxy. In yet further embodiments, the Z substituent is selected from the following:
In some embodiments, R is selected from the R substituents of compounds 866-1329, 1484-2127, 2129-2545.
Nonlimiting examples of R substituents include the following:
In some embodiments, the R substituent is the following:
In some embodiments, Ri is selected from the Ri substituents of compounds 866-1329, 1484-2127, 2129-2545.
Nonlimiting examples of Ri substituents include the following:
In some embodiments, the Ri substituent is a hydrogen; a halogen; a nitro group; a 5 or 6 membered heterocycle; an alkoxy optionally substituted with a C& to Cg aryl; or a Ce to Cs aryl optionally substituted with an alkoxy. In other embodiments, the Ri substituent is selected from the following:
In some embodiments, R2 is selected from the R2 substituents of compounds 866-1329, 1484-2127, 2129-2545.
Nonlimiting examples OfR2 substituents include the following:
In some embodiments, the R2 substituent is a nitro group; a hydrogen; a halogen; a hydroxy group; a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); an alkoxy group optionally substituted with one or more halogen(s), a -OCORx group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl, or -a 5 or 6 membered heteroaryl group; -an amide group; or a -NHSOiRx group, where Rx is as defined above.
In other embodiments, the R2 substituent is selected from the following:
In yet other embodiments, the R2 substituent is a hydrogen; a Ci to Cβ alkyl group, optionally substituted with one or more halogens; or an alkoxy group optionally substituted with one or more halogens, a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl, or a 5 or 6 membered heteroaryl group.
In yet further embodiments, the R2 substituentis selected from the following:
In some embodiments, R3 is selected from the R3 substituents of compounds 866-1329, 1484-2127, 2129-2545.
Nonlimiting examples of R3 substituents include the following:
In some embodiments, the R3 substϊtuent is the following:
Nonlimiting examples of compounds of formula I include the following:
W
In some embodiments, the compound is selected from Compounds 866-1329, 1484- 2127, 2129-2545.
B. Preparation of Compounds of the Invention. The compounds of the invention can be obtained via standard, well-known synthetic methodology. Many of the indole starting materials can be prepared using the routes described below or by those skilled in the art.
Compounds of formula I, represented by structure II can be prepared by the methodology depicted in Scheme A below: An α-nitroketone derivative A2 can be derived from treatment of the anion of nitromethane, obtained from the treatment of nitromethane with a base, such as, e.g., sodium or potassium t-butoxide or sodium hydride, with an activated carboxylic acid derivative, e.g., the acyl imidazolide Al . Reaction of the α-nitroketone A2 with amine derivative A3 can afford the nitro enamine A4 by mixing the components A3 and A4 and heating in a suitable solvent such as an alcohol or an aprotic solvent Treatment of the nitro enamine A4 with quinone A5 in a polar protic solvent such as acetic acid at or near ambient temperature gives the compound of formula II.
I. Scheme A
Compounds of formula I, represented by structure III can be prepared as shown in Scheme B below:
Treatment of Bl with a reactive alkyl or aryl group containing a leaving group L in a suitable solvent, with or without heat in the presence of a base, such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., triethylamine, can afford the compound of structure III. Examples of leaving groups include but are not limited to halogens (e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates. II. Scheme B
Compounds of formula I, represented by structure IV can be prepared as shown in Scheme C below:
Compounds of structure IV can be obtained by nitrating an indole of structure Cl, to give the 3-mtroindole C2. The nitration can be carried out by treatment of Cl with a nitrating agent, such as nitric acid or sodium nitrite in a solvent such as acetic acid, acetic anhydride, sulfuric acid or in a mixed solvent system containing an organic solvent such as dichloromethane. The reaction can be carried out a temperature of— 3O0C to +500C. Treatment of C2 with a reactive functional group R9 containing a suitable leaving group L (C3) can give compounds of structure IV. Reactive functional groups can consist of but are not limited to alkyl and aralkyl. L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate. The reaction between C2 and C3 can be carried out in a suitable solvent in the presence of an inorganic base such as potassium carbonate or sodium hydride or an organic base such as a trialkylamine. Alternatively, the group R9 can represent an aryl or heteroaryl group and L can represent a halide, particularly chloro, bromo or iodo. The reaction can be carried out in a polar or nonpolar solvent at a temperature from ambient to 2000C in the presence of a copper catalyst, e.g., CuI, a base such as CS2CO3 or K3PO4, and optionally an amine ligand such as l,2-bis(methylamino)ethane or 1,2-cyclohexanediamine.
An alternative pathway is to convert Cl into C4 in similar fashion as described above and then carry out the nitration reaction to afford compounds of structure TV.
III. Scheme C
R9-L (C3) R9-L <C3)
Compounds of formula I5 represented by structure V can be prepared as shown in Scheme D.
Treatment of β-ketoesters of structure Dl with, amines D2 gives the amino crotonate derivatives D3 by heating in a suitable solvent such as an alcohol or an aprotic solvent. Reaction between D3 and quinone D4 in a polar protic solvent, such as acetic acid gives compounds of structure V.
IV. Scheme D
Compounds of the present invention, represented by structure VI compounds can be prepared by the chemistry described in scheme E below.
Indole-3-carboxylic esters El can be converted to indole-3-carboxylic acids E2 by treatment of compounds of structure El with, for example, either acid or base in aqueous or mixed aqueous-organic solvents at ambient or elevated temperature or by treatment with nucleophilic agents, for example, boron tribromide or trimethylsilyl iodide, in a suitable solvent. Compounds of type E2 can then be activated and treated with amines of type E3 to give compounds E4. Activation of the carboxylic acid can be carried out, for example, by any of the standard methods. For example, the acid E2 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine E3, or alternatively the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment of the amine E3. Compounds E4 can be converted to compounds of structure VI by treatment of E4 with a reactive functional group Rg containing a suitable leaving group L (ES) as described previously. Alternatively, compounds of type El can be converted to compounds of structure E6 by treatment with E5. Indole-3- carboxylic esters E6 can then be converted to indole-3-carboxylic acids E7 by the methods described above. Conversion of E7 to compounds of structure VI can be carried out by the activation and reaction with an amine E3 as described above.
V. Scheme E
Compounds of the present invention, represented by structure VII compounds can be prepared by the chemistry described in scheme F below. Indoles Fl can be formylated with reagents such as phosphorous oxychloride in the presence of DMF to give the indole-3-carboxaldehydes F2. Conversion to compounds of structure VII can be accomplished by treatment of F2 with compounds F3 as described previously. Alternatively, compounds of type Fl can first be converted to F4 and then be formylated to compounds of structure VH VI. < Scheme F
Compounds of formula G, represented by structure VIII can be prepared as shown, in Scheme G.
Indole-3-carboxaldehydes of structure Gl can be converted to the indole-3-carboxylic acid derivatives by oxidation with reagents such as potassium permanganate under aqueous conditions.
VII. Scheme G
G1 VlIl
Compounds of formula H, represented by structure DC can be prepared as shown in Scheme H.
Indole-3-carboxaldehydes of structure Hl can be converted to the indole-3-carbonitrile derivatives H2 by a variety of methods. Treatment of Hl with a nitroalkane, e.g., nitropropane, in the presence of an amine source, e.g., ammonium hydrogen phosphate gives the indole-3- carbonitrile H2 derivative. An alternative pathway to compound H2 is via the intermediate H3. Conversion of Hl to the oxime derivative H3 can be followed by dehydration, e.g., treatment of the oxime with acetic anhydride and a base, or reaction of the oxime with thionyl chloride to give H2. The compound H2 can then be reacted with a reactive functional group R9 containing a suitable leaving group L (H4) as described previously to afford compounds of structure IX.
Alternatively, Hl can be reacted with a reactive functional group R9 containing a suitable leaving group L (H4) to give the intermediate H5, which can be reacted with a nitroalkane as above to give the indole-3-carbonitrile DC compound. Compound IX can also be obtained by conversion to the oxime H6 followed by a dehydration reaction as described above.
VIII. Scheme H
H6
Compounds of the present invention, represented by structure X can also be prepared as described in scheme I below.
Indoles Il can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (12) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CEbCN or dioxane, to afford compounds of structure 13. The compound 13 can then be reacted with a reactive functional group R9 containing a suitable leaving group L (14) as described previously afford the compound X.
Alternatively, compound Il can be reacted with a reactive functional group R9 containing a suitable leaving group L to give compounds of structure 15 that can then be cyanated as above to give compounds of formula X.
IX. Scheme I
15
Compounds of formula J, represented by structure XI can be prepared as shown in Scheme J.
Amino crotonates Jl can be reacted with amines J2 to give J3. Reaction of J3 with quinone in the presence of a polar, protic solvent, e.g., acetic acid, gives the compound of structure XI.
X. Scheme J
Compounds of the present invention, represented by structure XII and XIII can be prepared as described in scheme K below. Aldehydes of structure Kl can be reacted with an alkyl azidoacetate K2 by heating the components together in a suitable organic solvent, e.g., a protic or non-protic solvent, in the presence of an organic or inorganic base, to give the α-azidoacrylate K3. Heating K3 in the presence of a suitable non-reactive organic solvent, e.g., toluene or xylenes can give the 2- alkoxycarbonylindoles K4. Reduction of the ester functionality with a suitable reducing reagent, for example, lithium aluminum hydride, in a suitable solvent, e.g., ether or THF can give the intermediate K5. Reaction of K5 with a reactive functional group R9 containing a suitable leaving group L (K6) as described previously affords the compound K7. Cyanation of K7 with a cyanating agent, e.g., chlorosulfonyl isocyanate as described previously can give compound XII. Alternatively, cyanation of K5 with chlorosulfonyl isocyanate gives K8, which can be reacted with a reactive functional group R9 containing a suitable leaving group L (K6) as described previously, affords, the compound XII.
An alternative use of intermediate K4 is exemplified below. Hydrolysis of the 2- alkoxycarbonyl group of the indole K4 either under acidic or basic conditions followed by decarboxylation can give the intermediate K9. Decarboxylation can be carried out thermally, i.e., heating in an appropriate solvent, e.g., toluene, xylenes, or quinoline. Alternatively, a source of copper can be added, for example, copper bronze, to facilitate decarboxylation. Reaction of K9 with a reactive functional group R9 containing a suitable leaving group L (K6) ' as described above can afford the compounds KlO. Cyanation of KlO with a cyanating agent, e.g., chlorosulfonyl isocyanate as described previously can give compound XIIL Alternatively, cyanation of K9 with chlorosulfonyl isocyanate gives Kl 1, which can be reacted with a reactive functional group R? containing a suitable leaving group L (K6) as described previously, affords the compound XIII.
XI. Scheme K
Compounds of formula L, represented by structure XTV can be prepared as shown in Scheme L.
Compounds of formula Ll can be halogenated on the 2-methyl group to give 2- bromomethyl or chloromethyl indoles L2. The halogenation reaction can be conducted with reagents, e.g., N-bromo- or chlorosuccύώnide. The reaction can be conducted in a suitable solvent, such as chloroform, carbon tetrachloride, or THF and carried out in a range between ambient temperature and 8O0C. Optionally, a radical initiator may be added, e.g., benzoyl peroxide or AIBN. The compound L2 can then be reacted with a nucleophile R5-W (L3) to give compounds of structure XIV. The reaction can be conducted in a suitable solvent, e.g., THF, CH2CI2 or DMF, within a temperature range of O0C to 1200C. A base, e.g., an inorganic base, such as potassium carbonate or an organic base, such as a trialkylamine can be used to remove the acid formed in the reaction. The group W can refer to an N, O or S atom. xπ. Scheme L
Compounds of the present invention, represented by structure XV can be prepared as described in scheme M below.
Anilines of structure Ml can be diazotized and the resulting diazonium salt can be reduced to give the phenyl hydrazine compound M2. Reaction between the hydrazine M2 and a ketone M3 under acidic conditions can give the indole compound M4. The conditions for the cyclization reaction can be carried out under typical conditions utilized by one skilled in the art, for example, acidic conditions, utilizing acids such as a Bronstead acid, e.g., acetic acid, hydrochloric acid or polyphosphoric acid or a Lewis acid, e.g., zinc chloride. The reaction can be carried out in the presence of a co-solvent, e.g., CH2CI2 or THF typically within a temperature range of 00C to 12O0C. Reaction of M4 with a reactive functional group R9 containing a suitable leaving group L (M5) as described previously, can afford compounds M6. Cyanation of the indole M6 with a cyanating agent such as chlorosulfonyl isocyanate can give the compound of structure XV.
Alternatively, the indoles M4 can be cyanated to give compounds of structure M7. Reaction of M7 with a reactive functional group R9 containing a suitable leaving group L (M5) as described above can give compounds of structure XV.
xπi. Scheme M
M1 M2
O
[H+] R X. <M3)
M7 XV
Compounds of formula I, represented by structure XVI can be prepared as shown in Scheme N.
Compounds of formula Nl can be reacted with a dialkylformamide dialkyl acetal, N2, e.g., dimethylfoπnamide dimethyl acetal, optionally in the presence of a suitable solvent, e.g., DMF or dioxane, at a temperature range from ambient to 1500C to give the compound of structure N3. Reduction of the nitro group of compounds of type N3 under standard conditions can give the indole compounds of structure N4. The reduction can be carried out via hydrogenation, using a sub-stoichiometric amount of a hydrogenation catalyst, e.g., platinum or palladium, in the presence of a hydrogen source in a protic or aprotic solvent. The reduction can be carried out in a temperature range of ambient to 8O0C. Alternatively, the reduction can be carried out via chemical reduction, e.g., in the presence of stoichiometric amounts of Fe or Sn compounds in a suitable solvent at a temperature range of ambient to 10O0C. The compound N4 can then be reacted with a reactive functional group R9 containing a suitable leaving group L (NS) as described previously to afford compounds of structure N6. Cyanation of N6 with a cyanating agent such as chlorosulfonyl isocyanate in a suitable solvent can give the compounds of structure XVI.
Alternatively, compounds of structure N4 can be cyanated to give compounds of structure N7. Reaction of N7 with a reactive functional group R9 containing a suitable leaving group L (N5) as described above can give compounds of structure XVI.
XIV. Scheme N
N7 XVI
Compounds of formula I, represented by structure XVII can be prepared as shown in Scheme O.
Compounds of structure Ol can be converted to 2-iodo- or bromoindoles O2. Typically, a strong base, such as n-butyllithium or s-butyllithium or lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed, with formation of the 2-indolyl anion generated in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of -780C to ambient temperature. The 2-indolyl anion can then be quenched with an electrophilic source of halogen, including but not limited to iodine, bromine or N-bromosuccinimide to give compounds of structure O2. Reaction of 2-iodo- or bromoindoles O2 with aboronic acid (commonly referred to as a Suzuki reaction) or trialkyl stannane (commonly referred to as a Stille reaction) can give the compounds of structure XVII. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (IT) dichloride or palladium acetate with added phosphine ligand. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 1500C. For the Suzuki reaction, a base is usually added. The base can be in aqueous solution, e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride. For the Stille reaction a copper co- catalyst, e.g., copper iodide, can be added.
Alternatively, indoles Ol can be converted to the indole-2-boronic acid or indole-2- trialkylstarmane derivatives O3 by reacting the 2-indolyl anion described above with a trialkylborate or chlorotrialkyl stannane derivative, respectively. Compounds of type O3 can be reacted with aryl and heteroaryl bromides and iodides under similar conditions to those described above to form compounds of structure XVII. XV. Scheme O
Compounds of formula I, represented by structure XVIII can be prepared as shown in Scheme P.
Compounds of structure Pl can be converted to compounds P3 by treatment of Pl with an aryl or heteroaryl halide (P2) in the presence of organometallic catalysis. Such catalyst combinations can include palladium catalysts, e.g., palladium acetate and a source of copper, e.g., copper iodide. The reaction can be carried out in the presence of a base, e.g., cesium carbonate. The reaction can be carried out within a temperature range of ambient temperature to 15O0C. Cyanation of the indole P3 with a cyanating agent such as chlorosulfonyl isocyanate can give the compound of structure XVIII.
XVI. Scheme P
P1 Cs2CO3 P3 XVIII
Compounds of the present invention, represented by structure XTX can be prepared as described in scheme Q below.
Compounds of structure XIX can be prepared by protecting an indole compound of structure Ql as e.g., the N-Boc derivative Q2. Alternatively, other protecting groups that can be utilized but not limited to include , e.g., benzyl, alkyl or aryl sulfonyl, or πϊalkyl silyl. Treatment of Q2 with a strong base, e.g., lithium diisopropyl amide in an aprotic solvent, e.g., THF followed by quenching with a trialkylborate derivative can give the indolyl-2-boronic acid Q3. Reaction with an aryl or heteroaryl halide Q4 in the presence of palladium catalysis, e.g., tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloiide or palladium acetate with added phosphine ligand, can give the compound Q5. Removal of the protecting group can give Q6. Reaction with Q6 with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure Q7. Cyanation of compound Q7 can give the compounds of structure XTX.
XVII. Scheme Q
Compounds of formula I, represented by structure XX can be prepared as shown in Scheme R. Compounds of structure R2 can be prepared by protecting an indole compound of structure Rl as e.g., the N-Boc derivative R2 as above. Compounds of structure R2 can be converted to 2-iodo- or bromoindoles R3. Typically, a strong base, such as n-butyllithium or s- butyllithium or lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed, with formation of the 2-indolyl anion generated in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of — 78°C to ambient temperature. The 2-indolyl anion can then be quenched with an electrophilic source of halogen, including but not limited to iodine, bromine or N- bromosuccinimide to give compounds of structure R3. After removal of the protecting group, compounds of R4 can be reacted with aryl or heteroaryl boronic acids or esters (R5) (commonly referred to as a Suzuki reaction) to give compounds of structure R6. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis (triphenylphosphine) palladium (O), bis (triphenylphosphine) palladium (H) dichloride or palladium acetate with added phosphine ligand. Reaction of R6 with a reactive functional group Rg containing a suitable leaving group L as described above can give compounds of structure XX. XVIII. Scheme R
Compounds of the present invention, represented by structure XXI can be prepared as described in scheme S below.
2-iodo- or bromoindoles of structure S 1 can be reacted with alkenes in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XXI. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described previously.
XIX. Scheme S
Compounds of formula I, represented by structure XXII can be prepared as shown in Scheme T.
2-Iodo- or 2-bromoindoles of structure Tl can be reacted with acetylenes in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XXII. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indoles of structure Tl with an acetylene compound T2 in the presence of a source of palladium, a copper co-catalyst and an amine source. The reaction is carried out in a suitably unreactive solvent and conducted within a temperature range from ambient to 15O0C.
XX. Scheme T
T1 XXIl
Compounds of formula I, represented by structure XXIII can be prepared as shown in Scheme U.
Compounds of structure XXIII can be obtained from the reduction of compounds XXI and XXII. Conditions for the reduction can include, but are not limited to catalytic reduction, e.g., hydrogenation over a source of platinum or palladium in a suitable solvent, e.g., CH2CI2, ether, THF, methanol or solvent combinations.
XXI. Scheme U
XXl XXIII XXIl
Compounds of the present invention, represented by structure XXIV can be prepared as described in scheme V below.
Indoles of structure Vl can be reacted with a suitable base, such as lithium diisopropylamide or potassium hexamethyldisilazide to generate the 2-indolyl anion in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of -78°C to ambient temperature. The 2-indolyl anion can then be quenched with a source of zinc halide, e.g., zinc halide metal or solutions containing them to give organozinc compounds of structure V2. Reaction of V2 with an arylhalide (V3) in the presence of a palladium catalyst (commonly referred to as the Negishi reaction) gives compounds of structure XXTV. Alternatively, 2-iodo or bromoindoles of structure V4, prepared from compounds Vl as described previously, can be reacted with organozinc compounds of structure V5 in the presence of a suitable palladium, catalyst to give compounds of structure XXIV. The organozinc compound V5 can be derived from, e.g., an alkyl or alkenyl halide after treatment with activated zinc or an aryl or heteroaryl lithium or magnesium compound after treatment with zinc halide. Furthermore, the reactions of V2 or V4 can be carried out in the presence of a palladium source, e.g., as tetrakis (triphenylphosphine) palladium (0) or bis (triphenylphosphine) palladium (II) dichloride in a suitable solvent and at a temperature range from ambient to 1500C.
XXII. Scheme V
Compounds of formula I, represented by structure XXV-XXVIII can be prepared as shown in Scheme W.
2-Iodo- or bromo indoles of structure Wl can be reacted with acetylenes of structure W2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XXV. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indoles of structure Wl with an acetylene compound W2 in the presence of a source of palladium, an optional copper co-catalyst and an amine source. The reaction is carried out in a suitably unreactive solvent and conducted within a temperature range from ambient to 1500C. Reaction with XXV with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure XXVI.
2-iodo- or bromoindoles of structure Wl can also be reacted with alkenes in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XXVII. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described previously. Reaction with XXVII with a reactive functional group Rg containing a suitable leaving group L as described above can give compounds of structure XXVIII. XXIII. Scheme W
XXVlIl
Compounds of formula I, represented by structure XXIX can be prepared as shown in Scheme X.
Indoles of structure Xl and be acylated with acyl halides of structure X2 to give compounds of structure XXTX. The reaction can be promoted with a Lewis acid. The choice of Lewis acid can be chosen from, but is not limited to aluminum chloride, ferric chloride, stannic chloride or diethyl aluminum. The reaction is typically earned out in a suitable non-reactive solvent including CEtCl2, carbon disulfide or dichloroethane and is typically conducted within a temperature range of -200C to 800C.
XXIV. Scheme X
X1 XXIX Compounds of formula I, represented by structure XXX can be prepared as shown in Scheme Y.
3-Cyanoindoles of structure Yl can be converted to tetrazoles of structure Y2 by treatment with, e.g., sodium azide. Heating a mixture of Y2 and the reagent Y3 can give the 3- (1 ,2,4-oxadiazolyl)indole compound XXX. The reagent Y3 can be, e.g., an acyl halide or an acid derivative activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. The reaction can be carried out in a variety of solvents, including e.g., toluene, dioxane, pyridine and dichloroethane and can be carried out by heating Y2 and Y3 at a temperature range of 30° to 13O0C.
XXV. Scheme Y
Compounds of formula I, represented by structure XXXI can be prepared as shown in Scheme Z.
3-Cyanoindoles of structure Zl can be treated with hydroxyamine to give hydroxyamidine compounds of formula Z2. Reaction of hydroxyamidines of structure Z2 with compounds of structure Z3 can give O-acylhydroxyamidines Z4. Compounds Z3 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Heating compounds of structure Z4 in a non- reactive organic solvent, .e.g., toluene, dichloroethane or dioxane in a temperature range of 3O0C to 1500C can give compounds of structure XXXI.
XXVL Scheme Z
Compoxmds of the present invention, represented by structure XXXII can be prepared as described in scheme AA below.
Keto indoles of type AAl can be converted to oximes of structure AA2 by heating the ketoindoles with hydroxyamine (free base or acid salt) in a suitable solvent. Bis-deprotonation of compounds of type AA2 with a strong organic base (e.g., n-butyllityium or sec-butyllithium or tert-butyllitbium) followed by reaction with DMF can give compounds of formula XXXH-
XXVII. Scheme AA
AA1 AA2 XXXII
Compounds of formula I, represented by structure XXXIII can be prepared as shown in Scheme AB. 3-Ketoindoles of structure AB 1 can be homologated to vinylogous amides of structure
AB3 by reaction with dialkyl amide dialkyl acetals AB2. The dialkyl amides can include e.g., lower alkyl amides such as formamide, acetamide and propioπamide. Examples would include dimethlformamide dimethyl acetal and dimethyl acetamide dimethyl acetal. The reaction can be conducted by reacting ABl and AB2 with or without additional solvent at a temperature from ambient to 15O0C. Treatment of AB3 with hydroxyamine (free base or acid salt) in a suitable solvent can give compounds of structure XXXIII. The reaction is typically conducted within a temperature range from ambient to 12O0C.
xxvπi. Scheme AB
XXXIII
Compounds of formula I, represented by structure XXXIV can be prepared as shown in Scheme AC.
Vinylogous amides of structure ACl (as prepared above) can be treated with hydrazines AC2 in a suitable organic solvent (DMF, alcohol or acetic acid) at temperatures ranging from ambient temperature to 150°C to give compounds of structure XXXIV.
XXIX. Scheme AC
XXXIV
Compounds of the present invention, represented by structure XXXV can be prepared as described in scheme AD below.
Indole-3-carboxaldehydes of structure ADl (as prepared in Scheme F) can be reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC) in the presence of a base to give compounds of structure XXXV. Bases can include potassium carbonate or 1,8- diazabicyclo[5.4.0]undec-7-ene and the reaction can be carried out in a suitable organic solvent from ambient temperature to 1500C. XXX. Scheme AD
Compounds of formula I, represented by structures XXXVI and XXXVII can be prepared as shown in Scheme AE.
3-Indolecarboxylic acids of structure AEl (from Scheme E) can be converted to amides of structure AE2. Compounds of structure AE2 can be activated by any of the standard methods. For example, the acid AEl can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of ammoma. Alternatively, the acid can be activated as the acid chloride or as the acyl imidazolide as described previously, followed by treatment of ammonia.
The indole-3-carboxamides of structure AE2 can be reacted with substituted aldehydes or ketones (AE3) containing a suitable leaving group L, in a suitable solvent at temperatures above ambient and up to 2000C. The reaction can be performed with or without added base to afford oxazoles of structure XXXVI-
The indole-3-carboxamides of structure AE2 can also be converted to tbioamides of structure AE4 by treating the primary amides with Lawesson's reagent or phosphorous pentasulfide at or above ambient temperature in a suitable organic solvent. The resulting tbioamides AE4 can be reacted with substituted aldehydes or ketones containing a suitable leaving group L (AE3), in a suitable solvent at temperatures above ambient and up to 1500C. The reaction can be performed with or without added base to afford thiazoles of structure XXXVII. XXXL Scheme AE
XXXVI
Compounds of the present invention, represented by structure XXXVIII and XXXIX can be prepared as described in scheme AF below.
3-Ketoindoles of structure AFl can be halogenated (e.g., brominated) to give compounds of structure AF3. Suitable brominating agents can include but are not limited to phenyltrimethylammonium tribromide (AF2), N-bromosuccinimide or bromine and can be carried out in a variety of organic solvents.
Treatment of compounds AF3 with amides of type AF4 in a suitable solvent at temperatures above ambient and up to 2000C with or without added base can give oxazoles of structure XXXVHI.
Treatment of compounds AF3 with thioamϊdes of type AF5 in a suitable solvent at temperatures above ambient and up to 15O0C with or without added base can give thiazoles of structure XXXIX.
XXXVlH XXXIX
Compounds of formula I, represented by structure XL can be prepared as shown in Scheme AG.
Indoles of structure AGl can be brominated or iodinated to give compounds of structure AG2. Brominating agents may include but are not limited to bromine or N- bromosuccinimide and iodinating reagents may include iodine monochloride or bis- trifluoroacetoxy iodobenzene. Reaction of 3-iodo- or bromoindoles AG2 with a boronic acid AG3 (commonly referred to as a Suzuki reaction) can give the compounds of structure XL.
The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride or palladium acetate with added phospbine ligand. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 15O0C and typically in the presence of a base e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.
Alternatively, indole AG2 can be converted to the indole-3-boronic acid derivative AG5 by reacting the 3-haloindole AG2 with a strong organic base (alkyllithium or Grignard reagent) and reacting the resultant anion with a trialkylborate reagent AG4. Compounds of type AG5 can be reacted with aryl and heteroaryl bromides and iodides under similar conditions to those descπbed above to form compounds of structure XL.
XXXIII. Scheme AG
AG1 AG2 AG5
Pd0 Pd0 R12-B(OH)2 R12-L
(AG3) (AG6)
XL
Compounds of the present invention, represented by structure XLI can be prepared as descπbed in scheme AH below.
3-iodo- or bromoindoles of structure AHl can be reacted with alkenes AH2 in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XLI. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described in Scheme AG. xxxrv. Scheme AH
Compounds of formula I5 represented by structure XLII can be prepared as shown in Scheme AI.
3-Iodo- or bromoindoles of structure All can be reacted with acetylenes AI2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XLII. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indole of structure All with an acetylene compound AI2 in the presence of a source of palladium, a copper co- catalyst and an amine source and carrying out the reaction at a temperature range of ambient to 15O0C.
XXXV. Scheme AI
Compounds of the present invention, represented by structure XLIII and XLIV can be prepared as described in scheme AJ below.
Nitroanilines of structure AJl can be converted to indoles of structure XLIII by condensation and cyclization with nitriles of structure AJ2. The reaction can be carried out in a suitable organic solvent, e.g., DMF or dioxane. Treatment of compounds of structure XLIJJ with a base followed by reaction with a reactive functional group R9 containing a suitable leaving group L can give the compounds of formula XLIV.
XXXVT. Scheme AJ
-
AJ 1 XLIII
Compounds of formula I, represented by structure XLV-XLVIII can be prepared as shown in Scheme AK. 2-aminoindoles of structure XLV can be alkylated with a reactive functional group R] 5 containing a suitable leaving group L in the presence of a base, e.g., sodium hydride or potassium carbonate in a suitable organic solvent to give compounds of structure XLVI. A second alkylation utilizing a reactive functional group R'u containing a suitable leaving group L similarly can give compounds of structure XLVII. x
Acylation of compounds of structure XLV with acyl chlorides of structure AKl can give compounds of structure XLVIII. The reaction is typically carried out in the presence of an organic base, e.g., a trialkylamine or an inorganic base, e.g., potassium carbonate in a suitable organic solvent.
XXXVII. Scheme AK
Compounds of the present invention, represented by structure XLIX can be prepared as described in scheme AL below.
Indole-3-carboxylic acids of structure ALl can be activated to give compounds of structure AL2. Compounds of structure AL2 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Reaction of compounds of structure AL2 with hydroxyamidines of structure AL3 can give O-acylhydroxyamidines AL4. Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxyamine. Heating compounds of structure AL4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 300C to 1500C can give compounds of structure XLIX. XXXVIII. Scheme AL
Compounds of formula I, represented by structure XLX can be prepared as shown in Scheme AM.
Compounds of formula AMI (in which Ri 7, defined above, is 1-3 substituents placed on the indole) when treated with a base, copper (I) iodide and a substituted amine (Z-NH2 where Z is defined above) to provide compounds of structure AM2. Acylation with 2-chloroacetyl chloride and a base such as triethylamine in solvents such as but not limited to dichloromethane, tetrahydrofuran or toluene at temperatures from ambient to reflux provides intermediate AM3 which is subsequently cyclized to form compounds of structure AM4 employing palladium (II) acetate as catalyst, a phosphine ligand and abase such as triethylamine in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux. Reduction and elimination with a hydride source such as DIBAL-H in solvents such as but not limited to dichloromethane, tetrahydrofuran or toluene at temperatures from O0C to reflux provides intermediate AM5. The subsequent steps leading to product XLX are described above.
XXXDC. Scheme AM
R17 k Z-NH2 flW ClCOCH2Cl
K3PO4/ CuI GX NH base Z
AM1 AM2
AM3 AM4
AM5 AM6
AM7 XLX
Compounds of formula I, represented by structure XLXI can be prepared as shown in Scheme AN.
Compounds of formula ANl can be treated with a triflate source, such as triflic anhydride, and a base, such as pyridine, in solvents such as but not limited to tetxahydroforan, dichloromethane or toluene at temperatures from ambient to reflux to provide intermediate AN2. AN2 can either be directly reacted with palladium (0) and a Ri 2 substituted trϊalkyl tin compound in the presence of cesium fluoride and copper (I) iodide in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux to provide product XLXI or reacted in a two step sequence of coupling with a pinacol borane source, such as bis-pinacol diborane, in the presence of palladium (II) and a base, such as potassium acetate, in solvents such as but not limited to tetrahydrofuran, dioxane or toluene at temperatures from ambient to reflux to provide AN3 and then a second coupling with palladium (0), cesium fluoride and an appropriate R12L compound in solvents such as but not limited to tetrahydrofiiran, dimethoxy ethane or toluene at temperatures from ambient to reflux would provide XLXI.
XL. Scheme AN
AN1 AN2 AN3
XLXl
C. Methods of the Invention Another aspect of the invention relates to a method for treating Hepatitis C viral (HCV) infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) of formula I or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of formula I or one or more pharmaceutically acceptable salt(s) thereof, as described above.
As used herein, the term "treating" refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting a disease, disorder or condition, i.e., arresting its development; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
As used herein, the term "subject" refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Nonlimiting examples include members of the human, equine, porcine, bovine, murine, canine and feline species. Li some embodiments, the subject is a mammal or a warm-blooded vertebrate animal. In other embodiments, the subject is a human. As used herein, the term "patient" may be used interchangeably with "human".
Without being limited to any particular theory, it is believed that the compounds of the present invention inhibit IRES-mediated initiation, elongation and termination, i.e., translation by interfering with function of the IRES directly and/or with the interaction of the IRES and a cellular and/or viral factor. Thus, another aspect of the invention relates to a method for treating an infection by a wild type virus or a virus that is resistant to a currently available antiviral agent, in a subject in need thereof, wherein the wild type or resistant virus comprises an internal ribosome entry site (IRES), comprising administering to the subject an effective amount of one or more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, as described above. Nonlimiting examples of such virus include viruses of the picornavirus genus, such as poliovirus, hepatitis A virus, coxsackievirus and rhinovirus; viruses of the coronaviridae genus, such as SARS; viruses of the arbovirus genus; viruses of the fiavivirus genus, such as yellow fever, dengue, and West Nile virus; herpesviruses, such as herpes simplex virus and Kaposi's sarcoma-associated herpesvirus, and other viruses with a similar mode of replication; and HTV, human leukemia viruses (HTLV) and other viruses with ' a similar mode of translation.
Yet another aspect of the invention relates to a method for inhibiting HCV IRES- mediated initiation, translation and/or replication in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) of formula I or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of formula I or one or more pharmaceutically acceptable salt(s) thereof, as described above.
Some methods of the present invention comprise administering one or more compound(s) of formula I, or a pharmaceutical composition comprising one or more compound(s) of formula I wherein: X is: -a nitro group; -a cyano group; -a -CORa group, where Ra is: -a Ci to CO alkyl,
-a Ce to Cs aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COORx group, where Rx is a Ci to Ce alkyl; -a formyl group;
-a Cg to Cs aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl,
-a Ce to Cs aryl optionally substituted with an alkoxy or one or more halogen(s), or
-a 5 to 6 membered heteroaryl; Y is: -a haloalkyl; -a halogen;
-an amino optionally substituted with one or more Cj to Ce alkyl(s); -a benzofuran; -a benzothiophene; -a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a Ci to Ce alkyl;
where Rb is a hydrogen or a Ci to Ce alkyl, and n is 0 or 1 ;
, where R0 is a hydrogen, a -CONHRx, where Rx is as defined above, or an -Sθ2Rx, where Rx is as defined above; or
where Rd is a Ci to Cs alkyl or a Ce to Cs aryl; -a -NHCORe group, where Re is: -a Ci to Cδ alkyl;
-a Ce to Cs aryl optionally substituted with: -a Ci to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or
-a halogen;
-a -NHCOORx group, where Rx is as defined above; -a -CH2O-Rf group, where Rf is a Ce to Cg aryl;
-a -NRgRh group, where Rg is a C1 to Ce alkyl or a hydrogen and Rh is a Ce to Cs aryl optionally substituted with an alkoxy; -a Ci to C6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
-a Ci to Ce alkyl, optionally substituted with a Ce to Cg aryl,
-a Cβ to Cs aryl, optionally substituted with -COORx, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above, or -a -NHCOORx group, where Rx is as defined above; -a Ce to C8 aryl, optionally substituted with one or more of die following: -an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy,
-one or more halogen(s),
-a 5 or 6 membered heterocycle, optionally substituted with:
-a Ci to Ce alkyl, or -a hydroxy,
-an amino group optionally substituted with one or more Ci to CO alkyl(s), -a -NRiSOzRx group, where Rx is as defined above and Ri is: -a hydrogen, -a Ci to C6 alkyl, -a -CORx group, where Rx is as defined above,
-a halo alkyl, or -a haloalkoxy, -a -NRjCORk group, where Rk is:
-a Ci to C6 alkyl, -a hydro gen, or
-an amino optionally substituted with one or more Ci to Ce alkyl(s), and Rj is:
-a hydrogen, -a Ci to Cs alkyl, - a -CORx group, where Rx is as defined above,
-a haloalkyl, or -a haloalkoxy, -a -N=N+=N" group, or
-a -CORi, where Ri is a 5 or 6 membered hetero cycle optionally substituted with a hydroxy,
-an amino optionally substituted with one or more Ci to Ce alkyl(s),
-a nitro group,
-a Ci to Cβ alkyl group, optionally substituted with:
-a -NHSOaRx group, where Rx is as defined above, or -a -NRxSOaRx group, where Rx is as defined above,
-a haloalkoxy, -a halogen, -a hydroxy, -a -COORx group, where Rx is as defined above, -a -CORm group, where Rm is:
-an amino optionally substituted with one or more Ci to Ce alkyl(s), where the one or more Cj to Cg alkyl(s) is/are optionally substituted with, -a hydroxy
-a 5 or 6 membered heterocycle,
-an amino optionally substituted with one or more Cj to Ce alkyls, and/or
-an alkoxy,
-a 3 to 7 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a dialkyl-amino, -a -NHRn group, where Rn is: -a -CH2CONH2, or
-a Ce to Cg aryl optionally substituted with: -an alkyl,
-one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with: -a halogen, -an alkoxy, or -a Cg to C8 aryl,
-a 5 or 6 membered heterocycle, -a Ce to Cg aryl, optionally substituted with a halogen,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Cβ alkyl(s),
-a hydrogen,
and where R0 is:
,- -a hydrogen, -a Ci to C6 alkyl, -a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy,
-a -NRqCONRqRr group, where Rq is: -a hydrogen,
-a Ci to C6 alkyl, -a haloalkyl, -a haloalkoxy, or
-a -CORx group, where Rx is as defined above, and where R1- is:
-a CO to Cs aryl optionally substituted with:
-a Ci to C6 alkyl, -a haloalkyl, -a -OR5 group, where Rs is a Ce to Cs aryl, or
-a -COORx group, where Rx is as defined above,
-a Ci to Cg alkyl optionally substituted with one or more of the following: -a halogen, -an alkylene, -a C6 to C8 aryl, and/or •
-a -COORx group, where Rx is as defined above, -a -COORx group, where Rx is as defined above, -a -NR(COORu group, where Ru is:
-a C] to Ci 2 alkyl, optionally substituted with: -a Ce to Cg aryl optionally substituted with a Ci to C$ alkyl or an alkoxy,
-an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a Ce to Cg aryl, optionally substituted with: -an alkoxy, -a halogen, or -a Ci to Ce alkyl, or
-a 5 or 6 membered heterocycle,
-a hydrogen, -a Ci to C6 alkyl, -a -CORx group, where Rx is as defined above,
-a haloalkyl, or -a haloalkoxy, -a -NRvSOzRw group, where Rv is:
-a hydrogen, -a -CORx, where Rx is as defined above, or
-a Ci to Ce alkyl, optionally substituted with: -a halogen,
-a -CORx group, where Rx is as defined above, -a -OCORx group, where Rx is as defined above, -a hydroxy, or
-an alkoxy, and where Rw is:
-a Ci to Ce alkyl optionally substituted with:
-a halogen, -a haloalkyl,
-a Ce to C8 aryl, or -a 5 or 6 membered heterocycle, -a C2 to CQ alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or
-a 5 or 6 membered heteroaryl optionally substituted with: -a Ci to C6 alkyl, -a 5 or 6 membered heterocycle, or
, optionally substituted with a Ci to Ce alkyl, where Ry is a
Ci to Cg alkyl or hydrogen,
where R2 is hydrogen or a Ci to Qs alkyl, optionally substituted with a Cβ to Cg aryl,. -a -SRx group, where Rx is as defined above, -a -Sθ2Raa group, where R38 is:
-a Ci to C6 alkyl,
-an amino group,
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -COORx group, where Rx is as defined above,
-a 5 or 6 membered heteroaryl, -a Cδ to C8 aryl, and/or -a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or
-a -PO(ORX)2 group, where Rx is as defined above; — Rcc group, where R∞ is:
-a naphthalene,
-a 5 or 6 membered heteroaryl,
-a Cβ to C8 aryl, optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halogen,
-a Ci to C^ alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to Ce alkyl(s), -a -NHPORxRx, where Rx is as defined above,
-a -NRccCONRffRff group, where R66 is a hydrogen or a Ci to Cg alkyl, optionally substituted with a halogen, and RfT is: -a hydrogen, -a haloalkyl, -a haloalkoxy,
-a Ci to C$ alkyl, or
-a -CORx, where Rx is .as defined above, -a -NRggCORhh group, where Rhh is:
-a hydrogen, -a Ci to Cg alkyl optionally substituted with:
-an alkoxy, -a halogen, or
-an amino optionally substituted with one or more Ci to Ce alkyl(s), ^ -an amino optionally substituted with one or more Ci to Ce alkyl(s), where the alkyls are optionally substituted with a halogen, -a 5 or 6 membered heteroeycle, -a 5 or 6 membered heteroaryl, and Rgg is: -a hydrogen,
-a Ci to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or
-a -CORx group, where Rx is as defined above, -a haloalkyl, -5 or 6 membered heteroeycle groups,
-an amino optionally substituted with one or more Ci to Cg alkyl(s), and/or -a -NRj,SO2Rx group, where Rx is as defined above, and RU is: -a hydrogen, -a Ci to C6 alkyl, -a haloalkyl, -a haloalkoxy,
-a -CORx group, where Rx is as defined above; Z is:
-a Ci to CO alkyl optionally substituted with: -an alkoxy,
-one or more halogen(s), or -a Cβ to Cg aryl; -a C2 to C6 alkylene;
-a Ce to Cg aryl optionally substituted with an alkoxy or one or more Cj to C$ alkyl(s); -a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy; R1 is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl; -a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an. alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl, or
-a 5 or 6 membered heterocycle;
-a C6 to Cg aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above;
-a Ci to Ce alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or R] joins together with R2 to form:
R2 is:
-a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
-a Cj to Cή alkyl group, optionally substituted with one or more halogen(s); -an amino group; -an alkoxy group optionally substituted with:
-one or more halogen(s),
-an -OCORx group, where Rx is as defined above,
-a dialkyl-amino optionally substituted with an alkoxy,
-a 5 or 6 memberedheterocycle group optionally substituted with a Ci to Ce alkyl, -a 5 or 6 membered heteroaryl group, or
-a C6 to Cs aryl group;
-a -COORx group, where Rx is as defined above, -a haloalkyl;
-an amide group optionally substituted with: - a hydroxy group, or
-a Ce to C& aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORjj group, where R1,- is: -an alkoxy, or
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; -a -NHSO2RK group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is:
-a hydrogen; or
-CKbOCORx, and Rx is as defined above. As used herein, the term "effective amount" refers to the amount required to produce a desired effect. For example, the effective amount may be the amount required to treat a Hepatitis C viral (HCV) infection, the amount required to treat an infection by a virus which comprises an internal ribosome entry site (IRES), the amount required to inhibit HCV IRES- mediated initiation and/or translation, or the amount required to inhibit viral replication or infectivity, in a subject or, more specifically, in a human. In some instances, the desired effect can be determined by analyzing (1) the presence of HCVRNA; (2) the presence of anti-HCV antibodies; (3) the level of serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) (ALT and AST are elevated in patients chronically infected with HCV); (4) hepatocellular damage resulting from HCV infection, including steatosis, fibrosis and cirrhosis; (5) hepatocellular carcinoma as a result of chronic HCV infection; and (5) extrahepatic sequelae (non-limiting examples include pruritis, encephalopathies, mental disorders such as anxiety or depression) of infection with HCV or other viruses which contain an IRES element. The effective amount for a subject will depend upon various factors, including the subject's body weight, size and health. Effective amounts for a given patient can be determined by routine experimentation that is within the skill and judgment of the clinician. For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as chimpanzees, marmosets and tamarins. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED™ (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. In some embodiments, the effective amount is such that a large therapeutic index is achieved. In further embodiments, the dosage is within a range of circulating concentrations that include an ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
More specifically, the concentration-biological effect relationships observed with regard to the compound(s) of the present invention indicate an initial target plasma concentration ranging from approximately 0.1 μg/mL to approximately 100 μg/mL, from approximately 1 μg/mL to approximately 50 μg/mL, from approximately 5 μg/mL to approximately 50 μg/mL, or from approximately 10 μg/mL to approximately 25 μg/mL. To achieve such plasma concentrations, the compounds of the invention may be administered at doses that vary from 0.1 μg to 100,000 mg, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and is generally available to practitioners in the art. In general, the dose will be in the range of about lmg/day to about lOg/day, or about O-Ig to about 3g/day, or about 0.3g to about 3g/day, or about 0.5g to about 2g/day, in single, divided, or continuous doses for a patient weighing between about 40 to about 100 kg (which dose may be adjusted for patients above or below this weight range, particularly children under 40 kg).
The exact dosage will be determined by the practitioner, in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, ethinicity, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, experience with other HCV therapies, and tolerance/response to therapy. Long- acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation. The compounds and compositions of the present invention may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.
D. Metabolites of the Compounds of the Invention
Also falling within the scope of the present invention are the in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterifϊcation and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radio-labeled (e.g. C^ or H^) compound of the invention, administering it in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating its conversion products from urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e-g-> by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no biological activity of their own.
E. Pharmaceutical Compositions of the Invention Yet another aspect of the invention relates to a pharmaceutical composition comprising:
(i) an effective amount of one or more comρound(s) of formula I or one or more pharmaceutically acceptable salt(s) thereof, as described above; and (ii) one or more pharmaceutically acceptable excipient(s).
In some embodiments, the pharmaceutical composition comprises one or more compound(s) of formula I wherein: X is:
-a nitro group; -a cyano group; -a -COIU group, where Ra is: -a Ci to C6 alkyl,
-a Ce to Cs aryl optionally substituted with an alkoxy or a halogen, or
-a dialkyl-amino;
-a -COORx group, where Rx is a Ci to C6 alkyl; -a formyl group; -a Cg to Cg aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a Ci to C5 alkyl,
-a C6 to Cg aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl; Y is:
-a haloalkyl; -a halogen; -an amino optionally substituted with one or more Ci to Q alkyl(s); -a benzofuran; -a benzothiophene; -a dibenzofuran; -a dibenzothiophene; -a benzothiazole; -a naphthalene; -an indole, optionally-substituted on the nitrogen with a Cj to Ce alkyl;
Rb , where Rb is a hydrogen or a Ci to Ce alkyl, and n is 0 or 1;
where R0 is a hydrogen, a -CONHRx, where Rx is as defined above, or an -SOaRx, where Rx is as defined above; or , where Rd is a Cj to Ce alkyl or a Cβ to Cs aryl; -a -NHCORe group, where R6 is: -a Ci to C6 alkyl;
-a Cg to Cg aryl optionally substituted with: -a Ci to C6 alkyl,
-an alkoxy, -a cyano group, -a nitro group, or -a halogen; -a -NHCOORx group, where Rx is as defined above; -a -CH2O-Rf group, where Rf is a C6 to Cs aryl;
-a -NRgRh group, where Rg is a Ci to Ce alkyl or a hydrogen and Rh is a CO to Cs aryl optionally substituted with an alkoxy; -a Ci to C6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
-a Ci to Ce alkyl, optionally substituted with a CQ to C8 aryl,
-a CO to C8 aryl, optionally substituted with -COORx, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above, or
-a -NHCOORx group, where Rx is as defined above; -a C6 to Cg aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy,
-one or more halogen(s),
-a 5 or 6 membered heterocycle, optionally substituted with: -a Ci to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more Ci to Ce alkyl(s), -a -NR1SOzRx group, where Rx is as defined above and R1- is: -a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or
-a haloalkoxy,
-a -NRjCORic group, where R^ is: -a Ci to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Ci to Ce alkyl(s), and R, is:
-a hydrogen, -a Ci to C6 alkyl,
- a -CORx group, where Rx is as defined above, -a haloalkyl, or
-a haloalkoxy, -a -N=N+=N" group, or
-a -CORi, where Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more Ci to C6 alkyl(s),
-a nitro group, -a Ci to Ce alkyl group, optionally substituted with:
-a -NHSOiRx group, where Rx is as defined above, or -a -NRxSO∑Rx group, where Rx is as defined above, -a haloalkoxy,
-a halogen, -a hydroxy,
-a -COORx group, where Rx is as defined above, -a -CORn, group, where Rra is: -an amino optionally substituted with one or more Ci to Ce alkyl(s), where the
Ci to C6 alkyls are optionally substituted with: -a hydroxy
-a 5 or 6 membered heterocycle, -an amino optionally substituted with one or more Ci to C6 alkyl(s), -an alkoxy,
-a 3 to 7 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a dialkyl-amino, -a -NHRn group, where Rn is: -a -CH2CONH2, or
-a Ce to Cs aryl optionally substituted with: -an alkyl,
-one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NRoCORp group, where Rp is:
-a Ci to C6 alkyl optionally substituted with: -a halogen, -an alkoxy, or -a C6 to Cg aryl,
-a 5 or 6 membered heterocycle, -a Ce to Cg aryl, optionally substituted with a halogen,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to Ce alkyl(s), -a hydrogen,
and where R0 is:
-a hydrogen,
-a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above,
-a haloalkyl, or
-a haloalkoxy, -a -NR1CONRqRr group, where Rq is:
-a hydrogen,
-a Ci to C6 alkyl,
-a haloalkyl, -a haloalkoxy, or
-a -CORx group, where Rx is as defined above, and where R1 is:
-a Ce to Cg aryl optionally substituted with:
-a Ci to C6 alkyl,
-a haloalkyl,
-a -ORs group, where Rs is a CO to Cg aryl, or
-a -COORx group, where Rx is as defined above, -a C] to Ce alkyl optionally substituted with one or more of the following;
-a halogen,
-an alkylene,
-a Ce to Cg aryl, and/or
-a -COORx group, where Rx is as defined above, -a -COORx group, where Rx is as defined above,
-a -NRtCOORu group, where Ru is:
-a Ci to Ci2 alkyl, optionally substituted with:
-a Ce to Cg aryl optionally substituted with a Ci to C& alkyl or an alkoxy, -an alkylene, -an alkoxy,
-an alkyne, -a halogen, or
-a 5 or 6 membered heterocycle, -a Ce to Cg aryl, optionally substituted with: -an alkoxy,
-a halogen, or -a Ci to Ce alkyl, or -a 5 or 6 membered heterocycle, -a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy,
-a -NRvSθ2Rw group, where Rv is: -a hydrogen,
-a -CORx, where Rx is as defined above, or -a Ci to Ce alkyl, optionally substituted with:
-a halogen,
-a -CORx group, where Rx is as defined above,
-a -OCORx group, where Rx is as defined above,
-a hydroxy, or
-an alkoxy, and where Rw is:
-a Ci to Ce alkyl optionally substituted with:
-a halogen,
-a haloalkyl,
-a Ce to Cg aryl, or
-a 5 or 6 membered heterocycle, -a Cz to Ce alkylene, • .
-an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl,
-a 5 or 6 membered heterocycle, or
s optionally substituted with a Ci to Ce alkyl, where Ry is i
Ci to Ce alkyl or hydrogen,
where Rz is hydrogen or a Ci to Ce alkyl, optionally substituted with a Ce to Cs aryl, -a -SRx group, where Rx is as defined above, -a -SC^Raa group, where R33 is:
-a C, to C6 alkyl, - -an amino. group, _ _. _ _ _ .
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -COORx group, where Rx is as defined above,
-a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, and/or -a -NHRbb group, where Rbb is:
-a -PO(ORX)2 group, where Rx is as defined above; = Rcc group, where RcC is:
-a naphthalene,
-a 5 or 6 membered heteroaryl,
-a Cβ to Cs aryl, optionally substituted with one or more of the following: -an alkoxy, -a hydroxy, -a halogen,
-a Ci to Ce alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Cj to C$ alkyl(s), -a -NHPORxRx, where Rx is as defined above,
-a -NReeCONRffRff group, where R∞ is a hydrogen or a Ci to Ce alkyl, optionally substituted with a halogen, and Rfr is:
-a hydrogen,
-a haloalkyl,
-a haloalkoxy,
-a Ci to Cδ alkyl, or -a -CORx, where Rx is as defined above, -a -NRggCORhh group, where Rhh is: -a hydrogen,
-a C1 to C6 alkyl optionally substituted with: -an alkoxy,
-a halogen, or
-an amino optionally substituted with one or more Ci to Ce alkyl(s),
-an amino optionally substituted with one or more Ci to C6 alkyl(s), where the alkyls are optionally substituted with a halogen,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, is:
-a hydrogen, -a Ci to C 6 alkyl,
-a haloalkyl, -a haloalkoxy, or
-a -CORx group, where Rx is as defined above, -a haloalkyl, -5 or 6 membered heterocycle groups,
-an amiαo optionally substituted with one or more Ci to C6 alkyl(s), and/or -a -NRnSOiRx group, where Rx is as defined above, and RH is: -a hydrogen, -a Ci to C6 alkyl, -a haloalkyl,
-a haloalkoxy,
-a -CORx group, where Rx is as defined above; Z is:
-a Ci to C6 alkyl optionally substituted with: -an alkoxy,
-one or more halogen(s), or -a C6 to C8 aryl; -a C2 to Ce alkylene; -a C6 to Cg aryl optionally substituted with an alkoxy or one or more Ci to C6 alkyl(s); -a -COORx group, where Rx is as defined above, or
R is a hydrogen, a halogen or an alkoxy;
Ri is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s),
-a Ce to Cg aryl, or
-a 5 or 6 membered heterocycle; -a C(y to Cg aryl optionally substituted with an alkoxy; -a -CORx group, where Rx is as defined above;
-a Ci to Cβ alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or Ri joins together with R2 to form:
R2 is:
-a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
-a Ci to Cβ alkyl group, optionally substituted with one or more halogen(s); -an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s),
-an -OCORx group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy,
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Cβ alkyl,
-a 5 or 6 membered heteroaryl group, or
-a C6 to Cs aryl group;
-a -COORx group, where Rx is as defined above; -a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or
-a Ce to Cg aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORjj group, where Rj,- is:
-an alkoxy, or
-an amino optionally substituted with one or more Cj to Cg alkyl(s); -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; -a -NHSO2RJC group, where Rx is as defined above; or R2 joins together with Rj to form:
R3 is:
-a hydrogen; or -CH2OCORx, and Rx is as defined above; provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Ri is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is:
-a Ci to Ce alkyl substituted with: -an alkoxy,
-one or more halogen(s), or -a C6 to C8 aryl; -a C2 to Ce alkylene;
-a Ce to Cs aryl optionally substituted with an alkoxy or one or more Ci to Ce alkyl(s); -a -COORx group, where Rx is as defined above; or
or one or more pharmaceutically acceptable salt(s) thereof.
The pharmaceutical composition may be formulated to achieve a physiologically compatible pH, ranging from a pH of about 3 to a pH of about 11. In some embodiments, the pharmaceutical composition is formulated to achieve a pH of about 3 to a pH of about 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of about 5 to a pH of about 8.
The pharmaceutical composition may comprise a combination of compounds of the present invention, or may include a second active ingredient useful in the treatment of viral infections, such as anti-viral agents that include, but are not limited to: pegylated interferon, including by way of non-limiting example pegylated α-interferon; un-pegylated interferon, including by way of non-limiting example, un-pegylated α-interferon; ribavirin or prodrugs or derivatives thereof; protease inhibitors; polyermase inhibitors; p7 inhibitors; entry inhibitors, including fusion inhibitors such as Fuzeon™ (Tiimeris); helicase inhibitors; a Toll-like receptor agonist, a caspase inhibitor, anti-fϊbrotics; drugs that target IMPDH (inosine monophosphate dehydrogenase inhibitors), such as Merimepadib™ (Vertex Pharmaceuticals Inc.); synthetic thymosin alpha I (ZADAXIN™, SciClone
Pharmaceuticals Inc.); a glycosidase inhibitor; a glucosidase inhibitor; therapeutic viral vaccines, such as those produced by Chiron and Immunogenics; and immunomodulators, such as histamine, antibodies against HCV, such as XTL-6865 and XTL-002 (XTL Biopharmaceuticals), antisense RNA, ribozymes, RNAi, and anti-HCV agents with unknown mechanism of action.
The term "pharmaceutically acceptable excipient" refers to an excipient for administration of a pharmaceutical agent, such as the compounds of the present invention. The term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients may be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form. Nonlimiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington's Pharmaceutical Sciences).
Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.
The pharmaceutical compositions of the invention may be formulated in any form suitable for the intended method of administration. Suitable formulations for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhaleable formulations for pulmonary administration include liquids and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration. When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
Pharmaceutically acceptable excipients suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscaπnellose sodium, cross- linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer peπod For example, a tune delay mateπal such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil
In other embodiments, pharmaceutical compositions of the invention may be formulated as suspensions comprising one or more compound(s) of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension In yet other embodiments, pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of one or more excipient(s).
Excipients suitable for use m connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g , lecithin), a condensation product of an alkylene oxide with a fatty acid (e g , polyoxyethylene stearate), a condensation product of ethylene oxide with a long cham aliphatic alcohol (e g , heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester deπved from a fatty acid and a hexitol anhydride (e g., polyoxyethylene sorbitan monooleate), and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-ρropyl p-hydroxy-benzoate; one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin
The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these Suitable emulsifying agents include naturally-occurπng gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids, hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
Additionally, the pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-proρane-diol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. The compounds of the invention may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids. Thus, contemplated in the invention are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g. , increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterifϊcation, glycosylation, PEGylation, etc.
In some embodiments, the compound of the invention is formulated for oral administration in a lipid-based composition suitable for low solubility compounds. Lipid- based formulations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions of the invention may comprise a effective amount of one or more compound(s) of the invention, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polyoxyl 40 hydrogenated castor oil.
In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextπn include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin, and hydroxypropyl-β-cyclodextrin (HPBC). In some embodiments, the pharmaceutical composition further comprises about 0.1% to about 20% hydroxypropyl-β-cyclodextrin, about 1% to about 15% hydroxypropyl-β-cyclodextrin, or about 2.5% to about 10% hydroxypropyl-β-cyclodextrin. The amount of solubility enhancer employed may depend on the amount of the compound of the present invention in the composition.
F. Combination Therapy
It is also possible to combine any compound of the present invention with one or more other active ingredients useful in the treatment of HCV infection, including compounds, in a unitary dosage form, or in separate dosage forms intended for simultaneous or sequential administration to a patient in need of treatment. When administered sequentially, the combination may be administered in two or more administrations. In an alternative embodiment, it is possible to administer one or more compounds of the present invention and one or more additional active ingredients by different routes.
The skilled artisan will recognize that a variety of active ingredients may be administered in combination with the compounds of the present invention that may act to augment or synergistically enhance the viral inhibiting activity of the compounds of the invention. Such active ingredients include anti-HCV agents. Anti-HCV agents include agents that target the virus as well as agents that have an immunomodulatory effect. For example, anti-HCV agents include, but are not limited to, interferon, including, for example without limitation, IFN-α, ribavirin or prodrugs or derivatives thereof; protease inhibitors, polymerase inhibitors, helicase inhibitors, a Toll-like receptor agonist, a caspase inhibitor and a glycosidase inhibitor, antibodies against HCV, such as XTL-6865 and.XTL-002 (XTL Biophatrmaceuticals), antisense RNA, ribozymes, RNAi, and anti-HCV agents with unknown mechanism of action.. Furthermore, the compounds of the invention may also be administered in combination with other compounds that affect IRES activity.
According to the methods of the invention, the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods of the invention may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used.
To assist in understanding the present invention, the following Examples are included. The experiments relating to this invention should not, of course, be construed as specifically limiting the invention and such variations of the invention, now known or later developed, which would be within the purview of one skilled in the art are considered to fall within the scope of the invention as described herein and hereinafter claimed.
It will be apparent to those skilled in the art that specific embodiments of the present invention may be directed to one, some or all of the above-indicated aspects as well as other aspects, and may encompass one, some or all of the above- and below- indicated embodiments, as well as other embodiments.
Other than in the working examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified by the term "about". Accordingly, unless indicated to the contrary, such numbers are approximations that may vary depending upon the- desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application, of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques. While the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the working examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
EXAMPLES
The present invention is described in more detail with reference to the following non-limiting examples, which are offered to more fully illustrate the invention, but are not to be construed as limiting the scope thereof. The examples illustrate the preparation of certain compounds of the invention, and the testing of these compounds in vitro and/or in vivo. Those of skill in the art will understand that the techniques described in these examples represent techniques described by the inventors to function well in the practice of the invention, and as such constitute preferred modes for the practice thereof. However, it should be appreciated that those of skill in the art should in light of the present disclosure, appreciate that many changes can be made in the specific methods that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Example 1: Preparation of Compounds of the Invention
Example IA: Preparation of l-ethyl-ό-methoxy-lH-indole-S-carbonitrile (compound 5).
Step A: A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120 mL) is cooled to O0C and treated with chlorosulfonyl isocyanate (7.72 mL, 88.4 mmol). After the addition, the reaction mixture is stirred at this temperature for Ih. The dark solution is poured into ice water (600 mL) and the light brown solid is collected by filtration, washed with additional H2O and dried to afford 9.9 g (85%) of ό-methoxy-lH-indole-S-carbonitrile as a light brown solid. Step B: To a solution of 6-meώoxy-lH-mdole-3-carbonitrile (9.9 g, 57.6 mmol) in DMF (150 mL) is added NaH (60% dispersion in mineral oil, 3.45 g, 86.3 mmol). The reaction mixture is stirred for 15 min and then ethyl iodide (5.53 mL, 69.1 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is then diluted with H2O and extracted with EtOAc (2X). The organic phases are washed with H2O (3X) and saturated NaCl and then dried and concentrated to a semi-solid. The crude product is purified via column chromatography on silica gel (200 g) using CH2Cl2/hexanes (50-100%) as eluent to yield 6- methoxy-l-ethyl-lH-indole-3-carbonitrile as a tan solid.
Utilizing steps A and B above and substituting different indoles and alkyl halides gives < the following compounds: Compounds 43, 45, 51, 52, 108, 109, 115, 118, 120, 123, 126, 179 and 714.
Example IB: Preparation of 6-ethoxy-l-ethyl-lH-indole-3-carbonitrile (compound 9).
Λ
Step A: To a solution of l-ethyl-ό-methoxy-lH-indole-S-carbonitrile (2.85 g, 14.2 mmol), prepared by example IA, step B, in CH2CI2 (40 mL) is added a IM solution of BBr3 in CH2CI2 (28.5 mL, 28.5 mmol) at O0C. The mixture is allowed to warm to room temperature and kept for 2.5h. The dark reaction mixture is then poured onto ice and sufficient IM NaOH is added until the pH is 8-9. The product is extracted with CH2Cl2 (3X) and the combined organic phases are washed with saturated NaHCC>3, H2O and saturated NaCl. After drying over MgSO4, the solution is concentrated and the product is purified by chromatography (EtOAc/CH2Cl2, 0-10%) to afford 2.15 g (82%) of 6-hydoxy-l-ethyl-lH-ώdole-3-carborutrile as a yellow solid.
Step B: To a solution δ-hydoxy-l-ethyl-l/if-indole-S-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodoethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H2O and extracted with EtOAc (3X). The combined organic phases are dried and concentrated. Flash chromatography (CH2Cl2) gives 94 mg (100%) of 6-ethoxy-l -ethyl- IH- indole-3-carbonitrile as a white wax.
In similar fashion, following steps A and B, above, the following compounds are also prepared: Compounds 6, 10, 11, 12 and 24
Example 1C: Preparation of 5-(4-methoxyphenyl)-5H-[l,3]diox.olo[4,5-fjindole-7- carbonitrile (compound 44).
CuI, ligand toluene, reflux
A mixture of p-iodoanisole (85 mg, 0.36 mmol), anhydrous K3PO4(102 mg, 0.48 mmol), CuI (4.6 mg, 0.024 mmol) and N,N'-Dimethyl cyclohexane-l,2-diamine (14 mg, 0.096 mmol) is added to 5H-[l,3]dioxolo[4,5-fJindole-7-carbonitrile (45 mg, 0.24 mmol), prepared as described by the method of example IA, step A, in anhydrous toluene (0.4 mL). After heating at reflux for 24h, the solvent is evaporated under vacuum. The residue is dissolved with CH2Cl2 (5 mL) and the mixture is filtered. The filtrate is concentrated to afford crude product, which is purified by silica gel chromatography using EtOAc/petroleum ether (1 :4) as eluent to yield 5-(4-methoxyρhenyl)-5H-[l ,3]dioxolo[4,5-fJindole-7-carbonitrile. Utilizing the procedure above and substituting different aryl iodides gives the following compounds: Compounds 4, 8, 102, 103, 111, 112, 117, 119, 124, 125, 127, 154.
Example ID: Preparation of l-ethyl-6-(pyrazin-2-yloxy)-li7-indole-3-carbonitrile (compound 13).
DMF, 110°C
To a solution of l-ethyl-6-hydroxy-lJϊ-indole-3-carbonitrile (60 mg, 0.32 mmol) prepared as described in example IA, step A, in DMF (5 mL) is added K2CO3 (55 mg, 0.40 mmol) and 2-chloropyridazine (45 rng, 0.40 mmol). The mixture is heated at 11O0C for 18h. After cooling to room temperature, the reaction mixture is diluted with H2O and extracted with EtOAc (3X). The combined organic phases are washed with H2O and saturated NaCl, dried and concentrated. The product is isolated by chromatography (EtOAc/CH2Cl2, 1-3%) over silica gel to afford 76 mg (96%) of the title compound, l-ethyl-6-(ρyrazin-2-yloxy)-lH'-indole- 3-carbonitrile, as an off-white solid.
Example IE: Preparation of S-cyano-l-ethyl-lH-indole-β-carboxylic acid phenylamide (compound 15).
Step A: A solution of methyl 3-cyano-l-ethyl-li/-indole-6-carboxylate (1.6Og, 7.02 rαmol), prepared by the method described in example IA from methyl liϊ-indole-6- carboxylate, in THF (35 mL) is treated with IN NaOH (7.7 mL, 7.7 mmol) and heated at reflux for 2.5h. After cooling to room temperature, most of the THF is removed and the solution is diluted with H2O and extracted with ether (2X). The ether extracts are discarded. The aqueous phase is then acidified with 6N HCl to pH 2 and then extracted with EtOAc (3X). The EtOAc layers are combined, washed with saturated NaCl and then dried and concentrated to afford 1.43 g (95%) of S-cyano-l-ethyl-lH-indole-ό-carboxylic acid as a white solid.
Step B: A suspension of 3-cyano-l-ethyl-lH-indole-6-carboxylic acid (0.42 g, 1.96 mmol) in CΗ2CI2 (15 mL) is cooled to 00C. The suspension is treated with DMF (2 drops) and then oxalyl chloride (0.34 mL, 3.92 mmol) is added via syringe during 2 minutes after which the ice bath is removed and the reaction mixture is allowed to warm to ambient temperature during 1.5h during which time the reaction becomes a yellow solution. The solution is then concentrated in vacuo to afford 0.46 g (quantitative yield) of 3-cyano-l-ethyl-liϊ-indole-6- carbonyl chloride as a yellow solid.
Step C: A suspension of 3-cyano-l -ethyl- lH-indole-6-carbonyl chloride (70 mg, 0.30 mmol) in TΗF (5 mL) is cooled to 00C and treated with aniline (0.08 mL, 0.90 mmol). After the addition, the reaction is warmed to ambient temperature and after stirring for an additional 16 hours, the reaction mixture is diluted with Η2O and extracted with EtOAc (2X). The combined organic phases are washed with saturated NaCl and then dried and concentrated to afford the product. Chromatography (EtOAc/CH2Cl2, 2/98) over silica gel gives 44 mg (51%) of 3-cyano-l -ethyl- lH-indole-6-carboxylic acid phenylamide.
Utilizing essentially the procedure above gives the following compound: Compound 89.
Example IF: Preparation of t-butyl (3-cyano-l-ethyl-lH-indol-6-yl)-carbamate (compound 16).
A solution of S-cyano-l-ethyl-lH-indole-ό-carboxylic acid (0.60 g, 2.80 mmol) from Example IE, step A, in t-butanol (20 mL) is treated with Et3N (0.46 mL, 3.36 mmol) and diphenylphosphoryl azide (0.73 mL, 3.36mmol) and then heated at reflux for 4h. After cooling to room temperature, most of the t-butanol is removed in vacuo to give an oil, which is then dissolved in EtOAc. After washing with Η2O, the organic phase is back-extracted with EtOAc and the organic layers are combined and washed sequentially with additional H2O, saturated
NaHCO3 and saturated NaCl. The organic phase is dried, concentrated and the resulting crude product is purified by chromatography over silica gel using EtOAcZCH2Cl2 (0-1%) to afford 0.52 g (65%) of t-butyl (S-cyano-l-ethyl-lH-indol-ό-y^-carbamate as a white solid. The following compound is made in similar fashion. Compound 90.
Example IGa: Preparation of 2-(4-aminophenyl)-l-ethyl-6-methoxy-lH-indole-3- carbonitnle via Suzuki route (compound 55).
reflux
Step A- A 2M solution of lithium diisopropyl amide in THF/hexanes (Acros) (3.9 mL, 7 8 mmol) is diluted with TKDF (5 mL) in a flame-dried flask. After cooling the reaction to — 3O0C, a solution of l-ethyl-β-methoxy-lH-indole-B-carbomtrile (1.30 g, 6.5 mmol) in THF (10 mL) is added dropwise during 10 mm, maintaining the temperature at -3O0C After stirring for an additional 30 min at this temperature, a solution of iodine (2 31 g, 9 1 mmol) in THF (5 mL) is added during 10 min After the addition, the reaction is warmed to ambient temperature during Ih. The reaction is then diluted with ice-H2O and extracted with EtOAc (2X). The combined organic phases are washed with IM sodium tibiosulfate and saturated NaCl and then concentrated to a brown solid. Chromatography (CH2Cl2/hexanes, 1/1) over silica gel gives 1.31 g (62%) of l-ethyl-2-iodo-6-methoxy-li/-indole-3-carbomtrile as an off-white solid
Step B: A mixture of l-eώyl-2-iodo-6-methoxy-lH-indole-3-carbonitrile (1.25 g, 3.83 mmol), 4-(4,4,5,5-tetramethyl)-l,3-2-dioxaboralanyl-2-yl-anilrne (0.96 g, 4.90 mmol), CsF (1.46 g, 9.58 mmol) and Pd(PPh3)2Cl2 (110 mg, 0.15 mmol) in DME (20 mL) is added to a flask and alternatively evacuated and flushed with N2. The reaction is men heated at reflux for 24h and then cooled to room temperature. The reaction mixture is diluted with H2O and extracted with EtOAc (2X). The combined organic phases are washed with H2O and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix is purified by flash chromatography on silica gel using EtOAc/CH2Cl2 (5/95) as eluent to afford 765 mg (69%) of 2-(4-ammophenyl)-l-ethyl-6-methoxy-lJτT-indole-3-carbomtπle as a yellow solid.
Utilizing essentially the same procedure described above and substituting different boronic acids gives the following compounds: Compounds 19, 20, 21, 22, 53, 63, 70, 71, 74, 76, 77, 79, 80, 100, 110, 229, 239, 240, 247, 250, 254, 255, 256, 257, 258, 259, 260, 281, 282, 283, 284, 286, 335, 336, 337, 338, 339, 347, 348, 426, 427, 428, 429, 476, 543, 578, 758.
Example IGb: Preparation of 2-(4-aminophenyl)-l-butyl-6-methoxy-lH-indole-3- carbonitrile via alternative Suzuki route.
DMF
To a solution of (i-Pr)2NH (1.35 mL, 9.65 mmol) in THF (30 mL) cooled to -780C is added n-BuLi (3.7 mL, 2.5M in hexanes, 9.21 mmol) in one portion. The acetone/dry ice bath . is exchanged for ice/water bath and the solution is stirred further for 40 miri. The solution is cooled to — 78°C and solution of l-butyl-6-me&oxy-lH-mdole-3-carbonitrile, prepared as in example IA (2.0 g, 8.77 mmol) in THF (10 mL) is added dropwise. This solution is stirred for 15 min at -780C, following by 20 min at -200C. Trimethyl borate (1.0 mL, 8.77 mmol) is added, the reaction mixture is stirred for 15 min at -200C after which the cooling bath is removed and this solution is stirred further at room temperature for Ih. A solution OfKsPO4 is added (11.7 mL, 3M aqueous solution, 35.1 mmol) followed by a solution of 4-iodoaniline (2.5 g, 11.40 mmol) and PdCl2dppf catalyst (640 mg, 0.88 mmol) in DMF (40 mL, plus a 5 mL rinse). The reaction mixture is stirred overnight (ca. 18h) and then water (80 mL) is added and the product is extracted with EtOAc (3X50 mL). The combined organic fractions are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified via flush chromatography on silica gel (5—»60% EtOAc/Hexanes as eluant) to afford the desired 2-(4-aminophenyl)-l-butyl-6-methoxy-lH-indole-3-carbonitrile as a tan solid (2.4 g, 86% yield).
The following compounds are prepared in similar fashion utilizing other indole and aryl and hereroaryl bromides and iodides: Compounds 656, 659, 660, 661, 682, 683, 712, 731, 732, 733, 806, 807, 808, 809, 810, 811, 812, 813, 814, 827. Example IGc: Preparation of 2-(4-aminophenyl)-6-methoxy-l-propyl-lH-indole-3- carbonitrile via Negishi route.
A nitrogen-purged flask fitted with a septum and a nitrogen needle is charged with dry TΗF (all additions performed by syringe) (20 mL). Diisopropylamine (Aldrich Sure-Seal, 2.00 mL, 14.3 mmol) is added, and the solution is cooled to O0C. n-Butyllithium (8.50 mL of 1.6 M solution in hexane, 13.6 mmol) is added slowly. The flask is allowed to warm to room temperature briefly, and then is cooled to -78°C. A concentrated TΗF solution of 6-methoxy- l-propyl-l/f-indole-3-carbonitrile (2.77 g, 12.9 mmol; prepared analogously to compound 5 of Example IA) is added slowly, and the resulting solution is maintained at -78°C for 30 min. The flask is then transferred to a water-ice bath and allowed to come to 00C for about 15 minutes. The solution is once again cooled to -78°C, and ZnCk (0.5 M solution in TΗF, 27.0 mL, 13.5 mmol) is slowly added. A precipitate is observed at this point, which may be the bis(indole)zinc compound, but the solution becomes homogeneous when the entire volume of zinc chloride solution is added. After about 10 minutes, the solution is allowed to come to room temperature, and a TΗF solution (5 mL) of 4-iodoaniline (3.47 g, 15.8 mmol) and triphenylphosphine (338 mg, 1.29 mmol) is added. The septum is removed, and solid Pd2(dba)3 (295 mg, 0.322 mmol) is added. A reflux condenser is fitted to the flask, and the solution is degassed by three successive cycles of vacuum pumping/N2 purging. The solution is then heated to reflux overnight. After cooling to room temperature, the solution is poured into 4 volumes of water, and 4 volumes of ethyl acetate are added. The resulting mixture is vigorously stirred for 30 minutes, then filtered through celite (with ethyl acetate washing) to remove solid Zn- and Pd-containing material. The phases are separated, and the aqueous phase is extracted with more ethyl acetate. The organic phases are washed in sequence with saturated brine, combined, dried over anhydrous sodium sulfate, filtered and evaporated. A solid precipitate forms at this point, which is sufficiently pure product and is collected by trituration with ether and filtration. The remaining material is purified by column chromatography (eluting 1:2 ethyl acetate-hexane on silica gel 60). Total yield of the product, 2-(4-amino- phenyl)-6-methoxy-l -propyl- li/-indole-3-carbonitrile, is 2.75 g (8.99 mmol, 70%). The following compounds are made using essentially the same procedure and substituting other aryl or heteroaryl iodides or bromides: Compounds 393, 408, 430, 431, 436, 437, 438, 459, 460, 461, 462, 483, 484, 632, 633, 634, 635, 636, 650, 651.
Example IGd: Preparation of l-ethyl-2-(3-hydroxyphenyl)-6-methoxy-lH-indole-3- carbonitrile (Compound 288).
Step A: A solution of THF (60 mL) and diisopropylamine (5.5 mL, 39 mmol) is cooled to -78°C. n-Butyllithium (14.5 mL, 2.5M in hexanes, 36.2 mmol) is added dropwise over 5 minutes. The LDA mixture is stirred at -780C for 10 minutes, and then at 00C for 20 minutes. The solution is re-cooled to -780C. l-ethyl-6-methoxy-li/-indole-3-carbonitrile (5.0 g, 25 mmol), prepared as in example IA, is taken up in THF (30 mL) and added dropwise to the LDA mixture over 15 minutes. The reaction is stirred at -780C for 10 minutes, and at 00C for 30 minutes. Once again, the reaction mixture is cooled to -780C. Tributyltin iodide (10 mL, 35 mmol) is added dropwise. This is stirred at -78°C for 15 minutes, and then at O0C for 30 minutes. The reaction mixture is absorbed onto silica gel and concentrated. Purification by chromatography (CH2CI2) yields l-ethyl-6-methoxy-2-tributylstannanyl-lif-indole-3- carbonitrile (12.05 g, 98%).
Step B: l-Ethyl-6-methoxy-2-tributylstannanyl-l//-indole-3-carbonitrile (1.0 g, 2.05 mmol), prepared in step A, is combined with 3-iodophenol (474 mg, 2.15 mmol), Pd(PPl^Ck (67 mg, 0.102 mmol), CuI (75 mg, 0.39 mmol) and THF (4.0 mL). This mixture is heated at 65°C overnight. The reaction mixture is diluted in EtOAc, and is filtered through celite. The filtrate is concentrated and the residue is purified by silica gel chromatography (4:1, CH∑Cb/EtOAc) to yield crude product. Ether trituration yields l-ethyl-2-(3-hydroxy-ρhenyl)- 6-methoxy-l//-indole-3-carbonitrile (430 mg, 72%) as a yellow-white solid.
The following compounds are prepared similarly as above, using other commercially available iodides and bromides, or using iodides derived from a one step amidation of p- iodophenylsulfonyl chloride: Compounds 275, 276, 277, 278, 331, 363, 364, 373, 374, 375, 474, 475, 678. Example IGe: Preparation of ethanesulfonic acid [4-(3-cyano-6-difluoromethoxy-l- ethyl-l//-indol-2-yl)-phenyl]-amide via Heck route (compound 519).
Step A: A solution of 6-difluoromethoxy-l -ethyl- lH-indole (402.8 mg, 2.04 mmol), ethanesulfonic acid (4-iodo-phenyl)-amide (712.1 mg, 2.29 mmol), cesium carbonate (733.2 mg, 3.82 mmol), triphenylphosphine (33.1 mg, 0.13 mmol) and palladium acetate (5.7 mg, 0.025 mmol) in DMF (5 ml) is heated to 135°C for 48h. The reaction mixture is diluted with water and extracted with EtOAc (2 X 10 mL). The combined organic phases are washed with brine, dried over MgSO4, and then concentrated. The residue is purified via column chromatogrphy on silica gel (25 g) using EtOAc/Ηexanes (10-20%) as eluent to afford 298.2 mg (37.1% yield) of ethanesulfonic acid [4-(6-difluoromethoxy-l -ethyl- lΗ-iodo-2-yl)-phenyl]- amide, compound 516, as a light brown solid.
Step B: Following the procedure IA5 step A, ethanesulfonic acid [4-(6- difluoromethoxy-l-ethyl-lH-iodo-2-yl)-phenyl]-amide is converted to ethanesulfonic acid [4- (3-cyano-6-difluoromethoxy-l -ethyl-liϊ-indol-2-yl)-ρhenyl]-amide, compound 519.
Following steps A and B above, the following compounds are prepared in similar fashion: Compounds 343, 344, 345, 346, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 515, 517, 518, 520, 521, 522, 523, 524, 575, 577, 579, 580, 611, 612, 613, 614
Example IH: Preparation of l-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-l/?-indole- 3-carbonitrile (compound 67).
DMF Et3N 8O0C
A mixture of l-ethyl-2-iodo-6-methoxy-lH-indole-3-carbonitrile (150 mg, 0.46 mmol), prepared as described in example IGa, step A, 4-fiuorophenylacetyleiie (80 mg, 0.0.69 mmol), bis(triphenylphosphine) palladium (II) dichloride (6 mg, 0.009 mmol) and CuI (4 mg, 0.018 mmol) is added to a sealable tube and alternately evacuated and flushed with N2. To the tube is then added DMF (4 mL) and Et3N (0.25 mL, 1.84 mmol) and the reaction is heated at 800C for 2Oh and then cooled to room temperature. The reaction mixture is diluted with H2O and extracted with EtOAc (2X). The combined organic phases are washed with H2O (3X) and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix is absorbed on silica gel (0.6 g) and chromatographed over silica gel using EtOAc/hexanes (10- 20%) as eluent to afford 120 mg (82%) of l-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-l/f- indole-3-carbonitrile as a yellow solid.
Utilizing essentially the same procedure described above and substituting different acetylene derivatives gives the following compounds: Compounds 64, 65, 66, 68, 69, 91, 92, 93, 94, 95, 96, 133, 134, 135, 136, 137, 143, 144, 145, 146, 147, 148, 149, 150, 151, 158, 159, 160, 161, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 184, 185, 186, 187, 188, 196, 197, . 198, 199, 200, 201, 202, 223, 230, 231, 232, 233, 234, 235, 236, 237, 238.
Example II: Preparation of l-ethyl-3-(5-ethyl-[l,2,4]oxadiazol-3-yl)-6-methoxy-li?- indole (compound 28).
Step A: A solution of l-ethyl-6-methoxy-lH-indol6-3-carbonitrile (1.00 g, 5.00 mmol) in MeOH (10 mL) is treated with a 50% aqueous solution of hydroxyaxnine (0.38 mL, 6.25
2S3 mmol) and heated at reflux for 18h. After cooling to room temperature, the heterogeneous mixture is filtered to afford 525 mg of desired product as a tan solid. The filtrate is concentrated to an oil, which is then dissolved in CH2CI2 and chromatographed over silica gel using EtOAc/CH2Cl2 (15-50%) to afford an additional 295 mg of product as a tan solid. Total yield of l-ethyl-N-hydroxy-ό-methoxy-lH-indole-S-carboxamidine is 820 mg (70%).
Step B: The N-hydroxycarboxamidine above (50 mg, 0.21 mmol), polystyrene- diisopropylethylamine 165 mg, 3.90 mmol/g loading) and propionyl chloride (0.03 mL, 0.32 mmol) in CH2CI2 (10 mL) are placed in a tube and rotated for 22h at room temperature. After this time, trisamine resin (77mg, 2.71 mmol/g loading) is then added and the tube rotated for an additional 30 min at room temperature. Solids are filtered and then the filtrate is concentrated and diluted with toluene (5 mL) and heated at 1100C overnight. The crude reaction mixture is concentrated and purified by chromatography (EtOAc/CϊfeCk, 2/98) to afford 27 mg (46%) of l-ethyl-3-(5-ethyl-[l,2,4]oxadiazol-3-yl)-6-methoxy-lH-indole as a white solid.
The following compound is prepared utilizing the above procedure with substitution of the appropriate acyl halide: Compound 29.
Example IJ: Preparation of l-ethyl-6-methoxy-3-(5-ethyl-[l,3,4]oxadiazol-2-yl)-lH- indole (compound 54).
Step A: A mixture of l-ethyl-6-methoxy-li7-indole-3-carbonitrile (1.00 g, 5.00 mmol) in toluene (30 mL) is treated with triethylamine hydrochloride (1.03 g, 7.50 mmol) and sodium azide (0.49 g, 7.50 mmol) and is heated at reflux for 16h. After cooling to room temperature, the reaction mixture is diluted with saturated NaHCC>3 and extracted with EtOAc. The organic layer is then washed with additional NaHCθ3 (2X). The combined aqueous phases are acidified to pH 2 with 6N HCl. The resultant thick precipitate is extracted with hot EtOAc (3X) and the combined organic phases are washed with saturated NaCl and dried and concentrated to give 0.55 g (45%) of l-ethyl-o-methoxy-S^lH-tetrazol-S-y^-lH-indole as a yellow solid.
Step B: A suspension of the tetrazole above (50 mg, 0.21 mmol) and propionyl chloride (0.03 mL, 0.31 mmol) in dichloroethane (5 mL) is heated at reflux for 21h. After cooling the reaction mixture to room temperature, polystyrene trisamine resin (70 mg, 3.4 meq/g) is added and the reaction is rotated for 4h at room temperature. After filtering off the resin, and removal of the solvent, the crude product is absorbed on silica gel and the product is isolated by silica gel chromatography (EtOAcZCH2Cl2, 5-10%) to afford 30 rng (53%) of l-ethyl-6-methoxy-3- (5-ethyl-[l,3,4]oxadiazol-2-yl)-lH-indole as a tan solid.
Example IK: Preparation of ethyl 5-difiuoromethoxy-l-(4-methoxyphenyl)-2-methyl- lif-indole-3-carboxylate (compound 49).
Freon-22 (HCF2Cl) gas is bubbled into a solution of ethyl 5-hydroxy-l-(4- methoxyphenyl)-2-methyl-l//-indole-3-carboxylate (250 mg, 0.77 mmol) in CH2Cl2 (5 mL) at 00C containing a small amount of tetrabutylammonium bromide as a phase transfer catalyst. A 50% solution of NaOH is added dropwise at O0C. After the addition, the mixture is stirred at 00C for 2h. After the addition OfH2O, the organic phase is separated and washed with brine and dried over Na2SO4. The solvent is then concentrated and the residue is purified by column chromatography over silica gel using EtOAc/petroleum ether (1/2) as eluent to yield the desired product in 40% yield.
The following compounds are prepared utilizing the above procedure with substitution of the appropriate hydroxyindole: Compounds 18, 46, and 50.
Example IL: Preparation of l-[5-methoxy-l-(4-methoxyphenyl)-l-H-indol-3-yl]- ethanone (compound 42).
5-Methoxy-l-(4-methoxyphenyl)-l-i?-indole (50 mg, 0.2 mmol), prepared by the method of example 1C, is dissolved in 1 mL OfCH2Cl2 at O0C. Et2AlCl (300μL, IM in hexanes, 0.3 mmol) is then added. After stirring at O0C for 30 min, a solution of acetyl chloride (22 μL, 0.3 mmol) in 1 mL OfCH2Cl2 ;s added dropwise. This is stirred at O0C for a further 90 min. The reaction mixture is quenched with H2O and is extracted with CH2Cl2 and concentrated in vacuo. Purification by column chromatography on silica gel EtOAc/CH2Cl2 (5/95) yields the title compound as a white solid (42 mg, 71%).
Utilizing essentially the same procedure described above and substituting different acyl chlorides, the following compounds are prepared: Compounds 32, 33,.34, 37, 38, 39, 47, 48.
Example IM: Preparation of l-ethyl-3-isoxazol-3-yl-6-methoxy-l-iϊ-indole (compound
57).
Step A: A mixture of l-(l-ethyl-6-methoxy-l-H-indole-3-yl)ethanone (200 mg, 0.92 mmol), prepared from l-ethyl-6-methoxy-lH-indole by the procedure described in example IL, hydroxyamine hydrochloride (128 mg, 1.84 mmol), NaOAc (151 mg, 1.84 mmol) and EtOH (7mL) is heated at 85°C for 4h. The reaction mixture is then partitioned between H2O and EtOAc. The organic phase is dried and concentrated in vacuo. Purification by column chromatography using EtO Ac/CH2Cl2 (1/9) yields l-(l-ethyl-6-methoxy-l-H-indole-3- yl)ethanone oxime as a white solid (189 mg, 92%).
Step B: l-(l-Ethyl-6-methoxy-l-H-indole-3-yl)ethanone oxime (100 mg, 0.43 mmol) is dissolved in THF (900 μL) at O0C. n-BuLi (450 μL, 2.5 M in hexanes, 1.12 mol) is added dropwise, resulting in instant precipitation of solids. DMF (70 μL, 0.9 mol) in 260 μL of THF is then added dropwise. This is stirred at 00C for Ih, then at room temperature for Ih. The reaction mixture is pipetted into a mixture containing 1 mL of H2O, 1 mL of THF, and 100 μL of concentrated H2SO4. This mixture is heated at 750C for Ih and then is partitioned between H2O and EtOAc. The organic phase is dried and concentrated. Purification by column chromatography (CH2Cl2) yields l-ethyl-3-isoxazol-3-yl-6-methoxy-l-/7-indole product as a white solid (13 mg, 12%). Example IN: Preparation of l-ethyl-3-isoxazol-5-yl-6-methoxy-lH-indole (compound
58).
l-(l-Ethyl-6-methoxy-lH-indol-3-yl)ethanone (100 mg, 0.46 mmol), prepared from 1- ethyl-ό-methoxy-liT-indole by the procedure described in example IL, is heated with 1.5 mLof dimethylformamide dimethylacetal and 100 μL of pyrrolidine at HO0C overnight. The dimethylformamide dimethylacetal is then concentrated in vacuo. The residue is redissolved in 1.25 mL of EtOH and 250 μL OfH2O3 and is treated with hydroxyamine hydrochloride (66 mg, 0.95 mmol) and heated at 800C for 2h. Partitioning between H2O and EtOAc and drying and concentration of the organic phase followed by purification by silica gel chromatography (EtOAc/CH2Cl2, 5/95) gives l-e&yl-3-isoxazoI-5-yl-6-methoxy-l/7-indole as a white solid (72 mg, 66%).
Utilizing essentially the same procedure described above, the following compound is prepared: Compound 60.
Example 1O: Preparation of l-ethyl~6-methoxy-3-(2H-pyrazol-3-yl)-li?-uidole (compound 59).
l-(l-Ethyl-6-me&oxy-lH-indol-3-yl)-ethanone (100 mg, 0.46 mmol), prepared from 1- ethyl-6-methoxy-l /^-indole by the procedure described in example IL, is heated with 1.5 mL of dimethylformamide dimethyl acetal and 100 μL pyrrolidine at 1100C overnight. The DMF dimethyl acetal is removed in vacuo. The residue is redissolved in 3 mL of acetic acid, hydrazine hydrate (70 μL, 1.38 mmol) is added, and the mixture is heated to 1000C for 2h. The acetic acid is removed in vacuo, and the residue is partitioned between EtOAc and saturated NaHCO3. The organic phase is dried and concentrated and the product purified by silica gel chromatography (EtO Ac/Hex, 1/1) to give 59 mg of l-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)- 1/7-indole (54%) as a colorless semisolid. Trituration in Et2θ gives a white crystalline powder. The following compound is prepared utilizing the above procedure: Compound 61.
Example IP: Preparation of methyl l-ethyl-3-oxazol-5-yl-lH-indole-6-carboxylate (compound 72).
Step A: l-Ethyl-lH-indole-6-carboxylic acid methyl ester (900 mg, 4.45 mmol) is dissolved in DMF (3.3 mL). This is added dropwise to an ice-cold solution of POCI3 (430 μL, 4.5 mmol) in DMF (1.5 mL). The reaction mixture is stirred at room temperature for 90 minutes. The reaction mixture is then treated with 6N NaOH (3.5 ml). The mixture is then partitioned between H2O and ethyl acetate. Purification by silica gel chromatography (5-10% EtOAc/CEbCk) yields l-ethyl-3-formyl-lif-indole-6-carboxylic acid methyl ester (985 mg, 96%) as a white solid.
Step B: l-Ethyl-S-formyl-lH-indole-ό-carboxylic acid methyl ester (100 mg, 0.42 mmol), TOSMIC (100 mg, 0.52 mmol), K2CO3 (178 mg, 1.29 mmol), and MeOH (800 μL) are heated at 8O0C overnight. The reaction mixture is then partitioned between H2O and ether. After drying and concentrating the organic phase, the product is purified by silica gel chromatography (EtOAc/CH2Cl2, 10/90) to give methyl l-e£hyl-3-oxazol-5-yl-l/7-indole-6- carboxylate (26 mg, 23%) as an off-white solid.
Example IQ: Preparation of methyl l-ethyl-3-oxazol-2-yl-lH-indole-6-carboxylate (compound 75).
DMF
Step A: l-Emyl-3-formyl-l,ff-iiidole-6-carboxylic acid methyl ester (800 mg, 3.5 mmol), prepared as shown in example IP, step A, is dissolved in acetone (98 mL). A solution Of KMnO4 (655 mg, 4.15 mmol) in H2O (31 mL) is added. The reaction mixture is stirred at room temperature for 90 minutes. Another addition OfKMnO4 (108 rug) in H2O (6 mL), followed by stirring for another 45 minutes is required to drive the reaction to completion. The reaction mixture is then quenched with 10% H2O2 (1.5 mL). The mixture is filtered through celite. The filtrate is stripped down under vacuum to roughly 1/3 of the volume. The residue is acidified with 6N HCl, and is extracted into ethyl acetate. The solids isolated from the ethyl acetate layer are triturated with acetone to yield l-ethyl-lH~indole-3,6-dicarboxylic acid 6- methyl ester (696 mg, 79%) as a light orange solid.
Step B: l-Ethyl-lH-indole-Sjό-dicarboxylic acid 6-methyl ester (600 mg, 2.43 mmol) is suspended in a solution of CH2Cl2 (27 ml) and DMF (20 μL). Oxalyl chloride (470 μL, 5.38 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH4OH (10 mL). This is then partitioned in H2O and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 6-methoxycarbonyl-l -ethyl- lH-indole-3-carboxamide (511 mg, 85%) as a white solid.
Step C: A mixture of 150 mg (0.61 mmol) of 6-methoxycarbonyl-l -ethyl- li?-indole-3- carboxamide in diglyme (3.6 mL), and bromoacetaldehyde dimethyl acetal (430 μL, 3.7 mmol) is heated at 125°C for 2h. The reaction mixture is cooled and partitioned in H2O and EtOAc. The organic phase is dried and concentrated and the product is purified by silica gel chromatography (EtOAc/CH2Cl2 5-10%). The product containing fractions are combined and concentrated and the solid is triturated with hexanes to yield methyl l-emyl-3-oxazol-2-yl-lH- indole-6-carboxylate (75 mg, 46%) as a yellow solid.
Example IR: Preparation of l-emyl-6-memoxy-3-thiazol-2-yl-liif-indole (compound
73).
Step A: l-Ethyl-6-methoxy-lH-indole (900 mg, 5.14 mmol) is dissolved in DMF (1.5 mL). This is added dropwise to an ice-cold solution of POCI3 (500 μL, 5.2 mmol) in DMF (1.75 ml). After stirring at room temperature for 90 minutes, the reaction, mixture is re-cooled in an ice bath and is slowly quenched with 6N NaOH (4 mL). The reaction mixture is partitioned between EtOAc and H2O. Purification by silica gel chromatography (EtOAc/CH2Cl2, 5/95) yields l-ethyl-6-methoxy-l/f-indole-3-carbaIdehyde (849 mg, 81%) as a yellow solid.
Step B: l~Ethyl-6-methoxy-lH-indole-3-carbaldehyde (600 mg, 2.95 mmol) is dissolved in acetone (85 mL). A solution OfKMnO4 (450 mg, 2.85 mmol) in H2O (28 mL) is added. This is stirred at room temperature for 5 hours. Another solution OfKMnO4 (450 mg, 2.85 mmol) in H2O (25 mL) is then added. After stirring for another hour at room temperature, the reaction is complete. The reaction mixture is quenched with 10% H2O2 (1.5 mL), and is then filtered through celite. The filtrate is stripped down under vacuum to roughly 1/3 of the volume. The residue is acidified with 6N HCl, and is extracted into ethyl acetate. Purification by silica gel column (hexanes/acetone/acetic acid, 70/30/1) yields crude product. Trituration with ether yields pure l-ethyl-6-methoxy-lH-indole-3-carboxylic acid (365 mg, 56%) as a yellow solid.
Step C: l-Ethyl-6-methoxy-liJ-indole-3--carboxylic acid (250 mg, 1.14 mmol) is suspended in a solution Of CH2Cl2 (12.5 mL) and DMF (10 μL). Oxalyl chloride (230 μL, 2.64 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH4OH (5 mL). This is then partitioned in H2O and EtOAc The residue from the ethyl acetate layer is triturated with acetone to yield l-emyl-6-memoxy-l//-indole-3-carboxamide (134 mg, 54%) as a white solid.
Step D: l-Ethyl-6-methoxy-l/Z-indole-3-carboxamide (120 mg, 0.55 mmol), Lawesson's reagent (240 mg, 0.6 mmol), and toluene (2 mL) are heated at 9O0C for 90 min. The reaction mixture is concentrated and purified by silica gel chromatography (EtOAc/CH2Cl2, 1/9) to yield l-ethyl-6-methoxy-lH"-indole-3-thiocarboxamide as a yellow solid (92 mg, 71%).
Step E: l-E&yl-6-me&oxy-lH-indole-3-thiocarboxamide (83 mg, 0.36 mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 μL, 1.86 mmol) are heated at 8O0C for 16h. More bromoacetaldehyde dimethyl aceial (250μL) is added. This is heated at 8O0C for 2h. Addition of 250 μL more bromoacetaldehyde dimethyl acetal is followed by heating for another 2 hours. The reaction mixture is cooled to room temperature, absorbed onto silica and purified by silica gel chromatography (hexanes/EtOAc, 7/3) to afford l-ethyl-6-methoxy-3- thiazol-2-yl-l //-indole as a brown oil (44 mg, 47%).
The following compounds are prepared following the procedure described above: Compounds 78, 101, 104, 105 and 106.
Example IS: Preparation of l-ethyl-6-methoxy-2-phenoxymethyl-lH-indole-3- carbonitrile (compound 99).
CISO2NCO DMF
Step A: To a suspension of LiAlHU (7.6 g, 0.2 mol) in dioxane (100 mL) is added dropwise a solution of methyl 6-methoxy-lH/-indole-2-carboxylate (8.2 g, 0.04 mol) in dioxane (50 mL) at 00C. After the addition, the mixture is stirred at room temperature for Ih and then heated at reflux for 5h. After cooling to 00C, the reaction is quenched by water (dropwise) and then 15% aqueous NaOH. After stirring at room temperature for Ih, the mixture is filtered through Celite. The solid is washed with a large amount of EtOAc. The solvent is washed with brine, dried over Na2SC>4 and evaporated under vacuum. The residue is purified by flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 61% of 6-methoxy-2-methyl- lH-indole.
Step B: To a solution of 6-methoxy-2-methyl-liϊ-indole (3.9 g, 24 mmol) in acetonitrile (200 mL) and DMF (20 mL) is added dropwise a solution OfClSO2NCO (4 mL, 1.3eq.) in acetonitrile (31 mL) at 00C. After the addition, the mixture is stirred at room temperature for 3h. Then it is poured into ice water and saturated NaΗCθ3 is added to it until it becomes basic. The aqueous phase is extracted with CH2Cl2 and then evaporated. The residue is purified with flash column chromatography on silica gel using EtO Ac/petroleum ether (1/5) as eluent to yield 81% of 6-methoxy-2-methyl-lH-indole-3-carbonitrile. Step C: To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) is added a solution of 6- methoxy-2-methyl-li7-indole-3-carbonitrile (1.3 g, 7.0 mmol) in DMF (8 mL) followed by ethyl iodide (1.2 mL, 2 eq.) at 00C. After stirring for Ih, the mixture is poured into ice water and then extracted with CEfeCk- The organic layer is washed with brine and dried with Na2SO4. The solvent is evaporated under vacuum and purified with flash column chromatography on silica gel using EtO Ac/petroleum ether (1/5) as eluent to yield 92% of 1- ethyl-6-methoxy-2-methyl-l/7-indole-3-carbonitriIe.
Step D: To a solution of l-ethyl-ό-methoxy^-methyl-lH-indole-S-carbonitrile (1.38 g, 6.45 mmol) in benzene (130 mL) is added benzoyl peroxide (226 mg) and NBS (1.2 Ig, 1.05eq.)- Then the mixture is heated to reflux for 3h. After cooling and filtering, the filtrate is concentrated under vacuum. The crude 2-bromomethyl-l-ethyl-6-methoxy-lH-indole-3- carbonitrile (1.6 g, 86%) is used without further purification.
Step E: To a solution of NaH (44 mg, 4 eq.) in DMF (0.5 mL) is added 2-bromomethyl- l-ethyl-6-methoxy-lH-indole-3-carbonitrile (80 mg, 0.274 mmol) and phenol (2 eq.). After stirring for 2Oh, the mixture is poured into ice water and extracted with CH2CI2. The organic layer is washed with brine and dried with Na2SO4. The solvent is evaporated under vacuum and purified with flash column chromatography on silica gel using EtO Ac/petroleum ether (1/5) as eluent to yield l-ethyl-δ-methoxy^-phenoxymethyl-lH-mdole-S-carbonitrile, compound 99.
Example IT: Preparation of 6-nitro-2-pyrrol-l-yl-lH-indole-3-carbonitrile (compound 7).
Step A: A solution of 2-fluoro-5-nitroaniline (11.7 g, 74.9 mmol) in dimethylformamide (120 mL) is treated with malononitrile (5.28 g, 80.0 mmol) and potassium carbonate (11.05 g, 80.0 mmol) (Modification of Chem. Heterocyclic Cpd. Engl. Trans., 9, 37 (2001)). The resulting heterogeneous mixture is heated to gentle reflux for 3h, then cooled and poured into water (500 mL). The resulting precipitate is collected by filtration and taken up into ethyl acetate (300 mL). This solution is dried over Na2SO4, filtered and partially evaporated to give a precipitate, which is collected by filtration. Further evaporation and filtration give a second crop. The two crops are combined and dried under vacuum to give 2-amino-l -ethyl-6-nitro- lH-indole-θ-carbonitrile (7.90 g, 52%) as an orange powder.
Step B: A solution of 2-amino-6-nitro-lH-mdole-3-carbonitrile (362 mg, 1.79 mmol) in acetic acid (5 mL) is treated with 2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution is heated to reflux for 14h. After cooling to ambient temperature, the solution is poured into water (100 mL), and solid sodium bicarbonate is added until CO∑ evolution ceased. The mixture is extracted with EtOAc (2 X 100 mL), and the extracts are washed with saturated brine, combined, dried over MgSd), filtered and concentrated. The residual material is separated by silica gel chromatography (EtOAc/hexanes, 1/4) to afford 6-nitro-2-pyrrol-l-yl- l/?-indole-3-carbonitrile, compound 5, as a yellow solid (232 mg, 51%).
Example IU: Preparation of N-(3-cyano-l-ethyl-6-nitro-lH-indol-2-yl)acetamide (compound 25).
chloride O.,N
Step A: Sodium hydride (42 mg, 1.05 mmol, 60% w/w suspension in mineral oil) is washed with hexane and taken up in dimethylsulfoxide (1 mL). A solution of 2-amino-6-nitro- l/-r-indole-3-carbonitrile (prepared in procedure IT) in dimethylsulfoxide (1 mL) is added by. syringe, and the resulting mixture is stirred for 20 min. Then, iodoethane (77 μL, 0.96 mmol) is added by syringe, and the mixture is stirred for 14h. The reaction is then poured into EtOAc (50 mL), and this solution is washed with water (3 X 50 mL) and saturated brine (40 mL). The aqueous phases are back-extracted with EtOAc, and the organic extracts are combined, dried over Na2SO4, filtered and evaporated. The residual material is separated by column chromatography over silica gel (EtOAc/hexanes, 1/1) to afford first a small amount of a dialkylated analog, then the desired compound, 2-amino-l -ethyl-6-nitro-l/f-indole-3- carbonitrile (114 mg, 52%), and finally unreacted starting material. The desired product is isolated as an orange powder.
Step B: Sodium hydride (44 mg, 1.10 mmol, 60% w/w in mineral oil) is washed with hexanes and suspended in 1,4-dioxane (3 mL). A solution of 2-amino-l-ethyl-6-nitro-lH- indole-3-carbonitrile (120 mg, 0.521 mmol), prepared in step B, above, in dioxane (2 mL) is added, and the resulting mixture is allowed to stir for 30 min. Then, acetyl chloride (45 μL, 0.63 mmol) is added by syringe, and the solution is stirred for an additional 12h. The reaction is partitioned between water and EtOAc (20 mL each), and the organic phase is washed with brine. The aqueous phases are back-extracted in sequence with ethyl acetate, and the organic extracts are combined, dried over MgSO4, filtered and evaporated. The resulting solid is triturated with Et2O, collected by filtration and dried under vacuum to afford N-(3-cyano-l- ethyl-6-nitro-li/-indol-2-yl)-acetamide (100 mg,.71%), compound 25, as an off-white powder. Using this procedure and substituting the appropriate acid chlorides or chloroformates gives the following compounds: Compounds 23, 26, 35, 36, 203, 204, 214, 215, 216.
Example IV: Preparation of Ν-ethyl-3-phenyl-5-nitroindole (compound 41).
DME
Na2CO3
Step A: To a solution of 5-nitroindole (5.00 g, 30.8 mmol) in pyridine (200 mL) at -4°C is added a solution of pyridinium bromide perbromide (10.99 g, 34.3 mmol) in pyridine (200 mL) dropwise under nitrogen with stirring. After complete addition, the reaction mixture is stirred for 5 min at 00C. The reaction mixture is diluted in 00C water (200 mL) and extracted with 200 mL OfEt2O. The organic layer is washed with 6 M HCl (300 mL), 5% NaHCO3 (300 mL), and brine (300 mL). The organic phase is dried over MgSO4 and solvent is removed to give 3-bromo-5-nitroindole as a yellow powder, 80% pure with 20% 5-nitroindole (6.80 g, 74%yield).
Step B: A solution of 3-bromo-5-nitroindole from above (625 mg, 2.1 mmol), phenylboronic acid (381 mg, 3.13 mmol), triphenylphospbine (109.3 mg, 0.417 mmol) in dimethoxyethane (4.16 mL) is degassed. To this mixture 2N sodium carbonate (6.25 mL) is added, and the reaction mixture is degassed again. To the reaction is added palladium (II) acetate (23.4mg, 0.104 mmol), and the reaction is refluxed under dry nitrogen with stirring for 8 hours. The reaction mixture is then diluted with 1 M HCl (100 mL), and extracted with ethyl acetate (100 mL). The organic phase is washed with water (100 mL), and brine (100 mL). The organic phase is dried over MgSC>4 and concentrated in vacuo. The crude product is purified by chromatography over silica gel (EtOAc/hexanes, 10/90) to afford 3-phenyl-5-nitroindole as an orange powder (45 mg, 9% yield).
Step C: To a mixture of 60% NaH in mineral oil (8.7 mg, 0.630 mmol) and DMF (1.0 mL) is added dropwise a solution of 3 -phenyl-5-nitroindole (40.0 mg, 2.1 mmol) in DMF (0.75 mL). The reaction mixture is stirred for 20 min at O0C under N2. Ethyl iodide (14.8 μL, 0.185 mmol) is added dropwise and the reaction mixture is stirred for an additional 3 hours. The reaction mixture is diluted with water (250 mL), and extracted with EtOAc (30 mL). The organic phase is washed with water (250 mL) and is then dried over MgSO4 and the solvent is removed in vacuo. The desired N-ethyl-3-phenyl-5-nitroindole is obtained as a yellow powder (40.0 mg, 89.5% yield). hi similar fashion the following compound is prepared: Compound 40.
Example IW: Preparation of [3-Cyano-l-(4-methoxyphenyl)-lH-indol-6-yl]-carbamic acid propyl ester (compound 97).
6-Amino-l-(4-methoxyphenyl)-lH-indole-3-carbonitrile (30 mg, 0.12 mmol), is suspended in EtOH (300 μL). Propyl chloroformate (168 μL, 1.5 mmol) is added, and this mixture is stirred at room temperature overnight. The addition of triethylamine (300 μL), followed by another hour of stirring at room temperature, completes the reaction. This reaction mixture is loaded directly onto a silica column, and is eluted with CΗ2CI2. Another silica column (3/2, ether/hexanes) is needed to fully purify the product, [3-cyano-l-(4-methox.y- phenyI)-lH-indol-6-yl]-carbamic acid propyl ester (19 mg, 45%), as a white solid. Example IX: Preparation ofN-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yletliynyl)- phenyl]-methanesulfonamide (compound 130).
2-(4-Arαinoρhenylethynyl)-l-ethyl-6-methoxy-lH-iαdole-3-carbonitrile (50 mg, 0.16 mmol), prepared as described by the method of Example IH, is dissolved in pyridine (550 μL) at room temperature. Methanesulfcmyl chloride (17 μL, 0.21 mmol) is added dropwise. This is stirred overnight at room temperature. The reaction mixture is then diluted in ethyl acetate and is washed with aqueous HCl, followed by brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1. CH2Cl2ZEtOAc) yields N-[4-(3-cyano-l-ethyl- 6-methoxy-li7-indol-2-ylethynyl)-phenyl]-methanesuIfonamide (58 mg, 92%) as an off-white solid.
The following compounds are made using the procedure shown above, by substituting the appropriate aminophenylethynyl indoles and sulfonyl chlorides: Compounds 131, 132, 208, 209, and 210.
Example IY: Preparation of N-[4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]- methanesulfonamide (compound 129).
rt
A solution of 2-(4-aminophenyl)-l-ethyl-6-metb.oxy-lH-iiidole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example IGa, step B in TΗF (3 mL) is cooled to O0C and treated with triethylamine (0.04 mL, 0.31 mmol) and methanesulfonylchloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3X). The organic phase is washed with HaO and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 60 mg (68%) of N-[4-(3-Cyano-l-ethyl-6-methoxy-lH- indol-2-yl)-phenyl]-methanesulfonamide as a tan solid.
Using essentially the same procedure as above and substituting the appropriate ammophenylindole and sulfonyl chloride or carrying out the reaction in pyridine as both base and solvent gives the following compounds: Compounds 83, 85, 86, 87, 88, 243, 251, 252, 272, 273, 287, 289, 365, 366, 367, 368, 369, 370, 371, 394, 439, 440, 448, 449, 451, 452, 477, 487, 488, 495, 505, 510, 548, 549, 550, 551, 552, 562, 563, 598, 599, 601, 602, 608, 609, 610, 615, 616, 617, 621, 622, 623, 629, 630, 631, 639, 655, 657, 658, 662, 669, 670, 671, 674, 675, 701, 702, 703, 706, 707, 708, 709, 710, 711, 713, 715, 720, 789, 790, 791, 850, 851, 867, 868, 890, 891, 912, 919, 920, 921, 922, 923, 924, 932, 933, 934, 935, 941, 953, 968, 982, 988, 990, 995, 996, 997, 998, 1035, 1038, 1041, 1103, 1105, 1115, 1116, 1117, 1123, 1140, 1141, 1155, 1160, 1161, 1170, 1175, 1181, 1182, 1188, 1189, 1228, 1229, 1230, 1231, 1280.
Example IZa: Preparation of N-[4-(3-cyano-l-ethyl-6-methoxy-li7-indol-2-ylethynyl)- phenyl]-acetamide (compound 138)
2-(4-Aminophenylethynyl)-l-ethyl-6-methoxy-l//-nidoIe-3-carbonitrile (95 mg, 0.29 mmol), prepared as descπbed in Example 1 H, is dissolved m THF (1.4 mL) Tπethylamine (84 μL, 0.6 mmol) is added, followed by dropwise addition of acetyl chloride (44 μL, 0.5 mmol). This is stirred at room temperature for Ih. The reaction mixture is partitioned between H2O and EtOAc The organic layer is dried and concentrated. Purification by silica chromatography (9/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2- ylethynyl)-phenyl]-acetamide (103 mg, 96%) as a yellow solid.
The following compounds are prepared by the procedure shown above, substituting the appropriate aminophenylethynyl indoles and acid chlorides: Compounds 82, 139, 152, 153, 162, 163, 165, 167, 205, 206, 207, 211, 212, 213, 219, 224, 225, 228. Example IZb: Preparation of N-[4-(3-cyano-l-ethyl-6-methoxy-lH"-indol-2-ylethynyl)- phenyl]-formamide (compound 241).
Acetic anhydride (2.5 mL) and 98% formic acid (1.0 mL) are heated at 65°C for 1 hour. This is cooled to O0C. 2-(4-Aminophenylethynyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as in example IH, is taken up in THF (1.2 mL) and added to the formic acetic anhydride mixture. This is stirred at O0C for 30 minutes. The reaction mixture is then partitioned between H2O and EtOAc. The EtOAc layer is washed with saturated NaHCO3, followed by saturated brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CHaC^/EtOAc) yields of N-[4-(3-cyano-l- ethyl-6-methoxy-lH"-indol-2-ylethynyl)-phenyl]-foπnamide (105 mg, 96%) as a yellow solid.
The following compound is prepared similarly as described above: Compound 218.
Example IAA: Preparation of N-[4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)- phenyl]-acetamide (compound 128).
A solution of 2-(4-aminophenyl)-l-ethyl-6-methoxy-177-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example IGa, step B in TΗF (3 mL) is cooled to 00C and treated with triethylamine (0.04 mL, 0.31 mmol) and acetyl chloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture is then diluted with Η2O and extracted with ethyl acetate (3X). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30- 50%) to afford 57 mg (71%) of N-[4-(3-cyano-l-ethyl-6-methoxy-lH-mdol-2-yl)- phenyl]acetamide as a tan solid.
Using essentially the same procedure as above and substituting appropriate aminophenyl indoles and the acid chlorides, the following compounds are prepared:
Compounds 81, 242, 244, 324, 325, 326, 327, 328, 329, 330, 383, 420, 421, 422, 423, 424, 425, 544, 558, 559, 560, 561, 565, 566 567, 644, 645, 646, 755, 756, 757, 759, 760, 761, 762, 763, 764, 765, 766, 798, 799, 801, 802, 803, 804, 854, 855, 856, 857, 858, 859, 895, 896, 897, 898, 899, 900, 901, 913, 914, 915, 916, 983.
Example IAB: Preparation of l-[3-(3-cyano-l-ethyl-6-methoxy-l//-indol-2- ylethynyl)phenyl]-3 -ethyl urea (compound 220).
EtNCO pyridine
2-(3-Aminophenylethynyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1Η, is dissolved in pyridine (670 μL). Ethyl isocyanate (62 μL, 0.75 mmol) is added. The reaction mixture is then heated at 1000C for 2h. The mixture is then diluted in EtOAc, and is washed with aqueous HCl, followed by brine. The organic layer is dried and concentrated. Purification by silica chromatography (4/1, CH2Cl2ZEtOAc), followed by trituration with hexanes/acetone (1/1), yields l-[3-(3-cyano-l- ethyl-6-methoxy-lff-indol-2-ylethynyl)-phenyl]-3-ethyl urea (44 mg, 36%) as a white solid.
Example IAC: Preparation of l-(2-cMoroemyl)-3-[4-(3-cyano-l-ethyl-6-methoxy-li/- indol-2-ylethynyl)-phenyl] urea (compound 156).
2-(4-Aminophenylethynyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1Η, is suspended in toluene (600 μL). 2-Chloroethyl isocyanate (32 μL, 0.37 mmol) is added, and the mixture is heated at 1000C for 5h. The reaction mixture is then cooled, diluted in acetone, and absorbed onto silica. Purification by column chromatography (5-10% EtOAc in CH2Cl2) yields l-(2-chloro-ethyl)-3-[4-(3-cyano-l- ethyl-6-methoxy-lif-indol-2-ylethynyl)-phenyl] urea (73 mg, 54%) as a yellow solid.
The following compound is prepared using the procedure above: Compound 221. Example IAD: Preparation of Ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH- indol-2-ylethynyl)-phenyl]methyl amide (compound 157).
N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)phenyl] ethanesulfonamide (70 mg, 0.17 mmol), prepared as in Example IX, is combined with K2CO3 (49 mg, 0.35 mmol), and DMF (1.0 mL). Iodomethane (16 μL, 0.26mmol) is added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is then diluted in EtOAc, and is washed with Η2O and then brine. The organic layer is dried and concentrated. Purification by silica chromatography (95/5, CEfcCk/EtOAc) yields a light tan solid. Trituration gives ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-l//-indol-2-ylethynyl)-phenyl]methyl amide (61 mg, 85%) as an orange-white solid.
The following compounds are prepared using the procedure above, substituting the appropriate sulfonamide: Compound 182, 652, 840.
Example IAE: Preparation of l-ethyl-5-methoxy-2-[4-(morpholine-4-carbonyl)- phenyl]-li/-indole-3-carbomtrile (compound 245).
Step A: Methyl 4-(3-cyano-l-ethyl-5-methoxy-lif-indol-2-yl)-benzoate (350 mg, 1.05 mmol), prepared as described in Example IGa step B, is combined with NaOH (40 mg, 1 mmol), H2O (0.8 mL), and THF (3.4 mL) and is heated at 8O0C for 1 hour. The reaction mixture is diluted in H2O and is then ether-washed. The aqueous layer is acidified with aqueous HCl, and is extracted into EtOAc. The organic layer is dried and concentrated to yield 4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-benzoic acid (311 mg, 92%) as a pure white solid.
Step B: 4-(3-cyano-l-ethyl-6-methoxy-l//-indol-2-yl)-benzoic acid (50 mg, 0.16 mmol) is suspended in CH2Cl2 (2.2 mL) and catalytic DMF (2 μL). Oxalyl chloride (22 μL, 0.25 mmol) is added. The reaction mixture is stirred at room temperature for 1 hour, at which time full dissolution occurred. This reaction mixture is pipetted dropwise into a vigorously stirring solution of morpholine (1.0 mL) in CH2Cl2 (5ml). After addition is complete, the reaction mixture is washed with aqueous HCl solution. The organic layer is dried and concentrated. Purification by silica column (1:1 CH2Cl2ZEtOAc) yields l-ethyl-6-methoxy-2-[4-(morpholine- 4-carbonyl)-phenyl]-lH-indole-3-carbonitrile (56 mg, 90%) as a white solid.
The following compounds are prepared similarly as described above: Compounds 113, 114, 246, 270, 271 290, 291, 292, 323, 377, 378, 379, 380, 381, 382, 384, 385, 386, 387, 388, 389, 390, 391, 392, 432, 433, 564, 568, 569, 570, 571, 572, 573, 647, 648, 853, 860, 861, 862.
Example IAF: Preparation of cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6- hydroxy-lJy"-indol-2-ylethynyl)-phenyl] amide (compound 194).
Cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)- phenylj-amide (60 mg, 0.16 mmol), prepared as described in Example IZa, is stirred in BBr3 (800 μL, IM in CH2Cl2, 0.8 mmol) at room temperature for 1 hour. The reaction mixture is quenched with H2O, and is extracted with CH2Cl2. The organic layer is dried and concentrated. Purification by silica chromatography (EtOAC) gives impure product. This crude product is triturated with 1/1 hexanes/acetone to yield cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl- 6-hydroxy-lH-indol-2-ylethynyl)-phenyl]-amide (32 mg, 54%) as an off-white solid.
The following compounds are prepared using the procedure above, substituting the appropriate sulfonamides (from Example IX) or amides (from Example IZ): Compounds 164, 168, 183, 193, 195. Example IAG: Preparation of l-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-l-yl)- phenylethynyl]-lH-indole-3-carbonitrile (compound 166).
l-(2-Chloroethyl)-3-[4-(3-cyano-l-ethyl-6-methoxy-li3r-indol-2-ylethynyl)-phenyl] urea (55 mg, 0.13 mmol), prepared as in Example IAC, is combined with K2CO3 (50 mg, 0.36 mmol) and DMF (550 μL). This mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted in EtOAc, and is washed with H2O, and then with brine. The organic layer is dried and concentrated. Purification by silica chromatography (10-50%, EtO Ac/CH2C12) yields I-eώyI-6-methoxy-2-[4-(2-oxo-imidazolidin-l-yl)-phenylethynyl]-l/-r- indole-3-carbonitrile (47 mg, 94%) as a white solid.
The following compound is prepared using the above procedure, substituting the appropriate urea: Compound 222..
Example IAH: Preparation of N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2- ylethynyl)-phenyl]-dϊmethylρhosphinic amide (compound 227).
2-(3-Aminophenylethynyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1Η, is dissolved in pyridine (300 μL) at 00C. Dimethylphosphinic chloride (60 mg, 0.53 mmol) in TΗF (300 μL) is added. The reaction is stirred at room temperature for 2 hours. The reaction mixture is diluted in EtOAc, and is washed with aqueous HCl followed by brine. The organic layer is dried and concentrated. Purification by silica chromatography (acetone) yields N-[4-(3-cyano-l-ethyl-6-methoxy-lH- indol-2-ylethynyl)-phenyl]-dimethylphosphinic amide (65 mg, 52%), compound 227, as a pure white solid. The silica column is then flushed with 9/1 CΗ2Cl2/MeOΗ to yield 9 mg of N-[4- (3-cyano- 1 -ethyl-6-methoxy- li7-indol-2-ylethynyl)-phenyl]-bis-(dimethylphosphinic) amide as a by-product. Example IAI: Preparation of l-e&yl-6-methoxy-3-[5-(4-methoxyphenyl)-isoxazol-3- yl]-lH-indole (compound 116).
Step A: A mixture of l-ethyl-ό-methoxy-lH-indole^-carbaldehyde oxime (0.20 g, 0.92 mmol), prepared from the aldehyde precursor in example IR, in dichloroethane (3 mL) is treated with N-chlorosuccinimide (0.12 g, 0.92 mmol) and pyridine (0.04 mL, 0.46 mmol) and stirred at room temperature for Ih. The reaction mixture is then poured into H2O and acidified with IN HCl until the pH is 2. The mixture is extracted with EtOAc and the organic phases are washed with H2O and saturated NaCl and dried and concentrated to a mixture of chlorooximes, which are used in the next step without further purification.
Step B: The mixture of chlorooximes prepared above is dissolved in CH2CI2 (5 mL) and to this is added 4-methoxyphenylacetylene (0.24 g, 1.84 mmol) and triethylamine (0.25 mL, 1.84 mmol) at 00C and the reaction is then stirred overnight warming to room temperature. The reaction is then diluted with H2O and extracted with EtOAc (3X). The organic phases are washed with H2O and saturated NaCl and dried and concentrated. Chromatography over silica gel (EtOAc/hexanes, 10-20%) gives 76 mg (24%) of l-ethyl-6-methoxy-3-[5-(4-methoxy- ρhenyl)-isoxazol-3-yl]-li7-indole as a tan solid.
Example IAJ: Preparation of [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]- . carbamic acid ethyl ester (compound 121).
CICOOEt
NaHCO3 EtOAc
A biphasic mixture of 2-(4-amino-phenyl)-l-ethyl-6-mefhoxy-lH:-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in example IGa step B, and ethyl chloroformate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at 00C and then allowed to warm to room temperature and stirred for 24h. The reaction is then diluted with H2O and extracted with EtOAc (2X). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 20- 40%) gives 48 mg (55%) of [4-(3-cyano-l-ethyl-6-methoxy-l//-indol-2-yl)-phenyl]-carbamic acid ethyl ester as an off-white solid.
The following compounds are prepared in similar fashion: Compound 122, 293, 294, 296, 297, 298, 299, 300, 301 , 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 372, 434, 435, 450, 453, 454, 455, 457, 485, 486, 489, 490, 500, 501, 502, 503, 506, 507, 508, 509, 545, 546, 547, 553, 554, 555, 556, 557, 58I1 582, 583, 584, 585, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 603, 604, 605, 606, 607, 618, 619, 624, 625, 637, 640, 641, 664, 665, 676, 677, 721, 722, 723, 734, 735, 736, 737, 738, 739, 744, 745, 746, 747, 787, 788, 792, 793, 794, 795, 796, 797, 819, 822, 823, 824, 825, 826, 849, 925, 926, 945, 946, 947, 948, 949, 950, 951, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 981, 984, 985, 986, 991, 992, 993, 1015, 1020, 1021, 1022, 1029, 1030, 1031, 1032, 1033, 1034, 1037, 1040, 1042, 1044, 1055, 1056, 1057, 1058, 1059, 1062, 1063, 1064, 1065. 1071, 1073, 1074, 1075, 1077, 1078, 10791107, 1109, 1111, 1112, 1113, 1114, 1122, 1127, 1128, 1129, 1145, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1169, 1174, 1176, 1177, 1178, 1179, 1180, 1186, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1211, 1222, 1232, 1233, 1300, 1302.
Example IAK: Preparation of l-ethyl-S-thiophen-S-yl-lH-indole-S-carbonitrile (compound 141).
DME
A tube is charged with a mixture of 5-bromo-l-ethyl-liϊ-indole-3-carbonitrile (100 mg, 0.40 mmol), thiophene-3-boronic acid (72 mg, 0.56 mmol), PdCl2(PPh3)2 (11 mg, 0.016 mmol) and CsF (152 mg, 1 mmol) and then alternately evacuated and filled with nitrogen (3X) and diluted with dimethoxyethane (3 mL) and then heated to 9O0C for 19h. After cooling, the crude reaction mixture is diluted with saturated NaHC(>3 and extracted with EtOAc (2X). The combined organic phases are washed with saturated NaCl and dried and concentrated. Flash chromatography over silica gel (CH2Cl2/hexanes, 40/60) gives 25 mg (25%) of l-ethyl-5- thiophen-3-yl-lH-indole-3-carbonitrile as a white solid.
The following compounds are prepared in similar fashion: Compounds 140 and 142.
Example IAL: Preparation of N-[4-(3-cyano-l-ethyl-6-methoxy-liϊ-indol-2-yl)- phenyl]-N-methyl methanesulfonamide (compound 180).
A solution of N-[4-(3-cyano-l-ethyl-6-methoxy-l/f-indol-2-yl)-phenyl] methanesulfonamide (130 mg, 0.35 mmol), prepared as in Example IY, in DMF (10 mL) is treated with NaH (21 mg, 0.53 mmol), and stirred at room temperature for 10 min. Iodomethane (0.03 mL, 0.53 mmol) is added, and the mixture is stirred at room temperature for 18h. The reaction mixture is then diluted with H2O, and extracted with EtOAc (2X). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Purification by flash chromatography over silica gel (EtOAcZCH2Cl2, 0-1%) gives 60 mg (45%) of N- [4-(3 -cyano- 1 -ethyl-6-methoxy- 1 /f-indol-2-yl)-phenyl]-N-methyl methanesulfonamide as a white solid.
In similar fashion the following compounds are prepared: Compounds 181, 642, 643, 672, 673, 816, 852, 1002, 1003, 1004, 1005, 1006, 1007.
Example IAM: Preparation of N-[4-(3-cyano-l-ethyl-6-hydroxy-lH-indol-2-yl)- phenylj-methanesulfonamide (compound 189).
A solution of N-[4-(3-cyano-l-ethyl-6-methoxy-li/-indol-2-yl)-phenyl] methanesulfonamide (85 mg, 0.23 mmol) in CH2Ck (2 mL) is cooled to -50C. A solution of boron tribromide (1.15 mL, 1.15 mmol, IM solution in CH2CI2) is added and the reaction mixture is allowed to warm to 1O0C over 4h. The reaction mixture is poured into H2O and extracted with EtOAc (3X). The combined organic phases are washed with H2O and saturated NaCl and dried and concentrated. Chromatography over silica gel (EtOAc/CHαCb, 5-10%) gives 18 mg (22%) of N-[4-(3-cyano-l-ethyl-6-hydroxy-lH-indol-2-yl)-plienyl] methanesulfonamide as a tan solid.
The following compounds are made similarly: Compounds 190, 191, 192.
Example IAN: Preparation of methyl 3-[5-(3-cyano-6-methoxy-lH-indol-2-yl)- [l,2,4]oxadiazol-3-yl]benzoate (compound 226).
2. Δ
Step A: To a mixture of 6-methoxy-liϊ-indole-3-carbonitrile (5.88 g, 40 mmol), prepared as described in the previous examples, and (Boc)2θ (9.59 g, 44.0 mmol) in DCM (50 mL) is added DMAP (0.10 g, 0.8 mmol). The mixture is stirred at room temperature for 48h, then treated with water (30 mL) and dried over anhydrous Na2SC>4. The crude product is chromatographed over silica gel (hexanes/EtOAc, 7/1) to furnish the desired intermediate, 3- cyano-6-methoxyindole-l-carboxylic acid tert-bntyl ester (8.48 g, 86%).
Step B: The above intermediate (2.72 g, 10.0 mmol) is dissolved in anhydrous THF (20 mL), and cooled at— 78°C, followed by the addition of LDA (1.5 M monoTHF in cyclohexane, 10.O mL, 15 mmol). After stirring for 45 min, CO2 gas is introduced for 2h. The mixture is then brought to room temperature and the solvent is removed in vacuo, and the residue is treated with water and acidified to pH = 2 with 6 N HCl. The precipitate is collected and washed with water and dried to provide the acid intermediate, 3-cyano-6-methoxy-indole-l ,2- dicarboxylic acid 1-teit-butyl ester (2.40 g, 73%).
Step C: To a solution of 3-cyano-6-memoxyindole-l,2-dicarboxylic acid 1-fe/t-butyl ester (474 mg, 1.5 mmol) prepared above, and HOBt (200 mg, 1.5 mmol) in DCE/DMF (10 mL/1 mL), is added DCC (310 mg, 1.5 mmol), followed by 3-(N- hydroxycarbamimidoyl)benzoic acid methyl ester (291 mg, 1.5 mmol). The mixture is stirred at room temperature for 2h and filtered. The filtrate is collected and the solvent is replaced with chlorobenzene, followed by the heating at 1500C for 48h. After cooling to room temperature, the solvent is removed in vacuo and the residue is chromatographed (silica gel, CH2CyEtOAc, 8/2) to furnish the intermediate, 3-cyano-6-methoxy-2-[3-(3- me&oxycarbonylphenyty-fl^^oxadiazol-S-ylJ-mdole-l-carboxylic acid /erf-butyl ester, which is treated with 50% TFA in DCM (10.0 mL) at room temperature for Ih. After removal of the volatiles in vacuo, the residue is suspended in water and neutralized with K2CO3 to provide the desired product, methyl 3-[5-(3-cyano-6-methoxy-lH-mdol-2-yl-)[l:,2,4]oxadiazol- 3-yl]benzoate, compound 226 (350 mg, 62%).
Example IAO: Preparation of l-ethyl-2-(4-methanesulfonylphenyl)-6-methoxy-liϊ^ indole-3-carbonitrile (compound 265).
A solution of l-ethyl-6-methoxy-2-(4-methyisulfanylρhenyl)-l/-'-uidole-3-carbonitrile (0.12 g, 0.37 mmol) in CH2CI2 (5 mL) is treated with m-chloroperbenzoic acid (Aldrich, < 77%, 0.26 g,) in one portion and the reaction is stirred for 1Oh at room temperature. The reaction is then diluted with H2O and saturated NaHCO3 and extracted twice with EtOAc. The organic phases are washed with NaHCθ3 (2X) and saturated NaCl and dried and concentrated to a dark semi-solid. The crude product is purified by flash chromatography (EtOAc/CH2Cl2, 0-3%) through a 5 gram silica cartridge topped with 1 gram of basic alumina to give 72 mg (55%) of l-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-lH'-indole-3-carbonitrile as an off- white solid.
Example IAP: Preparation of N-{4-[3-cyano-l-ethyl-6-(2-moφholin-4-yl-ethoxy)-liϊ- indol-2-yl]-ρhenyl} methanesulfonamide (compound 478).
Δ A solution of N-{4-[6-(2-chloroethoxy)-3-cyano-i -ethyl-lH-indol~2-yl]-phenyl} methanesulfonamide (90 mg, 0.21 mmol), moipholine (0.06 mL, 0.65 mmol), NaI (32 mg, 0.21 mmol) and diisopropyl ethylamine (0.06 mL, 0.32 mmol) in CH3CN (2 mL) is heated in a sealed tube at 1000C for 25h. The reaction mixture is cooled to room temperature, diluted with H2O and extracted with EtOAc (3X). The combined organic phases are washed with saturated NaCl, dried and concentrated. The crude solid is triturated with EtOAc and filtered to give 41 mg (41%) ofN-{4-[3-cyano-l-ethyl-6-(2-morpholin-4-yl-ethoxy)-l/f-indol-2-yl]-ρhenyl} methanesulfonamide as a tan solid.
The following compounds are made similarly: Compounds 479, 480, 481, 482, 496, 497 and 498.
Example IAQ: Preparation of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-l- ethyl-6-methoxy-l/T-indol-2-yl)-phenyl] amide (compound 653).
Step A: A solution of 2-(4-aminophenyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile, prepared by example IGa step B, (0.82 mg, 2.82 mmol), in pyridine (10 mL) is treated dropwise with chloroethyl sulfonylchloride (0.38 mL, 3.66 mmol) at room temperature. After stirring for 4h, the reaction mixture is quenched with ice-water and enough 6N HCl is added until the pΗ is lowered to 2. The suspension is extracted with hot EtOAc (3X). The organic phases are then washed sequentially with IN HCl, H2O and saturated NaCl and dried and concentrated to give ethenesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)- phenyl] amide as a pale orange solid which is used directly in the next step without further purification.
Step B: A suspension of ethenesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-liϊ-indol- 2-yl)-phenyl] amide, prepared above, (70 mg, 0.18 mmol), morpholine (0.05 mL, 0.55 mmol) in CH3CN (1.5 mL) is heated at reflux for 1.5h. After cooling to room temperature, the reaction is concentrated and the residue is purified by flash chromatography (acetone/EtOAc, 2/98) over silica gel to afford 89 mg (100%) of 2-moφholin-4-yl-ethanesulforiic acid [4-(3- cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl] amide as a tan foam. The following compound is made similarly: Compound 654.
Example IAR: Preparation of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-l- ethyl-6-methoxy-lH-indol-2-yl)-phenyl] methyl amide (compound 668).
A solution of 2-morρholin-4-yl-ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-l/f- indoI-2-yl)-ρhenyl] amide, prepared in example IAQ (60 mg, 0.13 mmol) in DMF (3 mL) is treated with K2CO3 (35 mg, 0.26 mmol) and methyl iodide (0.02 mL, 0.26 mmol). After stirring at room temperature for 1.5h, the reaction mixture is diluted with H2O and extracted with EtOAc (2X). The organic phases are then washed with H2O (3X) and saturated NaCl, and then dried and concentrated to afford a residue. Flash chromatography over silica gel (acetone/EtOAc, 0-2%) gives 31 mg (50%) of 2-morpholin-4-yl-ethanesulfonic acid [4-(3- cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl] methyl amide as an off white solid.
The following compounds are made similarly: Compounds 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698.
Example IAS: Preparation of 2-[4-(l5l-dioxo-lλ6-isothiazolidin-2-yl)phenyl]-l-ethyl- 6-methoxy-lif-indole-3-carbonitrile (compound 84).
Step A: A solution of 2-(4-aminophenyl)-l-ethyl-6-methoxy-lH-indole-3-carboiiitrile, prepared by example IGa step B, (2.78 g, 9.55 mmol) in pyridine (40 mL) is treated dropwise with 3-chloropropanesulfonyl chloride (1.45 mL, 11.9 mmol) and the reaction is stirred for 4h at room temperature. The reaction is diluted with water and enough 6N HCl to lower the pH to 2. The reaction mixture is extracted with EtOAc (3X) and the combined organic layers are washed sequentially with IN HCl, water and saturated NaCl and then dried and concentrated to give 3.9 g (95%), of 3 -chloropropane-1 -sulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-l/f-indol- 2-yl)-phenyl] amide as a brown foam which is used directly in the next step.
Step B: A solution of 3-chloropropane-l -sulfonic acid [4-(3-cyano-l-ethyl-6-methoxy- li/-indol-2-yl)-phenyl] amide, prepared above (3.65 g, 2.33 mmol) in DMF (100 mL) is treated with K2CO3 and heated at 7O0C for 2h. After cooling to room temperature, the reaction mixture is diluted with H2O and extracted 3X with hot EtOAc. The hot organic layers are washed with warm H2O (3X) and saturated NaCl and dried and concentrated to a solid. Trituration (CH2Cl2/hexanes) gives 2.27g (68%) of 2-[4-(l,l-dioxo-lλ6-isothiazolidin-2-yl)phenyl]-l- ethyl-6-methoxy-lH-indole-3-carbonitrile as a light brown solid.
The following compounds are made in similar fashion: Compound 649, 775, 809, 969, 980.
Example IAT: Preparation of 2-[4-(l,l-dioxo-lλ6-isothiazolidin-2-yl)phenyl]-l-ethyl- 6-methoxy-lH-indole-3-carbonitrile (compound 666).
Step A: Following the procedure in examplelB step A, 2-[4-(l,l-dioxo-lλ6- isothiazolidin-2-yl)phenyl]-l-ethyl-6-methoxy-lH-indole-3-carbonitrile is treated with IM BB r3 solution in CΗ2CI2 at -15°C for 1.5h and then poured into ice-water and filtered and dried to afford 2-[4-(l ,1 -dioxo- 1 λ6-isothiazolidin-2-yl)phenyl]-l-ethyl-6-hydroxy- l/f-indole-3- carbonitrile in nearly quantitative yield.
Step B: Following the procedure in examplelB step B, 2-[4-(l,l-dioxo-lλ6- isothiazolidin-2-yl)phenyl]-l-ethyl-6-hydroxy-lH-indole-3-carbonitrile, K2CO3, 2-iodopropane and methyl ethyl ketone are heated at reflux to give, after flash chromatography (EtOAc/CH2Cl2, 0-2%), 61% of 2-[4-( 1,1 -dioxo- lλ6-isothiazolidin-2-yl)phenyl]-l-ethyl-6- isopropoxy-lH-indole-3-carbonitrile as an off-white solid. The following compounds are made similarly: Compounds 667, 699.
Example IAU: Preparation of 2-[4-(l,l-dioxo-lλ6-isothiazolidin-2-yl)-phenyl]-l-ethyl- 6-(2-morpholin-4-yi-ethoxy)-li/-indole-3-carbonitxile (compound 729).
1000C
A mixture of 2-[4-( 1 , 1 -dioxo- 1 λ6-isothiazolidin-2-yl)phenyl] - 1 -ethyl-6-hydroxy- IH- indole-3-carbonitrile, prepared in example IAT above (70mg, 0.25 mmol), K2CO3 (75 mg, 0.51 mmol), sodium iodide (27 mg, 0.18mmol), 4-(2-chloroethyl) morpholine hydrochloride (42 mg, 0.25 mmol) in methyl ethyl ketone (3 mL) is heated in a sealed tube at 1000C. After 13 hours, DMF (3 mL) is added and the reaction is heated for an additional 6h. After this time, an additional 42 mg of 4~(2-chIoroethyl) morpholine hydrochloride and 135 mg of K2CO3 is added and the reaction is heated for an additional 6h to complete the reaction. The reaction mixture is cooled to room temperature, diluted with water, and extracted with EtOAc (3X). The combined organic phases are washed with water (2X) and saturated NaCl and dried and concentrated. Pure 2-[4-( 1 , 1 -dioxo-1 λδ-isothiazolidin-2-yl)-phenyl]- 1 -ethyl-6-(2-morpholin-4- yl-ethoxy)-liy-indole-3-carbonitrile is obtained by flash chromatography (MeOH/CEbCk, 0- 6%) to give 29 mg (34%) of a tan solid.
The following compounds are made similarly: Compounds 728 and 730.
Example IAV: Preparation of 2-[4-(2,5-dioxo-imidazolidin-l-yl)-phenyl]-6-ethoxy-l- ethyl-lH-indole-3-carbonitrile (compound 779).
Step A: A solution of 2-(4-aminophenyl)-6-ethoxy-l -ethyl- lH-indole-3-carbonitrile (585 mg, 1.92 mmol) in 10 mL of 1,4-dioxane is treated with ethyl isocyanatoacetate (0.25 mL, 2.12 mmol), and the resulting solution is heated to reflux overnight. The solution is allowed to cool, and the solvent is removed by rotary evaporation. The residual material is triturated with ether, and the resulting precipitate is collected by filtration and dried under vacuum to afford compound 773 (587 mg, 1.35 mmol, 70%).
A similar procedure is used to prepare methyl 2-{3-[4-(3-cyano-6-ethoxy-l-ethyl-lHr- indol-2-yl)-phenyl]-ureido}-3-ρhenyl-propionate (compound 777).
Step B: A solution of ethyl {3-[4-(3-cyano-6-ethoxy-l-ethyl-lH-indol-2-yl)-phenyl]- ureido} -acetate (compound 773, 101 mg, 0.232 mmol) in THF (10 mL) is treated with a solution of potassium tert-butoxide in tert-butanol (0.30 mL, 1.0 M, 0.30 mmol), and the resulting mixture is allowed to stir overnight. The reaction mixture is partitioned between water and ethyl acetate (50 mL each), and the organic phase is washed with saturated brine. The aqueous phases are extracted with more ethyl acetate, and the extracts are combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by column chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford 2-[4- (2,5-dioxo-imidazolidin- 1 -yl)-ρhenyl]-6-ethoxy- 1-ethyl- 17y-indole-3 -carbonitrile, compound 779, which is purified further by trituration with ether, collection by filtration and drying under high vacuum (76 mg, 0.196 mmol, 84%).
Example IAW: Preparation of 2-[4-(2,4-dioxo-imidazolidin-l-yl)phenyl]-6-ethoxy-l- ethyl-l/f-indole-3-carbonitrile (compound 776).
A solution of 2-(4-aminophenyl)-6-ethoxy- 1-ethyl- liϊ-indole-3-carbonitrile (319 mg, 1.04 mmol) in 1,4-dioxane (3 mL) is treated with chloroacetyl isocyanate (0.10 mL, 1.17 mmol), and the resulting solution is warmed to 600C overnight. The solution is cooled, and DBU (0.20 mL, 1.31 mmol) is added. This mixture is stirred at ambient temperature overnight, and then is partitioned between water and ethyl acetate (50 mL each). The organic layer is washed with saturated brine, and then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is triturated with ether, and the resulting solid is collected by filtration and dried under high vacuum to afford the title product (319 mg, 0.821 mmol, 79%).
Example IAX: Preparation of N,N-Dimethyl-2-[4-(3,4-dimethyl-2,5-dioxo- imidazolidin-l-yl)-phenyl]-6-ethoxy-l-ethyl-lH-indole-3-carboxamide (compound 780) and N, JV~Dimethyl-6-ethoxy- 1 -ethyl-2-[4-(3-methyl-2,5-dioxo-imidazolidin- 1 -yl)-phenyl]- IH- indole-3-carboxamide (compound 781).
Step A. A solution of ethyl {3-[4-(3-cyano-6-ethoxy-l-ethyl-lH-indol-2-yl)-ρhenyl]- ureido} acetate (compound 773, 325 mg, 0.748 mmol), prepared in procedure IAV, step A, in acetone (5 mL) is treated with HCl (3 mL, 6 N), and the resulting solution is heated to reflux overnight. The reaction mixture is cooled, and the resulting precipitate is collected by filtration, washed with ether and dried under high vacuum to afford the product, 6-ethoxy-l- ethyl-2-[4-(2,5-dioxo-imidazolidin-l-yl)-phenyl]-liϊ-indole-3-carboxamide (264 mg, 0.650 mmol, 87%).
Step B. Sodium hydride dispersion in mineral oil (75 mg) is washed with a small portion of hexane, and the hexane layer is decanted off. A solution of 6-ethoxy-l-ethyl-2-[4- (2,5-dioxo-imidazolidin-l-yl)-phenyl]-lH-indole-3-carboxamide (190 mg, 0.468 mmol) in dimethylformamide (2 mL) is added, and the mixture is stirred for 1 hour. Then, methyl iodide (0.10 mL, 1.61 mmol) is added by syringe. The resulting mixture is allowed to stir at ambient temperature overnight and then is poured into 50 mL of ethyl acetate. The organic phase is washed with water (3 X 50 mL) and saturated brine (20 mL), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by column chromatogaphy (1/1 ethyl acetate/hexane, eluting on silica gel 60) to afford the title products, compounds 780 and 781. Example IAY: Preparation of N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)- phenyl]-N-(2-hydroxyethyl)-methanesulfonami<ie (compound 828).
Step A: Sodium hydride dispersion in mineral oil (108 mg) is washed with a small portion of hexane, and the hexane layer is decanted off. A solution of N-[4-(3-cyano-l-ethyl-6- methoxy-lH-indol-2-yl)-ρhenyl] methanesulfonamide (compound 129, 500 mg, 1.35 mmol) in DMF (5 mL) is slowly added. After gas evolution is complete, 2-bromoethyl acetate (0.30 mL, 2.64 mmol) and sodium iodide (20 mg) are added. The mixture is stirred at ambient temperature overnight, and then is poured into 50 mL of ethyl acetate. This is washed with water (3 X 50 mL) and saturated brine (20 mL), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by column chromatogaphy (1/1 ethyl acetate/hexane, eluting on silica gel 60) to afford compound 815 (364 mg, 0.799 mmol, 59%).
Step B: A mixture of iV-(2-acetoxyethyl)-N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2- yl)-phenyl] methanesulfonamide (compound 815, 164mg, 0.360 mmol) and lithium hydroxide hydrate (45 mg, 1.07 mmol) in 5 mL THF/1 mL water is warmed to 600C overnight. The mixture is cooled and poured into ethyl acetate (50 mL). This is washed with water (50 mL) and brine (20 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to afford a solid. The solid is triturated with ether, collected by filtration and dried under high vacuum to afford N-[4-(3-cyano-l-ethyl-6-methoxy-lJ:-'-mdol-2-yl)-phenyl]-N-(2-hydroxyethyl) methanesulfonamide, compound 828 (137 mg, 0.331 mmol, 92%).
Example IAZ: Preparation of l-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-lH- indole-3-carbonitrile (compound 248).
l-Ethyl-2-(4-hydroxy-phenyl)-6-methoxy-lH-indole-3-carbonitrile (40 mg, 0.14 mmol), prepared as in example IGa step B, is combined with K2CO3 (77 mg, 0.56 mmol), bromoethyl methyl ether (26 μL, 0.28 mmol), and DMF (450 μL). This is stirred at room temperature for 1 hour, and then, at 750C for 3 hours. The reaction mixture is then partitioned between Η2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2, 0-5% EtOAc) yields l-ethyl-6-methoxy-2-[4-(2- methoxyethoxy)-phenyl]-lH"-indole-3-carbonitrile (44 mg, 90%) as a white solid.
The following compound is prepared similarly as above: Compound 249.
Example IBA: Preparation of l-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)- ρhenyl]-li3T-indole-3-carbonitrile (compound 261).
Step A: l-Ethyl-6-methoxy-2-[4-(2-hydroxyethoxy)-ρhenyl]-lH-indole-3-carbomtrile (450 mg, 1.34 rnmol), prepared as in example IAZ, is combined with PPh3 (878 mg, 3.35 mmol) in CH2CI2 (32 roL) at 00C. N-bromosuccinimide (600 mg, 3.37 mmol) is added in one portion. The reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is washed with aqueous NaHCθ3 The organic layer is dried and concentrated, and purified by silica gel chromatography (CH2CI2) to yield 2-[4-(2-bromoethoxy)-phenyl]-l-ethyl- 6-methoxy-lH-indole-3-carbonitrile (506 mg, 95%), compound 253 as a white solid.
Step B: 2-[4-(2-bromoethoxy)-phenyl]-l-ethyl-6-methoxy-li/-mdole-3-carbonitrile (40 mg, 0.1 mmol), prepared as in step A above, is combined with morpholine (50 μL, 0.58 mmol) and acetonitrile (1.0 mL). This is heated at 85°C for 2h. The reaction mixture is then partitioned between CH2CI2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (6/4, acetone/hexanes) yields 1 -eth,yl-6-methoxy-2- [4-(2-morpholin-4-yl-ethoxy)-phenyl]-liϊ-indole-3-carbonitrile (39 mg, 96%) as a white solid. The following compounds are prepared similarly as above, using different amines: Compounds 262, 263, 264.
Example IBB: Preparation of N-{2-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)- phenoxy]-ethyl} methanesulfonamide (compound 268).
Step A: 2-[4-(2-Bromoethoxy)phenyl]-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (258 mg, 0.65 mmol), prepared in example IBA, step A, is combined with NaN3 (144 mg, 2.2 mmol), and MeOH (3.2 mL). This is heated overnight at 75°C. The reaction mixture is then partitioned between CH2CI2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2CI2) yields 2-[4-(2-azidoethoxy)phenyl]-l- emyl-6-methoxy-l//-indole-3-carbonitrile (187 mg, 80%), compound 266 as a white solid.
Step B: 2-[4-(2-Azidoethoxy)phenyl]-l-ethyl-6-methoxy-l/f-indole-3-carbonitrile (410 mg, 1.14 mmol), prepared as in step A, above, is suspended in a solution of MeOH (20 mL) and concentrated HCl (500 μL). Pd/C (150 mg, 10%) is added, and this mixture is hydrogenated at 30 p.s.i. for Ih. This is filtered and the filtrate is concentrated. The filtrate residue is partitioned between EtOAc and 0.5N NaOH. The organic layer is dried and concentrated. Purification by silica gel chromatography (10-30%, MeOH/CHaC^) yields 2-[4- (2-aminoethoxy)phenyl]-l-efliyl-6-methoxy-lH:-mdole-3-carbonitrile (298 mg, 78%), compound 267, as a white solid.
Step C: 2-[4-(2-Aminoethoxy)phenyl]-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared in step B, above, is dissolved in pyridine (300 μL). Methanesulfonyl chloride (8 μL, 0.1 mmol) is added. This is stirred at room temperature for 45 minutes. More methansulfonyl chloride (4 μL, 0.05 mmol) is added. Stirring continues for another hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (1/1 CH2Cl2/EtOAc) yields N-{2- [4-(3-cyano-l -ethyl-6-methoxy-lH-indol-2-yl)plienoxy]ethyl} methanesulfonamide, compound 268 (32 mg, 86%) as a white solid.
The following compound is prepared similarly as above: Compound 269.
Example IBC: Preparation of N-{2-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)- phenoxy]-ethyl} acetamide (compound 274).
2-[4-(2-Amiαoethoxy)phenyl]-l-ethyl-6-methιoxy-liϊ-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example IBB, step B, is dissolved in THF (400 μL), and ΕtiN (24 μL, 0.17 mmol). Acetyl chloride (10 μL, 0.14 mmol) is added, and the reaction mixture is stirred at room temperature for 2h. The reaction mixture is partitioned between EtOAc and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (EtOAc) yields N-{2-[4-(3-cyano-l-ethyl-6-methoxy-l/7-indoI-2-yl)phenoxy]ethyl} acetamide (33 mg, 97%) as a white solid.
Example IBD: Preparation of ϊ-{2-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)- ρhenoxy]ethyI}-3-ethyl-urea (Compound 279).
2-[4-(2-Aminoethoxy)phenyl]--l-ethyl-6-methoxy-lH-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example IBB, is combined with ethyl isocyanate (18 μL, 0.21 mmol) and pyridine (300 μL). This mixture is stirred at room temperature for 90 minutes, and is then partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (EtOAc) yields l-{2-[4-(3-cyano-l- ethyl-6-methoxy-lH.-indol-2-yl)-phenoxy]-ethyl}-3-ethyl-urea (34 mg, 93%) as a white solid. Example IBE: Preparation of N-{2-[4-(3-cyano-l~ethyl-6-methoxy-lH-indol-2-yl)- phenoxy]ethyl}formainide (compound 280).
Acetic anhydride (700 μL) and 98% formic acid (280 μL) are heated at 650C for Ih. This is cooled to 00C. 2-[4-(2-Aminoethoxy)ρhenyl]-l-ethyl-6-methoxy-lH-indole-3- carbonitrile (30 mg, 0.09 mmol), prepared as in example IBB, is taken up in TΗF (400 μL), and added to the mixed anhydride. This is stirred at O0C for 45 minutes. The mixture is then portioned between EtOAc and aqueous NaΗCC>3. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CH2Cl2/acetone) yields N-{2-[4-(3-cyano-l- ethyl-6-methoxy-li7-indol-2-yl)ρhenoxy] -ethyl} formamide (28 mg, 86%) as a white solid.
Example IBF: Preparation of l-ethyl-2-{4-[2-(3-hydroxypyrrolidin-l-yl)-2-oxo- ethoxy]ρhenyl}-6-methoxy-lH-"indole-3-carbonitrile (compound 285).
Step A: l-Ethyl-2-(4-hydroxyphenyl)-6-methoxy-l//-indole-3-carbonitrile (559 mg, 1.91 mmol), is used to prepare [4-(3-cyano-l-ethyl-6-methoxy-l/?-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (780 mg, 100%) utilizing essentially the same procedure as example IAZ.
Step B: [4-(3-Cyano-l-ethyl-6-methoxy-li7"-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (745 mg, 1.83 mmol) is stirred in 20% TFA in CH2CI2 at room temperature for 3 hours. This is concentrated and the residue is partitioned between H2O and EtOAc. The organic layer is dried and concentrated. The residue is triturated with CH2CI2 to yield [4-(3-cyano-l-ethyl-6- methoxy-lH-indol-2-yl)-phenoxy] -acetic acid (634 mg, 99%) as a white solid.
Step C: [4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy]-acetic acid (40 mg, 0.12 mmol) is suspended in CH2Cl2 (1.65 mmol) and DMF (2 μL). Oxalyl chloride (17 μL, 0.19 mmol) is added. This is stirred at room temperature for 30 minutes. The resulting solution is then pipetted into a stirring solution of 5-3-hydroxypyrrolidine (150 μL) and CH2CI2 (3.0 mL). The mixture is washed with aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (3/2 yields l-ethyl-2- {4-[2-(3-hydroxy-pyrrolidin-l-yl)-2-oxo-ethoxy]-phenyl}-6~methoxy-lH/-indole-3-carbonitrile (40 mg, 79%), compound 285 as a white solid.
Example IBG: Preparation of l-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5- yl)-lH*-indole-3-carbonitrile (Compound 332).
Step A: l-EUiyl-2-(4-hydroxy-3-nitrophenyl)-6-methoxy-lH-indole-3-carbonitrile (369 mg, 1.1 mmol), prepared as in example IGd5 is combined with EtOAc (20 mL) and Pd/C (150 mg, 10%). This mixture is hydrogenated at 30 p.s.i. for Ih. This is filtered through celite. The filtrate is concentrated and triturated with ether to yield 2-(3-amino-4-hydroxyphenyl)-l-ethyl- 6-memoxy-lH-indoIe-3-carbonitrile (307 mg, 91%), compound 322, as a white solid.
Step B: 2-(3-Amino-4-hydroxyphenyl)-l-ethyi-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.33 mmol), prepared as in step A, is combined with CDI (83 mg, 0.51 mmol), and TΗF (1.1 mL). This is heated at 650C for 1 hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CΗ2Cl2/EtOAc) yields l-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro- benzooxazol-5-yl)-lH-indole-3-carbonitrile (89 mg,,81%) as a white solid. Example IBH: Preparation of l-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H- benzo[l,4]oxazin-6-yl)-liy-indole-3-carbonitrile (compound 334).
Step A: Bromoacetic acid (52 mg, 0.37 mmol) is combined with EDCI hydrochloride (62 mg, 0.4 mmol) and acetonitrile (900 μL) to form a homogeneous solution. 2-(3-Amino-4- hydroxyphenyl)-l-ethyl-6-methoxy-li7-indole-3-carbonitrile (100 mg, 0.33 mmol), prepared as in example IBG, step B, is added to the solution. A thick paste soon forms. Another 1.1 mL of acetonitrile is added and the mixture is then stirred at room temperature for 2 hours. The reaction mixture is then partitioned between ΗfeO and EtOAc. The organic layer is dried and concentrated Purification by silica gel chromatography (4/1 , CΗsGb/EtOAc) yields 2-chloro- N-[5-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-2-hydroxyphenyl] acetamide (82 mg, 60%), compound 333, as a white solid.
Step B: 2-Chloro-N-[5-(3-cyano-l -ethyl-6-methoxy- lH-indol-2-yl)-2-hydroxy-phenyl] acetamide (57 mg, 0.13 mmol), prepared in step A, is combined with K2CO3 (55 mg, 0.4 mmol), and DMF (400 μL). This is heated at 8O0C for 1 hour. The reaction mixture is then partitioned between Η2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2CVEtOAc) yields l-ethyl-6-methoxy-2-(3-oxo-3,4- dmydro-2H-benzo[l74]oxazm-6-yl)-lHκLndole-3-carbonitrile (45 mg, 90%) as a white solid.
Example IBI: Preparation of l-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6- yl)-l/f-indole-3-carbonitrile (Compound 340).
Step A: 4- Aminosalicylic acid (4.0 g, 26 mmol) is suspended in H2SO4 (26 mL, 2.7M) at -5°C. Sodium nitrite (1.8 g, 26.1 mmol) in H2O (6.5 mL) is cooled to ice bath temperature and is added dropwise to the aminosalicylic acid mixture over 5 minutes. The resulting suspension is stirred at -5°C for 15 minutes. A solution of KI (6.8 g, 41 mmol) in H2SO4 (13 mL, IM) is added dropwise to the diazonium salt, with considerable evolution OfN2. The reaction mixture is heated at 700C for 20 minutes. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (7/3, hexanes/acetone, 1% acetic acid) yields 4-iodosalicylic acid (5.33g, 85-90% pure).
Step B: Crude 4-Iodosalicylic acid (1.0 g, 3.8 mmol) is dissolved in THF (28 mL) and Et3N (1.15 mL, 8.2 mmol). DPPA (1.7 mL, 7.8 mmol) is added. This is heated at 700C overnight. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2ZEtOAc) yields 472 mg crude intermediate. Trituration with ether yields 6-iodo-3J7- benzooxazol-2-one (369 mg, 37%) as a white solid.
Step C: 6-Iodo-3uf-ben20oxazol-2-one (118 mg, 0.45 mmol) is used to prepare 1-ethyl- 6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-l/J-indole-3-carbonitrile, compound 340 (75 mg, 55%), utilizing essentially the same procedure as in example IGd. Example IBJ: Preparation of l-ethyl-6-meώoxy-2-(4-methyl-3-oxo-3,4,-dihydro-2/f- benzo[l,4]oxazin-6-yl)-lH-indole-3-carbonitrile (compound 339).
l-Ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-ben2o[l,4]oxazin-6-yl)-lH-indole-3- carbonitrile (20 mg, 0.058 mmol), prepared as in example 1BΗ, is combined with NaH (14 mg, 60% suspension in oil, 0.35 mmol). THF (300 μL) is added. This is stiiτed at room temperature for 5 minutes. A solution of methyl iodide (4.4 μL) in THF (100 μL) is added. This is stirred at room temperature for 1 hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields l-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4,- dmydro-2H-beiLzo[l,4]oxazm-6-yl)-lH-mdole-3-carbonitrile (16 mg, 76%) as a white solid.
The following compound is prepared similarly: Compound 341.
Example IBK: Preparation of l-ethyl-2-iodo-6-methoxy-5-nitro-lif-indole-3- carbonitrile (compound 499).
l-Ethyl^-iodo-o-methoxy-lH-indole-S-carbonitrile (50 mg, 0.15 mmol), prepared as in example IGa, Step A, is suspended in acetic acid (620 μL) at 00C. Nitric acid (4.25M in AcOH) is added. This is stirred at room temperature for 2 hours. The reaction mixture is then partitioned between CH2CI2 and H2O. The organic layer is washed with aqueous NaHCθ3, and then is dried and concentrated. Purification by silica gel chromatography (6/4, CHiCk/hexanes), followed by ether trituration, yields l-ethyl-2-iodo-6-methoxy-5-nitro-lH- indole-3-carbonitrile (16 mg, 29%) as a yellow solid. Example IBL: Preparation of F-ethanesulfonyH-emyl-6-methoxy-2\3'-dihydro- IH7IH -[2,6']biindolyl-3-carbonitrile (compound 753).
Step A: 6-Nitroindoline (3.0 g, 18.3 mmol) is dissolved in THF (45 mL) and Et3N (3.4 mL, 24.4 mmol) at O0C. Acetyl chloride (1.5 mL, 21 mmol) is added dropwise. The mixture is stirred at room temperature for 30 minutes. The mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated to yield l-acetyl-6-nitroindoline (3.8 g, 100%) as a yellow solid.
Step B: l-Acetyl-6-nitroindoline (3.8 g, 18.3 mmol) is suspended in EtOAc (200 mL). Pd/C (650 mg, 10%) is added, and the mixture is hydrogenated at 40-55 p.si.i. for 2 hours. The mixture is then filtered through celite. The filtrate is concentrated, and the residue is triturated with ether to yield l-acetyl-6-aminoiαdoline (3.18 g, 99%) as an orange solid.
Step C: l-Acetyl-6-aminoindoline (1.5 g, 8.5 mmol) is used to prepare l-acetyl-6- iodoindoline (1.06 g, 43%), utilizing essentially the same procedure in example IBI, Step A.
Step D: l-Acetyl-6-iodoindoline (1.06 g, 3.7 mmol), NaOH (1.16g, 29 mmol), EtOH (8 mL), and H2O (6 mL) are heated at 9O0C overnight. The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is extracted into aqueous HCl. The aqueous layer is in turn basified with NaOH, and is extracted with EtOAc. The organic layer is dried and concentrated. Hexane trituration yields 6-iodoindoline (577mg, 64%) as a brown solid.
Step E: 1-Iodoindoline (600 mg, 2.45 mmol) is used to prepare l-ethyl-6-methoxy- 2\3'-dihydro-lH,lH -[2,6']biindolyl-3-carbonitrile (535 mg, 67%), utilizing essentially the same procedure as in example IGd, Step B. Step F: l-Ethyl-6-methoxy-2',3'-dihydro-lH,li?'-[236']biindolyl-3-carbonitrile (30 mg, 0.095 mmol) is used to prepare r-Ethanesulfonyl-l-Ethyl-6-methoxy-2',3'-dihydro-lH,lH'- [2,6']biindolyl-3-carbonitrile (24 mg, 62%), utilizing the procedure in example IY.
The following compounds are prepared similarly as above: Compounds 752 and 754.
Example IBM: Preparation of 5-acetyl-l-ethyl-6-methoxy-2-(4-nitro-phenyl)-lH- indole-3-carbonitrile (compound 844).
DCE
l-Ethyl-6-methoxy-2-(4-πitrophenyl)-lH-indole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example IGc is suspended in 1 ,2-dichloroethane (500 μL) at 00C. Acetyl chloride (50 μL, 0.69 mmol) is added, followed by AICI3 (55 mg, 0.4 mmol) in one portion. This is stirred at 00C for 1 hour, at room temperature for 4 hours, and at 45°C overnight. The reaction mixture is then partitioned between CΗ2CI2 and H2O. The organic layer is dried and concentrated. Purification by silica gel chromatography (195:5 CBbCb/EtOAc) yields 5-acetyl- 1 -ethyl-6-methoxy-2-(4-nitro-phenyl)- lif-indole-3 -carbonitrile (33 mg, 29%) as an orange solid.
Example IBN: Preparation of l-ethyl-6-methoxy-5-moφholin-4-yhnethyl-2-(4-nitro- phenyl)-lH-indole-3-carbonitrile (compound 845).
Step A: l-Ethyl-6-methoxy-2-(4-nitrophenyl)-lH-indole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example IGc, is combined with 1,3,5-tnoxane (64 mg, 0.71 mmol) and acetic acid (2 0 mL). 33% HBr in acetic acid (2.0 mL) is added. This is stirred at room temperature for 4 hours. The reaction mixture is then partitioned between CH2CI2 and H2O. The organic layer is washed with aqueous NaHCθ3, and is subsequently dried and concentrated. The crude mateπal is carried through to the next step
Step B. Crude 6-bromomethyl-l-ethyl-6-methoxy-2-(4-ni1io-phenyl)-lH-iiidole-3- carborutnle (0.3 mmol) is heated with morpholine (150 μL, 1 75 mmol) and DCE (1.0 mL) at 9O0C overnight The reaction mixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated Purification by silica gel chromatography (50-100%, EtOAc/CBbCla), followed by trituration with 1/1 hexane/acetone yields l-ethyl-6-methoxy-5- moφholui-4-yhnethyl-2-(4-nitrophenyl)-liϊ-indole-3-carbomtrile (57 mg, 44% overall yield) as a yellow solid.
Example IBO: 2-[4-(14-dioxidoisotmazohdm-2-yl)phenyl]-l-cyclopropylmethyl-6- metBoxy-lH-indole-3-carborutrtle (compound 716).
Step A: To a solution of 6-methoxyϊndole (5 88 g, 40.0 mmol) and di-/er/-butyl dicarbonate (9.59 g, 44.0 mmol) in DCM (50 mL) is added, at 400C while stirring, DMAP (0.10 g). After stirring overnight, the mixture is washed sequentially with 0.1 N HCl5 water and brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is chromatographed (silica gel, EtOAc/hexanes, 1/7) to provide tert-butyl 6-methoxy-lH-indole- 1-carboxylate (8.48 g, 86%).
Step B: The above Boc-indole (3.08 g, 12.5 mmol) and isopropylborate (4.83 mL, 21.9 mmol) are dissolved in anhydrous THF (20 mL) and the solution is cooled at 00C. While stirring, LDA (12.5 mL, 1.5 M mono-THF complex in cyclohexane, 18.7 mmol) is added dropwise. The mixture is stirred at 00C for 15 min and then room temperature for 0.5h, followed by the addition of HCl (6 N, 3.0 mL, 18 mmol) in an ice-water bath. The organic solvent is removed in vacuo and the residue is suspended in H2O (100 mL) and acidified with HCl (6 N) to pH 4~5. The precipitate is collected via filtration and washed with water and hexanes and dried in air to provide l-Boc-6-mehoxyindole-2-boronic acid (3.38 g, 93%).
Step C: To a solution of 4-iodoanilline (3.18 g, 14.5 mmol) in pyridine (15 mL) at 00C, is added 3-chloropropanesulfonyl chloride (2.3 mL, 18.9 mmol). After the addition, the mixture is stirred for 2h at room temperature, and poured into ice-water (200 mL). The organic is separated and the aqueous layer is extracted with DCM (2 X 50 mL). The combined organics are washed with HCl (2 N, 2 X 15 mL), water (2 X 50 mL) and brine (20 mL) consecutively and dried over anhydrous Na2SCv The solvent is then evaporated and the residue is chromatographed to furnish 3-chloro-N-(4-iodophenyl)propane-l-sulfonamide (4.68 g, 90%). The chlorosulfonamide obtained (3.47 g, 9.6 mmol) is then treated with K2CO3 (3.33 g, 24.1 mmol) in DMF (50 mL) at 500C for 2h. The mixture is poured into ice-water (300 mL) and the precipitate is collected and dried in air to provide essentially pure 2-(4- iodoρhenyl)isothiazolidine- 1,1 -dioxide (3.11 g5 100%).
Step D: To a mixture of l-Boc-6-mehoxyindole-2-boronic acid prepared in step B above (0.36 g, 1.25 mmol), 2-(4-iodophenyl)isothiazolidiαe-l,l -dioxide (0.32 g, 1.0 mmol) and PdCl2(dppf) (0.037 g, 0.05 mmol) in DMF (4.0 mL), is added aqueous K2CO3 solution (1.5 mL, 2.0 M, 3.0 mmol). The mixture is stirred at room temperature overnight and then poured into ice-water (100 mL). The precipitate is collected and washed with water and purified by flash column chromatography (silica gel, DCM /EtOAc1 9/1) to furnish 1- Boc-2-[4-(l,l- dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-lH-indole (0.43 g, 98%).
The following compound is made similarly: Compound 768
Step D: 1- Boc-2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-lH-indole (1.63 g, 3.7 namol) is treated with TFA (25 mL) in DCM (25 mL) at room temperature for 4h. After the removal of the volatiles, the residue is carefully stirred with saturated NaHCO3 for 0.5h. The precipitate is collected via filtration and washed with water thoroughly and dried to provide essentially pure l-H-2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (1.17 g, 92%).
Step E: At 00C, l-H-2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (0.95 g, 2.8 πunol) is dissolved in DMF (10 mL) and treated with chlorosulfonyl isocyanate (0.36 mL, 4.2 πunol). The mixture is then stirred at room temperature overnight and poured into ice-water (150 mL) then stirred for 0.5h. The precipitate is collected via filtration and washed thoroughly with water and dried in air to furnish l-H-2-[4-(l ,l-dioxidoisothiazolidin-2- yl)phenyl]-6-methoxyindole-3-carbonitrile (0.89 g, 87%).
The following compound is prepared in the same fashion as described above: Compound 829
Step F: To a solution of 1 -H-2-[4-(l , 1 -dioxidoisothiazolidin-2-yl)phenyl]-6- methoxyindole-3-carbonitrile (73 mg, 0.2 mmol) and K2CO3 (69 mg, 0.5 mmol) in DMF (3.0 mL) is added cyclopropylmethyl iodide (0.029 mL, 0.3 mmol). The mixture is stirred at 500C overnight and poured into ice-water (10 mL). The precipitate is collected via filtration, washed with water and purified by column chromatography to provide 2-[4-(l,l-dioxidoisothiazolidin- 2-yl)phenyl]-6-methoxy-l-cyclopropyhnethylindole-3-carbonitrile, compound 716 (73 mg,
The following compounds are prepared in the same fashion as described above: Compounds 717, 718, 719, 782, 783, 784.
Example IBP: Preparation of 2-[4-(l,l >-dioxo-lλ6-isothiazolidin-2-yl)-6-methoxy-3- oxazol-5-yl-l-ρropyl-liϊ-indole (compound 805).
Step A: 2-[4-(l,l'-Dioxo-lλ -isothiazolidin-2-yl)-6-methoxy-indole (900 mg, 2.62 mmol), prepared in example IBO, step D is used to prepare 2-[4-(l,l'-dioxo-lλ6- isothiazolidin-2-yl)-6-methoxy-l-proρyl-lH-indole (608 mg, 60%), utilizing essentially the same procedure as example IA, Step B.
Step B: 2-[4-(l,r-Dioxo-lλ6-isothiazolidm-2-yl)-6-methoxy-l-ρropyl-lH-indole (50 mg, 0.13 mmol) is used to prepare 2-[4-(l,r-dioxo-lλ6-isothiazolidin-2-yl)-6-methoxy-3- oxazol-5-yl-l-propyl-lH-indole (9 mg, 15% overall yield) according to the protocol in example IP.
Example BQ: Preparation of 2-[4-(cyclopropylsulfonyl)piperazin-l-yl]-l-ethyl-6- (trifluoromethyl)-lH-indole-3-carbonitrile (compound 842).
Step A: To a solution of l-ethyl-ό-trifluoromethylindole-S-carbonitrile (2.54 g, 10.0 mmol), prepared by the method of procedure IA, in anhydrous THF (20.0 mL), at -78°C is added LDA (8.3 mL, 1.5 M mono-THF in cyclohexane, 12.5 mmol) dropwise. The mixture is continued for 0.5h after the addition, followed by the addition of hexachloroethane and the mixture is then brought to room temperature slowly and stirred for 0.5h. The solvent is then evaporated and the residue is treated with water. The organics are extracted with dichloromethane, washed with water and brine and dried over anhydrous Na2SO4. The crude product obtained after the removal of the solvent is chromatographed (silica gel, dichloromethane/hexanes, 3 /2) to provide 2-chloro-l-ethyl-6-(trifluoromethyl)-lH-indole-3- carbonitrile (1.75 g, 64%).
Step B: The chloroindole obtained above (0.27 g, 1.0 mmol), K2CO3 (0.35 g, 2.5 mmol) andN-Boc-piperazine (0.28 g, 1.5 mmol) are stirred at 700C in DMF (5.0 mL) for 3 days and then poured into water (50 mL). The precipitate is collected via filtration and washed with water. Chromatography of this crude product (silica gel, dichloromethane/ethyl acetate, 9/1) provides 4-(3-cyano-l-ethyl-6-trifiuoromethyl~ l/y-indol-2-yl)-piperazine~ 1 -carboxylic acid tert-butyl ester, compound 785 (0.30 g, 71%).
The following compounds are prepared in the same fashion as described above, by using other amines: Compounds 514, 785, 786. Step C: 4-(3 -cyano- 1 -ethyl-6-trifluoromethyl- lH-indol-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester (0.26 g, 6.1 mmol) is treated with TFA (5 mL) in dichloromethane (5 mL) for Ih at room temperature. After the removal of the volatiles, the residue is treated with saturated NaΗCθ3 and the precipitate is collected via filtration, washed with water thoroughly and dried in air to furnish essentially pure l-ethyl-l-piperazin-l-yl-ό-Ctrifluoromethyl)-!//- indole-3-carbonitrile (0.20 g, 100%).
Step D: To a solution of l-ethyl-2-piperazin-l-yl-6-(trifluoromethyl)-lH-indole-3- carbonitrile (32 mg, 0.1 mmol), pyridine (0.1 mL) in dichloromethaene (1.0 mL) is added cyclopropanesulfonyl chloride (28 mg, 0.2 mmol) and the mixture is stirred at room temperature overnight. This is then diluted with dichloromethane (5 mL), washed with HCl (2 N, 2 X 2 mL), water (2 X 5 mL) and brine (5 mL) and chromatographed over silica gel (dichioromethane/ethyl acetate, 9/1) to provide 2-[4-(cyclopropylsulfonyl)ρiperazin-l-yl]-l- ethyl-6-(trifluoromethyl)-li?-indole-3-carbonitrile, compound 842 (30 mg, 70%).
The following compounds are prepared in the same fashion as described above, using corresponding sulfonyl chlorides: Compounds 841, 843.
Example IBR: Ethanesulfonic acid [3-cyano-2-(4-ethoxyphenyl)-l-ethyl-lJftT-indol-6- yl]-amide (compound 835).
Step A: 6-Bromo-2-(4-ethoxyphenyl)-l-ethyl-lH-indole-3-carbonitrile (0.74 g, 2.0 mmol), compound 831, prepared from 6-bromoindole as described in example IGb, is mixed with K2CO3 (0.55 g, 4.0 mmol), CuI (0.02 g, 0.1 mmol), tert-butyl carbamate (0.35 g, 3.0 mmol), N, N'-dimethylcyclohexane-l,2-diamine ligand (0.028 g, 0.2 mmol) and anhydrous toluene (5.0 mL) in a sealed tube. The reaction system is flushed with nitrogen and then stirred at 1100C overnight. After cooling, the solvent is replaced with dichloromethane and chromatographed (silica gel, dichloromethane) to provide [3-cyano-2-(4-ethoxy-phenyl)-l- ethyl-lH-indol-6-yl]-carbamic acid ter/-butyl ester (0.68 g, 84%), compound 832. Step B: Compound 832 prepared in step A above (0.63 g, 1.56 mmol) is treated with TFA/DCM (7.5 mL/7.5 mL) at room temperature for 2h, and the volatiles are removed in vacuum. The residue is treated with saturated NaHCθ3 and the precipitate is collected via filtration and washed thoroughly with water, dried in air to provide 6-amino-2-(4- ethoxyphenyl)-l-ethyl-liJ-indole-3-carbonitrile (0.45 g, 96%), compound 833.
Step C: The above amine (31 mg, 0.1 mmol) is treated with ethanesulfonyl chloride (19 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperature overnight to provide, after purification using column chromatography, ethanesulfonic acid [3-cyano-2-(4-ethoxy-phenyl)- l-ethyl-l#"-jLndol-6-yl]-amide (83%), compound 835.
The following compounds are prepared in the same fashion as described above: Compounds 830, 834, 836 and 837.
Example IBS: Preparation of [3-cyano-2-(4-ethoxyphenyl)-l-ethyl-lH-indol-6-yl]- carbamic acid ethyl ester (compound 838)
EtOCOCl pyndιnβ
6-Amino-2-(4-ethoxyphenyl)-l -ethyl- lH-indole-3-carbonitrile (31 mg, 0.1 mmol), compound 833, prepared in example IBR, step B is treated with ethyl chloroformate (16 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperature overnight to furnish, after purification using column chromatography [3-cyano-2-(4-ethoxyphenyl)-l -ethyl- lif-indol-δ-ylj-carbamic acid ethyl ester (30 mg, 79%).
Example IBT: Preparation of l-[3-cyano-2-(4-ethoxyphenyl)-l-ethyl-lH-indol-6-yl]-3- ethyl-urea (compound 839).
EtNCO Pyridine
6-Amino-2-(4-ethoxyphenyl)-l-ethyl-lH-indole-3-carbonitril6 (31 mg, 0.1 mmol) is treated with ethyl isocyanate (14 mg, 0.2 mmol) in dichloromethane (1.0 mL) at 4O0C overnight. The precipitate is collected via filtration, washed with dichloromeύiane an dried in air to furnish, l-[3-cyano-2-(4-ethoxy-phenyl)-l-ethyl-lH-indol-6-yl]-3-ethyl-urea (36 mg,
95%). Example IBU: Preparation of l-(2-cMoroethyl)-3-[4-(3-cyano-l-ethyl-6-rnethoxy-lH- indol-2-yl)-phenyl]-urea (compound 442).
To a solution of 2-(4-aminoplienyl)-l-ethyl-6-inethoxy-l/f-indole-3-carbonitrile (50 mg, 0.172 mmol) in THF (2 mL) is added 2-chloroethyl isocyanate (22 uL, 0.258 mmol) at room temperature. After stirring overnight at reflux, the reaction mixture is concentrated in vacuo and the residue is diluted with ethyl acetate. The resulting semi-solid is triturated with hexane and the precipitate collected is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford (62 mg, 91%) of l-(2-chloroethyl)-3-[4-(3- cyano-l-ethyl-6-methoxy-liϊ-indol-2-yl)-phenyl]-urea.
Utilizing essentially the same procedure, the following compounds are prepared: Compounds 295, 362, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 443, 444, 445, 446, 511, 512, 513, 600, 620, 626, 627, 628, 679, 680, 681, 740, 741, 742, 743, 748, 749, 750, 751, 774, 817, 818, 846, 847, 848, 954, 955, 956, 957, 958, 987, 999, 1000, 1001, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1016, 1017, 1018, 1019, 1023, 1024, 1027,1036,1039, 1043, 1045, 1060,1061, 1066, 1067,1070, 1080, 1092, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1106, 1108, 1118, 1120, 1124, 1125, 1126, 1136, 1137, 1138, 1139, 1143, 1144, 1156, 1157, 1162, 1163, 1164, 1165, 1171, 1172, 1173, 1197,1190, 1214,1221, 1223, 1224, 1225, 1225, 1227, 1256, 1279, 1301, 1303, 1304, 1305,
Example IBV: Preparation of l-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-l-yl)- phenyl]-l/7-indole-3-carbonitrϊle (compound 771).
To a solution of l-(2-chloroethyl)-3-[4-(3-cyano-l-ethyl-6-methoxy-lH'-indol-2-yl)- phenyl]-urea (100 mg, 0.252 mmol) in MeOH (10 mL) is added aqueous IM KOH (504 uL) and then stirred at 49°C for 24h. The solvents are removed under reduced pressure. The residue is diluted with ethyl acetate and then washed with water. The organic layer is dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue is diluted with ethyl acetate and then triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford 1- ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-l-yl)-ρhenyl]-lH-indole-3-carbonitrile (56 mg,
Using essentially the same procedure, the following compounds are prepared: Compounds 770, 778
Example IBW: Preparation of l-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)- phenyl]-lJEf-indole-3-carbonitrile (compound 638).
To a solution of ^-(S-cyano-l-ethyl-o-isopropoxy-lii-indol^-y^-phenylj-carbamic acid 2-chloro-ethyl ester (30 mg, 0.07 mmol) in DMF (1 mL) is added aqueous K2CO3 (10 mg) and then stirred at 500C for 18h. The reaction mixture is poured into cold water and the precipitate collected by filtration and washed with hexane and dried in vacuo to afford the title compound (21 mg, 81%).
The following compounds are made in similar fashion: Compounds 820, 821, 863, 864.
Example IBX: Preparation of {3-[3-cyano-l-ethyl-6-(3-pyrrolidm-l-yl-propoxy)-li/- indol-2-yl]-phenyl}-carbamic acid ethyl ester (compound 530).
Step A: To a solution of [3-(3-cyano-l-ethyl-6-methoxy-li7-indol-2-yl)-phenyl]- carbamic acid ethyl ester (1.65 g, 4.37 mmol) in DCM (20 mL) is added IM BBr3 in DCM (13.12 mL) over aperiod of 20 min. The reaction mixture is stirred further lh at room temperature and then the solvents are removed under reduced pressure. The residue is dissolved in MeOH and then poured into cold water. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [3-(3-cyano-l-ethyl-6-hydroxy-lH-indol- 2-yl)-phenyl]-carbamic acid ethyl ester (1.5 g, 98%).
Step B: To a solution of [3-(3-cyano-l-ethyl-6-hydroxy-lH-indol-2-yl)-phenyl]- carbamic acid ethyl ester (1.2 g, 2.91 mmol) in DMF (10 mL) is added K2CO3 (538 mg, 3.9mmol) and 3-bromo-l-chloropropane (383 uL, 3.9 mmol) and the reaction is stirred for overnight at 500C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 1.1 g, 89% of the desired product.
Step C: To a solution of {3-[3-cyano-l-ethyl-6-(3-ρyrrolidin-l-yl-propoxy)-lH-indol-2- yl] -phenyl} -carbamic acid ethyl ester (50 mg, 0.12 mmol) in CH3CN (2 mL) is added DIPEA (31 uL, 0.18 mmol), sodium iodide (20 mg, 0.132 mmol) and pyrrolidine (30 uL, 0.36 mmol). The resulting mixture is stirred at reflux temperature for overnight. The solvent is evaporated and the residue is diluted with ethyl acetate and then triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford 1 -ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]- lH-indole-3-carbonitrile, compound 638 (46 mg, 85%).
The following compounds are made in similar fashion following steps A-C, above: Compounds 441, 447, 491, 492, 493, 504, 525, 526, 527, 528, 529, 531, 532, 533, 534, 535, 536, 537, 538, 539.
Example IBY: Preparation of [3-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]- thiourea (Compound 767).
Step A: The starting material 2-(3-amino-phenyl)-l-ethyl-6-methoxy-lH-indole-3- carbonitrile (187 mg, 0.642 mmol) is dissolved in anhydrous acetone (3.0 mL). Benzoyl isothiocyanate (107 mg, 0.656 mmol) is added to the solution at room temperature and the mixture is stirred for 17h during which time a precipitate forms. The precipitate is filtered, washed with acetone and dried to give 264 mg of l-benzoyl-3-[3-(3-cyano-l-ethyl-6-methoxy- 1 Jf-indol-2-yl)-ρhenyl] -thiourea (90% yield) as a light yellow solid.
Step B: A suspension of l-benzoyl-3-[3-(3-cyano-l-ethyl-6-methoxy-lif-indol-2-yl)- phenyl]-thiourea (241 mg, 0.530 mmol) in methyl alcohol (2.0 ml) and water (0.5 mL) is stirred at room temperature as sodium hydroxide (31 mg, 0.78 mmol) is added. The reaction mixture is heated to 50°C for 17h. The reaction mixture is concentrated to remove methyl alcohol. Water is added to the mixture and the solid is filtered, washed with water and dried to give 179 mg of [3-(3-cyano-l-ethyl-6-methoxy-lH-indoi-2-yl)-phenyl]-thiourea, compound 767 (96% yield) as a white solid.
Example IBZ: Preparation of l-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)- phenyl]-l£T-indole-3-carbonitrile (Compound 458)
A solution of 2-(4-aminophenyl)-l-ethyl-6-methoxy-li7-indole-3-carbonitrile (100 mg, 0.343 mmol), 4-chloro-2-phenyl-quinazoline (83 mg, 0.34 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in absolute ethanol (3 mL) is heated to reflux overnight. The solution is cooled and evaporated, and the residue taken up in ethyl acetate (50 mL). This is washed with water and saturated brine (50 mL each), then dried over anhydrous sodium sulfate, filtered and evaporated. The resulting solid is triturated with ether, collected by filtration and dried under vacuum to afford l-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-lH-indole- 3-carbonitrile (139 mg, 0.280 mmol, 82%).
Example ICA: Preparation of diethyl [4-(3-cyano-6-ethoxy-l-ethyl-lH-indol-2-yl)- phenyLj-phosphoramidate (compound 772).
A solution of 2-(4-aminophenyl)-6-ethoxy-l-ethyl-lif-indole-3-carbonitrile (148 mg, 0.484 mmol), diethyl chlorophosphate (0.086 mL, 0.58 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in 1,4-dioxane (5 mL) is stirred at ambient temperature for 12 hours, then heated to 800C for an additional 24 hours. The solution is cooled and poured into 50 mL of ethyl acetate. This is washed with water and saturated brine (50 mL each), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by flash chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford diethyl [4-(3- cyano-6-ethoxy-l-ethyl-lH-indol-2-yl)-ρhenyl]-phosphoramidate (108 mg, 0.245 mmol, 51%) as a white powder after evaporation.
The following examples are made in similar fashion: Compounds 936, 937, 942, 943, 944, 1081.
Example ICB: Preparation of l-ethyl-6-methoxy-2-[4-(5-methyl-l,l-dioxo-lλ - [l,2,5]thiadiazolidm-2-yl)-phenyl]-li74ndole-3-carbom'trile (compound 726).
Step A: To a solution of 2-(4-aminophenyl)-l-ethyl-6-methoxy-li/-indole-3- carbonitrile (202 mg, 0.693 mmol) in pyridine (2.0 rnL) is added the N-β- (chloroethylamino)sulfonyl chloride (222 mg, 1.39 mmol). The mixture is stirred at room temperature for 17h then water (12.0 mL) is added and the mixture is extracted with ethyl acetate (3 X2 mL). The extract is washed with 10% aqueous HCl (2 X2 mL), water (2 X 2 mL), dried over MgSO4, filtered and concentrated on a rotary evaporator. The crude product is purified by flash chromatography (0-5%, ethyl acetate/methylene chloride) to give 217 mg of N-(2-chloro-ethyl)-iV-[4-(3-cyario-l-ethyl-6-methoxy-l/f-indol-2-yl)phenyl] sulfamide, compound 724, as a tan solid (75% yield).
Ih similar fashion the following compounds are prepared: Compounds 540, 541, 542, 574, 576, 704.
Step B: To a solution of N-(2-chloro-ethyl)-iV-[4-(3-cyarLO-l-ethyl-6-methoxy-lH'- indol-2-yl)phenyl] sulfamide (100 mg, 0.241mmol) in anhydrous DMF (1.25 mL), is added potassium carbonate (71.0 mg, 0.514 mmol), The mixture is stirred at room temperature for 17h, then diluted with water (7.5 mL). The reaction mixture is extracted with ethyl acetate (3 X 2 mL) and the extract is washed with water (2 X 2 mL), dried over MgSO4 and concentrated to give 2-[4-( 1 , 1 -dioxo- 1 λ6-[ 1 ,2,5] thiadiazolidin-2-yl)phenyl]-l -ethyl-6-methoxy- 1 H-indole-3 - carbonitrile, compound 725, as a white solid (84 mg, 88% yield).
In similar fashion the following compound is prepared: Compound 705.
Step C: To a solution of 2-[4-(l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-2-yl)phenyl]-l-ethyl- 6-methoxy-lH-indole-3-carbonitrile (34 mg, 0.086mmol) in anhydrous DMF (1.0 mL) is added potassium carbonate (25 mg, 0.18 mmol) and iodomethane (20.4 mg, 0.144 mmol). The mixture is stirred at room temperature for 2h and then diluted with water (6.0 mL) to give a precipitate. The precipitate is filtered, washed with water and dried to give l-ethyl-6-methoxy- 2-[4-(5-methyl-l,l-dioxo-lλ6-[l,2,5]thiadiazolidin-2-yl)-phenyl]-lH-indole-3-carbonitrile, compound 726, as a white solid (35 mg, 98% yield).
In similar fashion the following compounds are prepared: Compounds 727, 1110.
Example ICC: Preparation of [4-(3-cyano-l-ethyl-6-methoxy-liJ-indol-2-yl)-2- fluorophenyl]-carbamic acid propyl ester (compound 877).
A biphasic mixture of 2-(4-amino-3-fluorophenyl)-l-ethyl-6-methoxy-lH/-indole-3- carbonitrile (74 mg, 0.24 mmol), prepared as described in example IGb, and propyl chloroformate (0.033 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at 00C and then allowed to warm to room temperature and stirred for 24h. The reaction is then diluted with H2O and extracted with EtOAc (2X). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 10-40%) gives 60 mg (63%) of [4-(3-cyano-l-emyl-6-methoxy-lif-indol-2- yl)-2-fluoroρhenyl]-carbamic acid propyl ester as an off-white solid.
The following compounds are prepared in a similar fashion: Compounds 875, 876, 878, 879. By utilizing 2-(4-arnino-3-methylρhenyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile the following compounds are prepared: Compounds: 963, 964, 965.
Utilizing the same starting material and procedures described in examples IY, the following compounds are prepared: Compounds 871, 872, 873, 874. Ln. similar fashion, utilizing 2-(4-amino-3-methylρhenyl)-l-ethyl-6-methoxy- lH-indole-3-carbonitrile, the following compounds are prepared: Compounds 959, 960, 961, 962.
Utilizing the same starting material and procedures described in examples IBU, the following compounds are prepared* 909, 910, 911. In a similar fashion, utilizing 2-(4-amino-3- methylphenyl)-l-ethyl-6-methoxy-lH-indole-3-carbonitrile, the following compounds are prepared: Compound: 966, 967. Example CD: Preparation of cyclopropanecarboxylic acid {4-[3-cyano-l-ethyl-6-(2- imidazol-l-yl-ethoxy)-lif-indol-2-yl]-ρhenyl} -amide (compound 1183).
reflux
Step A: To a solution of compound 2-(4-aminophenyl)-6-ethoxy-l-ethyl-lH-indole-3- carbonitrϊle (3.66 g, 12 mmol), prepared as described in example IGb, in 20 mL of THF is added Et3N (3.37 ml) and cyclopropanecarbonyl chloride (1.6 mL, 18mmol). The mixture is stirred for 3h at room temperature. Then water and ethyl acetate are added to the reaction mixture. The organic layer is separated, washed with brine (2X), dried over anhydrous Na?SO4, filtered and concentrated. The residue is recrystallized with ethyl acetate and hexane to yield 99% of cyclopropanecarboxylic acid [4-(3-cyano-6-ethoxy-l-ethyl-lH-indol-2-yl)- phenyl]-amide.
Step B: To a solution of cyclopropanecarboxylic acid [4-(3-cyano-6-ethoxy-l-ethyl-lH- indol-2-yl)-phenyl]-amide (4.4 g, 11.8 mmol) in 60 mL of DCM is added BBr3 (6.65 mL, 70 mmol) at — 100C. After the addition, the mixture is stirred for 3h at 00C. Then aqueous NaHCO3 is added to the mixture carefully until it became basic. The crude solid is collected by filtration to give 91% of cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6-hydroxy-lH- indol-2-yl)-phenyl]-amide and is used for the next step without further purification.
Step C: To a solution of cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6-hydroxy- lH-indol-2-yl)-phenyl]-amide (4 g, 11.6 mmol) in 15 mL of MEK is added K2CO3 (8 g, 58 mmol) and l-bromo-2-chloro-ethane (6.7 mL, 70 mmol). Then the mixture is heated at reflux overnight. After it is cooled to room temperature, water and ethyl acetate are added. The organic layer is separated, washed with brine (2X), dried over anhydrous Na2SO4, filtered and concentrated to yield 81% of the crude cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)-3- cyano-l-ethyl-lH-indol-2-yl]-phenyl}-amide.
Step D: To a solution of cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)-3-cyano- 1 -ethyl- lH-indol-2-yl]-phenyl} -amide (102 mg, 0.25 mmol) in 1.5 mL of acetonitrile are added NaI (46 mg, 0.275 mmol), K2CO3 (138 mg, 1 mmol) and imidazole (51 mg, 0.75 mmol) in a sealed tube. Then the mixture is heated to 900C and stirred overnight. After it is cooled to room temperature, water and ethyl acetate are added. The organic layer is separated, washed with brine (2X), dried over anhydrous Na2SO4, filtered and concentrated. The crude compound is purified by preparative ΗPLC to give 71% of cyclopropanecarboxylic acid {4-[3-cyano-l- ethyl-6-(2-imidazol-l-yl-ethoxy)-lH-indol-2-yl]-phenyl}-amide.
Using the same procedure and substituting the appropriate nucleophilic reagents gives the following compounds: Compounds 952, 1025, 1054, 1090, 1091, 1092, 1093, 1184.
Example CE: Preparation of ethanesulfonic acid [4-(3-cyano-l-ethyl-6- trifluoromethoxyindol-2-yl)phenyl]amide (compound 881).
Step A: To a suspension of .-BuONO (8.01 mL, 67.5 mmol) and CuCl2 (7.26 g, 54 mmol) in acetonitrile (50 mL), at 6I0C with gentle stirring, is added 2-nitro-4- trifluoromethoxyaniline (10.0 g, 45.0 mmol) portionwise. The mixture is stirred at this temperature for 2h after the addition. The solvent is removed on a rotorvap and the residue is treated with HCl (6 N, 200 mL), and extracted with dichloromethane (3 x 100 mL). The extracts are combined, dried over anhydrous Na2SC>4, and passed through a short silica gel pad. The solvent is removed and the residue is added to a suspension of benzyl cyanoacetate (7.88 g, 45 mmol) and K2CO3 (12.42 g, 90 mmol) in DMF (100 mL). This mixture is then stirred at 450C overnight and poured into ice-water (700 mL), and extracted with dichloromethane (3 x 100 mL). The organics are dried over anhydrous Na2SC>4 and again passed through a short silica gel pad, eluting with ethyl acetate. The solvent is then replaced with EtOH (160 mL), acetic acid (16 mL) and water (16 mL), and the reaction mixture is hydrogenated over 5% Pd/C (2.80 g) at 50 psi overnight. The mixture is filtered over Celite and the volatiles are removed in vacuo. The residue is dissolved in dichloromethane (200 mL), washed withNa2CO3 (2 M, 2 x 50 mL), water (2 x 50 mL), brine (50 mL) and dried over anhydrous Na2SC>4. The crude product, obtained after the removal of the solvent, is chromatographed (silica gel, DCM/ Hexanes, 1/1) to provide 6-trifluoromethoxyindole (5.70 g, 63% based on 2-nitro-4- trifluoromethoxyaniline).
Step B: To a solution of 6-trifluoromethoxyindole (2.68 g, 13.3 mmol) in dry DMF (10 mL) at 00C, is added chlorosulfonylisocyanate (2.35 g, 1.44 mL, 16.6 mmol). The mixture is then brought to room temperature slowly and stirred for Ih. The mixture is poured into ice (100 mL) and stirred for Ih. The precipitate is collected by filtration and washed thoroughly with water and dried in vacuo, which is then dissolved in DMF (15 mL). To the solution is added K2CO3 and EtI (2.59 g, 1.34 mL, 16.6 mmol), and the mixture is stirred at 5O0C overnight. It is then poured into ice-water (200 mL). The precipitate is collected by filtration and washed with water, dried in air and purified by chromatography (silica gel, DCM) to furnish l-ethyl-6-trifluoromethoxymdole-3-cafbonitrile (2.90 g, 86%).
Step C: To a solution of the intermediate (2.03 g, 8.0 mmol) obtained above, triisopropylborate (2.16 g, 2.65 mL, 12.0 mmol) in dry THF (15 mL) at -780C is added LDA (6.7 mL, 1.5 M, 10.0 mmol). The mixture is stirred at-78°C for 15 min after the addition, then slowly brought to room temperature and stirred for 30 min. It is then cooled at — 78°C and followed by the addition of 4-iodoaniline (2.10 g, 9.6 mmol), PdCl2(dppf) (0.29 g, 0.4 mmol), DMF (30 mL) and K2CO3 (12.0 mL, 2.0 M, 24.0 mmol). The mixture is brought to room temperature slowly and stirred overnight and poured into ice-water (400 mL). The precipitate is collected and washed with water, chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to furnish 2-(4-aminophenyl)-l-ethyl-6-trifluoromethoxyindole-3-carbonitrile (1.99 g, 72%). Step D: To a solution of the compound obtained in step C (31 mg, 0.1 mmol) in dry pyridine (LO mL) is added ethanesulfonyl chloride (14 μL, 0.15 mmol). The mixture is stirred at room temperature overnight and diluted with water (5 mL). The organic is extracted with DCM (5 mL) and washed with HCl (2N, 2 x 3 mL), water (2 x 4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, ethanesulfonic acid [4-(3-cyano-l-ethyl-6-trifluoromethoxyindol-2-yl)ρhenyl]amide (33 mg, 83%).
Compounds 882, 883, 884, 885, 886, 887, 888, 889 are prepared utilizing the above route using either the appropriate alkylsulfonyl chlorides (procedure IY) or chloroformates (procedure IAJ).
Example ICF: Preparation of 2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl]-l-etliyl-6- (trifluoromethoxy)indole-3-carbonitrile (compound 903).
-A (Boc)2O/DMAP B(O1Pr)3ZLDA 2N HCI
F3CO' -N DCM F3 "C*O" -N THR O 0C - RT O 0C - RT
Boc
Step A: To a solution of 6-trifluoromethoxyindole (3.01 g, 15.0 mmol) and di-tert-butyl dicarbonate (3.59 g, 16.5 mmol) in DCM (30 mL) at 4O0C is added DMAP (0.04 g) while stirring. After stirring overnight, the mixture is washed sequentially with 0.1 N HCl, water and brine and dried over anhydrous Na2SC>4. The solvent is evaporated and the residue is chromatographed (silica gel, EtOAc/Hexanes, 1/9) to provide tert-butyl 6-trifluoromethoxy- lH-indole-1 -carboxylate.
Step B: The above Boc-indole and triisopropylborate (4.73 g, 5.8 mL, 26.3 mmol) are dissolved in anhydrous THF (20 mL) and the solution is cooled to 00C. While stirring, LDA (15.0 mL, 1.5 M mono-THF complex in cyclohexane, 22.5 mmol) is added dropwise. The mixture is stirred at 00C for 15 min and then room temperature for 0.5h, followed by the addition of HCl (6 N, 3.75 mL, 22.5 mmol) in an ice-water bath. The organic solvent is removed in vacuo and the residue is suspended in H2O (100 mL) and acidified with HCl (6 N) to pH 4~5. The precipitate is collected via filtration and washed with water and hexanes and dried in air to provide l-Boc-6-trifluoromehoxyindole-2-boronic acid (2.56 g, 49%).
Step C: To a mixture of l-Boc-δ-trifluoromehoxyindole^-boronic acid prepared above (0.74 g, 2.1 mmol), 2-(4-iodophenyl)isothiazolidine- 1,1 -dioxide (0.76 g, 2.4 mmol), and PdCl2(dppf) (0.08 g, 0.1 mmol) in DMF (6.0 mL), is added K2CO3 solution (3.2 mL, 2.0 M, 6.4 mmol). The mixture is stirred at room temperature overnight and then poured into ice-water (100 mL). The precipitate is collected and washed with water and purified by flash column chromatography (silica gel, DCM/EtOAc, 9/1) to furnish 1- Boc-2-[4-(l,l- dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole, which is treated with 50% TFA in DCM (15 mL) at room temperature for Ih. After the removal of the volatiles, the residue is carefully stirred with saturated NaHCO3 for 0.5h. The precipitate is collected via filtration and washed thoroughly with water and dried to provide essentially pure l-H-2-[4-(l,l- dioxidoisothiazolidin-2-yl)plienyl]-6-trifluoromethoxyindole.
Step D: At O0C, a solution of the intermediate obtained above in dry DMF (10 mL) is treated with chlorosulfonyl isocyanate (0.38 g, 0.23 mL, 2.68 mmol). The mixture is then stirred at room temperature overnight and poured into ice-water (150 mL) then stirred for 0.5h. The precipitate is collected via filtration and washed thoroughly with water and dried in air to furnish l-H-2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl3-6-trifluoromethoxyindole-3- carbonitrile (0.81 g, 90%).
Step E: To a solution of l-H-2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl]-6- trifluoromethoxyindole-3-carbonitrile (63 mg, 0.15 mmol) and K2CO3 (62 mg, 0.45 mmol) in DMF (2.0 mL) is added ethyl iodide (36 μL, 0.45 mmol). The mixture is stirred at 5O0C overnight and poured into ice-water (10 mL). The precipitate is collected via filtration, washed with water and purified by column chromatography to provide 2-[4-(l,l-dioxidoisothiazolidin- 2-yl)phenyl]-6-trifluoromethoxy-l-ethylindole-3-carbonitrile (59 mg, 88%).
The following compounds are prepared in the same fashion as described above: Compounds 902, 904, 905, 906. Example ICG: Preparation of [4-(3-cyano-l-cyclopropyl-6-methoxyindol-2- yl)phenyl]carbamic acid isopropyl ester (compound 1234).
Step A: To a suspension of 2-bromo-4-methoxyphenylacetic acid (24.5 g, 100 mrαol) in DCM (100 mL), while stirring, is added DMF (~10 mL) until all the solid disappears, which is followed by the addition of DCC (22.66 g, 110 mmol) and HOBt (14.85 g, 110 mmol). After stirring at RT for 10 min, cyclopropylamine (8.55g, 10.4 mL, 150 mmol) is added to the mixture, and the resulting mixture is stirred at room temperature for 4h. The solid is filtered and washed thoroughly with DCM (300 mL). The filtrate is cooled to — 100C and gently stirred for Ih and filtered again to remove additional urea by-product. The filtrate is passed through a silica gel pad and eluted with DCM/EtOAc, 8/2). After the removal of the solvent, the cyclopropyl amide intermediate is obtained as white solid (28.34 g, 100%).
Step B: A mixture of above amide (14.2 g, 50.0 mmol), K2CO3 (13.8 g, 100 mmol), CuI (0.74 g, 5.0 mmol) andN.N -dimethylcyclohexanediaπiine (1.42 g, 1.57 mL, 10.0 mmol) in toluene (150 mL) is stirred at 1100C under Ν2 atmosphere for 48h. After cooling to room temperature, the mixture is filtered over Celite and washed thoroughly with DCM. The filtrate is evaporated under reduced pressure to dryness and the residue is chrorαatographed (DCM/EtOAc, 9.5/0.5) to provide the product, l-cyclopropyl-6-methoxyoxindole as pale yellow solid (4.30 g, 42%).
Step C: To a solution of the oxindole obtained above (5.0 g, 24.6 mmol) in dry DCM (25 mL), at O0C, is added DIBAL-H (1.0 M in DCM5 35.0 mL, 35.0 mmol). After the addition, the mixture is stirred at room temperature for 4h and re-cooled to 00C, followed by the addition of HCl (2 N) dropwise. The DCM layer is washed with HCl (2 N, 10 mL) water and brine and dried over anhydrous Na2SC>4. The crude product obtained after the removal of the solvent is chromatographed (hexanes/EtOAc, 9.5/0.5) to provide the l-cyclopropyl-6-methoxyindole as a colorless oil (4.52 g, 98%).
Step D: To a solution of l-cycloproρyl-6-methoxylindole (3.29 g, 17.6 mmol) in dry DMF (30 mL), at O0C, is added chlorosulfonyl isocyanate (3.11 g, 1.91 mL, 22.0 mmol). After the addition, the mixture is stirred at room temperature for 2h, followed by aqueous work-up. Chromatography (silica gel, hexanes/EtOAc, 9/1) furnishes S-cyano-l-cyclopropyl-ό- methoxyindole (3.05 g, 82%).
Step E: To a solution of the intermediate (2.65 g, 12.5 mmol) obtained above and triisopropyl borate (3.38 g, 4.14 mL, 18.8 mmol) in dry THF (18 mL) at-78°C is added LDA (1O mL, 1.5 M, 15.0 mmol). The mixture is stirred at -780C for 15 min after the addition, then slowly brought to room temperature and stirred for 30 min. It is then cooled at -78°C and followed by the addition of 4-iodoaniline (3.29 g, 15.0 mmol), PdCl2(dppf) (0.46 g, 0.6 mmol), DMF (40 mL) and K2CO3 (18.8 mL, 2.0 M, 37.6 mmol). The mixture is brought to room temperature slowly and stirred overnight and then poured into ice-water (400 mL). The precipitate is collected and washed with water, and after drying, is chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to furnish 2-(4-aminophenyl)-l-cyclopropyl-6-methoxyindole-3- carbonitrile (2.84 g, 75%).
Step F: To a solution of the compound obtained in step E (61 mg, 0.2 mmol) in dry pyridine (2.0 mL) is added isopropylchloroformate (0.3 mL, 1.0 M, 0.3 mmol) in toluene. The mixture is stirred at room temperature overnight and diluted with water (10 mL). The organic layer is extracted with DCM (10 mL) and washed with HCl (2N, 2 x 3 mL), water (2 x 4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, [4-(3-cyano-l-cyclopropyl-6-methoxyindol-2-yl)phenyl]earbamic acid isopropyl ester (66 mg, 85%).
Compounds 1235 and 1236 are prepared by utilizing the above chemistry.
Example ICH: Preparation of l-allyl-6-methoxy-2-[4-(2-oxopyrrolidin-l-yl)-phenyl]- lH-indole-3-carbonitrile (compound 938)
Utilizing the procedure described in Example IGb, substituting l-allyl-6-methoxy-lif- indole-3-carbonitrile (92.3 mg, 0.43 mmol) and l-(4-iodoρhenyl)-pyrrolidin-2-one gives 99.0 mg (61.3% yield) of compounds 938.
Example ICI: phenylJ-l-emyMH-indole-θ-carbonitrile (compound 1046)
Step A: Utilizing the procedure described in Example IB (Step A) gives 6-hydoxy-l- ethyl- 1 H-indole-3 -carbonitrile.
Step B: To a solution of 6-hydoxy-l-eώyl-lH-mdole-3-carbonitrile (503.9 mg, 2.70 mmol) in 5 mL of DMF is added anhydrous K2CO3 (1.12 g, 8.12 mmol) and 1-bromo 2- fluoroethane (413.7 mg, 3.29 mmol). The resulting mixture is stirred at 800C until complete consumption of the starting material as determined by TLC. The reaction mixture is cooled, potassium tert-butoxide (IM solution in THF, 5.5 ml, 5.43 mmol) is added, and stirring continued at 800C overnight. The mixture is partitioned between EtOAc (30 mL) and IN HCl (20 mL). The organic phase is washed with saturated NaHCO3, saturated NaCl and dried and concentrated. The product is isolated by chromatography (EtOAc/hexanes, 10-25%) over silica gel to afford 430.2 mg (74.9%) l-ethyl-β-vinyloxy-lH-indole-S-carbonitrile as a white solid.
Step C: Via a syringe, diethyl zinc is added to a mixture of l-ethyl-6-vinyloxy-lH- indole-3-carbonitrile (288.1 mg, 1.36 rαmol), chloroiodomethane (268.9 mg, 1.53 mmol) and 5 ml of 1,2-dichloroethane over a period of 10 min, maintaining the temperature at -100C. The mixture is warmed to 20-250C for 20 min., and then cooled back to 00C. Saturated NH4Cl (15 mL), concentrated ammonium hydroxide (15 mL), and ethyl acetate (15 mL) are added in sequence at this temperature, and stirred for 10 min. After the phases are separated, the aqueous phase is back-extracted with ethyl acetate (10 mL). The combined organic phases are washed with saturated NH4Cl (10 mL), dried over MgSO4 and then the solution is concentrated, and the product is purified by chromatography, eluting with 15-30% ethyl acetate / hexanes to afford 140.5 mg (45.7% yield) of δ-cyclopropoxy-l-ethyl-lH-mdole-S-carbonitrile as a yellow solid.
Step D: Utilizing the same procedure described in Example IGb substituting 4- iodoaniline with 2-(4-iodo-phenyl)-isothiazolidine 1,1-dioxide gives the title compound.
In similar fashion, following steps A to D, above, compound 1047 is also prepared.
Example CJ: Propane-1 -sulfonic acid [4-(3-cyano-6-difluoromethoxy-l-ethyl-lH- indoel-2-yl)-phenyl]-amide (compound 928).
4. K2CO3 (3M, aq.) PdCI2dppf
Step A: A solution of 6-difluoromethoxy-l -ethyl- lH-indole-3-carbonitrile (316.3 mg, 1.34 mmol) and triisopropyl borate (402.9 mg, 2.14 mmol) in TΗF ( 15 mL) is cooled to -78°C and treated with LDA (1.5 M mono-TΗF in cyclohexane, 1.07 mL, 1.61 mmol). After the addition, the acetone/dry ice bath is exchanged for an ice water bath and the solution is stirred further for 30 min. The solution is cooled to -78°C and a solution of 4-iodoaniline (299.5 mg, 1.37 mmol) in DMF (8 mL), K2CO3 (2M, 2.01 mL, 6.02 mmol) and PdCl2dppf (51.3 mg, 0.07 mmol) are added in sequence. The mixture is degassed by three successive cycles of vacuum pumping/Nj purging and is stirred overnight (ca. 16h.). The reaction mixture is poured into 4 volumes of water, and 4 volumes of ethyl acetate are added. The phases are separated, and the aqueous phase is extracted with more ethyl acetate. The organic phases are washed by water, saturated NaCl and then dried over anhydrous MgSO4, filtered and evaporated. The remaining material is purified by column chromatography, eluting with 5-15% ethyl acetate/hexanes on silica gel to yield 304.5 mg (70%) of the aniline intermediate as a white solid.
Step B: Utilizing the same procedure described in Example IY and substituting n- propylsulfonyl chloride gives the title compound.
The following compounds are made using essentially the same procedure and substituting other sulfonyl chlorides: Compounds 929, 930, 931.
Example ICK: [4-(3-cyano-6-difluoromethoxy-l-ethyl-l/T-indol-2-yl)-phenyl]- carbamic acid methyl ester (compound 1130).
A solution of 2-(4-aminophenyl)-6-difluoromethoxy-l-ethyl-lHLindole-3-carbonitrile (200 mg, 0.611 mmol) and methyl chloro formate (95 μL, 1.23 mmol) in ethyl acetate (2 mL) is treated with 2 M aqueous potassium carbonate solution (0.370 mL, 0.74 mmol), and the resulting mixture is stirred vigorously overnight. Saturated brine solution (1 mL) is added, and the mixture is stirred for 10 minutes. The organic layer is removed, dried over anhydrous . magnesium sulfate, filtered and evaporated. The resulting solid is triturated with 1/1 ether- hexane, collected by filtration and dried under vacuum to afford the title product as a white solid.
Similarly prepared from appropriate reagents are: Compounds 1131, 1132, 1133, 1134, 1135. Example ICL: l-[4-(3-cy£fflθ-6-difluoromemoxy-l-emyl-lH-mdol-2-yl)-phenyl]-3- propyl-urea (Compound 893).
A solution of 2-(4-aminophenyl)-6-difluoromethoxy-l-ethyl-lH-indole-3-carbonitrile (200 mg, 0.611 nunol) in 1 ,2-dichloroethane (2 mL) is treated with n-propylisocyanate (115 mL, 1.23 mmol) and triethylamine (170 mL, 1.22 mmol). The resulting solution is stirred at ambient temperature for 12 hours, and then concentrated. The residual material is separated by silica gel chromatography (1/2 ethyl acetate-hexane) to afford the title product as a solid.
Similarly prepared from appropriate reagents are: Compounds 892, 894.
Example ICM: Preparation of morpholine-4-carboxylic acid [4-(3-cyano-l-cyclobutyl- 6-ethoxy-lH-indol-2-yl)-phenyl]-amide (compound 1166).
DMF
Step A: 6-Ethoxy-lH-indole-3-carbonitrile (2.8 g, 15 mmol), prepared as shown in example IA, step A5 is combined with CS2CO3 (11.6 g, 35.6 mmol), DMF (21 mL), and cyclobutyl bromide (1.73 mL, 17.9 mmol) in a capped tube. The reaction mixture is heated at 8O0C for 8h. This is then quenched with H2O (200 mL) and is extracted with EtOAc. The EtOAc layer is backwashed with H2O, and then with brine. The organic phase is dried and concentrated. Purification by silica gel chromatography (hexanes/CH2Cl2, 50-100%) yields I- cyclobutyl-ό-ethoxy-lH-indole-S-carbonitrile (3.00 g, 83%) as a white solid.
Step B: Following essentially the procedure in example IGb, l-cyclobutyl-6-ethoxy- lH-indole-3-carbonitrile (3.0 g, 12.4 mmol) is converted via Suzuki coupling to yield 2-(4- amrnophenyl)-l-cyclobutyl-6-ethoxy-lϋr-indole-3-carbonitrile (2.60 g, 68%) as an off-white solid.
Step C: 2-(4-aminophenyl)-l-cyclobutyl-6-ethoxy-l//-indole-3-carbonitrile (40 mg, 0.12 mmol), 4-nitroρhenyl chloroformate (60 mg, 0.30 mmol), CR2Ch(AOO μL), and pyridine (25 μL, 0.31 mmol) are stirred at room temperature for 1 hour. Morpholine (60 μL, 0.70 mmol) is added. After stirring at room temperature for an additional 30 minutes, the reaction mixture is diluted in CH2CI2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol byproduct. The organic layer is dried and concentrated. Purification by silica gel chromatography (CF^Cla/EtOAc, 7/3) yields morpholine-4-carboxylic acid [4-(3-cyano-l- cyclobutyl-6-ethoxy-l/f-indol-2-yl)-phenyl]-amide (53 mg, 100%) as a white solid.
The following compounds are prepared in a similar fashion, using the appropriate amine in the final step: compounds 1087, 1088, 1089, 1119, 1159, 1168, 1191, 1266, 1288, 1324, 1325, 1326.
Example ICN: Preparation of røc-[4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)- ρhenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 1147).
2-(4-Aminophenyl)-l-cyclobutyl-6-ethoxy-l/7-indole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example ICM, step B, ias combined with 4-nitrophenyl chloroformate (76 mg, 0.38 mmol), DCE (0.5 mL), and pyridine (30 μL, 0.37 mmol). This suspension is stirred at room temperature for Ih. Rac-cyclopropyl methyl carbinol (100 μL, 0.98 mmol) is added. This mixture is heated at 750C overnight. The reaction mixture is then diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol byproduct. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2) yields røc-[4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (40 mg, 60%) as a white solid.
The following compounds are prepared in a similar fashion, using the appropriate alcohols: Compounds 1146, 1158, 1167, 1192, 1208, 1209, 1210, 1215, 1216, 1240, 1241, 1242, 1243, 1244, 1246, 1247, 1248, 1249, 1250, 1264, 1265, 1267, 126S, 1281, 1282, 1283, 1286, 1287, 1289, 1290, 1291, 1292, 1294, 1295,1296, 1297,1298, 1299, 1312, 1313.
Example ICO: Preparation of l-cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-lH- indole-3-carbonitrile (compound 1239).
Step A: 2-(4-Aminophenyl)-l-cyclobutyl-6-ethoxy-liT-indole-3-carbonitrile (600 mg, 1.81 mmol), prepared as in example ICM, step B, is suspended in CΗ2CI2 (18 mL), andEtsN (390 μL, 2.7 mmol). Trifluoroacetic anhydride (310 μL, 2.2 mmol) is added dropwise. The reaction mixture is stirred at room temperature for 30 minutes, after which time dissolution is complete. The reaction mixture is then washed with saturated NaHCθ3 solution. The organic layer is dried and concentrated to yield N-[4-(3-cyano-l -cyclobutyl-6-ethoxy-lH-indol-2-yl)- phenyl]-2,2,2-trifluoro-acetamide (802 mg, 100%) as a yellow solid.
Step B: N-[4-(3-Cyano-l -cyclobutyl-6-ethoxy-l/-f-indol-2-yl)-phenyl]-2,2,2-trifluoro- acetamide (800 mg, 1.8 mmol) is dissolved in DMF (10 mL). NaH (140 mg, 60% oil suspension, 3.5 mmol) is added. This is stirred at room temperature for a few minutes, after which ethyl iodide (176 μL, 2.2 mmol) is added. This is stirred at room temperature overnight, and then at 75°C for 6h. Additional portions of NaH (200mg, 5.0 mmol) and iodoethane (200 μL, 2.5 mmol) are necessary to push the reaction further. This is heated overnight at 75°C. Additional ethyl iodide (200 μL, 2.5 mmol) is added. This is heated for another 2h. The reaction mixture is then diluted in H2O and is extracted into EtOAc. The EtOAc layer is dried and concentrated. Silica gel chromatography (CH2CI2) yields 384 mg of an inseparable mixture of expected N^-P-cyano-l-cyclobutyl-ό-ethoxy-lH-indol^-yty-phenylj-N-ethyl- 2,2,2-trifluoro-acetamide and hydrolyzed l-cyclobutyl-6-ethoxy-2-(4-ethylamino-phenyl)-lH- indole-3-carbonitrile.
Step C: The crude mixture from the previous step is dissolved in methanol (5 mL). 6N NaOH (1.0 mL, 6 mmol) is added, and the mixture is heated at 8O0C for Ih. The reaction mixture is then diluted in Η2O and is extracted into CH2CI2. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2CI2) yields pure l-cyclobutyl-6- ethoxy-2-(4-ethylamiαophenyl)-lH-indole-3-carbonitrile (343 mg, 53% over two steps) as a white solid. l-Cyclobutyl-2-(4-diethylamino-phenyl)-6-ethoxy-lif-indole-3-carbonitrile (compound 1217, 77 mg, 11%) is isolated as a byproduct of the reaction described in example ICO, step B.
Example ICP: Preparation of [4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)- phenyl]-ethyl-carbamic acid cyclopentyl ester (compound 1251).
l-Cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-lH-indole-3-carbonitrile (35 mg, 0.10 mmol), prepared as in example ICO, step C, is dissolved in pyridine (300 μL). Cyclopentyl chloroformate (25 μL, 0.17 mmol) is added. The reaction mixture is stirred at room temperature for 2.5h. More chloroformate (lOμL, 0.07 mmol) is added to drive the reaction to completion. After an additional 90 min of stirring, the reaction mixture is partitioned between aqueous HCl and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography yields ^-(S-cyano-l-cyclobutyl-ό-ethoxy-l/ϊ-indol^-y^-pheiiylj-ethyl- carbamic acid cyclopentyl ester (41 mg, 87%) as a white solid.
Compound 1252 is prepared similarly using the appropriate chloroformate. Example ICQ: Preparation of {4-[3-cyano-l-cyclobutyl -6-(3-[l,2,4]triazol-l-yl- propoxy)-l/f~indol-2-yl]-ph.enyl}-carbamic acid isopropyl ester (compound 1255).
Step A: To a solution [4-(3-cyano-l-cyclobutyl-6-methoxy-lH-indol-2-yl)-phenyl]- carbamic acid isopropyl ester (950 mg, 2.35 mmol) in DCM (10 mL) is added BBr3 (556 uL, 5.9 mmol) over a period of 20 min. The reaction mixture is stirred further for Ih at room temperature and then water (ImL) is added. The solvents are removed under reduced pressure. The residue is dissolved in MeOH and then poured into cold water. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford ^-(S-cyano-l-cyclobutyl -6- hydroxy-lH-indol-2-yl)-ρhenyl]-carbamic acid isopropyl ester (650 mg, 71%).
Step B: To a solution of [4-(3-cyano-l-cyclobutyl -6-hydroxy-li7-iiidol-2-yl)-phenyl]- carbamic acid isopropyl ester (340 mg, 0.87 mmol) in DMF (2 mL) is added K2CO3 (132 mg, 0.96 mmol) and 3-bromo-l-chloroproane (172 uL, 1.75 mmol) and the reaction is stirred for 5h at 6O0C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 370 mg (92%) of the desired product.
Step C: To a solution of {4-[6-(3-chloro-propoxy)-3-cyano-l-cyclobutyl-lH-indol-2- yl]-phenyl}-carbamic acid isopropyl ester (37 mg, 0.08 mmol) in CΗ3CN (1 mL) is added sodium iodide (71 mg, 0.48 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is then evaporated and the residue is diluted with anhydrous DMF (1 mL) and then treated with the sodium salt of 1,2,4-triazole (0.16 mmol) at room temperature overnight. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and then washed with water. The organic layer is concentrated and triturated with hexane and the precipitate is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-l-cyclobutyl -6-(3-[l,2,4]triazol-l-yl- propoxy)-lH-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1255 (31 mg, 78%).
The following compounds are made in similar fashion following steps A-C, above: Compounds 1253, 1254, 1260, 1261, 1262.
Example ICR: Preparation of {4-[3-cyano-l-cyclobutyl-6-(2-[l,2,4]triazol-l-yl- ethoxy)-lH-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1276).
Step A: To a solution of [4-(3-cyano-l-cyclobutyl -6-hydroxy-l//-indol-2-yl)-ρhenyl]- carbamic acid isopropyl ester (390 mg, 1.0 mmol) in CH3CN (5 mL) is added K2CO3 (414 mg, 3.0 mmol) and 3-bromo-l-chloroetahne (250 uL, 3.0 mmol) and the reaction is stirred for 18h at 8O0C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 420 mg, 93% of the desired product.
Step B: To a solution of {4-[6-(3-chloroethoxy)-3-cyano-l-cyclobutyl-lH-indol-2-yl]- phenyl}-carbamic acid isopropyl ester (42 mg, 0.09 mmol) in CH3CN (1 mL) is added sodium iodide (56 mg, 0.37 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is evaporated and the residue is diluted with anhydrous DMF (1 mL) and then treated with the sodium salt of 1,2,4-triazole (0.18 mmol) at room temperature for overnight. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and then washed with water. The organic layer is concentrated and triturated with hexane. The precipitate is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-l-cyclobutyl -6-(3-[l,2,4]triazol-l-yl-ethoxy)-l//-indol-2- yl]-ρhenyl}-carbamic acid isopropyl ester, compound 1276 (28 mg, 64%). The following compounds are made in similar fashion following steps A and B, above: Compounds 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278.
Example ICS: Preparation of {4-[3-cyano-l-cyclobutyl-6-(2-[l,2,4]triazol-l-yl- ethoxy)-lH-indol-2-yl]-ρhenyl}-carbamic acid 1-cyclopropyl-ethyl ester (compound 1329).
Step A: To a solution of 2-(4-aminophenyl)-l-cyclobutyl-6-hydroxy-lf/-indole-3- carbonitrile (909 mg, 3 mmol) in pyridine (5 mL) is added 4-nitrophenyl chloroformate (6 mmol) at room temperature and then stirred for 2h at room temperature. To the reaction is added cyclopropyl methyl carbinol and then stirred for 8h at 800C. The reaction mixture is diluted with IN HCl and then extracted with ethyl acetate. The organic layer is concentrated and the residue is dissolved in EtOAc and triturated with hexane. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [4-(3-cyano-l-cyclobutyl-6- hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid 1-cycloproρyl-ethyl ester (996 mg, 80%).
Step B: To a solution of [4-(3-cyano-l-cyclobutyl-6-hydroxy-l/7-indol-2-yl)-phenyl]- carbamic acid 1-cycloproρyl-ethyl ester (1.5 g, 3.61 mmol) in CH3CN (8 mL) is added K2CO3 (1.5 g, 10.8 mmol) and 2-bromo-l-chloroethane (895 uL, 10.8 mmol) and the reaction is stirred for 18h at 8O0C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 1.46 g, 84% of the desired product.
Step C: To a solution of {4-[6-(2-chloroethoxy)-3-cyano-l-cyclobutyl-lH-indol-2-yl]- phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (1.46 g, 3.05 mmol) in CH3CN (10 mL) is added sodium iodide (1.84 g, 12.22 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is evaporated and the residue is diluted with anhydrous DMF (20 mL) and then used without further purification. To 1 mL of the DMF solution containing the iodoethyl intermediate (0.153 mmol) is added the sodium salt of 1,2,4-triazole (0.31 mmol) and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with 0.5 mL DMF and the desired product is purified by preparative LC to give {4-[3- cyano- 1 -cyclobutyl-6-(2-[ 1 ,2,4]triazol- 1 -yl-ethoxy)- 1 JT-indol-2-yl] -phenyl} -carbamic acid 1 - cyclopropyl-ethyl ester, compound 1329 (23 mg, 29%).
The following compounds are made in similar fashion following steps A-C, above: Compounds 1327, 1328.
Example ICT: Preparation of l-{4-[3-cyano-l-cyclobutyl-6-(3-[l,2,4]triazol-l-yl- propoxy)-li7-indol-2-yl]-phenyl}-3-isopropyl-urea (compound 1314).
Step A: To a solution of l-[4-(3-cyano-l-cyclobutyl-6-methoxy-lH-indol-2-yl)- phenyl]-3-isoρroρyl-urea (2.21 g, 5.49 mmol in CΗ2CI2 (30 mL) is added a IM solution of BBr3 in CH2Cl2(16.5 mL, 16.5 mmol) at O0C. The mixture is allowed to warm to room temperature and kept for Ih. The reaction mixture is then poured onto ice and aqeouslM NaHCO3 is added until the pH is 7-8. The product is extracted with 100 mL of ethyl acetate (3X) and the organic phases are washed with 100 mL of saturated NaCl. The organic phases are combined and dried over MgSO4. Solvent is removed to recover 1.95 g (92%) of l-[4-(3- cyano-l-cyclobutyl-β-hydroxy-liϊf-indol^-y^-phenyll-S-isopropyl-urea, as a tan solid.
Step B: To a solution of ^^-(S-cyano-l-cyclobutyl-β-hydroxy-lH-indol^-y^-phenyl]- 3-isopropyl-urea (750 mg, 1.93 mmol) in 10 mL of acetonitrile is added anhydrous K2CO3 (800 mg, 5.79 mmol) and l-bromo-3-chloropropane (382 μL, 3.86 mmol). After stirring overnight at 800C, the reaction mixture is cooled and solvent is removed. The reaction is re-suspended in 100 mL of ethyl acetate. The organic phase is washed with 200 mL of H2O5 and the aqueous phase is re-extracted 2X with 100 mL of ethyl acetate. The organic phases are combined, dried over MgSO4 and the solvent is removed to afford 769 mg (86%) of l-{4-[6-(3-chloropropoxy)- 3-cyano-l-cyclobutyl-lH-indol-2-yl]-ρhenyl}-3-isoproρyl-urea as a tan powder.
Step C: To a solution of l-{4-[6-(3-chloroproρoxy)-3-cyano-l-cyclobutyl-lH-indol-2- yl]-phenyl}-3-isopropyl-urea (400 mg, 0.860 mmol) in 8 mL of acetonitrile/DMF, (4/1) is added anhydrous NaI (258 mg, 1.72 mmol). After stirring overnight at 600C, the reaction shows conversion to product by LCMS-UV. The reaction mixture is cooled, the solvent is removed and redissolved in DMF to 14.0 mL total volume.
Step D: To 1 mLof the DMF solution above, l-{4-[3-cyano-l-cyclobutyl-6-(3- iodopropoxy)-lH-indol-2-yl]-phenyl}-3-isopropyl-urea (34 mg, 0.062 mmol) is added anhydrous 1 ,2,4-triazole, sodium salt (10.0 mg, 0.110 mmol). After stirring overnight at rt, the reaction mixture is filtered and purified by preparatory LC/UV purification. The solvent is removed to obtain 12.3 mg (40%) of l-{4-[3-cyano-l-cyclobutyl-6-(3-[l,2,4]triazol-l-yl- proρoxy)-l/f-indol-2-yl]-phenyl}-3-isopropyl-urea (compound 1314), as a white powder.
' The following compounds are prepared following the above procedure: Compounds 1306, 1307, 1308, 1309, 1315, 1316, 1317, 1318, 1319, 1320, 1321, 1323 and 1324.
Example ICU. Preparation of ^-(S-cyano-l-cyclobutyl-ό-pyrimidin^-yl-lΗ-indol^- yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 2419).
dppf
Step A. Into a solution of [4-(3-Cyano-l-cyclobutyl-6-hydroxy-lΗ-indol-2-yl)-phenyl]- carbamic acid 1-cyclopropyl-ethyl ester (1.8 g, 4.3 mmol) in CH2Cl2 (20 mL) at 00C was added pyridine (2.74 g, 34.6 mmol), followed by the slow addition of a solution OfTf2O (3.67 g, 13.0 mmol) in CH2CI2 while maintaining the temperature below 100C. Upon completion the reaction mixture was washed with dilute HCl, water and brine, and then dried over MgSO4, concentrated and triturated with hexanes to provide the product as a solid (1.8 g, 96%).
Step B. A mixture of trifluoro-methanesulfonic acid 3-cyano-l-cyclobutyl-2-[4-(l- cyclopropyl-ethoxycarbonylamino)-phenyl]-lH-indol-6-yl ester (1.1 g, 2.0 mmol), bis(pinacolato)diboron (0.56 g, 2.2 mmol), Pd(dppf)Cl2 (49 mg, 0.06 mmol), dppf (24 mg, 0.06 mmol) and potassium acetate (0.59 g, 6.0 mmol) in dioxane (12 mL) was stirred at 80°C overnight. The reaction mixture was diluted with EtOAc, washed with. H2O and brine, dried over Na2SC»4, concentrated and purified on silica gel (CH^Ck/EtOAc) to provide the product as a solid (0.96 g, 91%).
Step C. A mixture of {4-[3-cyano-l-cyclobutyl-6-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-lH-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (0.2 g, 0.38 mmol), 2-chloroρyrimidine (39 mg, 0.34 mg), Pd(PPh3)4 (22 mg, 0.095 mmol) and cesium fluoride (0.116 g, 0.76 mmol) in DME (2.0 mL) was stirred at 100 0C for 16 h. The mixture was then diluted with EtOAc (20 mL), washed with water and brine, dried over Na2SO4, concentrated and purified on silica gel (CH2CkZEtOAc) to provide [4-(3-cyano-l- cyclobutyl-6-ρyrimidin-2-yl-lH-indol-2-yl)-phenyl]-carbamic acid 1 -cyclopropyl-ethyl ester as a solid (0.15 g, 82%).
Example ICV. Preparation of [4-(3-cyano-l-cyclobutyl-6-pyridin-2-yl-lH-indol-2-yl)- phenyl]-carbamic acid 1-cycloρroρyl-ethyl ester (compound 2417).
To a solution of of trifluoro-methanesulfonic acid 3-cyano-l-cyclobutyl-2-[4-(l- cycloρropyl-ethoxycarbonylamino)-phenyl]-lH-indol-6-yl ester prepared as in Example ICU Step A (200 mg, 0.37 mmol) in DMF (2.0 mL) was added 2-(tributylstannyl)pyridine (160 mg, 0.44 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol), CuI (7 mg, 0.037 mmol) and CsF (111 ing, 0.73 mmol). The mixture was stirred at 80 0C for 2 h, treated with ether (20 mL) and potassium fluoride (0.5 g). The mixture was stirred for another hour and filtered. The filtrate was washed with water and brine, dried over Na2SO4, concentrated and purified on silica gel (CH2Cl2ZEtOAc) to provide [4-(3-cyano-l-cyclobutyl-6-pyridin-2-yl-lH-indol-2-yl)-phenyl]- carbamic acid 1-cyclopropyl-ethyl ester as a solid (82 mg, 47%).
Example ICW: Preparation of (i?)-{4-[3-cyano-l-cyclobutyl-6-(pyrimidin-2-yloxy)- lH-indol-2-yl]-ρhenyl}carbamic acid 1-cyclopropyl-ethyl ester (compound 2210).
Step A: To a suspension of 4-iodophenylisocyanate (0.84 g, 3.5 mmol) in CH2CI2 (6 mL) was added ('Λj-l-cyclopropylethanol (0.67 mL, 6.9 mmol). The solution was then directly subjected to silica gel chromatography (CH2Cl2) to provide (R)- (4-iodo-phenyl)carbamic acid 1-cyclopropyl-ethyl ester (1.05 g, 93%).
Step B: To a solution of (i?)-l-cyclobutyl-6-hydroxy-lH-indole-3-carbonitrile (0.53 g, 2.5 mmol), triisopropylborate (0.86 mL, 3.75 mmol) in THF (7.5 mL) at -78 0C was added LDA (1.5M monoTHF in cyclohexane, 3.83 mL, 5.75 mmol). The mixture was stirred at — 78°C for 10 minutes and then at room temperature for 30 minutes, followed by the addition of (4- iodo-phenyl)-carbamic acid 1-cycloρropylethyl ester (0.83 g, 2.5 mmol) and PdCl2(dρpf) (0.055 g, 0.075 mmol). The reaction mixture was cooled to -780C and flushed with nitrogen before the addition of DMF (15 mL) and aq. K2CO3 (2.0M, 3.75 mL, 7.5 mmol). The cooling bath was removed and the mixture was stirred overnight, poured into ice water (100 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water, dried in air and dissolved in CH2Cl2, purified on silica gel (CH2Cl2ZEtOAc, 9: 1) to provide (i?)-[4-(3-cyano-l- cyclobutyl-6-hydroxy-lH-indol-2-yl)-ρhenyl]-carbamic acid 1-cycloρroρyl-ethyl ester as a solid (0.58 g, 56%).
Step C: A mixture of (^-^-(S-cyano-l-cyclobutyl-ό-hydrox.y-lH-indol^-yO-phenyl]- carbamic acid 1-cyclopropyl-ethyl ester (0.083 g, 0.2 mmol), Cs2Cθ3 (0.163 g, 0.5 mmol), 2- chloropyrimidine (0.046 g, 0.4 mmol) in DMF (2.0 mL) was stirred at 70 0C for 2 h. After cooling to room temperature, the mixture was poured into water (15 mL) and the precipitate was collected via filtration and washed with water, purified on silica gel (CEkCk/EtOAc, 9 5:0.5) to provide (Λ)-{4-[3-cyano-l-cyclobutyl-6-(pyπmidin-2-yloxy)-lH-indol-2-yl]- phenyl}carbamic acid 1-cyclopropyl-ethyl ester (0 073 g, 74%).
Example ICX: Preparation of (i?)-{4-[3-cyano-l-cyclopropyl-6-(pynmidin-2-yloxy)- lH-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester (compound 2217).
Step A- A mixture of 3-iodoaniso (2.38 mL, 20.0 mmol), cyclopropylamine (2.10 mL, 30 0 mmol), K3PO4 (8 48 g, 40.0 mmol), CuI (0.19 g, 1 0 mmol), ethylene glycol (2 23 mL, 40 0 mmol) and isopropanol (20 mL) was stirred at 80 0C overnight The reaction mixture was concentrated and suspended in CH2CI2 (100 mL) and water (100 mL). This mixture was then treated with 28% aq. ammonia hydroxide until the solids dissolved. The organic layer was separated, dried over Na2SO4 and purified on silica gel (CtbCk/hexane, 6.4) to provide cycloρropyl(3-methoxyphenyl)amine as colorless oil (1.52 g, 47%).
Step B. To a mixture of cyclopropyl(3-methoxyphenyl)amine (1.52 g, 9 3 mmol), KOH (1.57 g dissolved in 8 mL H2O) and EtOAc (15 mL) at 00C was added dropwise, with vigorous stirring, chloroacetyl chloride (1.12 mL, 14.0 mmol). The mixture was stirred for additional 30 minutes, washed with water (3X350 mL), concentrated and purified on silica gel (CH2Cl2/hexane, 1 : 1) to provide 2-chloro-N-cyclopropyl-N-(3-methoxy-phenyl)acetamide as a solid (1.80 g, 81%).
Step C: A mixture of 2-chloro-N-cyclopropyl-N-(3-methoxy-phenyl)-acetamide (1.25 g, 5.2 mmol), Pd(OAc)2 (0.06 g, 0.26 mmol), Et3N (0.79 g, 1.10 mL, 7.8 mmol), biphenyl-2-yl- di-tert-butyl-phosphane (0.155 g, 0.52 mmol) in toluene (6.0 mL) was stirred at 80 0C overnight. After cooling to room temperature the mixture was purified on silica gel (CH2Cl2/ EtOAc, 9.5:0.5) to provide l-cyclopropyl-6-methoxy-l,3-dihydro-indol-2-one as a solid (0.89 g, 84%).
Step D: To a solution of l-cyclopropyl-6-meώoxy-l,3~dihydro-indol-2-one (5.0 g, 24.6 mmol) in CH2Cl2 (25.0 mL), at 00C was added DIBAL-H (1.0 M in CH2Cl233.3 mL, 33.3 mmol). The mixture was then stirred at room temperature for 4h and treated with HCl (1.0 N). The organic layer was separated, washed with water and purified on silica gel (CH2Cl2) to provide the indole intermediate, which was then dissolved in dry DMF (40.0 mL) and cooled at 00C. The solution was treated with chlorosulfonyl isocyanate (5.09 g, 3.13 mL, 36.0 mmol), and stirred at 00C for 2h and poured into ice-water (300 mL). The precipitate was collected by filtration and washed with water and purified on silica gel (hexane/EtOAc, 9:1) to provide 1- cyclopropyl-ό-methoxy-lH-indole-S-carbonitrile as a solid (3.60 g, 69%).
Step E: A solution of l-cyclopropyl-δ-methoxy-lH-indole-S-carbonitrile (3.60 g, 17.0 mmol) in CH2Cl2 (50.0 mL) was cooled to -78°C and treated with BBr3 (21.27 g, 8.03 mL, 84.9 mmol), stirred for 10 min and then brought to room temperature and stirred for additional 30 minutes. The reaction mixture was poured into ice-water (150 mL), neutralized with NaHCO3 and the precipitate was collected by filtration, washed with water and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide l-cyclopropyl-β-hydroxy-lH-indole-S-carbonitrile as a solid (3.02 g, 90%).
Step F: To a solution of l-cyclopropyl-δ-hydroxy-lH-mdole-θ-carbonitrile (0.59 g, 3.0 mmol) and triisopropylborate (1.03 mL, 4.5 mmol) in THF (15 mL) at -780C was added LDA (1.5M mono THF in cyclohexane, 4.60 mL, 6.9 mmol) with stirring. The mixture was stirred at -78°C for 10 min and at room temperature for 30 min followed by the addition of (/?)-(4-iodo- phenyl)-carbamic acid 1-cyclopropyl-ethyl ester (1.19 g, 3.6mmol) and PdCl2 (dppf) (0.11 g, 0.15 mmol). The reaction mixture was cooled to -78°C and flushed with nitrogen whereupon DMF (30 mL) and aq. K2CO3 (2.0M, 4.5 mL, 9.0 mmol) was added. The cooling bath was removed and the mixture was stirred overnight, poured into ice water (100 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water, dried in air and purified on silica gel (CH2Cl2ZEtOAc, 9:1) to give (^-^-(S-cyano-l-cyclopropyl-ό-hydroxy-lH-indol^- yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (1.16 g, 97%).
Step G: A mixture of (i-)-[4-(3-cyano-l-cycloρropyl-6-hydroxy-lH-indol-2-yl)- phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (0.060 g, 0.15 mmol), Cs2CO3 (0.122 g. 0.375 mmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (1.5 mL) was stirred at 700C for 2h. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate was collected via filtration, washed with, water, and purified on silica gel (CH2Cl2/EtOAc, 9.5:0.5) to provide (Λ)-{4-[3-cyano-l-cycloρropyl-6-(pyrimidin-2-yloxy)-lH- indol-2-yl]-phenyl}carbamic acid 1-cycloproρyl-ethyl ester as a solid (72 rug, 100%).
Example ICY: Preparation of l-{4-[3-cyano-l-cyclobutyl-6-(pyrimidin-2-yloxy)-lH- indol-2-yl]-phenyl}-3-isopropylsulfonylurea (compound 2263).
Step A: To a solution of tert-butanol (10.5 mL, 110.0 mmol) in CH2Cl2 (100 mL) at 0 0C was added chlorosulfonyl chloride (9.55 mL, 110.0 mmol). The mixture was stirred for 5 min and added to a stirred cold (0 "C) mixture of 4-iodoaniline (21.9 g, 100.0 mmol), Et3N (15.43 mL, 110.0 mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred at 00C for 30 minutes and at room temperature for 4.5h. The reaction mixture was concentrated, treated with water (1000 mL) and stirred overnight. The precipitate was filtered, washed thoroughly with water and dried in vacuum to provide N-Boc-N'-4'-iodophenyl sulfonylurea (36.11 g, 91%).
Step B: To a solution OfPPh3 (7.32 g, 30.0 mmol) in CH2Cl2 (20 mL), at 00C, was added DIAD (5.94 mL, 30.0 mmol), and stirred for 0.5 h, then added to a mixture of N-Boc- N'-4'-iodophenyl sulfonylurea (7.96 g, 20.0 mmol), and isopropanol (2.29 mL, 30.0 mmol) in DCM (20 mL) at 0 0C while stirring. The resulting mixture was stirred at 00C for 1 h and then room temperature for 4 h, and chromatographed (silica gel, CH2CI2). The crude product obtained was suspended in hexanes, stirred for 20 min, filtered and washed with hexanes and dried in air. This was then suspended in CH2Cb (40 mL) and treated with TFA (10 mL) for 4 h at room temperature. The mixture was carefully neutralized with NaHCO3 and the CH2CI2 layer was purified on silica gel (CHbCVEtOAc, 9:1) to provide N-isoproρyl-N'-4'- iodophenylsulfonylurea as a solid (4.89 g, 72%).
Step C: To a solution of l-cyclopropyl-δ-hydroxy-lH-indole-S-carbonitrile (0.42 g, 2.0 mmol), triisopropylborate (0.80 mL, 3.5 mmol) in THF (6 mL), at -78°C, was added LDA (1.5M monoTHF in cyclohexane, 3.33 mL, 5.0 mmol) with stirring. The mixture was stirred at -78°C for 10 min and at room temperature for 30 min, followed by the addition of N-isopropyl- N'-4'-iodophenylsulfonylurea (0.96 g, 2.4 mmol) and PdCl2 (dppf) (0.07 g, 0.1 mmol). The reaction mixture was cooled at — 78°C and flushed with nitrogen before the addition of DMF (12 mL) and aq. K2CO3 (2.0M, 3.0 mL, 6.0 mmol). The cooling bath was removed and the mixture was stirred overnight, poured into ice water (100 mL) and neutralized with acetic acid. The precipitate was filtered and washed with water, dried in air and purified on silica gel (CH2Cl2/EtOAc, 8:2) to give l-^^S-cyano-l-cyclobutyl-o-hydroxy-lH-indol^-yO-phenylj-S- isopropylsulfonylurea as a solid (0.45 g, 74%).
Step D: A mixture of l-[4-(3-cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-3- isopropylsulfonylurea (0.085 g, 0.2 mmol), CS2CO3 (0.163 g, 0.5 mmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (2.0 mL) was stirred at 7O0C overnight. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate collected via filtration, washed with water and purified on silica gel (CHbCb/EtOAc, 8.5: 1.5) to provide 1- {4-[3-cyano-l-cyclobutyl-6-(pyrimidin-2-yloxy)-lH-indol-2-yl]-phenyl}-3- isopropylsulfonylurea (0.061 g, 61%).
Example ICZ: Preparation of l-cyclopropyl-2-(4-isopropylamino-phenyl)-6- (pyritnidin-2-yloxy)-lH-indole-3-carbonitrile (compound 2434).
Step A: A mixture of 4-iodoaniline (4.38 g, 20.0 mmol), Cs2CO3 (16.3 g, 50.0 mmol), isopropyliodide (3.0 mL, 30.0 mmol) in DMF (20 mL) was stirred in a sealed tube at 700C for 24h. The mixture was cooled to room temperature and poured into water (200 mL). The organic layer was separated and washed with water and brine and purified on silica gel (ClfeCh/hexanes, 1:1) to provide (4-iodophenyl)-isopropylaimne (3.26 g, 63%).
Step B: To a solution of l-cyclopropyl-ό-hydroxy-lH-indole-S-carbonitrile (0.59 g, 3.0 mmol), triisopropylborate (1.03 mL, 4.5 mmol) in THF (15 mL) at -780C was added LDA (1.5M mono THF in cyclohexane, 4.60 inL, 6.9 mmol) with stirring. The mixture was stirred at -780C for 10 min and at room temperature for 30 min, followed by the addition of (..?)-(4-iodo- phenyl)-carbamic acid 1-cyclopropyl-ethyl ester (1.19 g, 3.6mmol) and PdCl2 (dppf) (0. H g, 0.15 mmol). The reaction mixture was cooled to -78°C, flushed with nitrogen and DMF (30 mL) and aq. K2CO3 (2.0M3 4.5 mL, 9.0 mmol) added. The cooling bath was removed and the mixture was stirred overnight, poured into ice water (100 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water and CH2CI2 and dried in air to provide 1- cyclopropyl-6-hydroxy-2-(4-isopropylamino-phenyl)-lH-indole-3-carbonitrileas a solid (0.85 g, 86).
Step C: A mixture of (l-cyclopropyl-6-hydroxy-2-(4-isopropylamino-phenyl)-lH- indole-3-carbonitrile (0.099 g, 0.3 mmol), Cs2CO3 (0.244g, 0.75 mmol), 2-chloropyrimidine (0.069 g, 0.6 mmol) in DMF (2.0 mL) was stirred at 700C overnight. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate was collected via filtration and washed with water and purified on silica gel (CH2Cl2ZEtOAc3 9:1) to provide 1- cycloproρyl-2-(4-isopropylamino-phenyl)-6-(pyrimidin-2-yloxy)-lH-indole-3-carbonitrile as a solid (0.104 g, 85%).
Example IDA: Preparation of [4-(3-cyano-l-cyclobutyl-6-cyclopropyl-lH-indol-2-yl)- phenyl]-carbamic acid tert-butyl ester (compound 2513).
Step A: To a solution of δ-bromo-l-cyclobutyl-lH-indole-S-carbonitrile (1.38 g, 5.0 mmol), and triisopropylborate (1.37 mL, 60 mmol) in THF (15.0 mL) at -78°C was added LDA (1.5M mono THF in cyclohexane, 3.83 mL, 5.75 mmol) with stirring. The mixture was stirred at — 78°C for 10 min and at room temperature for 30 min followed by addition of (4- iodophenyl)-carbamic acid tert-butyl ester (1.75 g, 5.5 mmol) and PdCl2(dpρf) (0.37 g, 0.5 mmol). The reaction mixture was cooled to -78°C, flushed with nitrogen and DMF (30 mL) and aq. K2CO3 (2.0M, 7.5 mL, 15.0 mmol) added. The mixture was stirred at -780C for 20 min, room temperature overnight and poured into ice water (200 mL). The precipitate was filtered, washed with water and purified on silica gel (hexaαes/EtOAc, 9:1 to 8:2) to give [4-(6-bromo- 3-cyano-l-cyclobutyl-lH-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester as a solid (1.23 g, 53%).
Step B: A mixture of [4-(6-bromo-3-cyano-l-cyclobutyl-lH-indol-2-yl)-phenyl]- carbamic acid tert-butyl ester (0.17 g, 0.4 mmol), cyclopropylboronic acid (0.047 g, 0.55 mmol), (tert-butyl)3PHBF4 (0.014 g, 0.048 mmol), KF (0.093 g, 1.6 mmol), and Pd2(dba)3- CHCl3, 0.021 g, 0.02 mmol) in THF (2.0 mL) was stirred at 6O0C overnight. The mixture was concentrated, taken up in CH2Cl2 and filtered through Celite. The solid was washed with CH2Ck and the filtrate was purified on silica gel (CH2CI2) to provide [4-(3-cyano-l-cyclobutyl- 6-cyclopropyl-lH-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester as a solid (0.10 g, 59%). Example IDB: {2-chloro-4-[3-cyano-l-cyclobutyl-6-(pyrimidin-2-yloxy)-lH-indol-2- yl]-ρhenyl}-carbamic acid isopropyl ester (compound 2339):
Step A: To a solution, of l-cyclobutyl-ό-hydroxy-lH-indole-S-carbonitrile (3.0 g, 14.1 mmol) and isopropylborate (5 mL, 21.1 mmol) in. anhydrous THF (40 mL) at O0C was added LDA (16.2 mL, 2.0 M in heptane/THF/ethylbenzene, 32.4 mmol) dropwise. The mixture was stirred at 0 0C for 15 min and then at room temperature for Ih. After cooling the reaction mixture to 0 0C a solution of 2-chloro-4-iodo-phenylamine (3.9 g, 15.5 mmol) in DMF (40 mL) was added followed by addition of PdCl2(dppf) (0.3 g, 0.4 mmol) and aq. K2CO3 (14 mL, 2.0 M). The mixture was warmed to room temperature and continued to stir overnight. The reaction was diluted with water and then extracted with ethyl acetate. The organic layers was dried, concentrated and triturated with chloroform to provide 2-(4-amino-3-chloro-phenyl)-l- cyclobutyl-ό-hydroxy-lH-indole-S-carbonitrile (3.1 g, 64%) as an off-white solid.
Step B : 2-(4- Amino-3-chloro-phenyl)- 1 -cyclobutyl-6-hydroxy- 1 H-indole-3 - carbonitrile (0.67 g, 2 mmol), prepared in step ZA, was dissolved in DMF (7 mL), followed by the addition of 2-chloro-pyrimidine (0.34 g, 3 mmol) and cesium carbonate (1.3 g, 4 mmol). The mixture was brought to 70 0C and stirred for 1 h. After cooling, the solid was filtered and washed with EtOAc. The filtrate was washed with water and brine, dried, concentrated and triturated with ether to provide 2-(4-amino-3-chloro-phenyl)-l-cyclobutyl-6-(pyrimidin-2- yloxy)-lH-indole-3-carbonitrile (0.76 g, 91%) as a white solid.
Step C: To 2-(4-amino-3-chloro-phenyl)-l-cyclobutyl-6-(pyrimidin-2-yloxy)-lH- indole-3-carbonitrile (0.26 g, 0.6 mmol) in CH2Cl2 (0.5 mL) and pyridine (0.5 mL) was added a solution of isopropyl chloroformate in toluene (LOM, 0.8 mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with aq. HCl (IN) and extracted with 0996
CH2CI2. The organic layer was washed with water and brine, dried, concentrated and purified on silica gel (40% EtOAc/hexane) to provide {2-chloro-4-[3-cyano-l-cyclobutyl-6-(pyrimidin- 2-yloxy)-lH-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (0.29 g, 93%) as a white solid.
Example 2: Screening of low molecular weight compounds using a cell-based HCV IRES monocistronic translation assay
Chemical libraries are screened using a cell-based monocistronic HCV IRES-regulated translation assay designed to closely mimic natural HCV mRNA translation and then compound analogs are made based on hits in the chemical libraries and screened as well. A DNA construct is prepared, termed pHCVIRESmono, in which HCV IRES sequences (HCV 2b, nucleotides 18-347) are inserted between a promoter and the firefly luciferase (Flue) reporter gene. A stably transfected HepG2 (hepatoblastoma) cell line (termed HepG mono-4) or a Huh.7 cell line (termed Huhmono 7), or a Helacell line (termed Helamono), are established by transfection with the pHCVIRESmono DNA by selecting for resistance to hygromycin.
Example 3: Determination of selectivity for HCV IRES-regulated translation using the cell-based cap-dependent translation assays
Since translation assays are used to screen HCV IRES inhibitors, the selected hits may specifically act on HCV IRES-driven translation or may modulate general protein synthesis in mammalian cells. The compounds that act on general translation will most likely have significant toxicity. To address this possibility, various cell-based cap-dependent translation assays are established for the further evaluation of all selected compounds. Plasmid DNAs containing 130 nucleotides of vector sequence 5' to Flue are constructed. This construct is referred to herein as pLuc. A stable cell line is established in cap-dependent translation assays using 293T cells (a human embryonic kidney cell line). HepGmono-4 and pLuc are treated with compound for 20 hours and activity is determined by quantifying the Flue signal. A fivefold selectivity between the HCV IRES and cap-dependent translation is considered to be desirable. For example, using these cell-based cap-dependent translation assays, Applicants identified compounds that showed IC50 values that were at least 5-fold greater in the cap- dependent translation assays than in the HCV IRES translation assay. Fig. 1 shows an example of a hit that was selective against HCV IRES-regulated translation over cap-dependent pLuc translation. Importantly, the compound had the same level of activity in an HCV IRES monocistronic 293T cell line as in HepGmono-4 (data not shown). It is thus unlikely that the selectivity of the compounds between HepGmono-4 (HepG 2) and the cap-dependent translations (293T) is due to the different cell types used.
Additionally, western blotting assays are used to further demonstrate that the compounds selectively inhibit HCV ERES-driven translation. Both HepGmono-4 and pLuc cells are treated with the compounds as described above, following treatment with the test compounds for 20 hours, cells are collected and lysed in Laemmli buffer containing 0.5% SDS. Proteins are separated on a 10% SDS-PAGE, then transferred onto a nitrocellulose membrane, and blotted using antibodies against Flue (RDI) and β-actin (Oncogene). For example, some of the compounds of the present invention were tested in this manner and as expected, the compounds that selectively inhibited HCV IRES-driven translation in assays using Flue signal as an end point showed comparable reductions of the luciferase reporter protein levels in HepGmono-4 cells and were relatively inactive against pLuc in the Western blot (data not shown). Importantly, these compounds did not inhibit the expression of endogenous β-actin, the translation of which is cap-dependent in both cell lines. Consistently, compounds that did not show selectivity in the translation assays inhibited protein accumulation in both the HCV IRES and cap-dependent translation assays (data not shown). As expected, the general protein translation inhibitor puromycin also inhibited both the HCV IRES-driven and cap-dependent protein production (data not shown). Therefore, the Western blot results confirm that the compounds of the present invention selectively inhibit HCV IRES-driven translation.
Testing conditions for these cell lines are optimized and the effects of mRNA level on activity of the compounds are controlled by quantitating Flue mRNA levels by RT real-time PCR. For example, some of the compounds of the present invention were tested in this manner, and no significant differences in Flue mRNA levels were observed between the HepGmono-4, or the Helamono cells, or the Huhmono cells, and cap-dependent translation cell lines used (data not shown).
Example 4: Evaluation of the selectivity for HCV IRES-driven translation using cellular IRES-mediated translation assays
A number of human inRNAs have been shown to harbor IRES elements (18, 19, 39, 44, 45, 91, 126, 130). Although the primary sequences and secondary structures of the HCV ERES are different from those of cellular IRES, an important test for selectivity is to determine whether the selected compounds are active against cellular ERES. The VEGF IRES has poor initiation activity in in vitro assays, but demonstrates substantial activity in cell-based translation assays (45). For example, some of the compounds of the present invention were tested and all of the compounds that had good selectivity with, respect to cap-dependent translation exhibited at least 5-fold higher IC50 values against the VEGF IRES than against the HCV IRES (data not shown). These data indicate that the selected compounds have selectivity against viral IRES. In addition to having different structures, the VEGF IRES also have different interactions with non-canonical cellular translation factors. These differences may contribute to the selectivity of the HCV IRES inhibitors that we have identified.
Example 5: Evaluation of cytotoxicity
Effects on cell proliferation are a critical issue for any drug discovery effort. Therefore, a cell proliferation/cytotoxicity assay is used to eliminate any compounds that affect mammalian cell growth. The effects of the selected hits on cell proliferation are tested in human cell lines 293 T and Huh7 (a human hepatoblastoma cell line). Cells are grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, L- glutamine, penicillin, and streptomycin. Cells in log phase are treated with test compounds for three days, with 250 μM being the highest concentration of test compound used. The effect of the compounds on cell proliferation is assessed by using the CellTiter 96 AQueous One Solution Cell Proliferation Assay (Promega, Madison, WI). Compounds that have at least 5- fold higher CC50 values relative to IC50 values in HepGmono-4 are considered to have a sufficient window between activity and cytotoxicity and, hence, are selected for further evaluation. For example, some of the compounds of the present invention were tested in this manner, and importantly, all compounds that had good selectivity with respect to cap- dependent translation also demonstrated a greater than 5-fold ratio of CC50 to IC50 values.
Example 6: Evaluation of the efficacy of the compounds in the HCV replicon system
The lack of reliable and readily accessible cell-culture and small animal models permissive for HCV replication has limited the development of new anti-HCV agents. Self- replicating subgenomic HCV systems, termed HCV replicons, have been described and have been widely used to assess the efficacy of anti-HCV inhibitors (8, 9, 46, 70, 103, 104). Interferon (IFN) q and inhibitors of the HCV protease and polymerase have been reported to be active in the HCV replicon system (8, 17, 32, 68, 69, 117).
HCV replicons that include bicistronic and monocistronic systems are available and can be used for testing the HCV inhibitors. In the bicistronic replicons, the HCV IRES directs the expression of the selective marker (Neo and/or a Flue reporter), and the EMCV IRES mediates the expression of viral non-structural proteins. In the monocistronic replicon, the HCV IRES directly mediates viral protein synthesis. The HCV IRES inhibitors are analyzed in the bicistronic repliconby quantitating the Flue reporter signal. Replicon-containing cells are cultured with the compounds of the invention for 2 days or for 3 days. Interferon (EFN) α is used as a positive control- For example, the compounds of the present invention were tested in this manner, and the experiments showed that compounds that selectively inhibited HCV IRES-mediated translation inhibited Flue expression in the bicistronic replicon. In the following table (Table 1),
* = replicon or HCV-PV IC50 > 2μM
** = replicon or HCV-PV IC50 between 0.5 uM and 2μM
*** = replicon or HCV-PV IC50 < 0.5 μM
Replicon IC50 values are determined by firefly luciferase signal.
V
HCV-PV IC50 values are determined by viral RNA reduction.
Table 1
00996
007/000996
996
0996
2007/000996
Example 7: Evaluation of the activity of compounds using an HCV-poliovirus chimera
In an HCV-poliovirus (HCV-PV) chimera, the PV 5' UTR is replaced by the HCV 5' UTR and partial (the first 123 amino acids) core coding sequences (nucleotides 18 to 710 of HCV Ib) as shown in Fig. 1 (139, 140). As a consequence, the expression of poliovirus proteins is under regulation of the HCV IRES. Poliovirus is a picornavirus in which protein translation initiation is mediated by an IRES element located in the 5' UTR. At the 5' end of the HCV-PV chimeric genome, there is the cloverleaf-like RNA structure of PV, an essential ezs-acting replication signal ending with the genome-linked protein VPg. Replication kinetics of the HCV-PV chimera matches that of the parental poliovirus (Mahoney) and can result in cytopathic effects (CPE) in cell culture. Heptazyme (29), a ribozyme that targets the HCV IRES, was shown to be active against the chimeric virus in cell culture (76, 77).
To evaluate compounds for activity against the chimeric virus, HeLa cells are seeded and incubated at 37°C under 5% CO2 for 24 hours. The cells are then infected with HCV-PV at a multiplicity of infection (MOI) at 0.1 for 30 min and then treated with compound for 1 day (treatment time will be optimized). The activity of compounds is determined by a change hi cytopathic effect, plaque assay, and/or viral RNA production (see e.g., Table 1).
Example 8: Evaluation of the activity of compounds against a wild- type poliovirus (WT-PV) and the poliovirus IRES translation assay (WT-PV mono luc)
A DNA construct is prepared, termed pPVERESmono, in which PV IRES sequences are inserted (nucleotide number 1-742) between a promoter and the firefly luciferase (Flue) reporter gene. A stably transfected 293 T cell line, is established by transfection with the pPVTRESmono DNA by selecting for resistance to hygromycin. As previously described, cells are treated with compounds for 20 hours, and activity is determined by quantifying the Flue signal. Additionally, to evaluate compounds activity against wild-type poliovirus, Helacells are seeded and incubated at 37°C under 5% CO2 for 24 hours. Cells are then infected with wild- type poliovirus at a MOI at 0.1 for 30 minutes, and then treated with compound for one day. The activity of compounds is determined by changes in cytopathic effect, plaque assay, and RT-PCR using poliovirus IRES primers and probes (see e.g., Table 2).
Furthermore, if compounds are active against the poliovirus and other virus IRES, then the compounds are useful for treating viral infection by any virus containing an IRES.
TABLE 2
Example 9: /// vitro translation assay
In vitro translation assays can be used to distinguish between the compounds that act on HCV IRES RNA or cellular translation factors. In exemplary assays, the mRNA that will direct translation is a transcribed runoff product from the T7 RNA polymerase promoter of the pHCVIRESmono plasmid DNA generated with Ambion RNA MegaTranscript kit (Ambion, Inc., Austin, TX). In vitro translation is performed using HeLa cell lysates using methods known to one of skill in the art. Preliminary results indicate that one or more of the compounds of the present invention has significantly higher activity against HCV IRES regulated translation after preincubating the compound with the HCV IRES RNA transcripts than after preincubating with HeLa cell lysate for 30 min at 370C or without preincubation (data not shown). This suggests that this compound may interact with the HCV IRES RNA in the in vitro translation assay. To demonstrate whether the compounds selectively act on the HCV IRES, pLuc is used together with cellular IRES mRNA transcripts as controls for in vitro translation. All publications and patent applications cited herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
Although certain embodiments have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments without departing from the teachings thereof. All such modifications are intended to be encompassed within the claims of the invention.
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All documents referred to herein are incorporated by reference into the present application as though fully set forth herein.

Claims

We claim:
1. A compound of formula I
wherein: X is:
-a nitro group; -a cyano group; -a -CORa group, where Ra is: -a C1 to C6 alkyl,
-a C6 to Cs aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COORx group, where Rx is a Ci to CO alkyl; -a formyl group; -a Ce to Cg aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with: -a C1 to C6 alkyl,
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl; Y is:
-a haloalkyl; -a halogen; -a benzofuran; -a benzothiophene; -a dibenzofuran;
-a dibenzothiophene; -a benzothiazole; -a naphthalene; W
-an indole, optionally substituted on the nitrogen with a Ci to CO alkyl;
Rb , where Rb is a hydrogen or a Ci to Ce alkyl, and n is 0 or 1 ;
where R0 is a hydrogen, a -CONHRx, where Rx is as defined above, or an -SOaRx, where Rx is as defined above; or
where Rj is a Ci to Ce alkyl or a Ce to Cs aryl; -a -NHCORe group, where Re is:
-a Ci to C6 alkyl; 0 -a Cf, to Cs aryl optionally substituted with:
-a Ci to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or 5 -a halogen;
-a -NHCOORx group, where Rx is as defined above; -a -CH2O-Rf group, where Rf is a Cβ to Cg aryl; -a -NRgRh group, where Rg is hydrogen or a Ci to C6 alkyl and Rh is hydrogen or a C6 to C8 aryl optionally substituted with an alkoxy; -a C] to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with: -a Ci to Ce alkyl, optionally substituted with a Ce to Cg aryl,
-a C5 to Cs aryl, optionally substituted with -COORx, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above, or -a -NHCOORx group, where Rx is as defined above;
-a Ce to Cg aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with: -an alkoxy, -a hydroxy, -one or more halogen(s),
-a 5 or 6 membered heterocycle, optionally substituted with: -a Ci to Ce alkyl, or -a hydroxy,
-an amino group optionally substituted with one or more Ci to Cs alkyl(s), -a -NRΪSOΪRX group, where Rx is as defined above and Rj is:
-a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy,
-a -NRjCORk group, where Rk is: -a C1 to C6 alkyl, -a hydrogen, or
-an amino optionally substituted with one or more Cj to C6 alkyl(s), and R1- is:
-a hydrogen,
-a Ci to C6 alkyl,
- a -CORx group, where Rx is as defined above,
-a haloalkyl, or -a haloalkoxy, -a -N=N+=N" group, or
-a -CORi, where Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more Cj to Ce alkyl(s),
-a Ci to Cβ alkyl group, optionally substituted with:
-a -NHSO2Rx group, where Rx is as defined above, or -a -NRxSOiRx group, where Rx is as defined above, -a haloalkoxy, -a halogen,
-a hydroxy,
-a -COORx group, where Rx is as defined above, -a -CORn, group, where Rn, is:
-an amino optionally substituted with one or more Ci to C(, alkyl(s), where the • one or more C i to Ce alkyl(s) is/are optionally substituted with:
-a hydroxy
-a 5 or 6 membered heterocycle,
-an amino optionally substituted with one or more Ci to Ce alkyl(s), -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a dialkyl-amino, -a -NHRn group, where Rn is: -a -CH2CONH2, or
-a Cβ to Cs aryl optionally substituted with: -an alkyl,
-one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NR0CORp group, where Rp is: -a Ci to Ce alkyl optionally substituted with:
-a halogen, -an alkoxy, or -a Ce to Ca aryl,
-a 5 or 6 membered heterocycle, -a Ce to Cs aryl, optionally substituted with a halogen,
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to CO alkyl(s),
-a hydrogen,
and where R0 is:
-a hydrogen,
-a Ci to Ce alkyl,
-a -CORx group, where Rx is as defined above,
-a haloalkyl, or
-a haloalkoxy, -a -NRqCONRqRr group, where Rq is:
-a hydrogen,
-a C1 to C6 alkyl,
-a haloalkyl,
-a haloalkoxy, or
-a -CORx group, where Rx is as defined above, and where Rr is:
-a Cβ to Cs aryl optionally substituted with:
-a Ci to C5 alkyl, -a haloalkyl,
-a -OR5 group, where R3 is a Ce to Cs aryl, or -a -COORx group, where Rx is as defined above,
-a Ci to Ce alkyl optionally substituted with one or more of the following: -a halogen, -an alkylene, -a Ce to Cg aryl, and/or
-a -COORx group, where Rx is as defined above, -a -COORx group, where Rx is as defined above, -a -NRiCOORu group, where Ru is:
-a Ci to Cu alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a Ci to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne,
-a halogen, or
-a 5 or 6 membered heterocycle, -a Ce to Cg aryl, optionally substituted with:
-an alkoxy, -a halogen, or
-a Ci to C6 alkyl, or -a 5 or 6 membered heterocycle,
-a hydrogen, -a Ci to C6 alkyl,
-a -CORx group, where Rx is as defined above, -a haloalkyl, or -ahaloalkoxy,
-a -NRvSO∑Rw group, where Rv is: -a hydrogen,
-a -CORx, where Rx is as defined above, or -a Cj to C$ alkyl, optionally substituted with: -a halogen,
-a -CORx group, where Rx is as defined above, -a -OCORx group, where Rx is as defined above,
-a hydroxy, or -an alkoxy, and where Rw is:
-a Ci to C6 alkyl optionally substituted with: 007/000996
-a halogen,
-a haloalkyl,
-a Ce to Cg aryl, or
-a 5 or 6 membered heterocycle, -a C2 to Ce alkylene,
-an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl,
-a 5 or 6 membered heterocycle, or
-a ; optionally substituted with a Ci to Ce alkyl, where Ry is a
Ci to Ce alkyl or hydrogen,
where Rz is hydrogen or a Ci to Cs alkyl, optionally substituted with a C6 to Cg aryl, -a -SRx group, where Rx is as defined above, -a -SO∑Raa group, where R38 is:
-a C, to C6 alkyl,
-an amino group,
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -COORx group, where Rx is as defined above,
-a 5 or 6 membered heteroaryl, -a C6 to Cg aryl, and/or -a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or
-a -PO(ORχ)2 group, where Rx is as defined above;
-a * == R0C group, where Rc0 is: -a naphthalene,
-a 5 or 6 membered heteroaryl,
-a Ce to Cs aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy,
-a halogen,
-a Cj to C(, alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ci to Cs alkyl(s), -a -NHPORxRx, where Rx is as defined above, -a -NReeCONRffRff group, where R∞ is a hydrogen or a Ci to CO alkyl, optionally substituted with a halogen, and Rff is: -a hydrogen, -a haloalkyl, -a haloalkoxy, -a Ci to C6 alkyl, or
-a -CORx, where Rx is as defined above, -a -NRggCORhh group, where RM, is: -a hydrogen,
-a Ci to Ce alkyl optionally substituted with: -an alkoxy,
-a halogen, or
-an amino optionally substituted with, one or more Ci to Ce alkyl(s), -an amino optionally substituted with one or more Ci to C6 alkyl(s), where the one or more Ci to C6 alkyl(s) is/are optionally substituted with a halogen,
-a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl,
-a hydrogen, -a Ci to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or
-a -CORx group, where Rx is as defined above, -a haloalkyl,
-5 or 6 membered heterocycle groups,
-an amino optionally substituted with one or more Ci to Cg alkyl(s), and/or -a -NRjjSθ2Rx group, where Rx is as defined above, and R;; is:
-a hydrogen, -a Ci to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -CORx group, where Rx is as defined above;
Z is:
-a Ci to Ce alkyl optionally substituted with: -an alkoxy,
-one or more halogen(s), or -a C6 to C8 aryl;
-a d to C6 alkylene;
-a C(, to Cg aryl optionally substituted with an alkoxy or one or more Ci to C6 alkyl(s); -a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy; -a hydrogen;
-a hydroxy;
-a halogen; -a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an. alkoxy optionally substituted with: -one or more halogen(s),
-a Cδ to Cg aryl, or -a 5 or 6 membered heterocycle;
-a Cg to Cs aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above; -a Ci to Ce alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
Ri joins together with R2 to form:
R2 is: -a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
-a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); -an amino group;
-an alkoxy group optionally substituted with: -one or more halogen(s),
-an -OCORx group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Cj to Ce alkyl, -a 5 or 6 membered heteroaryl group, or
-a C6 to C8 aryl group;
-a -COORx group, where Rx is as defined above; -a haloalkyl; -an amide group optionally substituted with:
- a hydroxy group, or
-a Ce to Cg aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORjj group, where Ry is:
-an alkoxy, or
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; -a -NHSO2RX group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is:
-a hydrogen; or
-CHaOCORx, and Rx is as defined above; provided that when X is phenyl substituted with alkoxy, Y is phenyl, R is hydrogen, Ri is a halogen, R2 is hydrogen, and R3 is hydrogen, and provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Ri is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is: -a Ci to C6 alkyl substituted with: -an alkoxy,
-one or more halogen(s), or -a Ce to Cs aryl; -a Cz to Ce alkylene; -a CO to Cs aryl optionally substituted with an. alkoxy or one or more Ci to Ce alkyl(s); -a -COORx group, where Rx is as defined above; or
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein X is a nitro group or a cyano group.
3. The compound of claim 1, wherein X is a cyano group.
4. The compound of claim 1 , wherein:
Y is a Ce to Cs aryl, optionally substituted with one or more of the following: -an amino optionally substituted with one or more Ci to C6 alkyl(s), -a Ci to Cs alkyl group, optionally substituted with a -NHSOiRx group, -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with: -a halogen, or -a Ce to Cg aryl, or -a 5 or 6 membered heterocycle, and where R0 is a hydrogen,
-a -NRqCONRqRr group, where Rq is: -a hydrogen, or -a Ci to C6 alkyl, and where Rr is a Ci to Cs alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, or -a Cδ to Cg aryl,
-a -NR1COORu group, where Ru is: -a Ci to Ci2 alkyl, optionally substituted with:
-a Ce to Cg aryl optionally substituted with a Ci to Ce alkyl or an alkoxy. -an alkylene, -an alkoxy, -an alkyne, -a halogen, or
-a 5 or 6 membered heterocycle, -a Ce to C8 aryl, optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle, and where Rt is:
-a hydrogen, or -a Ci to C6 alkyl,
-a -NRvSChRw group, where Rv is a hydrogen, and where Rw is a Ci to Ce alkyl optionally substituted with a halogen;
where Rz is a Ci to Ce alkyl, and/or
-a -NHRbb group, where Rt>b is a -PO(ORX)2 group.
5. The compound of claim 4, wherein Y is a C$ to Cg aryl substituted with: -a -NRqCONRqRr group,
-a -NR1COOR1, group,
-a -NRvSθ2Rw group, or
-a -NHRbb group, where Rbb is -a -PO(ORX)2 group.
6. The compound of claim 5, wherein, the CO to Cg aryl is phenyl.
7. The compound of claim 6, wherein the phenyl is substituted at the para position.
8. The compound of claim 7, wherein Y is phenyl substituted with a -NRqCONRqRr group at the para position.
9. The compound of claim 7, wherein Y is phenyl substituted with a -NR1COORu group at the para position.
10. The compound of claim 7, wherein Y is phenyl substituted with a -NRvSθ2Rw group at the para position.
11. The compound of claim 7, wherein Y is phenyl substituted with a -NHPO(ORX)2 group at the para position.
12. The compound of claim 1, wherein Z is: -a C] to Ce alkyl optionally substituted with
-an alkoxy, or -one or more halogen(s), or -a C2 to Ce alkylene.
13. The compound of claim 1, wherein Z is a Ci to Ce alkyl.
14. The compound of claim 13, wherein Z is a -a C2 to C5 alkyl.
15. The compound of claim 14, wherein Z is cyclobutyl, cycloprόpyl, cyclopropylmethyl, ethyl or cyclopentyl. 007/000996
16. The compound of claim 1 , wherein R is hydrogen.
17. The compound of claim 1 , wherein Ri is: -a hydrogen;
-an alkoxy group optionally substituted with:
-one or more halogen(s),
-a Cs to Cs aryl group, or
-a 5 or 6 membered heterocycle; or Ri joins together with R2 to form:
18. The compound of claim 1, wherein Rz is:
-a hydrogen; -a halogen; -a hydroxy group;
-a Ci to C6 alkyl group, optionally substituted with one or more halogen(s); -an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s),
-an -OCORx group, where Rx is as defined above,
-a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Ci to Cs alkyl,
-a 5 or 6 membered heteroaryl group, or
-a Ce to Cs aryl group; -a -COORx group; or R2 joins together with Ri to form:
19. The compound of claim 1 , wherein: at least one of Ri and R2 is a hydroxy group or an alkoxy group optionally substituted with:
-one or more halogen(s), -a Ce to Cg aryl group, or -a 5 or 6 membered heterocycle group; or
R2 is a -OCORx group, a -ORkk group, or an alkoxy group substituted with: -an -OCORx group,
-a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a Ci to Cg alkyl; or -a 5 or 6 membered heteroaryl group.
20. The compound of claim 19, wherein R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl; or -a 5 or 6 membered heteroaryl group.
21. The compound of claim 20, wherein R2 is a Ci to Cg alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl; or -a 5 or 6 membered heteroaryl group
22. The compound of claim 1, wherein R3 is a hydrogen.
23. The compound of claim I, wherein: X is a cyano group;
Y is a C^ to Cg aryl substituted with: -a -NRqCONRqRr group,
-a -NR1COORu group, -a -NRvSOiRw group, or -a -NHPO(ORX)2 group; Z is: -a Ci to Ce alkyl optionally substituted with -an alkoxy, or -one or more halogen(s), or
-a C2 to Ce alkylene; R is hydrogen; at least one of Ri and R2 is a hydroxy group or an alkoxy group optionally substituted with:
-one or more halogen(s),
-a CO to C8 aryl group, or -a 5 or 6 membered heterocycle group; or
Ra is a -OCORx group, a -ORkk group, or an alkoxy group substituted with:
-an -OCORx group,
-a dialkyl-amino optionally substituted with an alkoxy,
-a 5 or 6 membered heterocycle group substituted with a Ci to Cs alkyl; or -a 5 or 6 membered heteroaryl group; and
R3 is hydrogen.
24. The compound of claim 23, wherein Y is a phenyl substituted with a
-NRqCONRqRr gTOUp.
25. The compound of claim 24, wherein: Z is a Ci to C6 alkyl; and
R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Cj to Ce alkyl; or -a 5 or 6 membered heteroaryl group.
26. The compound of claim 23, wherein Y is a phenyl substituted with a - NR1COOR1, group.
27. The compound of claim 26, wherein: Z is a Ci to Ce alkyl; and
R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to C$ alkyl; or -a 5 or 6 membered heteroaryl group.
28. The compound of claim 23, wherein Y is a phenyl substituted with a - NRySO2Rw group.
29. The compound of claim 28, wherein. Z is a Ci to Ce alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl; or -a 5 or 6 membered heteroaryl group.
30. The compound of claim 23, wherein Y is -a -NHPO(ORX)2 group.
31. The compound of claim 30, wherein: Z is a Ci to C6 alkyl; and
R-2 is an alkoxy group optionally substituted with: -a 5 or 6 membered heterocycle group optionally substituted with a C] to CO alkyl; or
-a 5 or 6 membered heteroaryl group.
32. The compound of claim 1, wherein: X is:
-a cyano group; or -a formyl group;
Y is:
-a 5 or 6 membered heteroaryl, optionally substituted with a C6 to Cs aryl, optionally substituted with -COORx, where Rx is as defined above; or -a C6 to Cs aryl, optionally substituted with one or more of the following: -a C1 to Ce alkyl group;
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -a halogen; -a hydroxy;
-a -CORm group, where Rn, is an amino optionally substituted with one or more C, to C6 alkyl(s);
-a -NR0CORp group, where Rp is a Ci to C6 alkyl optionally substituted with an alkoxy, and where R0 is a hydrogen;
-a -KRqCONRqRr group, where Rq is hydrogen and where R1- is a Ci to C6 alkyl; -a -NRtCOORu group, where R1 is hydrogen, and where Ru is a C] to Ci 2 alkyl, optionally substituted with:
-a C6 to C8 aryl; -a halogen; or
-a 5 or 6 membered heterocycle;
-a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is -a Ci to C6 alkyl; or
-an alkyl- or dialkyl-amino;
or a Ci to C& alkyl; -a -SO2R33 group, where R33 is: -an amino group; or
-an alkyl or dialkyl amino group; or
-a -NHRbb group, where Rbb is a -PO(ORX)2 group, where Rx is as defined above; Z is: -a Ci to C6 alky; or
-a -COORx group, where Rx is as defined above; R is a hydrogen, Ri is:
-a hydrogen; -a 5 or 6 membered heterocycle; or
-an alkoxy optionally substituted with: -one or more halogen(s); or -a 5 or 6 membered heterocycle; R2 is: -a hydrogen;
-a hydroxy group;
-a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); -an alkoxy group optionally substituted with: -one or more halogen(s); -a 5 or 6 membered heterocycle group optionally substituted with a Ci to CQ alkyl; or
-a 5 or 6 membered heteroaryl group; -a -COORx group, where Rx is as defined above; -an amide group;
-a 5 or 6 membered heteroaryl; or
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; and Rj is a hydrogen.
33. The compound of claim 32, wherein: X is a cyano group;
Y is a Cδ to Cs aryl substituted with one or more of the following:
-an amino optionally substituted with one or more Cj to Cg alkyl(s);
-a -NRqCONRqRr group, where Rq is hydrogen and where Rr is a C] to Ce alkyl;
-a -NRtCOORu group, where Rt is hydrogen, and where Ru is a Ci to Cn alkyl, optionally substituted with a Ce to Cg aryl; or
-a -NRvSOoRw group, where Rv is hydrogen and where Rw is a Ci to Cg alkyl; Z is a Ci to C6 alky; R is a hydrogen, Ri is a hydrogen; R2 is an alkoxy group optionally substituted with:
-one or more halogen(s);
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to C6 alkyl; or
-a 5 or 6 membered heteroaryl group; or R3 is a hydrogen.
34. The compound of claim 32, wherein:
X is a cyano group;
Y is a Ce to C8 aryl substituted with one or more of the following:
-a C] to Ce alkyl group;
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -a halogen;
-a -NR[COORu group, where R1 is hydrogen, and where Ru is:
-a Ci to Ci2 alkyl;
-a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is: -a Ci to Ce alkyl; or -an alkyl- or dialkyl-amino; Z is a Ci to Ce alky; R is a hydrogen; Ri is a hydrogen;
R2 is a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; and R3 is a hydrogen.
35. The compound of claim 32, wherein: X is a cyano group; Y is a C& to Cs aryl substituted with one or more of the following: -a Ci to C6 alkyl; -a halogen;
-a -NRtCOORu group, where Rt is hydrogen, and where Ru is a Ci to C12 alkyl; -a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is: -a Ci to Ce alkyl; or
-an alkyl- or dialkyl-amino; or
-a -NRqCONRqRr group, where Rq is hydrogen and where Rr is a Ci to Cs alkyl; Z is a Ci to Cβ alkyl; R is a hydrogen, R) is a hydrogen; R2 is:
-an alkoxy group optionally substituted with one or more halogen(s); -an amide;
-a -ORick group, where Rkk is a 5 to 6 membered heteroaryl; or -a 5 or 6 membered heteroaryl; and
R3 is a hydrogen.
36. The compound of claim 35, wherein: X is a cyano group;
Y is a CO to Cg aryl substituted with one or more of the following: -a halogen;
-a -NR1COORn group, where R1 is hydrogen, and where Ru is a Ci to Ci 2 alkyl; or -a -NRuSOaRw group, where Rv is hydrogen and where Rw is a Ci to Ce alkyl;
Z is a CJ to Ce alkyl; R is a hydrogen;
Ri is a hydrogen;
R2 is a -ORkk group, where R^ is a 5 to 6 membered heteroaryl; and
R3 is a hydrogen.
37. The compound of claim 36, wherein the C$ to C8 aryl is phenyl.
38. The compound of claim 37, wherein the phenyl is substituted at the para position.
39. The compound of claim 38, wherein Y is a phenyl substituted with a -NR(COORu group, where Rt is hydrogen, and where R11 is:a Q to C12 alkyl.
40. The compound of claim 38, wherein Y is a phenyl substituted with a halogen and a -NRtCOORu group, where Rt is hydrogen, and where Ru is Ci to Q2 alkyl.
41. The compound of claim 38, wherein Y is a phenyl substituted with a - NRvSθ2Rw group, where Rv is hydrogen and where Rw is Ci to Ce alkyl.
42. The compound of claim 38, wherein Y is a phenyl substituted with a Ci to Cs alkyl and a -NRtCOORu group, where R1 is hydrogen, and where Ru is a Ci to Cn alkyl.
43. The compound of claim 35, wherein: X is a cyano group;
Y is a Ce to C8 aryl substituted with -NR(COOR1, group, where Rt is hydrogen, and where Ru is a Ci to C12 alkyl; Z is a Ci to C6 alkyl; R is a hydrogen; Ri is a hydrogen;
R2 is an alkoxy group optionally substituted with one or more halogen(s); and R3 is a hydrogen.
44. The compound of claim 35, wherein R2 is an alkoxy group substituted with one or more halogens.
45. The compound of claim 43, wherein the Cδ to Cg aryl is phenyl.
46. The compound of claim 45, wherein, the phenyl is substituted at the para position.
47. The compound of claim 35, wherein: X is a cyano group;
Y is a Ce to Cg aryl substituted with one or more of the following:
-a -NRtCOORu group, where Rt is hydrogen, and where Ru is a Cj to Ci 2 alkyl; or -a -NRqCONRqRr group, where Rq is hydrogen and where R1- is a Ci to Ce alkyl; Z is a Ci to C6 alkyl;
R is a hydrogen,
Ri is a hydrogen;
R2 is a 5 or 6 membered heteroaryl; and
R3 is a hydrogen.
48. The compound of claim 47, wherein the Ce to Cg aryl is phenyl.
49. The compound of claim 48, wherein the phenyl is substituted at the para position.
5O- The compound of claim 49, wherein Y is a phenyl substituted with a -NR1COORa group, where Rt is hydrogen, and where Ru is a Cj to C12 alkyl.
51. The compound of claim 49, wherein Y is a Ce to Cg aryl substituted with a
NRqCONRqRr group, where R1, is hydrogen and where Rr is a Ci to Ce alkyl.
52. The compound of claim 35, wherein: X is a cyano group;
Y is a C(, to Cg aryl substituted with a -NR1COOR,, group, where Rt is hydrogen, and where R11 is a Ci to Ci2 alkyl;
Z is a Ci to C6 alkyl; R is a hydrogen; Ri is a hydrogen; R2 is an amide; and R3 is a hydrogen.
53. The compound of claim 52, wherein the Ce to C8 aryl is phenyl.
54. The compound of claim 53, wherein the phenyl is substituted at the para position.
55. The compound of claim 35, wherein R2 is an alkoxy group substituted with one or more halogen(s) .
56. The compound of claim 35, wherein R2 is a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl.
57. The compound of claim 32, wherein: X is a forrαyl group; Y is a Ce to Cs aryl substituted with one or more of the following:
-a -NRtCOORu group, where Rt is hydrogen, and where Ru is a Ci to C12 alkyl; or -a -NRqCONRqRr group, where Rq is hydrogen and where Rr is a Ci to Cδ alkyl; Z is a Ci to C6 alkyl; R is a hydrogen; Ri is a hydrogen;
R2 is an alkoxy group; and R3 is a hydrogen.
58. The compound of claim 32, wherein: X is a cyano group; Y is a C6 to Cg aryl substituted with one or more of the following: -a Ci to CO alkyl group; -a halogen;
-a -NRtCOORu group, where R1 is hydrogen, and where Ru is a Ci to C12 alkyl, optionally substituted with a Ce to Cs aryl; -a -NRvSO2Rw group, where Rv is hydrogen and where Rw is:
-a C] to Ce alkyl; or -an alkyl- or dialkyl-amino; or
Z is a Ci to C6 alkyl; R is a hydrogen; Ri is a hydrogen;
R2 is an alkoxy group substituted with one or more halogen(s); and R3 is a hydrogen.
59. The compound of claim 32, wherein: X is a cyano group;
Y is a Gs to Cs aryl, optionally substituted with one or more of the following:
-a -NR0CORp group, where Rp is a C1 to C6 alkyl optionally substituted with an alkoxy, and where R0 is a hydrogen; Z is a Ci to Ce alkyl; R is a hydrogen; Rt is a hydrogen;
R2 is an alkoxy group substituted with a 5 or 6 membered heteroaryl group; and R3 is a hydrogen.
60. The compound of claim 32, wherein:
X is a cyano group;
Y is a Ce to Cg aryl, optionally substituted with one or more of the following:
-a Ci to Ce alkyl group;
-an amino optionally substituted with one or more Cj to Cg alkyl(s); -a halogen;
-a -NR0CORp group, where Rp is a C] to Cs alkyl, and where R0 is a hydrogen; -a -NRqCONRqRr group, where Rq is hydrogen, and where Rr is a Ci to Ce alkyl; -a -NRtCOORu group, where Rt is hydrogen, and where Ru is a Ci to C 12 alkyl; -a -NRvSOiRw group, where Rv is hydrogen, and where Rw is a Ci to C^ alkyl; or -a -NHRbb group, where Rbb is a -PO(ORX)2 group, and where Rx is as defined above;
Z is a Ci to C6 alkyl; R is a hydrogen, Ri is a hydrogen;
R2 is a 5 or 6 membered heteroaryl; and R3 is a hydrogen.
61. The compound of claim 32, wherein: X is a cyano group;
Y is a Cg to Cs aryl, optionally substituted with one or more of the following:
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -a -NRqCONRqRr group, where R4, is hydrogen and where Rr is a Ci to Ce alkyl;
-a -NR1COORu group, where R1 is hydrogen, and where Ru is a Ci to Ci 2 alkyl, optionally substituted with: -a Ce to C8 aryl; or -a 5 or 6 membered heterocycle; -a group, where Rv is hydrogen and where Rw is a Ci to Cβ alkyl;
R2 is hydrogen or a Ci to Ce alkyl; Z is a Ci to C6 alkyl; R is a hydrogen,
-a 5 or 6 membered heterocycle; or -an alkoxy substituted with: -one or more halo gen(s); or
-a 5 or 6 membered heterocycle; R2 is a hydrogen; and R3 is a hydrogen.
62. The compound of claim 61, wherein Ri is a 5 or 6 membered heterocycle.
63. The compound of claim 61, wherein Ri is an alkoxy substitued with one or more halogen.
64. The compound of claim 61, wherein:
Y is a Cg to Cg aryl substituted with a -NRtCOORu group, where Rt is hydrogen, and where Ru is a C] to Ci 2 alkyl, optionally substituted with: -a C6 to Cs aryl; or
-a 5 or 6 membered heterocycle; and Ri is an alkoxy substitued with one or more halogen.
65. A compound of formula Ilia
wherein: X is hydrogen;
Y is a Ce to Cg aryl, optionally substituted with one or more of the following:
-a -NRqCONRqRr group, where Rq is hydrogen and where Rr is a Ci to Cδ alkyl; -a -NRtCOORu group, where R1 is hydrogen, and where Ru is a Ci to Cn alkyl; or -a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is a Ci to Ce alkyl;
Z is a Ci to C6 alkyl;
R is a hydrogen,
Ri is a hydrogen;
R2 is:
-an alkoxy group optionally substituted with one or more halogen(s); or -a -ORkk group, where R^ is a 5 to 6 membered heteroaryl; and
R3 is a hydrogen.
66. The compound of claim 65, wherein: X is hydrogen;
Y is a C& to Cs aryl substituted with a -NR1COORu group, where Rt is hydrogen, and where R11 is a Ci to C12 alkyl; Z is a Ci to C6 alkyl; R is a hydrogen; Ri is a hydrogen;
R2 is a -ORicic group, where Rkk is a 5 to 6 membered heteroaryl; and R3 is a hydrogen.
67. The compound of claim 65, wherein the Ce to Cs aryl is phenyl.
68. The compound of claim 65, wherein the phenyl is substituted at the para position.
69. A pharmaceutical composition comprising: (i) a compound of formula I
wherein: X is: -a nitro group; -a cyano group; -a -COR3 group, where R3 is:
-a Ci to C6 alkyl;
-a C6 to Cg aryl optionally substituted with an alkoxy or a halogen; or -a dialkyl-amino;
-a -COORx group, where Rx is a Ci to C6 alkyl; -a formyl group;
-a Cδ to Ci aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with: -a C, to C6 alkyl;
-a Ce to Ci aryl optionally substituted with an alkoxy or one or more halogen(s); or
-a 5 to 6 membered heteroaryl; Y is:
-a haloalkyl; -a halogen;
-an amino optionally substituted with one or more Ci to C6 alkyl(s); -a benzofuran; -a benzothiophene; -a dibenzofuran; -a dibenzothiophene; -a benzothiazole; -a naphthalene; -an indole, optionally substituted on the nitrogen with a Ci to C6 alkyl;
Rb , where Rb is a hydrogen or a Ci to Ce alkyl, and n is 0 or 1 ;
where R0 is a hydrogen, a -CONHRx, where Rx is as defined above, or an -SOiRx, where Rx is as defined above;
where R<j is a Ci to Ce alkyl or a Ce to Cg aryl; -a -NHCORe group, where R6 is: -a Ci to Cs alkyl; or -a Ce to Cs aryl optionally substituted with:
-a Ci to CQ alkyl; -an alkoxy; -a cyano group; -a nitro group; or -a halogen; -a -NHCOORx group, where Rx is as defined above; -a -OHbO-Rf group, where Rf is a C6 to C8 aryl; -a -NRgRh group, where Rg is a Ci to Ce alkyl or a hydrogen and Rj, is a C6 to Cg aryl optionally substituted with an alkoxy; -a Ci to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with: -a Ci to Ce alkyl, optionally substituted with a Ce to Cg aryl;
-a C6 to Cg aryl, optionally substituted with -COORx, where Rx is as defined above; or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COORx group, where Rx is as defined above; or -a -NHCOORx group, where Rx is as defined above;
-a Ce to Cs aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with: -an alkoxy; -a hydroxy; -one or more halogen(s);
-a 5 or 6 membered heterocycle, optionally substituted with: -a Ci to C6 alkyl; or -a hydroxy;
-an amino group optionally substituted with one or more Ci to Ce alkyl(s), -a -NR1SO2Rx group, where Rx is as defined above, and where R; is:
-a hydrogen; -a Ci to C6 alkyl;
-a -CORx group, where Rx is as defined above; -a haloalkyl; or -a haloalkoxy;
-a -NRjCORic group, where Rk is: -a Ci to C6 alkyl; -a hydrogen; or
-an amino optionally substituted with one or more Ci to C6 alkyl(s); and where Rj is:
-a hydrogen; -a C1 to C6 alkyl;
-a -CORx group, where Rx is as defined above; -a haloalkyl; or -a haloalkoxy; -a -N=N+=N" group; or
-a -CORi, where R| is a 5 or 6 membered heterocycle optionally substituted with a hydroxy; -an amino optionally substituted with one or more Ci to Cβ alkyl(s);
-a nitro group; -a C] to Cg alkyl group, optionally substituted with:
-a -NHSO2Rx group, where Rx is as defined above; or -a -NRxSO2Rx group, where Rx is as defined above; -a haloalkoxy;
-a halogen; -a hydroxy;
-a -COORx group, where Rx is as defined above; -a -CORn, group, where Rm is: -an amino optionally substituted with one or more Ci to Ce alkyl(s), where the
Ci to Cs alkyls are optionally substituted with: -a hydroxy;
-a 5 or 6 membered heterocycle;
-an amino optionally substituted with one or more Ci to Cg alkyl(s); or -an alkoxy;
-a 3 to 7 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a dialkyl-amino; -a -NHRn group, where Rn is:
-a -CH2CONH2; or -a Ce to Cs aryl optionally substituted with:
-an alkyl;
-one or more halogen(s); -a nitro group; or -one or more alkoxy(s); -a -NR0CORp group, where Rp is:
-a Ci to Ce alkyl optionally substituted with: -a halogen; -an alkoxy; or
-a C6 to C8 aryl; -a 5 or 6 membered heterocycle;
-a CO to Cg aryl, optionally substituted with a halogen;
-a 5 or 6 membered heteroaryl optionally substituted with one or more C] to Ce alkyl(s);
-a hydrogen;
and where R0 is:
-a hydrogen;
-a Ci to C6 alkyl;
-a -CORx group, where Rx is as defined above;
-a halo alkyl; or
-a haloalkoxy; -a -NRqCONRqRr group, where Rq is:
-a hydrogen;
-a Ci to C6 alkyl;
-a haloalkyl;
-a haloalkoxy; or
-a -CORx group, where Rx is as defined above, and where Rr is:
-a Ce to Cs aryl optionally substituted with:
-a Ci to C6 alkyl; -a haloalkyl;
-a -ORS group, where Rs is a C6 to Cs aryl; or -a -COORx group, where Rx is as defined above;
-a C] to CΘ alkyl optionally substituted with one or more of the following: -a halogen; -an alkylene; -a C6 to Cg aryl; and/or
-a -COORx group, where Rx is as defined above; or -a -COORx group, where Rx is as defined above;
-a -NRtCOOR11 group, where Ru is:
-a Ci to Cu alkyl, optionally substituted with:
-a Ce to Cg aryl optionally substituted with a Ci to Ce alkyl or an alkoxy; -an alkylene; -an alkoxy;
-an alkyne; -a halogen; or
-a 5 or 6 membered heterocycle; -a Ce to Cg aryl, optionally substituted with: -an alkoxy;
-a halogen; or -a Ci to Ce alkyl; or -a 5 or 6 membered heterocycle; -a hydrogen;
-a Ci to C6 alkyl;
-a -CORx group, where Rx is as defined above; -a haloalkyl; or -a haloalkoxy; -a -NRvSθ2Rw group, where Rv is:
-a hydrogen;
-a -CORx, where Rx is as defined above; or -a Ci to Ce alkyl, optionally substituted with:
-a halogen; -a -CORx group, where Rx is as defined above;
-a -OCORx group, where Rx is as defined above; -a hydroxy; or -an alkoxy; and where Rw is: -a Ci to C6 allcyl optionally substituted with:
-a halogen;
-a haloalkyl;
-a Cβ to Cs aryl; or
-a 5 or 6 membered heterocycle; -a C2 to Ce alkylene;
-an allcyl- or dialkyl-amino optionally substituted with a halogen; -a 5 or 6 membered heterocycle; or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to Ce alkyl;
-a 5 or 6 membered heterocycle; or
-a , optionally substituted with a C] to Ce alkyl, where Ry is a
Ci to Cg alkyl or hydrogen;
where Rz is hydrogen or a Ci to Ce alkyl, optionally substituted with a Cs to Cs aryl;
-a -SRx group, where Rx is as defined above;
-a -SOaRaa group, where R33 is:
-a Ci to C6 alkyl;
-an amino group;
-art alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -
COORx group, where Rx is as defined above, or
-a 5 or 6 membered heteroaryl; -a Ce to Cg aryl; and/or -a -NHRbb group, where Rw, is:
-a -C(=S)NH2 group; or
-a -PO(ORX)2 group, where Rx is as defined above; or = Rcc group, where R00 is:
-a naphthalene;
-a 5 or 6 membered heteroaryl;
-a Cδ to Cg aryl, optionally substituted with one or more of the following: -an alkoxy; -a hydroxy; -a halogen;
-a Ci to Ce alkyl, optionally substituted with a cyano group; -an amino optionally substituted with one or more Cj to Cg alkyl(s); -a -NHPORxRx, where Rx is as defined above;
-a -NReeCONRffRff group, where Ree is a hydrogen or a Ci to Ce alkyl, optionally substituted with a halogen, and Rfr is: -a hydrogen; -a haloalkyl; -a haloalkoxy; -a C] to Cβ alkyl; or
-a -CORx, where Rx is as defined above; -a -NRggCORhh group, where Rhh is: -a hydrogen;
-a Ci to Cβ alkyl optionally substituted with: -an alkoxy; -a halogen; or
-an amino optionally substituted with one or more Ci to C6 alkyl(s); -an amino optionally substituted with one or more Ci to C≤ alkyl(s), where the alkyls are optionally substituted with a halogen; -a 5 or 6 membered heterocycle; -a 5 or 6 membered heteroaryl;
-a hydrogen; -a Ci to Cβ alkyl; -a haloalkyl; -a haloalkoxy; or -a -CORx group, where Rx is as defined above;
-a haloalkyl;
-5 or 6 membered heterocycle groups;
-an amino optionally substituted with one or more Ci to C6 alkyl(s); and/or -a -NRuSChRx group, where Rx is as defined above, and R;, is: -a hydrogen;
-a C, to C6 alkyl; -a haloalkyl; -a haloalkoxy; or
-a -CORx group, where Rx is as defined above; Z is:
-a Ci to Cs alkyl optionally substituted with: -an alkoxy;
-one or more halogen(s); or -a C6 to C8 aryl; -a Cz to Cβ alkylene;
-a Cs to Cg aryl optionally substituted with an alkoxy or one or more Ci to Cβ alkyl(s); -a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy; Ri is: -a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl; -a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s); -a Ce to Cg aryl; or
-a 5 or 6 membered heterocycle;
-a Ce to Cg aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above;
-a C1 to Ce alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
R] joins together with R2 to form:
R2 is:
-a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
-a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); -an amino group; -an alkoxy group optionally substituted with: -one or more halogen(s),
-an -OCORx group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy,
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to Cg aryl group,
-a -COORx group, where Rx is as defined above; -a haloalkyl;
-an amide group optionally substituted with: -a hydroxy group; or
-a C6 to C8 aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORjj group, where Rjj is: -an alkoxy; or
-an amino optionally substituted with one or more Ct to Ce alkyl(s); -a -ORkk group, where Rkiς is a 5 to 6 membered heteroaryl; -a -NHSθ2Rχ group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is:
-a hydrogen; or
-CKbOCORx, and Rx is as defined above; provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Ri is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is:
-a Ci to Cg alkyl substituted with: -an alkoxy;
-one or more halogen(s); or -a C6 to C8 aryl;
-a C2 to Cg alkylene;
-a Cg to Cs aryl optionally substituted with an alkoxy or one or more Ci to Cβ alkyl(s);
-a -COORx group, where Rx is as defined above; or or one or more pharmaceutically acceptable salt(s) thereof; and (ii) one or more pharmaceutically acceptable excipient(s).
70. A method for treating an infection by a virus in a subject in need thereof, wherein the virus contains an internal ribosome entry site (IRES), comprising administering to the subject one or more compound(s) of formula I or a pharmaceutical composition comprising one or more compound(s) of formula I
wherein: X is:
-a nitro group;
-a cyano group;
-a -CORa group, where Ra is:
-a Ci to C6 alkyl; -a Cδ to Cs aryl optionally substituted with an alkoxy or a halogen; or
-a dialkyl-amino;
-a -COORx group, where Rx is a Ci to Ce alkyl; -a formyl group;
-a CQ to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl;
-a Ce to Cs aryl optionally substituted with an alkoxy or one or more halogen(s); or
-a 5 to 6 membered heteroaryl; Y is:
-a haloalkyl; -a halogen;
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -a benzofuran;
-a benzothiophene; -a dibenzofuran; -a dibenzothiophene; -a benzothiazole; -a naphthalene;
-an indole, optionally substituted on the nitrogen with a Ci to C& alkyl;
or 1;
above, or an -SC»2Rχ, where Rx is as defined above; or
where R1 is a Cj to Ce alkyl or a Ce to Cg aryl; -a -NHCORe group, where R6 is: -a Ci to C6 alkyl; or -a C6 to C8 aryl optionally substituted with:
-a Ci to C6 alkyl; -an alkoxy;
-a cyano group; -a nitro group; or -a halogen;
-a -NHCOORx group, where Rx is as defined above; -a -CH∑O-Rf group, where Rf is a Ce to Cs aryl;
-a -NRgRh group, where Rg is a Ci to Ce alkyl or a hydrogen and Rh is a Ce to Cs aryl optionally substituted with an alkoxy; -a Ci to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with: -a Ci to C6 alkyl, optionally substituted with a Cg to Cs aryl;
-a Ce to Cg aryl, optionally substituted with -COORx, where Rx is as defined above; or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above; or -a -NHCOORx group, where Rx is as defined above;
-a C6 to Cs aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with: -an alkoxy; -a hydroxy; -one or more halogen(s);
-a 5 or 6 membered heterocycle, optionally substituted with: -a Ci to C6 alkyl; or -a hydroxy;
-an amino group optionally substituted with one or more Ci to C6 alkyl(s); ' -a -NR;SO2RX group, where Rx is as defined above and R1 is:
-a hydrogen; -a C] to C6 alkyl;
-a -CORx group, where Rx is as defined above; -a haloalkyl; or -a haloalkoxy;
-a -NRjCORk group, where Rk is: -a Ci to C6 alkyl; -a hydrogen; or -an amino optionally substituted with one or more Ci to Cβ alkyl(s); and where Rj is: -a hydrogen; -a Ci to C5 alkyl;
- a -CORx group, where Rx is as defined above; -a haloalkyl; or
-a haloalkoxy; -a -N=N+=N" group; or
-a -CORi, where Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy; -an amino optionally substituted with one or more Ci to Cs alkyl(s);
-a nitro group; -a Ci to Ce alkyl group, optionally substituted with:
-a -NHSO2RX group, where Rx is as defined above; or -a -NRxSO2Rx group, where Rx is as defined above; -a haloalkoxy;
-a halogen; -a hydroxy;
-a -COORx group, where Rx is as defined above; -a -CORn, group, where Rn, is: -an amino optionally substituted with one or more C] to Cg alkyl(s), where the one or more Cj to Ce alkyl(s) is/are optionally substituted with: -a hydroxy;
-a 5 or 6 membered heterocycle;
-an amino optionally substituted with one or more Ci to Ce alkyls; and/or
-an alkoxy;
-a 3 to 7 membered heterocycle, optionally substituted with a Ci to Ce alkyl, optionally substituted with a dialkyl-amino;
-a -NHRn group, where Rn is: -a -CH2CONH2; or
-a Cβ to Cs aryl optionally substituted with: -an alkyl;
-one or more halogen(s); -a nitro group; or -one or more alkoxy(s); -a -NR0CORp group, where Rp is:
-a Ci to Cs alkyl optionally substituted with: -a halogen; -an alkoxy; or -a C6 to Cs aryl;
-a 5 or 6 membered heterocycle; -a C6 to Cs aryl, optionally substituted with a halogen;
-a 5 or 6 membered heteroaryl optionally substituted with one or more C\ to C6 alkyl(s); -a hydrogen;
and where R0 is:
-a hydrogen;
-a Ci to C6 alkyl;
-a -CORx group, where Rx is as defined above;
-a haloalkyl; or
-a haloalkoxy; -a -NRqCONRqRr group, where Rq is:
-a hydrogen;
-a Ci to C6 alkyl;
-a haloalkyl;
-a haloalkoxy; or
-a -CORx group, where Rx is as defined above; and where Rr is:
-a C6 to Cg aryl optionally substituted with:
-a Ci to Q5 alkyl; -a haloalkyl;
-a -OR3 group, where Rs is a C^ to Cg aryl; or -a -COORx group, where Rx is as defined above;
-a Ci to Ce alkyl optionally substituted with one or more of the following: -a halogen; -an alkylene; -a Ce to Cg aryl; and/or -a -COORx group, where Rx is as defined above;
-a -COORx group, where Rx is as defined above; RtCOORu group, where R11 is:
-a C] to Cu alkyl, optionally substituted with:
-a Ce to Cs aryl optionally substituted with a Ci to Ce alkyl or an alkoxy; -an alkylene;
-an alkoxy; -an alkyne; -a halogen; or
-a 5 or 6 membered heterocycle; -a Ce to Cg aryl, optionally substituted with:
-an alkoxy; -a halogen; or -a Ci to Ce alkyl; or -a 5 or 6 membered heterocycle; and where R1 is:
-a hydrogen; -a Ci to C6 alkyl; -a -CORx group, where Rx is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -NRySChRw group, where Rv is: -a hydrogen;
-a -CORx, where Rx is as defined above; or -a Ci to Ce alkyl, optionally substituted, with:
-a halogen;
-a -CORx group, where Rx is as defined above;
-a -OCORx group, where Rx is as defined above;
-a hydroxy; or
-an alkoxy; and where Rw is:
-a Ci to Ce alkyl optionally substituted with:
-a halogen;
-a haloalkyl;
-a Ce to Cg aryl; or
-a 5 or 6 membered heterocycle; -a C2 to Ce alkylene;
-an alkyl- or dialkyl-amino optionally substituted with a halogen; -a 5 or 6 membered heterocycle; or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl;
-a 5 or 6 membered heterocycle; or
optionally substituted with a C1 to Cg alkyl, where Ry is a
Ci to Ce alkyl or hydrogen;
where Rz is hydrogen or a Ci to Ce alkyl, optionally substituted with a C6 to C8 aryl;
-a -SRx group, where Rx is as defined above;
-a -SCbRaa group, where R83 is:
-a Ci to C6 alkyl,
-an amino group; -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a
COORx group, where Rx is as defined above; or
-a 5 or 6 membered heteroaryl; -a CQ to Cs aryl; and/or -a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group; or
-a -PO(ORX)2 group, where Rx is as defined above; or = Rcc group, where R00 is:
-a naphthalene;
-a 5 or 6 membered heteroaryl;
-a Ce to Cs aryl, optionally substituted with one or more of the following:
-an alkoxy;
-a hydroxy;
-a halogen;
-a Ci to Ce alkyl, optionally substituted with a cyano group;
-an amino optionally substituted with one or more Ci to Cβ alkyl(s);
-a -2MHPORxRx, where Rx is as defined above;
-a -NReeCONRffRfr group, where Ree is a hydrogen or a C i to CO alkyl, optionally substituted with a halogen, and Rff is: -a hydrogen; -a haloalkyl; -a haloalkoxy; -a Ci to C(, alkyl; or
-a -CORx, where Rx is as defined above; -a -NRggCORhh group, where RM, is: -a hydrogen;
-a Ci to Ce alkyl optionally substituted with: -an alkoxy; -a halogen; or
-an amino optionally substituted with one or more Cj to Ce alkyl(s);
-an amino optionally substituted with one or more Ci to Ce alkyl(s), where the alkyls are optionally substituted with a halogen; -a 5 or 6 membered heterocycle; -a 5 or 6 membered heteroaryl; and Rgg is:
-a hydrogen; -a Ci to C6 alkyl; -a haloalkyl; -a haloalkoxy; or -a -CORx group, where Rx is as defined above;
-a haloalkyl;
-5 or 6 membered heterocycle groups;
-an amino optionally substituted with one or more Ci to Ce alkyl(s); and/or -a -NRjjSθ2Rx group, where Rx is as defined above, and R1-; is: -a hydrogen;
-a Ci to C6 alkyl; -a haloalkyl; -a haloalkoxy; or
-a -CORx group, where Rx is as defined above; Z is:
-a Ci to Cs alkyl optionally substituted with: -an alkoxy; -one or more halogen(s); or
-a C6 to C8 aryl; -a C2 to Ce alkylene;
-a Co to Cs aryl optionally substituted with an alkoxy or one or more Ci to Ce alkyl(s);
-a -COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy;
-a hydrogen;
-a hydroxy;
-a halogen; -a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with: -one or more halogen(s);
-a Ce to Cs aryl; or -a 5 or 6 membered heterocycle;
-a Cs to Cs aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above; -a Ci to Ce alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
Ri joins together with R2 to form:
R2 is: -a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
-a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); -an amino group; -an alkoxy group optionally substituted with:
-one or more halogen(s);
-an -OCORx group, where Rx is as defined above;
-a dialkyl-amino optionally substituted with an alkoxy;
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl; -a 5 or 6 membered heteroaryl group; or
-a Ce to Cg aryl group;
-a -COORx group, where Rx is as defined above; -a haloalkyl;
-an amide group optionally substituted with: - a hydroxy group; or
-a Cs to C8 aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORy group, where Rg is: -an alkoxy; or
-an amino optionally substituted with one or more Cj to Ce alkyl(s); -a -ORkj. group, where Rkk is a 5 to 6 membered heteroaryl; -a -NHSO∑Rx group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is:
-a hydrogen; or
-CEtOCORx, where Rx is as defined above; or one or more pharmaceutically acceptable salt(s) thereof.
71. A method for treating a Hepatitis C viral (HCV) infection in a subject in need thereof, comprising administering to the subject one or more compound(s) of formula I or a pharmaceutical composition comprising one or more compound(s) of formula I
wherein: X is:
-a nitro group; -a cyano group; -a -CORa group, where Ra is: -a Ci to C6 alkyl;
-a Ce to Cg aryl optionally substituted with an alkoxy or a halogen; or -a dialkyl-arnino;
-a -COORx group, where Rx is a Cj to Ce alkyl; -a formyl group; -a Ce to Cs aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with: -a Ci to C6 alkyl;
-a CO to Cs aryl optionally substituted with an alkoxy or one or more halogen(s); or -a 5 to 6 membered heteroaryl; Y is:
-a haloalkyl; -a halogen;
-an amino optionally substituted with one or more Ci to CO alkyl(s); -a benzofuran; -a benzothiophene; -a dibenzofiiran; -a dibenzothiophene; -a benzothiazole; -a naphthalene;
-an indole, optionally substituted on the nitrogen with a Ci to C& alkyl;
Rb , where Rb is a hydrogen or a Cj to C6 alkyl, and n is 0 or 1 ;
where R0 is a hydrogen, a -CONHRx, where Rx is as defined above, or an -SOaRx, where Rx is as defined above;
, where Rd is a Ci to C& alkyl or a Ce to Cs aryl;
-a -NHCORe group, where Re is: -a Ct to Ce alkyl;
-a Ce to Cs aryl optionally substituted with: -a C, to C6 alkyl; -an alkoxy; -a cyano group; -a nitro group; or
-a halogen;
-a -NHCOORx group, where Rx is as defined above; -a -CHaO-Rf group, where Rf is a C6 to Cg aryl;
-a -NRgRh group, where Rg is a Cj to C6 alkyl or a hydrogen and Rh is a C6 to Cs aryl optionally substituted with an alkoxy; -a Ci to C6 alkyl; -a 5 or 6 membered heteroaryl, optionally substituted with:
-a Ci to Cg alkyl, optionally substituted with a C6 to C8 aryl;
-a C6 to Cg aryl, optionally substituted with -COORx, where Rx is as defined above; or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with: -a -COORx group, where Rx is as defined above; or
-a -NHCOORx group, where Rx is as defined above; -a Cg to Ce aryl, optionally substituted with one or more of the following: -an alkoxy, optionally substituted with:
-an alkoxy; -a hydroxy;
-one or more halogen(s);
-a 5 or 6 membered heterocycle, optionally substituted with: -a Ci to C6 alkyl; or -a hydroxy; -an amino group optionally substituted with one or more C] to Ce alkyl(s);
-a -NRjSO∑Rx group, where Rx is as defined above and R1- is: -a hydrogen; -a Ci to C6 alkyl;
-a -CORx group, where Rx is as defined above; -a haloalkyl; or
-a haloalkoxy;
-a -NRjCORk group, where Rk is: -a Ci to C6 alkyl; -a hydrogen; or -an amino optionally substituted with one or more Ci to C6 alkyl(s); and Rj is:
-a hydrogen; -a Ci to C6 alkyl;
-a -CORx group, where Rx is as defined above; -a haloalkyl; or -a haloalkoxy; -a -N=N+=N" group; or
-a -CORi, where R] is a 5 or 6 membered heterocycle optionally substituted with a hydroxy;
-an amino optionally substituted with one or more Cj to Ce alkyl(s);
-a nitro group;
-a C] to Cs alkyl group, optionally substituted with:
-a -NHSOiRx group, where Rx is as defined above; or -a -NRxSθ2Rx group, where Rx is as defined above;
-a haloalkoxy; -a halogen; -a hydroxy;
-a -COORx group, where Rx is as defined above; -a -CORn, group, where Rm is:
-an amino optionally substituted with one or more Ci to C$ alkyl(s), where the one or more Ci to Ce alkyl(s) is/are optionally substituted with: -a hydroxy;
-a 5 or 6 membered heterocycle; -an amino optionally substituted with one or more Ci to C^ alkyl(s);
-an alkoxy;
-a 3 to 7 membered heterocycle, optionally substituted with a Ci to C6 alkyl, optionally substituted with a dialkyl-amino; or -a -NHRn group, where Rn is: -a -CH2CONH2; or
-a Ce to Cg aryl optionally substituted with: -an alkyl;
-one or more halogen(s); -a nitro group; or -one or more alkoxy(s);
-a -NR0CORp group, where Rp is:
-a Ct to Cδ alkyl optionally substituted with: -a halogen; -an alkoxy; or -a C6 to C8 aryl;
-a 5 or 6 membered heterocycle; -a Ce to Cg aryl, optionally substituted with a halogen;
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyl(s); -a hydrogen;
and where R0 is:
-a hydrogen;
-a Ci to Ce alkyl;
-a -CORx group, where Rx is as defined above;
-a haloalkyl; or
-a haloalkoxy; -a -NRqCONR5R1. group, where R, is:
-a hydrogen;
-a Ci to Cβ alkyl;
-a haloalkyl;
-a haloalkoxy; or
-a -CORx group, where Rx is as defined above; and where Rr is:
-a Cβ to Cg aryl optionally substituted with:
-a Ci to C6 alkyl; -a haloalkyl;
-a -ORS group, where R3 is a Ce to Cs aryl; or -a -COORx group, where Rx is as defined above; -a Ci to Ce alkyl optionally substituted with one or more of the following: -a halogen; -an alkylene; -a Cδ to Cg aryl; and/or -a -COORx group, where Rx is as defined above;
-a -COORx group, where Rx is as defined above; -a -NRtCOORu group, where Rn is:
-a Ci to Ci 2 alkyl, optionally substituted with:
-a Cβ to Cs aryl optionally substituted with a Cj to Ce alkyl or an alkoxy; -an alkylene;
-an alkoxy; -an alkyne; -a halogen; or
-a 5 or 6 membered heterocycle; -a Ce to Cs aryl, optionally substituted with:
-an alkoxy; -a halogen; or -a Cj to C6 alkyl; or -a 5 or 6 membered heterocycle; and Rt is:
-a hydrogen; -a Ci to C6 alkyl;
-a -CORx group, where Rx is as defined above; -a haloalkyl; or -a haloalkoxy;
-a -NRvSθ2Rw group, where Rv is: -a hydrogen;
-a -CORx, where Rx is as defined above; or -a Ci to Ce alkyl, optionally substituted with: -a halogen;
-a -CORx group, where Rx is as defined above; -a -OCORx group, where Rx is as defined above; -a hydroxy; or -an alkoxy; and where Rw is:
-a C] to Ce alkyl optionally substituted with:
-a halogen;
-a haloalkyl;
-a C^ to Cs aryl; or
-a 5 or 6 membered heterocycle; -a C2 to Ce alkylene;
-an alkyl- or dialkyl-amiπo optionally substituted with a halogen; -a 5 or 6 membered heterocycle; or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl;
-a 5 or 6 membered heterocycle; or
-a , optionally substituted with a Ci to Ce alkyl, where Ry is a
Ci to Cs alkyl or hydrogen;
Rz is hydrogen or a Ci to Qs alkyl, optionally substituted with a Ce to Cs aryl;
-a -SRx group, where Rx is as defined above;
-a -SO2Raa group, where R33 is:
-a Cj to C6 alkyl;
-an amino group;
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a -
COORx group, where Rx is as defined above; or
-a 5 or 6 membered heteroaryl; -a Ce to Cg aryl; and/or -a -NHRbb group, where R(,b is:
-a -C(=S)NH2 group; or
-a -PO(ORX)2 group, where Rx is as defined above; -a * == Rcc group, where R00 is: -a naphthalene;
-a 5 or 6 membered heteroaryl;
-a Cβ to Cs aryl, optionally substituted with one or more of the following:
-an alkoxy; -a hydroxy;
-a halogen;
-a C] to Cβ alkyl, optionally substituted with a cyano group; -an amino optionally substituted with one or more Ci to Cs alkyl(s); -a -NEKORxRx, where Rx is as defined above; -a -NReeCONRftRff group, where R^ is a hydrogen or a Ci to Cs alkyl, optionally substituted with a halogen, and Rfr is: -a hydrogen; -a haloalkyl; -a halo alkoxy; -a C1 to C6 alkyl; or
-a -CORx, where Rx is as defined above; -a -NRggCORhh group, where Rhh is: -a hydrogen;
-a Ci to Cδ alkyl optionally substituted with: -an alkoxy;
-a halogen; or
-an amino optionally substituted with one or more Ci to Ce alkyl(s); -an amino optionally substituted with one or more Cj to Ce alkyl(s), where the one or more Ci to Cs alkyl(s) is/are optionally substituted with a halogen;
-a 5 or 6 membered heterocycle; -a 5 or 6 membered heteroaryl; and Rgg is: -a hydrogen; -a Ci to C 6 alkyl; -a haloalkyl; -a haloalkoxy; or
-a -CORx group, where Rx is as defined above; -a haloalkyl;
-5 or 6 membered heterocycle groups;
-an amino optionally substituted with one or more Ci to Ce alkyl(s); and/or -a -NRiiSCkRx group, where Rx is as defined above, and RU is:
-a hydrogen; -a C1 to C6 alkyl; -a haloalkyl; -a haloalkoxy; or -a -CORx group, where Rx is as defined above;
Z is:
-a Ci to Ce alkyl optionally substituted with: -an alkoxy;
-one or more halogen(s); or -a C6 to C8 aryl;
-a C2 to Ce alkylene;
-a Ce to Cs aryl optionally substituted with an alkoxy or one or more Cj to C6 alkyl(s);
-a i -COORx group, where Rx is as defined above; or
R is a hydrogen, a halogen or an alkoxy; Ri is:
-a hydrogen;
-a hydroxy;
-a halogen; -a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with: -one or more halogen(s);
-a Ce to Cs aryl; or -a 5 or 6 membered heterocycle;
-a Cβ to Cg aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above; -a C1 to Ce alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; or
Ri joins together with R∑ to form:
R2 is: -a nitro group; -a hydrogen; -a halogen; -a hydroxy group;
-a Ci to Cβ alkyl group, optionally substituted with one or more halogen(s); -an amino group;
-an alkoxy group optionally substituted with: -one or more halogen(s);
-an -OCORx group, where Rx is as defined above; -a dialkyl-amino optionally substituted with, an alkoxy; -a 5 or 6 membered heterocycle group optionally substituted with a Ci to Ce alkyl; -a 5 or 6 membered heteroaryl group; or
-a CQ to Cg aryl group;
-a -COORx group, where Rx is as defined above; -a haloalkyl; -an amide group optionally substituted with:
-a hydroxy group; or
-a Cβ to Cg aryl; -a 5 or 6 membered heteroaryl; -a -OCORx group, where Rx is as defined above; -a -NHCORjj group, where Rjj is:
-an alkoxy; or
-an amino optionally substituted with one or more Cj to Ce alkyl(s); -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; -a -NHSOaRx group, where Rx is as defined above; or R2 joins together with Ri to form:
R3 is:
-a hydrogen; or
-CH2OCORx, where Rx is as defined above; or one or more pharmaceutically acceptable salt(s) thereof.
72. A compound of formula fflb
wherein:
X is hydrogen; Y is:
-a 5 or 6 membered heteroaryl, optionally substituted with a Ce to Cs aryl, optionally substituted with -COORx, where Rx is as defined above; or -a Cg to Cs aryl, optionally substituted with one or more of the following: -an amino optionally substituted with one or more Ci to Ce alkyl(s); -a halogen; -a hydroxy;
-a -CORn, group, where R1n is an amino optionally substituted with one or more Ci to C6 alkyl(s);
-a -NR0CORp group, where Rp is a Ci to Ce alkyl optionally substituted with an alkoxy, and where R0 is a hydrogen;
-a -NRqCONRqRr group, where Rq is hydrogen and where Rr is a Ci to Ce alkyl; -a -NRtCOORu group, where Rt is hydrogen, and where R11 is a Ci to C 12 alkyl, optionally substituted with: -a CO to C8 aryl; -a halogen; or
-a 5 or 6 membered heterocycle;
-a -NRvSθ2Rw group, where Rv is hydrogen and where Rw is: -a Ci to C6 alkyl; or
-an alkyl- or dialkyl-amino;
Rz is hydrogen or a Ci to CO alkyl; -a -Sθ2Raa group, where R33 is: -an amino group; or -an alkyl- or dialkyl-amino group; or
-a -NHRbb group, where Ry, is a -PO(ORX)2 group, where Rx is as defined above; Z is:
-a Ci to Ce alkyl; or
-a -COORx group, where Rx is as defined above; R is a hydrogen, Ri is: -a hydrogen;
-a 5 or 6 membered heterocycle; or -an alkoxy optionally substituted with: -one or more halogen(s); or -a 5 or 6 membered heterocycle; R2 is:
-a hydrogen; -a hydroxy group;
-a Ci to Ce alkyl group, optionally substituted with one or more halogen(s); -an alkoxy group optionally substituted with: -one or more halogen(s);
-a 5 or 6 membered heterocycle group optionally substituted with a Cj to CQ alkyl; or
-a 5 or 6 membered heteroaryl group; -a -COORx group, where Rx is as defined above; -an amide group;
-a 5 or 6 membered heteroaryl; or
-a -ORkk group, where Rk^ is a 5 to 6 membered heteroaryl; and R3 is a hydrogen.
73. The compound of claim 72, wherein: X is:
-hydrogen; Y is:
-a Cg to Cs aryl, substituted with -NR1COOR11 group, where Rt is hydrogen, and where Ru is a Cj to C12 alkyl; Z is:
-a Ci to C6 alky; R is: -a hydrogen;
Ri is:
-a hydrogen; R2 is:
-a -ORjcic group, where Rki< is a 5 to 6 membered heteroaryl; R3 is:
-a hydrogen.
74. A compound which is selected from the compound range: 866-1329, 1484- 2127, 2129-2545.
75. The compound of claim 74 selected from:
EP07716610A 2006-01-13 2007-01-16 Methods for treating hepatitis c Withdrawn EP1979315A2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US75852706P 2006-01-13 2006-01-13
US11/331,180 US7868037B2 (en) 2004-07-14 2006-01-13 Methods for treating hepatitis C
US65343507A 2007-01-13 2007-01-13
PCT/US2007/000996 WO2007084435A2 (en) 2006-01-13 2007-01-16 Methods for treating hepatitis c

Publications (1)

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EP1979315A2 true EP1979315A2 (en) 2008-10-15

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EP (1) EP1979315A2 (en)
CA (1) CA2636916A1 (en)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
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